100 Syndrome Flashcards
(238 cards)
1
Q
What are the most common heart defets in 22q11
A
TOF, Interrupted aortic arch, conotruncal
2
Q
Monitoring in 22q11
A
Ca level, PTH
Immune function: T/B cell subsets, immunoglobulins, and post vaccine antibodies (avoid live vaccines if immunodeficient)
Renal US
Laryngoscopy
3
Q
Cholestasis + pulmonary artery disease + butterfly vertebra
A
Alagille syndrome
AD JAG1, Notch 2
+ posterior embryotoxon, DD, FTT
Dysmoprhic face: prominent foreheard, deep set eyes, hypertelorism, bulbous nsoe tip
4
Q
ST segment abnormalities v1-V and norturnal agonal respirations
A
Brugada syndrome
SCN5A (AD), KCNE5 (XL)
FHx SIDS, unexpected death at night
Southeast Asian
Tx: Quinidine, defibrillator, avoid arrhythmogenic meds
5
Q
Pulmonic stenosis + TFF + ichthyosis + keratosis + cupid’s bow lips
A
Cardio-Facio-Cutaneous syndrome
BRAF, KRAS (AD - consitutive activation)
- Assoicated with ALL
+ sparse hair/eyebrows, bitemporal constriction, hypertelorism, downslanting PF
+ HCM, Pulmonic stenosis
+ atopic dermatitis + keroatosis + ichthyosis
6
Q
Coarse face, papillomata, wrinkled skin w/ deep creases, pulmonic stenosis
A
Costello syndrome
HRAS (AD)
+ HCM
+ bladder ca, rhabdomyosarcoma, neuroblastoma
7
Q
Epistaxis + GI bleed
A
HHT
ACVRL1, ENG, GDF2, SMAD4
- Look for juvenile polyps in SMAD4
- Screen for AVMs
8
Q
Carpal bone abnormality + CHD
A
Holt Oram
TBX5 (AD)
- Carpal defect always present, other hand malfromations possible
- monitor for arrhythmia (even if heart structurally normal)
9
Q
Lengtigines, HCM, short status, pectus, ptosis, hypertelorism
A
Noonan w/ Multiple lentigines
PTPN11, RAF1
Lentigines
EKG changes
Ocular hypertelorism
Pulm stenosis
Abnormalities of genetalia
Retardation of growth
Deafness
10
Q
What is the mechanism of disease for Noonan spectrum disorders?
A
Constitutive activation of Ras MAPK GTPase pathway
11
Q
Pulm stenosis, coarse face, cryptorchidism, bleeding disorder
A
Noonan
Rasopathy
Monitor: TTE, renal U/S, bleeding times
12
Q
7p11 deletion syndrome
A
Williams Syndrome
ELN
Supervalvular AS, hernia, joint issues, ID
Endo issues: Hypercalcemia, hypercalciruia, hypothyroidism
Monitor: Hearing loss, diabetes, Ca levels, Thyroid, renal US, TTE
13
Q
Stellate/Iacy iris, short nose w/ full tip, malar hypoplasia, full lips, wide mouth, small jaw, prominent earlobes
A
Williams
7p11.23 deletion (ELN)
Monitor: Ca, TFTs, TTE (aortic stenosis), Renal, hearing loss
14
Q
What is the mechanism of Ataxia Telangiectasia?
A
ATM gene (AR)
ds DNA repair
+ leukemia and lymphoma risk
15
Q
How do you manage Ataxia Telangeictasia?
A
Monitor for leukemia/lymphoma
IVIG if immunodeficiency
Avoid ionizing radiation
16
Q
Growth restriction, immunodeficiency, photosensitivity, insulin resistance, azoospermia
A
Bloom syndrome
BLM (DNA replicaton/repair gene)
- chromatid/chormosome breaks
- Risk of colon and other cancers
17
Q
Butterfly distribution sun sensitive telangiectasias
A
Bloom symdrome
BLM (AR)
- growth restriction, azoospermia in males, cancer risk, immunodeficiency
18
Q
Triradial and quadriradial figures on karyotype
A
Bloom syndrome
BLM
- Increased sister chromatid exchanges
- FTT, immunodeficiency, azoospermia in males, butterfly rash
Cancers (colon +)
19
Q
Bone marrow failure, short stature, multiple congenital anomalies
A
Fanconi anemia
FANCA (A, C, D2, E, F, G), BRCA2 (AR), RAD51 (AD), FANCB (XL)
marrow failure (Pancytopenia)
Malignancy (solid tumors, AML)
Malformations (CNS, heart, GI, GU, ear, skeletal)
Dx with chromosome breakage analysis
20
Q
Arachnodactyly + contractures + crumplied ears
A
Beals syndrome (congenital contractural arachnodactyly)
FBN2
+ Marfanoid
Managementt: TTE (IAA, VSD, aortic dilation) q2 yrs
Upper GI (duodenal/esophageal atresia)
21
Q
Hyperextensable skin, heaped up scar-like lesion over pressure points, cyst-like lesions over bony prominences, hypotonia
A
Classic EDS (I or II)
COL5A1, COL5A2 -AD
- Molluscoid pseudotumor (heaped up lesions)
- Subcutaneous spheroids (Cyst like lesions over prominences) - fibrosed/calcified fat globules
+ Root dilation
Management: TTE for aortic root
22
Q
What are the distinguishing features of EDSIII
A
No skin fragility, No heme manifestations (easy bruising, prolonged bleeding)
23
Q
Which gene can cause a phenocopy of hypermobile EDS
A
Tenascin X
24
Q
Organ rupture, translucent skin, easy bruising
A
Vascular EDS (type IV)
COL3A1
Major criteria: arterial/organ rupture, family Hx
Mino criteria: thin skin, joint hypermobility, easy bruising, club foot
Mointor by angriography
25
What are the dysmorphic features of vascular EDS
COL3A1
Thin philrum and lips
Cmall chin
Thin nose
Large eyes
Thin, transculent skin
26
Thin, hyperextensible skin + joint laxity + hypotonia + globe rupture + scoliosis
Kyphoscoliotic EDS (VI)
PLOD1 (AR) - crosslinking enzyme
EDS + severe hypotonia and scoliosis, scleral fragility, and rupture of globe
Tx: TTE for aortic root dilation, ophthal monitoring
