Hypertrichosis and Hirsutism

Key features

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Hypertrichosis refers to excessive growth of hair anywhere on the body, whereas hirsutism represents excessive hair growth within androgen-dependent sites in girls and women
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Hypertrichosis may be generalized or localized, with etiologies ranging from genodermatoses to underlying hamartomas to repeated trauma
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Hirsutism is related to hormonal factors, in particular an increase in circulating androgen levels and/or enhanced sensitivity of hair follicles to androgens
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In women, the major sources of androgens are the adrenal glands and the ovaries; dysfunction of these organs must be considered when a patient presents with hirsutism
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Depending on its etiology, treatment of hirsutism includes antiandrogens, glucocorticoids, insulin-lowering agents, and/or contraceptives, combined with topical medications and physical measures (e.g. laser hair removal)

Hypertrichosis

Introduction

Hypertrichosis describes the growth of excessive hair anywhere on the body. The term is frequently confused with hirsutism, which should only be applied to women with excessive growth of terminal hairs in androgen-dependent sites (i.e. a “male pattern”) due to hyperandrogenemia or increased end-organ sensitivity to androgens . Hypertrichosis can be classified based on its distribution (generalized versus localized), the age of onset (congenital or programmed from birth versus acquired), and the type of hair (lanugo or vellus versus terminal).

Clinical Features

Generalized hypertrichosis

In generalized hypertrichosis, there is lanugo hair, excess vellus hair, or terminal hair over much of the cutaneous surface, including an acquired transformation of terminal hair into lanugo hair ( Fig. 70.1 ) . Lanugo is the non-pigmented, non-medullated, fine hair that covers the fetus and can grow up to several centimeters in length; it is normally shed in utero or during the first few weeks of life and replaced by vellus hair on the body and terminal hair on the scalp. Age of onset can vary from infancy to prepubertal to adulthood.

Congenital generalized hypertrichosis

A number of distinctive but rare genetic syndromes are associated with congenital generalized hypertrichosis ( Table 70.1 ). While the majority of these disorders have extracutaneous manifestations such as gingival hyperplasia or facial dysmorphism, some have primarily hypertrichosis, including universal hypertrichosis. However, this latter entity is sometimes viewed as constitutional, i.e. simply exaggerated normal hairiness that may be familial. Genetic abnormalities associated with congenital generalized hypertrichosis lead to dysfunction of several proteins, ranging from those known to be involved in hair follicle development to membrane transporters (see Table 70.1 ).

Table 70.1

Hereditary disorders characterized by congenital generalized hypertrichosis.

ABC, ATP-binding cassette transporter; AD, autosomal dominant; AR, autosomal recessive; ARID, AT-rich interaction domain; ATP6V1B2, ATPase H+ transporting V1 subunit B2; FGF, fibroblast growth factor; GD, growth delay; GU, genitourinary; HTC, hypertrichosis; ID, intellectual disability; KCN, potassium voltage-gated channel; SMARC, SWI/SNF related, matrix associated, actin dependent regulator of chromatin; TRPS1, transcriptional repressor GATA binding 1/tricho-rhino-phalangeal syndrome 1 protein; TWIST, twist family BHLH transcription factor 2; XLD, X-linked dominant.

