Conditions Flashcards
Carney Complex (gene & inheritance)
PRKAR1A
Dominant
Carney Complex(tumors)
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)
Carney Complex(non-tumor features)
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
HBOC(genes & inheritance)
BRCA1 (17q21) & BRCA2 (13q21.3)
Dominant
Tumor suppressor genes
HBOC (tumors)
- 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)
HBOC (management)
- 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
FAP(gene & inheritance)
Familial Adenomatous Polyposis
APC gene (5q21-22)
Dominant
15-30% de novo rate
FAP(major features (excluding tumors) & testing criteria)
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
FAP(associated tumors & clinical features)
- 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
FAP(treatment)
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
AFAP
Attenuated Familial Adenomatous Polyposis
10-99 adenomatous colon polypsTumors typicaly more proximal in colon
**I130K polymorphism found in 6-7% of affected individuals
Gardner Syndrome (FAP Variant)
FAP with osteomas and soft tissue tumors (fibromas, desmoid, epidermoid)
Turcot Syndrome(FAP/HNPCC Variant)
FAP with CNS tumors, specifically medulloblastoma
**Caused by monoallelic MMR (1/3) or APC (2/3) mutation
HNPCC/Lynch Syndrome(genes & inheritance)
- 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
HNPCC(associated tumors)
Major associated tumors:
- Colorectal (R ascending)
- 80% lifetime risk
***Adenomatous tumors
- Uterine-Small bowel
- Ureter
- Renal pelvis
- Ovarian
Other associated tumors:
- Stomach**
- Gallbladder
- Brain
Amsterdam I Criteria
- 3 individuals with CRC (1 must be FDR of other 2)
- 2 generations
- 1 diagnosed <50yrs
**FAP excluded
Amsterdam II Criteria
**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
MLH1 & PMS2(tumor testing)
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
MSH2 & MSH6(tumor testing)
MMR genes
- HNPCC/Lynch
- Absence of both: MSH2 mutation OR EPCAM mutation
- Absence of MSH6: MSH6 mutation
HNPCC (treatment)
- 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
Bethesda Criteria
- 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%
HNPCC(testing criteria)
- Meets Amsterdam II criteria
- Meets Bethesda criteria
- Diagnosed with Uterine cancer <50yrs
- Known Lynch syndrome in family
- >=5% risk of Lynch on prediction model
MUTYH-associated polyposis(gene & inheritance)
MUTYH Recessive
-Base excision repair genes
**Mutations lead to G:C or T:A transversions can lead to Lynch-like features/cancer risks
MUTYH(associated features)
- Characterized by an increased risk for adenomatous colon polyps and CRC (80%)
- High amount of phenotypic heterogeneity (10-100 adenomas, 100+ adenomas, APC normal)
MUTYH(referral indication)
Any individual with a personal history of OR FDR with:
- 10+ cumulative adenomatous colon polyps with or without CRC
- MMR proficient CRC diagnosed
Li-Fraumeni(gene & inheritance)
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
Li-Fraumeni(associated tumors)
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
Li-Fraumeni(diagnostic criteria)
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
Chompret Criteria(Li-Fraumeni)
- 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
MEN1(gene & inheritance)
MEN1 (11q13)Dominant
**Sequencing detects most cases
**MEN1 - tumor suppressor gene
MEN1(associated tumors)
Parathyroid (100% by age 50)
Anterior pituitary (30-40%)
Well-differentiated endocrine (gastrinoma, insulinoma, glucagonoma, VIPoma)
Carcinoid
Adrenocortical (pheos are rare)
MEN1(growths)
Facial angiofibromas
Collagenomas
Lipomas
Cafe a lait macules
MEN1(diagnostic criteria)
Tumor in 2 of:
-parathyroid, enteropancreatic endocrine tissue, OR anterior pituitary; ORTumor in one and FDR with MEN1
MEN1(treatment)
- Head MRI @ 5yrs
- Abdominal CT or MRI @ 20yrs
- Calcium serum concentrations @ 8yrs
- Gastrin @ 20yrs
- Pancreatic polypeptide @ 10yrs
- Prolactin @ 5yrs
MEN2(gene & inheritance)
RET (10q11.2)Dominant
**PROTO-ONCOGENE
Sequencing detects majority of MEN2 cases (MEN2A exon 10&11; MEN2B exon 16)
MEN2A(clinical features)
- Medullary thyroid cancer (<35 yrs)
- Pheochromocytoma (50%)
- Hyperparathyroidism
- Parathyroid adenomas
- May present with cutaneous lichen amyloidosis
**Prophylactic thyroidectomy
**GoF mutations
MEN2B(clinical features)
- 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
Familial Medullary Thyroid Cancer
Medullary thyroid cancer without other symptoms of MEN2A/MEN2B
*No pheo or parathyroid adenoma/hyperplasia
**GoF mutations
Hirschprung’s disease
**LoF mutations (chromosome 10)
Megacolon
Constipation
Neurofibromatosis Type 2(gene & inheritance)
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
NF2(features)
-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
Tuberous Sclerosis Complex(gene & inheritance)
TSC1, TSC2
Dominant
**Lots of funky growths
**TSC2/PCKD contiguous gene deletion, features of TSC and AD PKD
**sequencing
TSC(major features)
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
TSC (minor features)
- “Confetti” hypopigmented skin lesions
- Dental enamel pits
- Intraoral fibromas
- Multiple renal cysts
- Nonrenal hamartomas
- Retinal achromic patch
Von Hippel-Lindau Disease(gene & inheritance)
VHL (3p25)Dominant
**sequencing followed by deletion analysis (by southern blot) gives very high detection rate
Von Hippel-Lindau Disease (associated tumors)
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
PTEN Hamartoma Tumor Syndrome(gene & associated syndromes)
PTEN
**start with sequencing
Variant syndromes:
- Cowden
- Bannayan-Riley-Ruvalcaba
- Proteus
- Proteus-like
PTEN(associated tumors)
- 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
PTEN (other features)
Macrocephaly, trichilemmomas, lipomas, pigmented macules of the glans penis,
Lhermitte-Duclos(PTEN variant)
PTEN with dysplastic gangliocytoma of the cerebellum
Cowden(PTEN variant)
