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Background  Adrenocortical carcinomas (ACCs) are among the most common childhood cancers occurring in infants affected with the Li-Fraumeni and Li- Fraumeni-like (LFS/LFL) syndromes, which are caused by dominant germline mutations in the  TP53  gene. In Brazil, a particular mutation, occurring in the tetramerisation domain of the gene, p.R337H, is exceedingly common due to a founder effect and is strongly associated with ACC. In this report, we describe the phenotype and long-term clinical follow-up of a female child diagnosed with ACC and homozygous for the  TP53  p.R337H founder mutation.    Case presentation  At age 11 months, the patient was diagnosed with a virilising anaplastic adrenal cortical tumour, which was completely excised without disturbing the adrenal capsule. Family history was consistent with an LFL tumour pattern, and genotyping identified the  TP53  p.R337H mutation in both alleles in genomic DNA from lymphocytes and fibroblasts. Haplotype analysis confirmed the occurrence of the mutation in the same founder haplotype previously described in other Brazilian patients. No other germline or somatic  TP53  mutations or rearrangements were identified. At age 9 years, the child was asymptomatic and had no evidence of endocrine derangements. Full body and brain magnetic resonance imaging (MRI) failed to detect any suspicious proliferative lesions, and cardiopulmonary exercise testing results were within the normal reference for the child’s age, ruling out a major exercise capacity deficiency.    Conclusion  This is the first clinical and aerobic functional capacity documentation of a patient who carries two mutant  TP53  alleles and no wild-type allele. Our results support the hypothesis that  TP53  p.R337H, the most common  TP53  mutation ever described in any population, is a conditional mutant. Furthermore, our observations over a long period of clinical follow-up suggest that  TP53  p.R337H homozygotes do not have a more severe disease phenotype than do heterozygote carriers of the same mutation. Patients with the homozygous  TP53  p.R337H genotype will require careful surveillance for lifetime cancer risk and for effects on metabolic capacity later in life.

TP53p.R337H is a conditional cancer-predisposing mutation: further evidence from a homozygous patient