Clinical characteristics: Myhre syndrome is a multisystem progressive connective tissue disorder that often results in significant complications. The highly distinctive (and often severe) findings of joint stiffness, restrictive lung and cardiovascular disease, progressive and proliferative fibrosis, and thickening of the skin usually occur spontaneously. Some proliferation such as abnormal scarring or adhesions may follow trauma, invasive medical procedures, or surgery. Effusions of the heart, airways, lungs, uterus, and peritoneum may occur and can progress to fibrosis. Most affected individuals have characteristic facial features (short palpebral fissures, deeply set eyes, maxillary underdevelopment, short philtrum, thin vermilion of the upper lip, narrow mouth, and prognathism) and developmental delay / cognitive disability, typically in the mild-to-moderate range. Neurobehavioral issues may include autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and/or anxiety. Although immunoglobulin (Ig) G and IgA deficiency are rare, affected individuals can experience recurrent infections (including otitis media, sinusitis, mastoiditis, or croup). Hearing loss can progress over time. Growth may be impaired in early life. Most adolescents develop obesity. Eye findings can include refractive errors, astigmatism, corectopia, and optic nerve anomalies. Gastrointestinal (GI) issues may include gastroesophageal reflux disease, constipation, and encopresis. Less commonly, stenosis of the GI tract, Hirschsprung disease, and/or metabolic dysfunction-associated liver disease may be observed.

Diagnosis/testing: The diagnosis of Myhre syndrome is established in a proband with characteristic clinical findings and a heterozygous (typically recurrent) pathogenic variant in SMAD4 identified by molecular genetic testing.

Management: Treatment of manifestations: Feeding therapy for those with poor weight gain or feeding issues; gastrostomy tube placement may be required for persistent feeding issues; referral to nutrition for those who develop obesity; consideration of balloon dilation or long-term tracheostomy for those with complete or recurrent tracheal stenosis; use of smaller-size, uncuffed endotracheal tubes for anesthesia; intralesional steroids for some keloids; physical therapy for decreased range of motion of joints; orthotics for tiptoe walking; dietary management, stool softeners, prokinetics, osmotic agents, or laxatives for constipation; guarded treatment with minimal instrumentation of the GI tract for gastrointestinal stenosis. Standard treatment for orofacial clefting, velopharyngeal insufficiency, developmental delay / intellectual disability, cardiovascular disease including systemic/pulmonary hypertension, restrictive lung disease, sleep apnea, immunodeficiency, tethered spinal cord, frequent fractures, eye/vision issues, hearing loss, protein-losing enteropathy, liver dysfunction, diabetes mellitus, cryptorchidism, hypospadias, and epilepsy.

Prevention of secondary complications: Limiting tissue trauma appears to be the single most important preventive measure. When possible, alternative noninvasive approaches should be pursued during diagnosis and management.

Surveillance: At each visit, measure growth parameters; right upper arm blood pressure (if tolerated); monitor for evidence of respiratory insufficiency and obtain pulse oxygen measurement; evaluate for signs/symptoms of upper airway stenosis and sleep apnea; monitor for constipation and signs/symptoms of GI stenosis; monitor developmental progress and educational needs, including mobility and self-help skills; assess for signs/symptoms of anxiety, ASD, and ADHD; assess for signs/symptoms of frequent infections; monitor for premature puberty in childhood; encourage nonstrenuous exercise, healthy eating, and weight management. Annually (or as clinically indicated), pulmonary function studies or impulse oscillometry in children age six years and older, if able to cooperate with test maneuvers; ophthalmology evaluation; hearing evaluation; assessment for abnormal scarring. Every two years, echocardiogram (in an asymptomatic person with a normal echocardiogram at initial diagnosis). Every five to ten years starting in childhood (age 5-10 years), CT or MR angiogram of the aorta, the exact frequency of which is based on the presence and degree of aortic disease. The decision to use CT or MR depends on the age and behavior of individual, the imaging center, and the availability of supportive services ("Child Life") to accomplish without anesthesia. Starting in the second decade, low threshold for fasting blood sugar and hemoglobin A1c to assess for diabetes mellitus; periodic DXA scan to assess bone mineral density; monitor for heavy menses. As clinically indicated, more extensive cardiovascular imaging in persons with abnormal findings at initial diagnosis; renal bladder ultrasound, if there is intractable incontinence. As needed, in the third decade of life, coronary CT angiography; evaluation for sleep apnea and need for intervention.

Agents/circumstances to avoid: Smoking; tissue trauma; elective tracheal surgery/intubation (if possible); tracheal resection; growth hormone therapy.

Genetic counseling: Myhre syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. De novo SMAD4 pathogenic variants that have been evaluated for parent of origin to date have all been paternal and have been associated with advanced paternal age. A few individuals diagnosed with Myhre syndrome have the disorder as the result of a SMAD4 pathogenic variant inherited from an affected parent. Each child of an individual with Myhre syndrome has a 50% chance of inheriting the SMAD4 pathogenic variant. Once the SMAD4 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.