- 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
Bannayan-Riley-Ruvalcaba(PTEN variant)
Macrocephaly
Hamartomatous polyposis
Lipomas
Pigmented macules of the glans penis
Proteus Syndrome(PTEN variant)
- CT nevi
- Disproportionate overgrowth
- Dysregulated adipose tissue
- Vascular malformation
- Risk of ovarian or parotid tumor in 2nd decade
Xeroderma Pigmentosum(gene & inheritance)
XPA, XPC, ERCC2, POLH
RecessiveDNA
-repair protein (NER pathway); UV induced DNA damage
Xeroderma Pigmentosum(features)
- 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
Birt-Hogg-Dube (gene & inheritance)
FLCN
Dominant
Birt-Hogg-Dube(clinical features)
-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
Constitutional Mismatch Repair Deficiency
-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
Familial Gastrointestinal Stromal Tumor (GIST)
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
Familial Pancreatic Cancer
At least two FDR with pancreatic ductal adenocarcinoma
Hereditary syndromes: BRCA2 and CDKN2A
Familial Prostate Cancer
AR, AD, and X-linked inheritance patterns
Hereditary Diffuse Gastric Cancer
- Gene: CDH1 (occurs in 25-50% who meet criteria)
- Increased risk for:
+Diffuse gastric cancer
+Lobular breast cancer
+Signet ring CRC
Hereditary Leiomyomatosis and Renal Cell Cancer
- Gene: FH
- Renal cancer (papillary type 2 “fried egg”)
- Cutaneous leiomyoma
- Uterine fibroids
- Pheos/Paras
Hereditary Melanoma (aka Familial atypical mole and malignant melanoma - FAMMM)
- Genes: CDKN2A, ARF
- Multiple melanotic nevi (usually >50) and fam hx melanoma
- Individuals have a 17% risk for pancreatic cancer by age 75
Hereditary Mixed Polyposis Syndrome
Atypical juvenile polyps
Colonic adenomas
Colorectal carcinomas
Inflammatory and metaplastic polyps
Duplication on chromosome 15q13-q14
Hereditary Papillary Renal Cell Carcinoma
- Gene: MET
- Risk of developing papillary type 1 RCC
Hereditary Paraganglioma-Pheochromocytoma Syndrome(genes)
-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
Hereditary Retinoblastoma
- RB1 (chr 13)
- Malignant tumor of the retina, usually occurring before 5yrs
+~40% of all retinoblastomas are hereditary
-Osteosarcoma
Juvenile Polyposis Syndrome(gene & inheritance)
SMAD4, BMPR1A
Autosomal dominant
25% de novo
Juvenile Polyposis Syndrome(features)
- 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
Nevoid Basal Cell Carcinoma Syndrome
- 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
Peutz-Jeghers Syndrome
- 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
Serrated Polyposis Syndrome(formerly hyperplastic)
- 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
Familial Colorectal Cancer, Type X(FCCTX)
- 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
BRCA Carrier Rate(AJ population vs. General Population)
AJ population: 1/40
General population: 1/800
BRCA VUS rate (African American vs. European Population)
African American: 20%
**AA cancers are more commonly triple negative
European Ancestry: 7%
What factors cause an increased risk for breast cancerProtective factors for breast cancer
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
BRCA facts
- Can BRCA1 tumors be treated with drugs that target the estrogen receptor?
- Is BRCA1 more likely to be invasive lobular?
- Is BRCA1 or BRCA2 more likely to be triple negative?
- Is BRCA1 or BRCA2 more likely to be estrogen receptor positive?
- No
- No
- BRCA1
- BRCA2
MUTYH-associated polyposis
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)
HNPCC/Lynch Syndrome
-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
Amsterdam I & II Criteria
-3 individuals with CRC (1 must be FDR of other 2)-2 generations-1 diagnosed <50yrs**FAP excluded
Bethesda Criteria
-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%
MLH1 & PMS2(tumor testing)
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
MSH2 & MSH6(tumor testing)
MMR genes - HNPCC/Lynch- Absence of both: MSH2 mutation OR EPCAM mutation-Absence of MSH6: MSH6 mutation
Li-Fraumeni(gene, inheritance & diagnostic criteria)
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
Li-Fraumeni(associated tumors)
NAME?
Chompret Criteria(Li-Fraumeni)
-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
MEN1
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
MEN1(treatment)
-Head MRI @ 5yrs-Abdominal CT or MRI @ 20yrs-Calcium serum concentrations @ 8yrs-Gastrin @ 20yrs-Pancreatic polypeptide @ 10yrs-Prolactin @ 5yrs
MEN2A
-Medullary thyroid cancer (<35 yrs)-Pheochromocytoma (50%)-Hyperparathyroidism-Parathyroid adenomas-May present with cutaneous lichen amyloidosis**Prophylactic thyroidectomy **GoF mutations
MEN2B
-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
Familial Medullary Thyroid Cancer
Medullary thyroid cancer without other symptoms of MEN2A/MEN2B**GoF mutations
Hirschprung’s disease
**LoF mutations (chromosome 10)MegacolonConstipation
Neurofibromatosis Type 2
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
Tuberous Sclerosis Complex
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
Von Hippel-Lindau Disease
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
PTEN
-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
Lhermitte-Duclos(PTEN variant)
PTEN with dysplastic gangliocytoma of the cerebellum
Cowden(PTEN variant)
-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
Bannayan-Riley-Ruvalcaba(PTEN variant)
NAME?
Proteus Syndrome(PTEN variant)
-CT nevi-Disproportionate overgrowth-Dysregulated adipose tissue-Vascular malformation-Risk of ovarian or parotid tumor in 2nd decade
Xeroderma Pigmentosum
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
Birt-Hogg-Dube
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
Constitutional Mismatch Repair Deficiency
-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
Familial Gastrointestinal Stromal Tumor (GIST)
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
Familial Pancreatic Cancer
NAME?
