CHAPTER 68
Inherited Hair Disorders

Eli Sprecher

Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

Definition

Congenital and inherited disorders of hair growth and differentiation, also known as genotrichoses, can be subdivided into conditions associated with either excessive hair growth, known as hypertrichoses, or defective hair development termed alopecias [1]. Diseases in which hair is absent from the entire surface of the skin are known as atrichias whereas disorders featuring hair paucity are named hypotrichoses. Some of these disorders are associated with structural abnormalities of the hair shafts. Finally, inherited disorders of the hair follicle unit can present in isolation or as part of more complex clinical entities in which case they are known as syndromic genotrichoses. In the following sections, the clinical and pathogenetic features of representative genotrichoses are provided. A list of all major disorders associated with hypertrichoses and alopecias is provided in Tables 68.1, 68.2 and 68.3.

Table 68.1 Hypertrichoses

Disease name	MIM	Inheritance	Gene or genetic defect	Cutaneous features	Extracutaneous features
A Hypertrichosis as main disease feature
Hypertrichosis universalis congenital, Ambras type	145701	AD	Complex rearrangements on chromosome 8/possible involvement of TRPS1	Excessive vellus hair growth involving entire body surface	Facial dysmorphism Skeletal abnormalities
Hypertrichosis universalis	145700	AD	Unknown	Excessive lanugo-type hair growth Double eyebrows	–
Generalized hypertrichosis terminalis	135400	AD	CNV variations on chromosome 17/possible involvement of SOX9 or ABCA5 (one case)	Excessive terminal hair growth involving face and body	Facial dysmorphism Gingival hyperplasia
Congenital generalized hypertrichosis	307150	RXL	Insertions on chromosome Xq27.1/possible involvement of FGF13	Congenital generalized hypertrichosis in males;patchy hypertrichosis in females	Scoliosis Dental/palate anomalies Deafness
Cantu syndrome	239850	AD	ABCC9	Hypertrichosis	Macrosomia Facial dysmorphism Gingival hyperplasia Bone abnormalities Cardiac defects Mild mental retardation
Histiocytosis and lymphadenopathy syndrome (H syndrome)	602782	AR	SLC29A3	Hyperpigmentation, localized hypertrichosis	Hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature, hyperglycaemia
Trichomegaly	190330	AR	FGF5	Long eyelashes. Hypertrichosis of eyebrows, cheeks and forehead.	–
B Hypertrichosis as minor disease feature
Hurler syndrome	607014	AR	IDUA	Hypertrichosis since early infancy or childhood Prominent over the eyebrows Dermal melanocytosis	Short stature, coarse face, gingival hyperplasia, abnormal dentition, macroglossia, eye problems, cardiac, gastroenterological, skeletal defects and neurological defects
Cornelia de Lange	122470 300590 610759 614701 300882	AD RXL AD AD RXL	NIPBL SMC1A SMC3 RAD21 HDAC8	Low posterior hairline Hypertrichosis Exuberant eyebrow growth Curly eyelashes Cutis marmorata Single transverse palmar crease	Short stature, hearing loss, microcephaly, facial dysmorphism, cleft lip/palate, cardiac defects, kidney defects, mental retardation
Congenital generalized lipodystrophy (Berardinelli–Seip syndrome)	608594 269700 612526 613327	AR	AGPAT2 BSCL2 CAV1 PTRF	Hypertrichosis Acanthosis nigricans	Decreased adipose tissue Diabetes Hypertriglyceridaemia Hepatic steatosis
Trisomy 18	–	–	–	Generalized hypertrichosis	See Chapter 76
Donohue syndrome (leprechaunism)	246200	AR	INSR	Hypertrichosis/hirsutism Acanthosis nigricans Dysplastic nails Keratoderma Loose and wrinkled skin due to loss of adipose tissue	Severe failure to thrive Elfin facies Abdominal protuberance Oversized penis/clitoris Polycystic ovaries Gingival hyperplasia Large hands and feet Premature breast and nipple enlargement
Coffin–Siris syndrome	135900	AR	ARID1B	Generalized hypertrichosis with scalp hypotrichosis Nail dysplasia Cutis marmorata	Short stature Psychomotor developmental delay Agenesis of the corpus callosum Coarse facial features Skeletal dysplasia Cardiac defects Kidney defects Gastrointestinal complications
Leigh syndrome	256000	AR	Mutations in genes encoding the various components of the mitochondrial respiratory chain complexes I–V	Generalized hypertrichosis	Progressive neurological deterioration, ophthalmoplegia, lactic acidosis
Zimmerman–Laband syndrome	135500	AD	?	Generalized hypertrichosis Gingival fibromatosis Nail dysplasia	Facial dysmorphism including bulbous soft nose, thick lips and thick floppy ears Skeletal dysplasia and joint hyperextensibility Hepatosplenomegaly Cardiovascular defects Mental retardation
Schinzel–Giedion midface retraction syndrome	269150	AD	SETBP1	Hypertrichosis Facial haemangioma Hypoplastic dermal ridges Clubbing	Failure to thrive Facial dysmorphism with proptosis due to shallow orbits, prominent forehead and macroglossia Genito-urinary abnormalities Skeletal dysplasia Neurological defects and mental retardation
Barber–Say syndrome	209885	AD	?	Hypertrichosis Lax and atrophic skin	Facial dysmorphism including prognathism, abnormal ears, bulbous nose, macrostomia and thin lips Hypoplastic nipples Abnormal external genitalia
Craniofacial dysmorphism, skeletal anomalies and mental retardation syndrome	614132	AR	TMCO1	Hypertrichosis Low hairline Gingival hyperplasia	Facial dysmorphism including wide nasal bridge with small nose, bushy eyebrows, flat face, low-set ears and macrocephaly Cleft lip/palate Skeletal dysplasia Neuropsychiatric manifestations
Lymphoedema–distichiasis syndrome	153400	AD	FOXC2	Growth of extra row of eyelashes	Lymphoedema

AD, autosomal dominant; AR, autosomal recessive; CNV, copy number variations; RXL, recessive X-linked.

Table 68.2 Atrichias

Disease name	MIM	Inheritance	Gene or genetic defect	Cutaneous features	Extracutaneous features
A Non-syndromic atrichias
Atrichia with papular lesions	209500	AR	HR	Atrichia Papular lesions	None
Alopecia universalis congenital	203655	AR	HR	Atrichia	None
Ectodermal dysplasia 9, hair/nail type	614931	AR	HOXC13	Atrichia (some cases hypotrichosis) Koilonychia and micronychia	None
Lethal acantholytic epidermolysis bullosa	609638	AR	DSP	Generalized atrichia Generalized skin blistering Anonychia	None
B Syndromic atrichias
Vitamin D dependent rickets, type 2A	277440	AR	VDR	Atrichia or near-atrichia Papular lesions	Growth retardation, rickets, dental abnormalities, delayed motor development, seizures
Ichthyosis follicularis, atrichia, photophobia syndrome (allelic to keratosis follicularis spinulosa decalvans)	308205	RXL	MBTPS2	Atrichia or near-atrichia Dystrophic nails Erythroderma Ichthyosis Follicular hyperkeratosis Palmoplantar keratoderma	Photophobia, vascularizing keratitis, BRESHECK syndrome
Keratitis–ichthyosis–deafness syndrome	148210	AD	GJB2	Atrichia/hypotrichosis Ichthyosis Oral leukoplakia Palmoplnatar keratoderma Squamous cell carcinoma	Keratitis Deafness
Growth retardation, alopecia, pseudoanodontia, optic atrophy (GAPO) syndrome	230740	AR	ANTXR1	Scalp hair permanently lost in childhood	Facial dysmorphism with protruding ears and prominent lips Failure of tooth eruption Optic atrophy
T-cell immunodeficiency, alopecia and nail dystrophy syndrome	601705	AR	FOXN1	Atrichia Dysplastic nails	Severe T-cell immunodeficiency
Frontonasal dysplasia type 2	613451	AR	ALX4	Atrichia	Frontonasal dysplasia (large skull defect, coronal craniosynostosis, hypertelorism, severely depressed nasal bridge and ridge, bifid nasal tip) Cryptorchidism Agenesis of the corpus callosum and mental retardation
AEC syndrome EEC syndrome Rapp-Hodgkin syndrome ADULT syndrome	106260 604292 129400 103285	AD AD AD AD	TP63	Sparse, coarse, wiry hair Scalp erosions and red peeling skin Palmoplantar keratoderma Dystrophic nails	Hearing loss Ankyloblepharon, lacrimal duct atresia, blepharoconjunctivitis Cleft lip/palate Abnormal dentition Syndactyly Cardiac defects Kidney defects Breast and mammary gland hypoplasia

