Myhre syndrome in a female with previously undescribed symptoms: Further delineation of the phenotype

Steensel, M.A.M. van; Vreeburg, Maaike; Steijlen, P.M.; Die‐Smulders, Christine de

doi:10.1002/ajmg.a.30988

Cited by 19 publications

(16 citation statements)

References 10 publications

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“…Other features noted included hearing loss, hypermetropia, congenital heart defect, cryptorchidism and pilonidal dimple. A total of 19 cases have subsequently been reported (6 females and 13 males) [2][3][4][5][6][7][8][9][10][11][12] highlighting variability in (i) the severity of the growth deficiency ranging from À6 to À2 SD and (ii) the degree of intellectual disability in which intelligence ranges from low to normal.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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 À5.5 to À2 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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Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…Recently, SMAD4 mutations have been reported to cause Myhre syndrome (OMIM: 139210) a rare developmental and connective tissue genetic disorder characterized by short stature, short hands and feet, dysmorphic facial features, muscular overgrowth, congenital heart defects (no aortic dilation), and deafness [Le Goff et al, 2012; Caputo et al, 2012; van Steensel et al, 2005]. In contrast to mutations identified in the patients reported here, all three unique SMAD4 mutations identified among 11 patients with Myhre syndrome were apparently de novo missense mutations disrupting the same amino acid (Ile500), and leading to a defect in SMAD4 monoubiquitination and depressed expression of downstream TGFβ target genes, Thus, the SMAD4 mutations causing Myhre syndrome may have a distinct functional consequence from the SMAD4 mutations causing JPS-HHT [Le Goff et al, 2012; Caputo et al, 2012].…”

Section: Discussionmentioning

confidence: 99%

Thoracic aortic disease in two patients with juvenile polyposis syndrome and SMAD4 mutations

Teekakirikul

Milewicz

Miller

et al. 2012

American J of Med Genetics Pt A

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Dilation or aneurysm of the ascending aorta can progress to acute aortic dissection (Thoracic Aortic Aneurysms and Aortic Dissections, TAAD). Mutations in genes encoding TGF-β related proteins (TGFBR1, TGFBR2, FBN1, and SMAD3) cause syndromic and inherited TAAD. SMAD4 mutations are associated with juvenile polyposis (JPS) and a combined JPS-hereditary hemorrhagic telangiectasia (HHT) known as JPS-HHT. A family with JPS-HHT was reported to have aortic root dilation and mitral valve abnormalities. We report on two patients with JPS-HHT with SMAD4 mutations associated with thoracic aortic disease. The first patient, an 11-year-old boy without Marfan syndrome features, had JPS and an apparently de novo SMAD4 mutation (c.1340_1367dup28). Echocardiography showed mild dilation of the aortic annulus and aortic root, and mild dilation of the sinotubular junction and ascending aorta. Computed tomography confirmed aortic dilation and showed small pulmonary arteriovenous malformations (PAVM). The second patient, a 34-year-old woman with colonic polyposis, HHT, and Marfan syndrome, had a SMAD4 mutation (c.1245_1248delCAGA). Echocardiography showed mild aortic root dilation. She also had PAVM and hepatic focal nodular hyperplasia. Her family history was significant for polyposis, HHT, thoracic aortic aneurysm, and dissection and skeletal features of Marfan syndrome in her father. These two cases confirm the association of thoracic aortic disease with JPS-HHT resulting from SMAD4 mutations. We propose that the thoracic aorta should be screened in patients with SMAD4 mutations to prevent untimely death from dissection. This report also confirms that SMAD4 mutations predispose to TAAD.

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“…Only 16 patients have been reported with this syndrome to date. [18][19][20][21][22][23][24][25][26][27][28] As patients with larger overlapping deletions do not have clear characteristics of Myhre syndrome and recessive inheritance for Myhre syndrome cannot be excluded, sequencing analysis of the coding genes residing in the SRO was performed on patient 3, who had the most resemblance with Myhre syndrome, as well as on two other unrelated patients with suspicion of Myhre syndrome. No mutations were however identified.…”

Section: Discussionmentioning

confidence: 99%