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Ectodermal dysplasias

Ectodermal dysplasias
Literature review current through: Jan 2024.
This topic last updated: Oct 27, 2023.

INTRODUCTION — The ectodermal dysplasias (EDs) are a heterogeneous group of at least 50 genetic disorders affecting the development of two or more ectodermal derivatives, including hair, teeth, nails, sweat glands, and certain other tissues [1-3]. Other structures derived from the primitive ectoderm involved in EDs may include the mammary glands, adrenal medulla, central nervous system, inner ear, retina, optic lens, pigment cells, and branchial arch cartilages. Advances in molecular genetics and developmental biology have led to the identification of the causative genes and developmental pathways in all the EDs, as reflected in the 2022 classification system (table 1A) [3].

This topic review will focus on the classic EDs caused by genetic variants affecting the ectodysplasin signal transduction pathway (EDA, EDAR, EDARADD, and IKBKG), GJB6, and WNT10A. These include:

X-linked hypohidrotic ectodermal dysplasia (XLHED; MIM #305100)

Ectodermal dysplasia and immunodeficiency 1 (EDAID1; MIM #300291)

Ectodermal dysplasia 2, Clouston type (ECTD2; MIM #129500)

Tumor protein p63-related disorders and focal dermal hypoplasia (Goltz syndrome) are discussed separately. (See "Tumor protein p63 (TP63)-related ectodermal dysplasias" and "Focal dermal hypoplasia (Goltz syndrome)".)

CLASSIFICATION — Freire-Maia offered the original major classification scheme in 1971, with primary emphasis on involvement of hair, teeth, nails, or eccrine sweat glands [4]. A new classification proposed in 2009 and updated in 2014 provided a comprehensive list of syndromes and their etiologies [5,6]. In 2019, a newer classification system of EDs that incorporated the molecular etiology and the associated molecular pathways was published [2]. This classification system was further updated in 2022 (table 1A-B) [3].

HYPOHIDROTIC ECTODERMAL DYSPLASIA — Hypohidrotic ectodermal dysplasia (HED) is primarily characterized by hypohidrosis (decreased ability to sweat) or anhidrosis (inability to sweat), hypotrichosis (sparse hair), and hypodontia (missing and abnormal teeth). In 50 to 60 percent of cases, HED is inherited as an X-linked disorder (X-linked hypohidrotic ectodermal dysplasia [XLHED, XHED]), with the rest of the cases showing autosomal recessive or autosomal dominant inheritance.

Epidemiology — HED has been reported worldwide. Based on European data, the estimated incidence is 6.7 per 100,000 births [7]. Since the X-linked form is the most common, males are predominantly affected, although female carriers of an X-linked variant can manifest partial symptoms. Males and females are equally affected in the autosomal dominant and recessive forms of HED.

Pathogenesis — Most HED cases are X-linked. The rest of the cases are inherited in an autosomal dominant or recessive manner.

X-linked hypohidrotic ectodermal dysplasia – XLHED is caused by variants in the EDA gene, encoding the transmembrane protein ectodysplasin, a member of the tumor necrosis factor (TNF)-related ligand family involved in the early epithelial-mesenchymal interaction that regulates ectodermal appendage formation.

Autosomal recessive or dominant hypohidrotic ectodermal dysplasia – Autosomal recessive and dominant forms are due to variants in the ectodysplasin receptor gene EDAR in 10 to 15 percent of cases, EDAR-associated death domain gene EDARADD in 2 to 3 percent, and WNT10A in 15 to 20 percent [1,8]. The WNT gene family includes a group of related genes encoding signaling molecules involved in the differentiation of various cell lineages through the canonical Wnt/beta-catenin signaling pathway. The canonical EDA pathway is illustrated in the figure (figure 1).

In approximately 10 percent of HED cases, the genetic defect is unknown.

Clinical manifestations

Cutaneous findings — Hypotrichosis and hypohidrosis are the two cardinal cutaneous features of HED.

Hypotrichosis – Almost all affected individuals have thin, lightly pigmented, and slow-growing scalp hair compared with unaffected siblings (picture 1A-B) [9]. Facial hair, axillary hair, and pubic hair are not affected. Individuals with HED are prone to develop facial milia-like papules [10].

