ETAS_03 genoderm


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ETAS_03 genoderm

  1. 1. 3  Genodermatoses Arash Kimyai-Asadi, MD Irene Vergilis-Kalner, MDC o n t e n t s3.1 X-linked Recessive Syndromes . . . . . . . . . . . . . . . . . 513.2 X-linked Dominant Syndromes . . . . . . . . . . . . . . . . . 513.3 Hereditary Blistering Disorders . . . . . . . . . . . . . . . . . 513.4 Ichthyoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523.5 Palmoplantar Keratodermas . . . . . . . . . . . . . . . . . . 533.6 Disorders with Hypopigmentation . . . . . . . . . . . . . 543.7 Disorders with Pigmented Lesions . . . . . . . . . . . . . 553.8 Vascular Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . 563.9 Connective Tissue Disorders . . . . . . . . . . . . . . . . . . 583.10 Diseases of the Hair and Nails . . . . . . . . . . . . . . . . . 603.11 Diseases with Malignant Potential . . . . . . . . . . . . . . 613.12 Disorders with Immunodeficiency . . . . . . . . . . . . . 633.13 DNA and Chromosomal Disorders . . . . . . . . . . . . . 643.14 Keratinopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653.15 Disorders of Metabolism . . . . . . . . . . . . . . . . . . . . . . 65 Genodermatoses  49
  2. 2. Committed to Your Future For practice exam questions and interactive study tools, visit the Dermatology In-Review Online Practice Exam and Study System at by
  3. 3. 3.1 X-LINKED RECESSIVE SYNDROMES • Chondrodysplasia punctata (Conradi-Hunerman MNEMONIC syndrome) X-Linked Recessive Syndromes • Hypohidrotic ectodermal dysplasia with CHAD’S KINKY WIFE GOT LUCKY immunodeficiency (NEMO mutation) Chronic granulomatous disease Hunter’ disease s3.2 X-LINKED DOMINANT SYNDROMES Anhidrotic ectodermal dysplasia Dyskeratosis congenita • Chondrodysplasia punctata (Conradi-Hunermann SCID syndrome) • CHILD syndrome Menke’s Kinky hair disease • Incontinentia Pigmenti Wiskott-Aldrich • Focal Dermal Hypoplasia Ichthyosis, X-linked • Bazex syndrome Fabry’s disease • MIDAS syndrome Ehler’s Danlos V and IX • Oral-facial-digital syndrome G6PD deficiency • Goltz Lesch-Nyhan • Albright’s hereditary osteodystrophy3.3 HEREDITARY BLISTERING DISORDERS • Epidermolysis bullosa simplex (EBS): AD, keratin 5 and 14 mutations resulting in bullae within basal cell keratinocytes. Rarely caused by mutations in the intracellular domain of bullous pemphigoid antigen 2 – Weber-Cockayne: Palmoplantar bullae developing in the 1st-3rd decade – Generalized (Koebner): Generalized bullae starting in infancy with mild mucosal involvement – Dowling-Meara: Widespread bullae (some herpetiform), significant mucous membrane and laryngeal/esophageal involvement, nail dystrophy, and early death – EBS with muscular dystrophy: Plectin mutation – EBS with pyloric atresia: Plectin mutation – EBS with mottle pigmentation: Keratin 5 mutation – Autosomal recessive EBS: Keratin 14 mutation – EBS Ogna variant: Plectin mutation. Above symptoms with generalized contusiform bruising • Junctional epidermolysis bullosa (JEB): AR, laminin 5 and bullous pemphigoid antigen 2 (BP180, collagen 17) mutations causing blisters in the lamina lucida – Herlitz type: Laminin 5 mutations. Generalized bullae, nonhealing perioral granulation tissue, nail dystrophy, tooth dysplasia (enamel defects), anemia, growth retardation, tracheobronchial infections. Fatal by age 3-4 – Non-Herlitz: Laminin 5 or BP180 mutations. Bullae that heal with atrophic scars, nail dystrophy, scarring alopecia. Normal lifespan – Non-Herlitz: Also b4 integrin – JEB localized: BP 180 mutation – Generalized atrophic benign epidermolysis bullosa (GABEB): BP180. Extensive atrophy of the anterior lower legsAD = autosomal dominant, AR = autosomal recessive Genodermatoses  51
  4. 4. – JEB with pyloric atresia: Mutations in either subunit of α6-β4 integrin – JEB inversa: Laminin 5. Acral bullae • Dystrophic epidermolysis bullosa: Collagen 7 mutations causing blisters in the sublamina densa – Dominant dystrophic EB: • Hyperplastic Cockayne-Touraine: Bullae localized to extremities resolving with milia and scarring, mild mucosal involvement, dystrophic nails • Albopapuloid Pasini variant: Widespread bullae healing with hypopigmented scar-like white papules, nail dystrophy, mild mucosal involvement • Bart’s syndrome: Congenital localized absence of skin usually of the shins, nail dystrophy • Transient bullous dermatosis of newborn: Transient form of the disease • Pretibial • Pruriginosa • With subcorneal cleavage (EB “simplex” superficialis) – Recessive dystrophic EB (Hallopeau-Siemens): Generalized bullae, healing with chronic scars that develop numerous fatal SCCs, digital fusion with mitten deformity, flexion contractures, significant mucosal scarring, dysplastic teeth, malnutrition, death • Non-Hallopeau Siemens • Inversa • Centripetalis • Epidermolytic hyperkeratosis: AD, keratins 1 & 10 gene. Bullae and erythroderma at birth, generalized verrucous ichthyosis later • Ichthyosis bullosa of Siemens: AD, keratin 2e gene. Fragile blisters at birth, hyperkeratotic plaques on the elbows and knees later • Hailey-Hailey disease: AD, calcium ATPase IIC1. Flexural erosions, acantholytic “dilapidated brick wall” appearance histologically • Kindler syndrome: AR, KIND1 (kindlin 1, expressed in basal keratinocytes, attaches actin cyctoskeleton to extracellular matrix). Acral blistering in infancy, photosensitivity, progressive poikiloderma, wrinkling (especially dorsal hands/feet), palmoplantar hyperkeratosis, nail dystrophy, dental caries, phimosis, digital webbing, pseudoainhum3.4 ICHTHYOSES • Ichthyosis vulgaris: AD, decreased conversion of profilaggrin to filaggrin, diminished granular layer. Scale on extensors and sparing flexures starting at puberty, atopic diathesis, hyperlinear palms. Mutation in filaggrin gene • X-linked ichthyosis: X-linked recessive, steroid sulfatase (arylsulfatase C) gene. Brown scale sparing palms, soles, and flexures, comma-shaped corneal opacities, failure of labor progression, cryptorchidism • Lamellar ichthyosis: AR, Type I - transglutaminase 1 gene or Type II - ATP binding Cassette A12 gene (ABCA12). Collodion baby at birth, with subsequent large thick plates of scale especially on the flexures, ectropion, and eclabium • Nonbullous congenital ichthyosiform erythroderma: AR, transglutaminase 1 gene, or 12R lipoxygenase gene (ALOX 12B) or lipoxygenase 3 gene (ALOX E3). Collodion baby at birth, with subsequent generalized mild erythroderma with fine white scale • Sjogren-Larsson syndrome: AR, fatty aldehyde oxidoreductase/alcohol dehydrogenase deficiency. Ichthyosis, spastic ditetraplegia, mental retardation, epilepsy, glistening dot retinal pigmentation, dental enamel dysplasia52  2011/2012 Dermatology In-Review l Committed to Your Future
