Ectodermal Dysplasia

Etiology

Ectodermal dysplasias are single-gene disorders with a variable mode of inheritance. Mutations in cell signaling processes involved in the induction and development of ectodermal structures and their interactions with mesodermal structures are central to the clinical manifestations of ectodermal dysplasias. For example, spontaneous mutations in the genes that affect the ectodysplasin signal transduction pathway resulting in signaling errors. This results in aplasia, hypoplasia, or dysplasia of epidermal appendages. This is classically observed in hypohidrosis ectodermal dysplasia.[1][2][3]

Epidemiology

The international prevalence of ectodermal dysplasia (ED) is approximately 7 per 10,000 births. The commonest variant is hypohydrotic ED, which is commonly X-linked with full-blown expression seen only in males.

History and Physical

The principal clinical features of ectodermal dysplasias (EDs) with prominent cutaneous features have been covered underneath.

1. Hypohidrotic Ectodermal Dysplasia: The most common form, X linked hypohidrotic ED, presents with a constellation of hair and tooth anomalies along with an inability to sweat. The affected neonates present with collodion like membrane along with prominent scaling. The scalp hair is sparse or absent with light-brown pigmentation. Affected infants clinically present with pyrexia of unknown origin and hyperthermia as early as the first few hours of life. This happens due to an inability to sweat to a detectable degree, which leads to elevation of core body temperature. In general, the history of heat tolerance is characteristic but not obligatory. The skin appears smooth due to disturbance in the dermatoglyphics due to absent eccrine pores. Facial dysmorphism is a diagnostic feature. Periorbital wrinkling, sebaceous hyperplasia of the face, saddle nose, fully everted lips, and prominent frontal bossing characterize the facial appearance. Teeth are usually peg-shaped with a reduced number. Basal secretions and cerumen are viscous, leading to recurrent respiratory tract infections. Atopic eczema is a common co-morbidity. Associated features include hoarseness of voice, gastroesophageal reflux, and unilateral or bilateral breast aplasia/hypoplasia. All of the above features are preferentially observed in males. Female patients show variability in the expression of clinical features ranging from a carrier state to a limited blaschkoid distribution or even a full-blown disease. This variability results from the random nature of X-inactivation. A subset of these patients present with immunodeficiency in the form of hypogammaglobulinemia and autoimmune cytopenias. In these patients, the decrease in sweating is relatively milder. Cutaneous manifestations in the form of erythroderma, seborrheic dermatitis, and intertrigo are common. Nails remain unaffected in hypohidrotic ED.[4][5]

 2. Hydrotic Ectodermal Dysplasia: It is also known as Clouston syndrome. This condition primarily affects the hair and nails with sparing of teeth and eccrine glands. The hair and nail changes manifest in early infancy and progress over time. The hair is 2. Hydrotic ectodermal dysplasia: it is also known as Clouston syndrome. This condition primarily affects the hair and nails with sparing of teeth and eccrine glands. The hair and nail changes manifest in early infancy and progress over time. The hair is wiry, brittle, and sparse. Patchy alopecia is a common feature. The nails are milky-white and small during infancy and show progressive thickening of the nail-plate with age, ultimately culminating in the separation from the distal end of the nail bed. Palmo-plantar keratoderma is a prominent feature. Palms and soles show stippled hyperkeratosis with a cobblestone-like pattern on the dorsal aspect. Oral leukoplakia has been observed. The sparseness of eyelashes predisposes to recurrent episodes of conjunctivitis and blepharitis.[6][7][8]

3. Wiktop Tooth and Nail Syndrome: Affected individuals present with thin, brittle nail plates that grow slowly. Koilonychia maybe evident since birth, which tends to improve overage. Nail abnormalities tend to involve toenails more. Both primary and secondary dentition is affected. The primary teeth may be conical or normal and show prolonged retention. Secondary dentition may be partially or totally absent, especially the mandibular incisors, maxillary canines, and second molars. Fried tooth and nail syndrome is a similar condition with additional consistent hair abnormalities and autosomal recessive inheritance.[9]

The above mentioned three disorders have been conventionally identified as classical ectodermal dysplasias.

4. Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome: Also known as Hay-Wells syndrome. Clinical features are evident right from birth. A classic erythrodermic presentation with peeling skin and underlying erosions is common, resulting in potentially fatal infections due to acute skin failure. The scalp is invariably involved in the form of a chronic oozing erosive dermatitis, patchy alopecia, and wiry hair—hair-shaft abnormalities such as the pili-torti range from hyperconvexity to anonychia. Sweating may be decreased with resultant thermal intolerance. Dental abnormalities include hypodontia and conical teeth. Additional features that differentiate this syndrome from other variants include hyper granulation tissue formation, recurrent skin infections, cribriform and stellate scarring of the shoulders and upper trunk, and reticulated pigmentation of the intertriginous areas. Congenital strands of tissue, also known as ankyloblepharon adnatum filiform, are observed between the eyelids, which might require surgical correction or resolve spontaneously. Lacrimal duct atresia may occur. External ear malformation may be observed. Almost all patients of AEC present with a cleft palate with or without cleft lip. Gastroesophageal reflux causing failure to thrive is present in most patients and is severe enough to warrant gastrostomy placement. Hypospadias, supernumerary nipples, and limb abnormalities are other associated features.[10][11]

