-Related Neurodevelopmental Disorder

CLINICAL CHARACTERISTICS

-related neurodevelopmental disorder (-NDD) typically occurs in females and very rarely in males. All affected individuals reported to date have developmental delay / intellectual disability ranging from mild to severe; about 50% of affected girls remain nonverbal after age five years. Hypotonia, a common finding, can be associated with feeding difficulty in infancy. Behavioral issues can include autism spectrum disorder, attention-deficit/hyperactivity disorder and hyperactivity, self-injurious behavior, poor impulse control, and aggression. Other findings can include seizures, movement disorders (dyskinesia, spasticity, abnormal gait), vision and hearing impairment, congenital heart defects, respiratory difficulties, joint laxity, and scoliosis. Neuroblastoma has been observed in three individuals.

DIAGNOSIS/TESTING: The diagnosis of -NDD is established in a female proband with suggestive findings and a heterozygous pathogenic variant identified by molecular genetic testing and in a male proband with suggestive findings and a hemizygous pathogenic variant.

MANAGEMENT

Treatment is symptomatic and focuses on optimizing the individual's abilities using a multidisciplinary approach that should also include psychosocial support for family members. Management of feeding difficulty, intellectual disability, behavioral issues, seizures, spasticity and other movement disorders, vision and hearing impairment, congenital heart defects, respiratory difficulties, joint laxity, and scoliosis as per standard care. Periodic evaluation by the multidisciplinary team regarding growth, developmental progress and educational needs, and psychiatric/behavioral issues; regular assessment of vision and hearing, of the spine for scoliosis, for seizure control (when relevant), and for cardiac and respiratory issues. Starting at age eight years, assess girls for evidence of precocious puberty.

GENETIC COUNSELING

-NDD is an X-linked disorder. Most female probands represent simplex cases (i.e., a single occurrence in a family) and have the disorder as the result of a pathogenic variant. -NDD in males is caused by either a pathogenic variant inherited from an unaffected heterozygous mother or a pathogenic variant. If the mother of an affected male has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and are not expected to manifest a neurodevelopmental phenotype. If the proband is female and represents a simplex case and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent – or the proband is male and the pathogenic variant cannot be detected in the leukocyte DNA of the mother – the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism. Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.