27
Aneurisms + scoliosis + bifid uvula
Loeys dietz syndrome
TGFBR1, TGFBR2, SMAD3, TGFB2
Vascular (aneuryism/dissection)
Skeletal (pectus, scoliosis)
Dysmoprhic (hypertelorism, cleft, bifid uvula, craniosyntosisis)
Skin (thin, easy bruising, atrophic scar)
Tx: vascular surveillance, B blocker, losartan
28
Arterial vessle tortuosity, hypertelorism
Loeys Dietz
TGFBR, SMAD3 (AD)
Vascular + skeletal + craniofacial or skin
Management: Vessel imaging surveillance + losartan, B blocker
29
Scoliosis, high arched palate, lumbosacral dural ectasia, joint hypermobility
Marfan
FBN1 (AD)
Aortic root dilation/dissection
Skeletal: Pectus, \< upper/lower segment,
ectopia lentis
Lumboscaral dural ectasia
Pneumothorax
Management: B blocker/losartan, ophtho
30
GJB6 diseases
Connexin 30 - gap junciton channel
Deletions = Deafness (AD or AR)
Trafficking mutations = Hidrotic ectodermal dysplasia
31
Palmoplantar keratosis, Malformed nails, hypotrichosis normal sweating
Hidrotic ectodermal dysplasia
GJB6 (AD) - missence variants that affect trafficking
ED with normal sweating and teeth
32
sparse hair, no sweat, hypodontia
Hypohidrotic Ectodermal Dysplasia
EDA, EDAR, EDARADD (XL, AD, AR)
Peeling skin and perioral hyperpigmentation at birth, rest may not be evident until childhood
Management: maintain hydration, dentist
33
What are the oculocutaneous albinism genes?
TYR - Tyrosinase (AR)
P - pigment (AR) - deletions common, part of PWS/Angelman region on 15q11
SLC45A2 (AR)
GPR143 (XL)
34
OCA1 vs OCA2
OCA1 has no melanin synthesis -\> born white. + nystagmus, strabismus, vision acuity issues
OCA2 has some melanin synthesis -\> vision better
35
Adrenal insufficiency, delayed puberty, cryptorchidism
X linked arenal hypoplasia congenita
NROB1, 1/3 is in Xp21 deletion syndrome (glycerol Kinase def)
- Adrenal
- Hypogonadotrophic hypogonadism (delayed puberty)
Tx: steroids, HRT
36
Salt wasting + Virilization
CAH
21 Hydroxylase deficiency (AR)
high 17-OHP (hydroxyprogesterone), high androgens/testosterone
Tx: Steroids
37
Female genetalia, 46XY
Androgen Insensitivity Syndrome
Androgen receptor (XL)
Can be complete or partial
Tx- remove testes after puberty OR prepubertal gonadectomy with estrogen replacement
38
delayed puberty, anosmia
Kallman
KAL (XL), FGFR1 (AD)
Can have ataxia, GU anomaly, high palate, pes cavus, CL/P, ID, choanal atresia, SNHL
39
Tall stature, azoospermia, gynecomastia, mild developmental delay
Klinefelter
47XXY
Tx: Testosterone replacement, sperm bank
40
GNAS Activating vs In activating mutations
Activating -\> high cAMP -\>Mccune albright (sporadic)
- fibrous dysplasia, fracture, CAL spots, hyPER thyroid, elevated hormone, ovarian systs
Deactivating -\> low cAMP -\> Albright osteodystrophy (AD)
- osteoma cutis (subQ nodules), osseous heteroplasia, pseudohypoparathyroidism
41
polyostotic fibrous dysplasia, cranial formaina thickening, ovarian cysts
Mccune albright
GNAS (activating mutations, sporadic)
Tx: bisphosphonates, octreotide, promocriptine, endo management
42
IUGR, diabetes in first 6 weeks of life - resolve by 18 months
Transient neonatal diabetes
HYMAI, PLAGL1
UPD1 (paternal), Paternal 6q25 Duplication
- high glucose, low insulin
43
Lymphedema, hypothyroidism, delayed puberty, low hairline, cubitus valgus
Turner
45X (SHOX gene)
- Cardiact: Coarctation, bicuspid AV, HLH
- Gonadal dysgenesis 10%
Tx: check if Y chromosome mosaic - risk for gonadoblastoma, cardiac f/u
44
Increased deoxypridinoline to pyridinoline radio in urine
Crosslinked telopeptides in urine
EDS VI (kyphoscoliotic)
PLOD1
45
cauliflower like collagen fibers
EDS type I and 2
COL5A1 and 5A2
46
Free melanin granules on biopsy hyperpigmented streaks
Incontinentia pigmenti
IKBKG (NEMO) - NF kappaB modulator
XL (male lethal)
4 stages: verucous, blistering, hyperpigmented, hypopigmented
+ nail, teeth hypoplasia, retinal neovascularization
47
FOXL2
Blepharophimosis, Ptosis, Epicanthus Inversus (BPES)
FOXL2 -AD
+ premature ovarian failure, lacrimal anomalies
Tx: Surgery, ovum donation
48
GJB2 and GJB6
Congenital hearing loss
Connection 26 and 30
- Can have palmar-plantar keratoderma (GJB2)
- Look for splice site and deletions (trafficking mutations in GJB6 = hydrodic ectodermal dysplasia)
Tx: Cocklear implants
49
Hypopigmented skin, nystagmus, pulmonary fibrosis, absent platelet dense bodies
Hermansky Pudluck
HPS genes (AR)
- Common in puerto ricans
Tx: DDAVP, skin protection, PFTs
50
SNHL + syncope, FHx sudden death
Jervell and Lange Nielsen
KCNQ1, KCNE1 (AR) - allelic with AD Long QT
- Abnormal repolarization in heart and depolarization in cochlea
Tx: Cochlear implants, BBlocker, pacemaker/defibrillator
51
Bilaterally progressive subacute vision loss in 20s and 30s
central retina vessel tortuosity, swelling of retinal nerve fibers, circumpapillary telaniectatic microangiopathy
Leber herdiatary optic neuropathy (LHON)
MTND1, MTND4, MTND6
Targarted variants: G11778A, G3460A, T14484C
- Complex 1 in ETC
