Dermatology

Hidrotic Ectodermal Dysplasia (Clouston syndrome, ectodermal dysplasia 2)

Are You Confident of the Diagnosis?

What to be alert for in the history

--Abnormally thick and wiry hair in infancy

--Progressive alopecia with age

--Progressively dystrophic nails

--Palmoplantar changes

--Painful, swollen distal digits

--Normal sweating ability

--Normal teeth

Characteristic findings on clinical examination

Nail findings

--Milky white nail plates in childhood

--Nail plates become progressively short, dark and thick with age

--Distal onycholysis

--Micronychia or partial anonychia

--Paronychia common

Hair findings (Figure 1)

Figure 1.

Clouston syndrome. (Courtesy of Maurice van Steensel, MD).

--Dry, wiry and brittle

--Slow growing

--Light in color

--Progressive alopecia of the scalp hair

--Sparse eyebrows and eyelashes

--Sparse body hair including secondary sexual hair

Skin findings

--Dry, rough skin

--Palmoplantar hyperkeratosis or keratoderma with transgradiens

--Rarely eccrine poromatosis or eccrine syringofibroadenomatosis

--Hyperpigmentation of the skin over the joints, at the axillae, areolae, and pubic area

--Thickened skin over the knees, elbows, and hand joints

--Normal sweating

Dental/oral findings

--Teeth usually normal

--Hypodontia is rare

--Natal teeth

--Dental caries

Ocular findings

--Strabismus

--Cataracts

--Conjunctivitis/blepharitis

--Myopia

Other findings

--Clubbing of the fingers/tufting of terminal phalanges

--Mental deficiency rare with normal intelligence in most cases

--Thickening of skull bones

--Short stature

Diagnostic studies

--Light microscopy of hair with disorganized fibrillar structure and reduced birefringence on polarized light

--Hair shafts are abnormal and may be square with longitudinal grooves and twisting

--Pigment in the hair may be absent

--Decreased cysteine and disulfide bonds in the hair

--Skin biopsy of the scalp reveals a reduced number of dystrophic hair follicles with thickened connective tissue sheaths

--Skin biopsy of the palmoplantar hyperkeratosis reveals thickened stratum corneum, pronounced orthohyperkeratosis, hypergranulosis and normal numbers of eccrine structures

--Genetic testing for the causative gene mutation in gap junction protein beta 6 (GJB6)is available

Differential diagnosis

--Unna Thost keratoderma can present with palmoplantar keratoderma but can be distinguished from HED2 by absence of hair and nail changes

--Pachonychia congenita type 1 presents with severe nail dystrophy and focal palmoplantar hyperkeratosis but typically has normal hair and can be distinguished by presence of oral leukokeratosis and early eruption of teeth

--Dyskeratosis congenita presents with nail dystrophy and palmoplantar hyperkeratosis but has reticulated hyperpigmentation and oral leukoplakia with associated pancytopenia

--Keratitis-icthyosis-deafness syndrome can present with dystrophic nails, palmoplantar hyperkeratosis and alopecia but also has keratotic plaques on the skin, sensorineural deafness and keratitis

Who is at Risk for Developing this Disease?

--Incidence is unknown but underdiagnosis is likely common

--Most common in French and French-Canadian populations

--Reported in individuals from many ethnic backgrounds including Chinese, Malaysian, Indian, African, Irish, Scottish, and Spanish populations

What is the Cause of the Disease?

Etiology

This syndrome is inherited in an autosomal dominant fashion and is due to mutations in the gap junction beta 6 (GJB6) gene that is located on chromosome 13q12 and encodes for the protein connexin 30.

Pathophysiology

Manifestations of the syndrome are due to mutations in connexin 30, which is a gap junction protein that functions to form channels between cells allowing diffusion of ions and metabolites, therefore affecting cell-to-cell coupling and communication.

