Ectodermal Dysplasias including Incontinentia Pigmenti and p63-associated disorders

Conditions

The following conditions are the main focus of the Thematic Group Ectodermal Dysplasias including Incontinentia Pigmenti and p63-associated disorders.

Hypo/anhidrotic ectodermal dysplasia (HED)

Hypo/anhidrotic ectodermal dysplasia (HED) is a genetic disorder of ectoderm development characterized by malformation of ectodermal structures such as skin, hair, teeth and sweat glands. It comprises three clinically almost indistinguishable subtypes with impaired sweating as the key symptom: Christ-Siemens-Touraine (CST) syndrome (X-linked), autosomal recessive (AR), and autosomal dominant (AD) HED, as well as a fourth rare subtype with immunodeficiency as the key symptom (HED with immunodeficiency). HED is characterized by a triad of signs comprising sparse hair (atrichosis/hypotrichosis), abnormal (e.g. conical) or missing teeth (anodontia/hypodontia), and decreased or absent sudation due to a lack of sweat glands (anhidrosis/hypohidrosis) which leads to heat intolerance and may cause recurrent, potentially life-threatening hyperthermic episodes. The skin is thin, dry and eczematous with regional hyperkeratosis. Most of the patients suffer from ”dry eye” problems (e.g. chronic conjunctivitis, blepharitis), nasopharyngeal dryness and asthma-like symptoms. HED is associated with typical facial features such as a protruding forehead, sparse and fine eyebrows and eyelashes, wrinkles under the eyes, characteristic periorbital hyperpigmentation, a saddle-bridged nose, and hypoplasia of the mandible. Hair pigmentation is often absent or light. Failure to thrive may be observed. HED has a prevalence of approximately 1/15,000. CST syndrome is the most frequent sub-type (80% of cases) with an incidence in males of 1/50,000 to 1/100,000 births.

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Clouston syndrome (or hidrotic ectodermal dysplasia)

Clouston syndrome (or hidrotic ectodermal dysplasia) is characterised by the clinical triad of nail dystrophy, alopecia, and palmoplantar hyperkeratosis.
Nail abnormalities are the most consistent feature and frequently manifest at birth or in early infancy. The nails are thickened, slow growing, brittle, often hyperconvex and discoloured with striation. Additional reported features include micronychia, onycholysis and recurrent paronychial infections leading to nail loss. Hair involvement manifests at birth or later during infancy or childhood, and ranges from total to partial, often progressive, alopecia. Residual scalp hair is slow growing, sparse, fine and brittle. Eyebrows and eyelashes are also frequently sparse and axillary, pubic and body hair can be affected. Palmoplantar hyperkeratosis is not a constant finding. When present, it usually begins in childhood and tends to worsen with age; some patients also develop hyperkeratosis and hyperpigmentation over the joints and bony prominences. The teeth are usually unaffected and sweating is normal.
The exact prevalence is unknown and the syndrome is likely to be underdiagnosed.

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Papillon-Lefèvre syndrome (PLS)

Papillon-Lefèvre syndrome (PLS) is a rare ectodermal dysplasia characterized by palmoplantar keratoderma associated with early-onset periodontitis. Diffuse palmoplantar keratoderma with erythematous plaques develops between the first and fourth years of life, with the soles being usually more severely affected than the palms. Psoriasiform hyperkeratosis can overflow onto the dorsal surfaces of the hands and feet (transgredient spread) and, less frequently, lesions can be seen on the limbs (knees, elbows). Skin lesions are followed by intense gingivitis that rapidly progresses into periodontitis with alveolar bone lysis and early loss of primary dentition. The skin lesions are aggravated by cold and during episodes of severe periodontitis. During childhood, the phenomenon of periodontal disease recurs with rapid loss of permanent dentition. Cases of PLS with mild and/or late-onset periodontal disease have been reported occasionally. PLS is accompanied, in half of the patients, by enhanced susceptibility to cutaneous and systemic infections (furunculosis, skin abscesses, pyoderma, hidradenitis suppurativa (see this term), respiratory tract infection…). Patients may also present with malodorous hyperhidrosis, follicular hyperkeratosis, nail dystrophy or dural calcifications.
The prevalence is estimated between 1/250,000 and 1/1,000,000 individuals.

