What's that smell?
MSUD- amnio acid disorder, AR inheritance
Symptoms- DD, lethargy, poor feeding, respiratory failure, encephalopathy with illness
Labs- plasma amnio acids
Treatment- limit dietary intake of protein LEUCINE
Retinoblastoma
RB1- two hit hypothesis origin
Bloom- double strand break repair gene BLM
short stature, "butterfly" skin rash, cancer risk, immune deficiency
Quad:
HCG MoM: 2.3
AFP MoM: 0.88
Inhibin MoM: 1.9
UE3 MoM: 0.75
T21
Clotting Disorder:
Factor 5
VWD
Hemophilia A
Hemophilia B
Hem A and B- F8 and F9 genes, excessive bleeding, poor wound healing
Factor5- AR F5 (some implications for heterozygous carriers), increases risk of thromboembolism, treat with anticoagulants
VWD- AD, VWF gene, easy bleeding/bruising, some types have thrombocytopenia
Greek Warrior Helmet
Wolf-Hirschhorn 4p16.3- ID, Coloboma, CHD, seizure, sleep problems, clefting, antibody deficiency, liver problems
Musty smell
PKU- amnio acid disorder, AR inheritance, break in phenylalanine to tyrosine pathway
Symptoms- ID & seizures if untreated, may still see some LD when treated
Labs- plasma amnio acids
Treatment- dietary limit on protein PHENYLALANINE intake
Fun Fact- tyrosine plays a role in pigmentation, so PKU kiddos have characteristically pale skin/hair
Melanoma
BRCA2- also: breast, ovarian, male breast, prostate
NOT BRCA1
XP- Excision Repair, also: other skin cancers, glioma
Werner Syndrome- Double Strand Break Repair, also: sarcoma, thyroid, liver
MSI: H
IHC: absence of PMS2
PMS2 germline mutation or MLH1 germline mutation
Lynch
Muscle weakness:
SMA
DMD
Facio-Scapulo-Humeral MD
Limb-Girdle MD
BMD
DMD and BMD- DMD gene, cardiomyopathy risk (also for carriers!), progressive muscle weakness starting with legs, calf pseudohypertrophy, toe walking
SMA- AR, SMN1 gene, variable presentation, impacts motor neuron function
FSHD- winged scapula! Weakness starts with face, scapula, and humeral muscles, no bulbar or ocular weakness
LGMD- AD and AR many genes, frequent falls and pseudohypertrophy, difficulty walking/stairs
Limb Reduction (not due to thalidomide exposure)
Holt-Oram- AD TBX5, also CHD (usually ASD), Cardiac conduction disease risk
Smelly Feet
Symptoms- protein aversion, metabolic acidosis, thrombocytopenia, poor feeding/vomiting, seizures, DD
Labs- acylglycines, acylcarnitine profile
Treatment- dietary restriction of LEUCINE intake, supplement with glycine during episodes
Fun Fact- half of cases have acute neonatal onset and other half of cases are chronic with episodes
Adrenocortical carcinoma
Li Fraumeni- TP53, AD inheritance, also: brain tumors (Choroid plexus carcinoma, glio, medulloblastoma, astrocytoma), multiple primary/rare tumors
MEN1- also: parathyroid, pituitary, pancreatic
CBC: reduced MCV, MCH
Hb Electrophoresis: increased HbA2, reduced HbA, HbF >2%
Beta thal- hemolytic anemia, hepatosplenomegaly, treated with transfusions
Which MPS?
