Clinical Heterogeneity of a TP53 Variant in a Consanguineous Omani Family: A Case Report Featuring a Homozygous...

Li-Fraumeni syndrome (LFS) is a rare, autosomal dominant cancer predisposition syndrome caused by germline mutations in the TP53 gene. While heterozygous TP53 variants are well-characterized, homozygous germline mutations are extremely rare, and their clinical significance remains poorly understood. Such cases are more likely to arise in consanguineous families, where shared genetic ancestry increases the risk of homozygosity.

We report a consanguineous Omani family with a homozygous TP53 missense variant, in a male infant who presented with multiple hypopigmented skin macules and a strong family history of childhood and adult-onset cancers. Several relatives were identified as heterozygous carriers of the same pathogenic variant. A deceased older sibling exhibited similar cutaneous findings and early malignancy, suspecting he may also have carried the homozygous variant. These skin manifestations may represent a novel phenotypic feature not previously associated with LFS.

This case adds to the limited literature on homozygous TP53 variants and raises the possibility of a link between cutaneous features and homozygosity. While heterozygous carriers often exhibit variable penetrance, the homozygous state may be associated with earlier and more severe phenotypes. Genetic counseling in such families is complex due to uncertainty in predicting clinical outcomes and the psychosocial burden of decision-making, particularly in children. Challenges in family communication further hinder risk awareness and testing uptake.

This is the first reported case of a homozygous TP53 p.Arg158His variant in the Omani population, expanding the phenotypic spectrum of LFS. Our findings underscore the importance of genetic counseling, cascade testing, and long-term surveillance in consanguineous families with hereditary cancer syndromes, and call for further research into genotype-phenotype correlations and associated dermatological findings.