boards’ fodder With contributions from Elise M. Herro, MD, Antoine Amado, MD, and Sharon E. Jacob, MD. (Updated July 2015*)

Gene Mechanism Disorder Inheritance Defect Clinical Manifestations Hypertrichosis Congenital Increased within the nevocellular

Smooth muscle Pigmented pebbly patch trunk, hypertrichosis, ↑hair size & hamartoma pseudo-Darier sign pigmentation

Elise M. Herro, MD, Nevoid hypertrichosis Usually solitary patch of w/o other abnormality; ↑# normal hair (HT) anywhere on body follicles is Health Sciences Clinical Instructor, Clinician-Educator HT with neurofibroma Periorbital cases track, in the Division of Dermatology, Department of HT Cubiti (hairy Sporadic Symmetric pattern, appears during infancy, resolves partly/ High percentage Medicine, UCLA. ) ? AD/AR completely by adolescence of hair follicles in *somatic anagen phase mosaicism

Hemihypertrophy ?Spontaneous Terminal hair limited to hypertrophic side ↑hair shaft Assoc. Beckwith-Wiedemann synd, , diameters & Congenital Klippel-Trenaunay-Weber synd & Proteus synd, Wilms tumor, terminal hair

(Circumscribed) hepatoblastomas, brain tumors, adrenocortic neop, internal follicles and GU malformations

Hairy cutaneous AD Patches of with hair follicles bilaterally on the palms and/ -sensitive malfor. palms & soles or soles. Vellus in women and children; males hair becomes N hair follicles terminal at

Spinal hypertrichosis Excess hair over the spine: discrete patch of sacral terminal Simultaneous hair [“faun-tail”] or midline vellus hair [“silky down”]. abn. skin and Antoine Amado, MD is Underlying spinal dysraphism [50% derm finding; 1/3 those --> a Contact hypertrichosis]: dermal or sinus, myelomeningocele, ectodermal origin Fellow at the Cleveland diastematomyelia, vertebral abn, subdural or extradural . Cervical spinal hypertrichosis ~ kyphoscoliosis. MRI Clinic, Ohio. evaluation.

Cervical hypertrichosis Anterior: AR Small patch of terminal hair superior to laryngeal prominence Posterior: AD, solitary (AD) or with peripheral neuropathy (AR) and hallux XLR valgus

Congenital HT AD, sporadic Cr8q22 hair (may be vellus) remains over the entire body lanuginosa after birth, sparing palms, soles & mucous membrane. Associated with dental abn.

Congenital Gen. HT XL X24-q27.1 Terminal hair on , trunk & limbs; sparing palms, soles & mucosa

Ambras Syndrome Cr8 Thicker, longer hair on face, , , as well as whole body, sparing glabrous regions; dysmorphism and Sharon E. Jacob, MD, dental anomalies

is an assistant Gingival fibromatosis AD Early childhood; hairiness on face, trunk, + professor of Clinical w HT progressive gingival . 50% mental retardation &/ Dermatology, director or seizures. ≠ Antiepileptics & cyclosporine of the Contact H Syndrome AR SLC29A3 (, hypertrichosis, hepatosplenomegaly, Dermatitis Clinic and Congenital hearing loss, heart anomalies, hypogonadism, low height

Medical Student (Generalized 1°) (short stature), hyperglycemia/diabetes mellitus, and hallux Education, Department valgus/flexion contractures) -- new form of histiocytosis. of Dermatology and Initially appear on the inner and shins but may be more widespread Cutaneous , University of Miami, Osteochondrosyplasia AR, Unknown Gen. HT, sparing glabrous skin & membranes. Also School of Medicine, W HT (Cantú AD macrosomia & cardiomegaly Syndrome) Miami, Florida. HT, pigmentary Gen. HT, sparing ant. , palms, soles & mucous memb; retinopathy & facial hyperpigmentation face & extrem; facial abn, regional abn lipoatrophy, pigmentary retinopathy. ~ SMH irectionsin D­Residency p. 1 • Spring 2007 boards’ fodder Hypertrichosis With contributions from Elise M. Herro, MD, Antoine Amado, MD, and Sharon E. Jacob, MD. (Updated July 2015*)

Gene Mechanism Disorder Inheritance Defect Clinical Manifestations Hypertrichosis

Brachamann-de Lange AD (most cases Cr5p 13.1 Thick & convergent eyebrows (synophrys) & ; low hairline; vellus synd (Cornelia de Lange sporadic) NIPBL HT trunk, post. , sacrum, elbows; marmorata; severe mental syndrome) ------retardation; upturned nostrils, depressed nasal bridge, low-set ears, small XL Cr & irregular teeth, micrognathia, high palate & bifid uvula; short & abn Xp11.22-p11.21 & feet SMC1L1

