A General Paediatric Approach to Ankyloblepharon–Ectodermal Dysplasia–Cleft Lip/Palate Syndrome in Infancy: A Case Report

A late preterm male infant, born at 35 + 4 weeks gestation, was transferred to a tertiary paediatric centre with erythroderma and ankyloblepharon. Additional examination findings included a cleft palate, foot syndactyly, hypoplastic nails, and renal cysts. Initial observation noted ichthyosiform erythroderma, with erosions to the scalp and folds. His condition posed immediate challenges, including significant insensible fluid losses, temperature instability, and loss of barrier function with a predisposition to cutaneous infection. Antenatal scans revealed a unilateral non-communicating renal cyst and left-sided 2/3 toe syndactyly. Amniocentesis at 20 weeks' gestation was completed, with a fluorescent in situ hybridisation and molecular karyotype not detecting a clinically significant genomic imbalance. Subsequent Clinical Exome Comprehensive Trio Analysis at 28 weeks' gestation was not suggestive of a monogenic disorder. There was no consanguinity and no relevant family history. On initial review, the infant was hypothermic. Widespread erythroderma (Figure 1) with fine superficial scale of the scalp quickly developed into erosions on the scalp and flexural surfaces. All ten hand nails were noted to be hypoplastic. There were no blisters on the skin or mucosal membranes. Nikolsky sign was negative. There was no history of collodion membrane. Trichoscopy was unremarkable, with no evidence of Trichorrhexis invaginate. Syndactyly and ankyloblepharon were noted. The preferred differential diagnoses were Ectrodactyly Ectodermal Dysplasia-Cleft Lip/Palate Syndrome 3 (EEC3; MIM#604292) syndrome, Ankyloblepharon-Ectodermal Dysplasia-Cleft Lip/Palate (AEC; MIM#106260) syndrome, or Rapp-Hodgkin Syndrome (RHS; MIM#129400). Clinical Genetics: The existing pre-natal Clinical Exome Comprehensive Trio Analysis included Polydactyl v0.275, Intellectual disability syndromic and non-syndromic v0.5767, Congenital abnormalities of the kidneys and urinary tract (CAKUT) SuperPanel v1.83, CAKUT Syndromic v0.138, Desmosomal disorders v0.5, Fetal Anomalies v1.231, and Mendeliome v1.1686. This was extended to include Ichthyosis v1.9, Immunological disorders_ SuperPanel v9.246, Clefting disorders v0.249, and Ectodermal Dysplasia v0.85. Additional Human Phenotype Ontology terms included erythroderma, fused eyelids, cleft palate, low-set ears, foot oligodactyly, and toe syndactyly. Results demonstrated a pathogenic variant in the TP63 gene, specifically c.1646 T>A; p.(IIe549Asn), consistent with a genetic diagnosis of RHS. Immunology: The patient was referred to immunology for CD4+ and CD8+ T cell lymphocytopenia with the differential of Omenn syndrome (MIM#603554). However, repeat lymphocyte sub-sets, eosinophil count, and immunoglobulins were normal. Nephrology: Serology demonstrated a peak creatinine of 130 (10–30 umol/L) following significant insensible fluid losses, which were managed with multiple fluid boluses and an incubator. His renal function normalised and he will continue to receive regular follow-up ultrasounds in view of the antenatally diagnosed renal cysts. General Paediatric: The risk of faltering growth was contributed to by his insensible fluid losses and difficulty feeding secondary to his cleft palate. The patient was fed via bottle with a pigeon teat and nasogastric thickened top-ups. His mild–moderate sensorineural hearing loss will be followed up by the audiology team in conjunction with the general paediatric team. Ophthalmology: The right-sided ankyloblepharon was surgically corrected by division and punctum exploration. He was referred for bilateral nasolacrimal duct probing with dilatation and stenting due to recurrent purulent discharge likely secondary to bilateral nasolacrimal duct obstruction. Plastic and Orthopaedic Surgery: The cleft palate repair was planned for 12–18 months of age, with concurrent correction of the syndactyly in consultation with the orthopaedic team. This case represented a management challenge. The aim of treatment was to improve skin integrity and prevent erosions and the complications with this, including secondary infection and subsequent scarring alopecia. Given the paucity of evidence for an optimal management plan, several different topical therapies were trialled. He was treated with the liberal application of emollients (50% white soft paraffin in liquid paraffin) with more frequent use on areas of erosion (Figure 2A). Frequent bleach baths were incorporated to prevent secondary infection. For the treatment of infected wounds, topical 2% mupirocin or 2% fusidic acid ointment was recommended. The discharge plan included twice-daily application of emollients to the whole body, with zinc oxide paste reserved for diaper areas. Regular bleach baths were a mainstay of ongoing management. For the heavily scaled areas (Figure 2B), overnight oil soaks and gentle de-scaling with a moist flannelette were recommended. This was followed by application of methylprednisolone aceponate ointment and topical clindamycin to the de-scaled areas. AEC syndrome (also known as Hay-Wells Syndrome) and RHS are rare autosomal dominant ectodermal dysplastic