  5. 5. • Refsum syndrome: AR, phytanoyl coenzyme A hydroxylase deficiency (PAHX gene) or peroxin 7 (PEX7) or PHYH gene. Mild ichthyosis, cerebellar ataxia, peripheral neuropathy, retinitis pigmentosa (salt & pepper), and deafness. Treatment: Diet low in green vegetable, dairy, and ruminant fats • Chondrodysplasia punctata (Conradi-Hunermann syndrome): Arylsulfatase E gene (X-Recessive), EBP gene (X-Dominant), PEX-7 (AR). Peroxisomal biogenesis disorder. Ichthyosiform erythroderma in lines of Blaschko, follicular atrophoderma, stippled epiphyses • CHILD syndrome: X-Dominant, lethal in males. NSDHL gene (NADPH steroid dehydrogenase-like protein). Peroxisomal biogenesis disorder. Unilateral ichthyosiform erythroderma, limb/visceral hypoplasia, and stippled epiphyses • Netherton syndrome: AR, SPINK 5 mutation. Ichthyosis linearis circumflexa (double- edged scale), trichorrhexis invaginata (bamboo, ball and socket hair), atopic dermatitis, anaphylaxis from food allergy • Darier’s disease (keratosis follicularis): AD, calcium ATPase IIA2 (SERCA2). Hyperkeratotic papules in seborrheic areas, acrokeratosis verruciformis of Hopf, palmar keratoses and pits, red-white longitudinal nail bands, v-shaped distal nail nicks, cobblestoning of oral and rectal mucosae. Worsened by lithium • KID syndrome: AD, connexin 26 mutation, keratitis-ichthyosis-deafness, sporadic inheritance, generalized mild hyperkeratosis, erythematous, keratotic plaques, palmoplantar keratoderma, nonprogressive sensorineural deafness, progressive bilateral keratitis, with secondary blindness • Harlequin fetus: AR/sporadic, ABCA12 gene reported. Large diamond-shaped plaques of scale, low birth weight, ectropion and eclabium. High mortality rate. Cross-beta keratin tonofilament structure • Chanarin-Dorfman syndrome (Neutral lipid storage disease with ichthyosis): Mutation in ABHD5 gene. Cannot break down triglycerides and these fats accumulate in skin, liver, muscles, intestine, eyes, and ears. Ichthyosis usually present at birth. Additional features: hepatomegaly, cataracts, ataxia, hearing loss, short stature, myopathy, nystagmus, and mild intellectual disability3.5 PALMOPLANTAR KERATODERMAS • Unna-Thost palmoplantar keratoderma (PPK) (non-epidermolytic): AD, keratin 1 • Vorner PPK (epidermolytic): AD, keratin 1 & 9 Diffuse symmetric, non-transgradient PPK • Striated PPK (Brunauer-Fohs-Siemens): AD, desmoglein 1 and desmoplakin 1 • Mal de Meleda: AR, SLURP-1. Malodorous transgradient PPK in glove and stocking distribution • Howel-Evans syndrome: AD, TOC gene. Focal, pressure-related, non-transgradient PPK; esophageal cancer; oral leukoplakia • Sclerotylosis (Huriez syndrome): AD. Sclerosis of skin, nail hypoplasia, PPK. 15% develop cutaneous SCC and increased risk of bowel cancer • PPK with deafness: AD, type 1: connexin-26; type 2: MTTS1. Mitochondrial serine tRNA mutation • Vohwinkel syndrome: AD, connexin 26 (GJB2 gene). Diffuse honeycombed PPK, pseudoainhum, starfish-shaped keratotic plaques over joints, deafness • Vohwinkel variant: AD, loricrin. Similar to classic Vohwinkel, plus ichthyosis but no deafness Genodermatoses  53
  6. 6. • Naxos syndrome: AR, plakoglobin. PPK + wooly hair + arrhythmogenic cardiomyopathy • PPK with dilated left-ventricular cardiomyopathy and wooly hair: Carvajal syndrome, AR, desmoplakin • Schopf-Schulz-Passarge syndrome: AR. PPK + cystic eyelids + hypodontia + eccrine tumors (eccrine syringofibradenoma) • Bart-Pumphrey syndrome: AD, connexin 26; PPK with knuckle pads, leukonychia, deafness • Olmsted syndrome: AD or XLR; mutilating PPK with periorificial plaques • Papillon-Lefevre syndrome: AR, Cathepsin C. Sharply demarcated, transgradient, stocking-glove PPK, periodontitis with tooth loss, asymptomatic dural calcification and choroids attachments • Haim-Munk syndrome: AR, Cathepsin C. PPK + periodontitis + acroosteolysis + onychogryphosis • Erythrokeratodermia variabilis: AD, connexin 31 & 30.3 mutations (gap junction components encoded by the GJB3, GJB4 genes). Erythematous migratory patches, fixed hyperkeratotic plaques, palmoplantar keratoderma • Symmetric progressive erythrokeratodermia: AD, loricrin. Hyperkeratotic plaques and palmoplantar keratoderma • Richner-Hanhart syndrome (tyrosenemia type II): AR, deficient hepatic tyrosine aminotransferases. Painful PPK, pseudoherpetic keratitis and blindness. Treatment: low- tyrosine/phenylalanine diet • Epidermal Nevus syndrome: Nevus unius lateris; sporadic inheritance, capillary malformations, café au lait macules, mental retardation and seizures, deafness, hemiparesis, hemihypertrophy of limbs, kyphoscoliosis; rare solid tumors. Biopsy to rule out epidermolytic hyperkeratosis, as if positive for EHK then offspring at risk for generalized EHK3.6 DISORDERS WITH HYPOPIGMENTATION • Oculocutaneous albinism (OCA) type 1 (tyrosinase negative albinism): AR, tyrosinase deficiency. Generalized pink-white skin color, snow-white hair color, pink nevi, blue/gray eyes with severe nystagmus. Increased skin cancers, especially SCC • OCA 2 (tyrosinase + albinism): ROCA, AR, P gene. Most common OCA. Generalized cream color, pigmented nevi, light brown hair, nystagmus. Allelic variant is brown oculocutaneous albinism (BOCA) • OCA 3: BOCA, AR, tyrosinase related protein 1. Light brown hair/skin, blue/brown iris, nystagmus. Allelic variant is rufous oculocutaneous albinism (ROCA) • Chediak-Higashi syndrome: AR, lysosomal transport gene (LYST, CHS1). Oculocutaneous albinism, ataxia, muscle weakness, giant lysosomal granules. Accelerated phase characterized by lymphohistiocytic infiltration of reticuloendothelial system, pancytopenia and death • Griscelli syndrome: AR, GS1: myosin 5A; GS2, RAB27A; GS3: MLPH. Mild albinism, pancytopenia, immunodeficiency, neurologic symptoms GS1. Accelerated phase GS2 similar to Chediak-Higashi but no lysosomal granules on smear • Elejalde syndrome (neuroectodermal melanolysosomal disease): Variant of GS1; prominent features of GS plus severe neurologic dysfunction but not associated with immunodeficiency54  2011/2012 Dermatology In-Review l Committed to Your Future
  7. 7. • Hermansky-Pudlak syndrome: AR, HPS (lysosomal transport protein), AP3B1 (endocytic/exocytic sorting). Oculocutaneous albinism, platelets without dense bodies causing excess bleeding, ceroid lysosomal storage disease resulting in pulmonary fibrosis, granulomatous colitis, cardiomyopathy, and renal failure • Piebaldism: AD, c-kit protooncogene. White forelock, depigmented patches on the face, extremities, and abdomen • Waardenburg syndrome: AD, PAX-3 gene (types 1 and 3), MITF gene (type 2), and SOX10, endothelin-3 ligand, endothelin 3-receptor genes (type 4). Dystopia canthorum, white forelock, synophrys, heterochromia irides, deafness. Type 2 has increased risk of deafness but no dystopia canthorum. Type 3 has axial limb defects. Type 4 is AR and has Hirschsprung disease • Hypomelanosis of Ito: Sporadic, male and female. Whorled hypopigmentation, occasional CNS defects, scoliosis, and anodontia • Tuberous sclerosis (Bourneville’s syndrome, epiloia): AD, TSC1 mutation (hamartin) and TSC2 mutation (tuberin) tumor suppressor genes. Ash leaf macule (1st sign), shagreen patch (collagenoma), adenoma sebaceum (facial angiofibroma), periungual angiofibroma (Koenen tumor), CALMs, seizures, retinal astrocytic hamartomas (phakomas), angioid streaks, renal angiomyolipoma (especially in familial cases), congenital cardiac rhabdomyomas, dental enamel pits • Westerhof syndrome: Similar to TS; growth retardation, mental retardation, hereditary congenital hypopigmented and hyperpigmented macules3.7 DISORDERS WITH PIGMENTED LESIONS • Neurofibromatosis I: AD, neurofibromin (NF-1). Two or more of: 1.) >5 café au lait macules (CALMs) that are >5mm in a prepubertal person or >15 mm in a postpubertal person, 2.) >1 neurofibroma or 1 plexiform neurofibroma, 3.) axillary/inguinal freckling (Crowe’s sign), 4.) optic glioma, 5.) >1 Lisch nodule (iris hamartoma), 6.) sphenoid dysplasia, 7.) 