Hereditary Diffuse Gastric Cancer
-Gene: CDH1 (occurs in 25-50% who meet criteria)-Increased risk for: +Diffuse gastric cancer +Lobular breast cancer +Signet ring CRC
Hereditary Leiomyomatosis and Renal Cell Cancer
-Gene: FH-Renal cancer (papillary type 2 “fried egg”)-Cutaneous leiomyoma-Uterine fibroids-Pheos/Paras
Hereditary Melanoma (aka Familial atypical mole and malignant melanoma - FAMMM)
-Genes: CDKN2A, ARF-Multiple melanotic nevi (usually >50) and fam hx melanoma-Individuals have a 17% risk for pancreatic cancer by age 75
Hereditary Mixed Polyposis Syndrome
NAME?
Hereditary Papillary Renal Cell Carcinoma
-Gene: MET-Risk of developing papillary type 1 RCC
Hereditary Paraganglioma-Pheochromocytoma Syndrome
-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
Hereditary Retinoblastoma
-RB1 (chr 13)-Malignant tumor of the retina, usually occurring before 5yrs +~40% of all retinoblastomas are hereditary
Juvenile Polyposis Syndrome
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
Nevoid Basal Cell Carcinoma Syndrome
-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
Peutz-Jeghers Syndrome
-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
Serrated Polyposis Syndrome(formerly hyperplastic)
-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
Familial Colorectal Cancer, Type X(FCCTX)
-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
Major Malformation
NAME?
Minor Anomaly
NAME?
Syndrome
NAME?
Association
NAME?
VACTERL
Vertebral anomaliesAnal atresiaCardiac defectsTracheoesophageal fistulaEsophageal atresiaRenal and radial anomaliesLimb defects
Malformation
NAME?
Sequence
NAME?
Potter Sequence
Renal agenesis/renal malformation leading to oligohydramnios which causes distinct physical appearance
Pierre-Robin Sequence
Micrognathia leads to cleft palate and glossoptosis and subsequent respiratory distress
Deformation
NAME?
Disruption
NAME?
Dysplasia
NAME?
CHARGE
ColobomaHeartchoanal Atresiagrowth RetardationGenital abnormalitiesEar abnormalities
Locus Heterogeneity
Mutations in DIFFERENT GENES can cause the SAME DISORDER/phenotypic presentation +ie. Noonan syndrome, Autism
Allelic Heterogeneity
DIFFERENT MUTATIONS/alleles on the SAME GENE can cause the SAME DISORDER +ie. Cystic Fibrosis
Phenotypic Heterogeneity
DIFFERENT MUTATIONS on the SAME GENE can cause DIFFERENT PHENOTYPES +ie. FBN1, FGFR3
Pleiotropy
One gene mutation influences many unrelated phenotypic traits +ie. PKU, Sickle-cell
Variable Expressivity
NAME?
Penetrance
NAME?
Arthrogryposis
Congenital joint contracture in two or more areas of the body
Amyoplasia
-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
Ectrodactyly
Deficiency or absence of one or more CENTRAL digits of the hand or foot
Klippel-Feil Anomaly
-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
Mesomelic shortening
Shortening of the DISTAL long bones
Rhizomelic shortening
Shortening of the PROXIMAL long bones
Micromelic shortening
Shortening of the DISTAL and PROXIMAL long bones
Talipes Equinovalgus/Equinovarus
Club foot-Valgus: feet turned outward-Varus: feet turned inward
Triploidy
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
Digyny
NAME?
Diandry
-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
Common features of triploidy
3,4 syndactylyCystic placenta
Can Triploidy be detected on NIPT?
Yes, only via SNP-method (ie. Natera)
Trisomy 13(Patau Syndrome)
-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
Trisomy 18(Edward Syndrome)
-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
Trisomy 21 - Prenatal findings(Down Syndrome)
-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:
Trisomy 21 - Postnatal findings(Down Syndrome)
-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
Cat Eye Syndrome
-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
Turner Syndrome
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
Klinefelter Syndrome
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
XYY Syndrome
47, XYY-Tall stature-DD-Learning difficulties-Behavior problems-No like to increased aggression-NORMAL sexual development
TRUE OR FALSE. The karyotype of a spontaneous abortion is more likely to be abnormal than that of a stillborn infant.
TRUE
Chromsomes where imprinting should be considered
6, 7, 11, 14, 15, 16
Russell-Silver Syndrome(mode of imprinting)
-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
Russell-Silver Syndrome(clinical features)
-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
Beckwith-Wiedemann Syndrome(mode of imprinting)
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)
Beckwith-Wiedemann Syndrome(Major features)
-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
Beckwith-Wiedemann Syndrome(Minor features)
NAME?
Angelman Syndrome(mode of imprinting)
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
Angelman Syndrome(major features)
-“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
Angelman Syndrome(minor features)
NAME?