syndromes caused by mutations in the tumour protein P63 (TP63), a gene within the p53 family. Despite several pathognomonic clinical features, there are seven TP63-related disorders with overlapping phenotypes [1]. This syndrome is part of a heterogeneous group of disorders classified as ectodermal dysplasia (ED) [1]. They are further distinguished into hypohidrotic ED or hidrotic ED [2]. The three most common and clinically ambiguous hypohidrotic ED syndromes include AEC syndrome, EEC3 syndrome, and RHS [2]. These three syndromes have varying combinations of ED, which are defined as affecting two or more ectodermal lineages such as hair, teeth, nails, and sweat glands [1]. The key overlapping features of AEC syndrome and RHS include ectodermal dysplasia and cleft lip/palate [3]. Less well-described features include syndactyly, as well as sensorineural hearing loss and immune dysregulation. Persistent erosive scalp lesions and ankyloblepharon filiforme adnatum differentiate AEC from RHS [3]. However, we describe a case with ankyloblepharon and a pathogenic variant consistent with RHS, adding weight to the fact that they likely represent variable expression of a single genetic disorder [3]. Other notable differentials include Generalised Epidermolysis Bullosa Simplex (EBS; MIM#131760), Dystrophic Epidermolysis Bullosa (DEB; MIM#226600), Congenital Ichthyosis (MIM#226600) and Netherton's Syndrome (MIM#256500). Epidermolysis bullosa is a common differential diagnosis in the preliminary stages, as skin erosions can often mimic blisters found in this condition [4]. Similarly, congenital ichthyosiform erythroderma is another common misdiagnosis in these patients, as the collodion membrane is difficult to distinguish from erythroderma and erosions initially [4]. Lastly, Netherton Syndrome presents in the neonatal period with generalised exfoliative erythroderma with or without Trichorrhexis invaginate (‘bamboo hairs’). Thus, AEC syndrome should be considered in patients with skin erosions and/or erythroderma [5]. Importantly, this report suggests that the presence of renal cysts and ectrodactyly, and absence of scalp erosions can assist in differentiation between EEC and AEC syndrome. Renal cystic dysplasia has been well documented in EEC syndrome; the contrary appears apparent for AEC syndrome [6]. However, the literature suggests that screening for genitourinary abnormalities may be beneficial, as a case report identified a patient with AEC syndrome requiring dialysis for chronic kidney disease [7]. Other documented features of AEC syndrome include conductive hearing loss, lacrimal duct obstruction, tooth abnormalities, dystrophic nails, sparse hair, hypohydrosis, and poor growth [4]. The wide heterogeneity of ED syndromes demonstrates the importance of the application of the Whole Exome Sequence and targeted gene panels. This is evidenced by another missense variant comparable to the one identified in this case that has previous evidence for pathogenicity. A similar base substitution at position 549 on Chromosome 3 has been previously reported de novo in an individual with ankyloblepharon-ectodermal defects and cleft lip and palate syndrome in an individual with RHS [3]. Dominant negative, loss of function, and gain of function are known mechanisms of disease in the TP63 gene. Dominant negative is associated with EEC3, Limb-Mammary Syndrome (MIM#103285), RHS, and AEC. While gain of function is associated with ADULT syndrome (MIM#103285), loss of function is likely associated with Orofacial cleft 8 (MIM#618149) [8]. Although patients with ED require a multidisciplinary approach, dermatological management plays a central role in all stages of care. TP63-related conditions are known to have wide phenotypic variability attributable to the variable expressivity of the mutations. Thus, management will depend on the clinical manifestations. In addition to the mainstay treatments for skin erosions that largely involve gentle cleansing and emollient use, there are emerging therapeutic strategies which include a novel cream termed PRIMA-1MET/APR-246. This therapy utilises a P53-reactivating compound that has been successfully shown to improve skin erosions in patients with AEC syndrome [9]. One study demonstrated that after 11 weeks of daily topical treatment, re-epithelialisation of skin erosions was observed and had a significant benefit to pain scores, as analysed with a visual analogue scale [9]. Continual improvement was witnessed at 33 weeks, with epidermalisation being almost complete but not fully cornified [9]. Thus, these findings suggest that PRIMA-1MET/APR-246 could be used in early epidermal differentiation, to improve wound healing and reduce epidermal barrier dysfunction [9]. Additionally, stem cell-based therapy has been considered to create genetically autologous keratinocytes to allow for effective treatment of skin erosions [10]. As such, future research should focus on characterising the likelihood of rejection from these transplanted keratinocytes [10]. The authors have nothing to report. Ethics approval is exempt as per The Royal Children's Hospital Ethics Committee. The patient's guardian provided written consent for publication. The authors declare no conflicts of interest.