INTRODUCTION — The ectodermal dysplasias (EDs) are a heterogeneous group of nearly 100 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 1) [1,2]. Other tissues derived from the primitive ectoderm that can be involved in EDs 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 at least 80 of the EDs.
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:
●Hypohidrotic ED
●Hypohidrotic ED with immune deficiency
●Hidrotic ED
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 most common major classification scheme in 1971, with primary emphasis on involvement of hair, teeth, nails, or eccrine sweat glands [3]. A new classification proposed in 2009 and updated in 2014 provided a comprehensive list of syndromes and their etiologies [4,5]. In 2019, a newer classification system of EDs, which incorporates the molecular etiology and the molecular pathways involved, was published (table 1) [2].
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 approximately two-thirds of cases, HED is inherited as an X-linked disorder, also called Christ-Siemens-Touraine syndrome (MIM #305100), with the rest of the cases showing autosomal recessive or autosomal dominant inheritance.
Epidemiology — HED has been reported worldwide. Its estimated incidence is 1 to 2 in 10,000 births [1]. 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 in a mosaic pattern due to X-inactivation. Males and females are equally affected in the autosomal dominant and recessive forms of HED.
Pathogenesis — Most hypohidrotic ectodermal dysplasia cases are X-linked (XLHED; MIM #305100). 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 and dominant forms are due to variants in the ectodysplasin receptor gene EDAR in 10 to 15 percent, EDAR-associated death domain gene EDARADD in 1 to 2 percent, and WNT10A in 5 to 6 percent [6]. 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 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. Almost all affected individuals have thin, lightly pigmented, and slow-growing scalp hair compared with unaffected siblings (picture 1A-B) [7]. Facial hair, axillary hair, and pubic hair are not affected. Individuals with HED are prone to develop facial milia-like papules [8].
Hypohidrosis is due to the reduced number and abnormal structure and function of eccrine sweat glands. Heat intolerance is virtually universal in affected individuals [7,9]. 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. In one survey, nearly 60 percent of children with HED had been initially misdiagnosed with eczema [10]. 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 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) [7,11,12]. 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.
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. Individuals with HED have a higher rate of allergic rhinoconjunctivitis and asthma than the general population [10]. 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 [9,13,14]. Abnormal meibomian glands lead to dry eye symptoms, including superficial, punctate keratitis [9]. A deep, raspy voice is a consequence of decreased saliva and abnormal respiratory mucous.
The height-for-age of HED patients 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 [9,15]. 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 [16]; difficulty with swallowing due to decreased saliva; and 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 [17,18].
Mild hypohidrotic ectodermal dysplasia — Milder manifestations of HED can be found in female carriers of XLHED and in both 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 dysfunction seen in carrier females with XLHED.
Pathology — The histopathologic examination of horizontally sectioned biopsies of scalp or palmar skin shows rudimentary or absent eccrine glands. Sweat glands are more likely to be absent in scalp than in palmar skin [19]. Apocrine glands may be hypotrophic. In the scalp skin, there is a reduction in the density of pilosebaceous units.
Trichogram examinations identify variable hair 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 [19,20].
Diagnosis — Hypotrichosis, hypohidrosis, and hypodontia are the key clinical features that suggest the diagnosis of HED. Supplementary diagnostic tests include starch iodide palmar imprints, confocal microscopy for sweat gland count, trichogram examination, and skin biopsy:
●Starch iodide paper test – The starch iodide paper test is performed to evaluate eccrine function [19]. It is administered by exposing a vinyl-gloved hand to an infrared light source for five minutes. The glove is then removed, and the palm is immediately placed on a piece of specially prepared starch iodide paper. Patterned, purple discoloration marks sweat production. However, the sensitivity of this test is low [19].
●Confocal microscopy – Confocal microscopy is a noninvasive method that shows decreased sweat gland density in the palm of individuals with HED [20-22].
●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 [19,20].
●Skin biopsy – Although not routinely performed, 4 mm punch biopsy of the scalp and/or palmar skin demonstrating on horizontal sections a reduced number or absence of sweat glands is diagnostic of HED [19]. Sweat glands are more likely to be absent in scalp skin than in palmar skin. (See 'Pathology' above.)