Hypohidrosis – Hypohidrosis is due to the reduced number and abnormal structure and function of eccrine sweat glands. Heat intolerance is virtually universal in affected individuals [9,11]. Hyperthermia due to the individual's inability to cool by sweating may be a life-threatening complication.

Newborn infants with HED may have unexplained fevers and are likely to have very dry, peeling skin [12]. In one survey, nearly 60 percent of children with HED had been initially misdiagnosed with eczema [13]. Darkened periorbital skin is also a common finding (picture 2). Individuals with HED tend to have a lack of dermal ridges. Occasionally, there are absent, hypoplastic, or accessory nipples (picture 3).

Extracutaneous manifestations

Hypodontia — Hypodontia is the third cardinal feature of HED. Children are often first suspected of having HED when eruption of the first tooth is delayed beyond 12 to 15 months of age. The average number of permanent teeth is nine. Central incisors and canines are often conical or peg shaped (picture 4) [9,14,15]. Alveolar ridges are hypoplastic due to the paucity of teeth. Absence of teeth and underdevelopment of the alveolar ridges lead to midface hypoplasia, a saddle nose deformity, and relative eversion of the lips.

Other eccrine gland abnormalities — Abnormalities and decreased numbers of other eccrine glands result in abnormal respiratory mucous (including in the lower airways), hard or sticky ear cerumen, decreased tears, and decreased saliva. Thick, tenacious respiratory mucous can cause nasal obstruction, and affected individuals have an increased risk of developing acute and chronic otitis media, sinusitis, nosebleeds, and pneumonia [11,16,17].

Individuals with HED have a higher rate of allergic rhinoconjunctivitis and asthma than the general population [13]. Abnormal meibomian glands lead to dry eye symptoms, including superficial, punctate keratitis [11]. A deep, raspy voice is a consequence of decreased saliva and abnormal respiratory mucous.

Low body mass index — The height-for-age of patients with HED does not differ significantly from that of the general population, but weight-for-age and body mass index (BMI) tend to be lower in the younger children, with gradual catch-up by early adulthood [11,18]. In infants and children, the cause of low BMI is due to multiple factors, including:

Abnormalities in mammary gland function in mothers affected by HED and carrier mothers, with subsequent nursing problems in affected infants [19]

Difficulty with swallowing due to decreased saliva

Difficulty with chewing due to hypodontia

Low weight-for-height may be somewhat protective against hyperthermia as these children have a relatively larger surface area-to-weight ratio and relatively more surface area to exchange heat with the environment.

The cognitive development in children and adolescents with HED is similar to that of the general population [20,21].

Mild hypohidrotic ectodermal dysplasia — Milder manifestations of HED can be found in female carriers of XLHED and in males and females with autosomal dominant hypohidrotic ectodermal dysplasia (ADHED) [1]. Females with XLHED may present with mild manifestations of any or all the cardinal features of HED, such as sparseness of hair; patchy alteration of sweat function; and presence of few, small, or missing teeth. Other features include underdeveloped nipples and reduced milk production.

Individuals with ADHED show similar, milder, and more generalized clinical manifestations than in XLHED yet lack the patchy, mosaic distribution of sweat gland dysfunction seen in some carrier females with XLHED.

Diagnosis

Clinical — Hypotrichosis, hypohidrosis, and hypodontia are the key clinical features that suggest the diagnosis of HED. Supplementary diagnostic tests include confocal microscopy for sweat gland count, trichogram examination, and skin biopsy.

Supplementary noninvasive tests — Noninvasive tests that support the clinical diagnosis of HED include:

Confocal microscopy – Confocal microscopy shows decreased sweat gland density in the palm of individuals with HED [22-24].

Trichogram examination – Trichogram examination (light microscopy examination of the proximal ends of shed hairs) identifies variable shaft abnormalities, including reduced thickness, trichorrhexis nodosa (picture 5), pili torti (picture 6), fewer terminal hairs, slower growth rate, fewer follicular units, and fewer hairs per unit [22,25].

Other – Other noninvasive methods include:

Inspection of the meibomian glands of the eyelid (meibography) [26].

Noninvasive measurement of tear film break-up time [27].

Evaluation of sweat production by pilocarpine iontophoresis [28].

Automated facial recognition is a promising noninvasive technology based on the analysis of facial images that may help in clinical diagnosis of XLHED [29].

