The clinical picture of hidrotic ectodermal dysplasia varies even among family members but the typical clinical triad consists of nail dysplasia, alopecia, and palmoplantar hyperkeratosis.

Nails

In this disorder, the nails are malformed, hypoplastic, thick, discolored (milky white), and unattached to the nail bed. Additionally, the deformed nails are prone to recurrent paronychial infections [7], which can lead to nail loss. Note that these nail changes are the sole features in about 30% of patients at the time of examination. These features appear at birth or in infancy.

Hair

Affected individuals may exhibit brittle, sparse, patchy, and pale scalp hair that may progress to full alopecia by puberty. The hair loss may be partial or complete. Moreover, eyebrows, eyelashes, axillary and pubic hair may be partially or fully absent [8]. Hair features develop as early as birth or as late as childhood.

Skin

Palmoplantar hyperkeratosis in childhood is another frequently observed sign but is not consistently observed. This can worsen with age.

Another dermatological finding is hyperpigmentation, which can be particularly found on the elbows, knees, and joints of the fingers and toes [8] [9].

Other

Other tissues such as the teeth, sweat glands, and sebaceous glands are not affected [8] [10]. The patient's physical growth and development are also normal.

Further manifestations may include sensorineural deafness and skeletal abnormalities such as syndactyly and polydactyly [8] [9]. Ocular complications such as strabismus, conjunctivitis, pterygium, and cataract may also develop [10]. Finally, clubbing of the fingers may also occur.

• Hyperthermia

  […] hypoplastic-absent eccrine sweat glands spoon-shaped nails hypotrichosis fine, brittle hair scanty hair absent or scanty eyelashes and eyebrows blonde, fine scalp hair hoarse voice due to dry laryngeal mucosa intolerance to heat and fevers susceptible to hyperthermia [humpath.com]

  Treatment for males with ED1 has changed little: avoid elevated environmental temperatures, prevent hyperthermia, and provide cosmetic and dental care. [kundoc.com]

  Prognosis Among males with hypohidrotic ectodermal dysplasia, unrecognized episodes of hyperthermia are a dangerous complication. [encyclopedia.com]

  An inability to sweat can lead to a dangerously high body temperature ( hyperthermia ) particularly in hot weather. In some cases, hyperthermia can cause life-threatening medical problems. [en.wikipedia.org]

  The inability to perspire can cause hyperthermia that may lead to febrile seizures and neurologic damage. [cancertherapyadvisor.com]

• Short Stature

  Short stature (5-10th centile) present in some cases is possibly a separate familial trait. The family demonstrates overlapping features with Clouston syndrome. [ncbi.nlm.nih.gov]

  short stature Natal tooth Abnormality of pelvic girdle bone morphology Proportionate short stature Atrioventricular canal defect Hypoplastic left heart Thoracic hypoplasia Dextrocardia Emphysema Short thorax Hydroureter Hypoplastic toenails Cubitus valgus [mendelian.co]

  stature (usually mild) Diagnosing Clouston Syndrome A physician can diagnose Clouston syndrome on the basis of physical features. [nfed.org]

  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. [dermatologyadvisor.com]

• Nail Abnormality

  Pure hair and nail affecting ectodemal dysplasias are exceedingly rare in occurance and have been known to be associated with multiple abnormalities, such as keratoderma or ichthyosis, skeletal and hematological abnormalities, cardiac irregularities, [ijpd.in]

  Showing of 43 | 80%-99% of people have these symptoms Abnormality of nail color Abnormality of nail colour 0100643 Alopecia Hair loss 0001596 Fragile nails Brittle nails 0001808 Generalized hyperpigmentation 0007440 Hyperconvex nail Nail overcurvature [rarediseases.info.nih.gov]

  Dental defects: Abnormal morphogenesis or absence of teeth as well as enamel defects may occur. [13] Nail dystrophy: Abnormal nail plate formation may result in brittle, thin, ridged, or grossly deformed nails. [emedicine.medscape.com]