Teratogens Fetal hydantoin syndrome: during first 9 weeks gestation have 10% risk; HT, hypoplasia, cleft , midfacial hypoplasia, long upper lip, low birth weight. After 9 weeks LBW w/o other congenital abn. Fetal alcohol syndorme: during any point in . HT [inconstant]; prenatal growth deficiency, develop. delay, mental retardation, & facial abn [microcephaly, short upturned nose, short palpebral fissures, thin upper lip, & poorly developed philtrum]

Lipodystrophy AR BSCL2 Berardinelli-Seip synd: HT , face, neck & extrem. ↑age. Gen. androgen-sensitive? (encodes lipoatrophy, acanthosis nigricans, , phlebomegaly, , lamins) NIDDM, genital hypertrophy, mental retard, corneal opacities, cardiac, renal, & ovarian abn., hepatosplenomegaly Insulin receptor Donohue syndrome (leprechaunism), more severe: HT face & gene trunk, acanthosis nigricans; loose & redundant skin. Lipoatrophy, genital hypertrophy, abdominal distension, slow growth, prominent & , low- set ears, flattened nasal bridge. Hyperinsulinemia w/ insulin resistance.

Mucopolysaccharidoses AR except XLR in Hurler’s: α-L- Short stature w typical facies, skeletal deformities, hepatosplenomegaly & Animal std: Hunter’s iduronidase cardiac abn. ↑glycosaminoglycans Hunter’s: Lanugo HT back & extrem, bushy eyebrows, low frontal hairline, abundant & skin iduronate coarse scalp hair. Hurler syndrome (MPS-I), Hunter (MPS-II), and Sanfilippo sulfatase syndrome (MPS-III) - hair-shaft dysmorphism. All types with generalized .

Stiff-skin syndrome Stony-hard skin, ↓ joint mobility, & mild HT; complication: restricted lung capacity

Winchester syndrome Cr16q13 MMP2 Thickened & HT of skin, short stature with severe osteolysis carpal/tarsal bones, corneal opacifications

Porphyrias CEP: AR UrogenIII Congenital erythropoetic porphiria (CEP/Gunther disease) photosensitivity

Congenital ______synthase birth → vesicles & bulla, hyperpigmentation, scarring, & HT.

(Generalized 2°) PCT: AD/sporadic/ ______PCT may present w/ HT (60%) face ( areas) & upper torso [ acquired Urogen sympt]. HEP homozygous form of PCT - similar to CEP. decarboxylase HT later stages Erythropoietic protoporphyria; Hereditary coproporphyria & Variegate

Rubinstein-Taybi syndrome Sporadic/ AD Cr22q13, HT, bird-like facies, , pilomatricomas, broad /great , short 16p13.3 stature, mental retardation. [cAMP-bind ] CREBBP; EP300 (genetic heterogeneity)

Schinzel-Giedion syndrome HT face & limbs, depressed nasal bridge, high , hypoplastic midface, club feet, abn. , limbs & skull. Hypoplastic dermal ridges, seborreic , suscep. infection

Barber-Say syndrome AD, XL HT forehead, neck & back; atrophic skin, macrostomia, growth retardation & ectropion

Coffin-Siris syndrome AR Cr7q32-34? Lumbosacral and HT. Hypoplastic or absent fingernails & toenails (5th), mental & growth retard, sparse scalp hair, joint laxity; coarse face [microcephaly, prominent lips, low nasal bridge, wide nasal tip]

Hemimaxillofacial dysplasia Unilateral enlarged maxilla, hypoplastic teeth, ipsilateral HT [inconstant]

Craniofacial dysotosis PDA, hypoplasia labia majora, dental & eyes abn, ↑ terminal HT limbs, back & low hair line

Hypomelanosis of Ito Not inherited Mosaicism Hypopigmented macular patches (Blaschko lines), neurological symptoms & Xp11 HT (also scalp alopecia) translocation

MELAS Syndrome Several (Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) mitochondrial Pruritus, scaling neck, terminal HT legs tRNA genes

Becker nevus Sporadic, Irregular hypermelanotic patch torso, ↑hair at puberty. ↑males, solitary, ↑# androgen receptors ?paradominant acquired & unilateral. Pigmentation before HT. - hamartoma Becker nevus syndrome: Becker nevus, ipsilateral hypoplasia girdle, or ; scoliosis or vertebral abn. ≠SMH

