Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

GC Boards > Conditions > Flashcards

Conditions Flashcards

1
Q

Carney Complex (gene & inheritance)

A

PRKAR1A

Dominant

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Carney Complex(tumors)

A

Tumors:

  • Myxomas (breast myxomatosis, osteochdromyoxma, cardiac myxoma)
  • Thyroid carcinoma
  • Skin tags, lipomas
  • Psammomatous melanotic schwannomas
  • Sertoli cell tumors
  • Pituitary & Breast adenomas

**Must always histologically confirm myxoma (connective tissue tumor)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Carney Complex(non-tumor features)

A

Pale brown to black lentigines; increase in number and appear anywhere on the body including the face, the lips, and mucosa around puberty

Epithelioid-type blue nevi (small bluish domed papules with a smooth surface), combined nevi, café au lait macules, and depigmented lesions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

HBOC(genes & inheritance)

A

BRCA1 (17q21) & BRCA2 (13q21.3)

Dominant

Tumor suppressor genes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

HBOC (tumors)

A
  • Breast (40-80% lifetime risk, higher in BRCA1)
  • Ovarian (11-40% lifetime risk, higher in BRCA1)
  • Male Breast Cancer
  • Prostate cancer (higher in BRCA2)
  • Pancreatic cancer (higher in BRCA2)
  • Melanoma (BRCA2 only)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

HBOC (management)

A
  • Breast awareness @ 18
  • Clinical breast exam every 6-12 mos @ 25 (female) OR @ 35 (male)
  • Annual MRI @ 25-Annual Mammogram @ 30
  • Option of prophylactic mastectomy
  • Recommend BSO @ 35-40
  • Prostate exams starting @ 40

**Gail=Tamoxifen (5 yr risk >1.6%)

**Claus=MR

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

FAP(gene & inheritance)

A

Familial Adenomatous Polyposis

APC gene (5q21-22)

Dominant

15-30% de novo rate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

FAP(major features (excluding tumors) & testing criteria)

A

Major features:

  • 100+ adenomatous colon polyps
  • Average age of onset for 1st polyps : 16yrs

Testing criteria:

  • 10+ polyps
  • Fam hx FAP
  • Fam hx adenomas & FAP-related extra-colonic findings
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

FAP(associated tumors & clinical features)

A
  • Colon (~100% lifetime risk)
  • Small bowel
  • Pancreatic
  • Bile duct
  • Stomach
  • Thyroid (papillary)
  • CNS
  • Liver (rarely hepatoblastoma in children)
  • Jaw osteoma
  • Abdominal desmoid tumors

Clinical Features:

  • absent/supernumerary/malformed teeth
  • CHRPE
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

FAP(treatment)

A

Colectomy is recommended after adenomas emerge

in approximately one third of individuals the colonic polyps are limited enough in number that surveillance with periodic colonoscopic polypectomy is sufficient

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

AFAP

A

Attenuated Familial Adenomatous Polyposis

10-99 adenomatous colon polypsTumors typicaly more proximal in colon

**I130K polymorphism found in 6-7% of affected individuals

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Gardner Syndrome (FAP Variant)

A

FAP with osteomas and soft tissue tumors (fibromas, desmoid, epidermoid)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Turcot Syndrome(FAP/HNPCC Variant)

A

FAP with CNS tumors, specifically medulloblastoma

**Caused by monoallelic MMR (1/3) or APC (2/3) mutation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

HNPCC/Lynch Syndrome(genes & inheritance)

A
  • Hereditary Non-Polyposis Colorectal Cancer
  • MLH1, PMS2, MSH2, MSH6, EPCAM
  • MLH1 & MSH2 most common | MSH6 rare
  • Most commonly caused by MLH1 SOMATIC mutations

***BRAF (V600E) somatic mutation =sporadic, causes MLH1 hypermethylation

-Dominant-Base pair su

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

HNPCC(associated tumors)

A

Major associated tumors:

  • Colorectal (R ascending)
  • 80% lifetime risk

***Adenomatous tumors

  • Uterine-Small bowel
  • Ureter
  • Renal pelvis
  • Ovarian

Other associated tumors:

  • Stomach**
  • Gallbladder
  • Brain
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Amsterdam I Criteria

A
  • 3 individuals with CRC (1 must be FDR of other 2)
  • 2 generations
  • 1 diagnosed <50yrs

**FAP excluded

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Amsterdam II Criteria

A

**Includes Lynch-related tumors (CRC, uterine, small bowel, ureter & renal pelvis)

  • 3 individuals with Lynch-related tumors(1 must be FDR of other 2)
  • 2 generations
  • 1 diagnosed <50yrs**FAP excluded

**50% of true Lynch families meet criteria

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

MLH1 & PMS2(tumor testing)

A

MMR genes

  • HNPCC/Lynch

**Most tumors are MSI-high (must rule out BRAF mutation)

  • Absence of both: MLH1 mutation OR MLH1 promotor hypermethylation (R/O through BRAF testing)
  • Absence of PMS2: PMS2 mutation or MLH1 mutation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

MSH2 & MSH6(tumor testing)

A

MMR genes

  • HNPCC/Lynch
  • Absence of both: MSH2 mutation OR EPCAM mutation
  • Absence of MSH6: MSH6 mutation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

HNPCC (treatment)

A
  • If CRC present, full colectomy with ileorectal anastomosis indicated
  • Colonoscopy every 1-2 years starting @ 25-Consider annual pap smear, transvaginal US, endometrial biopsy, and CA-125 level
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Bethesda Criteria

A
  • CRC diagnosed <50yrs-Personal history of 2 Lynch-related cancer diagnoses
  • CRC that is MSI-high dx <60yrs
  • Personal history of CRC & Fam hx (FDR) with Lynch cancer dx <50yrs
  • Personal history CRC with 2 FDR or SDR wit Lynch cancer at any age

**Has a 75%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

HNPCC(testing criteria)

A
  • Meets Amsterdam II criteria
  • Meets Bethesda criteria
  • Diagnosed with Uterine cancer <50yrs
  • Known Lynch syndrome in family
  • >=5% risk of Lynch on prediction model
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

MUTYH-associated polyposis(gene & inheritance)

A

MUTYH Recessive

-Base excision repair genes

**Mutations lead to G:C or T:A transversions can lead to Lynch-like features/cancer risks

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

MUTYH(associated features)

A
  • Characterized by an increased risk for adenomatous colon polyps and CRC (80%)
  • High amount of phenotypic heterogeneity (10-100 adenomas, 100+ adenomas, APC normal)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

MUTYH(referral indication)

A

Any individual with a personal history of OR FDR with:

  • 10+ cumulative adenomatous colon polyps with or without CRC
  • MMR proficient CRC diagnosed
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Li-Fraumeni(gene & inheritance)

A

TP53 (17p13) & CHEK2 (22q12.1)

Dominant

  • TP53 protects against cancer but causes premature aging; policing of cells is too strict - too many cells enter apoptosis; Upregulation occurs when mutation present
  • ~20% de novo
  • Multiple primary tumors with the first primary often occurring before age 30.

~100% lifetime risk for cancer.

**TP53 mutation analysis for female breast cancer <35 years

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Li-Fraumeni(associated tumors)

A

Sarcomas

Breast cancer

Brain tumpors (astrocytomas, glioblastomas, medulloblastomas, choroid plexus carcinomas)

Adrenocortical carcinomas

Other: GI cancers, GU cancers, leukemias and lymphomas, lung cancer, neuroblastoma, skin cancers, thyroid cancers

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

Li-Fraumeni(diagnostic criteria)

A

All of the following:

  • Proband with sarcoma <45yrs
  • FDR with cancer <45
  • AND FDR/SDR with any cancer <45 or sarcoma at any age

**Most important to screen for childhood brain cancers & breast cancer screening

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

Chompret Criteria(Li-Fraumeni)

A
  • Proband with tumor in LFS-spectum <46yrs AND at least 1 FDR/SDR with LFS tumor (except breast if proband also has breast) before age 56 or with multiple tumors; OR
  • Proband with multiple tumors (except multiple breast tumors) two of which belong to LFS tu
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

MEN1(gene & inheritance)

A

MEN1 (11q13)Dominant

**Sequencing detects most cases

**MEN1 - tumor suppressor gene

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

MEN1(associated tumors)

A

Parathyroid (100% by age 50)

Anterior pituitary (30-40%)

Well-differentiated endocrine (gastrinoma, insulinoma, glucagonoma, VIPoma)

Carcinoid

Adrenocortical (pheos are rare)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

MEN1(growths)

A

Facial angiofibromas

Collagenomas

Lipomas

Cafe a lait macules

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

MEN1(diagnostic criteria)

A

Tumor in 2 of:

-parathyroid, enteropancreatic endocrine tissue, OR anterior pituitary; ORTumor in one and FDR with MEN1

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

MEN1(treatment)

A
  • Head MRI @ 5yrs
  • Abdominal CT or MRI @ 20yrs
  • Calcium serum concentrations @ 8yrs
  • Gastrin @ 20yrs
  • Pancreatic polypeptide @ 10yrs
  • Prolactin @ 5yrs
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

MEN2(gene & inheritance)

A

RET (10q11.2)Dominant

**PROTO-ONCOGENE

Sequencing detects majority of MEN2 cases (MEN2A exon 10&11; MEN2B exon 16)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

MEN2A(clinical features)

A
  • Medullary thyroid cancer (<35 yrs)
  • Pheochromocytoma (50%)
  • Hyperparathyroidism
  • Parathyroid adenomas
  • May present with cutaneous lichen amyloidosis

**Prophylactic thyroidectomy

**GoF mutations

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

MEN2B(clinical features)

A
  • Medullary thyroid cancer in childhood (prophylactic thyroidectomy BEFORE age 1)
  • Pheochromocytoma (50%)
  • Marfanoid habitus, kyphoscoliosis
  • Hooded eyes, prominent lips
  • Growths: mucosal neuromas, diffuse ganglioneuromatosis of the digestive tract
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

Familial Medullary Thyroid Cancer

A

Medullary thyroid cancer without other symptoms of MEN2A/MEN2B

*No pheo or parathyroid adenoma/hyperplasia

**GoF mutations

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

Hirschprung’s disease

A

**LoF mutations (chromosome 10)

Megacolon

Constipation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

Neurofibromatosis Type 2(gene & inheritance)

A

NF2 (22q12.2)

  • tumor suppressor

Dominant

50% de novo rate; can have somatic mosaicism

**sequencing detects 75%; del/dup detects 10-15%

Diagnostic criteria:

  • bilateral vestibular schwannomas
  • first degree relative
  • unilateral 8 nerve mass OR two of the following:

+++meningioma, glioma, schwannoma, juvenile posterior subcapsular lens opacity-unilateral vestibular schwannoma AND 2 of the following:

+++meningioma, schwannoma, glioma, NF, posterior subcapsular lens opacity-multiple meningiomas AND unilateral vestibular schwannoma OR two of the following:

+++schwannoma, glioma, NF, cataract

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

NF2(features)

A

-Bilateral vestibular schwannomas by 30yrs

+conductive hearing loss

+tinnitus

+balance dysfunction (death by drowning key finding)

+decreased visual acuity

-Schwannomas elsewhere in body

+nerve sheath tumors

  • Ependymomas
  • Meningiomas
  • Cafe-au-lait macule
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

Tuberous Sclerosis Complex(gene & inheritance)

A

TSC1, TSC2

Dominant

**Lots of funky growths

**TSC2/PCKD contiguous gene deletion, features of TSC and AD PKD

**sequencing

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

TSC(major features)

A

Angiofibromas (>3) or fibrous cephalic plaqu

Cardiac rhabdomyoma

Cortical dysplasias, including tubers and cerebral white matter migration lines

Hypomelanotic macules

Lymphangioleiomyomatosis

Multiple retinal nodular hamartomas

Renal angiomyolipomas

Shagreen patch

Subependymal nodules

Ungual fibromas

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

TSC (minor features)

A
  • “Confetti” hypopigmented skin lesions
  • Dental enamel pits
  • Intraoral fibromas
  • Multiple renal cysts
  • Nonrenal hamartomas
  • Retinal achromic patch
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

Von Hippel-Lindau Disease(gene & inheritance)

A

VHL (3p25)Dominant

**sequencing followed by deletion analysis (by southern blot) gives very high detection rate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

Von Hippel-Lindau Disease (associated tumors)

A

Hemangioblastomas (brain,spinal, retinal)

Multiple and bilateral renal cysts

Renal cell carcinoma

Pheochromocytomas

Paraganglioma

Pancreatic lesions (cysts, neuroendocrine tumors)

Endolymphatic sac tumors

Epididymal and broad ligament cystadenomas

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
47
Q

PTEN Hamartoma Tumor Syndrome(gene & associated syndromes)

A

PTEN

**start with sequencing

Variant syndromes:

  • Cowden
  • Bannayan-Riley-Ruvalcaba
  • Proteus
  • Proteus-like
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
48
Q

PTEN(associated tumors)

A
  • 2 or more hamartomas in the colon
  • Breast cancer
  • Uterine cancer
  • FOLLICULAR thyroid cancer
  • Colon cancer
  • Renal cell carcinoma
  • Uterine leiomyomas (fibroids)
  • Mucocutaneous lesions +trichilemmomas +acral keratoses +papillomatous lesions +lipomas +fibromas
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
49
Q

PTEN (other features)

A

Macrocephaly, trichilemmomas, lipomas, pigmented macules of the glans penis,

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
50
Q

Lhermitte-Duclos(PTEN variant)

A

PTEN with dysplastic gangliocytoma of the cerebellum

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
51
Q

Cowden(PTEN variant)

A
  • Presents in 2nd or 3rd decade
  • Macrocephaly & autism
  • Mucocutaneous facial & oral Papules
  • Gingival cobblestoning
  • Acral keratosis
  • Benign hamartomas of breast, thyroid, uterus, GI
  • Dystrophic and adenomatous multinodular goiter, GI polyps, adenosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
52
Q

Bannayan-Riley-Ruvalcaba(PTEN variant)

A

Macrocephaly

Hamartomatous polyposis

Lipomas

Pigmented macules of the glans penis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
53
Q

Proteus Syndrome(PTEN variant)

A
  • CT nevi
  • Disproportionate overgrowth
  • Dysregulated adipose tissue
  • Vascular malformation
  • Risk of ovarian or parotid tumor in 2nd decade
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
54
Q

Xeroderma Pigmentosum(gene & inheritance)

A

XPA, XPC, ERCC2, POLH

RecessiveDNA

-repair protein (NER pathway); UV induced DNA damage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
55
Q

Xeroderma Pigmentosum(features)

A
  • Severe sun sensitivity
  • UV exposure to conjunctiva, cornea, and lids-> severe keratitis
  • Progressive neurologic deterioration

+acquired microcephaly

+decreased/absent DTRs

+progressive SNHL

+cognitive impairment

->1000x increased risk of skin and eye neoplasms

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
56
Q

Birt-Hogg-Dube (gene & inheritance)

A

FLCN

Dominant

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
57
Q

Birt-Hogg-Dube(clinical features)

A

-Skin lesions:

+Fibrofolliculomas

+Perifollicular fibromas

+Trichodiscomas

+Angiofibromas

+Acrochordons

-Bilateral and multifocal renal tumors (CHROMOPHOBE CLEAR CELL renal carcinoma, renal oncocytoma, oncocytic hybrid tumor, clear cell renal carcinom

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
58
Q

Constitutional Mismatch Repair Deficiency

A

-Characterized by:

+high risk of childhood cancers (including LS-associated cancers, hematologic malignancies, and embryonic tumors)

+NF1 type features with cafe-au-lait spots and skinfold freckling

+Lisch nodules, neurofibromas, & tibial pseudoart

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
59
Q

Familial Gastrointestinal Stromal Tumor (GIST)

A

Genes: KIT, PDGFRA, SDHB, SDHC

+Germline mutations in KIT: hyperpigmentation, mast cell tumors, dysphagia

+PDGFRA mutations: large hands

  • NF1 can develop GISTs
  • Wild type GISTs are defied as GISTs that do not have mutations in KIT, PDGFRA, or BRAF
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
60
Q

Familial Pancreatic Cancer

A

At least two FDR with pancreatic ductal adenocarcinoma

Hereditary syndromes: BRCA2 and CDKN2A

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
61
Q

Familial Prostate Cancer

A

AR, AD, and X-linked inheritance patterns

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
62
Q

Hereditary Diffuse Gastric Cancer

A
  • Gene: CDH1 (occurs in 25-50% who meet criteria)
  • Increased risk for:

+Diffuse gastric cancer

+Lobular breast cancer

+Signet ring CRC

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
63
Q

Hereditary Leiomyomatosis and Renal Cell Cancer

A
  • Gene: FH
  • Renal cancer (papillary type 2 “fried egg”)
  • Cutaneous leiomyoma
  • Uterine fibroids
  • Pheos/Paras
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
64
Q

Hereditary Melanoma (aka Familial atypical mole and malignant melanoma - FAMMM)