AD, autosomal dominant; ADULT, acrodermatoungual-lacrimal-tooth; AEC, ankyloblepharon-ectodermal defects–cleft lip/palate; AR, autosomal recessive; BRESHECK, brain anomalies, retardation, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear/eye anomalies, cleft palate/cryptorchidism, and kidney dysplasia/hypoplasia; EEC, ectrodactyly, ectodermal dysplasia and cleft lip/palate; GAPO, growth retardation, alopecia, pseudoanodontia and optic atrophy; HR, hairless.

Table 68.3 Hypotrichoses

Disease name	MIM	Inheritance	Gene or genetic defect	Cutaneous features	Extracutaneous features
A Non-syndromic hypotrichoses
Generalized hereditary hypotrichosis simplex (hypotrichosis type 1)	605389	AD	APCDD1 RPL21	Generalized hypotrichosis, progressing from childhood with sparing of eyebrows, eyelashes and facial hair	None
Hypotrichosis simplex of the scalp (hypotrichosis type 2)	146520	AD	CDSN	Scalp hypotrichosis, progressing from childhood	None
Hypotrichosis type 3	613981	AD	KRT74 KRT71	Scalp hypotrichosis Woolly hair	None
Marie Unna hereditary hypotrichosis (hypotrichosis type 4)	146550	AD	U2HR	Sparse to normal hair at birth;coarse, wiry, twisted hair in early childhood progressing to generalized hypotrichosis	None
Marie Unna hereditary hypotrichosis (hypotrichosis type 5)	612841	AD	EPS8L3		None
Localized, AR hypotrichosis, type 1 (hypotrichosis type 6)	607903	AR	DSG4	Generalized hypotrichosis with sparing of secondary sexual hairs Monilethrix and other structural hair shaft abnormalities Follicular hyperkeratosis	None
Localized, AR hypotrichosis, type 2 (hypotrichosis type 7)	604379	AR	LIPH	Sparse scalp, eyebrows, eyelashes, up to generalized hypotrichosis; woolly hair in some patients (as well as other hair shaft abnormalities)	None
Localized, AR hypotrichosis, type 3 (hypotrichosis type 8)	278150	AR	LPAR6	Sparse and short scalp, eyebrows, eyelashes, up to generalized hypotrichosis; woolly hair in some patients (as well as other hair shaft abnormalities); fair hair in some patients; nail pitting or longitudinal ridging in some patients	None
Hypotrichosis type 9	614237	AR	Mapped to 10q11.23-q22.3	Hypotrichosis involving scalp, arms, and legs. Eyebrows and eyelashes are spared	None
Hypotrichosis type 10	614238	AR	Mapped to 7p22.3-p21.3	Generalized hypotrichosis Scalp papules	None
Hypotrichosis type 11	615059	AD	SNRPE	Generalized hypotrichosis with sparing of pubic hair	None
Keratoderma and woolly hair	–	AR	KANK2	Generalized hypotrichosis Woolly hair Striate palmoplantar keratoderma Leukonychia Pseudoainhum	None
Monilethrix	158000	AD	KRT81 KRT83 KRT86	Hypotrichosis (regional to generalized) due to hair fragility, starting during early childhood and typically improving over time;occipital area most severely involved Follicular hyperkeratosis Nail dystrophy	None
Hypotrichosis and recurrent skin vesicles	613102	AR	DSC3	Generalized hypotrichosis Skin vesicles (?)	None
Skin fragility–woolly hair syndrome	607655	AR	DSP	Hypotrichosis Woolly hair Palmoplantar keratoderma Skin fragility and blistering Nail dystrophy	None
Ectodermal dysplasia with skin fragility	604536	AR	PKP1	Severe hypotrichosis Skin fragility Dystrophic nails Palmoplnatar erosive keratoderma	None
Ectodermal dysplasia type 4, hair/nail type	602032	AR	KRT85	Localized to generalized hypotrichosis (with pili torti) Dysplastic nails	None
AD generalized follicular hamartoma syndrome	605827	AD	?	Hypotrichosis Milia Palmar pits Hypohidrosis Basaloid follicular hamartomata	None
Rombo syndrome	180730	AD	?	Absent or dystrophic eyelashes and eyebrows Bluish discoloration of lips and hands Facial milia and telangiectasis Follicular atrophoderma Basal cell carcinomas	None
B Syndromic hypotrichoses
Naxos disease	601214	AR	JUP	Hypotrichosis Woolly hair Palmoplantar keratoderma	Arrhythmogenic right ventricular dysplasia Dilated cardiomegaly
Dilated cardiomyopathy with woolly hair and keratoderma	605676	AR	DSP	Hypotrichosis Woolly hair Palmoplantar keratoderma	Dilated left ventricular cardiomyopathy
AR ichthyosis with hypotrichosis	610765	AR	ST14	Generalized hypotrichosis with curly hair and long eyelashes Multiple hair shaft abnormalities Ichthyosis	Photophobia, corneal opacities, blepharitis Abnormal dentition
Netherton syndrome	256500	AR	SPINK5	Hypotrichosis with abnormal hair shaft structure (trichorrhexis invaginata)Congenital erythroderma Ichthyosis linearis circumflexa	Growth retardation Perinatal hypernatraemia Atopic diathesis Multiple food allergies Recurrent infections Gastroenteropathy High IgE levels
Neonatal ichthyosis-sclerosing cholangitis (NISCH) syndrome	607626	AR	CLDN1	Hypotrichosis with loss of lateral eyebrows Sparse eyelashes Ichthyosis Jaundice	Sclerosing cholangitis Hepatomegaly Hypodontia
Severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome	615508	AR	DSG1	Hypotrichosis Congenital erythroderma with acantholysis Palmoplantar keratoderma	Growth retardation Perinatal hypernatraemia Recurrent infections Oesophagitis Cardiac defects High IgE levels
Bazex syndrome	301845	XLD	Mapped to Xq25-27.1	Hypotrichosis with pili torti and trichorrhexis nodosa Facial hyperpigmentation and milia (which disappear in adulthood) Follicular atrophoderma Comedones Keratosis pilaris Localized hypohidrosis Basal cell carcinomas in second decade of life	Pinched long nose Joint hypermobility
Clouston syndrome	–	AD	GJB6	Hypotrichosis with wiry, brittle and pale hair Palmoplantar keratoderma Dysplastic nails	Short stature Ophthalmological manifestations including cataracts, conjunctivitis, strabismus, photophobia
Dermatopathia pigmentosa reticularis	125595	AD	KRT14	Alopecia Reticulate hyperpigmentation Hypo-/hyperhidrosis Absent fingerprints Palmoplantar keratoderma Dystrophic nails	Abnormal dentition
Hypotrichosis with juvenile macular dystrophy	601553	AR	CDH3	Generalized hypotrichosis with pili torti Light-coloured hair	Progressive retinal macular degeneration
Ectodermal dysplasia, ectrodactyly, and macular dystrophy	225280	AR	CDH3	Generalized hypotrichosis Light-coloured hair	Progressive retinal macular degeneration Abnormal dentition Ectrodactyly, syndactyly
Hypohidrotic ectodermal dysplasia types 1, 10A, 10B, 11A, 11B	305100 129490 224900 614940	XLR AD AR	EDA EDAR EDARADD	Generalized hypotrichosis Hypohidrosis Dysplastic nails Dry skin	Facial dysmorphism including pigmentation under the eyes, everted nose, prominent lips Conical teeth and hypodontia Heat stroke Hypoplastic mammary glands Hoarse voice
Ectodermal dysplasia-syndactyly syndrome 1	613573	AR	PVRL4	Generalized hypotrichosis with pili torti Dysplastic nails Palmoplantar keratoderma	Syndactyly Abnormal dentition
Ectodermal dysplasia–syndactyly syndrome 2	613576	AR	?	Generalized hypotrichosis Dysplastic nails Palmoplantar keratoderma Hyperhidrosis	Syndactyly Facial dysmorphism Abnormal dentition Cardiomegaly
Cleft lip/palate–ectodermal dysplasia syndrome	225060	AR	PVRL1	Hypotrichosis Palmoplantar keratoderma Dystrophic nails	Facial dysmorphism Cleft lip/palate Hypodontia Syndactyly
Oculodentodigital dysplasia	164200	AD	GJA1	Hypotrichosis Dry hair Palmoplantar keratoderma	Microphthalmia, cataracts, strabismus Abnormal dentition Cleft lip/palate Multiple skeletal abnormalities Hearing loss Lymphoedema Neurological defects
Hallerman–Streiff syndrome	234100	?	(GJA1 ?)	Hypotrichosis Light hair Skin atrophy and telangiectases	Short stature Multiple skeletal abnormalities Facial dysmorphism with small pointed nose, thin lips, microstomia, frontal bossing, micrognathia Microphthalmia, cataracts, strabismus, coloboma Abnormal dentition Tracheomalacia Pulmonary hypertension and infections Neurological defects