1st degree relative with NF-1 • Neurofibromatosis II: AD, schwannomin/merlin. Cutaneous schwannomas and neurofibromas, bilateral vestibular schwannomas, juvenile posterior subcapsular lenticular opacities • Watson syndrome: AD, neurofibromin. Pulmonic stenosis + CALMs • Russell-Silver syndrome: Sporadic. CALMs, short stature, musculoskeletal and craniofacial defects including asymmetry, clinodactyly and syndactyly, precocious puberty, and cryptorchidism • McCune-Albright syndrome: Sporadic somatic mutation in GNAS1 gene Gs subunit of adenylate cyclase. “Coast of Maine” CALM, polyostotic fibrous dysplasia, precocious puberty • Albright hereditary osteodystrophy: GNAS Gs subunit of adenylate cyclase. Calcification/ ossification, pseudohypoparathyroidism (low Ca, high PTH), absent 4th knuckle, hypogonadism • Incontinentia pigmenti (Bloch-Sulzberger syndrome): X-linked-dominant, male lethal, NEMO gene. Four stages: vesicular, verrucous, hyperpigmented and hypopigmented. Peg or conical teeth, eye abnormalities, CNS defects, alopecia Genodermatoses  55
  8. 8. • Hypohidrotic ectodermal dysplasia with immunodeficiency: X-linked-recessive, NEMO gene (IKK-gamma). Recurrent GI, pulmonary, skin infections, hypogammaglobulinemia, failure to thrive, decreased teeth, conical shaped maxillary lateral incisors, decreased hair, but normal pigmentation • LEOPARD syndrome: AD, PTPN11 gene (allelic to Noonan syndrome). Lentigines, EKG conduction defects, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, deafness • Carney complex: NAME (nevi, atrial myxoma, myxoid neurofibroma, ephelids) syndrome, LAMB syndrome (Lentigenes, Atrial myxomas, Mucocutaneous myxomas, Blue nevi), AD, PRKAR1A (protein kinase A regulatory subunit 1-alpha). Cardiac, cutaneous and/or mammary myxomas, pigmented skin lesions, endocrine abnormalities (pituitary, testicular, thyroid, etc.), primary pigmented nodular adrenocortical disease, psammomatous melanotic schwannoma • Tay syndrome: AR; growth retardation, mental retardation, triangular face, cirrhosis, trident hands, CALMs, premature canities, vitiligo • Canty (hyperkeratosis-hyperpigmentation syndrome): AD; punctuate PPK, macules on face, arms, hands, and feet • Dowling-Degos disease: AD; keratin 5; reticulated hyperpigmentation of axilla, groin, inframammary and anticubital fossa; starts in adulthood • Laugier-Hunziker syndrome: Hyperpigmented macules on the lips, buccal mucosa, genitalia and longitudinal melanonychia3.8 VASCULAR DISORDERS • Sturge-Weber syndrome: Sporadic, M = F. Facial capillary malformation at birth (trigeminal distribution, unilateral > bilateral); neurologic: seizures by 1–2 years, seizures, mental retardation, cerebral atrophy, ipsilateral leptomeningeal vascular malformations, tram-track cortical calcifications; opthmalmic: choroid malformations, ipsilateral glaucoma → blindness. Work-up: MRI, ophtho exam • Klippel-Trenaunay-Weber syndrome: Sporadic. Port-wine stains (lower > upper extremity), hemihypertrophy of limb, lymphatic and deep venous insufficiency of affected limb. Parkes-Weber syndrome has, in addition, arteriovenous fistulas • Beckwith-Wiederman syndrome (EMG) syndrome: Exophthalmos, macroglossia, gigantism: Sporadic 85%, 15% AD p57 (KIP2) gene (inhibitor of G1 cyclin/Cdk complexes). Facial capillary malformations, macroglossia, visceromegaly with omphalocele, hemihypertrophy associated with tumors (especially Wilm’s) • Von Hippel-Lindau syndrome: AD, VHL gene (tumor suppressor gene). Bilateral retinal hemangioblastomas, cerebellar and other CNS hemangioblastomas, renal cysts and renal cell carcinoma, pheochromocytomas, pancreatic cysts and carcinoma, capillary malformations • Proteus syndrome: Sporadic, mosaic mutation in PTEN. Subcutaneous lymphovenous malformations, capillary malformations, lipomas, connective tissue nevi of palms/soles, hemihypertrophy, frontal bossing, hyperostoses of epiphyses & skull (especially external auditory canal), scoliosis, bilateral ovarian cystadenomas, parotid monomorphic adenoma • Rubinstein-Taybi syndrome: Sporadic contiguous gene syndrome affecting transcriptional coactivator CREB-binding protein. Capillary malformation, short stature, broad thumbs, craniofacial abnormalities including beaked nose, mental retardation, congenital heart defects, cryptorchidism56  2011/2012 Dermatology In-Review l Committed to Your Future
  9. 9. • Maffucci syndrome: Sporadic, PTH/PTHrP type I receptor. Venous malformation of distal extremities, benign enchondromas compromising bone strength and leading to chondrosarcoma, and other less common sarcomas• Blue Rubber Bleb Nevus syndrome: Sporadic, some AD (TIE2 tyrosine kinase activating mutation). Multiple tender venous malformations of skin and gastrointestinal tract with gastrointestinal bleeding• Ataxia Telangiectasia (Louis-Bar syndrome): AR, ATM gene (chromosomal strand break repair enzyme) and MREII gene (milder form). Cerebellar ataxia (1st sign), telangiectases of conjunctiva and skin, thymic hypoplasia with increased infections. Increases sensitivity to ionizing radiation with increased hematologic and solid tumors. Female carriers have increased risk of breast cancer. Increased alpha-fetoprotein and decreased or absent IgG2, IgE, and IgA• Osler-Weber-Rendu syndrome (Hereditary hemorrhagic telangiectasia): AD, endoglin (TGF-beta binding protein), activin-receptor kinase 1 (binds TGFB1 and activin A), and bone morphogenetic protein receptor type II (TGF-b family receptor) mutations. Epistaxis, telangiectases of skin, mucous membranes, and gastrointestinal tract with bleeding, pulmonary arteriovenous fistulas with cerebral emboli. ALK1 gene mutation associated with increased hepatic AVMs• Cornelia de Lange syndrome: Sporadic (some AD due to nipped-beta-like gene NIPBL; x-linked form due to structural maintenance of chromosomes 1-like SMC1L1 gene). Cutis marmorata, hirsutism, synophrys, trichomegaly, numerous craniofacial abnormalities, severe mental retardation, deafness, low-pitched cry, short stature, clinodactyly and other abnormalities of the hands and feet, genitourinary abnormalities including cryptorchidism, congenital heart defects, and deafness• Hereditary lymphedema (Nonne-Milroy disease): AD, Type 1, FLT4 gene (VEGF receptor-3). Congenital lymphedema, chylous ascites, scrotal swelling, intestinal tract protein loss with hypoproteinemia, and persistent bilateral pleural effusions• Lymphedema-distichiasis syndrome: AD, FOXC2 (forkhead family transcription factor gene MFH1). Late-onset lymphedema, distichiasis (double row of eyelashes), corneal irritation, ectropion, webbed neck, congenital heart defect. Late-onset hereditary lymphedema (Type 2) - meige lymphedema• Lymphedema and ptosis: AD, MFH1• Diffuse congenital hemangiomatosis: Sporadic, multiple 0.2 to 2.0 cm hemangiomas in generalized distribution, involving any organ, liver hemangioma may be complicated by obstructive jaundice, portal hypertension, hemorrhage, high output CHF leading to death; hemangiomas undergo spontaneous regression• Hypotrichosis-lymphedema-telangiectasia: SOX18 mutation• Erythromelalgia: Burning, erythema, warmth of acral sites; associated with thrombocytopenia or SCN9A mutation (Na+ channels)• Familial Glomagioma: GLMN mutation• Capillary Malformation: Arteriovenous malformation: RASA1 mutation• CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): NOTCH3 mutation• Hypotrichosis-Lymphedema-Telangiectasia: SOX18 mutation Genodermatoses  57
