NFIX-Related Malan Syndrome

Excerpt

Clinical characteristics: NFIX-related Malan syndrome (MALNS) is characterized by prenatal and postnatal overgrowth, macrocephaly, advanced bone age and/or skeletal anomalies (scoliosis, pes planus), slender body habitus, developmental delay / intellectual disability (typically in the moderate-to-severe range), behavioral problems (including a specific anxious profile and attention-deficit/hyperactivity disorder [ADHD]), and ocular findings (most commonly strabismus, refractive errors, and blue sclerae). Affected individuals typically have distinctive facial features, including a long and triangular face, high anterior hair line with prominent forehead, depressed nasal bridge, deep-set eyes, downslanted palpebral fissures, short nose with anteverted nares and upturned tip, long philtrum, small mouth that is often held open, thin vermilion of the upper lip, an everted lower lip, and a prominent chin. Other findings may include autonomic signs (episodic ataxia with dizziness and nausea and/or postural fainting), seizures or EEG abnormalities, hypotonia, dental anomalies, long bone fractures, and (rarely) congenital heart defects. Four individuals with aortic root dilatation have been reported, with one adult individual experiencing progressive aortic dilation and dissection at age 38 years. Additionally, one individual with rib osteosarcoma and another with Wilms tumor have been reported (an overall prevalence of malignancy of about 2%). Therefore, MALNS appears to be in the same low risk group as Sotos syndrome and Weaver syndrome with respect to a low likelihood of developing cancer.

Diagnosis/testing: The diagnosis of MALNS is established in a proband with suggestive findings and either a heterozygous pathogenic variant in NFIX (~75% of affected individuals) OR a heterozygous deletion of 19p13.2 that includes NFIX (~25% of affected individuals) identified by molecular genetic testing.

Management: Treatment of manifestations: Feeding therapy with a low threshold for clinical feeding evaluation &/or radiographic swallowing study for those with clinical signs or symptoms of dysphagia; gastrostomy tube placement may be required for persistent feeding issues. Stool softeners, prokinetics, osmotic agents, or laxatives as needed for constipation. Symptomatic treatment for autonomic signs based on the underlying cause. Cognitive behavioral therapy (CBT) may be used to treat anxiety and ADHD. Symptomatic aids (i.e., colored glasses, low voice tone) may reduce anxiety outbursts. Hearing aids may be helpful per otolaryngologist. Standard treatment for epilepsy, Chari I malformation, developmental delay / intellectual disability, scoliosis/kyphosis, pes planus, pectus anomalies, refractive error, strabismus, tooth anomalies / malocclusion, aortic root dilatation / valvular issues, and cryptorchidism.

Surveillance: At each visit, measure growth parameters and evaluate nutritional status and safety of oral intake; monitor for signs/symptoms of constipation, Chari I malformation, and subtle and nonspecific neurovegetative findings; and assess for new manifestations, such as seizures and changes in tone. The first BMI evaluation should be performed after age two years; assess caloric intake and BMI every six months during the first two years of life, then at least annually. Monitor developmental progress, educational needs, and psychopathologic symptoms annually from age 12 months to age 36 months and then approximately every two years from age three to six years. Annual ophthalmology evaluation until puberty and then periodically in adults to evaluate for late-onset optic nerve degeneration. Annual audiology evaluation in childhood or as clinically indicated. At least annual routine dental/orthodontic evaluation. Consider DXA scan for bone mineral density periodically in those with a history of multiple fractures or previous low bone mineral density. If the baseline cardiovascular evaluation is normal, consider annual cardiology follow up; limited data on aortic root progression is available for adults. No tumor screening protocols have been proposed or recommended for individuals with MALNS.

Genetic counseling: MALNS is an autosomal dominant disorder typically caused by a de novo genetic alteration. Therefore, the risk to other family members is presumed to be low. Rarely, individuals diagnosed with MALNS have the disorder as the result of a genetic alteration inherited from a mosaic parent. Families with sib recurrence due to parental gonadal (or somatic and gonadal) mosaicism have been reported. Once an NFIX pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.