A
  • Genes: CDKN2A, ARF
  • Multiple melanotic nevi (usually >50) and fam hx melanoma
  • Individuals have a 17% risk for pancreatic cancer by age 75
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
65
Q

Hereditary Mixed Polyposis Syndrome

A

Atypical juvenile polyps

Colonic adenomas

Colorectal carcinomas

Inflammatory and metaplastic polyps

Duplication on chromosome 15q13-q14

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
66
Q

Hereditary Papillary Renal Cell Carcinoma

A
  • Gene: MET
  • Risk of developing papillary type 1 RCC
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
67
Q

Hereditary Paraganglioma-Pheochromocytoma Syndrome(genes)

A

-SDHB, SDHD, SDHC, SDHAF2, MAX, TEME127

+SDHB “Bad” - increased risk for malignancy, fewer tumors, renal cancer

+SDHD “Dad” - more tumors, decreased malignancy risk, IMPRINTED-Increased risk for Paras/Pheos

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
68
Q

Hereditary Retinoblastoma

A
  • RB1 (chr 13)
  • Malignant tumor of the retina, usually occurring before 5yrs

+~40% of all retinoblastomas are hereditary

-Osteosarcoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
69
Q

Juvenile Polyposis Syndrome(gene & inheritance)

A

SMAD4, BMPR1A

Autosomal dominant

25% de novo

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
70
Q

Juvenile Polyposis Syndrome(features)

A
  • 3-5 polyps with juvenile pathology (HAMARTOMAS)
  • Increased risk for CRC, stomach, upper GI tract, and pancreatic cancer
  • Extraintestinal features:

+valvular heart diesease (11%)

+telangiectasia or vascular anomalies (9%, all in SMAD4)

+Macrocephaly

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
71
Q

Nevoid Basal Cell Carcinoma Syndrome

A
  • Gene: PTCH1
  • Multiple jaw keratocysts beginning in teens
  • Multiple basal cell carcinomas beginning in 20s
  • Physical features:

+Macrocephaly, frontal bossing, coarse facial features, facial milia, skeletal anomalies, palmar plantar pits

+Cardiac fibromas, ovarian fibromas

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
72
Q

Peutz-Jeghers Syndrome

A
  • Gene: STK11
  • Mucocutaneous hyperpigmentation of the mouth, nose, lips, eyes, genitalia, or fingers
  • Multiple hamartomatous polyps in the GI tract
  • Increased risk for:

+CRC, pancreatic, gastric, small intestinal, breast cancers

+ovarian sex cord tumors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
73
Q

Serrated Polyposis Syndrome(formerly hyperplastic)

A
  • Unknown genetic causeReferral reasons:
  • >=5 serrated polyps near sigmoid (2 must be >10mm)
  • 20+ serrated polyps anywhere
  • Any number of serrated polyps near sigmoid if FDR with SPS
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
74
Q

Familial Colorectal Cancer, Type X(FCCTX)

A
  • Meets Amsterdam criteria (clinical dx Lynch)
  • MSI stable
  • IHC normal
  • Left sided tumors
  • CRC risk is 2-fold increase, later onset
  • CRC only (NO enometrial)
  • More polyps than lynch
  • Management: +c/scope every 5y starting 5-10yrs before earliest dx
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
75
Q

BRCA Carrier Rate(AJ population vs. General Population)

A

AJ population: 1/40

General population: 1/800

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
76
Q

BRCA VUS rate (African American vs. European Population)

A

African American: 20%

**AA cancers are more commonly triple negative

European Ancestry: 7%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
77
Q

What factors cause an increased risk for breast cancerProtective factors for breast cancer

A

Increased risk factors (prolonged estrogen exposure):

  • Menarche <12yrs-Nulliparity
  • Menopause >52yrs
  • Consuming >2-3 EtOH drinks per week

Protective factors:

  • 4 hours exercise per week-Breastfeeding
  • Maintaining ideal weight
  • Kids before 30
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
78
Q

BRCA facts

  1. Can BRCA1 tumors be treated with drugs that target the estrogen receptor?
  2. Is BRCA1 more likely to be invasive lobular?
  3. Is BRCA1 or BRCA2 more likely to be triple negative?
  4. Is BRCA1 or BRCA2 more likely to be estrogen receptor positive?
A
  1. No
  2. No
  3. BRCA1
  4. BRCA2
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
79
Q

MUTYH-associated polyposis

A

MUTYH**Mutations lead to G:C or T:A transversions can lead to Lynch-like features/cancer risks -Characterized by an increased risk for adenomatous colon polyps and CRC (80%)-High amount of phenotypic heterogeneity (10-100 adenomas, 100+ adenomas, APC normal)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
80
Q

HNPCC/Lynch Syndrome

A

-MLH1, PMS2, MSH2, MSH6, EPCAM- MLH1 & MSH2 most common | MSH6 rareMajor associated tumors:-Colorectal (R ascending) - 80% lifetime risk, Uterine, Small bowel, Ureter, Renal pelvisOther associated tumors:-Ovarian, Stomach**, Gallbladder, Brain Treatme

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
81
Q

Amsterdam I & II Criteria

A

-3 individuals with CRC (1 must be FDR of other 2)-2 generations-1 diagnosed <50yrs**FAP excluded

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
82
Q

Bethesda Criteria

A

-CRC diagnosed <50yrs-Personal history of 2 Lynch-related cancer diagnoses-CRC that is MSI-high dx <60yrs-Personal history of CRC & Fam hx (FDR) with Lynch cancer dx <50yrs-Personal history CRC with 2 FDR or SDR wit Lynch cancer at any age**Has a 75%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
83
Q

MLH1 & PMS2(tumor testing)

A

MMR genes - HNPCC/Lynch**Most tumors are MSI-high (must rule out BRAF mutation)-Absence of both: MLH1 mutation OR MLH1 promotor hypermethylation (R/O through BRAF testing)-Absence of PMS2: PMS2 mutation or MLH1 mutation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
84
Q

MSH2 & MSH6(tumor testing)

A

MMR genes - HNPCC/Lynch- Absence of both: MSH2 mutation OR EPCAM mutation-Absence of MSH6: MSH6 mutation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
85
Q

Li-Fraumeni(gene, inheritance & diagnostic criteria)

A

TP53 (17p13) & CHEK2 (22q12.1)Dominant-TP53 protects against cancer but causes premature aging; policing of cells is too strict - too many cells enter apoptosis; Upregulation occurs when mutation present-~20% de novo-Multiple primary tumors with the first primary often occurring before age 30. ~100% lifetime risk for cancer.**TP53 mutation analysis for female breast cancer <35 years -Proband with sarcoma <45yrs, FDR with cancer <45 AND FDR/SDR with any cancer <45 or sarcoma at any age

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
86
Q

Li-Fraumeni(associated tumors)

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
87
Q

Chompret Criteria(Li-Fraumeni)

A

-Proband with tumor in LFS-spectum <46yrs AND at least 1 FDR/SDR with LFS tumor (except breast if proband also has breast) before age 56 or with multiple tumors; OR-Proband with multiple tumors (except multiple breast tumors) two of which belong to LFS tu

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
88
Q

MEN1

A

MEN1**Sequencing detects most cases**MEN1 - tumor suppressor gene Associated tumors:-Parathyroid (hyperparathyroidism, hypercalcemia)-Pituitary (prolactinoma)-Pancreatic neuroendocrine (gastrinoma, insulinoma, glucagonoma)-Carcinoid tumors-Adrenocortical tumors Growths:-Angiofibromas, Collagenomas, Lipomas, Meningiomas, Ependymomas, Leiomyomas

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
89
Q

MEN1(treatment)

A

-Head MRI @ 5yrs-Abdominal CT or MRI @ 20yrs-Calcium serum concentrations @ 8yrs-Gastrin @ 20yrs-Pancreatic polypeptide @ 10yrs-Prolactin @ 5yrs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
90
Q

MEN2A

A

-Medullary thyroid cancer (<35 yrs)-Pheochromocytoma (50%)-Hyperparathyroidism-Parathyroid adenomas-May present with cutaneous lichen amyloidosis**Prophylactic thyroidectomy **GoF mutations

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
91
Q

MEN2B

A

-Medullary thyroid cancer in childhood (prophylactic thyroidectomy BEFORE age 1)-Pheochromocytoma (50%)-Marfanoid habitus, kyphoscoliosis-Hooded eyes, prominent lips-Growths: mucosal neuromas, diffuse ganglioneuromatosis of the digestive tract**ABSENCE OF

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
92
Q

Familial Medullary Thyroid Cancer

A

Medullary thyroid cancer without other symptoms of MEN2A/MEN2B**GoF mutations

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
93
Q

Hirschprung’s disease

A

**LoF mutations (chromosome 10)MegacolonConstipation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
94
Q

Neurofibromatosis Type 2

A

NF2 (50% de novo rate) - tumor suppressor-Bilateral vestibular schwannomas by 30yrs +conductive hearing loss +tinnitus +balance dysfunction (death by drowning key finding) +decreased visual acuity-Schwannomas elsewhere in body +nerve sheath tumors-Ependymomas-Meningiomas-Cafe-au-lait macules-Cataracts

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
95
Q

Tuberous Sclerosis Complex

A

TSC1, TSC2**TSC2/PCKD contiguous gene deletion, features of TSC and PKD**sequencing -SEIZURES (hypsarrhythmia noted on EEG)-CARDIAC RHABDOMYOMA-Angiofibroma-Cortical dysplasia-Hypomelanotic macules-LAMs (lymphangioleiomyomatosis)-Multiple retinal nodular hamartomas-SHAGREEN PATCH-Renal angiomyolipoma-SEGAs (subependymal giant cell astrocytoma)-Subependymal nodules-Ungual fibromas-Neuroendocrine tumors+pituitary adenoma, parathyroid adenoma, pancreatid adenoma, gastrinoma, pheochromocytoma, carcinoids Minor features:-“Confetti” hypopigmented skin lesions, Dental pits, Intraoral fibromas, Multiple renal cysts, Retinal achromic patch

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
96
Q

Von Hippel-Lindau Disease

A

VHL**sequencing followed by deletion analysis (by southern blot) -CLEAR CELL renal carcinoma-Spinal or cerebellar hemangioblastoma-Pancreatic neuroendocrine tumors-Endolymphatic sac tumors-Pheochromocytoma (secrete Norepi only)-Paraganglioma-Retinal angioma-Multiple renal and pancreatic cysts

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
97
Q

PTEN

A

-2 or more hamartomas in the colon-Breast cancer-Uterine cancer-FOLLICULAR thyroid cancer-Colon cancer-Renal cell carcinoma-Uterine leiomyomas (fibroids)-Mucocutaneous lesions +trichilemmomas +acral keratoses +papillomatous lesions +lipomas +fibromas Othe

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
98
Q

Lhermitte-Duclos(PTEN variant)

A

PTEN with dysplastic gangliocytoma of the cerebellum

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
99
Q

Cowden(PTEN variant)

A

-Presents in 2nd or 3rd decade- Macrocephaly & autism-Mucocutaneous facial & oral Papules-Gingival cobblestoning-Acral keratosis-Benign hamartomas of breast, thyroid, uterus, GI-Dystrophic and adenomatous multinodular goiter, GI polyps, adenosis a

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
100
Q

Bannayan-Riley-Ruvalcaba(PTEN variant)

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
101
Q

Proteus Syndrome(PTEN variant)

A

-CT nevi-Disproportionate overgrowth-Dysregulated adipose tissue-Vascular malformation-Risk of ovarian or parotid tumor in 2nd decade

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
102
Q

Xeroderma Pigmentosum

A

XPA, XPC, ERCC2, POLHRecessive; DNA-repair protein (NER pathway); UV induced DNA damage-Severe sun sensitivity-UV exposure to conjunctiva, cornea, and lids-> severe keratitis-Progressive neurologic deterioration +acquired microcephaly +decreased/absent DTRs +progressive SNHL +cognitive impairment->1000x increased risk of skin and eye neoplasms

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
103
Q

Birt-Hogg-Dube

A

FLCN-Skin lesions: +Fibrofolliculomas +Perifollicular fibromas +Trichodiscomas +Angiofibromas +Acrochordons-Bilateral and multifocal renal tumors (CHROMOPHOBE CLEAR CELL renal carcinoma, renal oncocytoma, oncocytic hybrid tumor, clear cell renal carcinoma)-Multiple bilateral lung cysts (lung blebs) often associated with spontaneous pneumothorax

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
104
Q

Constitutional Mismatch Repair Deficiency

A

-Characterized by: +high risk of childhood cancers (including LS-associated cancers, hematologic malignancies, and embryonic tumors) +NF1 type features with cafe-au-lait spots and skinfold freckling +Lisch nodules, neurofibromas, & tibial pseudoarthos

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
105
Q

Familial Gastrointestinal Stromal Tumor (GIST)

A

Genes: KIT, PDGFRA, SDHB, SDHC +Germline mutations in KIT: hyperpigmentation, mast cell tumors, dysphagia +PDGFRA mutations: large hands- NF1 can develop GISTs-Wild type GISTs are defied as GISTs that do not have mutations in KIT, PDGFRA, or BRAF

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
106
Q

Familial Pancreatic Cancer

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
107
Q

Hereditary Diffuse Gastric Cancer

A

-Gene: CDH1 (occurs in 25-50% who meet criteria)-Increased risk for: +Diffuse gastric cancer +Lobular breast cancer +Signet ring CRC

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
108
Q

Hereditary Leiomyomatosis and Renal Cell Cancer

A

-Gene: FH-Renal cancer (papillary type 2 “fried egg”)-Cutaneous leiomyoma-Uterine fibroids-Pheos/Paras

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
109
Q

Hereditary Melanoma (aka Familial atypical mole and malignant melanoma - FAMMM)

A

-Genes: CDKN2A, ARF-Multiple melanotic nevi (usually >50) and fam hx melanoma-Individuals have a 17% risk for pancreatic cancer by age 75

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
110
Q

Hereditary Mixed Polyposis Syndrome

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
111
Q

Hereditary Papillary Renal Cell Carcinoma

A

-Gene: MET-Risk of developing papillary type 1 RCC

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
112
Q

Hereditary Paraganglioma-Pheochromocytoma Syndrome

A

-SDHB, SDHD, SDHC, SDHAF2, MAX, TEME127 +SDHB “Bad” - increased risk for malignancy, fewer tumors, renal cancer +SDHD “Dad” - more tumors, decreased malignancy risk, imprinted-Increased risk for Paras/Pheos

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
113
Q

Hereditary Retinoblastoma

A

-RB1 (chr 13)-Malignant tumor of the retina, usually occurring before 5yrs +~40% of all retinoblastomas are hereditary

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
114
Q

Juvenile Polyposis Syndrome

A

SMAD4, BMPR1A -3-5 polyps with juvenile pathology-Increased risk for CRC, stomach, upper GI tract, and pancreatic cancer-Extraintestinal features: +valvular heart diesease (11%) +telangiectasia or vascular anomalies (9%, all in SMAD4) +Macrocephaly (11%)-SMAD4 may also show symptosm of hereditary hemorrhagic telangiectasia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
115
Q

Nevoid Basal Cell Carcinoma Syndrome

A

-Gene: PTCH1-Multiple jaw keratocysts beginning in teens-Multiple basal cell carcinomas beginning in 20s-Physical features: +Macrocephaly, frontal bossing, coarse facial features, facial milia, skeletal anomalies +Cardiac fibromas, ovarian fibromas, medul

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
116
Q

Peutz-Jeghers Syndrome

A

-Gene: STK11-Mucocutaneous hyperpigmentation of the mouth, nose, lips, eyes, genitalia, or fingers-Multiple hamartomatous polyps in the GI tract-Increased risk for: +CRC, pancreatic, gastric, small intestinal, breast cancers +ovarian sex cord tumors with

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
117
Q

Serrated Polyposis Syndrome(formerly hyperplastic)

A

-Unknown genetic causeReferral reasons:->=5 serrated polyps near sigmoid (2 must be >10mm)-20+ serrated polyps anywhere-Any number of serrated polyps near sigmoid if FDR with SPS

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
118
Q

Familial Colorectal Cancer, Type X(FCCTX)

A

-Meets Amsterdam criteria (clinical dx Lynch)-MSI stable-IHC normal-Left sided tumors-CRC risk is 2-fold increase, later onset-CRC only (NO enometrial)-More polyps than lynch-Management: +c/scope every 5y starting 5-10yrs before earliest dx

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
119
Q

Major Malformation

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
120
Q

Minor Anomaly

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
121
Q

Syndrome

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
122
Q

Association

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
123
Q

VACTERL

A

Vertebral anomaliesAnal atresiaCardiac defectsTracheoesophageal fistulaEsophageal atresiaRenal and radial anomaliesLimb defects

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
124
Q

Malformation

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
125
Q

Sequence

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
126
Q

Potter Sequence

A

Renal agenesis/renal malformation leading to oligohydramnios which causes distinct physical appearance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
127
Q

