TP63-Related Disorders

Excerpt

Clinical characteristics: The TP63-related disorders comprise six overlapping phenotypes:

1. Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (which includes Rapp-Hodgkin syndrome)

2. Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome

3. Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3)

4. Limb-mammary syndrome

5. Split-hand/foot malformation type 4 (SHFM4)

6. Isolated cleft lip/cleft palate (orofacial cleft 8)

Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. Findings associated with a single phenotype include ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids), skin erosions especially on the scalp associated with areas of scarring, and alopecia, trismus, and excessive freckling.

Diagnosis/testing: The diagnosis of a TP63-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in TP63 identified by molecular genetic testing.

Management: Treatment of manifestations: A multidisciplinary team of specialists in clinical genetics, dermatology, ophthalmology, otolaryngology, audiology, dentistry and prosthodontics, plastic surgery, nutrition/gastroenterology, and psychology is recommended. Skin erosions are treated with gentle wound care and periodic, dilute bleach soaks to prevent secondary infection, and infants with severe skin erosions are monitored and treated aggressively for dehydration, electrolyte imbalances, malnutrition, and infection. Wigs can be used for sparse hair and alopecia; dentures may be considered in early childhood and dental implants in the teens or early adulthood. Cleft lip/palate is managed per routine protocols; limb malformations are treated with occupational therapy and surgery as needed to optimize function.

Surveillance: Regular attention to dental needs and possible hearing loss.

Genetic counseling: The TP63-related disorders are inherited in an autosomal dominant manner. Approximately 30% of individuals diagnosed with a TP63-related disorder have an affected parent. The proportion of individuals with a TP63-related disorder caused by a de novo TP63 pathogenic variant is approximately 70%. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Once the TP63 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.