Hypertrichosis w/ local Chemically induced dermatitis [iodine or psoralen], orthopedic casts & splints Reg. effect healing Fx; [vellous], friction [insect bites, sack bearers], thrombophlebitis, osteomyelitis, Freq. scratching; ↑ reg. vaccination sites blood flow Acquired

(Circumscribed) HT of the pinna AD Older men. In AIDS, babies with XYY synd, babies diabetic mothers, diabetics

Trichomegaly Isolated HT eyelashes & in areas of linear . HIV, SLE, Latanoprost

irectionsin www.aad.org/DIR Spring 2007 • p. 2 D­Residency boards’ fodder Hypertrichosis With contributions from Elise Herro, MD, Antoine Amado, MD, and Sharon Jacob, MD. (Updated July 2015*)

Gene Mechanism Disorder Inheritance Defect Clinical Manifestations Hypertrichosis

Cerebral disturbances Gen. HT. Post viral encephalitis, posttraumatic head injury children, traumatic Hypothalamic factors shock, transient diencephalic, pitituitary or hypothalamic disturbances.

Acrodynia Reaction to chronic mercury exposure. Gen. HT, erythema , toes & nose; & salivation, painful hands/feet.

Infection TB: transient HT children, face & limbs AIDS: HT eyelashes, eyebrows & ears

Malnutrition Gen. vellus HT (marasmus, celiac dz), bulimia 36% & 77%

Dermatomyositis Juvenile DM ↑hair growth face & limbs, ↑male children & Mexican ancestry. PM adult also gen. HT

Thyroid abnormalities : HT children >adult, resolves w/ replacement Tx. : Localized HT over plaques of pretibial myxedema

Lawrence-Seip syndrome Lipoatrophic diabetes ~Berardinelli-Seip synd. HT after viral infection

Acquired Acquired ↑hair growth [PCT 2° hexachlorobenzene exposure] (Generalized )

Acquired HT lanuginosa Assoc. malignancies lung, colon, lymphomas, Ewing’s arcoma, rectum, Tumor-secreted (Malignant down) pancreas, breast, ovary & uterus. Precede CA 1 to 2 years. New lanugo: substance ↑hair growth workup POEMS syndrome (Crow- (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) Fukase synd) A/w plasma cell dyscrasias. Gen. HT 78-85% (lower extrem), hyperpigmentation, skin thickening, digital clubbing, cutanous glomeruloid Pharmacologic * HT: after 2-3 m; ↑limbs, face & trunk, resolve after 1 year Phenytoin: unknown hypertrichosis discont 75%. * glaucoma Tx, regional hypertrichosis: Acetazolamide Latanoprost: mitogenic [children, back & legs] & latanoprost topical (prostagalndine F2 analogue) pathw eyelashes & 77 %. *Streptomycin : Diff. TB. *Cyclosporine: Diazoxide: ↑follicles HTafter transp. 24-94%. * Psoralen: HT light-exposed areas. anagen Diazoxide. ↑terminal hair growth after 4 m. Minoxidil: Vel to Ter Abbreviations: AGPAT2: 1-acylglycerol-3-phosphate O-acyltransferase 2 CREBBP: Transcriptional coactivator CREB-binding protein HET: Hepatoerythropoietic Porphyria HT: hypertrichosis INSR: Insulin receptor gene MMP2: Matrix metalloproteinase-2 NIPBL: Nipped-B-like PCT: SMC1L1: Structural maintenance of chromosomes 1-like 1 UROGEN III Synthase: Uroporphyrinogen III synthase UROGEN Decarboxylase: Uroporphyrinogen decarboxylase


1. Wendelin DS, Pope DN, Mallory SB. Hypertrichosis. J Am Acad Dermatol 2003;48:161-79. 2. OMIM, Online Mendelian Inheritance in Man Database. Available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM 3. Polizzi A, Pavone P, Ciancio E, La Rosa C, Sorge G, Ruggieri M. Hypertrichosis cubiti (hairy syndrome): a clue to a malformation syndrome. J Pediatr Endocrinol Metab 2005;18:1019-25. 4. Spitz JL. Genodermatoses: A Clinical Guide to Genetic Skin Disorders. New York: Lippincott, Williams & Wilkins, 2005. 5. Molho-Pessach V, et al. H syndrome: The first 79 patients. J Am Acad Dermatol 2014;70(1):80-87. 6. Baumeister FA, et al. Ambras syndrome: delineation of a unique hypertrichosis universalis congenita and association with a balanced pericentric inversion (8) (p11.2; q22). Clin Genet. 1993 Sep;44(3):121-8. Review.

*Reviewed and updated July 2015 by: Alina Goldenberg, MD, Emily deGolian, MD, and Sharon Jacob, MD.

irectionsin D­Residency p. 3 • Spring 2007