Expanding the phenotypic spectrum of TP63‐related disorders including the first set of monozygotic twins

Abstract

Individuals with Tumor Protein P63 (TP63)-related disorders are known to present with a range of phenotypic features, including ectrodactyly, ectodermal dysplasia, cleft lip/palate, Rapp-Hodgkin, Hay-Wells, and limb-mammary syndromes. We present six individuals from three families, including a set of monozygotic twins, with pathogenic TP63 variants who had novel clinical findings. The twins were discordant for cleft lip and palate, and the type of hand malformations, but concordant for choanal atresia, and bilateral volar nail. Both failed newborn screening for severe combined immunodeficiency (SCID) due to T-cell lymphopenia. The second family included three family members across two generations. Two of these three family members had orofacial clefting, but the remaining child had a laryngeal web and hydrocele with no clefting or hand anomalies, highlighting the variable expressivity in TP63-related disorders. The individual from the third family had unilateral cleft lip and palate, hydronephrosis, and bilateral volar nails. Together, these cases illustrate that: there is significant familial variability, including discordant major but concordant minor anomalies in the first ever reported set of molecularly confirmed monozygotic twins with pathogenic variants in TP63; pathogenic variants in TP63 should be considered in individuals with volar nail, which was previously only strongly associated with 4q34 deletion syndrome; and failed SCID newborn screening due to abnormal immune functioning may be part of the phenotypic spectrum of TP63-related disorders, as it was reported in one prior individual and two of the individuals in our case series.

Familial cleft tongue caused by a unique translation initiation codon variant in TP63

“…Furthermore, alternative splicing at the 3ʹend of both the TAp63 and ΔNp63 transcripts generates at least three different C-terminal variants (α, β, and γ) [8,10]. Cleft tongue has not been linked as a characteristic feature to TP63-related disorders until now [21][22][23]. However, other TP63 variants have been described to cause forms of orofacial clefts including cleft lip, cleft palate and cleft uvula [24][25][26].…”

In this issue

“…Nine different missense mutations were identified, which were distributed across the entire CDC42 coding sequence, and the individuals with these heterozygous mutations in CDC42 displayed an unusually broad spectrum of anomalies. For example, in group I, mutations linked to impaired binding to regulators and effectors caused a syndromic form of thrombocytopenia, which has been previously reported in individuals with CDC42 mutations (Takenouchi et al, 2015). Other clinical manifestations in this group included intellectual disability, abnormalities in muscle tone, and a variety of other less common features including cardiac malformations.…”

Mutations in P63 and IRF-6 Present with Overlapping Craniofacial Defects: A study from Lebanon

“…CLP are cardinal features of Ectrodactyly-Ectodermal-Dysplasia-Cleft-lip/palate (EEC) Syndrome, Ankyloblepharon-Ectodermal dysplasia-clefting (AEC) syndrome, and Rapp-Hodgkin Syndrome (a milder form of AEC), all of which are P63-related disorders. This highlights the importance of P63 in craniofacial development [1]. A second important transcription factor in craniofacial development is Interferon Regulatory Factor 6 (IRF-6), which when anomalous also results in syndromes characterized by lip/palate clefting.…”

“…P63-related disorders are divided into six major groups, each is categorized by a constellation of phenotypic features and deleterious heterozygous mutations in p63. These six groups are at times hard to clinically differentiate as many features are overlapping, in addition there is a wide range of intra-syndromic, and intra-familial variability [1].…”