Odonto-onychodermal dysplasia	257980	AR	WNT10A	Hypotrichosis Dry and thin hair Dystrophic nails Palmoplantar keratoderma Hyperhidrosis Decreased number of tongue papillae	Hypodontia
Schopf–Schulz–Passarge syndrome	224750	AR	WNT10A	Hypotrichosis Dry and thin hair Dystrophic nails Palmoplantar keratoderma Hyperhidrosis Decreased number of tongue papillae	Hypodontia Bird-like facies Eyelid hydrocystomata Non-melanoma skin cancer
Hypotrichosis–lymphoedema–telangiectasia syndrome	607823	AD (?)AR	SOX18	Progressive hair loss since childhood involving scalp, eyebrows and eyelashes	Telangiectases (acral) Leg lymphoedema, congenital eyelid oedema, hydrocele, scrotal oedema
Tricho-rhino-phalangeal syndrome types I, II, III	190350 150230 190351	AD	TRPS1	Hypotrichosis Dysplastic nails	Growth retardation Skeletal dysplasia including various developmental abnormalities of hand and feet Late-onset osteopenia and osteoarthritis Facial dysmorphism including large ears and pear-shaped nose Abnormal dentition Hypotonia
Chondrodysplasia punctate 2	302960	XLD	EBP	Patchy alopecia Coarse sparse hair Ichthyosis Follicular atrophoderma along Blaschko lines	Short stature Frontal bossing Hearing loss Cataracts, microphtalmia Skeletal dysplasia with epiphyseal stippling Impaired mental function
Oro-facio-digital syndrome	311200	XLD	OFD1	Alopecia Sparse, coarse hair Facial milia	Short stature Microcephaly, frontal bossing, hypoplastic alar cartilage Hyperplastic oral frenulum, bifid/lobulated tongue, tongue hamartoma Cleft lip/palate Lip anomalies Abnormal dentition Liver, pancreas, ovarian, kidney cysts Clino-/syn-/brachy-/polydactyly Neuropsychiatric complications
Cranioectodermal dysplasia type 1	218330	AR	IFT122	Fine sparse hair Thin short nails	Abnormal dentition Facial dysmorphism
Cranioectodermal dysplasia type 2	613610	AR	WDR35		Craniosynostosis Brachydactyly, short limbs
Cranioectodermal dysplasia type 3	614099	AR	IFT43		Bicuspid aortic valve Liver disease
Cranioectodermal dysplasia type 4	614378	AR	WDR19		Renal failure Osteoporosis
Cartilage–hair hypoplasia	250250	AR	RMRP	Generalized hypotrichosis with fair sparse and fine hair	Skeletal dysplasia and short stature Malabsorption and Hirschprung disease Haematological anomalies Cellular immunodeficiency Increased risk of lymphoma and skin cancer
Noonan syndrome-like disorder with loose anagen hair	607721	AD	SHOC2	Sparse light-coloured hair Hyperpigmentation Wrinkled skin	Developmental delay Macrocephaly Cardiac defects Hypotonia and mental retardation Brain abnormalities
Nicolaides–Baraitser syndrome	601358	?	?	Hypotrichosis Low anterior hairline Wrinkled or eczematous skin	Short stature Skeletal dysplasia Facial dysmorphism Neuropsychiatric manifestations
Short stature, onychodysplasia, facial dysmorphism and hypotrichosis (SOFT) syndrome	614813	AR	POC1A	Generalized hypotrichosis Hypoplastic nails	Short long bones and other skeletal abnormalities resulting in short stature Macrocephaly Facial dysmorphism Oligospermia High-pitched voice
Macrocephaly, alopecia, cutis laxa, scoliosis (MACS) syndrome	613075	AR	RIN2	Alopecia Receding anterior hairline Cutis laxa	Short stature Coarse facies Abnormal dentition Scoliosis Joint hypermobility
Costello syndrome	218040	AD	HRAS	Curly sparse hair Dystrophic nails Cutis laxa Periorifical papillomas Acanthosis nigricans	Short stature Facial dysmorphism with full cheeks, macrocephaly, thick lips and macroglossia Cardiac defects Lung defects Pyloric stenosis Kidney defects Delayed psychomotor development and neurological defects Malignancies
Cardiofaciocutaneous syndrome	115150 615278 615279 615280	AD	BRAF KRAS MAP2K1 MAP2K2	Sparse, curly hair Absence of eyebrows and eyelashes Ichthyosis Haemangiomata Keratosis pilaris Lentigines Abnormal palmoplantar creases	Short stature Facial dysmorphism Eye defects Cardiac defects Osteopenia Neurological defects, including seizures and hypotonia Mental retardation
Yunis–Yaron syndrome	216340	AR	FIG4	Hypotrichosis involving scalp, eyebrows and eyelashes Palmar crease Hypoplastic nails	Growth retardation Facial dysmorphism including dysplastic ears and protruding eyes Abnormal dentition Heart defects Pyloric stenosis Micropenis and hypospadias Severe neurological defects
Alopecia–neurological defects–endocrinopathy (ANE) syndrome	612079	AR	RBM28	Variable degress of alopecia Flexural hyperpigmentation	Growth retardation Hypogonadism Addison disease Abnormal dentition
Woodhouse–Sakhati syndrome	241080	AR	DCAF17	Scalp and eyebrows alopecia	Deafness Hypogonadism Diabetes Extrapyramidal abnormalities, mental retardation and other neurological defects
Bjornstad syndrome	262000	AR	BCS1L	Hypotrichosis Coarse dry and fragile hair with pili torti	Nerve deafness Hypogonadism
Argininosuccinic aciduria	207900	AR	ASL	Dry, sparse brittle hair with trichorrhexis nodosa	Failure to thrive Hepatic fibrosis and hepatomegaly Encephalopathy Poor feeding, vomiting Neurological defects Mental retardation
Biotinidase deficiency	253260	AR	BTD	Alopecia Dermatitis Skin infections	Hepatosplenomegaly Vomiting, diarrhoea Hearing loss Vision loss Breathing problems Neurological defects
Neonatal inflammatory skin and bowel disease	614328	AR	ADAM17	Short and broken hair, disorganized eyebrows and eyelashes Perorificial erythema Pustular rash Dysplastic nails and paronychia	Chronic bloody diarrhoea, malabsorption Left heart ventricular dilatation High IgE
Trichohepatoenteric syndrome	222470614602	AR	TTC37 SKIV2L	Hypotrichosis with trichorrhexis nodosa and woolly hair	Failure to thrive Prominent cheeks and forehead Congenital heart defects Cholestatic jaundice, hepatomegaly, cirrhosis Severe secretory diarrhoea Mental retardation
Menkes disease	309400	XLR	ATP7A	Steely kinky sparse hair which can show pili torti, monilethrix and trichorrhexis nodosa Cutis laxa Hypopigmentation	Short stature Microcephaly Joint laxity Osteoporosis Neurodegenerative manifestations Variable vascular pathologies Chronic diarrhoea Urogenital anomalies Skeletal dysplasia (including occipital horns)
Trichothiodystrophy, photosensitive type	601675	AR	ERCC2 ERCC3 GTF2H5	Hypotrichosis resulting from brittle sulphur-deficient hair Ichthyosis Photosensitivity Brittle nails Lack of adipose tissue	Short stature Progeroid facies Microcephaly Various ocular manifestations including cataracts and microcornea Joint contractures Hypogammaglobulinaemia Recurrent infections Hypogonadism Asthma Mental retardation
Trichothiodystrophy, non-photosensitive type	234050	AR	MPLKIP	Hypotrichosis resulting from brittle sulphur-deficient hair	Short stature Mental retardation Decreased fertility
Rothmund–Thompson syndrome	268400	AR	RECQL4	Hypotrichosis involving scalp, face, eyebrows and eyelashes. Poikiloderma mainly evident in sun-exposed areas Photosensitivity Hyperkeratotic lesions over soles and knees Nail dystrophy Non-melanoma skin cancers	Short stature Skeletal dysplasia Hypogonadism Cataracts Abnormal dentition Risk of osteogenic sarcoma
Hutchinson–Gilford progeria syndrome	176670	AD	LMNA	Alopecia Absence of subcutaneous fat Wrinkled, atrophic and pigmented skin Scleroderma	Growth retardation Osteoporosis Premature ageing Premature cardiovascular disease Insulin resistance
Werner syndrome	277700	–	RECQL2	Premature balding Poikiloderma Scleroderma-like changes Loss of adipose tissue Hyperpigmentation Calcinosis cutis Ulcers	Short stature Prematurely aged facies Cataracts Retinal degeneration Osteoporosis and avascular necrosis Premature cardiovascular disease Diabetes Hypogonadism Malignancies