HEREDITARY DISORDERS CHARACTERIZED BY CONGENITAL GENERALIZED HYPERTRICHOSIS
Disorder	Inheritance (locus; genetic basis)	Other key features
Increased hair is the major feature
Congenital hypertrichosis lanuginosa	AD	Fetal vellus hair is not replaced by normal hair and continues to grow Fine, downy, silvery-gray to blond lanugo hair that may be up to 10 cm in length Can create a “dog” or “monkey” facial appearance Involves entire body surface (except for the palms, soles, dorsal surface of distal phalanges, and prepuce) but hair may be shed over the first year of life Occasional dental anomalies; rarely other associations (e.g. ear defects, glaucoma, pyloric stenosis, photophobia, ID)
Universal hypertrichosis	AD	Thicker, longer hair most prominent on the back, proximal extremities and the frontal, temporal, and preauricular areas of the face * Increases during infancy and tends to persist Considered by some authors to be simply exaggerated normal hairiness that may be familial
Ambras syndrome (hypertrichosis universalis congenita, Ambras type; HTC1)	AD (8q22–q24 breakpoints; position effect down-regulates TRPS1 expression)	Fine, silky, lightly colored, long hair involving the entire body but primarily the face, ears, and shoulders Uniformly distributed on the face, including the nose Persists for life Minor facial dysmorphism, dental anomalies, supernumerary nipples
*Generalized hypertrichosis with extracutaneous features*
X-linked hypertrichosis (congenital generalized hypertrichosis; HTC2)	XLD (Xq27.1; palindrome-mediated interchromosomal insertion; position effect down-regulates FGF13 expression)	Curly, shorter, dark hair most prominent on the face and upper body Anteverted nostrils, prognathism; occasional dental anomalies, deafness Female carriers may have nevoid hypertrichosis following lines of Blaschko
Congenital generalized hypertrichosis with or without gingival hyperplasia (HCT3)	AD or AR (17q24.2–q24.3 microdeletion or microduplication [AD]; position effect down-regulates SOX9 expression; also ABCA5 mutations [AR])	Dark terminal hairs on the peripheral face, central back, and extremities In addition to gingival hyperplasia, coarse facies, ID, seizures
Cantú syndrome (hypertrichotic osteochondrodysplasia)	AD (12p21.1; ABCC9 mutation)	Coarse facies, osteochondrodysplasia, macrosomia at birth, cardiomegaly
Zimmermann–Laband syndrome 1 & 2	1: AD (1q32.2; KCNH1 mutation) 2: AD (8p21.3; ATP6V1B2 mutation)	Gingival hyperplasia, coarse facies, hypoplastic nails and distal phalanges, joint hyperextensibility, splenomegaly, ID
Coffin–Siris syndrome 1–5 **	1: AD (6q25.3; ARID1B mutation) 2: AD (1p36.11; ARID1A mutation) 3: AD (22q11.23; SMARCB1 mutation) 4: AD (19p13.2; SMARCA4 mutation) 5: AD (17q21.2; SMARCE1 mutation)	Sparse scalp hair, coarse facies, hypoplastic fifth fingernails and toenails, GD, ID
Schinzel–Giedion midface retraction syndrome	AD (18q12.3; SETBP1 mutation)	Midfacial vascular stain, midfacial retraction, hyperconvex nails, hypoplastic distal phalanges and dermatoglyphs, GU anomalies, GD, ID
Gorlin–Chaudry– Moss syndrome	AR vs XLD	Craniofacial dysostosis with midfacial hypoplasia, hypoplastic distal phalanges, ocular and dental anomalies, genital hypoplasia, GD
Adducted thumbs syndrome	AR	Arthrogryposis, craniosynostosis, myopathy
Barber–Say syndrome	AD (2q37.3; TWIST2 mutation)	Lax skin, ectropion, macrostomia, coarse facies, hypoplastic nipples, GD
Amaurosis congenita, cone–rod type, with congenital hypertrichosis ^‡	AR	Photophobia, visual impairment due to retinal dystrophy
CAHMR syndrome ^‡	AR	Ca taracts, h ypertrichosis, m ental r etardation

* This pattern of distribution is also observed in prepubertal hypertrichosis (see text).

** Protein products of mutated genes are subunits of the SWI/SNF complex.

‡ Single family reported to date.

The possibility of intrauterine exposure to medications (e.g. minoxidil) also needs to be considered in infants with congenital generalized hypertrichosis. The differential diagnosis also includes inherited disorders in which hypertrichosis can involve multiple sites and may appear early in life ( Table 70.2 ).

Table 70.2

Hereditary diseases and congenital syndromes associated with regional hypertrichosis.