Tx: avoid smoking, EtOh
52
Enlarged vestibular aqueduct, cochlear hypoplasia, goiter
Pendred
SLC26A4 (AR) - Chloride/iodide exchange channel
SNHL, temporal bone anomalies, vestibular anomalies
- Most patients have goiter but euthyroid
Tx: Monitor thyroid, hearing aids
53
SNHL, RP, balance problems
Usher
MYO7A, USH2A (AR)
- RPE and inner hair cells abnormal
Tx: Vit A, cochlear implants
54
SNHL, heterochromic idrides, dystrophic canthorum
Waardenburg
PAX3 (AD)
Clinical: NTD, white forlock, hirschsprungs
- Calculate W index
Tx: Folic acid supplementation during pregnancy (NTD)
55
Episodic abd pain, neuropathy + Hepatocellular carcinoma
Acute intermittent porphyria
HMBS (AD)
- No Skin findings
- Urine changes color after oxidation
Tx: IV hemin, IV Destrose, Avoid triggers, liver transplant
Givosiran (Si RNA)
56
HB Bart
Loss of 4 alpha Thal alleles
- Hydrops, severe hypochromic anemia, neonatal death
- Tx: Intrauterine blood transfusions
57
HbH
Alpha Thal with 3 dysfunctional alleles
Microcytic hemolytic anemia, HSM, jaundice
Tx: splenectomy, transfusions
58
Alpha Thal Trait vs Carrier
Alpha Thal
HBA gene
Trait = 2 of 4 functional alleles; low MCV, high MCH
Carrier = 1 of 4 functional allele; no endophenotype
59
Beta Thal
HBB (beta subunit)
- 2 null alleles = Major - severe anemia, HSM w/ FTT
- Carrier - endophentoype
- No symptoms at birth (fetal Hgb present)
- Modified by a thal trait -\> imbalance between alpha and beta subunit is the problem
60
prolonged PTT, decreased factor VIII activity
Hemophilia A
F8 (XL)
- Inversion intron 22 = most common mutation type
- 10-30% females have increasd bleeding risk
Tx: IV factor 8, avoid bleeding
61
Prolonged PTT, decreased Factor IX activity
Hemophilia B
F9 (XL)
- FIV activates FVIII
- 10-30% of females have \<40% activity (increased bleeding risk)
Tx: recomobinant F IX concentrate
62
Cirrhosis, skin darkening, Diabetes, cardiomyopathy, hypogonadism, arthritis
Hemochromatosis
HFE (AR, low penetrance) - regulates iron absorption
C282Y homo or C282Y/H63D are most common genotypes
- Iron saturation \>60%(m) or 50%(f)
Tx: Phlebotomy if ferritin \> 300 (m) or \> 200 (f)
Goal ferritin \<50, iron sat \<50%
63
Recurrent infections, absent CD19 B cells
Bruton's Agammaglobulinemia
BTK (XL)
- lack of lymphoid tissue, low but measureable IgG levels
Tx: IV or SC IG injections
64
MEFV
Familial mediterranean fever
MEFV (AR) - Pyrin
Decreased IL1B activation -\> increased IL1 response
Recurrent inflammation
Amyloidosis -\> Renal failure
Tx: Colchicine
65
hypertelorism, brachydactyly, cryporchidism, ID, shawl scrotum
Aarskog
FGD1 (XL)
Rho-GTPase
Tx: orchiopexy
66
Cone-rod dystrophy, Obesity, delayed puberty, GU malformations, polydactyly
Bardet-Biedl
BBS1,BBS 10 (AR) - ciliopathy
- Renal diases = major COD
67
ambiguous genetalia, craniosynostosis, choanal atresia, hydrocephalus, bowing of long bones
- increased urinary progesterone metabolites
Antley Bixler
POR (NADPH-cytochrome P450 Reductase)
Lab: Abnormal steroids/sterols
Tx: steroids, surgery
68
Ear malformation, Branchil fistula, Renal hypoplasia
Branchio-Oto- Renal syndrome
EYA1, SIX1, SIX (AD) - developmental homeobox genes
69
Facial palsy, hearing loss, tracheal esophageal fistula, Cleft palate, interrupted aortic arch
CHARGE
CHD7 (AD)
Coloboma, Heart, Atresia (choanal), Retardation, Genitalurinary anomalies, Ear cahnges
+ CN palsy, TE fisula common
70
stimulus induced drop attacks, short/fleshy hands, small terminal phalanges, microcephaly, short stature
Coffin Lowry
RPS6KA3 (XL)
XRay - Anterior vertebrae beaking, metacarpal pseudoepiphyses
Tx: benzos for drop attacks, supportive
71
Hypoplastic middle phalax of index finger, hypoplastic thenar eminence, pulmonary valve stenosis, how anterior hairline, growth restriction
Cornelia De Lange
NIPBL, SMC1A, SMC3, HDAC8, RAD21 (most AD, de novo)
- hearing loss, , dental problems, ID
- Synophrys
72
5p deletion, abnormal laryngeal development
Found face, hypertelorism, epicanthal folds, low set ears
Cri-Du-Chat
5p15.2 del
Cat-like cry, ID, FTT, hpyotonia
73
Diaphragmatic hernia, olfactory tract atrophy, nail and phalages hypoplasia, coarse face
Fryns syndrome
unknown gene (AR)
Diaphgram + distal digit + dysmorphic face + multiple congenital malformations (heart, brain, GU)
74
macrocephaly, hypertelorism, polydactyly, hand and foot syndactyly (cutaneous), DD
Greig Cephalopolysyndactyly
GLI3 (AD) - SHH regulator
Macrocephaly + hypertelorism
Cutaneous syndactyly
75
Hypotonia, Developmental delay, central apnea, retinopathy, ocuolomotor apraxia
Joubert
NPHP1, AHI1, CEP290, TMEM67
- Ciliopathy
- Motor tooth sign
- May have renal or liver disease
76
Short columella with depressed nasal tip, fetal fingertip pads, large/cupped ears, ITP
Kabuki
KMT2D (AD), KDM6A (XLD)
- abnormal epigenetic control
+ eversion of lateral eyelids, ID, renal anomalies, CHD, joint laxity, anal atresia
77
What is the most common terminal deletion syndrome?