  10. 10. 3.9 CONNECTIVE TISSUE DISORDERS • Ehlers-Danlos syndrome (EDS) – Type 1 (Gravis): AD, collagen 5. Hyperextesible skin, gaping wounds, cigarette-paper scars, molluscoid pseudotumors, calcified subcutaneous nodules, bruises, hypermobile joints with dislocation, hernias, mitral valve prolapse, blue sclerae, Gorlin’s sign (tongue reaches nose), absence of lingual frenulum – Type 2 (Mitis): AD, collagen 5. Milder form of type 1 – Type 3 (Benign hypermobile): AD, collagen 3. Recurrent joint dislocations – Type 4 (Vascular): AD/AR, collagen 3: Translucent skin with visible venous network, arterial and visceral rupture resulting in early death – Type 5 (X-linked): X-recessive. Lysyl oxidase deficiency. Relatively mild – Type 6 (Ocular-scoliotic): AR, PLOD gene, lysyl hydroxylase deficiency. Severe kyphoscoliosis, retinal detachment and other eye abnormalities – Type 7 (Arthrochalasis multiplex congenita): AD/AR, COL1A/2, mutations in procollagen amino terminals (AD) or in procollagen aminopeptidase (AR), which cleaves the amino-terminals. Congenital hip dislocation, severe joint hypermobility (EDS Arthrochalasia type) – Type 8 (Periodontitis): Type 3 collagen. Mild symptoms of EDS with periodontitis and resulting tooth loss – Type 9 (Occipital horn syndrome): XR Lysyl oxidase. Mild symptoms of EDS with occipital exostoses and hernias – Type 10 (Fibronectin): AR, fibronectin. Ecchymoses and petechiae – Type 11 (Large joint hypermobile): AD: dislocation of large joints – Osteogenesis imperfecta: COL1A gene defect; Types 1 and 4: AD; Types 2 and 3: AD/ AR - most severe with fractures in utero – Progeroid EDS: AR, xylosylprotein 4-beta-galactotransferase. Thin, elastic skin, hair and teeth abnormalities, osteopenia, and hypotonia – EDS with congenital adrenal hyperplasia: AR, tenascin-X • Marfan syndrome: AD, fibrillin 1 and 2. Tall stature, arachnodactyly, pectus excavatum, high-arched palate, joint laxity, ectopia lentis with upward dislocation, aortic dilatation with rupture, mitral valve prolapse, striae, elastosis perforans serpiginosa • Congenital contractural arachnodactyly: AD, fibrillin 2. Long limbs, arachnodactyly, scoliosis, crumpled ear • Cutis laxa: AR, fibulin 4 gene, AD (elastin gene), X-Recessive (lysyl oxidase, allelic to EDS 9 and Menkes), acquired (Marshall syndrome). Loose, pendulous, inelastic skin, deep voice, lung abnormalities, arterial rupture, visceral diverticulae and hernias, and joint dislocation. Fibulin 5 (both AD and AR) • Pseudoxanthoma elasticum: AR, AD, sporadic, ABCC6 gene (anthracycline resistance protein, ATP-using cell transporter). Fragmented and calcified elastin of skin, eyes, and arteries. Plucked-chicken skin on flexures, yellow papules on mucous membranes, angioid streaks (rupture in Bruch’s membrane), gastric hemorrhage, arterial disease • Buschke-Ollendorf syndrome: AD. Dermatofibrosis lenticularis disseminata (elastomas) and osteopoikilosis (round opacities in bones). Caused by a loss-of-function mutation in LEMD3 (also called MAN1), which encodes an inner nuclear membrane protein. LEMD3 normally interacts with Bone Morphogenetic Protein and activin-TGF beta receptor- activated Smads and antagonizes both signaling pathways58  2011/2012 Dermatology In-Review l Committed to Your Future
  11. 11. • Focal dermal hypoplasia (Goltz syndrome): X-linked dominant, male lethal, PORCN gene. Linear atrophy following Blaschko’s lines with areas of fat herniation, mucocutaneous papillomas and pits, alopecia, nail dystrophy, tooth abnormalities, musculoskeletal defects (osteopathia striata), colobomas• Lipoid proteinosis: AR extracellular matrix protein 1 gene (ECM1). Scars and yellow papules of the face and orophraynx, eyelid string of pearls, hoarse voice, verrucous nodules of elbows and knees, bean-shaped temporal and hippocampal calcification with occasional seizures. PAS+ deposits histologically• Progeria (Hutchinson-Gilford syndrome): AD mutation in lamin A (nuclear envelope protein). Lipoatrophic sclerodermoid skin, alopecia, nail atrophy, craniomegaly with small face, muscle/bone wasting, severe premature atherosclerosis with early death• Beare-Stevenson Cutis Gyrata syndrome: Mutations in fibroblast growth factor receptor 2. Craniosynostosis, cutis gyrata, acanthosis nigricans, anogenital anomalies, skin tags, prominent umbilical stump, furrowed palms/soles. Apert syndrome (same gene): cranial synostosis, syndactyly, severe acne. Nevus comedonicus (same gene)• Skeletal dysplasia syndrome with acanthosis nigricans: FGFR3 mutation• Pachydermoperiostosis: AD, mostly males; clubbing of digits, soft tissue hyperplasia, periostial proliferation of arms and legs, cutis vertices gyrata on scalp• Berardinelli-Seip congenital lipodystrophy: BSCL2 gene (encodes nuclear lamins). Generalized lipodystrophy, hyperlipemia, hepatomegaly, acanthosis nigricans, elevated basal metabolic rate, non-ketotic insulin-resistant diabetes mellitus. Acquired generalized lipodystrophy (Lawrence syndrome). AR; Type I (AGPAT gene). Type II (BSCL2 gene)• Familial partial lipodystrophy (Dunnigan): Type 1: Kobberling; Type 2: Dunnigan, AD, LMNA (nuclear lamins A/C). Type 3: PPARG gene mutation. Symmetric lipoatrophy of trunk and limbs (sparing neck, shoulders, buffalo hump area, genitalia), tuberoeruptive xanthomas, acanthosis nigricans, hypertriglyceridemia• Acquired partial lipodystrophy (Barraquer Simons syndrome): Sporadic or AD; LMNB2 gene mutation; decreased fat on face, medial thighs, buttocks; increased fat in hips and legs. Acquired generalized lipodystrophy (Lawrence syndrome)• Leprechaunism (Donohue syndrome): Insulin receptor gene mutation; generalized lipodystrophy and elfin faces; death in infancy• Loeys-Dietz syndrome: AD, TGFβ receptors 1 and 2; translucent skin, aortic aneurism, arterial tortuosity, craniofacial and skeletal anomalies, joint hypermobility• Poland syndrome: Unilateral absence of breast +/- pectoralis major, ipsilateral syndactyly• Joffe-Campacci syndrome: Disseminated non-ossifying fibromas of long bones and jaw bones, hypogonadism, cryptorchidism, MR, giant cell granuloma (jaw)• Familial multiple lipomatosis: AD. Multiple lipomas of the upper and lower extremities• Aplasia cutis congenita (ACC): AD/AR/sporadic: Well-demarcated erosions at birth healing with atrophic, alopecic scars. Adams-Oliver syndrome: AD, midline scalp ACC with limb hypoplasia. Bart’s syndrome: AD, ACC of lower extremity with dominant dystrophic epidermolysis bullosa. ACC can be caused by teratogens, particularly methimazole• Osteogenesis imperfecta: COL1A1 gene defect. Types I and IV (AD), Types II and III (AD/AR) – most severe, with fractures in utero. Thin skin, easy bruising, blue sclera (except type III), multiple fractures with wormian bones, mitral valve prolapse (especially Type I) Genodermatoses  59
