Myhre Syndrome

A number sign (#) is used with this entry because Myhre syndrome (MYHRS) is caused by heterozygous mutation in the SMAD4 gene (600993) on chromosome 18q21.

Description

Myhre syndrome is a rare disorder characterized by mental retardation, dysmorphic facial features, including microcephaly, midface hypoplasia, prognathism, and blepharophimosis, typical skeletal anomalies, including short stature, square body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria, and cardiovascular defects with a striking fibroproliferative response to surgical intervention. All reported cases have been sporadic (summary by Bachmann-Gagescu et al., 2011 and Lin et al., 2016).

Clinical Features

Myhre et al. (1981) described 2 unrelated males with a characteristic syndrome. In addition to mental retardation, the patients, aged 24 and 18 years, showed pre- and postnatal growth deficiency (adult heights 140 and 146 cm), unusual facies (maxillary hypoplasia, prognathism, short palpebral fissures, short philtrum, small mouth), generalized muscle hypertrophy, decreased joint mobility, cryptorchidism, cardiac anomaly, early-onset deafness of mixed conductive and sensory type, and osseous peculiarities by x-ray (thickened calvaria, broad ribs, hypoplastic iliac wings, shortened long and tubular bones, and large, flattened vertebrae with large pedicles). Myhre et al. (1981) suggested that the syndrome may have resulted from dominant mutation because of advanced paternal age (37 and 38 years) at the time of the boys' birth.

Soljak et al. (1983) reported another case, also in a male. The father and mother were normal and unrelated, and were 42 and 38 years of age, respectively, at the child's birth. He was well until about age 6 when stiffness was first noted. Short stature first became evident at age 8. At age 16 his height was 145.9 cm. There was increased muscle bulk and osseous changes by x-ray similar to those reported by Myhre et al. (1981). Small eyelid slits were noted. The authors noted that the disorder they reported was clearly distinct from that reported by Moore and Federman (1965) (see 127200), in which stiffness and short stature were associated with normal intellect and ocular abnormalities.

Garcia-Cruz et al. (1993) reported 2 unrelated male patients, aged 19 and 6 years, with Myhre syndrome and compared these patients with the 3 patients previously reported. The main features were short stature, mental retardation, blepharophimosis, muscular hypertrophy, decreased joint mobility, thick calvarium, broad ribs, hypoplastic iliac wings, and short tubular bones. Paternal age was advanced in all cases.

Bottani and Verloes (1995) suggested that Myhre syndrome may be the same as GOMBO syndrome (233270).

Hopkin et al. (1998) described 3 patients with a progressive airway narrowing associated with short stature and joint stiffness. There was no evidence for infectious, inflammatory, or metabolic diseases as the cause of their condition. None had clinical findings indicative of known skeletal dysplasias or storage diseases. They had minor facial anomalies, which included deeply set eyes, bushy eyebrows, and flat midface. Patient 1 described by Hopkin et al. (1998) was a 28-year-old Caucasian man who first developed wheezing at the age of 21 years. Tracheostomy was required at the age of 23 years. His height was 145 cm. Patient 2 was a 34-year-old Caucasian woman who had had difficulty swallowing as an infant and a diagnosis of peptic ulcer at the age of 3 years. Limited mobility of multiple joints was present in this patient as in the other 2. Surgery for bilateral carpal tunnel syndrome was done at age 28 years. The third patient was a 28-year-old white woman with a height of 140 cm. A prominent chin was evident in all 3 patients and illustrated for patients 1 and 3. In patient 3, the diagnosis of constricted pericarditis had been made at the age of 10 years leading to pericardiectomy at age 12 years. Pericardial histology showed fibrosis but no evidence of viral or bacterial infection. Hopkin et al. (1998) compared and contrasted the disorder in these 3 patients with several other disorders. The Moore-Federman syndrome (127200) is autosomal dominant and has no tracheal stenosis. Geleophysic dysplasia (231050) has progressive tracheal narrowing and onset in childhood, but is an organomegaly disorder, which was absent in the cases of Hopkin et al. (1998). In the Weill-Marchesani syndrome (277600), short stature, joint stiffness, and brachydactyly occur but tracheal stenosis has not been described. Hopkin et al. (1998) also compared the syndrome they reported to acromicric dysplasia (102370).

Whiteford et al. (2001) reported a 13-year-old Scottish boy exhibiting the major features of Myhre syndrome, including mental retardation, deafness, short stature, muscle hypertrophy, limitation of joint movement, facial dysmorphism, and skeletal radiologic abnormalities. The authors reviewed the 6 patients described to date.