AD, autosomal dominant; AR, autosomal recessive; XLD, X-linked dominant.

Introduction and general description

The past 10 years have witnessed dramatic developments in the field of hair research and the number of inherited hair disorders, whose molecular basis has been discovered, has grown exponentially [2]. Two major reasons underlie this recent trend. First, the hair follicle is regarded today as a unique model for the study of complex developmental and regulatory interactions between epithelial and mesenchymal tissues [3–6]. Second, hair disorders are known to be the source of considerable morbidity. Absence (alopecia) or excess (hirsutism) of hair are obviously compatible with normal lifespan; yet individuals affected with these conditions often experience aberrant hair growth as a significantly detrimental event, affecting many aspects of their personal and social life [7–11].

Because most of these disorders are exceedingly rare, epidemiological data are mostly non-existent.

HYPERTRICHOSES

GENERALIZED HYPERTRICHOSES

This group of very rare disorders manifests generally at birth with generalized hypertrichosis (Figure 68.1). The various forms of generalized hypertrichosis are recognized on the basis of the presence of specific extracutaneous manifestations. Unfortunately, because the molecular basis of many of these diseases is still elusive, it is often not clear whether they are distinct entities or represent different clinical manifestations of common underlying genetic defects (see Table 68.1).

Image described by caption. — **Figure 68.1** Generalized hypertrichosis.

(Courtesy of Professor Peter Itin.)

Hypertrichosis universalis congenita, Ambras type

Children affected by this disorder present with generalized hypertrichosis which consists of large amounts of velus hair over the entire surface of the skin, with some predilection for the face, ears and shoulders. Hypertrichosis of the external ears is typical. Facial dysmorphism and skeletal abnormalities have also been reported [12]. The disorder has been found to be due to chromosomal rearrangements over 8q23.1 leading to down-regulation of the TRPS1 gene [13], also known to be involved in the pathogenesis of tricho-rhino-phalangeal syndrome, another complex hair disorder (see Chapter 67). Of interest, a similar defect was also found in a murine model of the disease, the ‘Koala’ mouse [13].

Generalized hypertrichosis terminalis

This disorder is inherited in an autosomal dominant fashion and is characterized by excess of terminal hair and a variable age of onset. Many patients demonstrate facial dysmorphism and often severe gingival hyperplasia [14]. In several cases, genomic changes on chromosome 17q24.2-q24.3 were found to segregate with the disease phenotype [15]. It has been suggested that these changes may impact on the function of SOX9, which is known to play a role in the regulation of hair growth. More recently, a mutation in the ABCA5 gene has been identified in a single case [15a].

Cantu syndrome

Cantu syndrome is inherited in an autosomal dominant fashion and features congenital hypertrichosis with long curly eyelashes, macrosomia, facial dysmorphism, gingival hyperplasia, skeletal anomalies, cardiac defects and occasionally mild mental retardation [16]. The disease was found to be caused by activating mutations in ABCC9 encoding the sulfonylurea receptor 2 [17, 18]. This is of interest as this molecule is part of an adenosine triphosphate (ATP)-sensitive potassium channel complex, targeted by minoxidil [19] which is used to treat male and female pattern baldness.

LOCALIZED HYPERTRICHOSES

Congenital localized hypertrichosis has been reported as an isolated finding around the elbows (hypertrichosis cubiti) and the neck (posterior and anterior cervical hypertrichosis) [20, 21]. Congenital localized hypertrichosis has been described in association with spinal (faun-tail naevus) or cranial dysraphism (hair collar sign) [22–25]. Localized hypertrichosis often accompanies pigmentation abnormalities as in congenital melanocytic naevi and Becker's naevus. Localized hypertrichosis is also a classical feature of congenital porphyrias (see Chapter 60).

The histiocytosis and lymphadenopathy syndrome (also known as H syndrome) is a complex disorder featuring a wide and variable constellation of cutaneous and systemic manifestations including skin hyperpigmentation, localized hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature and hyperglycaemia/diabetes [26, 27] (Figure 68.2). The disorder was found to be caused by mutations in SLC29A3 encoding the equilibrative nucleoside transporter (hENT3) [28, 29]. Although the exact mechanism underlying the disease pathogenesis remains elusive, it is of interest to note that the histiocytes present in dermal infiltrates in the skin of the patients resemble those seen in Rosai–Dorfman disease [30].