Pierre-Robin Sequence

A

Micrognathia leads to cleft palate and glossoptosis and subsequent respiratory distress

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
128
Q

Deformation

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
129
Q

Disruption

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
130
Q

Dysplasia

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
131
Q

CHARGE

A

ColobomaHeartchoanal Atresiagrowth RetardationGenital abnormalitiesEar abnormalities

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
132
Q

Locus Heterogeneity

A

Mutations in DIFFERENT GENES can cause the SAME DISORDER/phenotypic presentation +ie. Noonan syndrome, Autism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
133
Q

Allelic Heterogeneity

A

DIFFERENT MUTATIONS/alleles on the SAME GENE can cause the SAME DISORDER +ie. Cystic Fibrosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
134
Q

Phenotypic Heterogeneity

A

DIFFERENT MUTATIONS on the SAME GENE can cause DIFFERENT PHENOTYPES +ie. FBN1, FGFR3

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
135
Q

Pleiotropy

A

One gene mutation influences many unrelated phenotypic traits +ie. PKU, Sickle-cell

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
136
Q

Variable Expressivity

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
137
Q

Penetrance

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
138
Q

Arthrogryposis

A

Congenital joint contracture in two or more areas of the body

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
139
Q

Amyoplasia

A

-Literally “no muscle growth”-Replacement of skeletal muscle by dense fibrous tissue and fat-May also include vascular compromise-Form of arthrogryposis**Occurs sporadically due to lack of fetal movement which may be due to an external/environmental facto

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
140
Q

Ectrodactyly

A

Deficiency or absence of one or more CENTRAL digits of the hand or foot

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
141
Q

Klippel-Feil Anomaly

A

-Congenital fusion of any two of the seven cervical vertebrae-May be caused by mutations in GDF3 and GDF6-AD form at 8q22.2 also associated with laryngeal malformation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
142
Q

Mesomelic shortening

A

Shortening of the DISTAL long bones

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
143
Q

Rhizomelic shortening

A

Shortening of the PROXIMAL long bones

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
144
Q

Micromelic shortening

A

Shortening of the DISTAL and PROXIMAL long bones

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
145
Q

Talipes Equinovalgus/Equinovarus

A

Club foot-Valgus: feet turned outward-Varus: feet turned inward

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
146
Q

Triploidy

A

Entire extra set of chromosomes69, XXX / 69, XXY-Present in 1-2% of conceptions, 10% of miscarriages-Typically results in miscarriage in the FIRST TRIMESTER

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
147
Q

Digyny

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
148
Q

Diandry

A

-Extra set of paternal chromosomes-Large cystic/partial molar placenta-Normal growth or limited fetal growth restriction-Maternal serum screening 10x higher hCG -Maternal risk for pre-eclampsia and choriocarcinoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
149
Q

Common features of triploidy

A

3,4 syndactylyCystic placenta

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
150
Q

Can Triploidy be detected on NIPT?

A

Yes, only via SNP-method (ie. Natera)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
151
Q

Trisomy 13(Patau Syndrome)

A

-Maternal Meiosis I-Holoprosencephaly-Cleft lip-VSD, Double outlet right ventricle-Echogenic kidneys-Omphalocele**MSS does not adjust risk for this disorder-Few survive to term, most die within first year of life

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
152
Q

Trisomy 18(Edward Syndrome)

A

-Maternal Meiosis II-Clenched fists-Choroid Plexus cysts-Rocker bottom feet-IUGR-Polyhydramnios-Omphalocele**MSS: all markers low-Few survive to term, most die within first year of life

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
153
Q

Trisomy 21 - Prenatal findings(Down Syndrome)

A

-Maternal OR Paternal Meiosis I-Increased nuchal translucency in first trimester-Increased nuchal fold in second trimester (>6.0mm)-Structural heart defect (50%)-Hypoplastic nasal bone-Echogenic bowel-Echogenic intracardiac focus (weak association)**MSS:

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
154
Q

Trisomy 21 - Postnatal findings(Down Syndrome)

A

-Mild to moderate ID-Good social skills-CHD (~50% - VSD, ASD, ToF)-Increased risk for leukemia-Decreased risk for solid tumors-BRUSHFIELD SPOTS-GI problems-Hearing loss-Hypothyroidis-Upslanted palpebral fissures-Epicanthal folds-Sandal gap-Short stature

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
155
Q

Cat Eye Syndrome

A

-Partial trisomy or tetrasomy of Chromosome 22 +Associated with marker chromosome 22-Usually de novo but parents may be unaffected mosaic- Features +Coloboma +Preauricular pits/tags +Cardiac defects +Missing or underdeveloped kidneys +Short st

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
156
Q

Turner Syndrome

A

45, X-Due to paternal meiosis I-Features +Coarctation/Aortic stenosis +Obesity +Amenorrhea +STREAKED OVARIES +Learning difficulties +Horseshoe kidney +Short stature +Webbed neck +Cystic hygroma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
157
Q

Klinefelter Syndrome

A

47, XXY-Maternal or Paternal Meiosis I-Tall stature-Normal intelligence (may have reading/speech difficulties)-Feminization at puberty +Gynecomastia, broad hips, reduced/absent facial hair-Reduced fertility-Hypogonadism-Increased risk for Breast cancer and Thromboembolism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
158
Q

XYY Syndrome

A

47, XYY-Tall stature-DD-Learning difficulties-Behavior problems-No like to increased aggression-NORMAL sexual development

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
159
Q

TRUE OR FALSE. The karyotype of a spontaneous abortion is more likely to be abnormal than that of a stillborn infant.

A

TRUE

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
160
Q

Chromsomes where imprinting should be considered

A

6, 7, 11, 14, 15, 16

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
161
Q

Russell-Silver Syndrome(mode of imprinting)

A

-11p15.5 (30-50% of cases) +Hypomethylation on paternal chromosomes at IC1 leads to H19 expression and IGF2 silencing -Typically, IC1 is methylated with IGF2 expression +Duplication of maternal 11p15.5 (unknown prevalence)-Maternal UPD 7 (7-10

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
162
Q

Russell-Silver Syndrome(clinical features)

A

-Triangular face shape with delicate features-Head sparing IUGR –> SGA/low birth weight-Normal Head Circumference-Hypoglycemia –> sweating at night-Developmental delay, Learning Disabilities-BLUE SCLERA IN CHILDHOOD-Body asymmetry (small, arm span const

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
163
Q

Beckwith-Wiedemann Syndrome(mode of imprinting)

A

11p15 +Maternal loss of methylation IC2 (50%) (causes expression of IGF2 and silencing of H19 - BAD) +Paternal UPD (20% of cases) +Maternal gain of methylation at IC1 (5%) (causes expression of IGF2 and silencing of H19 - BAD) +Maternal CDKN1C mutation (40% familial; 5-10% sporadic) - CDKN1C stops cells from entering cell cycle, mutations allows for overgrowth/overproliferation**IGF2=overgrowth***Need mom expressed (H19)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
164
Q

Beckwith-Wiedemann Syndrome(Major features)

A

-Overgrowth-Macrosomia-Earlobe creases, helical ear pits-Macroglossia (enlarged tongue)-OMPHALOCELE-Visceromegaly-Increased risk for embryonic tumors (wilms, hepatoblastoma, neuroblastoma) +Test AFP, discontinue at age 4-Renal abnormalities-Cytomegaly o

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
165
Q

Beckwith-Wiedemann Syndrome(Minor features)

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
166
Q

Angelman Syndrome(mode of imprinting)

A

15q11.2q13 +Maternal 15q11.2q13 deletion including UBE3A (65-75%) +Paternal UPD (3-7%) +Maternal UBE3A mutation (5-11%) +Maternal imprinting defect of 15q11.2q13 (maintains methylation improperly)***Need Mom expressed

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
167
Q

Angelman Syndrome(major features)

A

-“Happy puppet syndrome”-Severe DD beginning at 6-12 months-Limited or absent speech-Ataxia-Hand Flapping-Seizures-PROGRESSIVE MICROCEPHALY (born normocephalic, microcephaly by age 2)-Laughter, smiling, excitability

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
168
Q

Angelman Syndrome(minor features)

A

NAME?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
169
Q

Prader-Willi Syndrome(mode of imprinting)

A

15q11.2q13 +Maternal UPD (20-30%) +Paternal deletion 15q11.2q13 (65-75%) +Paternal gene deletion of region responsible for methylation/imprinting (de novo OR inherited) +Unbalanced chromosomal rearrangement***Need Dad expressed

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
170
Q

Prader-Willi Syndrome(features)

A

-Hypotonia & FTT in neonatal/early development-GDD-Excessive eating (pica)-Obesity-Mild ID-Hypogonadism-Hypothyroidism-Sleep Abnormalities-Behavioral problems (Autistic beh., controlling/manipulative, tantrums, hyperactivity, psychosis, compulsive beh

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
171
Q

Birt-Hogg-Dube

A

Individual with a person OR FDR with 5 or more BHD associated facial or truncal papules

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
172
Q

Constitutional Mismatch Repair Deficiency

A

Any individual with a personal for FDR with:-LS-associated cancer in childhood-Another type of childhood cancer AND one or more of the following: +Cafe-au-lait macules, skinfold freckling, lisch nodules, neurofibromas, tibial pseudoarthrosis or hypopigmented skin lesions +Family history of LS-associated cancer +A second primary cancer +A sibling with a childhood cancer +Consanguineous parents

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
173
Q

Cowden Syndrome

A

Any individual with a personal history or FDR with:-Lhermitte-Duclose diagnosed after 18yrs-Any 3 criteria from the major or minor diagnostic criteria list in the same person

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
174
Q

FAP

A

Any individual with personal or FDR with:-10+ adenomatous colon polyps with or without a CRC or other FAP-assoc cancer-A cribriform morular variant of papillary thyroid cancer-A desmoid tumor-Hepatoblastoma diagnosed before age 5

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
175
Q

Familial GIST

A

Any individual with a personal history or FDR with:-3+ close relatives with GIST-Wild-type GIST-Individuals with 3+ GISTs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
176
Q

Familial Pancreatic Cancer

A

Any individual with a personal or FDR with:-AJ ancestry and pancreatic cancer at any age-Pancreatic cancer and a close relative with pancreatic cancer-3+ cases of breast, ovarian, pancreatic, and/or aggressive prostate cancer-3+ cases of pancreatic cancer and/or melanoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
177
Q

Familial Prostate Cancer

A

Any individual with a personal or FDR with:-3 or more FDR with prostate cancer-2 or more cases of prostate cancer diagnosed <55-Aggressive prostate cancer (Gleason score 7+) and 2+ cases of breast, ovarian, or pancreatic cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
178
Q

Hereditary Diffuse Gastric Cancer

A

Any individual with a personal or FDR with diffuse gastric cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
179
Q

Hereditary Leiomyomatosis and Renal Cell Cancer

A

Any individual with a personal or FDR with:-Cutaneous leiomyomas-RCC with histology characteristic of hereditary leiomyomatosis and renal cell cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
180
Q

Familial Atypical Mole and Malignant Melanoma(Hereditary Melanoma)

A

Any individual with a personal or FDR with:-3 or more melanomas in the same person-3 or more cases of melanoma and/or pancreatic cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
181
Q

Hereditary Mixed Polyposis Syndrome

A

Any individual with a personal or FDR with 10+ colorectal polyps with mixed histology

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
182
Q

Hereditary Papillary Renal Cell Carcinoma

A

Any individual with a personal or FDR with papillary type 1 RCC

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
183
Q

Hereditary Paraganglioma-Pheochromocytoma Syndrome

A

Any individual with a personal or FDR with a paraganglioma or pheochromocytoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
184
Q

Hereditary Retinoblastoma

A

Any individual with a personal or FDR with a retinoblastoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
185
Q

Juvenile Polyposis Syndrome

A

Any individual with a personal or FDR with:-3-5 cumulative histologically proven juvenile GI polyps-Any number of juvenile GI polyps with a positive family history of JPS-Multiple juvenile polyps located throughout the GI tract

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
186
Q

Lynch Syndrome

A

Any individual with a personal or FDR with:-CRC or endometrial cancer before 50-CRC or endometrial cancer diagnosed after 50 with a FDR with CRC or endometrial cancer at any age-Synchronous or metachronous CRC or endometrial cancer-Sebaceous adenoma or carcinoma and one or more additional case of any LS-associated cancer in the same person or relatives-A tumor exhibiting MMR deficiency-Fam hx of 3+ LS-associated cancers

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
187
Q

Melanoma Astrocytoma Syndrome

A

Any individual with a personal or FDR with:-Melanoma and astrocytoma in the same person-One case of melanoma and one case of astrocytoma in 2 FDR

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
188
Q

MEN1

A

Any individual with a personal or FDR with:-2+ different MEN1-associated tumors in the same person-Gastrinoma-Multiple different pancreatic neuroendocrine tumors in the same person-Parathyroid adenoma diagnosed before 30-Parathyroid adenomas involving multiple glands-Parathyroid adenoma with a fam hx of hyperparathyroidism or MEN1-associated tumors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
189
Q

MEN2

A

Any individual with a personal or FDR with:-MTC-Pheochromocytomas-Oral or ocular neuromas (lips, tongue, sclera, or eyelids)-Diffuse ganglioneuromatosis of the GI tract

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
190
Q

MUTYH-associated polyposis

A

Any individual with a personal or FDR with:-10+ cumulative adenomatous colon polyps with or without CRC-MMR proficient CRC diagnosed

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
191
Q

Nevoid Basal Cell Carcinoma Syndrome

A

Any individual with a personal or FDR with any 2 criteria-Multiple jaw keratocysts beginning in teens and multiple basal-cell carcinomas beginning in 20s-Macrocephaly-Frontal bossing-Coarse facial features-Facial milia-Skeletal anomalies-Cardiac fibromas, Ovarian fibromas, Medulloblastoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
192
Q

Peutz-Jeghers Syndrome

A

Any individual with a personal or FDR with:-2+ histologically confirmed PJ GI polyps-One or more PJ GI polyp with mucocutaneous hyperpigmentation-Ovarian sex cord tumor with annular tubules-Adenoma malignum of the cervix-Sertoli cell tumor-Pancreatic cacner and one or more PJ GI polyp-Breast cancer and one or more PJ GI polyp-One ore more PH polyp and a positive family history of PJS

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
193
Q

Rhabdoid tumor predisposition types 1 & 2

A

Any individual with a personal or FDR with a rhabdoid tumor, including small cell carcinoma of the ovary, hypercalcemic type

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
194
Q

Serrated Polyposis Syndrome

A

Any individual with a personal or FDR with:-At least 5 serrated polyps proximal to the sigmoid colon, 2 of which are >1 cm (10mm) in diameter->20 serrated polyps throughout the large bowel-Any number of serrated polyps proximal to the sigmoid colon and a positive family history of SPS

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
195
Q

Tuberous Sclerosis Complex

A

Any individual with a personal or FDR with any two criteria-Brain tumors-Kidney tumors-Heart tumors-Skin and neurological abnormalities-Skin lesions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
196
Q

Von-Hippel-Lindau Syndrome

A

Any individual with a personal or FDR with:-Clear cell RCC if he/she: +has bilateral or multifocal tumors +is diagnosed before age 50 +has a close relative with clear cell RCC-CNS hemangioblastoma-Pheochromocytoma-Endolymphatic sac tumor-Retinal capillary hemangioma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
197
Q

Monosomy 1p36

A

-Aggression/self-injurious behavior-Mild to severe ID-Microcephaly-Scoliosis/kyphosis-Brain MRI abnormalities (cerebral atrophy, ventricular asymmetry and/or enlargement, hydrocephalus)-Visual problems (cataracts, nystagmus, strabismus, hypermetropia)-Hea

198
Q

Wolf-Hirschhorn Syndrome

A

4p16.3-“greek warrior helmet” (microcephaly, ocular hypertelorism)-Preauricular tags-Growth restriction-Mild-to-profound ID-Coloboma-CHDs-Sleep disturbances-Seizures-Cleft lip/palate-Visceral problems-Antibody deficiency-Hand stereotypies

199
Q

Cri Du Chat Syndrome(chromosome location)

A

5p- syndromeDominant5p15.2 (critical region)5p15.3 (cat-cry region)Typically de novo (85-90%); PATERNAL de novo (80%)

200
Q

Cri Du Chat Syndrome(major features)

A

NAME?

201
Q

Cri Du Chat Syndrome(minor features)

A

NAME?

