DISEASE
GENE · CHROMOSOME
KEY FEATURES
CLUE
FGFR3 gain of function (ch 4); often de novo, ↑ paternal age
Short limbs, large head, normal trunk and intelligence
Impaired endochondral ossification
PKD1 (ch 16, ~85%) or PKD2 (ch 4)
Bilateral enlarging cysts, flank pain, hematuria, HTN, CKD; liver cysts, berry aneurysms, MVP
Tolvaptan slows cyst growth
Familial adenomatous polyposis
APC (ch 5q)
Hundreds–thousands of colon polyps from teens → 100% carcinoma without colectomy
Gardner (bone, soft tissue), Turcot (brain)
Familial hypercholesterolemia
LDLR (ch 19), ApoB, PCSK9
Very high LDL, tendon xanthomas (Achilles), early MI; homozygotes MI in childhood
Type IIa (10.04)
Hereditary hemorrhagic telangiectasia
ENG, ACVRL1 (TGF-β pathway)
Telangiectasias, recurrent epistaxis, GI bleeds, AVMs (lung, brain, liver)
Osler-Weber-Rendu
Ankyrin, spectrin, band 3
Spherocytes, hemolysis, splenomegaly, pigment stones, ↑ MCHC
EMA binding test ↓
HTT CAG repeat (ch 4)
Chorea, psychiatric changes, dementia
Anticipation (5.04)
TP53 (ch 17)
Sarcomas, breast, brain, adrenocortical, leukemia at young ages
Sarcoma, breast, brain, leukemia, adrenal cancers
FBN1 (ch 15)
Tall, arachnodactyly, lens up and out, aortic root dilation, MVP
See 3.06
MEN1 (menin, ch 11) · MEN2A/2B (RET, ch 10)
MEN1: pituitary, parathyroid, pancreas · MEN2: medullary thyroid, pheochromocytoma ± parathyroid/mucosal neuromas
Prophylactic thyroidectomy in RET carriers
NF1 neurofibromin (ch 17)
Café-au-lait, neurofibromas, Lisch nodules, axillary freckling, optic glioma, pheochromocytoma
Variable expressivity
NF2 merlin (ch 22)
Bilateral vestibular schwannomas, meningiomas, ependymomas, juvenile cataracts
"NF2 = 2 ears"
TSC1 hamartin (ch 9), TSC2 tuberin (ch 16) → mTOR overactive
Cortical tubers, seizures, ID, ash-leaf spots, angiofibromas, cardiac rhabdomyoma, renal angiomyolipoma, shagreen patch
Everolimus/sirolimus
VHL (ch 3p) → ↑ HIF
Hemangioblastomas (retina, cerebellum), bilateral clear-cell RCC, pheochromocytoma
Tumor suppressor; loss stabilizes HIF