DIFFERENTIAL DIAGNOSIS

The most important diagnosis to exclude in any form of hypertrichosis is hirsutism, which results from excessive growth of hair in a male pattern distribution and warrants thorough investigations in search for an endocrinological, drug or paraneoplastic cause (see Chapter 147). The late onset of hypertrichosis should always raise the possibility of an underlying malignancy [31].

TREATMENT

Hair removal using depilation or laser techniques has been successfully employed [32]. Surgical debulking of the gums and total tooth extraction have been reported to result in improved oral function in generalized hypertrichosis terminalis [33].

ATRICHIAS

Atrichias refer to a group of very rare disorders characterized by total or near total absence of visible scalp and body hair.

Atrichia with papular lesions

Clinical features

Children affected with atrichia with papular lesions (APL) are usually born with normal hair which is shed during the first months of life, never to regrow thereafter. During the first to second decade of life, patients develop a diffuse papular rash, which has been noted to be particularly prominent over the cheeks and scalp but can involve almost any part of the body [34–36] (Figure 68.3). Although APL has been described with mental retardation, gastrointestinal polyposis and delay in bone age, these associations are considered spurious. On histology, APL is characterized by the conspicuous presence of dermal cysts, which reflect abortive development of different regions of the hair follicles (Figure 68.3c) [37].

Pathogenesis

Atrichia with papular lesions is caused by mutations in the HR gene, encoding a transcription co-repressor factor called hairless [34, 36, 38]. Hairless has been shown to function as a histone H3K9 demethylase [39]. Hairless may regulate hair cycling through its effect on the WNT signalling pathway [40], through its effect on polyamine synthesis [41] or through additional targets [42]. Regardless of its exact mechanism of action, down-regulation of hairless is associated with abnormal catagen and interferes with normal hair cycle leading to the abnormal development of hair follicles into epidermal cysts that manifest at the clinical level as papules [43]. Of note, overexpression of hairless due to heterozygous mutations in a short regulatory open reading frame located upstream the HR gene, also leads to abnormal hair development in patients affected with Marie Unna hereditary hypotrichosis [44], indicating that absence or increased expression of hairless are equally detrimental to hair growth and development. Marie Unna hereditary hypotrichosis (also known as hypotrichoses 4 and 5) is in contrast with APL inherited in an autosomal dominant fashion. Affected individuals display sparse to normal hair at birth, develop coarse, wiry and twisted hair in early childhood, followed by the development of generalized alopecia in adulthood [45] (Figure 68.4).

Differential diagnosis

Another inherited form of congenital atrichia, termed alopecia universalis congenita (MIM203655), is also caused by mutations in HR and is clinically identical to APL except for the absence of skin papules [36, 38]. Vitamin D resistant rickets (VDRR; MIM277440) is inherited in an autosomal recessive fashion. It results from end organ unresponsiveness to 1,25-dihydroxycholecalciferol. Affected patients display normal serum 25-hydroxyvitamin D, high serum 1,25-(OH)²-cholecalciferol and profound hypocalcaemia, leading to rickets and loss of teeth [46]. VDRR with hair loss (type IIa) must be differentiated from VDRR without hair loss (type IIb). VDRR type IIa patients are born with normal hair, which is shed during the first year of life and never significantly regrows thereafter (Figure 68.5). In contrast, bony changes can improve with age. Milia-like lesions similar to those observed in APL have also been described in VDRR [46]. VDRR is caused by mutations in the gene encoding the vitamin D₃ receptor (VDR). Most VDRR type IIa-causing mutations affect the N-terminal DNA-binding domain of the receptor, which harbours two zinc finger domains responsible for DNA binding and interactions with other proteins. In contrast, mutations in the vitamin D binding domain, situated at the C-terminus, do not cause alopecia [47]. Thus, vitamin D binding to the VDR is not necessary for normal hair development, which may explain why other forms of inherited rickets, with defective vitamin D binding, are not associated with alopecia [46, 47]. These studies emphasized the importance of VDR binding to DNA and its interactions with other transcription factors during hair cycling. The fact that hairless functions under physiological conditions in association with the VDR explains the clinical similarities of the two phenotypes [42].

Bazex syndrome should also be included in the differential diagnosis of alopecia associated with a papular rash. This X-linked recessive disorder [48] manifests with hypotrichosis, milia, atrophoderma of the dorsa of the hands and feet, face and extensor surfaces of the elbows and knees, and hypohidrosis of the face [49, 50]. Hair microscopy can reveal trichorrhexis nodosa and pili torti. Basal cell neoplasms often develop after the second decade of life [50]. Generalized basaloid follicular hamartoma syndrome is clinically similar although basal cell carcinomas do not develop [51].

Another disorder featuring total absence of hair is the Growth retardation, Alopecia, Pseudoanodontia, Optic atrophy (GAPO) syndrome [52] (Figure 68.6). This autosomal recessive complex disorder is caused by mutations in the ANTXR1 coding for the anthrax toxin receptor, which seems to play an important role in actin assembly [53].

Treatment

An accurate diagnosis is critical to prevent unnecessary treatment of APL with systemic steroids when misdiagnosed as alopecia universalis. Oral or intravenous calcium and active vitamin D metabolites may attenuate the bone disease of patients with vitamin D resistant rickets but do not affect hair status [54].

Ichthyosis follicularis with atrichia and photophobia

Clinical features

This disorder manifests with congenital total or partial atrichia, severe and diffuse follicular hyperkeratosis, different degrees of scaling and vascularizing keratitis leading to photophobia and blindness [55]. Ichthyosis follicularis with atrichia and photophobia (IFAP) is transmitted as a recessive X-linked trait. Disease severity is highly variable. IFAP has been reported in association with a wide range of extracutaneous manifestations including the BRESHECK constellation of signs (Brain anomalies (including mental retardation, corpus callosum dysgenesis, olivopontocerebellar atrophy), growth Retardation, Ectodermal dysplasia, Skeletal deformities (scoliosis, rib and pelvic anomalies), Hirschsprung disease, Ear (hearing loss)/Eye anomalies, Cleft palate/cryptorchidism and Kidney dysplasia/hypoplasia) [56]. IFAP has been shown to overlap clinically with keratosis follicularis spinulosa decalvans (KFSD), which features scarring alopecia, typically prominent over the occiput and involving the eyelashes and eyebrows, facial erythema, follicular hyperkeratosis, keratoderma, blepharitis, conjunctivitis and keratitis [57].

Pathogenesis

IFAP, BRESHECK syndrome and KFSD have been found to result from mutations in the membrane-bound transcription factor protease, site 2 (MBTPS2) gene [56, 58, 59] which encodes a protein involved in endoplasmic reticulum stress response as well as in cholesterol homeostasis. MBTPS2 regulates the translocation of regulatory molecules and transcription activating factors to the nucleus [60]. As the MBTPS2 gene is located on the X chromosome, female carriers are either phenotypically normal or show patchy alopetic linear lesions of atrophoderma or follicular ichthyosis along the lines of Blaschko, reflecting Lyonization [61].

Treatment

Treatment is mainly aimed at maintaining visual function [62] as well as preventing or correcting systemic complications of the syndrome. A variable response to acitretin has been reported in several patients with improvement in ichthyosiform changes and corneal erosions but no change in alopecia or photophobia [55, 63, 64].