Titomanlio et al. (2001) reported a 14-year-old boy with clinical findings consistent with a diagnosis of Myhre syndrome, associated with autism and thickened skin. Histologic examination revealed dermal thickening and anomalous subcutaneous tissue. In the patient reported by Titomanlio et al. (2001), Caputo et al. (2012) identified a heterozygous de novo mutation in the SMAD4 gene (I500V; 600993.0016).

Lindor et al. (2002) reported 2 unrelated adult females with a disorder similar to that reported by Hopkin et al. (1998). Both women had striking physical changes, including short stature, deep-set eyes, midface hypoplasia, prognathism, and sparse, fine hair. One woman had a pear-shaped nose with hooked tip, short philtrum, microphthalmia, and low-set ears. Common tissue abnormalities included brachydactyly, thickened calvarium, vertebral fusions, progressive diffuse joint stiffness, and thickened skin. Laryngotracheal stenosis required a tracheostomy in both women as young adults. One patient had Dupuytren contractures, pseudopapilledema, keratoconus, anomalous middle ear bones, esophageal stenosis, pericardial fibrosis, and a thickened mitral valve. Both had mildly delayed development and intellectual disability, as well as menstrual abnormalities. Neither had a family history of a similar disorder. Lindor et al. (2002) proposed the designation 'LAPS syndrome' for this disorder, to reflect the most consistently recognized features: laryngotracheal stenosis, arthropathy, prognathism, and short stature. However, Lindor et al. (2012) determined that these patients had Myhre syndrome.

Burglen et al. (2003) reported 4 unrelated males with Myhre syndrome and reviewed the 7 previously reported cases. They noted that all 4 of their patients had thick skin (described as 'hard' in 1 case) and that 1 of their patients had an 'autistic-like condition.'

Davalos et al. (2003) reported the first female case of Myhre syndrome, a 15-year-old girl. As the father was 49 years of age, the authors suggested that this case could have been the result of a de novo dominant mutation. Lopez-Cardona et al. (2004) reported the second female patient with Myhre syndrome. Her father was 39 and her mother 38 years old at the time of her birth. Lopez-Cardona et al. (2004) noted that the female patients did not have microcephaly or ophthalmologic or neurologic anomalies. They suggested the possibility of X-linked inheritance.

Van Steensel et al. (2005) described a 16-year-old girl with Myhre syndrome who also had hypertrophic scar formation, marked thickness of the skin, and vertebral defects consisting of fusion at C2-3, partial fusions elsewhere, and irregular endplates. There were no abnormalities on skin biopsy.

Rulli et al. (2005) reported a female patient with Myhre syndrome and normal intelligence. She had characteristic facial features and skeletal findings, as well as delayed motor milestones due to decreased joint mobility, mixed conductive and sensorineural hearing loss, and short stature. In the patient reported by Rulli et al. (2005), Caputo et al. (2012) identified a heterozygous de novo mutation in the SMAD4 gene (I500V; 600993.0016).

Becerra-Solano et al. (2008) reported the fifth female patient with Myhre syndrome, a 13-year-old Mexican girl who had the typical facies, short stature, limited joint mobility, and short hands and feet of the disorder. The authors reviewed the clinical spectrum in both male and female patients and stated that a square body shape is clearly distinguished in all cases; noting that the typical muscular build is present mainly in male patients, they suggested that the muscular appearance may be hormonally influenced.

Bachmann-Gagescu et al. (2011) reported a 19-year-old girl with classic features of Myhre syndrome, including intrauterine growth retardation, ventricular septal defect, short stature, mental retardation, and skeletal anomalies, who also developed progressive cerebellar ataxia and cerebellar atrophy in her late teenage years. The authors noted that this feature had not previously been reported in this disorder.

Caputo et al. (2012) reported 8 unrelated patients with Myhre syndrome, including 2 reported by Rulli et al. (2005) and Titomanlio et al. (2001). All had a homogeneous phenotype including short stature, a recognizable facial appearance, generalized muscular hypertrophy, hearing loss, short hands, distinctive skeletal anomalies, and joint stiffness. Facial features included microcephaly, narrow palpebral fissures, midface hypoplasia, narrow mouth, thin upper lip, short philtrum, and prognathism. Three had cleft lip/palate. All subjects had low birth weight, but 5 became obese with age. Delayed psychomotor and/or language development and variable intellectual disability was documented in all but 1 individual. There was also a wide spectrum of congenital heart defects, such as septal defects, patent ductus arteriosus, aortic valve stenosis, and aortic coarctation, whereas macrocephaly, refractive errors, and hypertension were less prevalent. Autistic behavior was documented in 2 patients. None had any gross vascular anomaly or skin, pancreatic, or gastrointestinal malignancies.