Prader-Willi Syndrome(mode of imprinting)
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
Prader-Willi Syndrome(features)
-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
Birt-Hogg-Dube
Individual with a person OR FDR with 5 or more BHD associated facial or truncal papules
Constitutional Mismatch Repair Deficiency
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
Cowden Syndrome
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
FAP
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
Familial GIST
Any individual with a personal history or FDR with:-3+ close relatives with GIST-Wild-type GIST-Individuals with 3+ GISTs
Familial Pancreatic Cancer
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
Familial Prostate Cancer
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
Hereditary Diffuse Gastric Cancer
Any individual with a personal or FDR with diffuse gastric cancer
Hereditary Leiomyomatosis and Renal Cell Cancer
Any individual with a personal or FDR with:-Cutaneous leiomyomas-RCC with histology characteristic of hereditary leiomyomatosis and renal cell cancer
Familial Atypical Mole and Malignant Melanoma(Hereditary Melanoma)
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
Hereditary Mixed Polyposis Syndrome
Any individual with a personal or FDR with 10+ colorectal polyps with mixed histology
Hereditary Papillary Renal Cell Carcinoma
Any individual with a personal or FDR with papillary type 1 RCC
Hereditary Paraganglioma-Pheochromocytoma Syndrome
Any individual with a personal or FDR with a paraganglioma or pheochromocytoma
Hereditary Retinoblastoma
Any individual with a personal or FDR with a retinoblastoma
Juvenile Polyposis Syndrome
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
Lynch Syndrome
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
Melanoma Astrocytoma Syndrome
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
MEN1
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
MEN2
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
MUTYH-associated polyposis
Any individual with a personal or FDR with:-10+ cumulative adenomatous colon polyps with or without CRC-MMR proficient CRC diagnosed
Nevoid Basal Cell Carcinoma Syndrome
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
Peutz-Jeghers Syndrome
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
Rhabdoid tumor predisposition types 1 & 2
Any individual with a personal or FDR with a rhabdoid tumor, including small cell carcinoma of the ovary, hypercalcemic type
Serrated Polyposis Syndrome
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
Tuberous Sclerosis Complex
Any individual with a personal or FDR with any two criteria-Brain tumors-Kidney tumors-Heart tumors-Skin and neurological abnormalities-Skin lesions
Von-Hippel-Lindau Syndrome
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
Monosomy 1p36
-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
Wolf-Hirschhorn Syndrome
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
Cri Du Chat Syndrome(chromosome location)
5p- syndromeDominant5p15.2 (critical region)5p15.3 (cat-cry region)Typically de novo (85-90%); PATERNAL de novo (80%)
Cri Du Chat Syndrome(major features)
NAME?
Cri Du Chat Syndrome(minor features)
NAME?
Williams Syndrome
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
WAGR Syndrome
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
Smith-Magenis Syndrome
17p11.2 deletion-Inverted circadian rhythm-Aggression, anxiety, impulsiveness, ADHD-REDUCED pain sensitivity-Strabismus-Ear abnormalities-CONDUCTIVE hearing loss-Dysmorphic features-“page turning” motion
Miller-Dieker Lissencephaly Syndrome
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
DiGeorge Syndrome(VeloCardioFacial syndrome)CATCH
22q11.2 deletion-Cardiac anomalies (interrupted aortic arch, ToF)-Abnormal facies-Thymic aplasia (recurrent infection)-Cleft palate-Hypocalcemia/Hypoparathyroidism
DiGeorge Syndrome(other features)
-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
Smith Magenis Syndrome (inheritance)
-FISH for deletion (90-95%)-Sequencing only (5-10%)-Del/Dup analysis (90-95%); ~90% have 17p11.2 deletion that includes RAI1 gene
Alpha-1 Antitrypsin Deficiency
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)
Canavan Disease
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
Glucose-6-phosphate dehydrogenase deficiency
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
Hemochromatosis
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
Smith-Lemli-Opitz (SLOS)
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
Smith-Lemli-Opitz (SLOS)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
Wilson Disease
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
General stats of Metabolic conditions in the Neonatal period
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
Glutaric acidemia type I
GCDH; most common OA-macrocephaly-unusual fluid collections pre-frontal and temporal lobes-“metabolic stroke-like features” causing severe dystonia and motor impairment
Late onset Tay Sachs symptoms
psychiatric symptoms (e.g., psychosis)dystonia, ataxiamuscle weaknessno “cherry red spot”cognitive sparing
Metabolic conditions with psychiatric findings
MCADD, PKU, Galactosemia, Citrulinnemia (ASD), Homocystinuria
Batten Disease
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
Danon Disease
X-linked Dominant; LAMP2-hypertrophic cardiomyopathy-Wolff-Parkinson-White conduction-skeletal muscle myopathy-visual/retinal pigment disturbances-ID (usually absent in females)
Fabry Disease
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)
Fabry Disease(diagnosis)
X-linked; GLADeficient enzyme: alpha-galactosidase (GL-3)-Enzyme analysis is only useful for diagnosis in males
Gaucher DiseaseType 1
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
Gaucher DiseaseType 2
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
Gaucher DiseaseType 3
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
Gaucher Disease(treatment)
**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
Krabbe Disease
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
Mucopolysaccharidoses
GLYCOSAMINOGLYCANSMPSI - Hurler syndromeMPSII - Hunter syndrome (**X-LINKED)MPSIII - San-Filippo syndromeMPSIV - Morquio syndromeMPSVI - Maroteaux-Lamy syndromeMPSVII - Sly syndrome
MPSI - Hurler/Hurler-Sheie
RecessiveHurler-Scheie is milder form-DD/ID-REGRESSION-Hepatosplenomegaly-Skeletal anomalies-Short stature-Cardiac anomalies-Corneal clouding-Coarse facial features-Hearing loss
MPSII - Hunter
X-LINKED-DD/ID-REGRESSION-skeletal anomalies-short stature-cardiac anomalies-CLEAR corneas-Coarse facial features-hearing loss
MPSIII - San-Filippos
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
MPSIV - Morquio
Recessive-SEVERE skeletal phenotype (short trunked dwarfism)-NORMAL intellect-chest deformities-cardiac anomalies-bone malformation -macrocephaly
MPSVI - Maroteaux-Lamy
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
MPSVII - Sly
Recessive-DD-REGRESSION-cardiac anomalies-SEVERE hepatosplenomegaly-coarse facial features-recurrent ENT problems-distinct skeletal dysplasia
Niemann-Pick DiseaseType 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
Niemann-Pick DiseaseType B
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
Niemann-Pick DiseaseType C
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
Tay-Sachs disease
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
Tay-Sachs disease Adult-Onset
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
Skeletal MPS features
-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)
Name the lysosomal storage disease caused by defects in the degradation of Glycoaminoglycans (GAGs).
MPS GAGs are not broken down and accumulate throughout the body-Skeletal, liver/spleen, brain, pulmonary system, eyes (corneal clouding)
Name the feature of Gaucher disease that is most often the presenting feature.
Enlarged spleen
What is the cause of anemia/low white cell counts in Gaucher disease?
Entrapment of RBCs and platelets within the bone marrow. This can lead to thrombocytopenia.
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.
L44PIn general, onset tends to be earlier with this mutation
Gaucher Type____ does not respond to ERT
Gaucher Type II
Treatment for Krabbe disease
NAME?
