Dataset Information

Legius syndrome in fourteen families.

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.

SUBMITTER: Denayer E

PROVIDER: S-EPMC3038325 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Legius syndrome in fourteen families.

Denayer Ellen E Chmara Magdalena M Brems Hilde H Kievit Anneke Maat AM van Bever Yolande Y Van den Ouweland Ans M W AM Van Minkelen Rick R de Goede-Bolder Arja A Oostenbrink Rianne R Lakeman Phillis P Beert Eline E Ishizaki Takuma T Mori Tomoaki T Keymolen Kathelijn K Van den Ende Jenneke J Mangold Elisabeth E Peltonen Sirkku S Brice Glen G Rankin Julia J Van Spaendonck-Zwarts Karin Y KY Yoshimura Akihiko A Legius Eric E

Human mutation 20110101 1

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 clin ...[more]

PMID: 21089071

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Project description:BackgroundCongenital central hypoventilation syndrome (CCHS) is a rare autosomal dominant disorder caused by pathogenic variants in paired-like homeobox 2B (PHOX2B) gene. Characteristics of neonatal-onset CCHS cases have not been well assessed. The aim of this study is to expand current knowledge of clinical and genetic features of neonates with CCHS and provide data on the genotype-phenotype correlation.MethodsWe made a retrospective analysis of 14 neonates carrying PHOX2B pathogenic variants from 2014 to 2019 and we reviewed previously published neonatal-onset cases. Clinical and genetic data were analyzed. Moreover, genotype-phenotype correlation analysis was performed.ResultsWe identified a total of 60 neonatal-onset CCHS cases (35 males and 25 females) including 14 novel cases from our local cohort. Nearly 20% (18.2%) of the patients were born prematurely. Nearly half (46.2%) of the patients had abnormal family history. Polyhydramnios was observed in 21.3% (10/47) of the patients. About 90% of the patients manifested symptoms of hypoventilation in the first week of life. Fourteen patients (23.3%) were classified as mild-CCHS and the rest were severe-CCHS. Gastrointestinal manifestations were observed in 71.7% of the patients. Approximately twofold more males than females were affected by Hirschprung disease (HSCR)/variant HSCR (75.8% vs. 35%, P=0.003). Neural crest tumor occurred in 9.1% (4/44) patients. Half patients had polyalanine repeat expansion mutations (PARMs) in PHOX2B (seven with 25 PARM, nine with 26 PARM, twelve with 27 PARM, one with 28 PARM and one with 31 PARM) and the other half patients had 23 distinct non-polyalanine repeat expansion mutations (NPARMs) with one novel pathogenic variant (c.684dup). The prevalence of HSCR and mild-CCHS among patients with NPARMs was significantly greater than that of the patients with PARMs.ConclusionsThis report provides a large cohort of neonatal-onset CCHS cases. The results indicate that severe hypoventilation and HSCR are frequently observed in this group. NPARMs accounted for half of the cohort with some genotypes tend to be associated with mild phenotype. Molecular testing in neonates with suspicion of CCHS and genetic counseling for CCHS families are highly recommended.

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Legius syndrome in fourteen families.

Publications

Legius syndrome in fourteen families.

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