• Selective Tooth Agenesis

  The WNT10A gene in ectodermal dysplasias and selective tooth agenesis. Am J Med Genet A. 2014 Oct. 164A (10):2455-60. [Medline]. Tziotzios C, Petrof G, Liu L, Verma A, Wedgeworth EK, Mellerio JE, et al. [emedicine.medscape.com]

  tooth agenesis Ectrodactyly Sparse body hair Absent eyebrow Macular dystrophy Widely spaced teeth Macular degeneration Conjunctivitis Joint contracture of the hand Abnormality of retinal pigmentation Split hand Abnormality of the eye Retinopathy Postnatal [mendelian.co]

• Lacrimation

  In addition, some individuals with HED are unable to produce tears due to underdevelopment of the glands that secrete tears (hypoplastic lacrimal glands), hypoplasia of the ducts through which the tears pass (lacrimal ducts), and/or abnormal narrowing [rarediseases.org]

  We also found decreased salivary and lacrimal secretion and maxillary hypoplasia in both cases. [scielo.conicyt.cl]

  […] of two or more of the following: hair, teeth, nails, sweat glands and other ectodermal structures like  mammary gland, thyroid gland, thymus, anterior pituitary, adrenal medulla, central nervous system, external ear,melanocytes, cornea, conjunctiva, lacrimal [slideshare.net]

  Other Ectodermal Dysplasia Types Ackerman Syndrome Acrorenal Field Defect, Ectodermal Dysplasia, and Lipoatrophic Diabetes Acto-Dermato-Ungual-Lacrimal-Tooth Syndrome Ameloonychohypohidrotic Syndrome Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate [nfed.org]

  EEC syndrome and other related ectrodactyly syndromes (eg, acro-dermato-ungual-lacrimal-tooth [ADULT] syndrome and limb-mammary syndrome) are usually recognized at birth as a result of the characteristic limb deformities. [emedicine.medscape.com]

• Hyperpigmentation

  Synopsis small cranial length frontal bossing hypoplastic maxilla small chin small facial height prominent supraorbital ridges scand-absent eyebrows periorbital wrinkles periorbital hyperpigmentation absent tears absent miebomian glands scant-absent eyelashes [humpath.com]

  Affected people may also have palmoplantar hyperkeratosis (thick skin on the palms of the hands and soles of the feet), hyperpigmentation of skin (especially over joints) and/or clubbing of the fingers. [rarediseases.info.nih.gov]

  In contrast to the much more common X-linked form of ectodermal dysplasia, most of the patients with the autosomal dominant form have: normal sweat and sebaceous gland function; partial to total alopecia; nail hypoplasia and nail deformities; skin hyperpigmentation [genedx.com]

  […] often associated with patchy alopecia. [2] : 507,511,517-16 Presentation [ edit ] Hidrotic ectodermal dysplasia 2, or Clouston syndrome (referred to as HED2 throughout this entry) is characterized by partial or total alopecia, dystrophy of the nails, hyperpigmentation [en.wikipedia.org]

  […] spots for males Sparse eyelashes Sparse eyebrow Absent underarm hair Reduced hair strength Additional Features Include: Skin Normal sweating Abnormal thickening of the skin of the palms and soles (palmoplantar hyperkeratosis) that gets worse with age Hyperpigmentation [nfed.org]

• Sparse Hair

  Underdeveloped Thick, discolored Hair Fine, brittle, slow-growing Total balding (alopecia) Missing in spots for males Sparse eyelashes Sparse eyebrow Absent underarm hair Reduced hair strength Additional Features Include: Skin Normal sweating Abnormal [nfed.org]

  Sparse scalp hair and dysplastic nails are seen early in life. In infancy, scalp hair is wiry, brittle, patchy, and pale; progressive hair loss may lead to total alopecia by puberty. [en.wikipedia.org]

  Abnormal sparseness of hair (hypotrichosis) is also a primary characteristic of HED, and is due to incomplete formation and reduced numbers of hair follicles. [rarediseases.org]

  She had sparse scalp hair and eyebrows at birth, which totally lost over time. Besides, all her 20 nails wre dystrophic with palmoplantar keratoderma. Her teeth and sweating function were normal. [scinapse.io]

• Sparse Hair

  Underdeveloped Thick, discolored Hair Fine, brittle, slow-growing Total balding (alopecia) Missing in spots for males Sparse eyelashes Sparse eyebrow Absent underarm hair Reduced hair strength Additional Features Include: Skin Normal sweating Abnormal [nfed.org]