Varying degrees of hypertrichosis (predominantly facial or generalized) have also been observed in children with chromosomal anomalies, e.g. partial trisomy of 1q, 3q, 4p or 17q. NIPBL , SMC1A , SMC3 , and RAD21 encode components of the cohesin complex. RAD21 and EP300 encode a histone acetyltransferase and a histone deacetylase, respectively. AD, autosomal dominant; AR, autosomal recessive; CEP, congenital erythropoietic porphyria; GD, growth delay; HEP, hepatoerythropoietic porphyria; ID, intellectual disability; PCT, porphyria cutanea tarda; VP, variegate porphyria; XLD, X-linked dominant.

HEREDITARY DISEASES AND CONGENITAL SYNDROMES ASSOCIATED WITH REGIONAL HYPERTRICHOSIS
Disorder	Sites of hypertrichosis	Other key features
Dysmorphic syndromes
Cornelia de Lange syndrome 1–5	Forehead, lateral face, shoulders, back Low anterior hairline, synophrys, trichomegaly	Distinctive facies, upper extremity anomalies, microcephaly, GD, ID, “growling cry” AD (1,3,4): NIPBL > SMC3 , RAD21 mutations XLD (2,5): SMC1A , HDAC8 mutations
Rubinstein–Taybi syndrome 1 & 2	Lateral face, shoulders, back Thick eyebrows, trichomegaly	Midfacial vascular stains, keloids, pilomatricomas Broad thumbs/halluces, beaked nose, high-arched palate, short stature, ID AD; CREBBP mutation (or deletion) > EP300 mutation
*Disorders with primary cutaneous features*
Porphyrias	Sun-exposed areas Favors lateral face in PCT, HEP, VP Face, trunk, extremities in CEP	See Ch. 49
Lipodystrophy syndromes (e.g. Berardinelli–Seip syndrome, leprechaunism)	Face, neck, extremities Low hairline	See Ch. 101
Erythrokeratodermia variabilis	Trunk and extremities	See Ch. 57
Dystrophic epidermolysis bullosa *	Areas of previous blistering	See Ch. 32
Ichthyosis bullosa of Siemens *	Extremities	See Ch. 57
*Metabolic disorders*
Mucopolysaccharidoses ^†	Trunk, extremities	See Ch. 48
Congenital hypothyroidism	Back, extremities	See Ch. 46
*Mitochondrial disorders*
Leigh syndrome due to SURF1 mutations	Forehead, extremities	Progressive neurodegeneration
MELAS syndrome	Lower extremities	M itochondrial e ncephalopathy, l actic a cidosis, and s troke-like episodes
*Intrauterine exposures* ^‡
Fetal hydantoin syndrome	Face, back, extremities	Gingival hyperplasia, coarse facies, hypoplastic nails and distal phalanges, GD
Fetal alcohol syndrome	Face, back, extremities	Midfacial hypoplasia, GD, CNS anomalies
*Morpheaform or sclerodermoid disorders*
MONA (multicentric osteolysis, nodulosis, and arthropathy; previously known as Winchester syndrome)	Hypertrichosis and hyperpigmentation overlying areas of skin thickening	Gingival hyperplasia, carpal/tarsal osteolysis, osteoporosis, coarse facies, GD AR; matrix metalloproteinase-2 gene mutations
H syndrome ^§ ^,	Lower trunk and lower extremities (in association with areas of h yperpigmentation & induration) Histologic features in areas of induration include a polyclonal perivascular lymphohistiocytic infiltrate with numerous plasma cells in the dermis and subcutis	Sensorineural h earing loss, short h eight, h eart anomalies, h epatosplenomegaly, scrotal masses, hypergonadotropic h ypogonadism, antibody-negative insulin-dependent diabetes mellitus, facial telangiectasias AR; SLC29A3 mutations (encodes nucleoside transporter hENT3 which localizes to lysosomes and mitochondria)
Stiff skin syndrome	Variable	See Ch. 43
Linear melorheostosis (isolated melorheostosis) ^¶	Overlying affected skin and bone	Hyperostosis (“candle wax” appearance) with overlying scleroderma Isolated cases due to LEMD3 mutations

* Hypertrichosis is an uncommon feature.