General symptoms
NAME?
Why order citrulline?
Plasma concentration of citrulline helps to distinguish between proximal (CPS1, NAGS, OTC) and distal (ASS, ASL, ARG) disorders**Absent or LOW = proximal**ELEVATED = distal
Labs to order
Plasma concentration of citrullineArginine is often reduced in all except Arginase deficiency (ARG)
Treatment
NAME?
PROXIMAL urea cycle disorders
CPS1NAGSOTC**functions in the mitochondria
CPS1
-deficient enzyme: carbamoyl phosphate synthetase 1-severe lethal neonatal onset or less severe later onset-elevated ammonia levels
NAGS
NAME?
OTC
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
DISTAL urea cycle disorders
ASSASLARG**functions in the cytosol
ASS
ASS1-deficient enzyme: arginosuccinic acid synthetase-elevated citrulline
ASL
ASL-deficient enzyme: arginosuccinic acid lyase-elevated citrulline and arginosuccinic acid
ARG
ARG1-deficient enzyme: arginase-elevated arginine-hyperammonemia is RARELY present-different metabolic presentation - slower onset, muscle weakness often present
Brugada
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
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
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
CADASIL
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
Familial Hypercholesterolemia
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)
Hereditary Hemorrhagic Telangiectasia (HHT)
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)
Long QT Syndrome
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
Jervell and Lange-Nielsen syndrome
Recessive; KCNE1, KCNQ1-Long QT -congenital DEAFNESS
Timothy Syndrome
Dominant; CACNA1C - usually de novo-Long QT syndrome-Syndactyly-Autism-Structural cardiac malformation-ID-Dental anomalies
Hypertrophic Cardiomyopathy (HCM)
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
Dilated Cardiomyopathy (DCM)
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
Anderson-Tawil Syndrome
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,
Schwartz LQTS score
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
2011 Schwartz LQTS Diagnostic Criteria
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
Pulmonary Arterial Hypertension (PAH)
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
PAH and HHT
Note: Both can occur together when ACVRIL1 mutation present. ENG or SMAD8 rarely
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
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
Cardiac Amyloidosis
Deposits of abnormal protein (amyloid) in heart tissue. Deposits will begin to take place of normal heart tissue and can affect signaling.
Transthyretin Amyloidosis
Dominant: TTRDe novo rate: 66%Group of diseases caused by the accumulationof abnormal protein in the body, Onset 3rd-7th decade of life-Slowly 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%)
Hemophilia A(coagulopathy)
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
Hemophilia B(coagulopathy)
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
Factor V Leiden thrombophilia(coagulopathy)
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
von Willebrand Disease(coagulopathy)
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
Alpha-Thalassemia - types(hemoglobinopathy)
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
Alpha-Thalassemia - Hb Bart’s Hydrops Fetalis(hemoglobinopathy)
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
Alpha-Thalassemia - HbH disease(hemoglobinopathy)
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
Alpha-Thalassemia - Alpha Thal Minor(hemoglobinopathy)
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
Alpha-Thalassemia - Silent Carrier(hemoglobinopathy)
di-genic; HBA1, HBA2-deletion of 1 alpha-globin allele-typically asymptomatic-may have low mean corpuscular volume (MCV)**DEL/DUP ANALYSIS
Beta Thalassemia - types(hemoglobinopathy)
Recessive; HBBThalassemia Major - Hb SB-/SB-Thalassemia Intermedia - Hb SB+/SB+ OR SB-/SB+Thalassemia Minor - Hb SB-/SB or SB+/SB**SEQ ANALYSIS
Beta Thalassemia - Major(hemoglobinopathy)
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
Beta Thalassemia - Intermedia(hemoglobinopathy)
Recessive; HBB-SB+/SB+ or SB-/SB+-anemia-may need transfusions during illness or pregnancy depending on severity of anemia**SEQ ANALYSIS
Beta Thalassemia - Minor(hemoglobinopathy)
Recessive; HBB-SB-/SB or SB+/SB-Microcytic anemia-lower than normal mean corpuscular volume (MCV)**SEQ ANALYSIS
Sickle Cell Anemia(hemoglobinopathy)
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
Sickle Cell Trait(hemoglobinopathy)
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
Which models give breast cancer risk only?
GailClaus
Which models give breast cancer AND mutation risk?
Tyrer-CuzickBRCAProBOADICEACouch2/Penn2 & Myriad give BRCA mutation risk only
Which models can be used on an unaffected proband?
Gail (unaffected proband only)Claus (unaffected proband only)Tyrer-Cuzick (unaffected proband only)MyriadBRCAProBOADICEA
Which models can be used on both an affected & unaffected proband?
MyriadCouch2/Penn2BRCAProBOADICEA
In what models can only a female proband be used?
GailClausTyrer-Cuzick
Which models consider paternal family history?
ClausTyrer-CuzickMyriadBRCAProBOADICEA
Which models consider Breast Cancer?
GailClausTyrer-CuzickCouch2/Penn2MyriadBRCAProBOADICEA
Which models consider Ovarian Cancer?
Tyrer-CuzickCouch2/Penn2MyriadBRCAProBOADICEA
Which models consider other BRCA related cancers?
Tyrer-CuzickBRCAProBOADICEA
Which models consider bilateral BC?
Tyrer-CuzickCouch2/Penn2BRCAProBOADICEA
Which models consider contralateral BC?
BOADICEA
Which models consider male BC?
Couch2/Penn2MyriadBRCAProBOADICEA
Which models consider ONLY BC <50y
Couch2/Penn2Myriad
Which models consider FDR?
Gail (FDR only)ClausTyrer-CuzickCouch2/Penn2MyriadBRCAProBOADICEA
Which models consider FDR & SDR?
ClausTyrer-CuzickCouch2/Penn2MyriadBRCAProBOADICEA
Which models are not degree of relation specific, only cases with cancer?
Couch2/Penn2Myriad - must use one FDR or SDR, then can consider other cases
Which models consider TDR?
Tyrer-Cuzick (BC only)BRCAPro
Which models allow the use of only 2 relatives?