Systemic Implications and Complications

Skin, hair and nails are primarily affected in this syndrome. Short stature, mental deficiency (rare and not typically severe), clubbing of the digits and ocular issues (strabismus, cataracts, conjunctivitis, blepharitis, myopia) have been associated with this condition. Life span is normal.

Treatment Options

There are no specific treatments for this condition.

Medical treatment includes use of emollients and topical keratolytics (urea or lactic acid based) for softening of the nail plates and palmoplantar hyperkeratosis, topical antibiotics and antifungal medications for the paronychia, and topical retinoids with topical minoxidil for the alopecia has reportedly been helpful but is likely not clinically relevant.

Surgical treatment includes nail plate avulsion and nail matrix ablation to reduce risk of infection and pain associated with the recurrent paronychia. Paring and surgical debridement of the palmoplantar keratoderma can also be helpful.

Physical modalities include wigs for the alopecia and sculpting or bonding of artificial nails for cosmesis may be desired.

Optimal Therapeutic Approach for this Disease

Symptomatic treatment of the disease manifestions can be helpful but there is no effective therapy that leads to cure or resolution of the syndrome or its related findings.

If asymptomatic, no therapies are required.

If use of the topical emollients and keratolytics are ineffective and there is associated pain or dysfunction related to the keratoderma, then surgical treatment can be considered. Paring and surgical debridement will require repeated sessions over time as the underlying defect is still present and recurrence of the palmoplantar keratoderma is expected with time. Routine twice-yearly dental cleanings and examinations should be done.

If paronychia and pain is recurrent due to the abnormal nails and is unresponsive to topical therapies, nail matrix ablation can be performed but results in permanent loss of the nail.

Early school intervention may help if clinically apparent learning disability is recognized.

Patient Management

Patient should be informed that treatment is aimed at symptom control. If asymptomatic, then the manifestations of the syndrome do not require treatment. If symptoms of pain or recurrent infection develop, then treatment is warranted starting with topical medical therapy followed by surgical modalities. Therapies are safe but not always effective.

Patients should be aware that nail matrix ablation leads to permanent loss of the nail. Patients should be aware that paring and surgical debridement is only temporary for reducing the palmoplantar keratoderma and will have to be repeated.

Unusual Clinical Scenarios to Consider in Patient Management

Clinical features of the syndrome are quite variable among individuals. Underdetection of the syndrome likely occurs as the symptoms and signs of the disease are often mild.

Nail dystrophy is thought to be the sole manifestation of the syndrome in up to one-third of affected individuals. Swollen tufted terminal phalanges can be a diagnostic clue. Regular paring of the keratoderma can be helpful.

What is the Evidence?

Der Kaloustian, VM. "Hidrotic ectodermal dysplasia 2".

(This is a comprehensive reveiw of the genetic defect in hidrotic ectodermal dysplasia. Extensive information on genetic counseling, prenatal testing and differential diagnosis.)

Escobar, V, Goldblatt, LI, Bixler, D, Weaver, D. "Clouston syndrome: an ultrastructural study". Clin Genet. vol. 24. 1983. pp. 140-6.

(Discussion of HED based on the genetic cause of the disease.)

Kibar, Z, Dube, MP, Powell, J, McCuaig, C, Hayflick, SJ, Zonana, J. "Clouston hidrotic ectodermal dysplasia (HED): genetic homogeneity, presence of founder effect in the French Canadian population and fine genetic mapping". Eur J Hum Genet. vol. 8. 2000. pp. 372-80.

(Review of HED in the French Canadian population.)

Lamartine, J, Hunhoz Essenfelder, G, Kibar, Z, Lanneluc, I, Callouet, E, Laoudi, D. "Mutations in GJB6 cause hidrotic ectodermal dysplasia". Nat Genet. vol. 26. 2000. pp. 142-4.

(Discussion of the genetic mutation found in HED. )

Pierard, GE, Van Neste, D, Letot, B. "Hidrotic ectodermal dysplasia". Dermatologica. vol. 158. 1979. pp. 168-74.

(Early, excellent overall review of HED.)
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