  12. 12. 3.10 DISEASES OF THE HAIR AND NAILS • Menkes kinky hair syndrome: X-linked recessive, ATP7A, an ATP-dependent copper transporter, low levels of serum copper, pili torti most common, Trichorrhexis nodosa, Hypopigmented, sparse, short, brittle hair, sparse eyelashes and eyebrows, lax skin, Cupid’s bow upper lip, CNS progressive deterioration, seizures, skeletal abnormalities, tortuous arteries • Bjornstad syndrome: Pili torti, deafness, normal intelligence and lifespan • Argininocuccinic aciduria: AR, argininosuccinase, trichorrhexis nodosa, hyperammonemia, vomiting and hepatomegaly, seizures, lethargy, coma, ataxia, mental retardation • Monilethrix: mutations in hair cortex keratins 1 (hHb1 or KRT81) and 6 (hHb6 or KRT 86); Beaded hair → elliptical nodes along hair shaft, keratosis pilaris, brittle nails. Also mutation in the gene encoding K83. AR: mutation in gene encoding Desmoglein 4 • Uncombable hair syndrome: Pili trianguli et canaliculi, blonde hair • Autosomal recessive woolly hair: Mutation in P2RY5 gene – G protein coupled receptor, nested gene within the retinoblastoma 1 gene. Diffuse scalp woolly hair with variable hypotrichosis or sparse hair • Hypotrichosis simplex of scalp: Mutation in CDSN gene, encodes corneodesmosin. Normal hair at birth with progressive, gradual loss of scalp hair beginning at middle of the first decade to almost complete loss of scalp hair by third decade. Body hair, beard, eyebrows, axillary hair, teeth, and nails develop normally. Men and women are equally affected • Naxos disease: Plakoglobin, woolly hair, keratoderma, right sided cardiomyopathy • Trichothiodystrophy: AR, PIBIDS or Tay syndrome, photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility, short stature, low cysteine or methionine content in hair and nails, defect in DNA repair; same complementation group as XP group D, but no increased skin cancer; hair shows trichoschisis (“tiger-tail” banding) → alternating light and dark bands with polarizing microscope, sparse or absent eyelashes, eyebrows, axillary, pubic, and body hair • Anhidrotic ectodermal dysplasia: Christ-Siemens-Touraine syndrome, X-linked recessive, mutation in ectodysplasin A or ectodysplasin A receptor (EDA and DL, respectively), smooth, soft, dry, fine wrinkles with periorbital hyperpigmentation, hypo- or anhidrosis with hyperpyrexia, atopic dermatitis, hypopigmented, fine, short, sparse scalp and body hair with longitudinal groove on EM, dystrophic nails, frontal bossing, saddle nose, supraorbital ridging, thick everted lips, hypo-anodontia, peg-shaped/conical incisors and canines • Hidrotic ectodermal dysplasia: Clouston syndrome, AD, connexin 30 (GJB6 mutation), palmoplantar keratoderma with transgradiens, dystrophic nails, sparse hair with absent body, eyelash, eyebrow hair after puberty • EEC syndrome (Ectrodactyly-Ectodermal Dysplasia-Cleft lip/palate): AD, EEC1, EEC2, EEC3; p63 gene mutation • AEC (Ankyloblepharon-Ectodermal Dysplasia-Clefting) syndrome (Hay-Wells): p63 gene, ankyloblepharon filiforme adenatum, ectodermal dysplasia, cleft palate • Rapp-Hodgkin syndrome: p63 gene, mild form of AEC with no akyloblepharon • Branchio-oto-renal syndrome: EYAI gene. Ear pits, deafness, renal dysplasia • Tricho-rhino-phalangeal syndrome: AR/AD (TRPS1 gene) - Sparse hair, pear-shaped broad nose, cone -shaped epiphyses • Trichodentoosseous syndrome: DLX3 homeobox gene. Curly hair, dental pits, increased bone density60  2011/2012 Dermatology In-Review l Committed to Your Future
  13. 13. • Dermatopathia Pigmentosa Reticularis (DPR): AD, mutation in keratin-14 gene. Triad of cutaneous reticulate hyperpigmentation, noncicatricial alopecia, onychodystrophy. Keratin-14 mutation is shared with Naegeli-Franseschetti-Jadassohn syndrome. Shared clinical features in both are adermatoglyphia, palmoplantar keratoderma and hypohidrosis. However, alopecia is only seen in DPR and dental abnormalities are seen in only in Naegeli- Franceschetti-Jadassohn syndrome • Naegeli-Franceschetti-Jadassohn syndrome: Mutation in keratin-14. Reticulate pigmentation starting at age 2 and fading with age. Palmoplantar hypohidrosis and hyperkeratosis. Hypoplasia of dermatoglyphics or adermatoglyphics. Poor dentition progressing to loss of teeth • Costello syndrome (Faciocutaneoskeletal syndrome): Mutation in HRAS gene. Thin anterior hair, curly hair. Nasolabial facial and perianal papillomas. Redundant and thickened skin around neck, palms, and soles.Congenital myopathy with excess muscle spindles. Coarse facies, short stature. Cardiac and developmental disability • Cardiofaciocutaneous syndrome: Mutations in KRAS, BRAF, MEK1, MEK2 – all part of the common RAS/ERK pathway regulating cell proliferation, differentiation and apoptosis. Sparse friable hair, patchy hyperkeratosis or more generalized icthyosis. Heart defects (pulmonic stenosis, atrial septal defects). Mental retardation and characteristic facies (high forehead with bitemporal constriction, antimongoloid slant of palpebral fissures, posteriorly angulated ears) • Pachyonychia congenita: Jadassohn-Lewandowsky syndrome, keratin 16 and 17 mutations – Type I: Mutations in keratins 6a and 16 → focal PPK, distinctively thickened hyperkeratotic fingernails and toenails (all 20) with onycholysis and frequent Staph or Candidal paronychial infection, pincer nails, follicular hyperkeratosis of elbows and knees, oral leukokeratosis, palmar and plantar keratoderma with hyperhidrosis – Type II (Jackson-Lawler) syndrome involves mutations in keratins 6b and 17 and clinically resembles the type I syndrome with the additional findings of both natal teeth and steatocystoma multiplex; less severe palmoplantar keratoderma with milder or absent oral lesions – Type III (Schafer-Branauer) syndrome that features all the findings of the type I disease associated with leukokeratosis of the corneas – Type IV, pachyonychia congenita tarda, applies to a late-onset of the disease during the second or third decade of life • White sponge nevus: Autosomal dominant; K4 and K13 mutations, white spongy overgrowth of the mucous membrane, buccal muccosa most common site • Nail-patella syndrome: AD, mutations in LMX1B; triangular lunulae, micronychia with hemonychia and longitutinal splitting, anonychia, palmoplantar hyperhidrosis, absent or hypoplastic patella, bilateral posterior iliac horns, radial head subluxation, thickened scapula, scoliosis, glomerulonephritis, Lester iris (hyperpigmentation of the pupillary margin of the iris)3.11 DISEASES WITH MALIGNANT POTENTIAL • Nevoid Basal Cell Carcinoma syndrome (Gorlin syndrome): AD, patched gene (inhibits hedgehog signaling pathway). ↓ patched → ↑smoothened → uncontrolled cell proliferation through Gli 1-3 transcription factors. Innumerable BCCs, palmoplantar pits, painful odontogenic jaw keratocysts, frontal bossing, bifid ribs, calcification of falx cerebri, medulloblastoma, hypertelorism, and ovarian fibromas and fibrosarcomas Genodermatoses  61