Starr et al. (2015) reported 5 patients with Myhre syndrome, all of whom had significant cardiac and/or pulmonary pathology, with fibrosis, restrictive cardiomyopathy, and lung disease, as well as abnormal wound healing. A progressive and markedly abnormal fibroproliferative response to surgical intervention was a newly delineated complication that occurred in all of the patients. Starr et al. (2015) recommended routine cardiopulmonary surveillance for all Myhre patients and noted that surgical intervention required as little invasion as possible because severe fibrosis and scarring could lead to significant morbidity and mortality.

Lin et al. (2016) reported 4 patients with Myhre syndrome and reviewed 50 previously reported patients. They found that 70% of the patients had a cardiovascular abnormality, including congenital heart defects (63%), pericardial disease (17%), restrictive cardiomyopathy (9%), and systemic hypertension (15%). Pericarditis and restrictive cardiomyopathy were associated with high mortality (3 patients each among 10 deaths); 1 patient with restrictive cardiomyopathy also had epicarditis.

Garavelli et al. (2016) reported a patient with Myhre syndrome who exhibited pericarditis and cardiac tamponade as life-threatening complications. The authors reviewed 48 molecularly confirmed patients and described the natural history and life-threatening complications of the disorder.

Molecular Genetics

In all 11 patients with Myhre syndrome tested, Le Goff et al. (2012) identified a heterozygous de novo mutation involving the same codon, ile500, of the SMAD4 gene (I500T, 600993.0015; I500V, 600993.0016; and I500M, 600993.0017). The mutations were identified by exome sequencing of 2 index patients and candidate gene analysis of SMAD4 because of its role in TGFB (see, e.g., TGFB1, 190180) and BMP (see, e.g., BMP1, 112264) signaling. Fibroblast studies from 2 patients showed a defect in SMAD4 ubiquitination, resulting in stabilization of the mutant protein, as well as altered expression of downstream TGFB and BMP target genes associated with increased phosphorylation of multiple SMAD partners. The findings of Le Goff et al. (2012) indicated that defective transcriptional regulation during development plays a significant role in the disorder.

Simultaneously and independently, Caputo et al. (2012) identified 2 different heterozygous de novo mutations affecting residue ile500 in the SMAD4 gene in 8 unrelated patients with Myhre syndrome (I500T, 600993.0015 and I500V, 600993.0016). Caputo et al. (2012) specifically examined genes involved in the TGFB signaling network to identify SMAD4 as the causative gene, because the disorder GPHYSD (see 231050) shows overlapping features. Both SMAD4 mutations occurred in the MH2 domain, which is necessary for SMAD oligomerization and TGFB/BMP signal transduction. Based on the role of SMAD4 in developmental processes, dysregulation of SMAD4 function was expected to have pleiotropic effects, as seen in Myhre syndrome. Caputo et al. (2012) noted that the restrictive pattern of SMAD4 mutations suggested genetic homogeneity of Myhre syndrome, which was reflected in the clinically homogeneous presentation.

In 2 female patients with laryngotracheal stenosis, arthropathy, prognathism, and short stature ('LAPS syndrome'), originally described by Lindor et al. (2002) and believed to represent a distinct syndrome, Lindor et al. (2012) noted similarities to the Myhre syndrome phenotype and analyzed the SMAD4 gene. Each woman was heterozygous for a previously identified missense mutation in patients with Myhre syndrome (I500T, 600993.0015 and I500V, 600993.0016); the authors concluded that the syndrome they described in these patients was in fact Myhre syndrome. Lindor et al. (2012) provided follow-up on the 2 patients: the first patient had endometrial cancer and underwent a hysterectomy, experienced life-threatening adhesions of the bowel, and had chronically restrictive indices in echocardiography despite her prior pericardiectomy. The second patient also developed a constrictive pericardium requiring pericardiectomy, and died at 40 years of age due to progressive respiratory failure. Both patients had repeated procedures to address recurrent laryngotracheal stenoses, and both had clinically striking tight, thick-feeling skin. Lindor et al. (2012) noted that the range of potential medical complications in Myhre syndrome may be greater than previously recognized, particularly with aging.