1p36
hypotonia, DD, FTT, microcephaly, cleft, CHD, seizures, SNHL
78
Which poly T tract is linked to DeltaF508?
9T
79
Which poly T tract, when associated with R117H, can contribute to classic CFTR
5T + R117H in cis -\> classic CF
7T + R117H in cis -\> nonclassic
80
Maternal UPD 15
Prader Willi
Deletion (70%), Mat UPD (30%), imprinting defect (1%)
- Multiple paternally expressed genes in imprinted area
- Hhypotonia, DD, hyperphagia -\> Obesity, hypogonadism, small hands/feet
Tx: Monitor OSA, DM, osteopenia, feeding
81
broad thumbs/toes, ID, cryptorchidism, pilomatrixoma
Rubensteine Taybi
CREBBP, EP300 (AD) - histone acetyltransferase
+ Beaked nose
+ sleep apnea, tumors (meningioma, pilomatrixoma, leukemia)
Tx: vision, hearing, heart monitoring
82
self injury, stereotypies, upper body squeeze, brachydactyly, sleep disturbance, Ftt -\> Obesity
Smith Magenis
RAI1 (AD), 17p11 del
+ infantile hypotonia, neuropathy, facial features worsen over time
Tx: Sensory integration, behavioral, melatonin, anntual Thyroid/lipid monitoring
83
3/4 finger syndactyly, holoprosencephaly, 99% early miscarriage, 10% of all spont. abortions
Triploidy
If maternal: Small placenta, IUGR w/ MACROcephaly
If paternal: large placenta, good size w/ MICROcephaly
Serum hCG low
84
Midline cleft, holoprosencephaly, omphalocele, polydactyly
Trisomy 13
75% maternal nondysjunction, 20% due to translocation, 5% mosiac
+ cutis aplasia
44% die in first month, 70% in 1 year
85
Microophthalmia, Clenched hands with overlapping fingers 2/3 and 5/4, renal anomalies
Trisomy 18 (edwards)
90% mat nondj, 10% mosaic, 1% translocation
Triple screen: Low AFP, hCG, and UE3
+ IUGR, rocker bottomed feet, micrognathia, CHD
50% in 1 week, 90% 1 year
86
Hypotonia, myopia, hearing loss, macroglossia, hypotonia, hirschsprung, duodenal atresia
Down syndrome
90% mat nondysjunction (3/4 M1, 1/4M2), 5% robertsonian
+ upslanting PF, single creases, sandlegap toes
- ALL, alzheimers, CHD, thyroid disease
87
Tracheoesophageal fistula, esophageal atresia, limb abnormalities, TOF, vereberal abnormaltlities, anal atresia
VACTERL
Unknown gene
Vertebral, Anal, Cardiac, TEF, Esophageal atresia, Renal, Limb
- Variant has hydrocephalus
88
Broad bridge of nose continuing into forehead, short philtrum, downturned mouth, growth deficiency, igA deficiency, atypical absense seizures
Wolf Hirschorn
4pdel (WHSC1, and WHSC2) - 87% de novo, 13% translocation
- greek warrior helmet face, ID, facial assymetry, CL/P, structural brain anomalies
- Check IgA levels, EEG, MRI brain
- Seizures respond to VPA
89
VLCFA high, leukodystrophy
XALD
ABCD1 (transporter)
Childhood: ADHD -\> disability in 2 yrs
Adulthood: AMN
Addison's
Carrier females -\> 20% get spasticity with normal adrenal function
Tx: BMT, lorenzo's oil
90
Most common genes for AD Alzheimer's
PSEN1, APP, PSEN
Account for ~5% of all Alzheimers
- APP is on ch 21
91
Acquired microcephaly, ataxia, DD, happy demeanor, seizures
Face: Prognathia, light hair/eye, wide mouth with protruding tongue
Angelman
Maternal 15q11 del (70%), mat UBE3A mutation (10%), Imprinting defect (3%), paternal UPD
Testing: DNA methylation analysis defects deletion, imprinting, and pat UPD (80%), sequencing as second line
92
Electron dense grandules in tunica media of arterioles. FHx of classic migraines
CADASIL
NOTCH3 (AD)
93
Macrocephaly, hypotonia, leukodystrophy, NAA peak
CANAVAN
ASPA
- N-acetylaspartate buildup -\> demyelination
- Life expectancy teens
94
Hypotonia, decreased taste w/ smooth tongue, decreased reflexes, absent tears, pain insensitivity
Familial Dysautonomia
IKBKAP (AR) - ashkenazi jewish disease
- Abnormal sensory and autonomic nerve development
- 40% have autonomi crisis
- Progressive GI dysmotility
Recurrent pneumonia
Tx: Protect eye, PT/OT, BP management
95
Prominent forehead and jaw, long face, large ears, ID
Fragile X
FMR1 - CGG repeat
56-200 - premutation, 200+ = full mutation
Carriers: premature ovariant failure (F), ataxia/tremor
96
Movement disorder, psychiatric symptoms, cognitive decline
Huntingtons
CAG repeat
10-25: normal
26-35: at risk for expansion (especially if paternally inherited)
36-39: reduced penetrance
40-59: classic
60+: Juvenile HD
97
Classic: Elevated CSF protein, extreme Irritability, hypertonia, neuropathy, leukodystrophy
Late Onset: vision loss, cognitive decline, weakness
Krabbe
GLAC (galactocerebrosidase)
Tx: HSCT early on
98