Other noninvasive methods include inspection of the meibomian glands of the eyelid (meibography) [23], noninvasive measurement of tear film break-up time (NIBUT) [24], and evaluation of sweat production by pilocarpine iontophoresis [25]. Automated facial recognition is a promising noninvasive technology based on the analysis of facial images that may help in clinical diagnosis of XLHED [26].
Prenatal assessment can include sonography of the tooth germs and mandible [27,28].
Molecular diagnosis — Molecular testing is available to identify the specific genetic types of HED [1]:
●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.
●In a female proband, 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 other genes of interest (table 1). The genes included in these panels vary by laboratory.
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. 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 nearly 100 ED syndromes described, many of which have overlapping manifestations (table 1). In individuals with HED features and recurrent infections, HED with immune deficiency (HED-ID; MIM #300291) and ectodermal dysplasia, anhidrotic, with T cell immunodeficiency (MIM #612132) should be considered. (See 'Hypohidrotic ectodermal dysplasia with immune deficiency' 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.
Treatment 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; and 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.
Other manifestations of HED that may require specialist care include:
●Hypotrichosis – Wigs are often used due to sparse scalp hair. 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 girls with HED [29]. Topical minoxidil has also been used with favorable effects in a few patients [30,31]. 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 HED patients 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 eyes – Artificial 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 (EDA-A1) replacement molecule that binds to the EDA-A1 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 [32,33]. Similar results were observed in dog models after postnatal intravenous administration and prenatal intra-amniotic administration of soluble recombinant EDA [34,35].
However, a phase II clinical trial of Fc-EDA administered within 2 to 14 days of birth to newborn males with XLHED was inconclusive [36]. As the human sweat glands form between the 20th and 30th gestational week, 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 to treat in utero three male fetuses affected by XLHED [37]. Two of the treated infants (twins with an older affected brother) had a normal sweat duct density on the soles of the feet, normal pilocarpine-induced sweating at six months of age, and did not experience any hyperthermia episodes during the first 22 months of life. 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.
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 risk 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.
HYPOHIDROTIC ECTODERMAL DYSPLASIA WITH IMMUNE DEFICIENCY — Hypohidrotic ectodermal dysplasia with immune deficiency (HED-ID; MIM #300291) is an extremely rare form of X-linked hypohidrotic ectodermal dysplasia (XLHED) seen in males due to milder (hypomorphic) variants in the gene for IKK-gamma (IKBKG), previously known as NEMO [38]. Patients have clinical features similar to hypohidrotic ectodermal dysplasia (HED), although often milder, in addition to severe, recurrent infections.
Pathogenesis — HED-ID is most often caused by an X-linked pathogenic variant in IKBKG [39]. Incontinentia pigmenti (IP; MIM #308300) is allelic to X-linked HED-ID and is caused by a different pathogenic variant, usually a deletion, in IKBKG. IP is typically identified only in girls, as it is generally lethal in utero in males due to absence of the gene product. (See "Incontinentia pigmenti".)
HED-ID with osteopetrosis and lymphedema (MIM #300301) is also due to variants in IKBKG [40-42]. A rare form of HED with T cell dysfunction, due to variants in NFKBIA, is inherited in an autosomal dominant fashion (MIM #612132) [43].
Clinical features — Cutaneous and extracutaneous features of HED-ID are similar to those seen in XLHED but are often milder (see 'Clinical manifestations' above). Boys with HED-ID have rarely been noted to have a vesiculopapular eruption similar to that seen in girls with IP.
A wide range of immune defects have been described in patients with HED-ID, including natural killer cell dysfunction, hypogammaglobulinemia, and hypergammaglobulinemia M. (See "Combined 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 — HED-ID 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 — 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 "Combined immunodeficiencies", section on 'Treatment'.)
Allogenic HCT has been shown to cure most clinical immunodeficiency features, although it does not appear to cure colitis [44,45]. In a report on 29 patients with hypomorphic IKBKG/NEMO variants, the global survival rate after HCT among children with HED-ID was 74 percent after a median follow-up of 57 months (range 4 to 108 months) [45].
