Heterozygous mutations in the tumor protein p63 (TP63) gene underlie a spectrum of autosomal dominant syndromes, affecting ectodermal, limb, and orofacial development. We report an infant born with ectrodactyly (split-hand/foot malformation), cleft lip and palate, and a solitary kidney with hydronephrosis. Genetic testing revealed a heterozygous TP63 missense variant, c.740A>G (p.His247Arg), inherited from his affected father, confirming Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) syndrome. This case highlighted the clinical significance of the TP63 p.His247Arg mutation, previously reported as pathogenic in EEC. The infant's abnormalities required multidisciplinary management, including surgical, urologic, and nutritional support. Our findings emphasized the markedly variable expression associated with TP63-related disorders. The father, despite carrying the same mutation, exhibited only a milder clinical presentation. Early genetic diagnosis was crucial for tailored management and family counseling. This report underscores the importance of recognizing TP63 syndromes. It also reviews some relevant cases and studies from the literature and illustrates how genetic findings inform prognosis and guide comprehensive care in EEC syndrome.

Ectrodactyly, also called split hand/foot malformation, is a rare birth defect where some middle fingers or toes are missing or not formed properly, making the hand or foot look split. This condition can happen on its own or as part of more complicated syndromes such as ectrodactyly-ectodermal dysplasia-cleft syndrome. Surgery for young patients is usually tailored to their specific needs on the basis of how much the condition affects their ability to function and their appearance. In this manuscript, we reported a case of a Punjabi 6-year-old female presenting with difficulty in walking and an abnormal appearance of her left foot since birth. The clinical examination revealed the congenital absence of the second and third toes, syndactyly between the first and fourth digits, and a bony protrusion on the dorsum of the foot. The patient's radiological evaluation confirmed the absence of corresponding metatarsals and phalanges. The patient underwent a ray amputation of the first and fourth digits, along with the removal of the ectopic phalanx. The surgical procedure resulted in improved weight-bearing and cosmetic appearance. On the third postoperative day, the patient was discharged, and she demonstrated satisfactory healing and ambulation during follow-up. This case highlights the surgical management of a rare foot deformity associated with ectrodactyly in a child. Ray amputation proved to be a functional and aesthetically acceptable approach. Early recognition and tailored interventions are crucial for optimizing the patient outcomes in congenital limb anomalies.

Ectrodactyly-ectodermal dysplasia-cleft (EEC) syndrome is a rare genetic disorder presenting significant challenges for dental rehabilitation due to severe maxillary atrophy and altered anatomy. This report describes a 23-year-old female with EEC syndrome successfully rehabilitated using a custom-made subperiosteal implant. Despite multiple grafting procedures, conventional implants were not viable. A computer-aided design/computer-aided manufacturing-designed, laser-melted titanium subperiosteal implant was planned based on the cone beam computed tomography imaging and digital scans, ensuring optimal adaptation. At 18 months postsurgery, the implant remained stable, with no complications. This case highlights the potential of modern subperiosteal implants as a viable alternative for complex craniofacial reconstructions.

Recurrent somatic mosaic pathogenic variants of RHOA have been observed in a newly identified neuroectodermal syndrome, Ectodermal Dysplasia with Facial Dysmorphism and Acral, Ocular, and Brain Anomalies, Somatic Mosaic [EDFAOB]. All 12 previously reported patients had somatic mosaicism for RHOA variants. Conversely, no patients with non-mosaic germline variants of RHOA have been reported. The absence of non-mosaic patients has been explained by the presumed lethal effect of all RHOA variants in non-mosaic status. Here we report an 11-month-old female with EDFAOB-like features but without Blaschko's skin lesions or asymmetry. Characteristic features included hypertelorism, 2-3 toes cutaneous syndactyly, cleft palate and duplicated uterus and kidney malformations. She carried the non-mosaic de novo germline variant RHOA:c.202C>A,p.(Arg68Ser) near the hotspot in the switch II region in peripheral blood and buccal swabs. The documentation of a living patient with a non-mosaic germline variant of RHOA negates the previous notion that patients with RHOA variants are not viable. The differential diagnosis of a "non-mosaic" RHOA-related disorder would include Ectodermal Dysplasia-Ectrodactyly-Clefting syndrome, as both conditions share ectodermal dysplasia, finger anomalies, and clefting. This phenotypic similarity may be explained by the known molecular interaction between TP63, the gene responsible for EEC syndrome, and RHOA. RHOA is a member of the RAC subfamily of small Rho family guanosine triphosphatases, which include RHOA, RAC1, RAC3, and CDC42 (Takenouchi-Kosaki syndrome). The documentation of germline RHOA-associated intellectual disability in the present article establishes that variants in all three genes of the RAC subfamily of small Rho family GTPases are associated with neurodevelopmental disorders.

The TP63 gene is essential for epithelial proliferation, differentiation, and maintenance during embryogenesis. Despite considerable clinical variability, TP63-related symptoms are characterized by ectodermal dysplasia, distal limb malformations, and orofacial clefts. We identified a novel TP63 variant (c.619A > G, p.K207E) in a seven-month-old Chinese patient with orofacial clefts and ectrodactyly but no evident signs of ectodermal dysplasia. This phenotype was rarely reported before. We summarized the presence of the three main TP63-related manifestations in the literature and noted different distributions of CP- and CL/P-related variants regarding p63 structural domains.