Congenital Hypertrichosis Lanuginosa

For hundreds of years, societies have maintained a certain fascination with the bizarre and the unknown. In the past, persons with congenital disorders that cause excessive body-hair growth have been so dramatized and romanticized that individuals with rare hypertrichosis syndromes became crowd-drawing money-making phenomena in many 19th century sideshow acts. Most famously, Fedor Jeftichew, aka Jojo the Dog-faced boy, was exhibited by PT Barnum in the United States in the 1800s.

These individuals have been referred to as dog-men, hair-men, human Skye terriers, ape-men, werewolves, and Homo sylvestris.[1, 2] Since the Middle Ages, approximately 50 individuals with congenital hypertrichosis have been described, and, according to the most recent estimates, approximately 34 cases are documented adequately and definitively in the literature.[3, 4, 5]

Disorders of hypertrichosis are distinguished by the distribution of hair, as well as by the temporal pattern of growth, the possible associated congenital anomalies, and the possible inheritance pattern.

Congenital hypertrichosis lanuginosa (CHL) has been referred to variably as congenital hypertrichosis universalis, hypertrichosis universalis, hypertrichosis lanuginosa, and hypertrichosis lanuginosa universalis. The lack of definitive terminology can be confusing and may make the distinction of the related but unique hypertrichosis syndromes difficult.[1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21] Several solitary case reports describing hypertrichosis resembling congenital hypertrichosis lanuginosa in association with other physical findings may, in fact, represent variants in a spectrum of the disorder.

An X-linked syndrome of hypertrichosis associated with gingival hyperplasia has been described. The abnormally excessive body hair that these patients develop is of the terminal type, and this disorder will not be greatly discussed. However, the X-linked syndrome of hypertrichosis associated with gingival hyperplasia is often confused with congenital hypertrichosis lanuginosa. Of interest, Julia Pastrana (1834-1860), one of the most famous persons with generalized hypertrichosis, was long thought to have congenital hypertrichosis lanuginosa. After her death, her hairs were found to actually be terminal in nature, indicating that she likely had hypertrichosis with gingival hyperplasia and not congenital hypertrichosis lanuginosa. This illustrates the need to accurately determine the type of excess hair present on a given patient.

In addition, the localized hypertrichoses, including primary hypertrichosis cubiti (hypertrichosis of both elbows), primary cervical hypertrichosis, and primary faun tail deformity, are not addressed in this article.[22] These forms represent limited types of hypertrichosis that may be associated with underlying bone and neurologic abnormalities. Hence, they can be distinguished from congenital hypertrichosis lanuginosa on the basis of their clinical presentations.

In 1648, Aldrovandus first documented a family with hypertrichosis. Originally from the Canary Islands, Petrus Gonzales was brought to France as a curiosity for the nobles. He, his 2 daughters, a son, and a grandchild were affected. This kindred was dubbed the Family of Ambras after a castle near Innsbruck where their portraits were discovered. Over the next 300 years, more than 50 similar-appearing cases were described, and 34 patients with presumed congenital hypertrichosis were identified. In 1873, Virchow described an edentate form; in 1876, Bartles added the descriptor "universalis;" and, in 1890, Chiari called the syndrome "hypertrichosis of the dog-men."

Family of Petrus Gonzales, who lived in the 16th century.

The hairy family of Burma has a 4-generation pedigree of congenital hypertrichosis lanuginosa dating back to 1826. Earlier generations were in the employ of the Ava court, but later generations often earned a living as sideshow attractions in the 1880s.

In 1993, Baumeister et al noted that 9 of these 34 patients with hypertrichosis had a distinctive clinical presentation.[3] The term Ambras syndrome was coined, and subsequent genetic analyses in 2 patients have revealed an association with a paracentric inversion of band 8q22.

Patients in well-documented cases of Ambras syndrome. (A) Daughter of Petrus Gonzales. (B) Grandson of Schwe Maong. (C) Adrrian Jepticheff. (D) Fedor.

Two types of excessive hair disorders exist and must be distinguished.

