boards’ fodder #2 Inborn Errors of Metabolism by Kristina Burke, MD, and Erin Adams, MD

DISORDER DEFECT SKIN FINDINGS OTHER Alkaptonuria Homogentistic acid oxidase Blue-grey pigmentation of nose, - Large joint arthropathy (Endogenous ochronosis) ears, axillae, genitalia and - Intervertebral disc calcification AR Disorder of phenylalanine cartilage. Blue sclera (Osler’s - Mitral/aortic valve disease and tyrosine metabolism. sign), dark urine (pH >7), black - Nephrolithiasis Homogentistic acid accumu- cerumen lates

Fabry’s disease α-galactosidase A Angiokeratomas (esp lower - Renal failure, cardiovascular events, (Angiokeratoma Corporis (glycolipids accumulate in skin, extremities, scrotum, penis, and strokes Diffusum) heart, kidneys) lower trunk), whorl-like corneal - Acroparesthesias and painful crises XLR opacities, edema, hypohIdrosis - Maltese cross in urine A lysosomal storage disease - Enzyme replacement available

Fucosidosis α-L- fucosidase Angiokeratomas, coarse fea- - Mental retardation (MR), neurologic AR tures, facial dysmorphism deterioration A lysosomal storage disease

Gaucher disease Acid-β-glucosidase (glucocer- Type 1: diffuse hyperpigmenta- ALL: hepatosplenomegaly (HSM) AR ebrosidase) tion, petechiae, pingueculae of - Type I: Adult type, Ashkenazi Jews, no A lysosomal storage disease Leads to accumulation of glu- sclera CNS involvement cocerebroside in histiocytes - Type 2: infantile, rapid neuro (Gaucher’s cells) Type 2: congenital ichthyosis, deterioration, aspiration pneumonia collodian baby - Type 3: juvenile chronic neuropathic

Phenylketonuria Phenylalanine hydroxylase Pigmentary dilution of skin, hair, - MR, seizures AR (Phenylalanine not oxidized to eyes (fair complexion, blond hair, - Phenylpyruvic acid in urine (musty odor) tyrosine) blue eyes), pseudoscleroderma, - Screened for at birth eczematous dermatitis - Dietary restriction

Tyrosinemia II Tyrosine aminotransferase Painful palmoplantar kerato- - Herpetiform keratitis, blindness Kristina Burke, MD, is (Richner-Hanhart) (hepatic) derma - MR a third year resident at AR TAT gene - Corneal ulcers Walter Reed National Military Medical Center Homocystinuria Cystathionine β-synthase Fair complexion, malar flush, - Thromboembolic events (50% by 30yo) AR livedo reticularis, leg ulcers = common cause of death in Bethesda, Md. Sparse, fine hair - Ectopia lentis (downward) Marfinoid habitus - Osteoporosis - MR, developmental delay

Niemann-Pick disease Type A and B: Type A and B: ochre to brownish- Type A: severe, CNS deterioration, AR Sphingomyelinase (SMPD1) yellow discoloration of skin, HSM, failure to thrive Type C: NPC1 and 2 papular lesions face and upper Type B: spares CNS, survival to A lysosomal storage disease extremities, xanthomas adulthood Type C: childhood, HSM, developmental delay, psychomotor deterioration

Trimethylaminuria Mutation of flavin-containing Skin, urine, and sweat smell like - Smell due to accumulation of “Fish odor syndrome” monooxygenase type 3 (FMO3) “rotting fish” trimethylamine gene - Avoid choline in diet

Erin Adams, MD, is a Lesch-Nyhan HPRT1 gene leading to hypo- Loss of tissue around mouth and - MR, choreoathoid movements, staff dermatologist at (juvenile gout) xanthine-guanine fingers (due to self-mutilation) self-mutilation Walter Reed National XLR phosphoribosyl transferase Tophaceous deposits - Orange crystals in diaper Military Medical (HGPRT) deficiency (hyperuricemia) Center and also

academic staff Wilson’s disease Defect in ATP7B gene Blue lunulae, Kayser-Fleischer - HSM, cardiomyopathy, renal tubular for the National (Hepatolenticular (hepatic copper transporting rings (copper deposition in acidosis Capital Consortium degeneration) ATPase) Descemet’s membrane), green- - Progressive neurologic dysfunction Dermatology AR ish discoloration of face, neck (dysrthria, ataxia, dementia) and genitalia, pretibial hyperpig- - Lab: low ceruloplasmin Residency Program. mentation - Tx: penicillamine, trientine, zinc supple- ment