† Hypertrichosis may also be observed in other lysosomal storage diseases, e.g. Krabbe disease and GM1-gangliosidosis, as well as sialuria.

‡ Also minoxidil and diazoxide.

§ Allelic with pigmented hypertrichosis with insulin-dependent diabetes mellitus (PHID) syndrome, sinus histiocytosis with massive lymphadenopathy (SHML), and Faisalabad histiocytosis.

¶ Hypertrichosis has also been described overlying linear scleroderma in the absence of melorheostosis.

Prepubertal hypertrichosis

Prepubertal hypertrichosis is a relatively common finding in otherwise healthy infants and children, most often occurring in individuals of Mediterranean or South Asian descent. Pigmented hair is present in a widespread, diffuse distribution and becomes more obvious during childhood. There is involvement of the face (especially the forehead, temples, and preauricular area), proximal extremities, and back; hairs in the latter location assume an “inverted fir tree” pattern. Bushy eyebrows and a low anterior hairline represent additional features.

The facial distribution pattern of prepubertal hypertrichosis can overlap with that of familial hirsutism (see below), and there may be a family history of excessive hairiness. Mildly elevated levels of total and free testosterone have been observed in a subset of girls with prepubertal hypertrichosis, while others have a normal androgen profile . These findings suggest multiple etiologies for this clinical pattern of hypertrichosis, including androgen excess as well as an increased constitutional propensity for hair growth.

Acquired generalized hypertrichosis

Acquired generalized hypertrichosis is most often related to drug ingestion ( Table 70.3 ). Drug-induced hypertrichosis is characterized by slow growth of terminal hair of medium thickness. The findings are most evident on the forehead, temples, flexor aspects of the extremities, and trunk. Drug-related hypertrichosis is usually reversible, and differs in distribution from drug-induced hirsutism.

Table 70.3

Hypertrichosis due to drugs.

Most common drugs are in bold. EGFR, epidermal growth factor receptor.

HYPERTRICHOSIS DUE TO DRUGS
Antibiotics
Streptomycin
Anti-inflammatory drugs
Benoxaprofen	Corticosteroids
Vasodilators
Diazoxide Minoxidil	Prostaglandin E1
Diuretics
Acetazolamide
Anticonvulsants
Phenytoin
Immunosuppressives
Cyclosporine	Mycophenolate mofetil
Psoralens
Methoxypsoralen	Trimethylpsoralen
Antiseptic agents
Hexachlorobenzene
Chelators
Penicillamine
Other
Interferon-α Fenoterol	EGFR inhibitors (e.g. cetuximab, panitumumab, erlotinib, gefitinib)

Acquired generalized hypertrichosis can also represent a sign or consequence of a variety of systemic conditions, including disorders of the CNS (e.g. traumatic brain injuries), juvenile hypothyroidism, juvenile dermatomyositis, acromegaly (especially of the lower face), malnutrition (including anorexia nervosa), POEMS syndrome, and advanced HIV infection.

Acquired hypertrichosis lanuginosa

This is considered to be a paraneoplastic phenomenon as it is associated with internal malignancies, most often of the lung, colon, or breast. Occasionally, acquired hypertrichosis lanuginosa may precede the diagnosis of the neoplasm. In addition, it may be associated with other paraneoplastic dermatoses, such as acanthosis nigricans, palmoplantar keratoderma, the sign of Leser–Trélat, and acquired ichthyosis (see Ch. 53 ). The lanugo hair appears over the entire body within a short period of time, although in mild forms it may be localized to the face, leading to a “simian” appearance. Lanugo hair may even develop in areas of androgenetic alopecia.

Localized hypertrichosis

Most cases of localized hypertrichosis involve a switch from vellus to terminal hair in sites that do not usually bear terminal hair. Localized hypertrichosis can develop as a component of a hamartoma, as an isolated congenital lesion, as a manifestation of a systemic disease (inherited or acquired), or as a consequence of cutaneous trauma or inflammation.