Hypertrichosis is non–androgen-related pattern of excessive hair growth that may involve vellus, terminal, or lanugo type hair. Hypertrichosis can accompany certain genetic syndromes, or it can be induced secondarily by exogenous medications, most notably phenytoin, minoxidil, cyclosporine, diazoxide, corticosteroids, phenytoin (Dilantin), streptomycin, hexachlorobenzene, penicillamine, heavy metals, sodium tetradecyl sulfate, acetazolamide, and interferon.

The hypertrichosis seen in Ambras syndrome is believed to result either from an increase in the number of hairs in anagen or from an increased number of follicular units, although no one knows for certain.[23]

Alternatively, hirsutism commonly occurs in women and presents as androgen-induced male-pattern hair growth of the terminal type.[24, 25, 26, 27] Hirsutism may have a congenital or exogenous origin. More common causes of hirsutism include polycystic ovary syndrome (PCOS), idiopathic hirsutism, hyperprolactinemia, hyperthecosis, and medications (eg, danazol, androgenic oral contraceptives).[28] Less common causes of hirsutism include congenital adrenal hyperplasia, ovarian tumors, Sertoli-Leydig cell tumors, granulosa–thecal cell tumors, other tumors that stimulate the ovarian stroma, adrenal tumors, Cushing disease, tumors of the adrenal cortex, and severe insulin-resistance syndromes.[29]

Hypertrichosis lanuginosa and transient neonatal cutis laxa have been described as the initial presenting signs in Sotos syndrome. Other features of the syndrome include excessive early childhood growth; learning disabilities or attention-deficit disorder; a long, narrow face; high forehead; red cheeks; and a pointed chin.[30]

Congenital hypertrichosis lanuginosa

The pathogenesis of congenital hypertrichosis lanuginosa is unknown.

Congenital hypertrichosis lanuginosa is believed to be inherited in an autosomal dominant manner; most cases involve a familial component. Variable expressivity of inherited characteristics is noted.

The specific genetic abnormality in congenital hypertrichosis lanuginosa has not been defined.

No known hormonal or endocrinologic abnormalities have been identified.

Evidence suggests that some cases of congenital hypertrichosis lanuginosa are not familial. These cases likely represent spontaneous mutations .[6, 31]

Ambras syndrome

A genetic etiology is proposed for Ambras syndrome.

Two cases of Ambras syndrome.[3, 32] were associated with alterations in chromosome 8. Using fluorescence in situ hybridization (FISH), Tadin et al analyzed the original patient described by Baumeister and detected a pericentric inversion of chromosome 8, inv(8)(p11.2q22).[33]

In an analysis of findings in the second patient reported by Balducci, an association was made with an insertion of the q23-24 region into a more proximal region of the long arm of chromosome 8, most likely at the q13 band, as well as a complex deletion in 8q23 encompassing four separate chromosomal breakpoints.[32]

The inversion breakpoints in this latter patient have been cloned, and a detailed map of the inversion breakpoint interval has been generated.[34]

Some postulated that the common breakpoint in both patients at 8q22 suggests that this region of chromosome 8 contains a gene involved in regulation of hair growth.

Although the relationship of these genetic observations to the pathogenesis of hypertrichosis remains uncertain, it has been postulated that the common breakpoint in both patients with Ambras syndrome at 8q22 suggests that this region of chromosome 8 contains a gene involved in regulation of hair growth.

Frequency

Congenital hypertrichosis lanuginosa and Ambras syndrome are extremely rare. Fewer than 50 cases are documented worldwide.[2, 3, 35, 36] The incidence of congenital hypertrichosis lanuginosa is unknown; however, reported incidence ranges from 1 in a billion to 1 in 10 billion.[6, 20, 37, 38]

Congenital hypertrichosis lanuginosa and Ambras syndrome have no geographic predilection.

Race

No racial predilection is recognized.

Sex

No sex predilection is known.

Age

In both congenital hypertrichosis lanuginosa and Ambras syndrome, excessive hair is apparent at birth.

