JYY Poon, HM Luk, IFM Lo

What is the diagnosis?

The girl presents with ectodermal defects, ankyloblepharon and central cleft palate at birth with facial dysmorphism. The overall features were compatible with the diagnosis of Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome.

Tumour protein p63 (TP63) sequencing confirmed a heterozygous {NM_003722.4}:c.1747G>T, p.Asp583Tyr variant. It is a missense variant that changed the 583rd amino acid from Aspartic acid to Tyrosine. Parental testing confirmed paternal inheritance of the same variant. The variant has been reported in literature to be disease causing associated with AEC syndrome. It was not reported in ClinVar and has a REVEL score of 0.875. This variant is classified as pathogenic by American College of Medical Genetics and Genomics (ACMG) guideline 2015 and the molecular diagnosis of AEC syndrome was confirmed.

What are the clinical features?

The TP63-related disorders includes six disease entities with overlapping phenotypes, including AEC syndrome; Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome; Ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3), Limb-mammary syndrome, Split-hand/foot malformation type 4 (SHFM4) and Isolated cleft lip/cleft palate (orofacial cleft 8).¹

AEC syndrome [MIM#106260], also known as Hay-Wells syndrome, is a rare genetic disease and its prevalence is unknown currently. To date, over 100 patients have been reported in literature.² The features of AEC syndrome including ectodermal defects and clefting are usually present in affected newborn at birth, while 70% have ankyloblepharon. Ectodermal defects include skin erosions typically affecting the scalp and congenital erythroderma, which are prone to skin infections and subsequent post-inflammatory cutaneous depigmentation and scarring are common. Other ectodermal features become more apparent with age, including hair anomalies such as light coloured, wiry and brittle hair; nail anomalies such as dysplastic or hyperconvex nails with distal frayed edges; and dental anomalies such as hypodontia, conical shaped or widely spaced teeth.

Facial dysmorphism are present in 90% of affected individuals, with features including maxillary hypoplasia, micrognathia, broad nasal root, hypoplastic alae nasi, thin upper lip and short philtrum. Other limb deformities have been reports in 12% of affected individuals in a case series of patients with AEC syndrome, including the presence of split hand or foot malformations.³ Over 90% of individuals also have conductive hearing loss with subsequent speech delay and failure to thrive during infancy is also common.

What is the genetic basis of AEC Syndrome?

AEC syndrome is caused by pathogenic variants of the TP63 gene, which is mapped to chromosome 3q28. The p63 protein is a member of the p53 tumour suppressor family but does not function as a classic tumour suppressor.⁴ It is a DNA sequence specific transcription factor which is important for the regulation of proliferation and differentiation of the epidermal structures,² including the skin, hair, nails and teeth, as well as craniofacial and limb development. Missense variants account for the majority of mutations and those affecting the sterile alpha motif (SAM) domain and transactivation inhibitory (TI) domain of p63 protein are typically associated with AEC syndrome.^5,6 AEC syndrome shows an autosomal dominant inheritance and 70% of cases are de novo.²

What is the management of AEC Syndrome?

Multidisciplinary and individualised management are essential in the treatment of AEC syndrome, involving paediatricians, dermatologists, paediatric surgeons, ophthalmologists, clinical geneticists and speech therapists.

The overall prognosis is good with a normal life expectancy. However, the risk of serious complications including secondary skin infections requires early recognition and management. Surgical management is required for correction of ankyloblepharon, cleft palate and other complications such as lacrimal duct obstruction or limb deformities. Continual monitoring of growth and development, as well as psychosocial support is warranted.

References

1. Sutton VR, van Bokhoven H. TP63-Related Disorders. 2010 Jun 8 [Updated 2021 Apr 1]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

2. Serra G, Antona V, Giuffré M, et al. Novel missense mutation of the TP63 gene in a newborn with Hay-Wells/Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndrome: clinical report and follow-up. Ital J Pediatr 2021;47:196.

3. Sutton VR, Plunkett K, Dang DX, Lewis RA, Bree AF, Bacino CA. Craniofacial and anthropometric phenotype in ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (Hay-Wells syndrome) in a cohort of 17 patients. Am J Med Genet A 2009;149A:1916-21.

4. Sathyamurthy A, Freund SM, Johnson CM, Allen MD, Bycroft M. Structural basis of p63α SAM domain mutants involved in AEC syndrome. FEBS J 2011;278:2680-8.

5. Yang A, Schweitzer R, Sun D, et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 1999;398:714-8.

6. Rinne T, Bolat E, Meijer R, Scheffer H, van Bokhoven H. Spectrum of p63 mutations in a selected patient cohort affected with ankyloblepharonectodermal defects-cleft lip/palate syndrome (AEC). Am J Med Genet A 2009;149A:1948-51.