Clinical Guidance

, , and have been associated with isolated X-linked cardiac valvular dysplasia . Affected males were found to have more severe valvular disease . Females with PVNH typically have FLNA variants predicted to cause severe loss of function (e.g., nonsense, frameshift, and severe splicing variants) throughout the gene or missense variants in the N-terminal actin-binding domain . Surviving affected males. Nonsense variants in surviving males often affect the C terminus of the protein, consistent with partial loss of function, while missense variants in surviving males can be scattered throughout the gene . Presumably, these pathogenic variants lead to a partially functional protein .

Source: GeneReviews — "FLNA Deficiency"

Penetrance

All individuals with known deleterious loss-of-function FLNA variants typically have shown periventricular nodular heterotopia. Penetrance for other phenotypes has not been determined.

Source: GeneReviews — "FLNA Deficiency"

Diagnostic Criteria

Suggestive Findings

FLNA deficiency should be suspected in an individual with the following clinical features, neuroimaging findings, and family history. (Note: Affected males frequently show male lethality.)

Clinical features

• Seizure disorder

• Cardiovascular findings: dilated aortic root or thoracic ascending aorta, valvular heart disease, structural heart disease

• Pulmonary findings: pulmonary hypertension, alveolar hypoplasia, emphysema, asthma, chronic bronchitis

• Gastrointestinal manifestations: feeding difficulties, constipation, progressive weight loss, congenital short bowel, chronic intestinal pseudo-obstruction

• Joint hypermobility

Neuroimaging features

Source: GeneReviews — "FLNA Deficiency"

Differential Diagnosis

Periventricular nodular heterotopia (PVNH) has been reported in individuals with the disorders listed (whether each of these represents a truly distinct disorder or FLNA-related PVNH plus a concurrent condition remains to be determined). Table 3a. Disorders That May Be Associated with Periventricular Nodular Heterotopia (PVNH)

Management Guidelines

No clinical practice guidelines for FLNA deficiency have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with FLNA deficiency, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with FLNA Deficiency

Source: GeneReviews — "FLNA Deficiency"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "FLNA Deficiency"

Surveillance Guidelines

Table 6. Recommended Surveillance for Individuals with FLNA Deficiency

Source: GeneReviews — "FLNA Deficiency"