Skin biopsy and histopathology — Although not routinely performed, a 4 mm punch biopsy of scalp or palmar skin can confirm the diagnosis of HED. The examination of horizontally sectioned biopsies shows rudimentary or absent eccrine glands [25]. Sweat glands are more likely to be absent in scalp than in palmar skin. Apocrine glands may be hypotrophic. In the scalp skin, the density of pilosebaceous units is also reduced.

Molecular diagnosis — Molecular testing is available to identify the specific genetic types of HED [1].

Male proband – In a male proband, the identification of a hemizygous EDA pathogenic variant or biallelic EDAR, EDARADD, or WNT10A pathogenic variants confirms the diagnosis.

The identification of a heterozygous EDAR, EDARADD, or WNT10A pathogenic variant confirms the diagnosis of mild HED in a male proband with mild manifestations of the cardinal features.

Female proband – In a female proband, the identification of biallelic EDAR, EDARADD, or WNT10A pathogenic variants establishes the diagnosis of classic HED.

The identification of a heterozygous EDAR, EDARADD, or WNT10A pathogenic variant confirms the diagnosis of mild HED in a female proband with mild manifestations of the cardinal features.

The identification of a heterozygous EDA pathogenic variant establishes the diagnosis of XLHED carrier status.

Serial single-gene testing is appropriate if physical findings are classic and family history is consistent with X-linked inheritance.

The initial step is sequence analysis of EDA. If no pathogenic variant is found, then deletion/duplication analysis of EDA should be performed.

If the proband's findings are classic and consistent with autosomal recessive inheritance or mild and consistent with autosomal dominant inheritance, then sequence analysis of EDAR, EDARADD, and WNT10A should be performed, followed by deletion/duplication analysis if no pathogenic variant is found by sequence analysis [1].

Multigene panels are available, which include EDA, EDAR, EDARADD, WNT10A, and multiple other genes of interest (table 1A). The genes included in these panels vary by laboratory.

Exome sequencing and whole genome sequencing are broader methods of molecular diagnostic testing and may be considered depending upon the patient's clinical presentation.

Prenatal diagnosis

Ultrasonography — Prenatal ultrasonography can include the assessment of the tooth germs and mandible [30,31]. Ultrasonography has been shown to reliably identify fetal tooth germs at 20 to 22 weeks gestation, with individuals with HED having a reduced number of tooth germs (fewer than six tooth buds in either the mandible or maxilla), as well as thin, hypoplastic alveolar bone.

Prenatal genetic testing — Prenatal genetic testing for a specific ED in an ongoing pregnancy is available via chorionic villus sampling or amniocentesis if there is a known familial pathogenic variant in EDA, EDAR, EDARADD, or WNT10A. In the absence of a family history of an ED, prenatal testing with a gene panel could be done if there are features of an ED seen by ultrasound, such as missing tooth buds. (See 'Ultrasonography' above.)

Preimplantation genetic testing is also available at the time of in vitro fertilization but only when familial pathogenic variants have been identified.

Differential diagnosis — The differential diagnosis of HED may be difficult, as there are at least 50 ED syndromes described, many of which have overlapping manifestations (table 1B). In individuals with HED features and recurrent infections, ectodermal dysplasia and immunodeficiency 1 (EDAID1; MIM #300291) and ectodermal dysplasia and immunodeficiency 2 (EDAID2; MIM #612132) should be considered. (See 'Ectodermal dysplasia and immunodeficiency' below.)

Treatment — The treatment of HED should be individualized based upon the specific characteristics of the individual affected. It requires a multidisciplinary approach that may involve pediatricians; multiple dental specialists (pediatric dentists, orthodontists, prosthodontists, maxillofacial surgeons); geneticists and genetic counselors; dermatologists; plastic surgeons; orthopedic surgeons; otolaryngologists; ophthalmologists; nutritionists; and occupational, physical, and speech therapists.

Prevention of hyperthermia and oral function restoration — Treatment of HED is primarily directed at preventing hyperthermia and restoring oral function.