Ras GTPase LOF -\> AD disorder
NF1
Diagnostic criteria (need 2):
6x5mm (pre puberty) or 15mm (post puberty CAL spots
2+ neurofibromas
Plexiform neurofibroma
Axillary/inguinal freckling
Optic glioma
2+ lisch nodules
Sphenoid dysplasia or tibial pseudoarthrosis
1st degree relative
Tx: Selumetinib for plexiform NF (MAPK inhibitor)
99
What's the treatment for NF1
MAPK (MEK) inhibitor: Selumetinib
100
Juvenile onset (20-40) parkinson's disease main gene
PARK2 - Parkin (AR)
101
ID, Regression, acquired microcephaly, stereotyped hand movements, bruxism
Rett
MECP2 (XL) - bings methylated CpG islands
- Small subset due to CDKL5 mutations
- Some have long QT
102
Liver disease + movement do
Wilson diasese
ATP7B (AR) - Copper transporter
- Impaired holoceruloplasmin synthesis -\> decreased biliary copper excretion
+ Kaiser fletcher rings
- Low Copper and ceruloplasmin in serum, increased urinary excretion and liver storage
103
104
What is the pathogenesis of SOD1 ALS
Toxic gain of function
105
What are the 4 types of CMT
1) AD, demyelinating
2) AD, axonal
3) AD, both
4) XL
106
What are the mildest phenotypes for DMD/BMD
Asymptomatic elevated CK or cramps/myoglobinuria
107
What the the Friedreich ataxia repeat cutoffs, where is the expansion?
FRDA
GAA repeat
Intron 1
Normal: 5-33
Premutation 34-65
Disease 66-1700
108
Focal nerve enlargement on biopsy, recurrent multifocal demylinating mononeuropathy
HNPP
PMP22 deletion
109
PMP22 syndromes
Deletion: HNPP
Duplication: CMT
Both can have specific missense
110
Sarcoglycan, Dysferlin, Calpain, Lamin
Limb Girdle Muscular Dystrophy
- CAPN3, FKRP, LMNA, SGCA, SGCB, SGCG, DYSF
- High CPK
111
Cataracts, gynecomastia, frontal balding, termporal wasting, ptosis, arrhythmia
CK high
Myotonic dystrophy type 1
3'UTR CTG repeat expansion (DMPK) -\> splice-opthaly
+ arrhythmia
112
Myotonic dystrophy type 1 repeat exapnsion cutoffs
DMPK gene
CTG - 3'UTR
Normal: 5-34
Premutation: 35-49
Mild: 50-150
Classic: 151-1000
Congenital: 1000+
113
Myotonic dystrophy type II repeat expansion and cutoffs
CNBP gene
Intron 1 CCTG repeats
Normal: \<30
Premutation: 27-54
Path: 55-11000
114
Rod like inclusions in muscle biopsy
Nemaline myopathy
**ACTA1,** NEB, TNNT1, TPM2, etc
115
What is the modifier for SMA
SMN2
0 copies = lethal.
1-2 copies = neontal onset
3 copies = 6mo to 2 yr onset
4-8 copies = childhood onset
- 4% of pop have 2 copies of SMN1 in cis -\> they are carriers
116
FCMD, POMGNT1, POMT1, POMT2, MDC1D
Congetnial muscular dystrophies
Fukutin, POMT (Protein O-mannosidase acetylglucosaminyltransferase)
- O like CDG -\> disrupt alpha-dystroglycan
Myopathy
ophthalmologic issues
CNS malformations
117
Cherry red spot, vision issues, neurodegeneration, macrocephaly
15q23
Tay Sachs
HEXA
GM2 gangliosidosis
118
What are the main cancers in BRCA1 and 2?
Breast and ovarian (BRCA1 \>2)
+ Pancreatic cancer, prostate cancer, and male breast cancer (BRCA 2 \> 1)
119
Colon cancer + desmoid tumor, jaw osteoma, malformed teeth, epidermoid cyst
Familial Adenomatous Polyposis
APC - B-catenin proteosome degradation
- Also has hepatoblastoma, thyroid ca
Gardner = + soft tissue tumors and osteomas
Turcot = + CNS tumors (Medulloblastoma)
Tx: colectomy, start screening in 20s unless attenuated
120
Cancers: Colon, stomach, intestine, hepatobiliary, endometrial, urinary, CNS
Lynch syndrome
MLH1, MSH2, MSH6, PMS2 (mismatch repair)
- Microsatelite instability
Tx: colonoscopy every 1-2 years starting at age 20
121
choriod plexus carcinoma, adrenocortico carcinoma, relative with cancer \<45, sarcoma, breast cancer, neuroblastoma
Li Frameni
TP53 (AD)
Screening: MRI Brain, body, breast, abd
122
Ca: pitruitary, parathyroid, pancreas
+ angiofibroma, collagnoma, lipoma
MEN 1
MEN1 gene (Menin) - tumor suppressor
Monitoring:
5yo: MRI brain, prolactin
8-10yo - calcium level, pancreatic peptide
20yo: Gastrin, abd CT/MRI
123
Medullary thyroid carcinoma, pheochromocytoma, parathyroid adenoma
MEN2
RET (proto-onco tyrosine kinase)
MEN2A (exon 10,11) : thyroid, pheo, parathyroid
MEN2B (exon 16): + mucosal neuromas, marfanoid habitus
Tx: **thyroidectomy by age 1 for MEN2B, 5 for MEN2A**
screening with cholecholamines, calcitomin, PTH at 8
124
Hearing loss, tinnitus, balance problems, cataracts, neuropathy, meningioma
NF2
Neurofibromin 2 (merlin) - tumor suppressor
Acoustic schwannomas bilaterally + meningioma, ependymoma, astrocytoma
125
What does PTEN do?