202
Q

Williams Syndrome

A

7q11.23Dominant, typically de novoContains ELN gene-Cardiovascular disease: SUPRAVALVULAR AORTIC STENOSIS, pulmonic stenosis-Hoarse voice-Connective tissue anomalies: inguinal/umbilical hernia, rectal prolapse, joint limitation or laxity, soft/lax skin-Mild to severe ID-Strong verbal/language skills (poor visuospatial skills)-Friendly/talkative/empathetic/ANXIOUS personality-Endocrine dysfunction: hypothyroid, hypercalcuria, IDDM-STELLATE IRIS-Progressive SNHL-Coarse facies with coarsening over time

203
Q

WAGR Syndrome

A

11p13-Wilm’s tumor (50%)-Aniridia, may also have ptosis and/or cataracts-Genitourinary anomalies +more common in males +women may have streaked ovaries/increased risk for gonadoblastoma-Retardation-Subset have obesity**WT1 - wilms tumor gene**PAX6 - aniridia

204
Q

Smith-Magenis Syndrome

A

17p11.2 deletion-Inverted circadian rhythm-Aggression, anxiety, impulsiveness, ADHD-REDUCED pain sensitivity-Strabismus-Ear abnormalities-CONDUCTIVE hearing loss-Dysmorphic features-“page turning” motion

205
Q

Miller-Dieker Lissencephaly Syndrome

A

17p13.3 deletion-Lissencephaly (smooth brain)-ID-Epilepsy-Death in infancy or early childhood-Dysmorphic features: upturned nares, thickened upper lip, frontal bossing, small jaw, low-set posteriorly rotated ears, midface hypoplasia, hypertelorism

206
Q

DiGeorge Syndrome(VeloCardioFacial syndrome)CATCH

A

22q11.2 deletion-Cardiac anomalies (interrupted aortic arch, ToF)-Abnormal facies-Thymic aplasia (recurrent infection)-Cleft palate-Hypocalcemia/Hypoparathyroidism

207
Q

DiGeorge Syndrome(other features)

A

-ID/LD-Growth hormone deficiency-Skeletal anomalies-Renal anomalies-CONDUCTIVE & SENSORINEURAL hearing loss-Feeding and swallowing problems-Preauricular tags or pits-Ophthalmologic anomalies-Increased risk for embryonal tumors

208
Q

Smith Magenis Syndrome (inheritance)

A

-FISH for deletion (90-95%)-Sequencing only (5-10%)-Del/Dup analysis (90-95%); ~90% have 17p11.2 deletion that includes RAI1 gene

209
Q

Alpha-1 Antitrypsin Deficiency

A

Recessive; SERPINA1**PI*Z is most common pathogenic mutation (PI*M is normal)-deficient enzyme: alpha-1 antitrypsin (A1AT)-excess metabolite: decreased A1AT in the lungs, increased abnormal A1AT in the liver-metabolic testing: low serum A1AT-COPD with otherwise unknown etiology-liver disease at any age-C-ANCA positive vasculitis-necrotizing panniculitis (inflammation of the fatty fibrous tissue directly beneath the skin)

210
Q

Canavan Disease

A

Recessive; ASPA-deficient enzyme: aminoacylase 2-excess metabolite: n-acetylaspartic acid-metabolic testing: elevated urine NAA-symptoms onset in infancy and progress rapidly-TRIAD: hypotonia, had lag, macrocephaly-leukodystrophy-ID-motor skill regression-feeding difficulties-hypo/hypertonia-poor head control-macrocephaly-paralysis-blindness-seizures-shortened lifespan (teens)**milder form exists with mild DDNO treatment

211
Q

Glucose-6-phosphate dehydrogenase deficiency

A

X-LINKED recessive; G6PD**most common human enzymatic disorder-prolonged neonatal jaundice (can lead to kernicterus if untreated)-hemolytic crisis in response to tirggers:+illness+antimalarial drugs, sulfonamides, analgesics (aspirin)+FAVA BEANS+certain chemicals-diabetic ketoacidosis-severe crisis can lead to kidney failure-common in people of African, middle-eastern, and SE Asian descent

212
Q

Hemochromatosis

A

Recessive; HFEExcess metabolite: ironMetabolic testing: elevated serum ferritin-hepatomegaly-cirrhosis-hepatocellular carcinoma-diabetes-cardiomyopathy-hypogonadism-arthritis-progressive increase ins skin pigmentationTreatment:-low iron diet-therapeutic phlebotomy-liver transplant may be required if substantial damage

213
Q

Smith-Lemli-Opitz (SLOS)

A

Recessive; DHCR7-deficient enzyme: 7-dehydrocholesterol reductase-excess metabolite: 7-dehydrocholesterol (7DHC)-metabolic testing: elevated serum 7DHC-mod to severe ID-microcephaly-aggression, self-injury, autism-sensory hypersensitivity-strabismus, cataracts, functional eye abnormalities-congenital heart defects-GI issues-pyloric stenosis-feeding difficulties-renal anomalies-dysmorphic features:+2,3 toe syndactyly, postaxial polydactyly of hands or feet, ambiguous genitalia, hypospadias, bitemporal narrowing, short, upturned nose, ptosis, micrognathia, epicanthal folds, capillary hemangioma of the nose

214
Q

Smith-Lemli-Opitz (SLOS)Dysmorphic features

A

-2,3 toe syndactyly, -postaxial polydactyly of hands or feet-ambiguous genitalia-hypospadias-bitemporal narrowing-short, upturned nose-ptosis-micrognathia-epicanthal folds-capillary hemangioma of the nose

215
Q

Wilson Disease

A

Recessive; ATP7B-deficient enzyme: ceruloplasmin-excess metabolite: copper-metabolic testing: high urinary/hepatic/serum copper, low serum ceruloplasmin-liver disease (recurrent jaundice, hepatitis, fatty liver, hemolytic anemia)-neurologic disease (tremors, poor coordination, loos of fine motor control, chorea, spastic dystonia)-psychiatric manifestations (depression, aggression, phobias, antisocial behavior, poor memory, shortened attention span)KAYSER-FLEISCHER rings - visible on eye-renal problems-arthritis-pancreatitis-cardiomyopathy-SUNFLOWER cataracts

216
Q

General stats of Metabolic conditions in the Neonatal period

A

Metabolic conditions in Neonatal period:-Usually happen in term babies-Babies have good APGARS b/c the placenta will filter out built up metabolites-Are normal from birth to the first 24-48 hours. Takes time for metabolites to build up

217
Q

Glutaric acidemia type I

A

GCDH; most common OA-macrocephaly-unusual fluid collections pre-frontal and temporal lobes-“metabolic stroke-like features” causing severe dystonia and motor impairment

218
Q

Late onset Tay Sachs symptoms

A

psychiatric symptoms (e.g., psychosis)dystonia, ataxiamuscle weaknessno “cherry red spot”cognitive sparing

219
Q

Metabolic conditions with psychiatric findings

A

MCADD, PKU, Galactosemia, Citrulinnemia (ASD), Homocystinuria

220
Q

Batten Disease

A

RecessivePT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSD, DNAJC5, CTSF, ATP13A2, KCTD7Excess metabolite: Lipofuscins-symptom onset in childhood; disabling neurodegeneration leading to death between ages 6-teenage years-neurodegeneration-vision problems-seizures-personality/behavioral changes-echolalia-clumsiness-poor growth-poor circulation in lower extremities-decreased body mass-breath-holding spells-bruxism

221
Q

Danon Disease

A

X-linked Dominant; LAMP2-hypertrophic cardiomyopathy-Wolff-Parkinson-White conduction-skeletal muscle myopathy-visual/retinal pigment disturbances-ID (usually absent in females)

222
Q

Fabry Disease

A

X-linked; GLADeficient enzyme: alpha-galactosidase (GL-3)-acroparathesias (pain & tingling in limbs)-fabry pain crises-angiokeratomas-anhidrosis/hypohidrosis-corneal whorl-left ventricular hypertrophy-GI problems-renal insufficiency (proteinuria)-depression secondary to chronic painTreatment: Fabrazyme (ERT)

223
Q

Fabry Disease(diagnosis)

A

X-linked; GLADeficient enzyme: alpha-galactosidase (GL-3)-Enzyme analysis is only useful for diagnosis in males

224
Q

Gaucher DiseaseType 1

A

Recessive; GBADeficient enzyme: GlucocerebrosidaseExcess metabolite: GlucocerebrosideN370S mutation responds very well to ERT-LEAST SEVERE-hepatosplenomegaly-thrombocytopenia-pulmonary hypertension-gaucher cells/bone crises-erlenmeye flask deformity-NO CNS INVOLVEMENT

225
Q

Gaucher DiseaseType 2

A

Recessive; GBADeficient enzyme: GlucocerebrosidaseExcess metabolite: Glucocerebroside-MOST SEVERE-bulbar and pyramidal signs-ID-convulsions-hypertonia-apnea-NO BONE DISEASE/CRISES-hepatosplenomegaly-thrombocytopenia-pulmonary hypertension-dermatologic abnormalities-lifespan: 2-4 years

226
Q

Gaucher DiseaseType 3

A

Recessive; GBADeficient enzyme: GlucocerebrosidaseExcess metabolite: Glucocerebroside-intermediate phenotype-chronic neuropathic-progressive myoclonic epilepsy-oculomotor apraxia -hepatosplenomegaly-thrombocytopenia-pulmonary hypertension-gaucher cells/bone crises-Erlenmeyer flask deformities-survival into teens and adulthood

227
Q

Gaucher Disease(treatment)

A

**MOST COMMON DISEASE IN AJ POPULATIONERT-cerezyme, VPRIV, elelyso-most effective for individuals with type 1-not effective for individuals with type 2 (ERT cannot cross blood-brain barrier)-improves some symptoms with type 3Substrate reduction therapy-miglustate, eliglustat-for individuals with type 1, some type 3 who cannot do ERT due to allergic reaction/hypersensitivity/poor venous access

228
Q

Krabbe Disease

A

Recessive; GALCDeficient enzyme: GalactosylceramidaseExcess metabolite: psychosine-normal appearance at birth, symptom onset at 3-6 months-Psychosine can become stored in the brain-irritability (cry a lot more than most babies)-fevers-stiffening of limbs with sissoring of legs-opisthotonic posturing (arched back, head back)-seizures-feeding difficulties/vomiting-mental and motor delay-muscle weakness-spasticity-deafness (startled by loud noises)-optic atrophy and blindness-paralysis-no organomegaly present-death by age 2

229
Q

Mucopolysaccharidoses

A

GLYCOSAMINOGLYCANSMPSI - Hurler syndromeMPSII - Hunter syndrome (**X-LINKED)MPSIII - San-Filippo syndromeMPSIV - Morquio syndromeMPSVI - Maroteaux-Lamy syndromeMPSVII - Sly syndrome

230
Q

MPSI - Hurler/Hurler-Sheie

A

RecessiveHurler-Scheie is milder form-DD/ID-REGRESSION-Hepatosplenomegaly-Skeletal anomalies-Short stature-Cardiac anomalies-Corneal clouding-Coarse facial features-Hearing loss

231
Q

MPSII - Hunter

A

X-LINKED-DD/ID-REGRESSION-skeletal anomalies-short stature-cardiac anomalies-CLEAR corneas-Coarse facial features-hearing loss

232
Q

MPSIII - San-Filippos

A

Recessive-MILDER skeletal phenotype-MILDER hepatosplenomegaly-Coarse facial features-Progressive sleep and behavioral problems-Developmental Delays-NO cardiac anomalies-CLEAR corneas-Neuro involvement may be more prominent-Pulmonology problems

233
Q

MPSIV - Morquio

A

Recessive-SEVERE skeletal phenotype (short trunked dwarfism)-NORMAL intellect-chest deformities-cardiac anomalies-bone malformation -macrocephaly

234
Q

MPSVI - Maroteaux-Lamy

A

Recessive-coarse facial features-skeletal anomalies-short stature-cardiac anomalies-corneal clouding-NORMAL intellect-Very similar to MPSI/II, X-Ray findings help tell apart

235
Q

MPSVII - Sly

A

Recessive-DD-REGRESSION-cardiac anomalies-SEVERE hepatosplenomegaly-coarse facial features-recurrent ENT problems-distinct skeletal dysplasia

236
Q

Niemann-Pick DiseaseType A

A

Recessive; SMPD1Deficient enzyme: Acid sphingomyelinaseExcess metabolite: SphingomyelinMost common in the Ashkenazi Jewish population-development stops at 12 months and regresses-death by age 3-CHERRY RED spot on eye exam-hepatosplenomegaly (SEVERE)-failure to thrive-progressive nervous system deterioration-profound brain damage-pulmonary insufficiency-recurrent lung infections

237
Q

Niemann-Pick DiseaseType B

A

Recessive; SMPD1Deficient enzyme: Acid sphingomyelinaseExcess metabolite: SphingomyelinSame genes as Type A but Type B has more enzyme activity-similar symptoms, but later onset and milder-cognitive function may be spared

238
Q

Niemann-Pick DiseaseType C

A

Recessive; NPC1, NPC2Deficient enzyme: Defect in intracellular cholesterol trafficking Excess metabolite: Abnormal intracellular cholesterol homeostasis in cultured fibroblasts showing reduced ability to esterify cholesterol -onset from infantile to adult-hepatosplenomegaly (SEVERE)-dystonia-dysphagia-progressive neurological deterioration-cerebellar ataxia-dysarthria-vertical supranuclear gaze palsy-psychosis-progressive hearing loss

239
Q

Tay-Sachs disease

A

Recessive; HEXADeficient enzyme: Hexosaminidase A-normal development up to ~6 months of age followed by progressive neurodegeneration-average lifespan is ~2 years-failure to achieve motor milestones/motor regression-loss of responsiveness-visual deterioration-seizures-progressive head enlargement due to cerebral gliosis-recurrent infections-difficulties swallowing-CHERRY RED SPOT on eye exam

240
Q

Tay-Sachs disease Adult-Onset

A

Recessive; HEXADeficient enzyme: Hexosaminidase A-NO cherry red spot-slowly progressive neurodegeneration-progressive muscle wasting-dysarthria-fasciculations-cognitive dysfunction-dementia-psychiatric problems-psychosis-can be indistinguishable from progressive adolescent onset SMA or ALS

241
Q

Skeletal MPS features

A

-Coarse Facies-Joint stiffness-Claw hand deformity-Spindle shaped hands-Spinal Gibbus (Kink in spine)-Unable to raise arms above shoulders-Hip stiffness (cannot stand up straight)-Broad ribs-Dystosis multiplex (multiple X-Ray findings)

242
Q

Name the lysosomal storage disease caused by defects in the degradation of Glycoaminoglycans (GAGs).

A

MPS GAGs are not broken down and accumulate throughout the body-Skeletal, liver/spleen, brain, pulmonary system, eyes (corneal clouding)

243
Q

Name the feature of Gaucher disease that is most often the presenting feature.

A

Enlarged spleen

244
Q

What is the cause of anemia/low white cell counts in Gaucher disease?

A

Entrapment of RBCs and platelets within the bone marrow. This can lead to thrombocytopenia.

245
Q

This mutation causing Gaucher Disease Type III has the distinct finding of disturbance of the upward gaze where patients cannot move their eyes up an must move their head to look up.

A

L44PIn general, onset tends to be earlier with this mutation

246
Q

Gaucher Type____ does not respond to ERT

A

Gaucher Type II

247
Q

Treatment for Krabbe disease

A

NAME?

248
Q

General symptoms

A

NAME?

249
Q

Why order citrulline?

A

Plasma concentration of citrulline helps to distinguish between proximal (CPS1, NAGS, OTC) and distal (ASS, ASL, ARG) disorders**Absent or LOW = proximal**ELEVATED = distal

250
Q

Labs to order

A

Plasma concentration of citrullineArginine is often reduced in all except Arginase deficiency (ARG)

251
Q

Treatment

A

NAME?

252
Q

PROXIMAL urea cycle disorders

A

CPS1NAGSOTC**functions in the mitochondria

253
Q

CPS1

A

-deficient enzyme: carbamoyl phosphate synthetase 1-severe lethal neonatal onset or less severe later onset-elevated ammonia levels

254
Q

NAGS

A

NAME?