Congenital localized hypertrichosis

Hamartomas, including those with delayed clinical presentation, and congenital abnormalities characterized by hypertrichosis of a specific anatomic site ( Fig. 70.2 ; Tables 70.4 & 70.5 ) are included in this category.

Table 70.4

Hereditary hypertrichosis affecting specific anatomic sites.

Localized hypertrichosis as a sign of spinal dysraphism is discussed in Ch. 64 . AD, autosomal dominant; AR, autosomal recessive.

HEREDITARY HYPERTRICHOSIS AFFECTING SPECIFIC ANATOMIC SITES
Condition	Inheritance	Onset	Other features
Hypertrichosis cubiti (hairy elbow syndrome; Fig. 70.2 )	AD	Birth to early childhood	Short stature *
Hairy palms and soles	AD	Birth
Hypertrichosis of the auricle	AD ^†	Childhood or adolescence	Primarily affects males
Hypertrichosis of the eyebrows	?	Adolescence
Trichomegaly of the eyelashes	AR	Childhood
Hypertrichosis of the nasal tip	?	Adolescence	Primarily affects males
Anterior cervical hypertrichosis ( Fig. 70.5 )	AD ^‡	Birth to early childhood	Sensory and motor neuropathy * Mental retardation * Hallux valgus *
Posterior cervical hypertrichosis	AD	Birth	Kyphoscoliosis
Polythelia, including the hairy variant ^§ ^,	AD ^¶	Adolescence	Urinary tract anomalies *

* Occasional finding.

† Shown not to be Y-linked in a cohort of Indian men; congenital hypertrichosis of the pinna can be seen in the offspring of diabetic mothers and in individuals with XYY syndrome.

‡ Possible AR inheritance in a consanguineous family.

§ Tuft of hair along the “mammary line”.

¶ Approximately 10% of cases are familial.

Table 70.5

Hypertrichosis of the eyebrows and eyelashes.

EGFR, epidermal growth factor receptor.

HYPERTRICHOSIS OF THE EYEBROWS AND EYELASHES

Synophrys (“unibrow”)

Isolated trait
Waardenburg syndrome (see Ch. 66 )
Cornelia de Lange syndrome (see Table 70.2 )
Zimmerman–Laband syndrome (see Table 70.1 )
Amaurosis congenita, cone–rod type, with hypertrichosis (see Table 70.1 )
Mucopolysaccharidoses (see Ch. 48 )

Inherited and/or congenital trichomegaly

Trichomegaly of the eyelashes due to FGF5 mutations (AR)
Oliver–McFarlane syndrome *
Cornelia de Lange and Rubinstein–Taybi syndromes (see Table 70.2 )
Congenital hypertrichosis lanuginosa and Ambras syndrome (see Table 70.1 )
Cantú, Coffin–Siris, and Barber–Say syndromes (see Table 70.1 )
Amaurosis congenita, cone–rod type, with hypertrichosis (see Table 70.1 )
Hermansky–Pudlak syndrome (see Ch. 66 )
Kabuki and floating harbor syndromes ^†
Fetal alcohol syndrome (see Table 70.2 )

Acquired trichomegaly

HIV infection
Systemic medications: cyclosporine, EGFR inhibitors (e.g. cetuximab, gefitinib), topiramate, tacrolimus, interferon-α
Ophthalmic medications: latanoprost, bimatoprost
Hypothyroidism
Porphyrias
Dermatomyositis, systemic lupus erythematosus
Malnutrition, anorexia nervosa
Kala-azar

Distichiasis (double row of eyelashes)

Lymphedema–distichiasis syndrome ^‡
Setleis syndrome (double upper and absent lower lashes; see Ch. 64 )

* Autosomal recessive (AR) disorder also featuring sparse scalp hair, mental retardation (MR), short stature, and retinal pigmentary degeneration.

† Autosomal dominant (AD) disorders featuring distinctive facies, growth retardation, and, in the former, MR.