Phosphatidylinositol 3,4,5, triphosphate 3 phosphatase
- Downregulates PI3K/AKT pathway -\> regulator of G1 arrest/apoptosis
Cowden + BRR syndrome
- macrocephaly, lipomas, freckled penis, mucocutenous papules (gingival cobblestoning)
- breast/endometrial/thyroid/GI cancer
126
What proportion of TSC is de novo?
2/3
127
Giant cell astrocytoma, lymphangiomatosis, hypomelanotic macules, rhabdomyoma
Tuberous sclerosis complex
TSC1 and TSC2
- TSC2 and Polycystic kidney disease can be part of 16p13del syndrome
128
Endolymphatic sac tumor, tumor suppressor gene
VHL
Hemangioblastoma, Pheochromocytoma, RCC
129
Progressive microcephaly, hearing loss, cognitive impairment + sun sensitivity, skin/eye cancers
Xeroderma Pigmentosum
XPA, XPC, ERCC2, POLH
Nucleotide excision repair - repairs UV damage
130
Neonatal hypoglycemia, nevus flammeus, adrenocortical cytomegaly, hemihyperplasia, visceromegaly, ear pits
Beckwith-Wiedemann
CDKN1C, H19, KCNQ1OT1
CDKN1C (40%), Pat UPD 11p15 (15%), Loss of methylation in ICR2, gain of methylation at ICR1, 11p15del
Monitor w/ abd US q3 months until 8yo for wilms
- serum AFP for hepatoblastoma
131
5q35 microdeletion
Tall stature, macrocephaly, pointed chin, developmental delay
+ saccrococcygeal teratoma and neuroblastoma
Sotos syndrome
NSD1 - histone lysine N methyltransferase
Overgrowth + dolichodephaly/pointed chin
- Japanese, often microdeletion of 5q35
Text: MLPA or FISH for deletion, sequening NSD1
132
DNA single strand break repair pathway.
APTX, SETX
Atraxia with Oculomotor Apraxia
AR
progressive ataxia, oculomotor ataxia -\> ophthalmoplegia, axonal motor neuropathy
133
Leukodystrophy, RP, cataracts, neuropathy, postnatal FTT, hypogonadism, sunken eyes, photosensitivity
Abnormal DNA repair
Cockayne
ERCC6, ERCC8 - Transcription coupled repair
+ progeriod appearance
134
Normal at birth -\> FTT, relative macrocephaly, narrow nasal ride and nose tip, micrognathia
Loss of subcutaneous fat, delayed teeth, alopecia, coxa valga (increased angle of femoral neck and shaft)
Hutchinson Gilford Progeria
LMNA (c. 1824 C\>T, p. G608G) -\> abnormal splicing
AD, All de novo
- severe atherosclerosis w/ MI or stroke, average death at 15
135
Kids: Jaundice, elevated LFTs
Adult: COPD (40s if smoker, 60s if not), Cirrhosis
Mechanism: losss of protease inhibition
Alpha 1 Antitrypsin
Serpina1 (AR)
- Cam measure plasma AAT levels or by protease inhibitor typing
- Tx: liver transplant, IV Augmentation
136
Meconium ileus, malabsorption, azoospermia, chronic respiratory infections
Cystric fibrosis
CFTR
- convenital bilateral absense of vas deferens can occur as "atypical" phenotype
DeltaF508 = common mutation in caucasiaons
137
Anterior lenticonus, progressive nephropathy and hearing loss, corneal erosion
Alport syndrome
COL4A5 (80% XL) COL4A3, 4A4 (15% AR and 5% AD)
- Basement membrane
- Kidney (first involved) and hearing (usually teenage years) + eyes
Anterior lenticonus = conical protrusion of central lense surface
138
16p13 deletion
TSC and Polycystic kidney disease
139
Renal, liver, pancreas, intestine cysts
PKD
PKD1, PKD2, PKHD1 (AR)
Polycystin1, polycystin2, fibrocystin
- Also associated with valvular disease and aneurysms
Recessive form: oligohydramnios, impaired lung formation, renal failure, liver failure -\> early death
PKD1 can be deleted with TSC in 16p13
140
FGFR3 G1138A
Notch like sacraliliac groove
Achondroplasia
p. G380R
- Constitutive activation
Trident hand, rhizomelia, short stature, fontal bossing, midface hypoplasia
- OSA, cord compression
141
Wormian bones, open sutures, poor sinus pneumatization, hypoplastic scapulae, pseudoepiphysis, deformed middle phalanges
Runt-related transcription factor
Cleidocranial dysplasia
RUNX2 (AD, mostly de novo)
hypoplastic clavicles + large skull defects
Hearing loss, recurrent otitis media
142
hitchhiker thumb, short limb, cystic ear swelling, ulnar deviation of fingers, clubfoot - inward/upward turning of foot
XR: coronal clefting of thoracic and lumbar vertebra
Diastrophic dysplasia
SLC26A2 -\> Sulfate transporter (AR)
(Diastrophic = twisted)
Hitchhiker's thumb = twisted forearm/hand
Club foot w/ inward/upward tur = twisted metatarsals
- normal skull/intellect
143
FGFR1 craniosynostosis
\<5% of Pfeiffer
144
FGFR2 craniosynostosis
Apert (S252W and P253R)
Crouzon
Pfeiffer
145
FGFR3 craniosynostosis
Crouzon with acanthosis nigricans (A391E)
Muenke (P250R)
146
What are common features of FGFR craniosynostosis?