255
Q

OTC

A

X-LINKED-deficient enzyme: ornithine transcarbamylase-elevated ornithine, uracil, and orotic acid-females can be affected-may present neonatally or in childhood after illness or high protein intake**most common urea cycle disorder

256
Q

DISTAL urea cycle disorders

A

ASSASLARG**functions in the cytosol

257
Q

ASS

A

ASS1-deficient enzyme: arginosuccinic acid synthetase-elevated citrulline

258
Q

ASL

A

ASL-deficient enzyme: arginosuccinic acid lyase-elevated citrulline and arginosuccinic acid

259
Q

ARG

A

ARG1-deficient enzyme: arginase-elevated arginine-hyperammonemia is RARELY present-different metabolic presentation - slower onset, muscle weakness often present

260
Q

Brugada

A

Dominant; SCN5A, KCNE#, SCN#, CACN# (23 genes total)**Channelopathy-sudden death (mean age 40 yrs)-abnormal EKG : negative T wave, coved type ST segment-ventricular fibrillation-self-terminating polymorphic ventricular tachycardia-episodes of syncope-nocturnal agonal respiration (gasping)*CACNA1C also associated with timothy syndrome (LQTS)Management: ICD, avoid agents that induce arrhythmias

261
Q

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

A

Dominant:RYR2 (50%-55%), TRDN, CALM1Recessive: CASQ2-type of arrhythmia (ventricular tachycardia)-sudden death or syncope (80%) with exercise/excitement-hard to distinguish from LQTS when sudden death is presenting symptom, however CPVT is associated with normal baseline/resting EKG and abnormal EKG only after andrenergic event–QRS complexes with frequent and rapid changes inmorphology-major cause of sudden death in childhood with mean age onset 7-9yrs

262
Q

CADASIL

A

cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathyDominant; NOTCH3-onset between 35-55 yrs-migraines with aura-strokes-mood disturbances-progression to subcortical dementia-pseudobulbar palsy-leukoencephalopathy**most common form of hereditary stroke disorder

263
Q

Familial Hypercholesterolemia

A

Dominant/Recessive; LDLR, APOB, PCSK9, LDLRAP1-Xanthomas (chol rich fat depostis beneath skin around the eyes and tendons)-elevated cholesterol-premature atherosclerosis-coronary artery disease-increased risk for MI-homozygotes have more severe features and may require liver transplant/suffer MI much earlier+liver transplant is only for severe cases, but the major source of the problem/defective enzymes are in the liver, so this effectively treats the disease (however, risks for organ transplantation)

264
Q

Hereditary Hemorrhagic Telangiectasia (HHT)

A

Dominant; ACVRL (ALK1), ENG, SMAD4, GDF2-telangiectasias - mucosal lining of the nose, lips/tongue, GI tract-epistaxis (nose bleeds)-arteriovenous malformations (AVMs) - occur in large organs in lung, brain, heart, GI/liver may all cause lethal stroke/MI/cardiac failure-JUVENILE POLYPS (in SMAD4 only)

265
Q

Long QT Syndrome

A

Dominant & Recessive; 15 genesType 1: KCNQ1 - exercise/burst Type 2: KCNH2 - loud noisesType 3: SCN5A - sleep-prolonged QTc interval on EKG**Torsades de pointes are characteristic finding (generates from left ventricle)-Sudden death-Syncope

266
Q

Jervell and Lange-Nielsen syndrome

A

Recessive; KCNE1, KCNQ1-Long QT -congenital DEAFNESS

267
Q

Timothy Syndrome

A

Dominant; CACNA1C - usually de novo-Long QT syndrome-Syndactyly-Autism-Structural cardiac malformation-ID-Dental anomalies

268
Q

Hypertrophic Cardiomyopathy (HCM)

A

Dominant; sarcomeric genes - MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL3…-unexplained left ventricular hypertrophy causing decreased cardiac output-Seen in Noonan/Costello, Fabry, Timothy, GSDIII…PRKAG2 and LAMP2-Result in metabolic storage disease of myocardium-PRKAG2 associated with Wolf Parkinson-White syndrome-LAMP2 causes Danon disease, X-linked with cardiomyopathy, muscle weakness, and ID

269
Q

Dilated Cardiomyopathy (DCM)

A

Dominant, Recessive, X-linked Cytoskeletal genes - TTN, LMNA, MYH7, MYH6, SCN5A, MYBPC3, TNNT2…(lots more!)-stretching of muscle fibers (often in left ventricle) leads to dilation of the chamber and reduced cardiac output-Seen in DMD, mitochondrial diseases, dystorphinopathies, Alstrom, Barth, Emery-Dreifuss…-Mutations in TTN are most common known cause of DCM-TNNT2 mutations may be associated with early onset & aggressive disease

270
Q

Anderson-Tawil Syndrome

A

Dominant: KCNJ2-Skeletal abnormalities (dental anomalies, short stature and scoliosis)-Periodic paralysis and LQTS that is exacerbated by hypokalemia (low potassium)-Dysmorphic features (low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly,

271
Q

Schwartz LQTS score

A

Schwartz LQTS score• ≤1.0 point: low probability of LQTS• 1.5-3.0 points: intermediate probability of LQTS• ≥3.5 points: high probability of LQTS

272
Q

2011 Schwartz LQTS Diagnostic Criteria

A

Based on points with total giving LQTS score-represents probability of LQTS3 Domains: 1. EKG findings: LQTS score, Torsade pointes*, Twave alternans, Notched T wave in 3 leads, Resting heart rate below 2nd %tile for age2. Clinical history: Syncope (w/or w/o stress), Congenital deafness3. Family history: Family member with definite LQTS, Unexplained SCD <30 in immediate family member***In absence of medication/disorders effect EKG** Cannot count same person 2x

273
Q

Pulmonary Arterial Hypertension (PAH)

A

Wide spread obstruction and obliteration of the smallest pulm arteries causes resistance to blood flow through lungs. Leads to heart failure.Dominant: BMPR2 (75%) ACVRL1 (1%) ENG(1%)20% Pentrance when BMPR2Female:Male ratio is 2.5Initial symptomsDyspnea (60%)Fatigue (19%)Reynaud’s Phenomenon (10%) Mostly femalesSyncope (8%)Chest pain (7%)Mean survival is 2.8yrs after Dx

274
Q

PAH and HHT

A

Note: Both can occur together when ACVRIL1 mutation present. ENG or SMAD8 rarely

275
Q

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

A

Dominant: DSP (6-16%), PKP2(11%-43%), DSG2(12-40%)Reduced penetrance, variable expressivityProgressive fibrofatty replacement of the myocardium, predisposing to ventricular tachycardia and SCDCharacterized by 4 stagesSymptoms: Heart palpitations, Ventricular tachycardia +fibrillation, syncope, dyspnea, heart failureDiagnostic criteris has 6 Domains with major/minor criteria: Fhx, arrhythmias, Depolar/Conduction abnormalities, Repolarization abnormalities, Tissue biopsy, dysfunction/structural alterations

276
Q

Cardiac Amyloidosis

A

Deposits of abnormal protein (amyloid) in heart tissue. Deposits will begin to take place of normal heart tissue and can affect signaling.

277
Q

Transthyretin Amyloidosis

A

Dominant: TTRDe novo rate: 66%Group of diseases caused by the accumulationof abnormal protein in the body, Onset 3rd-7th decade of life-žSlowly progressive peripheral + autonomic sensorimotor neuropathy,-Cardiomyopathy, -Vitreous opacities-CNS amyloidosisMost mutations reported are singe bp substitution=AA substitutionTwo common mutations– V30M –Portuguese (1/538), Swedish and Japanese– V122I - African-American population (3.0-3.9%)

278
Q

Hemophilia A(coagulopathy)

A

Factor VIII deficiencyX-linked recessive; F8**30% de novointron 22 inversion>seq>del/dup-Diagnosis based on clotting factor assay-excessive bleeding-renewed bleeding after initial bleeding stops-deep-muscle, intracranial, GI tract bleeds without obvious trauma-poor wound healing-menorrhagia in symptomatic females-excessive bruising, deep-muscle hematomas-chronic joint disease from frequent bleeds which can lead to disability*heterozygous females may be affected, important to assess coagulation factor levels in bloodTreatment: regular factor VIII intravenous infusions, acute treatment with DDAVP

279
Q

Hemophilia B(coagulopathy)

A

Factor IX deficiencyX-linked recessive; F9Seq>Del/dup-Diagnosis based on clotting factor assay-excessive bleeding-renewed bleeding after initial bleeding stops-deep-muscle, intracranial, GI tract bleeds without obvious trauma-poor wound healing-menorrhagia in symptomatic females-excessive bruising, deep-muscle hematomas-chronic joint disease from frequent bleeds which can lead to disability*heterozygous females may be affected, important to assess coagulation factor levels in bloodTreatment: regular factor IX intravenous infusions, acute treatment with DDAVP

280
Q

Factor V Leiden thrombophilia(coagulopathy)

A

Dominant, Recessive; F5**Leiden refers to common allele c.1691G>A (p.R506Q)-increased risk for venous thromboembolism++slight increased risk in heterozygoes++significantly increased/likelihood for multiple VTE events in homozygotes-increased risk for pregnancy loss (2-3x risk in heterozygotes)Treatment: long-term oral anticoagulants is necessary, particularly in homozygotes**it is possible to be heterozygous for multiple coagulopathies which increases risk cumulatively

281
Q

von Willebrand Disease(coagulopathy)

A

Dominant (most), Recessive; VWF-mild to moderate mucocutaneous bleeding++easy bruising, nosebleeds, heavy periods-Types 2B and 2N may have thrombocytopenia-Type 2N has more severe bleeding and mimics hemophilia

282
Q

Alpha-Thalassemia - types(hemoglobinopathy)

A

di-genic; HBA1, HBA2Hb Bart’s Hydrops fetalis - del 4Hemoglobin H disease (HbH) - del 3Alpha Thal minor - del 2Silent Carrier - del 1**DEL/DUP ANALYSIS

283
Q

Alpha-Thalassemia - Hb Bart’s Hydrops Fetalis(hemoglobinopathy)

A

di-genic; HBA1, HBA2-deletion of all 4 alpha-globin alleles-complete absence of alpha globin-fatal in utero (30-36 weeks)-splenomegaly-pleural/pericardial effusions-generalized edema**DEL/DUP ANALYSIS

284
Q

Alpha-Thalassemia - HbH disease(hemoglobinopathy)

A

di-genic; HBA1, HBA2-deletion of 3 alpha-globin alleles-MICROCYTIC HYPOCHROMIC ANEMIA-hepatosplenomegaly-may have skeletal changes affecting facial features-those severely affected require regular blood transfusions**DEL/DUP ANALYSIS

285
Q

Alpha-Thalassemia - Alpha Thal Minor(hemoglobinopathy)

A

di-genic; HBA1, HBA2-deletion of 2 alpha-globin alleles-mild microcytic hypochromic anemia ++can be clinically mistaken for iron deficient anemia-Alpha-thal CIS (aa/–)++seen in SE and E Asian populations (1:20)-Alpha-thal TRANS (a-/a-)++seen in African Middle East and Mediterranean populations**DEL/DUP ANALYSIS

286
Q

Alpha-Thalassemia - Silent Carrier(hemoglobinopathy)

A

di-genic; HBA1, HBA2-deletion of 1 alpha-globin allele-typically asymptomatic-may have low mean corpuscular volume (MCV)**DEL/DUP ANALYSIS

287
Q

Beta Thalassemia - types(hemoglobinopathy)

A

Recessive; HBBThalassemia Major - Hb SB-/SB-Thalassemia Intermedia - Hb SB+/SB+ OR SB-/SB+Thalassemia Minor - Hb SB-/SB or SB+/SB**SEQ ANALYSIS

288
Q

Beta Thalassemia - Major(hemoglobinopathy)

A

Recessive; HBB-SB-/SB–severe microcytic hypochromic anemia-splenomegaly-severe bone deformities-death before 20 if untreatedTreatment: periodic blood transfusions, splenectomy, chelation of transfusion-induced iron overload**SEQ ANALYSIS

289
Q

Beta Thalassemia - Intermedia(hemoglobinopathy)

A

Recessive; HBB-SB+/SB+ or SB-/SB+-anemia-may need transfusions during illness or pregnancy depending on severity of anemia**SEQ ANALYSIS

290
Q

Beta Thalassemia - Minor(hemoglobinopathy)

A

Recessive; HBB-SB-/SB or SB+/SB-Microcytic anemia-lower than normal mean corpuscular volume (MCV)**SEQ ANALYSIS

291
Q

Sickle Cell Anemia(hemoglobinopathy)

A

HBB-Hb SS genotype (normal is Hb AA)-Hb S results from HBB p.E6V-Sickle-shaped red blood cells-chronic hemolysis-vaso-occlusive events (“sickle cell crises”) - damage to tissues, pain, acute or chronic injury++often affects bones, spleen, liver, brain, lungs, kidney, and joints-splenic dysfunction-acute chest syndrome - chest pain, fever, pulmonary infiltrate, respiratory problems, hypoxia++major cause of mortality-dactylitis - inflammation of an entire digit-stroke-pulmonary hypertension**SEQ ANALYSIS

292
Q

Sickle Cell Trait(hemoglobinopathy)

A

Hb AS genotype-usually non-symptomatic-extreme exertion, high altitude, or dehydration may cause vaso-occlusive events (“sickle cell crises”) - damage to tissues, pain, acute or chronic injury++often affects bones, spleen, liver, brain, lungs, kidney, and joints-may have higher risk for venous thromboembolism-protective advantage against malaria**SEQ ANALYSIS

293
Q

Which models give breast cancer risk only?

A

GailClaus

294
Q

Which models give breast cancer AND mutation risk?

A

Tyrer-CuzickBRCAProBOADICEACouch2/Penn2 & Myriad give BRCA mutation risk only

295
Q

Which models can be used on an unaffected proband?

A

Gail (unaffected proband only)Claus (unaffected proband only)Tyrer-Cuzick (unaffected proband only)MyriadBRCAProBOADICEA

296
Q

Which models can be used on both an affected & unaffected proband?

A

MyriadCouch2/Penn2BRCAProBOADICEA

297
Q

In what models can only a female proband be used?

A

GailClausTyrer-Cuzick

298
Q

Which models consider paternal family history?

A

ClausTyrer-CuzickMyriadBRCAProBOADICEA

299
Q

Which models consider Breast Cancer?

A

GailClausTyrer-CuzickCouch2/Penn2MyriadBRCAProBOADICEA

300
Q

Which models consider Ovarian Cancer?

A

Tyrer-CuzickCouch2/Penn2MyriadBRCAProBOADICEA

301
Q

Which models consider other BRCA related cancers?

A

Tyrer-CuzickBRCAProBOADICEA

302
Q

Which models consider bilateral BC?

A

Tyrer-CuzickCouch2/Penn2BRCAProBOADICEA

303
Q

Which models consider contralateral BC?

A

BOADICEA

304
Q

Which models consider male BC?

A

Couch2/Penn2MyriadBRCAProBOADICEA

305
Q

Which models consider ONLY BC <50y

A

Couch2/Penn2Myriad

306
Q

Which models consider FDR?

A

Gail (FDR only)ClausTyrer-CuzickCouch2/Penn2MyriadBRCAProBOADICEA

307
Q

Which models consider FDR & SDR?

A

ClausTyrer-CuzickCouch2/Penn2MyriadBRCAProBOADICEA

308
Q

Which models are not degree of relation specific, only cases with cancer?

A

Couch2/Penn2Myriad - must use one FDR or SDR, then can consider other cases

309
Q

Which models consider TDR?

A

Tyrer-Cuzick (BC only)BRCAPro

310
Q

Which models allow the use of only 2 relatives?

A

GailClaus

311
Q

Which models allow input for age of unaffected relatives?

A

Myriad (gives age ranges)BRCAPro

312
Q

Which models allow input for age of onset for family members?

A

ClausTyrer-CuzickMyriad (gives age ranges)BRCAPro

313
Q

Which models consider Ashkenazi Jewish ancestry?

A

Couch2/Penn2MyriadBRCAPro

314
Q

Which models consider the probands current age?

A

Gail ClausTyrer-CuzickBRCAPro

315
Q

Which models consider age of onset (if proband affected)?

A

BRCAPro

316
Q

Which model considers personal features including weight, height, and BMI?

A

Tyrer-Cuzick

317
Q

Which models consider the number of biopsies and biopsy outcome?

A

Gail Tyrer-Cuzick

318
Q

Which models consider tumor hormone status (f proband affected)?

A

BRCAPro

319
Q

Which models take into account BSO?

A

BRCAPro

320
Q

Which models take into account age at menarche?

A

GailTyrer-Cuzick

321
Q

Which models take into account age at first live birth?

A

Gail

322
Q

Which models take into account parity, age at menopause and HRT use?

A

Tyrer-Cuzick

323
Q

Which models take into account previous genetic testing or carrier status?

A

BRCAPro

324
Q

Which models consider genes other than BRCA or polygenic inheritance?

A

Tyrer-CuzickBOADICEA

325
Q

Gail Model

A

-Gives 5 year risk and lifetime risk-used for consideration of tamoxifen (5 yr risk >1.6%)-Breast cancer risk ONLY in UNAFFECTED FEMALE proband 35 or older-Family history (FDR only, BC only, max 2 relatives)-considers:++current age++#biopsies and outcome+

326
Q

Claus Model

A

-gives lifetime risk-used for consideration of annual breast MRI (lifetime risk >20%)-Breast cancer risk ONLY in UNAFFECTED FEMALE proband-Family history (FDR/SDR, BC only, max 2 relatives)-Considers:++age of onset in relatives (affected & unaffected)

327
Q

Tyrer-Cuzick Model

A

-estimates breast cancer risk AND mutation risk-used in unaffected FEMALE probandConsiders:-paternal family history-breast & ovarian cancer-FDR, SDR & TDR (breast only in TDR)-age of onset in affected relatives-proband factors (age, weight, height

328
Q

Couch2/Penn2 Model

A

-pre-test BRCA probabilityConsiders:-women with breast cancer <50-bilateral breast cancer-Ovarian cancer +/- breast cancer-MALE breast cancer-Prostate & pancreatic cancer-AJ ancestry

329
Q

Myriad Tables

A

-BRCA probability-proband options: ++no breast cancer, ++BC<50, ++BC >50, ++male BC, ++OV, ++BC & OC-Considers AJ ancestryLimitations: -biased population toward high risk/penetrant families-no exact ages of diagnosis or exact # of relatives-Breast &am

330
Q

BRCAPro

A

-estimates breast cancer risk AND mutation risk-proband can be affected or unaffectedConsiders:-paternal fam hx-family history of Breast AND Ovarian-Bilateral breast cancer-MALE breast cancer-FDR, SDR, TDR-age of unaffected AND affected relatives-Ashkenaz

331
Q

BOADICEA

A

-estimates breast cancer risk AND mutation risk-proband can be affected or unaffectedConsiders:-paternal fam hx-family history of Breast AND Ovarian AND other related cancers-Bilateral breast cancer-Contralateral breast cancer-MALE breast cancer-FDR, SDR-

332
Q

What are the typical symptoms of Neonatal onset?

