Ankyloblepharon-ectodermal defects-cleft lip-palate syndrome due to a novel missense mutation in the SAM domain of the TP63 gene

Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (MIM number: 106260), also called AEC syndrome and Hay-Wells syndrome [1], is one of the rarest ectodermal dysplasia forms. It is a rare autosomal dominant disorder with an unknown prevalence [2]. The manifestations of AEC syndrome are present at birth. The majority of researchers consider that the phenotype associating ankyloblepharon filiform adnatum (congenital adhérences of the eyelids), cleft lip and/or palate and ectodermal dysplasia is the key criterion for the diagnosis of AEC syndrome [2, 3, 4]. Ectodermal defects usually consist of sparse wiry hair, skin erosions, onychodystrophy, dental changes and decrease in transpiration capacity.

Subsequent studies showed that this disorder most often results from mutations in the TP63 gene that affect the sterile alpha motif (SAM) domain in the protein [2, 3, 4, 5]. The diagnosis of AEC syndrome is firstly clinical, genetic testing of the causal gene may be useful to ascertain diagnosis and to define the inherited or de novo character of genetic abnormality. We report a Moroccan patient with clinical features of AEC syndrome caused by a new mutation in the SAM domain of the TP63 gene.

Clinical Report. The proband, a 2-years-old girl, was the third child of no consanguineous Moroccan parents. She was bom at term after normal pregnancy and caesarean delivery with a birth weight of 2.5Kg. Congenital diffuse erythroderma was observed. Wiry hair, localized alopecia, scalp dermatitis and erosions, absence of eyebrows and eyelashes, in combination with eyelids fusion (Figure 1) and cleft palate were reported by the treating physician at birth. Her hair started to grow at age of one year and teething began around 18 months of age.

Figure 1

Physical examination findings were characteristic and included dysmorphic features such as hypertelorism, pointed nose, prominent and low set ears in addition to a median cleft palate. The ankyloblepharon was operated at age of 3 months. Dermatological evaluation showed dry skin, sparse and frizzy hair with small areas of alopecia, sparse eye-brows and absent eyelashes. Patient had also oligodontia and dystrophic teeth and nail (Figure 2). The parents report that the patient has decreased sweating and heat intolerance. They report also that she has slow growth of the hair, multiple scalp infections treated and constantly watering eyes. Ophthalmological examination revealed obstruction of the lacrymal ducts and normal visual acuity. The patient also has a vaginal atresia discovered during a systematic medical examination. There were no malformations in the hands or feet. The psychomotor development, her weight and height were normal for her age. Cardiac, abdominal and pelvic ultrasonography did not find any malformations.

Figure 2

The parents are healthy, without a positive history for congenital and genetic diseases. There were no similar cases in the family.

Genetic Testing. Informed parental consent was obtained. DNA was extracted from peripheral blood collected from the affected child and his parents. According to the approach described in the literature, we performed sequence analysis of TP63 gene focusing on exons 13 and 14, which include the SAM domain [2]. TP63 mutations were identified by bi-directional sequencing of genomic DNA. Alamut interface with Polyphen2 and SIFT softwares were used to perform bioinformatic predictions of mutation effects.

The sequencing of TP63 gene in the patient DNA has led to the identification of a missense variant in the heterozygous state in exon 14 (c.1798G>C; p.Gly600Arg) (Figure 3). To our knowledge, this variant has never been reported in the literature or in the variations databases. Referring to Polyphen2, this amino acid substitution was predicted to be more likely deleterious. In the same context, SIFT predicted a damaging effect. Gly600 is located in the SAM domain of TP63 gene and its substitution to arginine produces a significant chemical change. According to the standards and guidelines for the interpretation of clinical significance of ACMG sequence variation, the variant c.1798G>C (p.Gly600Arg) in TP63 gene was in line with the interpretation rule of “likely pathogenic” mutation [PM1+PM2+PM3+PP2+PP3]. This variant was not found in either of the parents (Figure 3) and was therefore treated as the disease-causing mutation.

Figure 3

Hay-Wells or AEC syndrome is an autosomal dominant genetic disease characterized the presence of ankyloblepharon, ectodermal abnormalities (including sparse and frizzy hair, skin defects, nail alterations, dental changes, and hypohidrosis) associated with a clefting of the lip and/ or the palate. The majority of authors consider these as the cardinal features suggestive of this syndrome [2, 3, 4, 5, 6, 7, 8, 9, 10]. It has been reported that AEC syndrome includes erythroderma at birth with desquamation, superficial erosion and crusting [2]. These clinical manifestations were found in the case reported here. Erosive dermatitis and recurrent scalp infection at birth and during infancy, as present in our case, are major signs that orient differential diagnosis with similar genetic disorders. [11,12]. Eyelids fusion can be partial or complete, this pathognomonic phenomenon is known as ankyloblepharon filiforme adnatum. Lacrymal duct obstruction is a common feature of this syndrome and other eye findings can be observed. Other rare clinical findings include ear canal atresia, supernumerary nipples, heart defects, and genitalia anomalies [11], Our patient has vaginal atresia, this exceptional finding has been reported in clinical databases as a very rare symptom in this syndrome [2].

The differential diagnoses include ichthyosis and epidermolysis bullosa, but AEC syndrome is distinguished by the type of skin lesions and the associated clefting and eye findings [11]. We have also eliminated other syndromes, especially acro-dermo-ungual-lacrimal-tooth syndrome (ADULT syndrome), ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome (EEC), split hand/foot malformation (SHFM) and limb-mammary syndrome (LM Syndrome). Although these syndromes present overlapping phenotypes, distinct clinical features may be useful to differentiate them [2,13].

AEC syndrome is due to mutations in TP63, an essential gene for the maintenance of progenitor-cell populations that promote epithelial development and morphogenesis [4]. There has been shown that the most cases of this syndrome are caused by heterozygous missense mutations in the SAM domain, corresponding to exons 13 and 14 of the TP63 gene [3, 4, 5]. We have identified in our patient a new heterozygous missense substitution (c.1798G>C) in exon 14 of this gene leading to a p.Gly600Arg substitution in the SAM domain of the protein. The unaffected parents were not carriers of the mutation, which indicated that the mutation is assumed to be de novo in our patient (except for a low risk of parental germline mosaicism [14]). Bio-informatics tools predicted the pathogenicity of this mutation.

The genetic testing result of the TP63 gene supports our clinical diagnosis of AEC syndrome and showed the non-inherited nature of the causal mutation. These clinical and molecular findings are important for genetic counseling to the family. Regular evaluation of the patient with a multidisciplinary team was introduced to ensure adequate management and treatment of disease manifestations.