Hypohidrosis and hyperthermia – Early diagnosis and close monitoring for hyperthermia is critical and possibly life-saving. Preventive measures include:

Avoiding hot environments as much as possible

Using air conditioning in the home, automobiles, and schools

Using cooling vests and hand-operated cool misters and fans

Dousing with cold water during athletic events

Additional information and suggestions can be found online at the National Foundation for Ectodermal Dysplasias.

The ability to recognize and manage hyperthermia improves with age. By older school age, many children can recognize that they are overheating and ask to move to a cooler environment, especially if an individualized education plan (IEP) is in place to guide teachers. One of the first signs of overheating may be increased redness. A "buddy system," so that friends in school can help notice increased redness and signs of overheating, may also be helpful.

Hypodontia, abnormal teeth – Early involvement with a pediatric dentist is essential, and ultimately, team management with a dentist, orthodontist, and prosthodontist is imperative. Early fitting with dentures (as young as two to four years of age) is essential for mastication, speech and language development, nutrition, and self-esteem. Dental procedures are not commonly covered by health insurance in the United States; the National Foundation for Ectodermal Dysplasias offers advice for insurance coverage strategies.

Management of other cutaneous and extracutaneous manifestations of HED — Other manifestations of hypohidrotic ectodermal dysplasia (HED) that may require specialist care include:

Hypotrichosis – Gentle hair products should be used for sparse and brittle hair. In one report, topical cetirizine and oral vitamin D supplementation improved hair density in three female children with HED [32]. Topical minoxidil has also been used with favorable effects in a few patients [33,34].

Wigs are often used due to sparse scalp hair. A written prescription for "cranial prosthesis" may be helpful for some patients to obtain a wig. In some cases, up to two wigs per year may be covered for growing children.

Eczema/dry skin – Gentle skin cleansers, moisturizers, and topical corticosteroids may be needed for patients with HED who have dry skin or frank eczema. (See "Treatment of atopic dermatitis (eczema)".)

Abnormal respiratory mucous – Close surveillance by a pediatrician; allergist; and ear, nose, and throat (ENT) specialist is needed to manage frequent respiratory infections and increased risk of atopy. Nasal saline rinses beginning at an early age are useful. Environmental smoke and other irritant exposures should be avoided.

Nutrition – Nasal passages should be cleared before meals. Drinking plenty of fluids with meals is helpful. Consultation with a nutritionist may be required for children failing to thrive.

Hearing – Close monitoring of hearing is important. Impaired hearing may result from hard cerumen impactions and chronic otitis media with effusion.

Speech and language – Speech therapy may help with management of complications of hypodontia, dry mouth, and hoarse voice.

Dry eyesArtificial tears can be used as needed.

Investigational therapies — Fc-EDA, a recombinant fusion protein consisting of the mouse receptor-binding domain of EDA (100 percent conserved between the mouse and human proteins) and the Fc domain of human immunoglobulin G1 (IgG1), is an ectodysplasin-A1 (EDA1) replacement molecule that binds to the EDA1 receptor (EDAR) and activates the signaling pathway for normal ectodermal development. In mouse models of XLHED, Fc-EDA administered intravenously or intra-amniotically to pregnant females resulted in permanent correction of the disease manifestations in the affected offspring [35,36]. Similar results were observed in dog models after postnatal intravenous administration and prenatal intra-amniotic administration of soluble recombinant EDA [37,38].

A phase 2 clinical trial of Fc-EDA administered within 2 to 14 days of birth to newborn males with XLHED was inconclusive [39]. Because the human sweat glands form between the 20th and 30th gestational weeks, the postnatal administration of ectodysplasin is unlikely to promote their development.

In a compassionate use setting, Fc-EDA was subsequently used by intra-amniotic administration for in utero treatment of three male fetuses affected by XLHED [40]. Two of the treated infants (twins with an older affected brother) had a normal sweat duct density on the soles of the feet, had normal pilocarpine-induced sweating at six months of age, and did not experience any hyperthermia episodes during the first five years of life [41].

Of note, postnatal magnetic resonance imaging (MRI) and radiographic imaging revealed the presence of 10 and 8 tooth germs in the twins, respectively. Similar findings were noted in the third treated infant, although he had a lower pilocarpine-induced sweat production at six months. Subsequently, three other male subjects were treated prenatally with Fc-EDA, with development of functional sweat glands.

A prospective, open-label, phase 2 trial of prenatal treatment of up to 20 male fetuses affected with XLHED is underway (NCT04980638) [42].