Evaluation

A patient presenting with typical phenotypic characteristics of ectodermal dysplasia (ED) is first evaluated clinically with special emphasis on the presence/absence of sweating, hair/nail, and teeth abnormalities. Although primarily diagnosed clinically, further diagnosis of specific syndrome/subtype requires a series of investigations as, for example, a trichogram in a patient of hypohydrotic ED shows barcode hair, which is absent in the hydrotic variant. Even though usually unnecessary, a skin biopsy shows the absence of eccrine structures in cases of hypohydrotic ED or eccrine syringofibroadenomatosis in the case of hydrotic ED. Other investigations, such as X- rays of the limbs, may aid in diagnosing variants of ED.[12][13]

Treatment / Management

Following management strategies are utilized to treat multi-organ manifestations.

• Temperature Maintenance: Heat exposure must be monitored with strict monitoring of body temperature. Heat generating activities in older children must be tackled with physical cooling measures such as frequent drinking of cold liquids, wearing special cooling vests and caps.
• Teeth: Early dental management may lead to improved function and cosmetic outcome of the teeth. Bone grafting or sinus lift procedures, dental implants, and dental prostheses under orthodontist guidance are strongly advocated.
• Hair: Recently, 3% minoxidil has been tried to encourage hair growth in HED patients.
• Skin: Emollients are the choice of treatment for xerosis and collodion like presentation. In patients with AEC syndrome, the oozing erosions and chronic erosive scalp dermatitis require aggressive wound care and topical and systemic antibiotics administration.
• Others: Limb defects, ocular abnormalities require expert reference at the earliest.[14]The management of ectodermal dysplasias (EDs) needs a multifaceted approach.
(B3)

Differential Diagnosis

Ectodermal dysplasias (EDs) have broad differentials, few are discussed below.

• Hypohidrotic ED: Sjogren syndrome should be ruled out in oligosymptomatic patients. In full-blown disease, other EDs should be differentiated. Early neonatal hyperthermia worsening on incubation and neonatal phototherapy should be differentiated from other causes of pyrexia of unknown origin.
• Hydrotic ED: The typical nail involvement, along with palmoplantar keratoderma and oral leukoplakia, should be differentiated from pachyonychia congenita. The presence of hair abnormalities in hydrotic ED is the differentiating feature. Hydrotic ED closely resembles the pure hair-nail type of ED.
• AEC Syndrome: Neonatal erythroderma of AEC syndrome is typically confused with epidermolysis bullosa or bullous congenital ichthyosis. Rapp Hodgkin syndrome, which is now considered a part of the AEC spectrum, has an absence of ankyloblepharon. AEC's clinical features also resemble those of CHANDS syndrome (curly hair, ankyloblepharon, and nail dysplasia).
• EEC Syndrome: The main differentials of EEC are limb mammary syndrome and ADULT syndrome (Acro-Dermato-Ungual-Lacrimal-Tooth). The presence of normal scalp hair and mild hypohidrosis with a decreased incidence of cleft palate and absence of cleft lip is characteristic of limb mammary syndrome. ADULT is characterized by prominent frontal alopecia, absence of clefting, and additional photosensitivity. Other ectodermal dysplasias that feature digital abnormalities include ectodermal dysplasia, ectrodactyly maculo-dystrophy syndrome, Goltz syndrome, and popliteal pterygium syndrome.

Prognosis

If detected early ectodermal dysplasias (EDs) usually have a good prognosis with a normal life span. Appropriate, timely management of associated dental and skeletal problems and regulation of body temperature in the case of hypohydrotic variants considerably improves these patient's quality of life.

Complications

Loss of the skin's thermoregulatory function in cases of hypohydrotic ectodermal dysplasias (EDs) gives rise to episodic hyperthermia over the first three years of life with increased mortality. In childhood, hypohydrotic ED- asthma, recurrent URTI, and atopic dermatitis are common complications. Dental caries, loss of dentition can lead to difficulty in feeding. Mental retardation, growth retardation, disability due to skeletal deformities are common complications of many variants of EDs such as EEC. The presence of ankyloblepharon, recurrent inflammation of the lacrimal apparatus, can cause ocular surface complications and interfere with the visual function. Genitourinary anomalies may predispose to early renal failure. Recurrent respiratory and cutaneous infections due to underlying immune deficiencies can increase mortality and morbidity. Scarring alopecia secondary to erosive scalp dermatitis may occur in the AEC syndrome.[15][16]