GailClaus
Which models allow input for age of unaffected relatives?
Myriad (gives age ranges)BRCAPro
Which models allow input for age of onset for family members?
ClausTyrer-CuzickMyriad (gives age ranges)BRCAPro
Which models consider Ashkenazi Jewish ancestry?
Couch2/Penn2MyriadBRCAPro
Which models consider the probands current age?
Gail ClausTyrer-CuzickBRCAPro
Which models consider age of onset (if proband affected)?
BRCAPro
Which model considers personal features including weight, height, and BMI?
Tyrer-Cuzick
Which models consider the number of biopsies and biopsy outcome?
Gail Tyrer-Cuzick
Which models consider tumor hormone status (f proband affected)?
BRCAPro
Which models take into account BSO?
BRCAPro
Which models take into account age at menarche?
GailTyrer-Cuzick
Which models take into account age at first live birth?
Gail
Which models take into account parity, age at menopause and HRT use?
Tyrer-Cuzick
Which models take into account previous genetic testing or carrier status?
BRCAPro
Which models consider genes other than BRCA or polygenic inheritance?
Tyrer-CuzickBOADICEA
Gail Model
-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+
Claus Model
-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)
Tyrer-Cuzick Model
-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
Couch2/Penn2 Model
-pre-test BRCA probabilityConsiders:-women with breast cancer <50-bilateral breast cancer-Ovarian cancer +/- breast cancer-MALE breast cancer-Prostate & pancreatic cancer-AJ ancestry
Myriad Tables
-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
BRCAPro
-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
BOADICEA
-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-
What are the typical symptoms of Neonatal onset?
NAME?
What categories of metabolic syndromes present with vomitting, lethargy, and coma?(Symptom complexes)
NAME?
What categories of metabolic syndromes present with Acidosis (Typically severe)?(Symptom complexes)
Organic Acidemias -Blood pH (Blood gases) of <7.1-Blood bicarbonate of <10
What categories of metabolic syndromes present with Respiratory Distress?(Symptom complexes)
NAME?
What categories of metabolic syndromes present with Hypoglycemia?(Symptom complexes)
NAME?
What categories of metabolic syndromes present with Organomegaly?(Symptom complexes)
NAME?
What categories of metabolic syndromes present with Seizure?(Symptom complexes)
-Urea Cycle Disorders (due to hyperammonemia)-Organic Acidemias (due to hyperammonemia/hypoglycemia)-Gluconeogenesis Defects-Lysosomal-usually later
Metabolic conditions that are due to primary neuromuscular dysfunction
Tay Sachs, Krabbe-Metabolites accumulate leading to storage in the Brain/CNS/Eye tissue-Muscular weakness is result of CNS involvement
Metabolic conditions that are due to primary muscular dysfunction
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
Disorders with Organomegaly
NAME?
Disorders with Fasting Intolerance
NAME?
Which GSD is X linked?
GSD Type IX -Fasting hypoglycemia-Mild lactic acidosis-Mild hyperlipidemia
Hypertrophic Cardiomyopathy can occur in this type of GSD.
GSD Type III or Cori Disease or Forbes DiseaseCaused by defects in the Debrancher enzyme the breaks chains of glycogen. Enzyme present in heart.
FAO: Lab trends
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
Which FAO has muscle involvement?
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
What time after a meal will metabolic disorders with fasting intolerance/hypoglycemia present?
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
Disorders of gluconeogenesis (Carbohydrate Metabolism defect)
Pyruvate Carboxylase DeficiencyHereditary Fructose IntoleranceInhibition of Gluconeogenesis -FTT w/ persistent fructose-Seizures-Hepatomegaly-Vomiting-HypoglycemiaNormal UOA except lactic acid w/c is elevated
Recommended labs when child presents with fasting intolerance/hypoglycemia
Anion Gap: Will be significantly highLactate: Tends to be highUric AcidTriglyceride levelsUrine/blood ketonesUOACarnitine profileAcyl-carnitine profile
Recommended labs when child presents with neuromuscular symptoms
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)
Recommended labs when child presents with organomegaly symptoms
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)
True or FalseAll cases of abnormal glycogen storage are caused by GSD.
False.All GSDs have glycogen storage, but not all cases of abnormal glycogen storage are due to defects of GSD.
True or FalseGSDs exist on a spectrum based on severity
TrueGSD Type I; most severe formGSD Type III: moderate, but have severe progressive cardiomyopathyGSD Type IV-IX: Least severe
Metabolic conditions with predisposition to infection
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
Disorders with diminished exercise intolerance
-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
Metabolic disorders with X-linked inheritance:
NAME?
Metabolic disorders with Autosomal dominant:
NAME?
What is the cause of hyperammonemia in Organic Acidemias?
High ammonia levels can occur due to secondary inhibition of the urea cycle by the abnormal organic acid metabolites.
What is the cause of hyperammonemia in Urea Cyle Disorders?
High ammonia levels occur because defects in that pathway block the ability of the body to convert ammonia to a less toxic form
What is the cause of hyperammonemia in Mitochondrial Disorders?
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
What is the cause of hyperammonemia in FAO Disorders?
High ammonia levels can occur due to secondary inhibition of the urea cycle by the abnormal fatty acid metabolites
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.
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
Which brain areas in particular are at risk in metabolic disease?
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
Leukodustrophies
Globoid cell (Krabbe) leukodystrophyMetachromatic leukodystrophyX-linked adrenoleukodystrophyCanavan diseaseMitochondrial disease
_________ ketone production is found in _____chain and ______chain defects and _____ transport disorders.______ chain defects are associated with significant ketosis.
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.
Presencce of glutarylcarnitine is seen in the FAO disorder
Glutaryic Acidemia Typs I and II
What are the metabolic differentials if patient has Isolated Developmental Delay?
Carbohydrate-deficient transferrinCreatine and guanidinoacetate
If diagnostic urine specimen is _____ for glucose (using a regular dipstick) but ____ for reducing substances, what disorders should be considered?
NEGATIVE for glucose POSITIVE for reducing substances. Consider galatosemia or fructose intolerance.