Genetic counseling — Consultation with a clinical geneticist is key for accurate diagnosis, recommendations for specialty assessments, and reproductive counseling. After a diagnostic visit, an updated genetic consultation is recommended prior to childbearing years, so that the affected individual can better understand their own reproductive risks and options.

Prognosis — With close monitoring to avoid the life-threatening complications of hyperthermia and multidisciplinary management of the clinical manifestations, the prognosis of HED for normal growth, development, and lifespan is excellent.

ECTODERMAL DYSPLASIA AND IMMUNODEFICIENCY

Ectodermal dysplasia and immunodeficiency 1 — Ectodermal dysplasia and immunodeficiency 1 (EDAID1; MIM #300291) is an extremely rare form of X-linked hypohidrotic ectodermal dysplasia (XLHED) seen in males due to hypomorphic variants in the gene for IKK-gamma (IKBKG), previously known as NEMO [43]. Patients have clinical features similar to hypohidrotic ectodermal dysplasia (HED), although often milder, in addition to severe, recurrent infections.

Pathogenesis — EDAID1 is caused by an X-linked pathogenic variant in IKBKG [44]. Incontinentia pigmenti (IP; MIM #308300) is allelic to X-linked EDAID1 and is caused by a different pathogenic variant (usually a deletion) in IKBKG. IP is typically identified only in female children, as it is generally lethal in utero in males due to the absence of the gene product. (See "Incontinentia pigmenti".)

HED with osteopetrosis and lymphedema is also due to variants in IKBKG [45-47] and is considered to be a subset of EDAID1.

Clinical features — Cutaneous and extracutaneous features of EDAID1 are similar to those seen in XLHED but are often milder (see 'Clinical manifestations' above). Male children with EDAID1 have rarely been noted to have a vesiculopapular eruption similar to that seen in female children with IP.

A wide range of immune defects have been described in patients with EDAID1, including natural killer cell dysfunction, hypogammaglobulinemia, and hypergammaglobulinemia M. (See "Syndromic immunodeficiencies".)

Affected individuals have severe, recurrent infections due to Staphylococcus aureus; Streptococcus pneumonia; Pseudomonas aeruginosa; Mycobacterium spp; and, more rarely, due to Pneumocystis, viruses, or Candida. Infections are often manifested as bronchiectasis, pneumonia, skin infections, osteomyelitis, or meningitis.

Inflammatory colitis occurs in approximately 20 percent of affected individuals, often with significant failure to thrive. Autoimmune hemolytic anemia occurs occasionally.

Diagnosis — EDAID1 should be suspected in male children with clinical features consistent with HED (hypohidrosis, hypodontia, hypotrichosis) and severe, recurrent infections. Extensive evaluation of the immune system should be directed by an immunologist. The diagnosis is confirmed by molecular genetic testing via IKBKG sequencing and deletion/duplication testing. Such testing is offered by several commercial genetic testing laboratories. In addition, sequencing and deletion/duplication testing for NFKBIA is available through single-gene testing and is also included in several immune deficiency gene sequencing panels.

Treatment — The management of the manifestations of HED is discussed above (see 'Treatment' above). Treatment of immunodeficiency involves immune globulin replacement; aggressive antibiotic treatment of severe, recurrent infections; and hematopoietic cell transplantation (HCT). (See "Syndromic immunodeficiencies".)

Allogenic HCT has been shown to cure most clinical immunodeficiency features, although it does not appear to cure colitis [48,49]. In a report on 29 patients with hypomorphic IKBKG/NEMO variants, the global survival rate after HCT among children with HED and immunodeficiency was 74 percent after a median follow-up of 57 months (range 4 to 108 months) [49].

Prognosis — Prognosis for long-term survival of individuals with EDAID1 and recurrent, severe infections is poor without HCT. Survival ranges from early infancy to late adolescence, with many patients dying in early childhood.

Ectodermal dysplasia and immunodeficiency 2 — Ectodermal dysplasia and immunodeficiency 2 (EDAID2; MIM #612132) is a rare form of HED with T cell dysfunction due to heterozygous variants in NFKBIA and is inherited in an autosomal dominant fashion [50]. (See "Syndromic immunodeficiencies".)