‡ AD condition due to FOXC2 mutations (see Ch. 104 ).

Congenital melanocytic nevi and plexiform neurofibromas

Congenital melanocytic nevi often have associated hypertrichosis. The increased hair growth may be noted at birth, but often becomes more prominent during infancy or early childhood. Hypertrichosis can be seen in small-, medium-, and large-sized congenital melanocytic nevi (see Ch. 112 ). A particularly dense growth of terminal hairs may accompany scalp nevi. Plexiform neurofibromas can also have associated hyperpigmentation and hypertrichosis.

Becker melanosis (nevus)

This is a hamartoma characterized by macular hyperpigmentation with irregular borders, usually located on the upper lateral trunk (anterior or posterior). Some patients have associated hypertrichosis while others do not. The pigmentation usually arises during the first decade of life, whereas the hypertrichosis typically appears in the second decade ( Fig. 70.3 ). Becker melanosis (nevus) most often occurs in boys and men, and in rare instances is inherited in an autosomal dominant pattern.

Occasionally, asymmetry of the extremities and hyperplasia or hypoplasia of the affected areas (especially ipsilateral mammary hypoplasia in women or, less often, the Poland anomaly) may be present. Rarely, there may be an association with genitourinary tract abnormalities (SNUB syndrome: supernumerary nipples, uropathies, Becker melanosis) . Because of its benign nature, surgical removal of Becker melanosis (nevus) is not recommended. Epilation can be performed by various techniques, but attempts at decreasing pigmentation via laser therapy are often not successful.

Smooth muscle hamartomas, which exist on a spectrum with Becker melanosis (nevus), may present as circumscribed hypertrichotic plaques with variable hyperpigmentation (see Ch. 117 ). A rare generalized form is characterized by extensive hypertrichosis and folding of the skin which has been reported under the term “Michelin tire baby” (see Table 97.6 ). Lastly, the hypertrichosis observed in the setting of hemimaxillofacial dysplasia (with facial asymmetry due to unilateral maxillary enlargement, gingival hyperplasia, and hypoplastic teeth) is often associated with Becker melanosis (nevus) or smooth muscle hamartoma.

Other hamartomas and infantile tumors

Hypertrichosis can also overlie the following skin lesions: plaque-type blue nevus, fibrous hamartoma of infancy, dermal dendrocyte hamartoma, eccrine angiomatous hamartoma, and tufted angioma.

Nevoid hypertrichosis

This is an uncommon congenital alteration characterized by the growth of terminal hairs in a circumscribed area. In general, there are no extracutaneous associations in primary nevoid hypertrichosis ; the skin within the affected area is normally pigmented and there is no underlying hamartoma ( Fig. 70.4 ). Table 70.4 outlines specific sites of localized hypertrichosis that can be familial. There is a report of one family with primary multifocal localized hypertrichosis . Nevoid hypertrichosis has also been observed to follow the lines of Blaschko, as reported in female carriers of X-linked hypertrichosis (see Table 70.1 ).

Fig. 70.5, Anterior cervical hypertrichosis.

Secondary nevoid hypertrichosis can be associated with lipodystrophy, hemihypertrophy, scoliosis, and abnormalities of the underlying vasculature. Nevoid hypertrichosis can also occur together with epidermal nevi or nevoid hypopigmentation.

Spinal dysraphism and the hair collar sign

Dysraphism is defined as an alteration of the formation of a fold or elevation which is constituted in the midline of the human body during the union of two lateral portions. In spinal dysraphism, abnormal closure of the neural tube leads to defects in the vertebral column and/or spinal cord (see Ch. 64 ). Skin lesions marking a hidden vertebral defect are usually located in the dorsal midline. The faun tail is most often a sign of spina bifida occulta or diastematomyelia (split spinal cord), and is typically located in the lumbosacral region. In addition, a ring of hypertrichosis on the scalp, referred to as the hair collar sign, can surround membranous aplasia cutis or ectopic neural tissue, reflecting the origin of these midline lesions as incomplete neural tube defects.

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