Paternal uniparental disomy 11p15.5 in the pancreatic nodule of an infant with Costello syndrome: Shared mechanism for hyperinsulinemic hypoglycemia in neonates with Costello and Beckwith–Wiedemann syndrome and somatic loss of heterozygosity in Costello syndrome driving clonal expansion

Abstract

Costello syndrome (CS) entails a cancer predisposition and is caused by activating HRAS mutations, typically arising de novo in the paternal germline. Hypoglycemia is common in CS neonates. A previously reported individual with the rare HRAS p.Gln22Lys had hyperinsulinemic hypoglycemia. Autopsy showed a discrete pancreatic nodule. The morphologic and immunohistochemistry findings, including loss of p57Kip2 protein, were identical to a focal lesion of congenital hyperinsulinism, however, no KCNJ11 or ABCC8 mutation was identified and germline derived DNA showed no alternation of the maternal or paternal 11p15 alleles. Here we report paternal uniparental disomy (pUPD) within the lesion, similar to the pUPD11p15.5 in Beckwith–Wiedemann syndrome (BWS). The similar extent of the pUPD suggests a similar mechanism driving hyperinsulinemia in both conditions. After coincidental somatic LOH and pUPD, the growth promoting effects of the paternally derived HRAS mutation, in combination with the increased function of the adjacent paternally expressed IGF2, may together result in clonal expansion. Although this somatic LOH within pancreatic tissue resulted in hyperinsulinism, similar LOH in mesenchymal cells may drive embryonal rhabdomyosarcoma (ERMS). Interestingly, biallelic IGF2 expression has been linked to rhabdomyosarcoma tumorigenesis and pUPD11 occurred in all 8 ERMS samples from CS individuals. Somatic KRAS and HRAS mutations occur with comparable frequency in isolated malignancies. Yet, the malignancy risk in CS is notably higher than in Noonan syndrome with a KRAS mutation. It is conceivable that HRAS co-localization with IGF2 and the combined effect of pUPD 11p15.5 on both genes contributes to the oncogenic potential.

Costello syndrome: Clinical phenotype, genotype, and management guidelines

“…Its etiology should be differentiated between an early rise in the central signal for puberty (early gonadotropin rise) or autonomous function of a sex steroid producing gonadal or other tumor. Different hormone producing tumors such as focal hyperinsulinism (Dickson et al, ; Gripp et al, ) and parathyroid adenoma (Cakir, Arici, Tacoy, & Karayalcin, ) have occurred.…”

Clinical practice guidelines for congenital hyperinsulinism

“…However, atypical cases with scattered patchy clusters of abnormal β cells have been reported (atypical CHI) ( 26 , 27 , 28 ). Furthermore, reports have described a case of Costello syndrome, with a mutation in the HRAS gene, presenting with a typical focal lesion indistinguishable from that caused by K ATP channel mutations ( 29 , 30 ). Even in patients with persistent CHI, the severity of hypoglycemia tends to improve over time and patients often achieve spontaneous remission without the need for medical treatment ( 31 ).…”

Hypoglycaemia represents a clinically significant manifestation of PIK3CA‐ and CCND2‐associated segmental overgrowth

“…A comparable endocrine picture is also seen in Beckwith‐Wiedemann (OMIM 130650) and Perlman (OMIM 267000) syndromes. Both disorders are associated with pancreatic islet cell hyperplasia and caused by pathogenic mechanisms considered distinct from the PI3K‐AKT cascade . Interestingly, mTORi have been showed as effective in treating BWS patients with resistant hypoglycaemia, suggesting that the cascade has at least some modifying effect on the underlying endocrine pathology .…”

“…Both disorders are associated with pancreatic islet cell hyperplasia and caused by pathogenic mechanisms considered distinct from the PI3K-AKT cascade. 10,11 Interestingly, mTORi have been showed as effective in treating BWS patients with resistant hypoglycaemia, suggesting that the cascade has at least some modifying effect on the underlying endocrine pathology. 11 These conditions have previously been described as "hyperinsulinism mimickers," presenting with clinical and biochemical sequel similar to congenital hyperinsulinism, without raised plasma insulin.…”