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Incontinentia pigmenti (IP)

Incontinentia pigmenti (IP) is a rare X-linked dominant multi-systemic ectodermal dysplasia usually lethal in males and presenting neonatally in females with a bullous rash along Blashko’s lines (BL) followed by verrucous plaques evolving over time to hyperpigmented swirling patterns. It is further characterized by teeth abnormalities, alopecia, nail dystrophy and affects occasionally the retina and the central nervous system (CNS). IP cutaneous findings typically present perinatally with an erythematous vesicular rash (bullous stage I) following BL: linear on extremities, swirled on trunk and head. Stage I evolves within a few months to a verrucous stage II characterized by wart-like plaques, lasting weeks to months. Stage III hyperpigmentation along BL occurs most frequently on the trunk and limbs and begins within months and can persist to adulthood. These three stages are not sequential, as stage I rash can recur during febrile illness. Stage IV, presenting from adolescence onwards, has hypopigmented, hairless regions following BL mostly evident on the lower extremities. About 50% of IP symptoms are extracutaneous. Delayed dentition, missing, and/or malformed cone shaped teeth occur in most cases. Other manifestations include onycodystrophy, alopecia and a wide range of ophthalmologic abnormalities with retinal neovascularization (RNV) conferring risk of retinal detachment and microphthalmia. CNS abnormalities may comprise microcephaly and neonatal stroke which can result in seizures, neurocognitive and motor impairments. The majority (>60%) of patients are neurologically normal.
Birth prevalence is approximately 1/ 143,000

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EEC syndrome

EEC syndrome is a genetic developmental disorder characterized by ectrodactyly, ectodermal dysplasia, and orofacial clefts (cleft lip/palate). The three cardinal signs of the syndrome are ectrodactyly and syndactyly of the hands and feet, cleft lip with or without cleft palate (that can result in speech defects), and abnormalities in several ectodermal structures including skin (i.e. hypopigmentated and dry skin, hyperkeratosis, skin atrophy), hair (i.e. fine and sparse hair and eyebrows), teeth (small, absent or dysplastic teeth), nails (nail dystrophy) and exocrine glands (reduction/absence of sweat, sebaceous and salivary glands). The syndrome presents a wide intra- and interfamilial clinical variability: the presence of the cardinal signs together is not mandatory and each one of them can be expressed in varying degrees of severity. Other associated clinical features include abnormalities of the genitourinary system (i.e. renal agenesis, urethral atresia, hydronephrosis), conductive or sensorineural hearing loss, choanal atresia, mammary gland/nipple hypoplasia, ophthalmological findings (i.e. lacrimal duct defects, photophobia, corneal ulcerations, keratitis, blepharitis, entropion), gland abnormalities (i.e. hypoplastic thymus, hypopituitarism, growth hormone deficiency), and on exceptional occasions, presence of a white sponge nevus, delayed developmental milestones, and malignant lymphoma. Patients do not have intellectual deficit.
The exact prevalence is not known. More than 300 cases have been described in the literature.

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Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC)

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is an ectodermal dysplasia syndrome with defining features of ankyloblepharon filiforme adnatum (AFA), ectodermal abnormalities and a cleft lip and/or palate. A history of skin erosions, especially of the scalp neonatally is typical. Congenital erythroderma occurs in 78%. Skin erosions often persist intermittently for many years, evolving into alopecia and cutaneous scarring of the skin. Wound healing appears to be delayed. Other prevalent skin manifestations include hyperpigmentation and/or hypopigmentation, often reticulated, and palmar and plantar changes with effaced dermatoglyphics. Nail changes are universal and variable and include hyperconvexity, pseudoptyergium and frayed distal margin with nail plate resorption. Hypotrichosis is common and hair is thin, brittle, wiry and uncombable. Mild hypohidrosis is always present. Nearly all cases have clefting abnormalities, ranging from submusous cleft palate, to soft and/or hard cleft palate, cleft lip or a combination. Other oroauditory findings include recurrent otitis media, canal stenosis and over 90% have a conductive hearing loss associated with a delay of speech development. AFA affects most neonates (70%) but is not always evident and eyes often are deficient of lacrimal puncta. In childhood, other facial features become more apparent and include broad nasal root, hypoplastic alae nasi, short philtrum, thin vermillion border, maxillary hypoplasia and small mandible. Over time, cone-shaped teeth and hypodontia become evident. Other anomalies are limb changes with syndactyly of fingers and toes most common, hypospadias (males 78%) and trismus (less frequently described). Failure to thrive, growth delay and gastrointestinal issues are also common.
The prevalence of AEC is unknown.

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Rapp-Hodgkin syndrome

Rapp-Hodgkin syndrome is a rare form of ectodermal dysplasia involving the hair, eyes, sweat glands, nails, teeth and palate. This syndrome is characterized by stiff sparse hair with the appearance of steel wool, sparse eyebrows and lashes, cleft palate, absence of lacrimal punctae, epiphora, a decreased number of sweat glands, and dystrophic nails. Cleft palate, hypodontia, abnormal tooth shape, multiple caries, delayed eruption of teeth are the main oral manifestations.

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ADULT (Acro-dermo-ungual-lacrimal-tooth) syndrome

ADULT (Acro-dermo-ungual-lacrimal-tooth) syndrome is a rare ectodermal dysplasia syndrome characterized by ectrodactyly, syndactyly, mammary hypoplasia, and excessive freckling as well as other typical ectodermal defects such as hypodontia, lacrimal duct anomalies, hypotrichosis, and onychodysplasia.

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