  Sparse scalp hair and dysplastic nails are seen early in life. In infancy, scalp hair is wiry, brittle, patchy, and pale; progressive hair loss may lead to total alopecia by puberty. [en.wikipedia.org]

  Abnormal sparseness of hair (hypotrichosis) is also a primary characteristic of HED, and is due to incomplete formation and reduced numbers of hair follicles. [rarediseases.org]

  She had sparse scalp hair and eyebrows at birth, which totally lost over time. Besides, all her 20 nails wre dystrophic with palmoplantar keratoderma. Her teeth and sweating function were normal. [scinapse.io]

• No Pubic Hair

  absent eyebrows short, thin, sparse, pale scalp hair short, sparse eyelashes sparse axillary and pubic hair Clinical features from OMIM: 601375 Human phenotypes related to Ectodermal Dysplasia, Hidrotic, Christianson-Fourie Type: 59 32 (show all 16) [malacards.org]

  Moreover, eyebrows, eyelashes, axillary and pubic hair may be partially or fully absent. Hair features develop as early as birth or as late as childhood. [symptoma.com]

  0001795 Irregular hyperpigmentation 0007400 Onycholysis Detachment of nail 0001806 Sparse axillary hair Little underarm hair 0002215 Sparse pubic hair Decreased sexual hair 0002225 Sparse scalp hair Scalp hair, thinning Sparse, thin scalp hair sparse-absent [rarediseases.info.nih.gov]

  After puberty, male patterns of hair growth (e.g., moustache and beard) can be normal, while in other cases, facial and pubic hair growth may be sparse. In affected males and females, pubic and underarm (axillary) hair is typically scant. [rarediseases.org]

  By puberty, the hair problems may worsen until all the hair on the scalp is lost (total alopecia). The eyelashes, eyebrows, underarm (axillary) hair, and pubic hair are also sparse or absent. [ghr.nlm.nih.gov]

• Eczema

  […] and obstruction atrophic mucosa causing dysphonia hypoplastic-absent mammary glands hypoplastic-absent nipples hypohidrosis anhidrosis sweat pore aplasia soft, thin skin dry skin mild localized pigmentation abnormalities skin peeling/scaling (newborn) eczema [humpath.com]

  The skin may be dry, thin, and prone to eczema, infection, cracking, bleeding, and other problems. In hypohidrotic ectodermal dysplasia, sebaceous glands (the oil glands within the skin) are absent, causing severe dryness. [encyclopedia.com]

  Many affected newborns have unusual scaling or peeling of the skin, while many children develop itchy (pruritic), scaling skin rashes (eczema). [rarediseases.org]

  An increased incidence of atopy is also noted in affected individuals, including eczema, wheezing, asthma, food allergy, and abnormal immunoglobulin production. Symptomatic treatments are well-tolerated with limited complications. [cancertherapyadvisor.com]

  Additional features of this condition include thin, wrinkled, and dark-colored skin around the eyes; chronic skin problems such as eczema ; and a bad-smelling discharge from the nose ( ozena ). [en.wikipedia.org]

Young children who present with the clinical triad of nail dystrophy, hypotrichosis, and palmoplantar hyperkeratosis should be evaluated for this disorder. Mild manifestations are diagnosed in childhood when the patients display abnormal growth and maturation of the nails or hair. However, severe cases are recognized in infancy.

The clinical assessment involves a full medical and family history, a complete physical exam (especially of the nails, hair, and skin) and key studies.

Molecular genetic testing offers confirmation of the diagnosis. Specifically, targeted mutation analysis identifies the most prevalent pathogenic variants in nearly 100% of patients with this disorder. The second-line test, sequence analysis, is performed if the targeted mutation analysis is not conclusive.

The therapeutic approach aims to address the manifestations. In terms of nail dystrophy, patients may wear artificial nails to improve appearance. Hair can be managed with wigs and special hair products. Furthermore, topical minoxidil and tretinoin may be beneficial for hair growth in patients with alopecia. Finally, palmoplantar hyperkeratosis may be treated with skin emollients, keratolytics, and topical vitamin D, and topical and systemic retinoids.