  14. 14. • Bazex syndrome: X-Dominant > AD. Follicular atrophoderma, hypohidrosis, hypotrichosis, multiple BCCs • Rombo syndrome: AD. Vermicular atrophoderma, multiple BCCs, trichoepitheliomas, hypotrichosis, acrocyanosis. No follicular atrophoderma or hypohidrosis as seen in Bazex syndrome • Braun-Falco-Marghescu syndrome: Atrophoderma vermiculata, PPK, keratosis pilaris • Tuzin syndrome: Atrophoderma vermiculata and scrotal tongue • Rasmusen syndrome: Milia, trichoepitheliomas, and cylindromas • Familial cylindromatosis: AD. CYLD gene (binds organelles to microtubules). Numerous turban tumors (cylindromas), eccrine spiradenomas • Brook-Spiegler syndrome: Multiple trichoepitheliomas and cylindromas • Nicolau-Balus syndrome: Micropapular eruptive syringomas, milia, atrophoderma vermiculata • Birt-Hogg-Dube syndrome: AD; multiple fibrofolliculomas, trichodiscomas, acro- collagenomas, lipomas, oral fibromas, renal cell carcinoma, medullary thyroid carcinoma, and colon cancer. Mutation FLCN (folliculin gene). BHD gene • Schopf-Schulz-Passarge syndrome: AR; hidrocystoma of eyelids, hypotrichosis, hypodontia, nail abnormalities, and multiple palmoplantar eccrine syringofibroadenomas • Myotonic dystrophy with multiple pilomatricomas: Activating beta catenin mutations (encoded by CTNNB1) • Gardner syndrome: AD, APC gene (b-catenin mediated transcription). Colonic polyposis with cancer (100% by age 50), epidermoid cysts with foci of pilomatricoma and calcification, congenital hypertrophy of retinal pigment epithelium, facial/skull osteomas, extranumerary teeth, desmoid tumors • Cronkhite-Canada syndrome: Sporadic. Gastrointestinal polyposis, nail atrophy, alopecia, generalized pigmentation of skin, melanotic macules on fingers • Peutz-Jeghers syndrome: AD, STK11/LKB1 (serine threonine kinase tumor suppressor gene). Pigmented macules of the mouth, fingers, and mucosae, gastrointestinal hamartomatous polyps (especially small bowel) with bleeding and intussusception, gastrointestinal adenocarcinomas, ovarian sex cord tumor, and breast, pancreatic, and endometrial cancers. Laugier-Hunziker syndrome • Muir-Torre syndrome: AD, MSH2 gene (DNA mismatch repair) or MLH1 gene (same function). Multiple cutaneous sebaceous neoplasms, keratoacanthomas and multiple primary GI and larynx carcinomas • Cowden syndrome (multiple hamartoma syndrome): AD, PTEN (phosphatase that dephosphorylates tyrosine, serine, and threonine). Facial trichilemmomas, oral papillomas, acral keratotic papules, sclerotic fibromas, breast fibroadenomas and adenocarcinomas, thyroid adenomas and adenocarcinomas, and hamartomatous polyps of the gastrointestinal tract • Bannayan-Riley-Ruvalcaba syndrome: AD, PTEN. Macrocephaly, genital lentigines, hamartomas, lipomas, hemangiomas, and mental retardation • Multiple endocrine neoplasia type I (Werner syndrome): AD, menin. Parathyroid, pancreatic and pituitary tumors. Angiofibromas, collagenomas, CALMs, lipomas, hypopigmented macules, gingival macules • Multiple endocrine neoplasia type 2a (Sipple syndrome): AD, RET proto-oncogene. Parathyroid tumors, pheochromocytomas, medullary thyroid cancer. Familial macular/ lichen amyloidosis62  2011/2012 Dermatology In-Review l Committed to Your Future
  15. 15. • Multiple endocrine neoplasia type 2b (multiple nucosal neuromas): AD, RET proto- oncogene. Pheochromocytoma, medullary thyroid cancer, rare parathyroid carcinoma. Mucosal neuromas, marfanoid habitus, GI ganglioneuromatosis • Dyskeratosis congenita: X-recessive—dyskerin gene (ribosomal RNA synthesis); AD— TERC gene (telomerase). Reticulate pigmentation of skin, poikiloderma, alopecia, nail atrophy, premalignant oral leukoplakia, Fanconi-type pancytopenia resulting in early death. Allelic to Hoyeraal-Hreidarsson syndrome (+ posterior fossa malformations) • Familial dysplastic nevi/melanoma: AD, CDKN2A (P16 tumor suppressor gene that inhibits cyclin dependent kinase 4), CDK4 (cyclin dependent kinase 4, proto-oncogene). Dysplastic nevi, melanoma, pancreatic cancer, and astrocytomas. Mutation in BRAF in common melanocytic nevi (ex: dermal) and in malignant melanoma • Familial multiple cutaneous leiomyomatosis (Reed syndrome): AD, fumarate hydratase. Multiple cutaneous leiomyomas, uterine leiomyomas and leiomyosarcoma, renal cell carcinoma • Li-Fraumeni syndrome: AD, p53 mutation; breast carcinoma, brain carcinoma, osteosarcoma, leukemia; skin cancers not typical3.12 DISORDERS WITH IMMUNODEFICIENCY • Wiskott-Aldrich syndrome: X-linked recessive WASP gene, an Arp2/3 complex interacting protein, atopic dermatitis on face, scalp, flexures, thrombocytopenia with petechiae, purpura, epistaxis, bloody diarrhea, hematemesis, intracranial hemorrhage, recurrent bacterial infections → otitis media, pneumonia, meningitis, sepsis, increased susceptibility to HSV, PCP, HPV, increased IgA, IgD, IgE, decreased IgM, impaired cell-mediated and humoral immune response, 20% risk of lymphoreticular malignancy in adolescence/young adulthood • Chronic Granulomatous disease: AR: mutation in CYBA (cytochrome subunit), XLR: mutation in CYBB (cytochrome subunit), AR: NCF 1 and 2 (neutrophil cytosol factors 1 and 2), diagnosed by nitroblue tetrazolium reduction assay → abnormal WBC’s cannot reduce dye, inability to produce respiratory burst needed to kill catalase positive organisms after phagocytosis, recurrent pyoderma (S. aureus, most commonly), periorificial dermatitis, ulcerative stomatitis and chronic gingivitis in mouth, suppurative lymphadenitis with abscesses and fistulas, pneumonia with empyema, hepatosplenomegaly with granulomas, abscesses, chronic diarrhea, osteomyelitis • Hyper IgE syndrome: Job syndrome, AD, IgE level markedly increased, peripheral eosinophilia, excoriated papules, pustules, furuncles, and abscesses → some cold, some with S. aureus; coarse facies, broad nasal bridge, eczematous dermatitis in flexures, postauricular, hairline; bronchitis, lung abscesses, pneumonia, otitis media, sinusitis, mutation in STAT3 • Severe combined immunodeficiency: X-linked recessive: most common, gamma chain IL-2 receptor gene (IL2RG), AR: from Janus kinase 3 gene (JAK3), AD: IL7R gene mutation, mixed group of disorders all sharing defect in cell-mediated and humoral immunity; 20% secondary to adenosine deaminase deficiency (ADA and PNP genes mutated), candidal infections, mucocutaneous, bacterial pyodermas, seborrheic-like dermatitis/lichen planus- like sclerodermatous changes, aplastic thymus, pneumonia • Omenn syndrome: AR form of SCID with erthroderma, RAG-1 and RAG-2 genes • Chronic mucocutaneous candidiasis: AR or AD (ICAMI) or AD with thyroid disease. Candida, severe, of skin, mouth, nails Genodermatoses  63
  16. 16. • APECED: AR, AIRE gene (autoimmune regulator gene). Addison’s hypoparathyroidism, candidiasis • X-linked agammaglobulinemia (Bruton): BTK gene, all Igs decreased; also AR, AD • Common variable immunodeficiency: ICOS, TNFRSF13, TNFRSF13C, CD19 genes; IgG and IgA decreased; +/- decreased in IgM • Selective IgA deficiency: TNFRSF13B gene; IgA decreased • Selective IgM deficiency: IgM decreased • X-linked hyperIgM syndrome: CD40LG; AR hyperIgM syndrome: Increased IgM; decreased IgA, IgE, and IgG3.13 DNA AND CHROMOSOMAL DISORDERS • Xeroderma pigmentosum: AR: defective DNA excision repair from UV. 8 complementation group: 1.) XPA: XPA gene 2.) XPB: ERCC3 gene 3.) XPC: XPC gene 4.) XPD: ERCC2 gene 5.) XPE: DDB2 gene 6.) XPF: ERCC4 gene 7.) XPG: ERCC5 gene 8.) XP variant: POLH gene. Acute sunburns from infancy, numerous lentigines, premalignant and malignant skin cancers including BCCs, SCCs, and melanomas, ectropion with vascularization, and mental retardation (some subtypes) • Cockayne syndrome: AR, several complementation groups (CSA, CSB, XP B/D/G, ERCC8), some overlapping with xeroderma pigmentosum complementation groups. CSA and CSB remove stalled RNA polymerase from damaged DNA. ↑ sister chromatid exchanges and chromosome breaks. Photosensitivity and poikiloderma, lipoatrophy