Clinical characteristics: Myhre syndrome is a multisystem connective tissue disorder involving the skin and the cardiovascular, respiratory, gastrointestinal, and musculoskeletal systems. Affected individuals may experience progressive and proliferative fibrosis. Fibrosis may occur spontaneously or following trauma, invasive medical procedures, or surgery, often resulting in significant complications. Characteristic facial features are found in almost all affected individuals and are more apparent in older children and adults. Cardiovascular issues can include aortic hypoplasia and stenosis, congenital heart defects, pericardial involvement, and restrictive cardiomyopathy. Joint limitations may progress with age and resemble mild joint contractures. Most individuals have developmental delay / cognitive impairment, typically in the mild-to-moderate range. Other findings may include autism spectrum disorder, conductive or mixed hearing loss, short stature, refractive errors, premature puberty, recurrent respiratory infections, mechanical respiratory issues (choanal stenosis, laryngeal narrowing), and stenosis of the upper gastrointestinal tract.
Diagnosis/testing: The diagnosis of Myhre syndrome is established in a proband with characteristic clinical findings and a heterozygous pathogenic (or likely pathogenic) variant in SMAD4 detected by molecular genetic testing.
Management: Treatment of manifestations: Feeding therapy with a low threshold for a clinical and/or radiographic swallowing study; referral to nutrition for poor weight gain or obesity; medical therapy for systemic and/or pulmonary hypertension; long-term tracheostomy may be required for those with complete or recurrent tracheal stenosis; aggressive medical management for constipation; physical therapy to keep joints mobile; hearing aids may be helpful for those with hearing loss; some keloids can be treated with intralesional steroids with minimal invasiveness for lesion removal; and standard treatment for orofacial clefting / velopharyngeal insufficiency, congenital heart defects / pericardial disease, restrictive lung disease, gastrointestinal stenosis, developmental delay / intellectual disability, refractive errors / strabismus / cataracts, persistent middle ear effusions, immunodeficiency, diabetes mellitus, and pubertal/menstrual irregularities. Note: Growth hormone therapy for short stature is not currently recommended for individuals with Myhre syndrome.
Prevention of secondary complications: Limiting tissue trauma appears to be the single most important preventive measure: the literature suggests increased risk of proliferative fibrosis following otherwise uncomplicated endotracheal intubation and surgical procedures. When possible, alternative noninvasive approaches should be pursued during diagnosis and management.
Surveillance: At each visit: measure growth parameters, blood pressure, and oxygen pulse oximetry; monitor for respiratory insufficiency, signs/symptoms of upper-airway stenosis, constipation, developmental issues, behavioral issues, physical skills and mobility issues, premature puberty (in children), and frequent and/or unusual infections. Annually: perform pulmonary function studies (in children age >6 years who are able to cooperate), ophthalmology evaluation, and audiology evaluation. In asymptomatic individuals with a normal echocardiogram, repeat the echocardiogram every one to three years. Starting in the second decade: low threshold for fasting blood sugar and hemoglobin A1c to assess for diabetes; periodic DXA scan to monitor bone mineral density; monitor females with the c.1486C>T (p.Arg496Cys) pathogenic variant for menstrual irregularities.
Genetic counseling: Myhre syndrome is inherited in an autosomal dominant manner. Most probands with Myhre syndrome have the disorder as a result of a de novo SMAD4 pathogenic variant; however, vertical transmission from a parent to child has been rarely observed. If the SMAD4 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism. Once the SMAD4 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at theoretic increased risk for Myhre syndrome and preimplantation genetic testing are possible.
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