Special consideration

Prenatal counseling can be offered for individuals with this genetic disorder and those with a positive family history. The optimal time for genetic counseling is preconception. Education about what the disorder entails, its cause, how it is transmitted, and other concerns can be provided to help couples plan accordingly. Additionally, genetic testing can be made available.

Patients with hidrotic ectodermal dysplasia have a normal life span and good quality of life. The condition is manageable with supportive measures such as wearing artificial nails and wigs.

Hidrotic ectodermal dysplasia is an autosomal dominant disorder resulting from mutations in the gene known as GJB6, which codes for the gap junction protein connexin 30. As the name suggests, connexins form channels between the cytoplasm of adjacent cells.

This pattern of inheritance was first recognized in a French Canadian family by Clouston in 1929 as he studied a 5 generation family in Quebec [1]. Specifically, the inheritance exhibits complete penetrance but variable clinical expression [4].

While the majority of cases are inherited through an autosomal dominant pattern, a few are acquired through de novo mutations.

While the prevalence of hidrotic ectodermal dysplasia has not been elucidated, this disorder has been observed particularly in those with French Canadian ancestry [5]. Specifically, there are reported cases in the French Canadian communities in Quebec as well as Louisiana, Vermont, and upstate New York.

Other populations noted to have this condition are the African, Chinese, Malaysian, Welsh, Irish, Danish, French, Spanish, German, and Ashkenazi Jewish.

Overall, hidrotic ectodermal dysplasia is likely underdiagnosed and more common than believed to be.

This disorder is one of many ectodermal dysplasias classified under a group of disorders that involve ectodermal structures.

This particular condition is caused by a mutated GJB6 gene (locus 13q12), which codes for connexin 30, the gap junction protein that is found in various tissues such as the skin, nail beds, and hair follicles. Alteration in this gene results in impaired growth, division, and maturation of the cells of these tissues.

Analytical biochemical investigations in hidrotic ectodermal dysplasia have demonstrated that the abnormal hair exhibits lower levels of disulfide bonds and cysteine, which account for the hair thinness as well as its decreased tensile strength and an unusual swelling capacity [6]. Furthermore, the reduction in disulfide bonds is likely responsible for the disorganization of hair fibrils and cuticle desquamation [1]. In conclusion, these cumulative findings indicate abnormal molecular changes in keratin.

Since this is an inherited disorder, it cannot be prevented. However, prenatal counseling and testing can be offered for individuals planning a family planning or those those already expecting.

Hidrotic ectodermal dysplasia (also known as Clouston syndrome) is a rare, autosomal dominant disorder initially described in the French-Canadian population in 1895 [1] [2] [3]. The etiology of this disorder is secondary to a mutation in the GJB6 gene that encodes a gap junction protein. Furthermore, hidrotic ectodermal dysplasia affects ectodermal structures and thus features the clinical triad of nail dystrophy, hair loss, and palmoplantar hyperkeratosis while sparing the teeth and sweat glands.

Deformities of the nails are the most predominant manifestations and usually appear at birth or in infancy. The nails are brittle, small, discolored, separated from the nail bed, and vulnerable to paronychial infections. Moreover, hair abnormalities develop at birth, infancy, or childhood and include partial or complete hair loss on the scalp, axillary, and pubic regions. Additionally, thickening of the palms and soles does not always occur. Further findings may include clubbing of the fingers, skin hyperpigmentation over the joints, sensorineural hearing loss as well as musculoskeletal and ocular abnormalities. However, the physical growth is unaffected.

Infants or children presenting with these manifestations should be suspected to have this disorder. The workup will consist of a medical and family history, a detailed physical examination, and molecular genetic testing. Specifically, targeted mutation analysis is the confirmatory diagnostic tool.

The treatment focuses on supportive measures such as applying artificial nails, wigs, and special hair products. Also, skin emollients, keratolytics, and other therapies may be used for the hyperkeratosis.

While this is not a preventable disorder, prenatal counseling and testing are options for affected individuals, those with a positive family history, eligible couples planning to have children.

What is hidrotic ectodermal dysplasia?

This is an uncommon genetic condition that affects the nails, hair, skin, and eyes. The gene responsible for this has a mutation (alteration). The majority of patients that have this disease have an affected parent. This type of inheritance is called autosomal dominant. In other words, the patient received one mutated (bad) copy of the gene from the affected parent and a good copy of the gene from the other parent.