on face with sunken eye appearance, cachectic dwarf with long contracted limbs, microcephaly, thin nose, large ears, diffuse CNS demyelination, peripheral neuropathy, mental retardation, intracranial calcification, deafness, salt/pepper retinal pigmentation, cataracts, optic atrophy, dental caries. No increased risk of cancer • Bloom syndrome: AR, BLM gene (RecQ protein-like-2, ATP-dependent DNA helicase activity), sister chromatid exchange and chromosome breaks/rearrangements. Photodistributed poikiloderma, facial dysmorphism, hypogammaglobulinemia with recurrent respiratory and gastrointestinal infections, hypogonadism, leukemias, lymphomas, gastrointestinal adenocarcinomas, oral/esophageal SCCs • Rothmund-Thompson syndrome (poikiloderma congenitale): AR, RECQL4 gene (DNA helicase). Poikiloderma of face and extensor extremities, photosensitivity, premalignant acral keratoses, alopecia, nail dystrophy, cataracts, hypogonadism, and solid tumors (uncommon) • Werner syndrome: AR, RECQL2 (DNA helicase). Sclerodermoid skin, chronic leg ulcers, alopecia and graying of hair, beaked nose, short stature, osteoporosis, hypogonadism, atherosclerotic disease, sarcomas and other tumors • Muir-Torre syndrome: AD, HMSH2 and MLH1 (DNA mismatch repair gene). Sebaceous adenomas, epitheliomas and carcinomas, keratoacanthomas, indolent colonic and other visceral adenocarcinomas [variant of HNPCC (Lynch syndrome)] • Down syndrome: Trisomy 21 (1:700 births, risk increased with maternal age). Single palmar crease, nuchal folds, syringomas, elastosis perforans serpiginosa, epicanthic folds with up-slanting palpebral fissures, Brushfield spots, scrotal tongue, mental retardation, atrioventricular septal defects, ventricular septal defects, numerous other defects. Prenatal diagnosis by low alpha-fetoprotein in maternal serum and amniocentesis • Trisomy 8: Short nail, no patella (Similar to nail-patella syndrome)64  2011/2012 Dermatology In-Review l Committed to Your Future
  17. 17. • Kleinfelter syndrome: X-aneuploidy (47XXY, 48 XXXY, etc) from X-chromosome nondisjunction during maternal or paternal meiosis. Tall stature, varicose veins, arterial and venous leg ulcers, scant androgenic hair (body, pubis), gynecomastia, testicular hypoplasia, and antisocial behavior • Turner syndrome: XO, 1:2500, partial or total loss of one X chromosome from nondisjunction during gametogenesis. Webbed neck (remnant of cystic hygroma), keloids, hypoplastic nails, low-set ears with low posterior hairline, short stature, short 4th and 5th metacarpals, congenital lymphedema of hands and feet, primary amenorrhea from gonadal dysgenesis, cardiovascular abnormalities including coarctation of the aorta, and horseshoe kidneys • Noonan syndrome: AD or sporadic. PTPN11, encoding the nonreceptor protein tyrosine phosphatase SHP2 which contains 2 Src homology-2 (SH2) domains. Lower extremity lymphedema, nevi, CALMs, webbed neck, craniofacial abnormalities, short stature, cardiovascular defects including pulmonic valve stenosis, hypogonadism, and mental retardation • Familial Dysautonomia (Riley-Day syndrome): IKBKAP mutation; lack of pain sensation, decreased corneal sensation/tear flow, no fungiform papillae 3.14 KERATINOPATHIES Keratin is expressed in pairs. Keratin type I (keratins 9-20) is acidic, has a lower molecu- lar weight, and is coded on chromosome 17q. Keratin type II (keratins 1-8) is basic, has a higher molecular weight, and is coded on chromosome 12q. Table 3-1. Keratins Type II Type I Location of Expression Associated Disease 1 10 Suprabasal keratinocytes Epidermolytic hyperkeratosis, Unna-Thost PPK 1 9 Palmoplantar suprabasilar epidermis Epidermolytic PPK, Vorner PPK K2e 10 Granular layer Ichthyosis bullosa of Siemens 3 12 Cornea Corneal dystrophy 4 13 Mucosal epithelium White sponge nevus 5 14 Basal cells Epidermolysis bullosa simplex 6a 16 Outer root sheath, hyperproliferative Pachyonychia congenita type I keratinocytes (Jadassohn-Lewandowsky), focal PPK 6b 17 Nail bed Pachyonychia congenita type II (Jackson-Lawler) 8 18 Simple epithelium Cryptogenic cirrhosis 3.15 DISORDERS OF METABOLISM • Alkaptonuria: Ochronosis, AR, homogentisic acid oxidase, blue-gray pigmentation → face, ears, cartilage, tendons, acral surfaces, cerumen, sweat, blue-gray sclera, arthropathy, intervetebral disk calcification, cartilage of pubic symphysis, ear, nose, dark urine (pH > 7.0) Genodermatoses  65
  18. 18. • Fabry disease: Angiokeratoma corporis diffusum, X-linked recessive, α-galactosidase A, Accumulation of glycosphingolipids in vascular endothelium → ischemia and infarction, angiokeratomas between umbilicus and knees, urine → “maltese crosses,” mulberry cells, renal insufficiency with proteinuria, Painful crises, (paresthesias) on hands and knees relieved by phenytoin, angina, MI, CVA’s, peripheral neuropathy, corneal opacities (“whorl- like” configuration), fucosidosis (a-L-fucosidase) and sialodosis are indistinguishable from Fabry’s on cutaneous exam, b-galactosidase deficiency and aspartylglucosaminururia show angiokeratomas, too • Gaucher disease: AR, acid beta-glucosidase (GBA) gene; Type I → adult; Type II → infants, Gaucher cells: glucocerebroside in histiocytes in spleen, liver, bone marrow, lymph nodes, brain. Ehrlenmeyer flask deformity in bone • Mucopolysaccharidoses: AR (except Hunter syndrome → X-linked recessive), deficiency of lysosomal enzymes responsible for breakdown of mucopolysaccharides; Skin findings: firm, ivory-colored papules between angles of scapula (Hunter), all patients have thick skin, increased dermatan and heparan sulfate (Hunter), all patients have generalized hirsutism, coarse facies with thick nose and depressed nasal bridge, thick lips and tongue, short neck, broad hands, short fingers, mental retardation, short stature, corneal clouding and retinitis pigmentosa, cardiac failure and valvular disease, bronchopneumonia, hepatosplenomegaly, dysostosis multiplex, osteoporosis, joint laxity – Hurler and Scheie: α-L-iduronidase – Hunter: Iduronate sulfatase – Sanfilippo: Multiple enzymes can be deficient – Maroteaux-Lamy: Arylsulfatase B – Morquio: Either hexosamine 6-sulfatase or b-galactosidase • Multiple Carboxylase deficiency: Biotinidase deficiency or holocarboxylase synthetase deficiency, decreased free serum biotin, periorificial/generalized dermatitis, Candida infection, alopecia, hypotonia, seizures, vomiting, optic atrophy, hearing loss, metabolic acidosis with hyperammonemia, treat with biotin 10 mg/day • Phenylketonuria: AR, phenylalanine hydroxylase (or its cofactor tetrahydrobiopterin), increased phenylalanine inhibits tyrosine in melanogenesis and toxic to CNS, generalized hypopigmentation, eczema, sclerodermoid changes to skin, blonde hair, blue eyes, mental retardation, urine with “mousy” odor • Homocystinuria: AR, cystathione β-synthase, increased homocystine and methionine levels in blood/urine, malar flush, DVT’s and emboli, cardiovascular disease, livedo reticularis, leg ulcers, blonde hair, fair complexion, downward lens dislocation (ectopia lentis), glaucoma, marfanoid habitus, mental retardation, seizures, psychiatric disorders • Acrodermatitis Enteropathica: AR (intestinal zinc specific transporter SLC39A4), bottle- fed infants; after weaning, breast-fed older infants, defect in zinc-absorption, periorificial, scalp, and acral dermatitis, scaling, vesicles/bullae, erosions, alopecia, diarrhea, stomatitis, glossitis, irritability, photophobia, treat with lifelong zinc supplementation • Wilson disease: Hepatolenticular degeneration, AR (ATP 7B gene, ATPase copper- transporting beta polypeptide), Defect in biliary excretion of copper → accumulation of copper in liver, brain, cornea, pretibial hyperpigmentation, blue lunalae, hepatomegaly, cirrhosis, Kayser-Fleischer ring (yellow-brown copper deposition in Descemet’s membrane of cornea), ataxia, dysarthria, dementia66  2011/2012 Dermatology In-Review l Committed to Your Future
