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To date, less than 100 cases have been reported, with no apparent ethnic or sex predilection.

The first manifestation is typically intrauterine growth retardation; however, diagnosis is typically later in childhood due to the absence of cardiac features early on. During the first years of life the main features are short length/stature, short palpebral fissures, brachydactyly with hyperconvex nails. The more common clinical features become recognizable in late childhood and include the distinctive facial features (short palpebral fissures, mid-face hypoplasia, short philtrum, prognathism, narrow mouth, small ears), short stature, limited joint mobility (with particular difficulty in fist-clenching and in arm-raising), thickened skin, and muscular pseudohypertrophy. Mild-to-moderate intellectual disability and developmental delay are common, but not constant. Autistic-like behavior has been reported. Morphological cardiovascular anomalies affect about 70% of patients (septal defects, patent ductus arteriosus, obstructive defects of the left heart, aortic coarctation and arterial obstructions), and pericarditis, restrictive cardiomyopathy and systemic and pulmonary hypertension are frequently observed. Respiratory involvement consists of choanal stenosis, laryngotracheal narrowing, obstructive airway disease, or restrictive pulmonary disease (increasing with age). Gastrointestinal (GI) involvement includes pyloric stenosis, duodenal atresia and severe constipation. Proliferative fibrosis/scarring (on the serosal surfaces of heart, airway, lungs, GI tract, skin) may occur spontaneously or following trauma, endotracheal intubation or surgery. Ocular anomalies may include refractive errors and strabismus. Recurrent infections (particularly otitis media and pneumonia) are frequently reported. Hearing loss is observed in most (83%) individuals. Additional anomalies include cleft lip and/or palate, velopharyngeal insufficiency, and facial nerve weakness/paralysis (rare).

Myhre Syndrome is due to heterozygous pathogenic variant in the SMAD4 gene (18q21.2).

The diagnosis may be challenging and relies on the characteristic clinical features and the radiological findings (thickened skull, brachydactyly, broad ribs, vertebral fusions, large vertebral pedicles and hypoplastic iliac wings) and is confirmed by genetic analysis.

Differential diagnosis include other genetic syndromes characterized by short stature, brachydactyly, stiff and thick skin, restricted joint mobility and cardiovascular involvement.

Prenatal genetic testing is possible for at-risk pregnancies, where a pathogenic variant has previously been identified in an affected family member.

The inheritance pattern is autosomal dominant, but most cases occur de novo. Penetrance seems to be complete, but data about familial cases are limited.

Treatment is mainly symptomatic, requiring a multidisciplinary medical team. Annual ophthalmologic, audiology, respiratory, cardiovascular, physical skill development and joint mobility evaluations are recommended. Hearing aids may be necessary for hearing loss. Oxygen supplementation may be necessary, as well as long-term tracheostomy. Limiting tissue trauma is important due to the increased risk of scarring/stenosis and proliferative fibrosis after surgical procedures and endotracheal intubation; alternative non-invasive approaches should be considered where possible. Restrictive lung disease, systemic/pulmonary hypertension and heart failure should be managed accordingly. Treatment may be necessary for constipation. Physical therapy may be helpful for joint mobility, as well as supportive management of intellectual disability and developmental delay.

Myhre syndrome is a progressive disorder with life-threatening complications. Restrictive and obstructive respiratory disease, pericarditis and laryngotracheal involvement are major causes of morbidity.