Alkaptonuria - features(Amino Acid Disorder)
Recessive; HGD-Black urine-Bone/cartilage necrosis (Ochronosis)-Height loss secondary to spinal changes-Aortic/mitral valve calcification
Alkaptonuria - labs to order & treatment(Amino Acid Disorder)
Recessive; HGDLabs: 24hr urinalysis for homogentisic acid (elevation)Treatment: -Dietary Phe and Tyr restriction-Nitisone can inhibit enzyme responsible for buildup of homogentisic acid
Homocystinuria - features(Amino Acid Disorder)
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
Homocystinuria - labs to order & treatment(Amino Acid Disorder)
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
Maple Syrup Urine Disease - features(Amino Acid Disorder)
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
Maple Syrup Urine Disease - labs to order & treatment(Amino Acid Disorder)
Labs: PAA, also on NBS, UOA :elevated ketoacids Treatment:-AVOID leucine-Dietary leucine restriction/high calorie leucine free formulas
Phenylketonuria - features if untreated(Amino Acid Disorder)
*Recessive; PAH*Inability to convert Phe to Tyr-Features if untreated:+severe ID+microcephaly+”musty odor”+seizures+behavioral problems+exaggerated neurologic reflexes
Phenylketonuria - features if treated(Amino Acid Disorder)
*Recessive; PAH*Inability to convert Phe to Tyr-Features if treated:+dependent on how well treatment is maintained+psychiatric problems+learning difficulties/lower IQ
Phenylketonuria - labs to order & treatment(Amino Acid Disorder)
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
Maternal PKU
-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
Tyrosinemia - type 1(Amino Acid Disorder)
Recessive; FAH-Most severe-Hepatosplenomegaly-Acute liver failure/jaundice-Renal failure-RICKETS-Failure to thrive-Chronic weaknessTreatment: Orfadin (prevents buildup of toxic metabolite)
Tyrosinemia - type 2(Amino Acid Disorder)
Recessive-Keratosis palmoplantaris (hyperkeratosis of hands and feet)-ID (~50%)-Ocular and cutaneous findings-Growth retardationTreatment: Dietary restriction of Phe and Tyr
Tyrosinemia - type 3(Amino Acid Disorder)
Recessive**Rarest form-Normal liver function-Mild ID-SeizuresTreatment: Dietary restriction of Phe, Tyr, and Met
Amino Acidopathies
-chronic & progressive-usually no neonatal crisis (except MSUD)-symptoms develop slowly
Fatty Acid Oxidation Disorders(signs and symptoms)
NAME?
Fatty Acid Oxidation Disorders(types)
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
Fatty Acid Oxidation Disorders(labs to order)
UOA, Acylcarnitine profile, acylglycines**labs may only be abnormal during crisesMolecular genetic confirmation
Fatty Acid Oxidation Disorders(treatments)
NAME?
X-linked Adrenoleukodystrophy - forms(FAO disorder)
*X-linked recessive; ABCD1 gene-Childhood Cerebral Form-Adrenomyeloneuropathy-Addison’s Disease
X-linked ALD - Childhood Cerebral Form(FAO disorder)
*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
X-linked ALD - Adrenomyeloneuropathy(FAO disorder)
*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
X-linked ALD - Addison’s Disease(FAO disorder)
*X-linked recessive; ABCD1 gene-Adrenal insufficiency in the absence of MRI/brain anomalies-Increased skin pigmentation from excess ACTH
X-linked ALD - Affected females(FAO disorder)
NAME?
X-linked ALD - Treatment(FAO disorder)
NAME?
CPT2
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
General features of Galactosemias
NAME?
GALT/Gal-1-P deficiency(features)
-Features:+neonatal onset+NO AVERSION to galactose containing foods+hyperbilirubinemia+liver dysfunction+renal tubular acidosis+ID+DD+cataracts+sepsis+POF
GALT/Gal-1-P deficiency(genetics & treatment)
-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
GALK deficiency
NAME?
GALE deficiency
-Deficient enzyme is Galactokinase empirase-Treatment: dietary LACTOSE & GALACTOSE restriction-SEVERE onset-psychomotor retardation-hyperbilirubinemia-liver dysfunction-renal tubular acidosis-ID/ DD-cataracts-sepsis
Von-Gierke Disease/GSD1 - features(glycogen storage disorder)
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
Von-Gierke Disease/GSD1 - treatment(glycogen storage disorder)
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
Pompe Disease/GSD2 - Infantile onset(glycogen storage disorder & lysosomal storage disorder)
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)
Pompe Disease/GSD2 - Late onset(glycogen storage disorder & lysosomal storage disorder)
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
McArdle Disease/GSD5(glycogen storage disorder)
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
Isovaleric Acidemia(organic acidemia)
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
Isovaleric Acidemia - labs & treatment(organic academia)
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
Lesch-Nyhan syndrome(organic academia)
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
Proprionic Acidemia- PA(Organic Acidemia)
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
Methylmalonic Acidemia-MMA(Organic Acidemia)
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
Amino acid restrictions for organic acidemia
VOMITV: ValineO: Odd chain FAM: Methionine I: IsoleucineT: Threonine
Organic Acidurias
-high risk of decompensation within 24-72 hours-acute presentation: toxic encephalopathy, decreased feeding, poor tone, seizures, irritability, lethargy -> coma-Treat with carnitine supplementation
Sinus node
Specialized group of cells in the right atrium that generates impulses that coordinate the pumping of blood
What is an Arrhythmia? Name 2 common types
Abnormal heart beatBradycardia: Excessively slow heart beatTachycardia: Excessiverly rapid heart beat
Ventricular Fibrillation
Ventricules quiver rather than pumping blood
Electrocardiogram
A study used to record the electrical activity of the heart using electrodes attached to the skin
What does each wave/interval on an EKG represent?P wave, St-T wavePR intervalQT interval
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)
What is the QRS complex?
Represents ventricular activation
Echocardiogram
A test that uses ultrasound to visualize the heart
What is the difference between a Transthoracic Echo (TTE) and a Transesophageal Echo (TEE)?