  19. 19. • Hemochromatosis: AR (HFE gene, hemojuvelin HJV gene, hepcidin antimicrobial peptide HAMP gene, transferring receptor 2 TFR2 gene), AD (ferroprotein SCL40A1 gene) increased intestinal iron absorption → iron overload, generalized metallic-grey hyperpigmentation, koilonychia, alopecia → scant pubic/axillary hair, cardiac failure, arrythmias, heart block, hepatomegaly with cirrhosis, diabetes (“bronze diabetes”), polyarthritis with chondrocalcinosis, screen with ferritin, susceptible to Vibrio vulnificus and Yersinia infections • Porphyrias (see Chapters 10 and 12) • Nieman-Pick disease: AR, sphingomyelinase (sphingomyelin phosphodiesterase I-SMPD-1) gene: – Type A: Onset in infancy: CNS, cherry red spot - leads to blindness – Type B: Onset in infancy, childhood: no CNS problems – Type C: Onset in childhood: psychomotor deterioration, hepatosplenomegally Table 3-2. Radiologic Findings in Genodermatoses and Other SyndromesFindings Associated DiseaseAccordion hand Multicentric reticulohistiocytosisAsymptomatic dural calcification Papillon-Lefevreand choroids attachmentsBifid ribs Nevoid Basal Cell Carcinoma syndromeBilateral bean-shaped calcification of Lipoid proteinosishippocampusBilateral posterior iliac horns, radial head Nail-patellasubluxation, hyperextensible joints, thickenedscapula, absent patella,bilateral 1st rib hypoplasiaBroad thumbs Rubinstein-TaybiCalcification of falx cerebri & basal ganglia Nevoid Basal Cell Carcinoma syndromeCalcification of ligament, intracranial calcification Pseudoxanthoma elasticum(dura, falx, pineal, choroids)Calcification of tubers in basal ganglia Tuberous sclerosisCerebellar, spinal, medullary hemangioblastomas Von-Hippel-LindauChondrodysplasia punctata Conradi-HunermannClinodactyly Down’s, Cornelia de Lange, Russell-SilverCongenital hip dislocation EDS 7Cystic defects in end of long bones and skull Infantile fibromatosisDouble-contoured railroad tram track Sturge-Webercalcification (meningeal angiomas)Dysostosis multiplex MucopolysaccharidosisEhrlenmeyer flask deformity GaucherEnchondromas, metacarpals with phleboliths, MaffuccichondrosarcomasHyperostosis of external auditory canal Proteus syndromeHypoplastic thumbs, radii, ulnae Rothmund-ThompsonIntracranial calcification Cockayne, TORCH infections, dyskeratosis congenitaLytic bone cysts of hands with honeycombed Sarcoidpattern Genodermatoses  67
  20. 20. Table 3-2. Radiologic Findings in Genodermatoses and Other Syndromes Findings Associated Disease Medulloblastoma Nevoid Basal Cell Carcinoma syndrome Melorheostosis (liner hyperostosis under Linear scleroderma affected skin) Occipital horns (exostoses) EDS 9, Menkes kinky hair disease Osteomas in maxilla, mandible Gardner’s Osteomyelitis-like Sweet’s syndrome Osteopathia striata (stripes on metaphases of Focal dermal hypoplasia (Goltz syndrome) long bones) Osteopoikilosis (round densities in long bones) Buschke-Ollendorf syndrome Phalangeal thickening with periosteal cysts Tuberous sclerosis Polyostotic fibrous dysplasia McCune Albright syndrome Resorption of distal phalanges Scleroderma Sclerotic bone lesions POEMS syndrome Sphenoid wing dysplasia Neurofibromatosis type 1 Supernumerary vertebrae with extra ribs Incontinentia pigmenti Thickening of calvarium Clouston Tufted phalanges Clouston Waferlike calcification of cartilage (spine, pubis, Alkaptonuria ear, nose) Wormian bodies in sagittal suture and Menkes kinky hair metaphyseal widening with spurs in long bones Table 3-3. Tooth Findings in Genodermatoses Tooth Finding Associated Disease Anodontia Hypomelanosis of Ito Anodontia/pegged teeth Incontinentia pigmenti Dental pits Tuberous sclerosis Enamel dysplasia Sjogren-Larsson, Herlitz JEB Natal teeth Pachyonychia congenita type II (Jackson- Sertole) Odontogenic cysts Nevoid Basal Cell Nevus syndrome, Gardner syndrome Odontoid hypoplasia Down’s & Hurler’s syndromes Odontomas and supernumerary teeth Gardner syndrome Peg shaped conical incisors/canines, molars Anhidrotic ectodermal dysplasia with hooked cusps Periodontitis Papillon-Lefevre, Haim-Munk, Ehlers-Danlos type 8 Resorption of alveolar ridge (floating teeth) Letterer-Siwe Retention of primary teeth Hyper IgE syndrome68  2011/2012 Dermatology In-Review l Committed to Your Future
  21. 21. MNEMONIC Blue Sclerae All DEMON Fly Past MNEMONIC Alkaptonuria Angioid Streaks Downs Ehlers Danlos APPLES Marfans Anemia, Sickle cell Osteogenesis Imperfecta Pseudoxanthoma elasticum Nevus of Ota Pagets disease of the bone Lead poisoning Fanconi’s Ehlers Danlos PXE Sclerosus tuberous Table 3-4. Eye Findings in Genodermatoses Eye Finding Associated Disease Angioid streaks (rupture of Bruch’s membrane) Pseudoxanthoma elasticum Ankyloblepharon CHANDS, Hay-Wells syndrome Atypical retinitis pigmentosa (glistening dot) Sjogren-Larsson Blue sclerae Osteogenesis imperfecta types 1, 2, and 3; Ehlers-Danlos syndrome Blue sclerae, retinal detachment, ruptured globe, Ehlers-Danlos syndrome type 6 keratoconus Blue to gray-blue eyes, prominent red reflex Tyrosinase negative albinism Blue to yellow-brown eyes Tyrosinase positive albinism Brushfield spots Down syndrome Cherry red spot Niemann-Pick, Tay-Sachs, generalized sialidosis, Sandhoff syndrome Choroid malformation Sturge-Weber syndrome Coloboma Focal dermal hypoplasia Comma-shaped corneal opacities X-linked ichthyosis Congenital hypertrophy of retinal pigment Gardner’s syndrome epithelium Corneal clouding, retinitis pigmentosa Mucopolysaccharidosis Corneal opacities, lipodermoid tumors Epidermal nevus syndrome Decreased corneal sensation to tear flow Riley-Day syndrome Dystopia canthorum with heterochromia irides Waardenburg syndrome Ectopia lentis (downward) Homocystinuria Ectopia lentis (upward) Marfan’s syndrome Eyelid papillomas Xeroderma pigmentosum Eyelid string of pearls Lipoid proteinosis Glaucoma Neurofibromatosis type 1, Sturge-Weber syndrome Juvenile posterior subcapsular lenticular opacity Neurofibromatosis type 2 Genodermatoses  69
  22. 22. Table 3-4. Eye Findings in Genodermatoses (cont.) Eye Finding Associated Disease Lester iris (hyperpigmentation of papillary Nail-patella syndrome margin of iris) Lisch nodules, optic gliomas Neurofibromatosis type 1 Optic atrophy Biotinidase deficiency Phakomas (astrocytic hamartomas of optic Tuberous sclerosis nerve) Pingeculae Gaucher syndrome Pseudoherpetic keratitis with blindness Richner-Hanhart syndrome Retinal hemangioblastomas Von-Hippel-Lindau syndrome Retinitis pigmentosa (salt & pepper) Refsum Salt and pepper retina Cockayne syndrome, Refsum syndrome70  2011/2012 Dermatology In-Review l Committed to Your Future
  23. 23. NOTES Genodermatoses  71
  24. 24. NOTES72  2011/2012 Dermatology In-Review l Committed to Your Future