A

NAME?

333
Q

What categories of metabolic syndromes present with vomitting, lethargy, and coma?(Symptom complexes)

A

NAME?

334
Q

What categories of metabolic syndromes present with Acidosis (Typically severe)?(Symptom complexes)

A

Organic Acidemias -Blood pH (Blood gases) of <7.1-Blood bicarbonate of <10

335
Q

What categories of metabolic syndromes present with Respiratory Distress?(Symptom complexes)

A

NAME?

336
Q

What categories of metabolic syndromes present with Hypoglycemia?(Symptom complexes)

A

NAME?

337
Q

What categories of metabolic syndromes present with Organomegaly?(Symptom complexes)

A

NAME?

338
Q

What categories of metabolic syndromes present with Seizure?(Symptom complexes)

A

-Urea Cycle Disorders (due to hyperammonemia)-Organic Acidemias (due to hyperammonemia/hypoglycemia)-Gluconeogenesis Defects-Lysosomal-usually later

339
Q

Metabolic conditions that are due to primary neuromuscular dysfunction

A

Tay Sachs, Krabbe-Metabolites accumulate leading to storage in the Brain/CNS/Eye tissue-Muscular weakness is result of CNS involvement

340
Q

Metabolic conditions that are due to primary muscular dysfunction

A

Pompe, VLCAD, Muscle GSD (Type V)-Metabolites may be stored in muscle (Pompe, GSD Type V)-Affect energy source used by cardiac muscle (VLCAD)-No CNS involvement, DD is due to muscle weakness influencing attainment of milestones

341
Q

Disorders with Organomegaly

A

NAME?

342
Q

Disorders with Fasting Intolerance

A

NAME?

343
Q

Which GSD is X linked?

A

GSD Type IX -Fasting hypoglycemia-Mild lactic acidosis-Mild hyperlipidemia

344
Q

Hypertrophic Cardiomyopathy can occur in this type of GSD.

A

GSD Type III or Cori Disease or Forbes DiseaseCaused by defects in the Debrancher enzyme the breaks chains of glycogen. Enzyme present in heart.

345
Q

FAO: Lab trends

A

UOA to make diagnosis-Dicarboxylic aciduria with acyl-gylcines-Hypoketotic hyppglycemia is keyLow Total carnitine levels High Esterified Carnitine RatioAcyl-Carnitine Profile: May or may not be normalNo lactic acidosisNo ketones detected in blood/urine with hypoglycemia suggest FAO

346
Q

Which FAO has muscle involvement?

A

VLCADCardiac muscle depends on long chain FA for fuel Skeletal muscle also use LC FA as energy source Lipid myopathy-Lipids will accumulate in skeletal muscle causing weaknessLCHAD:cardiomyopathy

347
Q

What time after a meal will metabolic disorders with fasting intolerance/hypoglycemia present?

A

Hepatic GSD: 4-8 hours after meal, body has used up blood glucose but cannot utilize glycogenFAO: 8-12-Energy after this time is made by FAO processHypoglycemia 2-4 hours after a meal are caused by intolerance to a food/component of the food-Ex Galactosemia Note: Timing can vary

348
Q

Disorders of gluconeogenesis (Carbohydrate Metabolism defect)

A

Pyruvate Carboxylase DeficiencyHereditary Fructose IntoleranceInhibition of Gluconeogenesis -FTT w/ persistent fructose-Seizures-Hepatomegaly-Vomiting-HypoglycemiaNormal UOA except lactic acid w/c is elevated

349
Q

Recommended labs when child presents with fasting intolerance/hypoglycemia

A

Anion Gap: Will be significantly highLactate: Tends to be highUric AcidTriglyceride levelsUrine/blood ketonesUOACarnitine profileAcyl-carnitine profile

350
Q

Recommended labs when child presents with neuromuscular symptoms

A

Lactate (mito)Creatinine KinaseMyoglobinBrain MRI—Leukodystrophy (Tay Sachs, Krabbe)Muscle biopsyEnzyme assayGenetic testingNote: Expect labs to be normal or non-specific (Think about reliability of CK)

351
Q

Recommended labs when child presents with organomegaly symptoms

A

Anion Gap; will be highLactateBlood glucoseBlood counts: LSDsUrine GAGs: MPSSkeletal SurveyLiver/Bone marrow biopsy-Histology provides clues: “Gaucher” cells in BM, glycogen granules in liver (GSD)

352
Q

True or FalseAll cases of abnormal glycogen storage are caused by GSD.

A

False.All GSDs have glycogen storage, but not all cases of abnormal glycogen storage are due to defects of GSD.

353
Q

True or FalseGSDs exist on a spectrum based on severity

A

TrueGSD Type I; most severe formGSD Type III: moderate, but have severe progressive cardiomyopathyGSD Type IV-IX: Least severe

354
Q

Metabolic conditions with predisposition to infection

A

Galactosemia –gram-negative sepsisPropionic acidemia, methylmalonic acidemia–neutropeniaMitochondrial disease (e.g., Pearson syndrome –pancytopeniaGaucher disease –neutropenia, splenomegalyGlycogen storage disease type Ib –neutropeniaLysosomal storage diseases –otitis media, respiratory infections, splenomegaly

355
Q

Disorders with diminished exercise intolerance

A

-Glycogen storage disease (type V)-Carnitine transport disorders (carnitine palmitoyltransferase [CPT] II deficiency)-Fatty acid oxidation defects (very long chain acyl CoA dehydrogenase [VLCAD] deficiency)-Mitochondrial diseases

356
Q

Metabolic disorders with X-linked inheritance:

A

NAME?

357
Q

Metabolic disorders with Autosomal dominant:

A

NAME?

358
Q

What is the cause of hyperammonemia in Organic Acidemias?

A

High ammonia levels can occur due to secondary inhibition of the urea cycle by the abnormal organic acid metabolites.

359
Q

What is the cause of hyperammonemia in Urea Cyle Disorders?

A

High ammonia levels occur because defects in that pathway block the ability of the body to convert ammonia to a less toxic form

360
Q

What is the cause of hyperammonemia in Mitochondrial Disorders?

A

The first part of the urea cycle is located in the mitochondrion. In certain mitochondrial diseases, the dysfunctional environment can compromise urea cycle function and produce high ammonia levels

361
Q

What is the cause of hyperammonemia in FAO Disorders?

A

High ammonia levels can occur due to secondary inhibition of the urea cycle by the abnormal fatty acid metabolites

362
Q

Metabolic disorders with prenatal onset of disease can occur when the defect is severe and integral to cellular metabolism. May see dysmorphy features or malformations. Name these disorders.

A

Peroxisomal disease–Zellweger syndromeFatty acid oxidation defects–glutaric acidemia IIMitochondrial disease–pyruvate dehydrogenase complex deficiencyDisorders of glycosylation–carbohydrate-deficient glycoprotein syndromesDefects in cholesterol synthesis –Smith-Lemli-Opitz syndrome

363
Q

Which brain areas in particular are at risk in metabolic disease?

A

Basal ganglia (stroke-like episodes):–Organic acidemias: glutaric acidemia type I, propionic and methylmalonic acidemia–Mitochondrial diseaseBrain stem –Leigh diseaseWhite matter–LeukodystrophiesMore randomly –Stroke-like episodes–Infarction from hyperammonemia–Mitochondrial disease

364
Q

Leukodustrophies

A

Globoid cell (Krabbe) leukodystrophyMetachromatic leukodystrophyX-linked adrenoleukodystrophyCanavan diseaseMitochondrial disease

365
Q

_________ ketone production is found in _____chain and ______chain defects and _____ transport disorders.______ chain defects are associated with significant ketosis.

A

Low ketone production is found in the medium chain and longer chain defects and the carnitine transport disorders.Short chain defects are associated with significant ketosis.

366
Q

Presencce of glutarylcarnitine is seen in the FAO disorder

A

Glutaryic Acidemia Typs I and II

367
Q

What are the metabolic differentials if patient has Isolated Developmental Delay?

A

Carbohydrate-deficient transferrinCreatine and guanidinoacetate

368
Q

If diagnostic urine specimen is _____ for glucose (using a regular dipstick) but ____ for reducing substances, what disorders should be considered?

A

NEGATIVE for glucose POSITIVE for reducing substances. Consider galatosemia or fructose intolerance.

369
Q

Alkaptonuria - features(Amino Acid Disorder)

A

Recessive; HGD-Black urine-Bone/cartilage necrosis (Ochronosis)-Height loss secondary to spinal changes-Aortic/mitral valve calcification

370
Q

Alkaptonuria - labs to order & treatment(Amino Acid Disorder)

A

Recessive; HGDLabs: 24hr urinalysis for homogentisic acid (elevation)Treatment: -Dietary Phe and Tyr restriction-Nitisone can inhibit enzyme responsible for buildup of homogentisic acid

371
Q

Homocystinuria - features(Amino Acid Disorder)

A

Recessive; CBS-Hypopigmentation-Seizures-Risk for MI-MVP-Psychiatric problems-Marfanoid habitus (pectus deformities, ectopia lentis)-Distinguishable from Marfan by:+present of intellectual disability+thromboembolitic events (strokes; vs vessel/aortic dilation seen in marfan)+joint contractures

372
Q

Homocystinuria - labs to order & treatment(Amino Acid Disorder)

A

Recessive; CBSLabs: PAA, also on NBSTreatment:-Vitamin B6 (pyridoxine)-Protein restricted diet-Betaine provides alternate pathway for breakdown of homocysteine (**risk for excess methionine with this treatment)-If residual enzyme activity is present, folate and vit B12 can optimize enzyme activity

373
Q

Maple Syrup Urine Disease - features(Amino Acid Disorder)

A

Recessive; BCKDHA, BCKDHB, DBT*isoleucine, leucine, valineDeficient enzyme: Branched Chain Ketoacid Dehydrogenase-Urine smells like maple syrup-Developmental delay-Poor feeding-Extreme Lethargy-Opisthotonic posturing-Respiratory failure-Encephalopathy with illness

374
Q

Maple Syrup Urine Disease - labs to order & treatment(Amino Acid Disorder)

A

Labs: PAA, also on NBS, UOA :elevated ketoacids Treatment:-AVOID leucine-Dietary leucine restriction/high calorie leucine free formulas

375
Q

Phenylketonuria - features if untreated(Amino Acid Disorder)

A

*Recessive; PAH*Inability to convert Phe to Tyr-Features if untreated:+severe ID+microcephaly+”musty odor”+seizures+behavioral problems+exaggerated neurologic reflexes

376
Q

Phenylketonuria - features if treated(Amino Acid Disorder)

A

*Recessive; PAH*Inability to convert Phe to Tyr-Features if treated:+dependent on how well treatment is maintained+psychiatric problems+learning difficulties/lower IQ

377
Q

Phenylketonuria - labs to order & treatment(Amino Acid Disorder)

A

Labs: PAA, NBS, Biopterin (BH4) is a cofactor for phe hydroxylase - need to rule out biopterin deficiencyTreatment: -Dietary restriction of Phe-Special low Phe foods/formulas-If an individual has residual enzyme activity, biopterin supplementation may help improve enzyme activity

378
Q

Maternal PKU

A

-High Phe levels are a teratogen-Mother’s with PKU who do not maintain treatment will expose their fetuses to high Phe levels-Fetal features:+microcephaly+IUGR+ID+increased risk for CHDs

379
Q

Tyrosinemia - type 1(Amino Acid Disorder)

A

Recessive; FAH-Most severe-Hepatosplenomegaly-Acute liver failure/jaundice-Renal failure-RICKETS-Failure to thrive-Chronic weaknessTreatment: Orfadin (prevents buildup of toxic metabolite)

380
Q

Tyrosinemia - type 2(Amino Acid Disorder)

A

Recessive-Keratosis palmoplantaris (hyperkeratosis of hands and feet)-ID (~50%)-Ocular and cutaneous findings-Growth retardationTreatment: Dietary restriction of Phe and Tyr

381
Q

Tyrosinemia - type 3(Amino Acid Disorder)

A

Recessive**Rarest form-Normal liver function-Mild ID-SeizuresTreatment: Dietary restriction of Phe, Tyr, and Met

382
Q

Amino Acidopathies

A

-chronic & progressive-usually no neonatal crisis (except MSUD)-symptoms develop slowly

383
Q

Fatty Acid Oxidation Disorders(signs and symptoms)

A

NAME?

384
Q

Fatty Acid Oxidation Disorders(types)

A

VLCAD - exhibit cardiomyopathy & generalize myopathy; ^C14LCHAD - exhibit cardiomyopathy & generalize myopathy; female carriers at risk for HELLP; ^C14-18MCAD (most common); ^C6-10SCAD - does not present with hypoketotic hypoglycemia

385
Q

Fatty Acid Oxidation Disorders(labs to order)

A

UOA, Acylcarnitine profile, acylglycines**labs may only be abnormal during crisesMolecular genetic confirmation

386
Q

Fatty Acid Oxidation Disorders(treatments)

A

NAME?

387
Q

X-linked Adrenoleukodystrophy - forms(FAO disorder)

A

*X-linked recessive; ABCD1 gene-Childhood Cerebral Form-Adrenomyeloneuropathy-Addison’s Disease

388
Q

X-linked ALD - Childhood Cerebral Form(FAO disorder)

A

*X-linked recessive; ABCD1 gene-Onset between 4-8 years of age-Progressive neurodegenerative decline-Behavioral and learning deficits-Seizures-Adrenocortical dysfunction-Total disability and early death 6 months-2 years after onset

389
Q

X-linked ALD - Adrenomyeloneuropathy(FAO disorder)

A

*X-linked recessive; ABCD1 gene-Onset in 20s-Progressive stiffness and weakness in the legs0Abnormal sphincter control-Sexual dysfunction-Adrenocortical dysfunction-Neuropathy-40-50% have brain MRI abnormalities (leukodystrophy)-10-20% of those with leukodystrophy have severely progressive cognitive decline and early death

390
Q

X-linked ALD - Addison’s Disease(FAO disorder)

A

*X-linked recessive; ABCD1 gene-Adrenal insufficiency in the absence of MRI/brain anomalies-Increased skin pigmentation from excess ACTH

391
Q

X-linked ALD - Affected females(FAO disorder)

A

NAME?

392
Q

X-linked ALD - Treatment(FAO disorder)

A

NAME?

393
Q

CPT2

A

CPT2-lethal neonatal form: liver failure, CM, death in days/months-severe infantile form: liver failure, CM, onset in 1st year, sudden death-myopathic form: most common, myalgia attacks, variable age of onset

394
Q

General features of Galactosemias

A

NAME?

395
Q

GALT/Gal-1-P deficiency(features)

A

-Features:+neonatal onset+NO AVERSION to galactose containing foods+hyperbilirubinemia+liver dysfunction+renal tubular acidosis+ID+DD+cataracts+sepsis+POF

396
Q

GALT/Gal-1-P deficiency(genetics & treatment)

A

-Recessive; FOXO3 gene (Duarte allele p.N314D)**Duarte allele is a much milder manifestation, attenuation of Gal-1-P rather than depletionTreatment:-dietary lactose restriction-calorie supplementation-non-dairy protein supplementation**AVOID LEGUMES

397
Q

GALK deficiency

A

NAME?