ECTODERMAL DYSPLASIA 2, CLOUSTON TYPE — Ectodermal dysplasia 2, Clouston type (ECTD2 [also known as Clouston syndrome]; MIM #129500) is characterized by nail dystrophy, hyperkeratosis of the palms and soles, and abnormal hair [51]. Individuals with ECTD2 are able to sweat and generally have normal teeth.

Epidemiology — The incidence and prevalence of ECTD2 are unknown. The syndrome was originally described in a large French-Canadian family in 1929 [52]. Later reports identified a large French kindred that had migrated to Scotland, Canada, and the northeastern United States. Clouston syndrome has been identified in families from China, Malaysia, Spain, Britain, and Africa.

Pathogenesis — ECTD2 is caused by variants in the gene encoding connexin-30, GJB6, on chromosome 13q11-q12.1 [53]. It is inherited in an autosomal dominant fashion, with nearly 100 percent penetrance. A rare form of ECTD2 with deafness is likely a contiguous gene syndrome with deletion of GJB6 and the connexin 26 gene, which is localized to 13q11-q12 [54].

Clinical features — Individuals with ECTD2 sweat normally and have normal dentition but with a tendency toward excess caries.

Hypotrichosis – In ECTD2, hair is described as fine, brittle, and sparse. Females are more likely to have total scalp alopecia than males, who may have patchy alopecia. Affected children may have sparse, fine hair early on, with progressive thinning to alopecia later. The eyebrows, eyelashes, and axillary and pubic hair are routinely affected and will be sparse or absent (picture 7).

Nail dystrophy – Fingernails and toenails are described as short, thick, and slow growing (picture 8). They can be discolored, hypoplastic, or absent. Nails can be cone shaped or triangular. Thickening of distal ends of fingers (clubbing) is also present.

Palmoplantar keratoderma – Affected individuals have palmoplantar hyperkeratosis, with thickening and dyskeratosis of the entire soles and parts of the palms (picture 9). (See "Palmoplantar keratoderma", section on 'Palmoplantar keratoderma associated with ectodermal dysplasia'.)

Skin hyperpigmentation – There can be hyperpigmentation of the skin over the knuckles, elbows, axillae, and areolae (picture 10). Breast development is normal.

Ocular abnormalities – Ophthalmologic defects reported in affected individuals include photophobia, strabismus, conjunctivitis, blepharitis, and premature cataracts.

Pathology — Hair from affected individuals is thin, with decreased tensile strength, disorganized fibrillary structure by light microscopy, reduced birefringence in polarized light, and abnormal cysteine and disulfide bonds [55]. There is disorganization of hair fibrils with loss of the cuticular cortex [56].

Diagnosis — The clinical diagnosis of ECTD2 is based upon the triad of hypotrichosis, nail dystrophy, and hyperkeratosis of the palms and soles. Molecular genetic testing to confirm the diagnosis should be performed via sequence analysis of GJB6.

Differential diagnosis — ECTD2 must be differentiated from other syndromes that primarily affect the nails and hair (table 1B):

Pachyonychia congenita – Pachyonychia congenita type 1 (MIM #167200) and type 2 (MIM #167210) are characterized by combinations of hypertrophic nail dystrophy, painful palmoplantar keratoderma, blistering, oral leukokeratosis, pilosebaceous cysts, palmoplantar hyperhidrosis, and keratosis on the trunk and extremities [51]. Of note, palmoplantar hyperkeratosis in Clouston syndrome is not painful. (See "Pachyonychia congenita".)

KID syndrome – KID (keratitis-ichthyosis-deafness) syndrome (MIM #148210) is an autosomal dominant disorder caused by heterozygous variants in the GJB2 gene, encoding connexin 26, and is characterized by erythrokeratoderma at birth (picture 11) and sensorineural deafness [57]. (See "Overview and classification of the inherited ichthyoses", section on 'KID syndrome'.)

Ectodermal dysplasia 5, hair/nail type – Ectodermal dysplasia 5, hair/nail type (MIM #614927) maps to chromosome 10q24.32-q25.1 and is characterized by dystrophic nails, thin scalp hair, fine eyebrows and eyelashes, and thin body hair [58]. No causative gene has been identified. The inheritance is autosomal recessive.

