Nephroblastomatosis or Wilms tumor in a fourth patient with a somatic PIK3CA mutation

Abstract

Wilms tumor and nephroblastomatosis are associated with syndromic conditions including hemihyperplasia. Hemihyperplasia is genetically heterogeneous and may be the result of genomic abnormalities seen in Beckwith–Wiedemann syndrome, mosaic chromosome or genomic abnormalities, or somatic point mutations. Somatic missense mutations affecting the PI3K-AKT-MTOR pathway result in segmental overgrowth and are present in numerous benign and malignant tumors. Here, we report a fourth patient with asymmetric overgrowth due to a somatic PIK3CA mutation who had nephroblastomatosis or Wilms tumor. Similar to two of three reported patients with a somatic PIK3CA mutation and renal tumors, he shared a PIK3CA mutation affecting codon 1047, presented at birth with asymmetric overgrowth, and had fibroadipose overgrowth. Codon 1047 is most commonly affected by somatic mutations in PIK3CA-related overgrowth spectrum (PROS). While the fibroadipose overgrowth phenotype appears to be common in individuals with PIK3CA mutations at codon 1047, individuals with a clinical diagnosis of Klippel–Trenaunay syndrome or isolated lymphatic malformation also had mutations affecting this amino acid. Screening for Wilms tumor in individuals with PROS-related hemihyperplasia may be considered and, until the natural history is fully elucidated in larger cohort studies, may follow guidelines for Beckwith–Wiedemann syndrome, or isolated hemihyperplasia. It is not known if the specific PIK3CA mutation, the mosaic distribution, or the clinical presentation affect the Wilms tumor or nephroblastomatosis risk in individuals with PROS.

Causal somatic mutations in urine DNA from persons with the CLOVES subgroup of the PIK3CA‐related overgrowth spectrum

“…Wilms tumor has been confirmed in 4 children and nephroblastomatosis confirmed in 2 children with PROS who have somatic PIK3CA mutations . In patients for whom clinical information has been published, most of these individuals’ phenotypic features fit best with the CLOVES syndrome subgroup .…”

“…Wilms tumor has been confirmed in 4 children and nephroblastomatosis confirmed in 2 children with PROS who have somatic PIK3CA mutations . In patients for whom clinical information has been published, most of these individuals’ phenotypic features fit best with the CLOVES syndrome subgroup . Additional case reports of Wilms tumor arising in individuals with KTS and MCAP were published before CLOVES syndrome was described and before somatic PIK3CA mutations were associated with CLOVES, KTS, and MCAP .…”

“…For example, a somatic missense mutation affecting the 1047th amino acid residue of PIK3CA (p.H1047R) was found in 15 of 162 individuals with PROS and in 160 of 1462 breast cancer specimens (cancer.sanger.ac.uk; accessed July 27, 2017) . Despite the frequent occurrence of somatic PIK3CA mutations in tumors, there are only a few case reports of individuals with mutation‐confirmed PROS developing cancer . This may be because of the short period of follow‐up available for most patients with PROS or because PIK3CA missense mutations enhance tumor growth but do not cause cell transformation.…”

Sonographic screening for Wilms tumor in children with CLOVES syndrome

“…Gripp and colleagues reported a fourth patient with asymmetric overgrowth due to a somatic PIK3CA mutation who developed WT. The infant had a small left kidney and large right kidney.…”

A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing

“…There are case reports of leukemia, meningioma, retinoblastoma, and Wilms tumor. Benign vascular tumors are common [Gripp et al, 2016].…”