398
Q

GALE deficiency

A

-Deficient enzyme is Galactokinase empirase-Treatment: dietary LACTOSE & GALACTOSE restriction-SEVERE onset-psychomotor retardation-hyperbilirubinemia-liver dysfunction-renal tubular acidosis-ID/ DD-cataracts-sepsis

399
Q

Von-Gierke Disease/GSD1 - features(glycogen storage disorder)

A

Recessive; G6PCGSD Type1a: Primary enzyme defect GSD Type 1b: Transporter defect, more difficult to treat-hypoglycemia-hyperlipidemia-hyperuricemia-lactic acidosis-liver dysfunction/hepatomegaly-DD-GI problems-growth retardation-renal problems/kidney stones-muscle weakness is uncommon

400
Q

Von-Gierke Disease/GSD1 - treatment(glycogen storage disorder)

A

Recessive; G6PC-Avoid fasting/maintain normal glucose to avoid hypoglycemia++body cannot release glycogen, so when it is made it builds up in the liver and kidneys, blood sugar levels are therefore dependent on diet-Nighttime glucose infusions to avoid-Cornstarch between meals-Complex carbs-High protein/fat diet-Liver transplant for severe cases

401
Q

Pompe Disease/GSD2 - Infantile onset(glycogen storage disorder & lysosomal storage disorder)

A

Recessive; GAAAlpha-glucosidase is deficient enzyme-cardiomegaly-hypotonia-cardiomyopathy-respiratory distress-recurrent respiratory infections-enlarged tongue-death in 1st year of life if untreatedTreatment: Myozyme (ERT)

402
Q

Pompe Disease/GSD2 - Late onset(glycogen storage disorder & lysosomal storage disorder)

A

Recessive; GAAAlpha-glucosidase is deficient enzyme-slowly progressive proximal muscle weakness++can mimic limb-girdle muscular dystrophy-hypotonia-impaired cough-delayed motor milestones-dysphagiaTreatment: Lumizyme

403
Q

McArdle Disease/GSD5(glycogen storage disorder)

A

Recessive; PYGMMyophosphorylase is deficient enzymeLabs: Enzyme assay/muscle biopsy-myoglobinuria-myopathy-skeletal muscle weakness-exercise intolerance-rhabdomyolysisTreatment:-B6 supplementation-Sucrose supplementation before exercise-High protein/fat diet

404
Q

Isovaleric Acidemia(organic acidemia)

A

Recessive; IVDPrevents breakdown of leucineDeficient enzyme: isovaleric acid CoA dehydrogenase deficiency-SMELLY FEET-metabolic acidosis-protein aversion-thrombocytopenia-vomiting, poor feeding, coma-seizures-DD-50% severe acute neonatal with rapid death-50% chronic, episodic with asymptomatic intervals**Biotin deficiency can mimic this disorder

405
Q

Isovaleric Acidemia - labs & treatment(organic academia)

A

Recessive; IVDPrevents breakdown of leucineDeficient enzyme: isovaleric acid CoA dehydrogenase deficiencyLabs to order: UOA: Isovaleric Acid, Acylglycines, Acylcarnitine profile: elevated C5, detected on NBS Treatment:-Dietary leucine restriction-Glycine supplementation during acute episodes**Biotin deficiency can mimic this disorder

406
Q

Lesch-Nyhan syndrome(organic academia)

A

X-LINKEDDeficient enzyme: hypoxanthine-guanine phosphoribosyltransferase-ID/DD-Growth retardation-Opisthotonic posturing-Dysphagia-Self-injuring behavior-Hyperuricemia-Renal failure-Treatment is based on management of symptoms-Affected females typically only present with hyperuricemia-Severe cases result in death, typically from renal failure, by 1st or 2nd decade of life-Phenotype is highly variable

407
Q

Proprionic Acidemia- PA(Organic Acidemia)

A

AR; PCCA, PCCB-Deficient enzyme: Proprionyl CoA carboxylase-Cofactor: Biotin-Excess Metabolite: Propionyl CoA-Metabolic testing: Acyl-carnitine profile (elevated C3), UOA*: Methyl Citrate, High Glycine, High Anion Gap-Severe ketoacidosis after 24 hours-Neutropenia -Thrombocytopenia-Hyperammonemia -Acute crisis-Hypotonia-Lethargy-Coma-Seizures -Poor appetite -Vomiting*UOA to distinguish PA from MMA

408
Q

Methylmalonic Acidemia-MMA(Organic Acidemia)

A

Recessive; MUT, MMAA, MMABDeficient Enzyme: methylmalonyl-CoA mutaseExcess metabolite: MMA CoACofactor: B12 (Synthesis defects may mimic MMA)Metabolic testing: Acyl-carnitine: elevated C3, UOA: methymalonic acid, Normal B12/methionine Neonatal symptoms-lethargy-vomiting-hypotonia-hypothermia-respiratory distress-severe ketoacidosis-hyperammonemia-neutropenia & thrombocytopenia

409
Q

Amino acid restrictions for organic acidemia

A

VOMITV: ValineO: Odd chain FAM: Methionine I: IsoleucineT: Threonine

410
Q

Organic Acidurias

A

-high risk of decompensation within 24-72 hours-acute presentation: toxic encephalopathy, decreased feeding, poor tone, seizures, irritability, lethargy -> coma-Treat with carnitine supplementation

411
Q

Sinus node

A

Specialized group of cells in the right atrium that generates impulses that coordinate the pumping of blood

412
Q

What is an Arrhythmia? Name 2 common types

A

Abnormal heart beatBradycardia: Excessively slow heart beatTachycardia: Excessiverly rapid heart beat

413
Q

Ventricular Fibrillation

A

Ventricules quiver rather than pumping blood

414
Q

Electrocardiogram

A

A study used to record the electrical activity of the heart using electrodes attached to the skin

415
Q

What does each wave/interval on an EKG represent?P wave, St-T wavePR intervalQT interval

A

P wave- Represents atrial activationST-T wave- Represents ventricular repolartizationPR interval- Represents the time from onset of arterial activation to onset of ventricular activationQT interval: Duration of ventricular activation and recovery (End of the PR interval to the end of the T wave)

416
Q

What is the QRS complex?

A

Represents ventricular activation

417
Q

Echocardiogram

A

A test that uses ultrasound to visualize the heart

418
Q

What is the difference between a Transthoracic Echo (TTE) and a Transesophageal Echo (TEE)?

A

TTE is non-invasive and most common echoTEE is invasive, comes down through the esophagus to look down at the heart–Gives a clearer image

419
Q

Ejection Fraction

A

Measurement of the blood ejected from the left ventricle with each heart beatNormal is 50% or higher

420
Q

Why might a heart catherization be performed?

A

Pulmonary arterial pressureMyocardial biopsy

421
Q

SyncopePalpatations

A

Fainting, bried loss of consciousness caused by temporary lack of oxygenated bloodFeelings or sensations that the heart is pounding/racing or skipped/stopped a beat

422
Q

Sudden cardiac death

A

Death from abrupt loss of heart function-Occurs within 1 hr of cardiac symptom onset-Natural, rapid, and unexpected-25%-50% have no prior heart medical history

423
Q

Pre symptomatic testingPredisposition testingPharmacogenetic testing

A

Presymptomatic: Asymptomatic individual Predisposition applies to multifactorial disordersPharmaco applies to analysis of genes responsible for drug response

424
Q

Traditional approaches to genetic testing are limited by these factors:

A

Low penetranceAge related penetrancePremature death*Negative family history does not exclude a genetic basis

425
Q

Cardiomyopathy

A

Disease of heart muscleCan lead to heart failure:—Swelling of lower extremities —DyspneaIncreases risk for arrhythmias, stroke and SCD

426
Q

Types of cardiomyopathy

A

Dilated: Most common, mostly happens in adultsHypertrophy: Affects all agesRestrictive: Mostly in older adults, scar tissue replaces normal muscleArrhythmogenic Right Ventricular Dysplasia (ARVD): Often teens and young adults, death of RV muscle replaced with scar tissue, palp&syncope after physical activity

427
Q

Describe DCM

A

-Muscle that makes up the left ventricle stretchesand becomes thinner, spreads to the rightventricle and atria-Dilated heart chambers cannot pump bloodefficiently (systolic dysfunction – ejectionfraction less than 50%)

428
Q

Describe HCM

A

NAME?

429
Q

Name 2 X-linked DCM genes & their associated diseases

A

DMD: DuchenneTaz: Barth syndrome

430
Q

What percentage of HCM are caused by mutations in sarcomere genes

A

60%-70%: Most are AD inheritanceMHY7 AND MYPBC3 each make up to 40% HCMMHY7 mutations are associated with younger age of dx, more severe HCM,nearly complete penetrance but with variable survival

431
Q

What % of individuals with HCM have more than 1 mutation?

A

5% -compound het-double heterozygous-homozygousReally limits predicting of clinical course!

432
Q

True of false, over half of Left Ventricular Non Compaction Cardiomyopathy is inherited(Non-Compaction Cardiomyopathy)

A

True. Aprroximately 70% LVNC inheritedWide range of onet-Adult form: 40yrs-Congenital form: 6yrsNormal heart development includes compaction betwen weeks 5-8 of pregnancy. If this does not happen properly, NCCM/LVNC results

433
Q

What is the clinical presentation of NCCM?

A

NAME?

434
Q

Screening guidelines for HCM

A

ž 12-18 years• ECG and echocardiography• Repeat evaluation every 12-18 monthsž >18-21 years• ECG and echocardiography• Repeat evaluation approximately every 3-5 years orin response to any change in symptoms• Tailor evaluation if the family has late-onset LVH orHCM-related complicationsAvoid competitive endurance training, bursts of activity, weight lifting

435
Q

This gene is associated with the highest percentage of NCCM cases

A

MYH7~15%LDB3~3%TAZ~3

436
Q

Tissues with high energy demand

A

Nerve: cortex, basal ganglia, brain stem, special sense, autonomic nerveMuscle: skeletal, cardiac, smoothEndocrine tissueRenal tubuleGrowth

437
Q

POLG-related Disorders

A

Alpers-Huttenlocher syndrome (AHS)Myoclonic Epilepsy Myopathy Sensory Ataxia (MEMSA)Ataxia Neuropathy Spectrum (ANS)Childhood Myocerebrohepatopathy Spectrum (MCHS)Progressive External Ophthalmoplegia (PEO)–Can be Autosomal Dominant or Recessive

438
Q

Neurologic Red Flags in Mito

A

Stroke-Non vascular distribution, MRI/ADC map shows mixture of hyper and hypo intensityBasal Ganglis Lesions-B/L symmetric (characteristic of Leigh’s) Encephalopathy-Hepatopathy -Precipitated by Valproic Acid exposure, associated with liver failureEpilepsy-Epilepsia Partialis Continua (EPC), myoclonis, status epilepticusCognitive Decline: Regrssion with illnessAtaxia-Associated with epilepsy, neuroimaging may show cerebellar atrophy, white matter lesions, basal ganglis lesionOcular signs-Optic nerve atrophy, ophthalmoplegia, ptosis, retinopathySensorineural hearing loss-At early age, accompanied by other systemmic symptoms

439
Q

Evaluation of a patient with suspected mito disease

A

FhxPhysical examMetabolic screening–Lactate, pyruvate, Ammonia, PAA, UOA, Carnitine, AcylcarnitineMolecular testing–mtDNA, nDNA, NGS panels, exomeTissue biopsy–Skin, muscle, liver–Histopathology, EM, mtDNA, RC/PDH,mtCNV

440
Q

Leigh Syndrome

A

Inheritance: X-linked or autosomal recessive, can also be mitochondrialGenes: Over 50 nuclear genes, MT-ATP6, MT-CO3, MT-ND1 through MT-ND6, MT-TK, MT-TL1, MT-TV, MT-TWMajor features:●Rapid developmental regression●Onset in first months/years of life●Onset after an energetically taxing event●Failure to thrive●Diarrhea●Vomiting●Dysphagia●Seizures●Lactic acidosis●Muscular deterioration●Hyptoonia●Dystonia●Ataxia●Ophthalmoparesis●Nystagmus●Cardiac and respiratory failure●Pyruvate dehydrogenase deficiency●VSDs●Peripheral neuropathy●Lifespan is 6-7 years oUsually death is caused by respiratory failure

441
Q

Leigh Syndrome genetics

A

Nuclear encoded Complex I: NDUFS 1,2,4,7,8 and NDUFVI cause Leigh and Leukpdystrophy Nuclear encoded Complex II genes cause Leigh with paragangliomas and pheochromocytomasNuclear encoded Complex IV genes code for assembly proteins: SURF1 (common), SCO2, COX10, 15

442
Q

Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE)nDNA

A

Inheritance: Autosomal Recessive Gene: TYMP (thymidine phosphorylase, abnormal function can lead to mtDNA abnormalities like depletions, deletions, duplicaitons) ●Progressive gastrointestinal dysmotility —early satiety, nausea, dysphagia, GERD, postprandial emesis, abdominal pain and/or distention, and diarrhea●Cachexia●Ptosis/ophthalmoplegia or ophthalmoparesis●Leukoencephalopathy●Demyelinating peripheral neuropathy —paresthesias (tingling, numbness, and pain)—symmetric & distal weakness more prominently affecting lower extremities60% will have symptoms before 20yrs

443
Q

Barth Syndrome

A

Inheritance: X-linked recessiveGene: TAZMajor features:●Cardiomyopathy oLeft ventricular non-compaction●Neutropenia●Underdeveloped muscles and muscle weakness●Growth delay●Exercise intolerance●Normal intelligence or Mild-to-moderate learning disabilities●Growth problems resolve after puberty●Major causes of death are CM and neutropenia

444
Q

POLG-related Disorders: Symptoms

A

Inheritance: Autosomal recessive, autosomal dominantGene: POLGDisorders caused by POLG exist on a spectrum with some overlap, features seen include:●Psychiatric illness oDepression, psychosis, dementia●Seizure disorders/epilepsy●Extrapyramidal movement disorders oParkinsonianism, chorea●Cerebrovascular involvement●Sensorineural deafness●Retinopathy●Myopathy●Exercise intolerance●Peripheral neuropathy●Endocrine/gonadal failure●GI problems●Liver failure●Cardiomyopathy●Cataracts●Early death may occur

445
Q

Pyruvate Dehydrogenase Deficiency

A

Inheritance: X-linkedMost common form is E1, Alpha Deficiency Metabolic form: ●Lactic acidosis/elevated blood lactate ●Hyperventilation secondary to metabolic acidosisNeurologic form: ●Onset in the first year of life ●Hypotonia ●Poor feeding ●Lethargy ●Brain MRI abnormalities ●Developmental delay ●Intellectual ●Seizures ●Microcephaly ●Blindness ●Spasticity ●Progressive disorderSevere infantile-onset cases have a lifespan of ~6 mosTreatment:●Sodium bicarbonate for acute metabolic episodes●Ketogenic diet

446
Q

Primary Coenzyme Q10 Deficiency

A

Inheritance: Recessive Genes: PDSS1, PDSS2, CoQ2,3,6,7,9, ADCK3, ETFDH, APTX. BRAF, CABC16 clinically distinct phenotypes●Encephalomyopathic form with seizures and ataxia●Multisystem infantile form with encephalomyopathy, cardiomyopathy, and renal failure●Predominantly carebellar form with ataxia and cerebellar atrophy●Leigh syndrome with growth retardation●Isolated myopathy ●Steriod resistant nephrotic syndromeTreatment: CoQ10 supplementation

447
Q

Common features of Mito Disorders

A

●Poor growth●Exercise intolerance●Muscle weakness●Vision/hearing loss●Learning disabilities●Seizures and strokes

448
Q

Three clinical categories of mtDNA depletion syndromes

A

nDNA mutations with downstream effects that cause the quantitative loss of mtDNA copiesMyopathic (TK2, RRM2B)Encephalomyopathic: (SUCLA2, SUCLG1, RRM2B, TYMP)Hepatocerebral: (DGUOK, MPV17, POLG, C10orf2)

449
Q

mtDNA Syndromes

A

MELAS: Mitochondrial Encephalopathy Lactic Acidosis Stroke-like episodesMERRF: Myoclonic Epilepsy with Ragged Red FibersNARP: Neuropathy Ataxia Retinitis Pigmentosa MILS: Maternally-Inherited Leigh Syndrome (same gene as NARP)LHON: Leber’s Hereditary Optic Neuropathy KSS/Pearson: Kearne-Sayre Syndrome

450
Q

MELAS

A

Inheritance: MitochondrialCommon mutation: 3243A>G point mutation in tRNA-leuMost common feature is diabetes w/ or w/o deafness●Generalized tonic-clonic seizures●Recurrent headaches●Anorexia●Recurrent vomiting● Exercise intolerance ●Proximal limb weakness ●Lactic Acidosis ●Seizures associated with stroke-like episodes of transient hemiparesis or cortical blindness. ● Stroke-like episodes associated with altered consciousness● Cumulative residual effects of the stroke-like episodes gradually impair motor abilities, vision, and mentation, often by adolescence or young adulthood. ●Sensorineural hearing loss i

451
Q

LHON

A

Inheritance: MitochondrialLow penetranceMajor features:●Rapid central vision loss in 20’s-30’s●Dystonia (mostly males)

452
Q

LHON Genetics

A

Most cases caused by 3 homoplastic mtDNA mutations in Complex I genes–11778G>A, 3460G>A, 14484T>CPossibly most common mitoSex bias: males are 4x more likely to go blind14484T>C is associated with vision recovery

453
Q

MERRF

A

Inheritance: MitochondrialCommon mutation: 8344A>GMajor features:●Myoclonic Epilepsy●Ragged Red Fibers – clumps of diseased mitochondria that accumulate in the muscle fibers●Symmetrical lipomatosis around neck●Hearing loss

454
Q

NARP

A

Inheritance: MitochondrialCommon mutation: 8993G>T or 8993G>C Major features:●Neuropathy●Ataxia●Retinitis Pigmentosa

455
Q

Kearne-Sayre Syndrome(mtDNA Deletion Syndrome)

A

Inheritance: MitochondrialGenes: Caused by large deletions of mtDNA that are present in all tissues in individuals with KSS●Chronic progressive external ophthalmoplegia (CPEO)●Pigmentary retinopathy- usually rod-cone dystrophy oFunduscopy reveals atypical “salt and pepper” retinopathy o Mild visual acuity loss●Cardiac conduction abnormalities oAV block●Onset before 20 years of age●Cerebellar ataxia may be seen●Some individuals with mtDNA deletions may present with CPEO without other symptoms of Kearns-Sayre

456
Q

Kearne-Sayre Syndrome: Genetics and recurrence risk (mtDNA Deletion Syndrome)

A

Single most common cause of heteroplasmy for 5kb mtDNA, “Common Deletion”, contains a tRNAKSS can be due to other deletions, deletions-duplications, AD AR genes-Duplications have a high recurrence risk-Low recurrence risk for deletions (~4%)5kb deletion can cause other phenotypes, inclduing Pearson syndrome

457
Q

Pearson Syndrome(mtDNA Deletion Syndrome)

A

Inheritance: MitochondrialGenes: Caused by large deletions of mtDNA which are predominantly seen in hematopoietic cells ●Fatal in infancy●Failure to thrive●Sideroblastic anemia●Exocrine pancreas dysfunctionNote: Children initially dx with Pearson can progess to develop signs and symptoms of KSS

458
Q

Chronic progressive external ophthalmoplegia (CPEO)(mtDNA Deletion Syndrome)

A

Inheritance: mtDNA deletion, AR/AD (RRM2B)●Ptosis●Ophthalmoplegia●Oropharyngeal dysfunction (Variable severerity)● Proximal limb muscle weakness.