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
Ejection Fraction
Measurement of the blood ejected from the left ventricle with each heart beatNormal is 50% or higher
Why might a heart catherization be performed?
Pulmonary arterial pressureMyocardial biopsy
SyncopePalpatations
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
Sudden cardiac death
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
Pre symptomatic testingPredisposition testingPharmacogenetic testing
Presymptomatic: Asymptomatic individual Predisposition applies to multifactorial disordersPharmaco applies to analysis of genes responsible for drug response
Traditional approaches to genetic testing are limited by these factors:
Low penetranceAge related penetrancePremature death*Negative family history does not exclude a genetic basis
Cardiomyopathy
Disease of heart muscleCan lead to heart failure:—Swelling of lower extremities —DyspneaIncreases risk for arrhythmias, stroke and SCD
Types of cardiomyopathy
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
Describe DCM
-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%)
Describe HCM
NAME?
Name 2 X-linked DCM genes & their associated diseases
DMD: DuchenneTaz: Barth syndrome
What percentage of HCM are caused by mutations in sarcomere genes
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
What % of individuals with HCM have more than 1 mutation?
5% -compound het-double heterozygous-homozygousReally limits predicting of clinical course!
True of false, over half of Left Ventricular Non Compaction Cardiomyopathy is inherited(Non-Compaction Cardiomyopathy)
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
What is the clinical presentation of NCCM?
NAME?
Screening guidelines for HCM
12-18 years• ECG and echocardiography• Repeat evaluation every 12-18 months >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
This gene is associated with the highest percentage of NCCM cases
MYH7~15%LDB3~3%TAZ~3
Tissues with high energy demand
Nerve: cortex, basal ganglia, brain stem, special sense, autonomic nerveMuscle: skeletal, cardiac, smoothEndocrine tissueRenal tubuleGrowth
POLG-related Disorders
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
Neurologic Red Flags in Mito
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
Evaluation of a patient with suspected mito disease
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
Leigh Syndrome
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
Leigh Syndrome genetics
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
Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE)nDNA
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
Barth Syndrome
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
POLG-related Disorders: Symptoms
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
Pyruvate Dehydrogenase Deficiency
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
Primary Coenzyme Q10 Deficiency
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
Common features of Mito Disorders
●Poor growth●Exercise intolerance●Muscle weakness●Vision/hearing loss●Learning disabilities●Seizures and strokes
Three clinical categories of mtDNA depletion syndromes
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)
mtDNA Syndromes
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
MELAS
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
LHON
Inheritance: MitochondrialLow penetranceMajor features:●Rapid central vision loss in 20’s-30’s●Dystonia (mostly males)
LHON Genetics
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
MERRF
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
NARP
Inheritance: MitochondrialCommon mutation: 8993G>T or 8993G>C Major features:●Neuropathy●Ataxia●Retinitis Pigmentosa
Kearne-Sayre Syndrome(mtDNA Deletion Syndrome)
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
Kearne-Sayre Syndrome: Genetics and recurrence risk (mtDNA Deletion Syndrome)
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
Pearson Syndrome(mtDNA Deletion Syndrome)
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
Chronic progressive external ophthalmoplegia (CPEO)(mtDNA Deletion Syndrome)
Inheritance: mtDNA deletion, AR/AD (RRM2B)●Ptosis●Ophthalmoplegia●Oropharyngeal dysfunction (Variable severerity)● Proximal limb muscle weakness.
Amyotrophic Lateral Sclerosis (ALS, Lou Gehrig’s Disease)
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
Charcot-Marie-Tooth Disease (CMT)
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
Duchenne Muscular Dystrophy
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
Becker Muscular Dystrophy
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
Emery-Dreifuss Muscular Dystrophy
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)
Facio-Scapulo-Humeral Muscular Dystrophy
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
Limb-Girdle Muscular Dystrophy
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
Nemaline Myopathy: General
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
Nemaline Myopathy: Severe congenital NM
Severe congenital NM ●Severe hypotonia and muscle weakness at birth ●Feeding difficulties ●GI reflux ●Respiratory insufficiency o Often leads to early mortality
Spinal Muscular Atrophy (SMA) Types I & II
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
Spinal Muscular Atrophy (SMA) Types III & IV
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
Walker Warburg Syndrome
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
Amish Nemalin Myopathy
Amish NM ●Neonatal onset with early childhood onset ●Hypotonia ●Contractures ●Muscle tremors ●Severe pectus carinatum ●Muscle atrophy ●Respiratory insufficiency
Intermediate Nemalin Myopathy
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)
Childhood-onset Nemaline Myopathy
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”
What does the Gower’s maneuver/sign indicate?
●Sign of proximal weakness●Not indicative of a speficic diagnosis but is seen in DMD& BMD
Trendelenburg Gait
Weakness of the abductor muscles of the lower extremity, gluteus medius and gluteus minimus
DMD/BMD carriers
●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
Genetic testing for DMD/BMD
Done in 2 tiersTier 1: Test for exonic del/dupsTeir 2: Full dystrophin gene sequencing if no exonix del/dup
Sarcoglyanopathies (LGMD 2C-F)
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
Ullrich CMD
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
Bethlem myopathy
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
SMA Genetics
~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
Ataxia Telangiectasia(gene, inheritance, disrupted repair)
ATMRecessiveDouble-stranded break repair (disrupted)**Heterozygous carriers of ATM mutations are at an increased risk for breast cancer
Ataxia Telangiectasia(features)
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)
Bloom syndrome(gene, inheritance, disrupted repair)
BLMRecessiveIncreased sister chromatid exchanges/double-stranded break repair**Common in AJ population - 1:100
Bloom syndrome (features)
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
Cockayne syndrome(gene, inheritance, disrupted repair, types)
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
Cockayne syndrome(features)
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
Fanconi Anemia(genes, inheritance, disrupted repair)
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
Fanconi Anemia(features)
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
Nijmegen Breakage Syndrome(gene, inheritance, disrupted repair)
NBN (NBS1)RecessiveHomologous recombination repair
Nijmegen Breakage syndrome(features)
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
