NSDHL-Related Disorders

Excerpt

Clinical characteristics: NSDHL-related disorders include CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, an X-linked disorder that is usually male lethal during gestation and thus predominantly affects females; and CK syndrome, an X-linked disorder that affects males.

CHILD syndrome is characterized by unilateral distribution of ichthyosiform skin lesions and ipsilateral limb defects that range from shortening of the metacarpals and phalanges to absence of the entire limb. Intellect is usually normal. The ichthyosiform skin lesions are usually present at birth or in the first weeks of life; new lesions can develop in later life. Onychodystrophy and periungual hyperkeratosis are common. Heart, lung, and kidney malformations can also occur.

CK syndrome is characterized by mild-to-severe cognitive impairment and behavior problems (aggression, attention-deficit/hyperactivity disorder [ADHD], and irritability). All reported affected males have developed seizures in infancy and have cerebral cortical malformations and microcephaly. All have distinctive facial features, a thin habitus, and relatively long, thin fingers and toes. Some have scoliosis and kyphosis. Strabismus is common. Optic atrophy is also reported.

Diagnosis/testing: The diagnosis of CHILD syndrome is established in a female proband with a heterozygous NSDHL pathogenic variant identified by molecular genetic testing that results in loss of functional decarboxylating sterol-4-alpha-carboxylate 3-dehydrogenase, the protein encoded by NSDHL. The diagnosis of CK syndrome is established in a male proband with a hemizygous NSDHL hypomorphic pathogenic variant identified by molecular genetic testing that results in partial loss of functional decarboxylating sterol-4-alpha-carboxylate 3-dehydrogenase.

Management: Treatment of manifestations: In CHILD syndrome, no one therapy described to date appears to ameliorate the cutaneous findings for every reported individual. Oral and topical ketoconazole may reduce lesions. Topical statin treatment alone or combined with cholesterol and/or glycolic acid can be beneficial. Treatment of an inflammatory nevus by grafting skin obtained from a contralateral unaffected region has been successful. Lactic acid 12% creams or lotions can reduce itching, and urea skin creams can reduce dryness. Scoliosis and joint contractures are treated with braces and/or corrective surgery. Standard management for heart, lung, kidney, and gastrointestinal manifestations.

In CK syndrome, developmental and educational support; behavior modification and/or drug therapy to control aggression and help with manifestations of ADHD; anti-seizure medication to control seizures; standard treatments for orthopedic and ocular manifestations; support transition to adult care; and social work and family support as needed.

Surveillance: In CHILD syndrome, monitor for new cutaneous lesions, musculoskeletal deformities such as scoliosis and joint contractures, and neurologic, cardiac, and/or kidney manifestations annually or as needed.

In CK syndrome, monitor for developmental and educational progress, behavioral issues, changes in seizures, and development of scoliosis and/or kyphosis annually or as needed. Follow-up ophthalmology examination per ophthalmologist.

Genetic counseling: NSDHL-related disorders are inherited in an X-linked manner. CHILD syndrome is usually male lethal during gestation and thus predominantly affects females. CK syndrome predominantly affects males.

CHILD syndrome: If the mother of a proband has an NSDHL pathogenic variant, the chance of transmitting it in each pregnancy is 50%. However, since studies suggest that male conceptuses with an NSDHL pathogenic variant generally abort or resorb spontaneously, the expected live-born distribution is: 33% heterozygous (typically) affected females; 33% unaffected females; and 33% unaffected males.

CK syndrome: If the mother of a proband is heterozygous for an NSDHL pathogenic variant, the expected 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 heterozygous and may have a range of behavioral problems. Identification of female heterozygotes requires prior identification of the NSDHL pathogenic variant in the family.

Once the NSDHL pathogenic variant has been identified in a family member with an NSDHL-related disorder, prenatal and preimplantation genetic testing are possible.