Midface retrusion and proptosis
Hearing loss
airway obstruction
Brachydactyly (not Apert or Crouzon)
Hydrocephalus and chiari I (not Crouson)
ID (not Crouzon)
147
Coronal craniosynostosis, cleft palate, dental anomalies, syndactyly/polydactyly with nail dystrophy, hyperhidrosis
Apert syndrome
FGFR2 S252W or P253R
+ midface retrusion and proptosis, hearing loss, airway issues
+ ID, chiari
+ acne, C5C6 fushion
148
Craniosynostosis, C2C3 vertebral fushion, normal intellect and limbs
Crouzon
FGFR2
+ midface retrusion and proptosis, Hearing loss, airway
+ hydrocephalus, chiari 1
149
Craniosynostosis, hearing loss, acanthosis nigricans
Crouzon with acanthosis nigricans
FGFR3 A391E
+Midface retrusion and proptosis, airway
+ hydrocephalus, chiari 1
150
craniosynostosis, Carpal and tarsal fushion, ADHD, Seizure
Muenke
FGFR3 (P250R)
+ midface retrusion and proptosis, SNHL
+ brachydactyly
+DD
151
Craniosynostosis, cloverleaf skull, board and medially deviated thumb/hallaces, fushions at elbows/knees, sacral appendages
Pfeiffer Syndrome
FGFR2 (95%), FGFR1 (5%)
+ midface retrusion and proptosis, hearing loss, airway obstruction, brachydactyly
+ hydrocephalus, chiari I, ID
152
Exostosis, limb length inequality, bowing of long bones
Hereditary multiple osteochondromas
EXT1, EXT2 (AD, 10% de novo)
- multiple benign cartilage capped bony growths from growth plate (long bones) or scapula
153
FGFR3 c.1620c\>a, c\>g
N540K
Hypochondroplasia
If not common mutation order sequencing
MIlder version of achondroplasia, no trident hands
154
Atraumatic fractures, ligament laxity, easy bruising, "frog leg" hips
Osteogenesis imperfecta
COL1A1 and COl1A2 (AD)
+ blue sclera
- Stop codon less severe than missense
Tx: Bisphosphontases decrease bone resorption, GH increase linear bone growth
155
craniosynostosis, small pinna with prominent crus, strabismus, ptosis, facial assymetry
Saethre-Chotzen
TWIST1 (AD)
+2/3 hand syndactyly, DD in some, vertebral fushions, maxillary hypoplasia
+ Short stature, OSA, increased ICP, CHD
Tx: Endo eval, surgical, monitor ICP with eye exam
156
FGFR3 disorders
Thanatophoric dysplasia - Arg248Cys, Tyr373Cys, Lys650Glu
Muenke - c.749C\>G, Pro250Arg
Achondroplasia - c.1138G\>A, Gly380Arg
Crouzon with acanthosis nigricans - Ala391Glu
Hypochondroplasia - c.1620C\>A, Asn540Lys
SADDAN (severe achondroplasia w/ DD and acanthosis nigricans) - Lys650Met
157
Immune deficiency and CHD
22q11
158
XL brugada syndrome
KCNE5
| (SCN5A is most common AD)
159
nocturnal agonal breathing, ST abnormalities in V1-V3
Brugada syndrome
SCN5A-AD
KCNE5-XL
160
BRAF, KRAS, MAPK1, MAPK2
CFC syndrome
161
Most common cancer in CFC syndrome
ALL
162
Most common mode of inheritance for CFC
AD de novo
163
Costello gene
HRAS
164
Cancers associated with Costello
Bladder
Rhabdomyosarcoma
Neuroblastoma
165
most penetrant finding in Holt Oram
Carpal bone anomaly
TBX5
166
Endocrine anomalies in williams syndrome
7q11, ELN
Hypercalcemia, hypothyroidism
167
Most common cancers in ATM
Patients: Leukemia + lymphoma
Carriers: Breast, colon, pancreas
168
Treatement for fanconi anemia
Androgens -\> help with marror failure
169
highest mobidity cancer in Fanconi
Oral squamous cell carcinoma
170
SMAD3
Loeys Dietz
TGFB genes + SMAD3
171
Velvety/translucent Skin
Loeys Dietz type 2 and EDS IV (vascular)
172
What drug to avoid in LDS?
Calcium channel blockers
173
Cauliflower deformity in electron microscopy
EDS classic
- COL5A1
174
Aged appearance of hands (acrogyria), large eyes, small chins
Vascular EDS
COL3
175
Globe rupture
Kyphoscoliotic EDS
PLOD1
176
Organs aside from skin involved in Incontinentia pigmenti
CNS, Eye + Skin/Teeth/Hair
177
GPR143
XL Ocular albinism (no skin changes)
178
NROB1 deletions
XL adrenal hypoplasia congenita
Continuous with Glycerol Kinase and DMD
- 100% deletions
179
CYP21A2
CAH
- high 17OHP
180
Treatment for CAIS
Take out testicles and give estrogen
AR gene
181
What proteins are missing in Kallman syndrome types 1 and 2?
Type 1 - KAL1 -anosmin
Type 2 - FGFR2
182
bimanual synkinesis and mirror movements
Kallman type 1
- also ataxia, GU anomaly, pes cavus
Type 2 (FGFR1) + hearing loss, CL/P
183
What conditions are klinefelter patients more at risk for?
