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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Acknowledgements
We thank Pr Brendan H Lee from the Department of Molecular and Human Genetics, Baylor College of Medicine; Howard Hughes from the Medical Institute, Houston, TX, USA; Dr Lewis B Holmes and Dr Patricia Blakely from the Massachusetts General Hospital; Meaghan Muir from the Brigham and Women’s Hospital; and Dr Nicola Brunetti-Pierri from the Telethon Institute of Genetics and Medicine, Naples, Italy. We also would like to thank all the patients and their families.
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Michot, C., Le Goff, C., Mahaut, C. et al. Myhre and LAPS syndromes: clinical and molecular review of 32 patients. Eur J Hum Genet 22, 1272–1277 (2014). https://doi.org/10.1038/ejhg.2013.288
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DOI: https://doi.org/10.1038/ejhg.2013.288
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