HYPOTRICHOSES

Hypotrichoses represent a very heterogeneous and vast group of disorders characterized by a reduced density of hair follicles. Phenotypic variability is the rule and can be striking even among affected members of the same family, which often complicates the diagnosis. These disorders are traditionally classified based on their mode of inheritance and based on the presence of extracutaneous features [2]. Table 68.3 provides a full list of this group of diseases. The major forms of hypotrichoses are described in details in the following subsections.

NON-SYNDROMIC AUTOSOMAL DOMINANT HYPOTRICHOSES

Autosomal dominant hypotrichosis comprises two major disorders known as generalized hereditary hypotrichosis simplex (also known as hypotrichosis type 1) and hypotrichosis simplex of the scalp (also known as hypotrichosis type 2).

Individuals with generalized hereditary hypotrichosis simplex typically show normal hair at birth, with progressive hair loss and thinning starting during early childhood and involving to a variable extent all parts of the body except for eyelashes, eyebrows and beard [65]. Hair pigmentation can be affected as well but hair shaft structure is normal. The disorder has been found to result from a recurrent mutation in the APCDD1 gene [65], encoding a regulator of the WNT signalling pathway, which is known to play a critical role during hair follicle development [40, 66, 67].

Similar clinical findings are observed in hypotrichosis simplex of the scalp except for the fact they are limited to the scalp (Figure 68.7). The disease has been found to result in several families from mutations in the CDSN gene encoding corneodesmosin, a component of the corneodesmosomes [68]. Of note, genetic alterations in the same gene have been linked to the inflammatory subtype of peeling skin syndrome [69] and to psoriasis [70, 71]. Each type of mutation seems to exert a different deleterious effect: dominant mutations associated with hypotrichosis result in the perifollicular accumulation of a toxic amyloidosis-like material [72]; recessive mutations causing peeling skin syndrome lead to absence of expression of corneodesmosin [69], while a polymorphism in the CDSN gene associated with an increased risk for psoriasis seems to result in increased CDSN mRNA stability [70].

NON-SYNDROMIC AUTOSOMAL RECESSIVE HYPOTRICHOSES

Autosomal recessive localized hypotrichosis (alias hypotrichosis types 7 and 8) features varying degrees of hair paucity over most parts of the body, with occasionally decreased pigmentation [73] (Figure 68.8). The disorder overlaps with woolly hair [74] which refers to the growth of fine and tightly curled hair (unlike normal curly hair, woolly hair grows slowly to a shorter distance than normal hair and can be associated with several structural anomalies such as trichorrhexis nodosa) [75]. The hypotrichosis is progressive and can be limited to the scalp or involve the whole body surface including the eyebrows, eyelashes and facial hair [75]. Autosomal recessive localized hypotrichosis has been found to be caused by mutations in two genes: LIPH [76] and LPAR6 [77, 78]. LIPH encodes lipase H, which promotes the synthesis of lysophosphatidic acid, the natural ligand of a G protein coupled receptor encoded by LPAR6 which is expressed in both the Henle and the Huxley layers of the inner root sheath of the hair follicle [79].

SYNDROMIC AUTOSOMAL DOMINANT HYPOTRICHOSES

Tricho-rhino-phalangeal syndrome

For a detailed description of the syndrome, see Chapter 67. Three subtypes of tricho-rhino-phalangeal syndrome (TRPS) have been described. TRPS I patients feature sparse scalp hair as well as thin and malformed nails associated with a typical bulbous nose, a long philtrum, abnormal dentition and large ears. Patients display short metacarpals and metatarsals, brachydactyly with cone-shaped epiphyses at the (middle) phalanges, scoliosis, lordosis, hip malformations, abnormal patellae, short stature and suffer from osteopenia and osteoarthritis in adulthood [80]. The disorder was found to be caused by mutations in the TRPS1 gene which codes for a GATA-type zinc finger transcription factor regulating cartilage, kidneys and hair follicle formation [81]. TRPS III is associated with more severe skeletal manifestations than TRPS I, but is also due to mutations in TRPS1 [82].

TRPS II (Langer–Giedion syndrome) is characterized by the same features as TRPS I apart from the conspicuous presence of multiple exostoses and borderline intelligence in some patients [83]. Eyebrows are thickened medially and absent laterally (signe du sourcil) in TRPS I and III but normal in TRPS II. TRPS II is a contiguous gene syndrome caused by deletion mutations affecting both TRPS1 as well as EXT1 encoding exostosin 1 [84].

Connexin disorders

A number of dominant syndromes caused by defective function of connexins are associated with various forms of alopecia [85]. Keratitis–ichthyosis–deafness syndrome can manifest with alopecia and dense follicular papules over the scalp (Figure 68.9) and result from mutations in the GJB2 gene encoding connexin-26 [86]. Clouston syndrome is characterized by focal to total alopecia (Figure 68.10) associated with palmoplantar keratoderma and nail dystrophy and results from mutations in the GJB6 gene encoding connexin-30 [87]. Mutations in the GJA1 gene coding for connexin-43, cause oculodentodigital dysplasia (ODDD) syndrome which presents with fine and slow-growing sparse hair, palmoplantar keratoderma, facial dysmorphism, a wide range of eye anomalies, abnormal teeth, cleft lip or palate, hyperostosis and other skeletal problems and numerous neurological defects [88, 89].

SYNDROMIC AUTOSOMAL RECESSIVE HYPOTRICHOSES

Hypotrichosis with juvenile macular dystrophy

In hypotrichosis with juvenile macular dystrophy (HJMD), short, light and sparse hair in early childhood is associated with the later development of progressive degeneration of the retinal macula leading to blindness during the second to third decade of life [90] (Figure 68.11). The disorder was found to result from mutations in the CDH3 gene [91], encoding P-cadherin, a component of the adherens junction which was shown to be expressed in the retinal pigment epithelium [92] and to regulate hair growth and pigmentation [93, 94]. HJMD has been shown to be allelic to Ectodermal dysplasia, Ectrodactyly, and Macular dystrophy (EEM) syndrome, which is characterized by the same clinical features as HJMD in association with abnormal development of the teeth and limbs [95].

Autosomal recessive ichthyosis with hypotrichosis

Affected individuals are born with sparse and short hair and display generalized scaling (Figure 68.12) with ophthalmological manifestations including photophobia, corneal opacities and pinguecula [96]. Abnormal dentition has also been noticed. Structural defects are observed on hair microscopy [96]. The disorder was found to result from mutations in the ST14 gene [96] which encodes matriptase, a serine protease that functions as a membrane-bound cell surface protein or as a soluble extracellular protease following release of its ectodomain [97]. Matriptase has been shown to have a role in filaggrin processing and regulates epidermal proliferation and differentiation [97, 98]. Mutations in the same gene have been found to cause a disorder called ichthyosis, follicular atrophoderma, hypotrichosis and hypohidrosis, which in many aspects resembles autosomal recessive ichthyosis with hypotrichosis [99].

HAIR SHAFT STRUCTURAL ABNORMALITIES

These disorders are easily identified when suspected since examination of a hair sample under a light microscope is very often sufficient to pose a diagnosis [100]. Rarely, scanning electron microscopy is needed to establish the diagnosis. More recently, dermoscopy has been recognized as a useful and cost-efficient adjunct technique for the rapid diagnosis of hair shaft abnormalities [101].

As a group, hair shaft disorders largely overlap at the clinical and molecular level with hypotrichoses as hair shaft anomalies often (but not always) result in hypotrichosis [75]. As with other genotrichoses, the first step in the diagnosis of hair shaft structural disorders is to determine whether the hair disease is isolated or is part of a more complex disorder. The following sections review those hair shaft disorders inherited as monogenic traits (see Table 68.3). This group of hair disorders is reviewed in details in Chapter 89.