Ectodermal dysplasia 4, pure hair/nail type – Ectodermal dysplasia 4, pure hair/nail type (MIM #602032) presents with variable to complete alopecia and dystrophic nails [59]. It is caused by pathogenic variants in KRT85 and maps to 12q13.13. The inheritance is autosomal recessive.

Darier disease – Nail dystrophy is present in most patients with Darier disease (MIM #124200) (picture 12). The presence of warty papules and plaques in a seborrheic distribution suggests the correct diagnosis. (See "Darier disease".)

Treatment — Dystrophic nails may be covered with artificial nails for cosmetic purposes. There is a single case report of hypotrichosis treated with topical minoxidil and tretinoin with benefit [33]. Special hair care products may be used to manage dry and sparse hair. Many individuals choose to wear a wig.

Emollients and keratolytics are useful for palmoplantar hyperkeratosis.

Prognosis — Individuals affected by ECTD2 have an excellent overall prognosis and life expectancy.

SUMMARY AND RECOMMENDATIONS

Definition and classification – The ectodermal dysplasias (EDs) are a heterogeneous group of nearly 50 inherited disorders characterized by anomalies in at least two of the structures derived from the embryonic ectoderm, with at least one involving the skin appendages (hair, nails, sweat glands) or teeth (table 1A-B). Other tissues derived from the primitive ectoderm that can be involved in ED syndromes include the mammary gland, adrenal medulla, pituitary gland, inner ear, optic lens, cranial and sensory ganglia and nerves, retina, pineal body, pigment cells, and branchial arch cartilages. (See 'Introduction' above and 'Classification' above.)

Hypohidrotic ectodermal dysplasia – Hypohidrotic ectodermal dysplasia (HED) is primarily characterized by hypohidrosis or anhidrosis (inability to sweat), hypotrichosis (sparse hair), and hypodontia (missing and abnormal teeth). It is inherited in an X-linked manner (X-linked hypohidrotic ectodermal dysplasia [XLHED]) in 50 to 60 percent of cases. (See 'Hypohidrotic ectodermal dysplasia' above.)

Clinical manifestations – Cardinal clinical signs of HED are hypotrichosis, hypohidrosis, and hypodontia (picture 1B and picture 4). Abnormalities and decreased numbers of other eccrine glands result in abnormal respiratory mucous (including in the lower airways), hard ear cerumen, decreased tears, and decreased saliva. Milder manifestations of HED can be found in female carriers of XLHED and in males and females with autosomal dominant forms of HED. (See 'Clinical manifestations' above.)

Diagnosis – The clinical diagnosis of HED is based upon the finding of hypotrichosis, hypohidrosis, and hypodontia. The clinical diagnosis can be confirmed by genetic testing. (See 'Diagnosis' above and 'Molecular diagnosis' above.)

Management – The management of patients with HED requires a multidisciplinary approach. Treatment is primarily directed at preventing hyperthermia and restoring oral function. Measures to prevent hyperthermia include:

-Avoiding hot environments as much as possible

-Using air conditioning in the home, automobiles, and schools

-Using cooling vests and hand-operated cool misters and fans

-Dousing with cold water during athletic events

The management of hypodontia requires early involvement with a pediatric dentist, orthodontist, and prosthodontist. Additional information and suggestions can be found online at the National Foundation for Ectodermal Dysplasias. (See 'Treatment' above.)

Ectodermal dysplasia and immunodeficiency 1 – Ectodermal dysplasia and immunodeficiency 1 (EDAID1) is a rare form of XLHED associated with a wide range of immune defects. Affected patients present with cutaneous and extracutaneous features and severe, recurrent bacterial infections. Treatment of immunodeficiency involves immune globulin replacement; aggressive antibiotic treatment of severe, recurrent infections; and hematopoietic cell transplantation (HCT). (See 'Ectodermal dysplasia and immunodeficiency 1' above.)

Ectodermal dysplasia 2, Clouston type – Ectodermal dysplasia 2, Clouston type (ECTD2), also known as Clouston syndrome, is characterized by nail dystrophy, hyperkeratosis of the palms and soles, and abnormal hair. Individuals with ECTD2 are able to sweat and generally have normal teeth. (See 'Ectodermal dysplasia 2, Clouston type' above.)

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Topic 110146 Version 6.0

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