- Autoimmune disorders (females are increased risk vs males)
- Mediastinal germ cell tumors
- Male Breast cancer (+gynecomastia)
184
Endo anomlaies in mccune albright
high GH (precocious puberty), prolactin, and parathyroid hormone
+ hyperthyoridism
185
CAL, fibrous dysplasia
Mcune Albright
GNAS GOF
186
Mechnaism of transient neonatal diabetes
**Overexpression** of paternally active genes (HYMAI, PLGL)
- UPD6 pat
187
4 clinical tests for turner syndrome
TSH, GH, echo, renal US
188
What diseases do GJB2 cause?
Hearing loss and KID (Keratosis, Ichthyosis, deafness) syndrome
- both AD
189
What diseases do GJB6 cause?
Hearing loss or hydrotic ectodermal dysplasia
both can be AD
190
Absent platelet dense bodies
hermansky pudluck syndrome
- Pale bleeding puerto rican
+ colitis, pulmonary fibrosis, skin cancer
191
KCNQ1, KCNE1
Long QT, hearing loss (Jervell and lange nielsen syndrome)
Carriers have long QT - romano ward
192
Genes for LHON
MTND1, MTND4, MTND6
- complex I
193
hearing loss and goiter
Pendred
SLC26A4
- 10% abnormal thyroid function tests
194
Dilated vestibular aqueduct with cochlear hypoplasia
Mondini malformation
Pendred
SLC26A4
195
PAX3 vs PAX6
PAX3 = wardenburg
PAX6 = aniridia
196
SIX3 vs SIX5
SIX3 = Holoprosencephaly
SIX5 = Branchio oto renal
197
PAX3
MITF
SOX10
Waardenburg
PAX3 - type 1 and 3 (+ limb hypoplasia, syndactyly)
MITF - type 2 - no dysrophia canthorum
SOX10 - type 4 (**hirschprung**)
Pass the mitten, pass the socks
198
What is the gene for piebaldism?
White forelock + patches of albinism
c-KIT - melanocyte migration defect
199
Treatment for AIP attacks
IV hemin, IV Dextrose
200
70% HbF, 30% HbA
Beta Thal minor
201
90% HbF in adulthood
B Thal Major
202
Prolonged PT or PTT in hemophilia?
PTT (intrinsic)
203
Treatment goal for hemochromatosis
ferritin \<**50** and Iron sat \<**50**%
204
Low CD19 cells
CD19 = b cells
BTK - XL bruton's agammaglobinuria
205
First line treatment for MEFV
Familial Mediterranean Fever
Cholchicine
206
Aarskog mode of inheritance
XLR
207
Management of Aarskog
Orchiplexy
208
high lanosterol, dihytrolanosterol, pregnenolone and progesterone
Antley Bixler
POR
209
Major cause of morbidity/mortality in ciliopathies
Renal disease
210
What test do coffin lowry patients need every 5-10 years
Echo -\> uncertain onset cardiomyopathy
211
SMC1L1
XL CDLS
212
Heard defects in CDLS
Pulmonary valve stenosis and VSD
213
2 syndromes with GLI3
Pallister Hall (endo hamartoma, anal, polydactyly) - Frameshift in middle third of gene
Greig cephalopolysyndactyly - deletions/missense/early frameshift
214
In joubert syndrome with retinal changes, what other organ is affected?
Renal is seen in those with retina involvement
215
XL kabuki syndrome
KDM6A
216
Coarctation, ITP, immunodeficiency, fused kidneys, fetal finger pads
Kabuki
KMT2D (AD)
KDM6A (XL)
217
17p11.2 vs 17p12
17p12 - CMT/HNPP
17p11.2 - Smith-Magenis/Potocki-Lupski
218
Lab monitoring for Smith Magenis
Lipid profile (hypercholesterol)
TFT
219
Immune abnormality in wolf hirschorn
IgA deficiency
220
Common variant for MEN1
D
221
everiolimus
mTOR inhibitor for TSC (progressive angiomyolipoma)
222
What does GLI3 do?
Zinc finger transcription factor -\> Downstream of SHH
Greig cephalopolysyndactyly
Pallister Hall (hypothalmaic hamartoblastoma)
223
Absent platelet dense bodies on EM
HPS
- look for pulmonary fibrosis
224
mechanism of disease in FAP
decreased APC (TSG) -\> activation of oncogenes c-MYC and cyclin D1
225
most common ca in LFS
Breast (especially before age 31)
226
what is the function of MEN1
Tumor supressor
227
surveillance for MEN1
MRI and prolactin at 5, endo tests at 8-10
228
function of RET
protooncogene - tyrosine kinase receptor
229
RET exon 16 mutation
MEN2B
| (Exon 10/11 for MEN2A)
230
Surveillance in PTEN
Thyroid at 15
Breast at 30
Colon/ovarian at 35
231
Pulmonary lyphangiomatosis
TSC2 - usually in females
232
VHL screening
Ophtho exam and metanephrines at 5
15 - abd U/S and MRI
233
most common causes of BWS and RSS
BWS: **Hypo**methylation of maternal IC2
RSS: **Hypo**methylation of paternal IC1
234
DNA single strand break repair
APTX, SETX
Ataxia with oculomotor apraxia
+ high cholesterol, low albumin, high AFP
235
RUNX2
Wnt signaling pathway, downstream of SMAD4 and NOTCH/JAG
236
lack of sulfated proteoglycans in cartilage matrix
Diastrophic dysplasia
SLC26A2 sulfate transporter
237
FGFR1 craniosynostosis
Pfeiffer (cloverleaf, board **medially deviated** thumbs/big toes)
- also FGFR2
238
100% penetrant finding in alagille
Paucity of bile duct + cholestasis
