Hypertrichosis and Hirsutism




Abstract


Hypertrichosis is defined as an excessive growth of hairs anywhere on the body. They are often terminal pigmented hairs but can be vellus or lanugo hairs. Hypertrichosis is frequently confused with hirsutism, but the latter term should be reserved for girls and women with excessive growth of terminal hairs in androgen-dependent sites. Hirsutism can result from hyperandrogenemia or increased end-organ sensitivity to androgens.


In addition to the type of hair, hypertrichosis is subdivided into congenital versus acquired as well as generalized versus localized. Acquired hypertrichosis lanuginosa can represent a paraneoplastic phenomenon while localized forms of hypertrichosis may be associated with trauma as well as underlying tumors or abnormalities of soft tissue and bone. Hypertrichosis is also a side effect of a number of medications. In addition to discontinuing incriminated drugs, treatment options include bleaching, physical and chemical depilatories, epilation, electrolysis, intense pulsed light therapy, and laser hair removal.


The evaluation of hirsutism involves measurement of serum androgen levels. In women, the ovaries and adrenal glands are the major sources of circulating androgens. If minimal or no hormonal abnormalities are detected, the hirsutism is categorized as constitutional or familial and presumed to be due to increased end-organ sensitivity. Depending on its etiology, treatment of hirsutism includes topical medications such as eflornithine, oral contraceptives, antiandrogens, glucocorticoids, gonadotropin releasing hormone agonists, and/or insulin-lowering agents in addition to the physical measures outlined for hypertrichosis.




Keywords

hypertrichosis, generalized congenital hypertrichosis, generalized acquired hypertrichosis, hypertrichosis lanuginosa, prepubertal hypertrichosis, drug-induced hypertrichosis, Becker melanosis, nevoid hypertrichosis, hirsutism, constitutional hirsutism, hyperandrogenemia, hyperandrogenism, SAHA syndrome, HAIR-AN syndrome, antiandrogens, glucocorticoids, gonadotropin-releasing hormone agonists

 





Key features




  • ▪

    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


  • ▪

    Hypertrichosis may be generalized or localized, with etiologies ranging from genodermatoses to underlying hamartomas to repeated trauma


  • ▪

    Hirsutism is related to hormonal factors, in particular an increase in circulating androgen levels and/or enhanced sensitivity of hair follicles to androgens


  • ▪

    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


  • ▪

    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.




Fig. 70.1


Approach to the patient with generalized hypertrichosis.

CAH, congenital adrenal hyperplasia; POEMS, p olyneuropathy, o rganomegaly, e ndocrinopathy, m onoclonal gammopathy, s kin lesions. The photograph is an example of universal hypertrichosis, which some authors view as simply exaggerated normal hairiness that may be familial.


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


Lipodystrophy syndromes (e.g. Berardinelli–Seip syndrome, leprechaunism)

  • •

    Face, neck, extremities


  • •

    Low hairline


Erythrokeratodermia variabilis

  • •

    Trunk and extremities


Dystrophic epidermolysis bullosa *

  • •

    Areas of previous blistering


Ichthyosis bullosa of Siemens *

  • •

    Extremities


Metabolic disorders
Mucopolysaccharidoses †

  • •

    Trunk, extremities


Congenital hypothyroidism

  • •

    Back, extremities


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


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.




Fig. 70.2


Hypertrichosis cubiti.

Multiple terminal hairs on both elbows in a child.


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 *

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Sep 15, 2019 | Posted by in Dermatology | Comments Off on Hypertrichosis and Hirsutism

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