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. 2014 Nov;22(11):1272-7.
doi: 10.1038/ejhg.2013.288. Epub 2014 Jan 15.

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

Caroline Michot  1 , Carine Le Goff  1 , Clémentine Mahaut  1 , Alexandra Afenjar  2 , Alice S Brooks  3 , Philippe M Campeau  4 , Anne Destree  5 , Maja Di Rocco  6 , Dian Donnai  7 , Raoul Hennekam  8 , Delphine Heron  9 , Sébastien Jacquemont  10 , Peter Kannu  11 , Angela E Lin  12 , Sylvie Manouvrier-Hanu  13 , Sahar Mansour  14 , Sandrine Marlin  15 , Ruth McGowan  16 , Helen Murphy  7 , Annick Raas-Rothschild  17 , Marlène Rio  1 , Marleen Simon  3 , Irene Stolte-Dijkstra  18 , James R Stone  19 , Yves Sznajer  20 , John Tolmie  16 , Renaud Touraine  21 , Jenneke van den Ende  22 , Nathalie Van der Aa  22 , Ton van Essen  18 , Alain Verloes  23 , Arnold Munnich  1 , Valérie Cormier-Daire  1
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Myhre and LAPS syndromes: clinical and molecular review of 32 patients

Caroline Michot et al. Eur J Hum Genet. 2014 Nov.

Erratum in

  • Eur J Hum Genet. 2014 Nov;22(11):1340

Abstract

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.

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Figures

Figure 1
Figure 1
Pictures of some patients with Myhre syndrome, with mutations altering the Ile500 (a–i: patients 3, 7, 9, 11, 13, 14, 16, 17 and 18), with the p.Arg496Cys mutation (j: patient 27) and without mutation (k: patient 28).
See this image and copyright information in PMC

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