MPS II- Hunter, DD, ID, CLEAR corneas, hearing loss, cardiac involvement, skeletal involvement, short stature
MPS I- Hurler, DD, ID, CLOUDED corneas, HSM, skeletal and cardiac involvement, hearing loss
MPS III- San Filippo, milder skeletal phenotype, NO cardiac involvement, CLEAR corneas, sleep and behavioral problems
MPS IV- Morquio, NO ID, severe skeletal involvement, cardiac and bone involvement
MPS VI- Martoeaux-Lamy, skeletal involvement, NO ID, cardiac involvement, CLOUDED corneas
MPS VII- Sly, DD, cardiac involvement, HSM, ENT problems
White forelock
Waardenburg- PAX3, MITF, WS2C, SNAI2, EDNRB, EDN3, SOX10
Hearing loss, blue eyes, Hirschprung's disease, normal intellect
Cabbage in the context of rickets
Tyrosinemia Type I- most severe, AR inheritance, amnio acid disorder
Symptoms- acute liver failure, renal failure, rickets, FTT, chronic weakness, hepatosplenomegaly
Treatment- dietary supplementation with Orfadin, which blocks pathway to prevent buildup of toxic byproducts
Rhabdomyoma
TSC- genes TSC1 & TSC2, AD inheritance
Other Tumors- neuroendocrine tumors (parathyroid, panc, gastrinoma, pheo, carcinoids), angiofibromas, retinal nodular hamartomas, renal angiomyolipoma, Subependymal giant cell astrocytoma (brain tumor)
Other features- shagreen patch (raised rash on lower back), hypopigmented skin lesions ("confetti"), hypomelanotic macules, renal cysts
24hr urinalysis shows elevation of homogentistic acid
Alkaptonuria (amnio acid disorder)- black urine, necrosis of bone/cartilage, calcification of heart valves
Treat with dietary protein restriction
Which fanconi associated gene?
FANCA
FANCB
FANCC
FANCD1
FANCB- Fanconi Anemia associated with limb abnormalities, skin lesions, DD, ID, bone marrow failure (pancytopenia)- Leukemia risk, Kidney & GI & Cardiac involvement, Hearing loss
FANCD1 = BRCA2
FANCC = most commonly carried FANC, AJ founder mutation
Ragged Red Fibers
MERRF- Myoclonic Epilepsy, Ragged Red Fibers (diseased mito in muscle cells accumulate)
Cabbage in the context of palmar keratosis
Tyrosinemia Type II- amnio acid disorder, AR inheritance
Symptoms- ID, keratosis of palms and feet, ocular & cutaneous findings, growth restriction
Treatment- dietary restriction of Phe and Tyr
Pheochromocytoma
VHL- also: clear cell renal carcinoma, hemangioblastoma, paraganglioma, renal & panc cysts
TSC- also: pituitary, parathyroid, panc, gastrinoma, carcinoids, brain tumor
MEN2A- also: medullary thyroid cancer, hyperparathyroidism, parathyroid adenoma
MEN2B- also: medullary thyroid cancer, marfanoid habitus (scoliosis), diffuse ganglioneuromatosis of GI tract
Blood test: hyperammonemia, reduced citrulline, increased glutamine
Urine test: elevated orotic acid, ornithine, and uracil
OTC- X-linked! Urea cycle disorder (hint: hyperammonemia), usually presents after illness or high protein intake
Crises can include lethargy, seizures, coma
Treat with dietary protein restriction
Which overgrowth?
Proteus
Simpson-Golabi-Behmel
Sotos
Weaver
BWS
Simpson-Golabi- genes GPC3 and CXORF5, distinguishing facial features (coarse, macrosomia, macroglossia, macrocephaly), ID, CHD, GI anomalies, Polydactyly, Vertebral fusion/scoliosis,
Proteus- usually MOSAIC/SOMATIC, disproportionate overgrowth of tissues (think: elephant man)
Sotos- AD NSD1 gene, 95% de novo, Macrocephaly, facial features (broad forehead, pointed chin, flushed cheeks), stuttering, DD, CHD, behavioral problems, renal anomalies, seizures,
Weaver- AD EZH2, tall, rapid growth, poor coordination, coarse facial features, umbilical hernia, hoarse cry in infancy, advanced bone age
Butterfly vertebrae
Alagille- JAG1, NOTCH2
Bile duct problems (see on liver biopsy), CHD (TOF or pulm stenosis), abnormal ocular exam (posterior embryotoxon)
Features- triangle face, deep set eyes, pointed chin, frontal bossing