Clinical characteristics: CASK disorders include a spectrum of phenotypes in both females and males. Two main types of clinical presentation are seen:

1. Microcephaly with pontine and cerebellar hypoplasia (MICPCH), generally associated with pathogenic loss-of-function variants in CASK

2. X-linked intellectual disability (XLID) with or without nystagmus, generally associated with hypomorphic CASK pathogenic variants

MICPCH is typically seen in females with moderate-to-severe intellectual disability, progressive microcephaly with or without ophthalmologic anomalies, and sensorineural hearing loss. Most are able to sit independently; 20%-25% attain the ability to walk; language is nearly absent in most. Neurologic features may include axial hypotonia, hypertonia/spasticity of the extremities, and dystonia or other movement disorders. Nearly 40% have seizures by age ten years. Behaviors may include sleep disturbances, hand stereotypies, and self biting.

MICPCH in males may occur with or without severe epileptic encephalopathy in addition to severe-to-profound developmental delay. When seizures are present they occur early and may be intractable.

In individuals and families with milder (i.e., hypomorphic) pathogenic variants, the clinical phenotype is usually that of XLID with or without nystagmus and additional clinical features. Males have mild-to-severe intellectual disability, with or without nystagmus and other ocular features. Females typically have normal intelligence with some displaying mild-to-severe intellectual disability with or without ocular features.

Diagnosis/testing: The diagnosis of a CASK disorder is established in a female who is heterozygous for a CASK pathogenic variant and in a male who is hemizygous for a CASK pathogenic variant on molecular genetic testing. Rarely, affected males have a mosaic pathogenic variant.

Management: Treatment of manifestations: Treatment is symptomatic and includes standard management of developmental delay and intellectual disability issues; medication for seizures; nutritional support; use of physiotherapy; and treatment of abnormal vision or hearing loss.

Genetic counseling: CASK disorders are inherited in an X-linked manner. Risk to the family members of a proband with a CASK disorder depends on the phenotype (i.e., MICPCH or XLID ± nystagmus) in the proband.

1. MICPCH. Most affected females and males represent simplex cases (i.e., the only affected family member) and have the disorder as the result of a de novo CASK pathogenic variant. Because heterozygous females manifest the phenotype, an asymptomatic mother is unlikely to be heterozygous for the CASK pathogenic variant. If a proband represents a simplex case, the recurrence risk to sibs appears to be low but greater than that of the general population because of the possibility of parental germline mosaicism.

2. XLID ± nystagmus. The father of a male with a CASK disorder will not have the disorder nor will he be hemizygous for the CASK pathogenic variant. If a male is the only affected family member, the mother may be a heterozygote or the affected male may have a de novo pathogenic variant. In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. If the mother of the proband has a CASK 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 typically be asymptomatic but may have a range of manifestations. If the CASK pathogenic variant cannot be detected in maternal leukocyte DNA, the risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism.

Once the CASK pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for a CASK disorder are possible.