Patients with congenital hypertrichosis lanuginosa have growth of the lanugo hair, which increases in length and extent of involvement from birth to approximately age 2 years (range, 1-8 y). As a result, the density, length, and extent of involvement may decrease; the rate of hair growth also slows. Many individuals with congenital hypertrichosis lanuginosa lose most, if not all, of their lanugo hair over time, and eventually, only limited areas of hypertrichosis may be present. Occasionally, the lanugo hair may be totally lost by the time the patient becomes an adult. A variant in which patients do not lose their lanugo hair over time is called congenital hypertrichosis universalis or persistent hypertrichosis universalis.[39]

Individuals with Ambras syndrome are classically described as having hypertrichosis at birth; however, the quantity of the excessive hair may be limited at that time. Unlike congenital hypertrichosis lanuginosa, Ambras syndrome may show increased hair growth in both distribution and density as the patient ages, and the hair does not spontaneously involute.

In congenital hypertrichosis lanuginosa, hair growth occurs until an average patient age of 2 years. Afterward, hair regresses during adolescence.[21]

In Ambras syndrome, patients are described as having increased hair growth throughout their lifetime.

Congenital hypertrichosis lanuginosa is not associated with an increased mortality rate. No documented long-term medical or physical morbidities are associated with congenital hypertrichosis lanuginosa. Psychological sequelae may occur because of the presence of excessive hair growth and the maintenance involved with removing the unwanted hair.

Patients should be aware that hypertrichosis may have a genetic component, and therefore may be inherited by subsequent generations.

Patients should be aware that the genetic basis for congenital hypertrichosis lanuginosa has not been identified, but the overall health of individuals with hypertrichosis is good.

The presenting complaint in congenital hypertrichosis lanuginosa (CHL) is an excess of body hair. Patients with congenital hypertrichosis lanuginosa are otherwise asymptomatic.

Patients with Ambras syndrome may complain of dysmorphic features of the face. These features do not impair function.

A family history of excessive body hair may exist.

No abnormalities in psychomotor, intellectual, or psychological development are known to occur.

Both congenital hypertrichosis lanuginosa and Ambras syndrome share the characteristic of abnormally excessive hair growth with a consistent pattern of areas that are spared. In both disorders, hair is found only in areas where it is usually present. The palms, soles, mucous membranes, dorsal terminal phalanges, labia minora, prepuce, and glans penis are spared.[21]

Congenital hypertrichosis lanuginosa

In congenital hypertrichosis lanuginosa, most of the body is covered with fine, blond or nonpigmented hair at birth. These hairs may reach up to 10 centimeters and often blend with the darker, terminal hairs of the scalp and/or eyebrows. Whorls of hair may be noted around the sacrum, preauricular region, and pinnae.

The length of the hair and its distribution may continue to increase until the individual is aged approximately 2 years. By adulthood, patients typically lose some or all of their excessive lanugo hair.

No abnormalities of other organ systems are associated with congenital hypertrichosis lanuginosa, although solitary case reports note abnormalities such as delayed tooth eruption, diffuse hamartoma of the arrector muscles, supernumerary teeth, glaucoma, pyloric stenosis, growth and/or developmental delay, aortic and cardiac valve abnormalities (including tetralogy of Fallot), and macromastia.[15, 17, 20, 40, 41, 42]

Ambras syndrome

The entire body is covered with long, fine vellus hair, which spares only the palms, soles, and genitalia. The hypertrichosis characteristically involves the shoulders, face, nose, and ears. In some areas, the hair may be noted as long as several centimeters.

The forehead, eyelids, nose, cheeks, and preauricular regions are uniformly covered with hair, which can reach a length of several decimeters. The hair is longest over the spine. Most patients have hair in a characteristic shawl distribution on their back.

The hair of the external auditory canal is typically long and thick, and it may hinder inspection of the auditory meatus.

Abnormalities of the teeth may be present. Adontia may occur, with an absence of the upper molars and the premolar teeth and a lag in the development of the first and second dentition.