In a few cases, the patient has a spontaneous mutation without affected parents or family members.

Which populations does this disorder affect?

Hidrotic ectodermal dysplasia is more commonly seen in people of French-Canadian descent such as the French-Canadian communities in Quebec, Louisiana, New York and Vermont.

Additionally, it is reported in people from other backgrounds such as African, Chinese, Malaysian, Welsh, Irish, Danish, French, Spanish, German, and Ashkenazi Jewish.

What are the signs and symptoms of this disorder?

The 3 main features of this condition are nail changes, hair loss, and thickening of the skin on the palms and soles. Also, skin discoloration is common. Nails are usually:

• Deformed
• Small
• Short
• Separated from the nail bed
• Susceptible to fungal infections

The following are the characteristics of the hair loss:

• Hair is brittle, patchy, and pale
• Slow hair growth

• Partial scalp hair loss may progress to complete hair loss
• Eyebrows, eyelashes, body and pubic hair may be partially or completely absent

The skin may be darker on the:

• Knees
• Elbows
• Joints of the fingers
• Joints of the toes

Patients may also have:

• Clubbed fingers
• Eye problems such as cataracts, conjunctivitis, and strabism
• Skeletal findings such as polydactyly, syndactyly
• Deafness

How is this diagnosed?

When a child presents with the above signs, the clinician will suspect this disorder as the diagnosis. The test that confirms hidrotic ectodermal dysplasia is genetic testing that identifies the genetic mutation.

How is it treated?

There is no specific treatment. However, artificial nails can help improve the appearance of the patient's nails, especially in girls and women.

Also, wigs and hair products can be used for individuals with fragile hair or alopecia.

Thickened skin on the palms and soles can be treated by skin emollients or keratolytics.

Family planning

The best time for learning about genetic risk is during the family planning stage. Individuals with an affected family member(s) and expecting parents have the opportunity to seek genetic counseling and genetic testing. Specifically, genetic counseling provides significant education about what this disorder means, how it is inherited, and the probability of passing this condition to offspring.

What is the prognosis?

Patients have a normal life expectancy. The manifestations of hidrotic ectodermal dysplasia can be managed by measures that improve appearance and confidence.

Can it be prevented?

This disorder is inherited and therefore cannot be prevented.

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2. Pierard GE, Van Neste D, Letot B. Hidrotic ectodermal dysplasia. Dermatologica. 1979. 158(3):168-74.[Medline].
3. Reynold JM, Gold MB, Scriver CR. The characterization of hereditary abnormalities of keratin: Clouston's ectodermal dysplasia. Birth Defects Original Article Series. 1971; 7(8):91-5.
4. Williams M, Fraser FC. Hydrotic ectodermal dysplasia--Clouston's family revisited. Canadian Medical Association Journal. 1967;96(1):36-8.
5. George DI Jr, Escobar VH. Oral findings of Clouston's syndrome (hidrotic ectodermal dysplasia). Oral Surgery, Oral Medicine, and Oral Pathology. 1984;57(3):258-62.
6. Gold RJ, Scriver CR. Properties of hair keratin in an autosomal dominant form of ectodermal dysplasia. American Journal of Human Genetics. 1972;24(5):549-61.
7. Ando Y, Tanaka T, Horiguchi Y, Ikai K, Tomono H. Hidrotic ectodermal dysplasia: a clinical and ultrastructural observation. Dermatologica. 1988;176(4):205-11.
8. Jan AY, Amin S, Ratajczak P, Richard G, Sybert VP. Genetic heterogeneity of KID syndrome: identification of a Cx30 gene (GJB6) mutation in a patient with KID syndrome and congenital atrichia. Journal of Investigative Dermatology. 2004; 122(5):1108-13.
9. Tan E, Tay YK. What syndrome is this? Hidrotic ectodermal dysplasia (Clouston syndrome). Pediatric Dermatology. 2000;17(1):65-7.
10. Wilkey WD, Stevenson GH. Family with Inherited Ectodermal Dystrophy. Canadian Medical Association Journal. 1945;53(3):226-30.