Monilethrix

Clinical features

Beaded hair is the hallmark of monilethrix. Scalp hair is fragile at constricted sites leading to apparent hypotrichosis [74, 100] (Figure 68.13). Gradual improvement with age is the rule with hair looking sometimes normal by puberty or early adulthood. Improvement has also been noted during pregnancy and summertime. Body hair as well as eyelashes and eyebrows are less frequently involved. Intrafamilial phenotypic variability is common [102]. Associated features include follicular papules in the nape area as well as keratosis pilaris and nail dystrophy [74, 100].

Pathogenesis

Monilethrix is usually transmitted in an autosomal dominant fashion and is due to mutations in genes encoding several hair keratins (KRT81, KRT83, KRT86) [103–105]. Recessive inheritance of mutations in the DSG4 gene encoding desmoglein 4 have been reported in localized autosomal recessive hypotrichosis which is characterized by monilethrix-like hairs, fragile scalp and body hairs that break easily, and are associated with hyperkeratotic follicular papules [106]. Monilethrix has been observed in syndromic forms of hypotrichosis such as Menkes disease [107].

Differential diagnosis

Monilethrix must be distinguished from pili torti in which hair shaft twisting can generate the false impression of beading [100]. Pseudomonilethrix refers to a poorly defined form of hypotrichosis due to fragile and easily breakable hair shafts. On electron microscopy, irregular nodes represent the edges of depressions within the shafts; in other cases, the beaded appearance of the hair shafts reflect irregular twisting without flattening of the hair shafts as in pili torti;finally, pseudomonilethrix can result from breaks within the shafts. Although autosomal inheritance of pseudomonilethrix has been described, many authorities considered it as an artefactual finding due to trauma to the hair shafts [108].

Treatment

Monilethrix has been successfully treated in uncontrolled studies with minoxidil [109, 110] and with oral retinoids [111–113].

Woolly hair

Clinical features

Woolly hair refers to generalized or localized occurrence of curly hair, which usually demonstrates slow growth and/or easy breakage, sometimes associated with hypopigmentation (Figure 68.14). The disorder can appear as an isolated dominant trait, and in this case can be allelic to autosomal recessive localized hypotrichosis [75] but has also been reported in the context of various cardiocutaneous disorders [114].

Patients with woolly hair may in some cases be affected with Noonan syndrome, especially in combination with ulerythema ophryogenes [115]. These patients tend to display a short stature, ptosis, borderline intelligence, a webbed neck and pulmonic stenosis.

Pathogenesis

Isolated autosomal recessive woolly hair has been shown to be allelic to autosomal recessive localized hypotrichosis (see Non-syndromic autosomal recessive hypotrichoses) caused by mutations in LPAR6 and LIPH [74, 78]. Autosomal dominant inheritance has also been described and linked to mutations in two hair keratin genes, KRT71 and KRT74 [116, 117].

Woolly hair has been described in the context of complex syndromes. Naxos disease and Carvajal syndrome manifest with woolly hair, hypotrichosis, diffuse palmoplantar keratoderma and cardiac disease, and are caused by recessive mutations in JUP and DSP, respectively, which encode two desmosomal proteins, plakoglobin and desmoplakin [118, 119].

Pili torti

Clinical features

Pili torti refer to hair showing 180 degree twists under the microscope [100] (Figure 68.15b). Patients with pili torti usually display breakable, short and sparse hair over the scalp (Figure 68.15a) and body. Isolated pili torti can be congenital but often becomes apparent in childhood only, with spontaneous improvement with time.

Pathogenesis

Pili torti can be inherited in an autosomal dominant fashion. The molecular cause for isolated pili torti remains elusive.

Differential diagnosis

Pili torti has been reported in the context of complex syndromes. Pili torti is typically found in Menkes disease (see Chapter 63), an X-linked metabolic disorder usually fatal in early life [120]. Menkes disease is characterized by paucity of hair which is fine, wiry, fragile and silver or white. Phenotypic variability is the rule. Hair microscopy usually reveals pili torti as well as monilethrix and trichorrhexis nodosa. The skin can show a mottled discoloration and is often lax. The upper lip has an exaggerated ‘cupid bow’ configuration. Of interest, asymptomatic female carriers can display foci of pili torti and uneven skin pigmentation along the Blaschko lines. Systemic manifestations include early onset of neurological signs including hypotonia, seizures, psychomotor retardation as well as periodic hypothermia. Tortuous vessels in the central nervous system can be seen on magnetic resonance angiogram (MRA) and are characterized on histology by fragmentation of the internal elastic lamina. Osteoporosis, skeletal dysplasia and dental and ocular anomalies are also observed [121]. The disorder is caused by mutations in the ATP7A gene [122, 123] which encodes a trans–Golgi membrane bound copper transporter. Accordingly, serum copper and ceruloplasmin levels are low. As a result, numerous copper-dependent enzyme activities are lost. Among the enzymes most prominently affected are tyrosinase, lysyl oxidase, monoamine oxidase, cytochrome oxidase and ascorbate oxidase which explains the pigment defects, lax skin, hair abnormalities, hypothermic episodes and skeletal changes typically found in patients, respectively. Occipital horn disease is allelic to Menkes disease and manifests with more severe skin changes, less prominent neurological manifestations and the presence of exostoses on the occiput (hence the name of the syndrome) and other bones [124].

Björnstad syndrome features a combination of pili torti and progressive sensorineural hearing loss [125]. The syndrome is caused by mutations in the BCS1L gene, which plays an important role in mitochondrial function [126]. Pili torti has also been seen in Netherton syndrome [127] (see below), hypotrichosis with juvenile macular dystrophy (see above) [91], Bazex syndrome [128], citrullinaemia [129] and autosomal recessive ichthyosis with hypotrichosis [96] (see above).

In addition to the inherited conditions mentioned above, pili torti has been described in association with systemic acquired diseases such as lupus erythematosus and other forms of cicatricial alopecia [130].

Trichorrhexis nodosa

Clinical features

Trichorrhexis nodosa is diagnosed under the microscope as irregularly spaced swellings along the hair shaft which appear to be the consequence of cuticle loss and exposure of cortical fibres. These areas are prone to fracture. Trichorrhexis nodosa has seldom been described as an isolated finding. It rather accompanies conditions manifesting with hair fragility, inherited and acquired alike [131–134].

Pathogenesis

No single gene has been associated with isolated trichorrhexis nodosa. Trichorrhexis nodosa has been described in the context of Netherton syndrome [127] (see Chapter 65), Menkes syndrome [107] (see Chapter 81) and trichothiodystrophy [135]. It is also typically found in argininosuccinic aciduria [133] also featuring failure to thrive, liver disease and neurological manifestations and caused by mutations in ASL encoding argininosuccinate lyase [136]. Trichorrhexis nodosa has also been observed in association with hypotrichosis as part of the trichohepatoenteric (THE) syndrome, which features intractable diarrhoea and is caused by mutations in two regulatory genes, TTC37 and SKIV2L [137, 138] (Figure 68.16).

Trichorrhexis invaginata

Clinical features

Hair is sparse, short, very thin and shows under the microscope the typical ball and socket (‘bamboo hair’) appearance in which the distal part of the hair shaft is compressed against the dilated and cupped proximal shaft. Trichorrhexis invaginata is considered as a hallmark of Netherton syndrome [139] (see Chapter 65) although it can be seen in other ichthyosiform disorders as well [140]. Trichorrhexis invaginata is often seen only after the first year of life. Examination of the eyebrows is recommended to demonstrate the hair shaft abnormality [141].

