Elsevier

Gene

Volume 512, Issue 2, 10 January 2013, Pages 194-197
Gene

Novel PTEN germline mutation in a family with mild phenotype: Difficulties in genetic counseling

https://doi.org/10.1016/j.gene.2012.09.134Get rights and content

Abstract

PTEN gene (phosphatase and tensin homolog deleted on chromosome ten, MIM 601628) is a tumor suppressor gene implicated in PTEN hamartoma tumor syndromes (PHTS) including Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome and Proteus-like syndrome. PTEN mutations have been more recently reported in children with macrocephaly and autism spectrum disorders or mental retardation, without other symptoms of PHTS. Although tumor risk has not been evaluated in these patients and their relatives, the same surveillance as for Cowden syndrome is usually proposed. We report a family including patients carrying a novel PTEN mutation and presenting with a mild phenotype consisting of macrocephaly, hypotonia during the first year of life and mild learning disabilities, without autistic features. None of these patients exhibited PTHS-related symptoms such as tumors, lipomas, vascular malformations or pigmented macules of the glans penis. This report raises the question of extending the indications of PTEN mutation screening to familial macrocephaly with learning disabilities. Detection of a mutation in this family led to difficult questions about surveillance, genetic counseling and familial information since the mother declined tumor screening and disclosure of genetic risk information to at-risk relatives.

Highlights

► We report patients with a novel familial PTEN mutation. ► Patients presented a mild phenotype with macrocephaly and learning disabilities. ► The diagnosis led to difficulties in genetic counseling regarding tumor risk.

Introduction

Phosphatase and tensin homolog deleted on chromosome ten (PTEN, MIM 601628) gene is a tumor suppressor gene on 10q23.3. PTEN is implicated in Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome (BRRS) and Proteus-like syndrome, gathered together in PHTS (PTEN hamartoma tumor syndrome) (Eng, 2003). PTEN gene mutations are thus implicated in both familial cancer predisposition disorders and malformative syndrome with possible mental retardation. There is no genotype–phenotype correlation (Marsh et al., 1999).

Recently, PTEN mutations were reported in children with macrocephaly and autism spectrum disorders or mental retardation or developmental delay (Boccone et al., 2006, Butler et al., 2005, Dasouki et al., 2001, Delatycki et al., 2003, Gorlin et al., 1992, Parisi et al., 2001, Zori et al., 1998). Most of these children did not present other symptoms of PHTS. Subsequent reports found mutations in PTEN in approximately 10% of children with autism spectrum disorders (ASD) and macrocephaly (Buxbaum et al., 2007, Herman et al., 2007, McBride et al., 2010, Orrico et al., 2009, Varga et al., 2009). Although the risk of developing malignancies has not been evaluated for these children and their relatives who carried the same mutation, the authors suggest that all individuals over 18 years should be offered cancer surveillance as currently recommended for CS.

We report a family in which a germline PTEN mutation is associated with macrocephaly and learning disabilities without other symptoms of PHTS or autism.

Section snippets

Patients

The proband (patient III 7, Fig. 1) was referred to our genetic clinic at the age of 8 months for hypotonia and macrocephaly. He was born to healthy nonconsanguineous parents and was the sixth child of his 35 year-old mother (patient II 3, Fig. 1). Two maternal brothers had been previously examined in our department of medical genetics in infancy for hypotonia (patient II 5, Fig. 1) and learning disabilities (patient II 4, Fig. 1). Both had macrocephaly (+ 3 and + 3.5 SD). These patients were

Discussion

The PTEN missense variant (c.402G>C) identified in this family had not been previously reported. However, most PTEN reported mutations are unique to a single individual or family (Bonneau and Longy, 2000). The variant perfectly segregated in the family as it was found in all five affected individuals and absent in the phenotypically normal sister (III 3). Another argument for causality was given by the fact that a mutation in the same codon (p.Met134Leu), responsible for partial reduction of

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