Genome sequencing analysis of a family with a child displaying severe abdominal distention and recurrent hypoglycemia

Abstract

Background Germline mutations in PTEN are associated with the PTEN hamartoma tumor syndrome (PHTS), an umbrella term used to describe a spectrum of autosomal‐dominant disorders characterized by variable phenotypic manifestations associated with cell or tissue overgrowth. We report a boy who developed severe progressive abdominal distention due to a dramatic adipose mass from the age of 7 months and developed recurrent hypoinsulinemic hypoglycemia that led to seizures at the age of 4 years. Methods Trio‐based whole‐genome sequencing was performed by using blood DNA from the child and his parents. The possible pathogenic variants were verified by Sanger sequencing. Functional characterization of the identified variant was completed by western blot. Results The child inherited a single‐nucleotide deletion NM_000314.6:c.849delA (p.Glu284Argfs) in the tumor suppressor gene PTEN from his father. The paternal family members have a history of cancer. It is conceivable that PTEN loss‐of‐function induced the adipose tumor growth and hypoglycemia, although the proband did not meet the usual diagnosis criteria of Cowden syndrome or Bannayan–Riley–Ruvalcaba syndrome that are characterized by germline mutations of PTEN. Conclusion This case underlines the variability of phenotypes associated with PTEN germline mutations and provides useful information for diagnosis and genetic counseling of PTEN‐related diseases for pediatric patients.

Syndromic forms of congenital hyperinsulinism

“…Further publications pointed out that hypoglycemia with a similar biochemical profile may also occur in a subset of patients with other PI3K-AKT pathway disorders caused by (mosaic) activating mutations in AKT3, PIK3CA, PIK3R2, and CCND2, thus suggesting that this type of metabolic dysregulation is in principle shared by the entire group of disorders (43, 44). Consistent with this, Saito et al described a case of AKT1-caused Proteus syndrome with hypoinsulinemic hypoglycemia (45), and Liu et al reported a case with PTEN-related overgrowth (OMIM #158350) and recurrent hypoketotic hypoglycemia (46). Onset of hypoglycemia in patients with PI3K-AKT pathway disorders was variable, mostly within the first years of life but not typically neonatal.…”

“…described a case of AKT1-caused Proteus syndrome with hypoinsulinemic hypoglycemia ( 45 ), and Liu et al. reported a case with PTEN-related overgrowth (OMIM #158350) and recurrent hypoketotic hypoglycemia ( 46 ). Onset of hypoglycemia in patients with PI3K-AKT pathway disorders was variable, mostly within the first years of life but not typically neonatal.…”

The Progress of Colorectal Polyposis Syndrome in Chinese Population

“…84 Liu et al identified a PTEN germline variant (c.849 delA, P.Lu284argfs) in genetic testing in a child with no typical phenotype, which was clinically manifested as a persistently enlarged abdominal tumor with high fat content and repeated episodes of hypoglycemia. 85…”