459
Q

Amyotrophic Lateral Sclerosis (ALS, Lou Gehrig’s Disease)

A

Inheritance: Most cases are idiopathic/familial, some are autosomal dominant or autosomal recessiveGenes: ALS1-ALS14Major features: ●Caused by motor neuron death ●Muscle weakness/atrophy ●Stiffness/cramping of muscles ●Difficulty swallowing ●Foot drop ●Progressive bulbar palsy ●Diffculty talking ●Progressive motor deterioration/muscle atrophy ●Loss of ability to walk/use hands and arms ●Loss of ability to speak/swallow ●Ventilator dependence ●Average survival from onset of symptoms is 4yrs ●Disease usually starts between ages 50-60

460
Q

Charcot-Marie-Tooth Disease (CMT)

A

Inheritance: Autosomal dominant, autosomal recessive, X-linkedGenes: Many, Duplications of PMP22 are responsible for 70-80% of cases (AD)Major features: ●Onset of symptoms in early childhood or early adulthood ●Foot drop oForefoot drops due to muscle weakness oCan cause hammer toe ●Muscle wasting and weakness ●Neuropathy and loss of feeling in feet, ankles, legs, hands, and arms ●Painful, spasmodic muscular contractions ●Damage of sensory nerves while pain nerves are left intact ●Bruxism ●Scoliosis ●Pregnancy and emotional stress can exacerbate disease progression ●Vocal tremor from muscle wasting ●Neuropathic pain ●Eventual wheelchair dependence ●Milder forms exist

461
Q

Duchenne Muscular Dystrophy

A

Inheritance: X-linked recessiveGene: DMD ●Out of frame deletions typically lead to DMDDuchenne Muscular Dystrophy ●Symptom onset between the ages of 2-3 ●Progressive proximal muscle weakness of legs and pelvis oWeakness spreads to rest of body oProximal to distal progression: Trunk, pelvid girdle, and shoulder girdle are lost first ●Awkward gait and/or difficulty with stairs ●Toe walking ●Clumsiness ●Easy fatigue ●Motor delay ●Lumbar hyperlordosis ●Muscle contractures ●Pseudohypertrophy of the calf ●Increased risk for behavioral and learning disorders ●Trouble standing from a lying/sitting position oPositive Gower’s sign ●Elevated serum CPK ●EMG showing destruction of tissue (rather than damage to nerves) ●Cardiomyopathy ●Arrhythmia ●Skeletal deformities ●Wheelchair dependence by 13 ●Late stage respiratory difficulties/ventilator dependence o Increased risk for pneumonia o Dysphagia ●Late stage congestive heart failure ●Average lifespan 20-30

462
Q

Becker Muscular Dystrophy

A

In frame deletions typically lead to BMD ●Slightly milder phenotype than DMD ●Later onset progressive muscle weakness thanDMD ●Severe upper extremity weakness ●Toe-walking ●Positive Gower’s sign ●Skeletal deformities oScoliosis ●Pseudohypertrophy of the calves ●Activity induced muscle cramps ●Preservation of neck flexor muscle strength oDifferentiaties BMD from DMD ●Wheelchair dependency by ~16 ●CardiomyopathyAverage lifespan is mid 40s

463
Q

Emery-Dreifuss Muscular Dystrophy

A

Inheritance: X-linked, autosomal dominant, autosomal recessiveGenes: EMD, LMNA, SYNE1, SYNE2, FHL1Major features: ●Muscle wasting and weakness ●Toe walking ●Joint contractures ●Arrhythmia ●Wheelchair dependency/respiratory insufficiency ●May have intellectual disability (X-linked)

464
Q

Facio-Scapulo-Humeral Muscular Dystrophy

A

Inheritance: Autosomal DominantGenes: Due to deletions of 4q35 which cause deletions of the microsatellite repeat D4Z4. Normally 11-100 repeats units on wild-type alleles. Deletions leading to 10 or fewer repeats lead to FSHDMajor features: ●Normal lifespan ●Slowly progressive weakness of the facial muscles, scapular muscles, and humeral muscles ● CK elevated but not >1500 ●No weakness in bulbar or ocular muscles ●Winged scapula ●Onset of symptoms by 20 years of age

465
Q

Limb-Girdle Muscular Dystrophy

A

Inheritance: Autosomal dominant, autosomal recessiveGene: Too manyMajor features: ●Symmetric proximal slowly progressive muscle weakness ●Elevated CK levels ●Difficulty walking and using stairs ●Difficulty bending over ●Frequent falls ●Difficulty holding arms above head ●Pseudohypertrophy ●Respiratory difficulties ●Lower back pain ●Heart palpitations ●Facial muscle weakness ●Distal muscle weakness ●Shoulder weakness ●Age of onset typically between 10-30 oFaster progression with earlier onset ●Not typically fatal, but can weaken heart or lungs and lead to death

466
Q

Nemaline Myopathy: General

A

Inheritance: Autosomal dominant, autosomal recessiveGenes: ACTA1, CFL2, KBTBD13, KLHL40, KLHL41, LMOD3, NEB, TNNT1, TPM2, TPM3Major features: ● Long face ●Muscle weakness, most severe in the face, neck flexors, and proximal limbs ●Hypotonia ●Depressed/absent deep tendon reflexesMuscle biospy shows myopathic changes and Nemaline bodies

467
Q

Nemaline Myopathy: Severe congenital NM

A

Severe congenital NM ●Severe hypotonia and muscle weakness at birth ●Feeding difficulties ●GI reflux ●Respiratory insufficiency o Often leads to early mortality

468
Q

Spinal Muscular Atrophy (SMA) Types I & II

A

Inheritance: Autosomal recessiveGene: SMN1SMAI: ●Onset 0-6 months ●Hypotonia with muscle weakness ●Absence of motor development ●Involuntary twitching of the tongue ●Mild joint contractures ●Absent tendon reflexes ●Normal brain function and intellect ●Respiratory failure ●Lethal by age 2SMAII ●Onset after age 6 months ●Can sit independently once placed in a seated position ●Hypotonia ●Absent tendon reflexes ●Normal intellect ●May live past age 4

469
Q

Spinal Muscular Atrophy (SMA) Types III & IV

A

SMAIII●Onset after age 10 months●Most motor milestones achieved●Muscle weakness manifesting as frequent falls and trouble with stairs●Proximal limb weaknessoLegs worse than armsSMAIV●Adult onset muscle weaknessSeverity can be affected by number of SMN2 copies. SMN2 can compensate for absent SMN1, the more SMN2 copies, the less severe the phenotype

470
Q

Walker Warburg Syndrome

A

Inheritance: Autosomal recessiveGenes: POMT1, POMT2Major features: ●Hypotonia ●Muscle weakness ●Developmental delay ●Absence of motor skill development ●Severe Intellectual disability ●Seizures ●Brain defects oLissencephaly (Cobblestone Lis for type 2) oHydrocephalus oPronto-cerebellar malformation ●Encephalocele oGap in skull that won’t seal oMeninges of brain can protrude through this gap ●Microphthalmia ●Retinal abnormalitiesLifespan of 1-3 years

471
Q

Amish Nemalin Myopathy

A

Amish NM ●Neonatal onset with early childhood onset ●Hypotonia ●Contractures ●Muscle tremors ●Severe pectus carinatum ●Muscle atrophy ●Respiratory insufficiency

472
Q

Intermediate Nemalin Myopathy

A

Intermediate NM ●Early development of joint contractures ●Motor delay due to muscle weakness ●Wheelchair/respiratory deficiency by age 11Typical (mild) congenital NM ●Hypotonia, weakness, and feeding difficulties ●Spontaneous anti-gravity movements ●Respiratory involvement is limited (recurrent lower respiratory tract infections and/or nocturnal hypoventilation)

473
Q

Childhood-onset Nemaline Myopathy

A

Childhood-onset NM ●Slowly progressive symmetric weakness of ankle dorsiflexion with foot drop ●Onset in 1st or 2nd decade of life ●Motor milestones usually metAdult-onset NM ●Generalized muscle weakness onset between ages 20-50 without antecedent symptoms ●May have cardiomyopathy ●May present with “head drop”

474
Q

What does the Gower’s maneuver/sign indicate?

A

●Sign of proximal weakness●Not indicative of a speficic diagnosis but is seen in DMD& BMD

475
Q

Trendelenburg Gait

A

Weakness of the abductor muscles of the lower extremity, gluteus medius and gluteus minimus

476
Q

DMD/BMD carriers

A

●Less than 5% of carriers also have weakness but not as severe●Dilated cardiomyopathy main concern and may be independent of X-inactivationDMD carriers: 5%-8% lifetime risk or DCM Up to 20% lifetime risk for LV dilationBMD carriers: <1% risk of DCM Up to 15% lifetime risk of LV dilation

477
Q

Genetic testing for DMD/BMD

A

Done in 2 tiersTier 1: Test for exonic del/dupsTeir 2: Full dystrophin gene sequencing if no exonix del/dup

478
Q

Sarcoglyanopathies (LGMD 2C-F)

A

Sarcolycan genes: SGCA,SGCB,SGCG, SGCDInitial muscle involvement is similar to DMD/BMD-Similar age onset (3-15yr), Elevated CK,Differentiate from DMD/BMD-Intellectually normal development-All AR and affect males and femalesSGs account for ~70% of all childhood onset LGMD ~10% of all adult onset LGMD

479
Q

Ullrich CMD

A

Inheritance: Autosomal Recessive or de novo dominantGenes: COL6A1, COL6A2, COL6A3●Significant hypotonia and weakness, initial contractures not obligatory●No or temporary ambulation●CK: normal to high●Charachteristic coexistence of very significant distal hyperlaxity and proximal contractures●Kyphoscoliosis, torticollis, hip dislocation, talipes●Skin: palmar softness, proximal keratosis pilaris, abnormal scars● Early respiratory compromise

480
Q

Bethlem myopathy

A

Inheritance: Autosomal Dominant or de novo Genes: COL6A1, COL6A2, COL6A3●Congenitial joint contractures●Torticollis (50%) may be present, but often resolve●CK: normal to mildly elevated●After initial joint hypermobility, new development of contractures:●Achilles tendons, elbows, deep finger flexors, pectoralis, quadriceps●Very slowly progressive, contractures may become major of a problem, +/- late loss of ambulation●Restrictive lung disease, nighttime hypoventilation

481
Q

SMA Genetics

A

~95% have homzygous deletion of exon 7 of MSN1~5% have heterozygous deletion of exon 7 of SMN1 gene and a point mutation in the other SMN1 alleleRare for SMA patients to have a homozygous non deletion mutationSecond most common lethal recessive disease after cystic fibrosisCarrier frequency: Caucasian 1/47 AJ: 1/67 Pan ethnic: 1/54

482
Q

Ataxia Telangiectasia(gene, inheritance, disrupted repair)

A

ATMRecessiveDouble-stranded break repair (disrupted)**Heterozygous carriers of ATM mutations are at an increased risk for breast cancer

483
Q

Ataxia Telangiectasia(features)

A

ATM; Recessive; Double-stranded break repair- Increased risk for cancer, especially lymphomas and leukemias- Ataxia- Telangiectasias in whites of eyes (may appear in other sun exposed areas)- Oculomotor apraxia- Involuntary movements- Recurrent ear/sinus/upper respiratory infections- Delayed puberty onset- Premature menopause- Growth delay- Drooling- Dysarthria (slurred speech)- Premature aging- Type 2 diabetes at young age- Neurologic symptoms typically stable in first 4-5 years and slowly progressive afterward- Shortened lifespan (25-50 years)

484
Q

Bloom syndrome(gene, inheritance, disrupted repair)

A

BLMRecessiveIncreased sister chromatid exchanges/double-stranded break repair**Common in AJ population - 1:100

485
Q

Bloom syndrome (features)

A

BLM; Recessive; Increased sister chromatid exchanges/double-stranded break repair-IUGR-short stature-extreme growth deficiency-“butterfly shape” skin lesions/rashes after sun exposure-HIGH PITCH VOICE-feeding difficulties-immune deficiency-premature menopause-azoospermia/oligospermia-COPD-intellectually normal, some may have learning problems-little subcutaneous fat tissue during childhood-risk for cancer: COLON, breast, liver, respiratory tract, lymphatic, sarcoma, germ-cell, CNS, retinoblastoma, Leukemia

486
Q

Cockayne syndrome(gene, inheritance, disrupted repair, types)

A

ERCC6, ERCC8RecessiveNucleotide Excision Repair-Type 1: “classic” or “moderate” form - normal prenatal growth with onset of growth and developmental abnormalities in first 2 years-Type 2: severe/early-onset; overlaps with cerebrooculofacioskeletal syndrome or Pena-Shokeir syndrome type 2-Type 3: mild/late-onset - essentially normal growth and cognitive development or by late onset-Xeroderma pigmentosum-Cockayne syndrome: facial freckling and early skin cancers typical of XP and some features typical of CS; DOES NOT include skelatl involvement, facial phenotype of CS, or CNS dysmyelination and calcifications

487
Q

Cockayne syndrome(features)

A

ECCD6, ECCD8; Recessive; Nucleotide excision repairMajor features:-postnatal growth failure-Progressive microcephaly-Leukodystrophy-Neurologic dysfunction-Developmental delay-Behavioral problems-Intellectual deteriorationMinor features: photosensitivity, demyelinating peripheral neuropathy, pigmentary retinopathy, cataracts, SNHL, dental anomalies, characteristic physical appearance (CACHECTIC DWARFISM), premature aging**Only XP-CS type has cancer/infection predisposition

488
Q

Fanconi Anemia(genes, inheritance, disrupted repair)

A

FANCA-FANCP, BRCA2, BRIP1, PALB2, RAD51C, SLX4Recessive, X-linked recessive (FANCB)Cross-link repair, homologous recombination repair**treatment with androgens and hematopoietic growth factors may help/stem cell transplant

489
Q

Fanconi Anemia(features)

A

Cross-link repair, homologous recombination repair-short stature-skeletal anomalies (abnormal limbs & digits, dysplastic, hypoplastic, or absent)-microcephaly-skin lesions: hyper & hypopigmentation, cafe-au-lait-dysmorphic facial features-gentiourinary abnormalities-azoospermia-DD & ID-CONDUCTIVE hearing loss (middle ear skeletal anomalies)-CHDs-GI issues (atresia, malrotation)-kidney problems-pituitary/CNS hypoplasia-PANCYTOPENIA/BONE MARROW FAILURE-significantly increased risk for cancer: lymphatic/leukemia & head/neck tumors

490
Q

Nijmegen Breakage Syndrome(gene, inheritance, disrupted repair)

A

NBN (NBS1)RecessiveHomologous recombination repair

491
Q

Nijmegen Breakage syndrome(features)

A

NBN (NBS1); Recessive; Homologous recombination repair-microcephaly-growth delay-recurrent sinopulmonary infections-progressive decline in intellecutal ability leading to borderline-to-moderate ID-dysmorphic features-T and B-cell lymphomas are common

GC Boards (3 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions