Legius syndrome in fourteen families

Ellen Denayer,Yolande Van Bever,Arja De Goede-Bolder,Kathelijn Keymolen,Rianne Oostenbrink,Elisabeth Mangold,Hilde Brems,Rick Van Minkelen,Jenneke Van Den Ende,Glen Brice,Takuma Ishizaki,Sirkku Peltonen,Phillis Lakeman,Tomoaki Mori,Magdalena Chmara,Julia Rankin,Eline Beert,Eric Legius,Akihiko Yoshimura,Ans M.w Van Den Ouweland ,Anneke Kievit ,Karin Y Van Spaendonck‐Zwarts

doi:10.1002/humu.21404

Abstract

Legius syndrome presents as an autosomal dominant condition characterized by café-au-lait macules with or without freckling and sometimes a Noonan-like appearance and/or learning difficulties. It is caused by germline loss-of-function SPRED1 mutations and is a member of the RAS-MAPK pathway syndromes. Most mutations result in a truncated protein and only a few inactivating missense mutations have been reported. Since only a limited number of patients has been reported up until now, the full clinical and mutational spectrum is still unknown. We report mutation data and clinical details in fourteen new families with Legius syndrome. Six novel germline mutations are described. The Trp31Cys mutation is a new pathogenic SPRED1 missense mutation. Clinical details in the 14 families confirmed the absence of neurofibromas, and Lisch nodules, and the absence of a high prevalence of central nervous system tumors. We report white matter T2 hyperintensities on brain MRI scans in 2 patients and a potential association between postaxial polydactyly and Legius syndrome. © 2010 Wiley-Liss, Inc.

Highlights

Legius syndrome (MIM# 611431) was recently identified as a Neurofibromatosis type 1 (NF1)- like syndrome caused by heterozygous germline loss-of-function SPRED1 (MIM# 609291) mutations (Brems et al, 2007)
Our results confirm previous findings that Legius syndrome is characterized by the presence of café-au-lait macules (CALM) with or without freckling and the absence of typical NF1 complications such as Lisch nodules and neurofibromas
In a subset of patients we find Noonan-like facial features (n=12) and/or sternal abnormalities (n=7; one of these patients had an additional diagnosis of Marfan syndrome, which is associated with sternal abnormalities)

Summary

Introduction

Legius syndrome (MIM# 611431) was recently identified as a Neurofibromatosis type 1 (NF1)- like syndrome caused by heterozygous germline loss-of-function SPRED1 (MIM# 609291) mutations (Brems et al, 2007). In the original report five families with an autosomal dominant inherited condition presenting with multiple café-au-lait macules (CALM), axillary freckling, macrocephaly and at times a Noonan-like facial appearance were described. Pasmant et al identified five probands with a SPRED1 mutation in 61 index cases. They confirmed a high prevalence of CALM, freckling and learning disability as well as absence of neurofibromas and Lisch nodules (Pasmant et al, 2009b). Noonan-like dysmorphism was not observed and macrocephaly was reported in only one individual. All affected probands but 1 satisfied NF1 diagnostic criteria None had Noonan-like features, macrocephaly, Lisch nodules or cutaneous neurofibromas.

Methods

Results

Conclusion