Ectodermal Dysplasias

Occasional Abnormalities

Hoarse voice, hypoplasia to absence of mammary glands or nipples, deficient milk production during nursing, absence of tears, failure to develop nasal turbinates, mild-to-moderate nail dystrophy, eczematous change in skin, asthmatic symptoms.

Natural History

Neonates with hypohidrotic ectodermal dysplasia may be diagnosed because of peeling skin, similar to that of “postmature” babies, and periorbital hyperpigmentation. In infancy irritability may occur because of heat intolerance. Hyperthermia as a consequence of inadequate sweating not only is a serious threat to life but may be the cause of intellectual disability, which is an occasional feature of this disorder. Living in a cool climate and cooling by water when overheated are important measures. The hypoplasia of mucous membranes plus thin nares may require a humidified environment and frequent irrigation of the nares to limit the severity of mucous clots and purulent rhinitis. External otitis and otitis media and lung infection may also be consequences of the mucous membrane defect. Mucous glands are hypoplastic to absent, not only in the respiratory tract, but in esophageal and colonic mucosa as well. Although the patient is often hairless at birth, some hair may develop. Short stature is not considered a feature of this disorder. Therefore, affected males with growth deficiency should be evaluated for other causes of short stature, such as endocrine deficiencies.

Etiology

The classic form of HED has, in 70% of cases, an X-linked recessive inheritance pattern. The gene ( EDA ) has been localized within the region Xq12-q13.1. It encodes a protein, ectodysplasin, which is important for normal development of ectodermal appendages. Deletions and duplications have been reported in 10% of cases, and still 10% of cases with the X-linked form do not have mutations or deletions identified in these genes. It has been estimated that 60% to 80% of female carriers can be identified by dental examination showing conic teeth. Sweat testing, coating the skin with an iodine solution that changes color with sweat, and raising temperature to induce sweating can identify a mosaic sweat pattern in greater than 90% of carrier females. Mutations in the ectodysplasin anhidrotic receptor ( EDAR ) gene located at 2q11-q13 (10% to 15%), as well as mutations in the ectodysplasin anhidrotic receptor–associated death domain ( EDARADD ) gene located at 1q42.2-q43 (1% to 2%), and loss-of-function and missense heterozygous mutations in the WNT10A gene, located on chromosome 2q35 (5-6%), are responsible for the autosomal dominant “mild” forms of HED, where as biallelic mutations of these three genes cause the recessive “classic” forms of HED. Nuclear factor kappa B (NF-κB) signaling responsible for ectodermal development is altered as a consequence of mutation in all those genes.

Comment

Loss-of-function and missense biallelic mutations in the WNT10A gene have been reported to cause Schopf-Schulz-Passarge syndrome (keratosis palmoplantaris with cystic eyelids, hypodontia, and hypotrichosis) and the odonto-onycho-dermal dysplasia, a rare form of severe ectodermal dysplasia. The phenotype may not be distinguished from classic HED, except for generalized microdontia. Heterozygous mutations can cause isolated hypodontia. Finger and toenails may be absent in cases with mutation of WNT10A .

Occasional Abnormalities

Short stature, ptosis, atretic ear canals, hearing loss, absent lingual frenulum and sublingual caruncles, glossy tongue, hypothelia, supernumerary nipples; in rare cases, ventricular septal defect or patent ductus arteriosus; micropenis, labial anomalies, vaginal dryness or erosions; split hand/split foot; camptodactyly; hypoplasia of toes; Wilms tumor.

Natural History

Surgical excision of the ankyloblepharon filiforme adnatum is required during the early neonatal period. However, photophobia is common. Surgical closure of facial clefting and early ophthalmologic evaluation of the lacrimal duct system are required. Hyperthermia occurs, in rare cases, in early childhood. Thereafter, although reduced sweating is described subjectively, heat intolerance is not usually a problem, and sweat studies may be normal. Superficial skin erosions vary from limited to severe full-body involvement. The erosions most typically affect the scalp at birth and during infancy. Severe scalp erosions often lead to scarring alopecia and hypotrichosis. Severe chronic granulomas of the scalp, which begin as infections, have been a serious problem. Otitis media occurs frequently.

Whereas the clefting seen in most genetic syndromes is consistent (i.e., either cleft lip with or without cleft palate [CLP] or cleft palate alone [CPA]), mixed clefting (the occurrence of CLP and CPA in the same family) occurs in this disorder. Deficient mucous coating of vocal cords can affect vocal quality. Speech and feeding may be affected.

Etiology

This disorder has an autosomal dominant inheritance pattern. Mutations of the TP63 gene located on 3q27 are responsible. More than 80% of documented mutations are found in the sterile alpha motif domain, with the remaining 20% occurring in. ΔNp63-specific N-terminal domain. Targeted studies of exons 13 and 14 can be done prior to whole gene sequencing.

Comment

Hay-Wells (AEC) syndrome and Rapp-Hodgkin syndrome are now thought to be the same condition with variable presence of ankyloblepharon. Mutations of the p63 gene have been identified in other phenotypes, including ectrodactyly–ectodermal dysplasia–clefting syndrome (EEC syndrome) type 3, dermato-ungual-lacrimal-tooth syndrome (ADULT syndrome), limb-mammary syndrome (LMS), and nonsyndromic split-hand/foot syndrome (SHFM) type 4, and isolated cleft lip and palate. Allelic heterogeneity for the same condi tion and marked clinical inter- and intrafamilial variability for single mutations are the rule within the wide spectrum of TP63 -associated disorders. Prenatal mutations testing should be accompanied by detailed ultrasound imaging for the presence of major defects such as ectrodactyly or clefting.

Occasional Abnormalities

Congenital heart defects, rhombencephalosynapsis, coloboma of the lower eyelids and/or iris, congenital cataract, Stahl deformity of the ear, prominent crus of the helix, natal teeth, absence of ear wax, hypospadias, diabetes mellitus, obesity, hair loss, hypertension, loss of libido.

Natural History

The area of aplasia cutis congenita heals over the first year with a lumpy surface consisting of bundles of connective tissue. The scalp hair is sparse in that area. Hypoplastic nipples are common. In some cases the breasts have not enlarged during pregnancy, nor has lactation occurred. The excess skin in the glabellar region has been excised and seen to be lipomatous. The frequency of urinary defects warrants investigation and follow up in order to prevent renal failure. Some cases suggest hypertension may also be a primary feature. Diabetes at an early age has been reported in only one family.

Etiology

Autosomal dominant inheritance. Both sporadic and familial cases with vertical transmission have been reported, as well as recurrence presumably owing to germline mosaicism. Potassium-channel tetramerization-domain-containing 1 ( KCTD1 ) mutations were found in a total of ten families affected by SEN syndrome. KCTD1 inhibits the transactivation of the transcription factor AP-2α (TFAP2A), and mutations in TFAP2A cause cutis aplasia in individuals with branchio-oculo-facial syndrome (BOFS).

Comment

The phenotypic features of SEN syndrome overlap with those of several syndromes, perhaps most notably ulnar-mammary syndrome and ectrodactyly with ectodermal dysplasia and cleft lip/palate syndrome (EEC), but also other ectodermal dysplasias.