Hartnup disease SLC6A19 gene Pellegra-like dermatitis (photo- - Cerebellar ataxia, MR AR (neutral amino acid transporter) sensitive eruption on face, arms, - Tends to improve with age neck, legs) - Defect in tryptophan transport

irinections D­Residency p. 4 • Fall 2012 boards’ fodder #2 Inborn Errors of Metabolism (continued) by Dr. Burke, MD and Dr. Adams, MD

DISORDER DEFECT SKIN FINDINGS OTHER Do you have an Prolidase deficiency Deficiency of the enzyme Skin fragility, lower - Mental deficiency, recurrent infections, interesting Boards’ prolidase extremity ulceration, syndromic facies telangiectasias, poliosis Fodder? We’re expanding our Citrullinemia Type 1: argininosuccinic acid Resembles zinc deficiency - Clears with arginine supplementation synthetase (ASS1 gene) Erythematous, erosive, scaling Boards’ Fodder Type 2: SLC25A13 gene patches periorally, lower archives and you abdomen, and diaper area can be a part of it. Contact Dean Farber disease Ceramidase deficiency Periarticular swelling, rubbery - Onset first month of life, death by age 2 Monti, managing A lysosomal storage disease SQ nodules - Weak, hoarse cry; pulmonary failure, MR editor, special publications, at Adrenoleukodystrophy ALD gene Hyperpigmentation, mild - Progressive demyelination of cerebral (Schilder’s disease) ichthyosis, sparse hair with white matter [email protected]. X-linked trichorrhexis nodosa-like features CADASIL NOTCH 3 gene Findings on skin biopsy - Depression, migraine headaches Cerebral autosomal dominant (eosinophilic granular material - Multiple cerebral infarcts leading to arteriopathy w/ subcortical in arterial walls) early dementia If you enjoyed this infarcts and leukoencepha- - Most common hereditary stroke special Boards’ lopathy disorder Fodder edition, let us know. Write to Lafora disease EPM2A- encoding laforin Few – rarely see papulonodular - Progressive epilepsy syndrome [email protected]. (Lafora progressive myoclonic EMP2B – encodes a ubiquitin lesions over ears, plaques on - Dementia and ataxia epilepsy) ligase arms - Best site to biopsy = axilla (Lafora bodies around eccrine ducts) Alagille syndrome JAG 1 -Xanthomas, jaundice - Congenital intrahepatic biliary Need more Boards’ AD -Unusual facies hypoplasia w/ cholestasis and pruritus. Fodder? Visit - Hyperlipidemia - Butterfly-shaped vertebra the Directions in Residency archive Sitosterolemia ABCG5 (encoding sterolin-1) or Tuberous and tendinous - Elevated plasma levels of plant sterols AR ABCG8 (encoding sterolin-2) xanthomas during the first - Arthritis, premature vascular disease, listed under “phytosterolemia” decade of life high risk of fatal cardiac events during “Publications” at teenage years www.aad.org. Hurler syndrome Deficiency of α-L-iduronidase Diffuse fine lanugo hair, extensive - MR, HSM, corneal opacities, umbilical AR blue pigmentation hernia “gargoylism” Facial dysmorphism, large - Dental abnormalities, persistent rhinitis A lysosomal storage disease tongue, thick lips Hunter syndrome Deficiency of iduronate-2-sul- Skin-colored pebbly lesions of - Dysotosis multiplex XLR fatase the upper back, neck, chest, A lysosomal storage disease proximal extremities

Tangier Disease ATP-binding cassette (ABCA1) Tonsils are yellow and enlarged. - HSM, lymph node enlargement, periph- AR transport protein: almost com- Maculopapular eruption over eral neuropathy, corneal (Familial α-lipoprotein defi- plete absence of plasma HDL trunk and abdomen infiltration in adults ciency) and massive deposition of cho- - Premature coronary artery disease lesterol esters in tissues References: 1. Bolognia JL, Jorizzo JL, Rapini RP, editors. Bolognia Textbook of Dermatology. 2 nd ed. Spain: Mosby Elsevier publishing; 2008: chapters 48 and 62. 2. James WD, Berger TG, Elston DM, eds. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, Pa: Saunders Elsevier; 2011: chap 26. 3. Spitz JL. Genodermatoses: A clinical guide to genetic skin disorders. Philadelphia: Lippincott Williams & Wilkins; 2005: chapters 8 and 11.

irinections Fall 2012 • p. 5 D­Residency