Myhre and LAPS syndromes: Clinical and molecular review of 32 patients

Caroline Michot, Carine Le Goff, Clémentine Mahaut, Alexandra Afenjar, Alice S. Brooks, Philippe M. Campeau, Anne Destree, Maja Di Rocco, Dian Donnai, Raoul Hennekam, Delphine Heron, Sébastien Jacquemont, Peter Kannu, Angela E. Lin, Sylvie Manouvrier-Hanu, Sahar Mansour, Sandrine Marlin, Ruth McGowan, Helen Murphy, Annick Raas-RothschildMarlène Rio, Marleen Simon, Irene Stolte-Dijkstra, James R. Stone, Yves Sznajer, John Tolmie, Renaud Touraine, Jenneke Van Den Ende, Nathalie Van Der Aa, Ton Van Essen, Alain Verloes, Arnold Munnich, Valérie Cormier-Daire*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Myhre syndrome is characterized by short stature, brachydactyly, facial features, pseudomuscular hypertrophy, joint limitation and hearing loss. We identified SMAD4 mutations as the cause of Myhre syndrome. SMAD4 mutations have also been identified in laryngotracheal stenosis, arthropathy, prognathism and short stature syndrome (LAPS). This study aimed to review the features of Myhre and LAPS patients to define the clinical spectrum of SMAD4 mutations. We included 17 females and 15 males ranging in age from 8 to 48 years. Thirty were diagnosed with Myhre syndrome and two with LAPS. SMAD4 coding sequence was analyzed by Sanger sequencing. Clinical and radiological features were collected from a questionnaire completed by the referring physicians. All patients displayed a typical facial gestalt, thickened skin, joint limitation and muscular pseudohypertrophy. Growth retardation was common (68.7%) and was variable in severity (from -5.5 to -2 SD), as was mild-to-moderate intellectual deficiency (87.5%) with additional behavioral problems in 56.2% of the patients. Significant health concerns like obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis, pericarditis and early death occurred in four. Twenty-nine patients had a de novo heterozygous SMAD4 mutation, including both patients with LAPS. In 27 cases mutation affected Ile500 and in two cases Arg496. The three patients without SMAD4 mutations had typical findings of Myhre syndrome. Myhre-LAPS syndrome is a clinically homogenous condition with life threatening complications in the course of the disease. Our identification of SMAD4 mutations in 29/32 cases confirms that SMAD4 is the major gene responsible for Myhre syndrome.

Original languageEnglish
Pages (from-to)1272-1277
Number of pages6
JournalEuropean Journal of Human Genetics
Issue number11
StatePublished - 5 Nov 2014
Externally publishedYes


  • LAPS
  • Myhre syndrome
  • SMAD4
  • long-term follow-up


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