Prognosis — Prognosis for long-term survival of individuals with HED-ID and recurrent, severe infections is poor without HCT. Survival ranges from early infancy to late adolescence, with many patients dying in early childhood.
HIDROTIC ECTODERMAL DYSPLASIA (CLOUSTON SYNDROME) — Hidrotic ectodermal dysplasia (HED2; MIM #129500), also known as Clouston syndrome, is characterized by nail dystrophy, hyperkeratosis of the palms and soles, and abnormal hair. Individuals with HED2 are able to sweat and generally have normal teeth.
Epidemiology — The incidence and prevalence of HED2 are unknown. The syndrome was originally described in a large French-Canadian family in 1929 [46]. 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 — HED2 is caused by variants in the gene encoding connexin-30, GJB6, on chromosome 13q11-q12.1 [47]. It is inherited in an autosomal dominant fashion, with nearly 100 percent penetrance. A rare form of HED2 with deafness is likely a contiguous gene syndrome with deletion of GJB6 and the connexin-26 gene, which is localized to 13q11-q12 [48].
Clinical features — Individuals with HED2 sweat normally and have normal dentition but a tendency toward excess caries. In HED2, hair is described as fine, brittle, and sparse. Women are more likely to have total scalp alopecia than men, 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).
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.
Affected individuals have palmoplantar hyperkeratosis, with thickening and dyskeratosis of the entire soles and parts of the palms (picture 9). There can be hyperpigmentation of the skin over the knuckles, elbows, axillae, and areolae (picture 10). Breast development is normal.
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 [49]. There is disorganization of hair fibrils with loss of the cuticular cortex [50].
Diagnosis — The clinical diagnosis of HED2 is based upon the triad of nail dystrophy, hyperkeratosis of the palms and soles, and hypotrichosis. Molecular genetic testing to confirm the diagnosis should be performed via sequence analysis of GJB6.
Differential diagnosis — HED2 must be differentiated from the other ED syndromes that primarily affect the nails and hair (table 1):
●Pachyonychia congenita – Pachyonychia congenita (MIM #167200) is characterized by 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 "The genodermatoses: An overview", section on '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 characterized by erythrokeratoderma at birth (picture 11) and sensorineural deafness [52]. (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 [53]. The inheritance is autosomal recessive.
●Ectodermal dysplasia 4, pure hair nail type – Ectodermal dysplasia 4, pure hair nail type (MIM #602032) maps at 12q13.13 and presents with variable to complete alopecia and dystrophic nails [54].
●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. Hypotrichosis was treated in one individual with topical minoxidil and tretinoin [30]. 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 HED2 have an excellent overall prognosis and life expectancy.
SUMMARY AND RECOMMENDATIONS
●The ectodermal dysplasias (EDs) are a heterogeneous group of nearly 100 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 1). 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.)
●Hypohidrotic ectodermal dysplasia (HED), also called Christ-Siemens-Touraine syndrome, 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 in 65 to 75 percent of the cases. (See 'Hypohidrotic ectodermal dysplasia' above.)
●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 X-linked hypohidrotic ectodermal dysplasia (XLHED) and in both males and females with autosomal dominant HED. (See 'Clinical manifestations' above.)
●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.)
●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 using air conditioning in the home, automobiles, and schools; using cooling vests and hand-operated cool misters and fans; and dousing with cold water during athletic events. Additional information and suggestions can be found online at the National Foundation for Ectodermal Dysplasias. (See 'Treatment' above.)
●Hypohidrotic ectodermal dysplasia with immune deficiency (HED-ID) 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 'Hypohidrotic ectodermal dysplasia with immune deficiency' above.)
●Hidrotic ectodermal dysplasia (HED2), also known as Clouston syndrome, is characterized by nail dystrophy, hyperkeratosis of the palms and soles, and abnormal hair. Individuals with HED2 are able to sweat and generally have normal teeth. (See 'Hidrotic ectodermal dysplasia (Clouston syndrome)' above.)
