Clinical characteristics: FLNA deficiency is associated with a phenotypic spectrum that includes FLNA-related periventricular nodular heterotopia (Huttenlocher syndrome), congenital heart disease (patent ductus arteriosus, atrial and ventricular septal defects), valvular dystrophy, dilatation and rupture of the thoracic aortic, pulmonary disease (pulmonary hypertension, alveolar hypoplasia, emphysema, asthma, chronic bronchitis), gastrointestinal dysmotility and obstruction, joint hypermobility, and macrothrombocytopenia.
Diagnosis/testing: The diagnosis of FLNA deficiency is established in a proband by identification of a heterozygous FLNA pathogenic variant in a female or a hemizygous FLNA pathogenic variant in a male.
Management: Treatment of manifestations: Treatment of epilepsy generally follows principles for a seizure disorder caused by a known structural brain abnormality. Anti-seizure medication is typically selected based on specific attributes (e.g., teratogenic risk during pregnancy, tolerability, and efficacy). Standard treatment for aortic or carotid dissection, congenital heart disease, and valvular disease. Because of the risk for aortic or carotid dissection, ensure good blood pressure control. Good pulmonary toilet is recommended to preserve lung function. Sildenafil and medical management for pulmonary hypertension. Standard treatments for impaired bowel motility. Treatment of joint hypermobility as recommended by orthopedist, physical therapist, and/or occupational therapist. Treatment of bleeding diathesis per hematologist. If needed, early intervention services and special education support may be considered.
Surveillance: Monitor for seizures, constipation, joint issues, bleeding diathesis, and developmental issues at each visit. Cardiology evaluations, echocardiogram, stress testing, and cardiac MRI as recommended by cardiologist. Follow up with pulmonologist for any lung issues.
Evaluation of relatives at risk: Given the risk for vascular disease in neurologically asymptomatic individuals, it is appropriate to evaluate the older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from echocardiogram and cardiac MRI to screen for FLNA-associated structural heart disease and thoracic aortic aneurysms.
Pregnancy management: The teratogenic risk to the fetus associated with the use of anti-seizure medication during pregnancy depends on the type of anti-seizure medication used, the dose, and the gestational age of the fetus. There are currently no guidelines regarding the most appropriate surveillance for and management of cardiac, vascular, and connective tissue problems during pregnancy.
Genetic counseling: FLNA deficiency is inherited in an X-linked manner. The condition is prenatally or neonatally lethal in most males; therefore, the majority of affected individuals are female. About 50% of affected females inherit the pathogenic variant from their mother and at least 50% have a de novo pathogenic variant. For women with FLNA deficiency, the risk of passing the pathogenic variant to each child is 50%. Because of the high rate of prenatal lethality in males, most sons born to women with FLNA deficiency are unaffected. Prenatal diagnosis by molecular genetic testing is possible once the pathogenic variant has been identified in an affected family member. Periventricular nodules may be visualized by imaging as early as 24 weeks' gestation; however, the sensitivity of imaging for the prenatal detection of PVNH is not known.
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