Features associated with facial dysmorphism include the following:

• Triangular, coarse face

• Large intercanthal distance

• Broad palpebral fissures

• Long, prominent back of the nose and a round nose tip

• Large interalar distance

• Anteverted nares

• Short integumental lower lip

• Flat sulcus mentolabialis

Other findings noted in solitary case reports include the following:

• Bushy eyebrows with hair darker and coarser than that of the rest of the face, shoulders, body, and extremities

• Hair on the forearms and legs, in excess of and darker than the rest of the hair on the extremity

• Six accessory nipples

No laboratory tests are indicated for patients with congenital hypertrichosis.

The diagnosis of congenital hypertrichosis lanuginosa (CHL) is based on clinical and histologic findings, and no laboratory workup is necessary; however, laboratory values may be used to exclude other causes of hypertrichosis.

The diagnosis of Ambras syndrome may be supported by inversions involving breakpoints in the region of band 8q22.

No imaging studies are indicated for patients with congenital hypertrichosis.

No additional tests are indicated for patients with congenital hypertrichosis.

Hair biopsy for histologic classification is indicated. Biopsy findings may be diagnostic because the type of hair and position of the follicle found on histopathologic analysis can be helpful in excluding alternative diagnoses.

Lanugo hairs tend to be nonpigmented. Vellus hair may be pigmented or nonpigmented. Lanugo and vellus hairs can be difficult to distinguish at histologic examination.

The use of eflornithine (Vaniqa cream) 13.9% or hair removal by means of repeated shaving, depilatory methods (eg, chemical, electric methods), or bleaching can improve congenital hypertrichosis lanuginosa (CHL) patients’ appearance.

Older techniques of hair removal are mentioned in the literature; these rarely used techniques include diathermy and radiation therapy.

Clinicians should consider the use of antidepressant medications in patients with psychological sequelae, including depression.

Laser hair removal has been proposed as a treatment option, although there are conflicting reports regarding the proposed efficacy of lasers in removing the vellus hairs in congenital hypertrichosis lanuginosa.

Littler found a 40-80% reduction in unwanted hair using the Q-switched Nd:YAG laser after the application of a topical carbon-based solution. This therapy may be a well-tolerated method of hair removal in children because the lower fluences required resulted in decreased associated pain during treatment.

Vashi et al suggest that because of the difference in the penetrance of laser light into nonpigmented hair versus pigmented hair, laser therapy may not be effective in unpigmented lanugo or vellus hairs.[22, 45]

Genetic consultation may be indicated for the family members of patients with congenital hypertrichosis or Ambras syndrome. Congenital hypertrichosis lanuginosa and Ambras syndrome may have an autosomal dominant pattern of inheritance; however, an association with a genetic defect has not been demonstrated in all patients. Belengeanu et al describe 2 siblings with purported Ambras syndrome born to normal parents and propose that these patients might represent either an autosomal recessive pattern or germline mosaicism.[46]

Psychiatric evaluation may be indicated in patients in whom the physical findings of the syndrome cause psychological morbidity.

Compliance issues are the major complications in patients with congenital hypertrichosis lanuginosa. Inconvenience, cost, and the patient's dissatisfaction with the appearance of the hair, may influence his or her compliance with a hair removal regimen.

Psychological sequelae may occur because of the presence of unwanted hair.

The goal of pharmacotherapy is to improve the patient's appearance.

Class Summary

Agents with antiprotozoal action (eg, eflornithine) are effective in patients with hypertrichosis.

Eflornithine cream (Vaniqa cream, 13.9%)

Eflornithine cream is indicated for the reduction of unwanted facial hair in women. It interferes with ornithine decarboxylase in skin hair follicles needed for hair growth. It is not a depilatory but appears to retard hair growth to improve the condition and patient's appearance. Eflornithine cream slows hair growth and improves the appearance where applied. Improvement may be seen in 4-8 weeks to 6 months. Clinical studies show that hair returns to its previous condition 8 weeks after treatment is stopped. It has only been studied on the face and adjacent involved areas under the chin of individuals with hypertrichosis; therefore, limit use in these areas. Patients will likely need to continue hair-removal methods along with eflornithine.