Pathogenesis

Netherton syndrome is caused by mutations in SPINK5, which encodes a serine protease inhibitor called LEKTI [142]. It is still unclear how LEKTI deficiency leads to hair shaft abnormality. LEKTI deficiency causes increased degradation of corneodesmosin and desmoglein 1 [143]; interestingly, corneodesmosin deficiency does not cause hair anomalies [69] and although defective desmoglein 1 has been linked to hypotrichosis in the context of severe dermatitis, multiple allergies and metabolic wasting (SAM syndrome) [144], hair microscopy did not reveal trichorrhexis invaginata, suggesting a specific role for LEKTI during hair shaft formation.

Trichothiodystrophy

Clinical features

Trichothiodystrophy refers to a strikingly heterogeneous group of disorders, all sharing in common brittle and fragile hair, which demonstrates on polarized hair microscopy a typical ‘tiger tail banding’ pattern [135, 145]. Various hair shaft defects such as pili torti and trichorrhexis nodosa have also been described. Hypotrichosis involves typically the scalp (Figure 68.17), eyebrows and eyelashes, but can also sometimes affect other areas. Nails demonstrate a wide range of dystrophic changes. Other clinical features include short stature, progeroid facies with loss of adipose tissue, microcephaly, various ocular manifestations including cataracts and microcornea, joint contractures and asthma [146]. The disorder has been reported in association with a number of clinical manifestations which demarcates distinct subsets including mental retardation and dental caries reported in Sabinas syndrome (MIM211390), infertility, developmental delay found in hair–brain syndrome (MIM234050), ichthyosis featured in Tay syndrome (MIM242170), photosensitivity seen in Photosensitivity Ichthyosis, Brittle hair, Intellectual impairment, Decreased fertility, and Short stature (PIBIDS syndrome) (MIM278720) and immune defects (MIM258360) (Table 68.4).

Table 68.4 Trichothiodystrophy variants

Type	Clinical features	Syndrome eponym
A	Hair ± nails	–
B	Hair ± nails + mental retardation	Sabinas
C	Hair ± nails + mental retardation, folliculitis, retarded bone age + caries	Pollitt
D	(Brittle) hair ± nails + infertility, developmental delay, short stature	BIDS
E	Ichthyosis + BIDS +mental retardation ± decreased gonadal function + cataracts + progeroid appearance + microcephaly ± ataxia ± basal ganglia calcifications	Tay/IBIDS
F	Photosensitivity and IBIDS	PIBIDS
G	Hair ± mental retardation + immune defects	Itin
H	Trichothiodystrophy with severe intrauterine growth retardation, developmental delay, recurrent infections, cataracts, hepatic angioendotheliomas	–

PIBIDS, photosensitivity ichthyosis, brittle hair, intellectual impairment, decreased fertility and short stature.

Pathogenesis

The hair defect results from a decrease in high sulphur protein contents in the hair shaft, which are a major component of the hair cuticle. The disorder has been found to be caused by mutations in a number of genes. Mutations in C7ORF11 (MPLKIP), encoding a protein whose function is poorly understood, cause non-photosensitive trichothiodystrophy [147]. Mutations in a number of genes encoding elements of the transcription factor complex, TTFIH [148], and involved in nucleotide excision repair cause photosensitive trichothiodystrophy including ERCC3, ERCC2 and GTF2H5 [149–151].

Pili triangulati et canaliculi

Clinical features

Isolated pili triangulati et canaliculi cause the uncombable hair syndrome [152]. This structural hair defect usually becomes apparent in early childhood as dry, coarse, frizzy and light hairs which stand straight up from the scalp and cannot be combed (Figure 68.18). Microscopic examination of pulled hair can be misleading as the triangular cross-sectional appearance (at the origin of the name of the hair shaft defect) and the typical longitudinal grooves, which confer to the hair its rigidity, are visible only on transverse section (or on scanning electron microscopy) [153].

Pathogenesis

The uncombable hair syndrome can occur sporadically or be transmitted as a recessive or dominant trait [154]. Its molecular cause remains elusive. In addition, it has been described in association with skeletal dysplasias and other complex syndromes [153].

Other inherited hair shaft defects

Pili annulati and pseudoannulati

Pili annulati reflect the presence of air-filled cavities within the hair shaft, which results in alternating dark and light bands under the microscope [155, 156]. The disorder has been shown to be inherited as an autosomal dominant trait [157]. Pili pseudoannulati results from reflection of the light over flattened or twisted surfaces of the hair shaft, and is considered as a normal variant.

Loose anagen syndrome

This disorder starts in early childhood and features hair which is easily pulled away from the scalp. The disease is thought to result from poor adhesion between the cuticle and the inner root sheath. Autosomal dominant inheritance has been suggested. Patients often seek medical advice because of slow-growing hair and ensuing patchy alopecia. Hair can be short, sparse, unruly and is often light coloured. Increased shedding is noted [158] (Figure 68.19). Improvement over time is the rule. A diagnosis of loose anagen hair syndrome is based on the presence of 70% or more loose anagen hairs on a standard trichogram [159].

Because symptoms are often mild, the disease may be underdiagnosed. However, because loose anagen hair can often be seen in normal children and adults, the disorder may also be overdiagnosed. A report suggesting that a keratin defect may underlie the disease [160] has not been subsequently replicated. Loose anagen syndrome has been reported in association with pili triangulati and canaliculi as well as with a Noonan-like phenotype [161].

Loose anagen syndrome should be distinguished from the short anagen syndrome [162] which is characterized by the inability to grow long hair because of an idiopathic short anagen phase. In contrast with loose anagen syndrome, it is not associated with hair unruliness, systemic diseases or skin disorders. Here too, some improvement is typical after puberty.

Kinky hair

Neonatal kinky hair is typical of the trichodento-osseous syndrome, caused by mutations in the DLX3 gene [163, 164]. The disorder is also associated with dysplastic nails, abnormal teeth and skeletal abnormalities including increased bone density and dolichocephaly due to premature fusion of the cranial sutures. Kinky hair is also found in Menkes disease, giant axonal neuropathy 1, Noonan syndrome and oculodentodigital dysplasia [165, 166].

Spiky hair

Spiky hair is a hallmark of the athyroidal hypothyroidism with spiky hair and cleft palate (Bamforth–Lazarus) syndrome, which also features choanal atresia and bifid epiglottis [167]. The disorder is transmitted in an autosomal recessive fashion and is caused by mutations in the FOXE1 gene [168], which is a downstream target of the Sonic hedgehog signalling pathway during hair follicle morphogenesis [169].

OVERALL APPROACH TO THE DIAGNOSIS OF GENOTRICHOSES

The most important step in the diagnosis of this group of disorders is to differentiate them from acquired diseases. Family history, neonatal or early onset, and associated clinical features can favour Mendelian inheritance although they cannot rule out an acquired form of hypertrichosis or alopecia. For example, the diagnosis of alopecia universalis congenita may require a skin biopsy as it is often difficult to distinguish this disorder from autoimmune alopecia areata.

Once it is clear that a patient is affected by an inherited form of hypertrichosis (see Table 68.1), atrichia (see Table 68.2) or hypotrichosis (see Table 68.3), it is important in order to make a diagnosis to establish: (i) the mode of inheritance;(ii) the absence (see Tables 68.1A, 68.2A and 68.3A) or presence (see Tables 68.1B, 68.2B and 68.3B) of extracutaneous manifestations; and (iii) the absence or presence of microscopic structural hair shafts abnormalities. Although evidence-based treatment options are mostly non-existent at this stage for most genotrichoses, a correct diagnosis may suggest the need for systemic work-up (see Tables 68.1B, 68.2B and 68.3B) and is essential to appropriately direct the subsequent molecular analysis, which in turn will set the stage for proper genetic counselling and prenatal diagnosis, when indicated.

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