IDEDNIK Syndrome

Excerpt

Clinical characteristics: IDEDNIK syndrome is characterized by enteropathy, poor weight gain, growth deficiency, skin manifestations (ichthyosis, erythroderma, and keratoderma), sparse hair, global developmental delay, mild-to-severe intellectual disability, and deafness. Additional manifestations can include liver disease, recurrent infections, and hematologic and ocular manifestations (photophobia, corneal scarring, and keratitis). Reduced serum ceruloplasmin and total copper levels are common. Some individuals have findings on brain MRI (cerebral atrophy, basal ganglia abnormalities, and thin corpus callosum). Death prior to age two years occurs in some individuals due to severe enteropathy or sepsis; in others survival into adulthood is reported.

Diagnosis/testing: The diagnosis of IDEDNIK syndrome is established in a proband by identification of biallelic pathogenic variants in AP1B1 or AP1S1 by molecular genetic testing.

Management: Targeted therapy: Treatment with oral zinc acetate therapy to reduce liver copper overload has been reported to improve behavioral disturbances, skin manifestations, and cognitive function in some individuals. Zinc sulfate may be an alternative, less expensive treatment option. Experience is limited with this targeted therapy.

Supportive care: Dietary modification and potential parenteral supplementation for enteropathy; feeding therapy; gastrostomy tube placement as needed; treatment options for skin manifestations include low-dose oral acitretin, skin emollients and topical lactic acid, frequent emollient application and short courses of topical cortical steroids or pimecrolimus ointment, and 50% urea ointments; developmental and educational support; hearing aids as needed for sensorineural hearing loss; community hearing services; standard treatment of seizures and peripheral neuropathy by an experienced neurologist; supportive treatment as needed for liver disease; standard treatment for recurrent infections; supportive treatment as needed for hematologic manifestations, and occasionally transfusion may be necessary; standard treatment of cataracts and other ocular manifestations per ophthalmologist; treatment of cryptorchidism per urologist; treatment of hypothyroidism and growth hormone deficiency per perinatologist; social work and family support.

Surveillance: At each visit, assess growth parameters, nutritional status, safety of oral intake, diarrhea, skin and hair manifestations, developmental progress and educational needs, mobility and self-help needs, seizures and peripheral neuropathy, behavioral issues, liver function tests, complete blood count, evidence of aspiration and respiratory infections, and family needs. Audiology evaluation as recommended by audiologist; ophthalmology evaluation for keratitis, cataract, and accommodative esotropia as recommended by ophthalmologist; assess thyroid function and for growth hormone deficiency as recommended by endocrinologist.

Evaluation of relatives at risk: Clarify the genetic status of apparently asymptomatic older and younger at-risk sibs in order to identify as early as possible those who would benefit from prompt initiation of zinc acetate treatment.

Genetic counseling: IDEDNIK syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an AP1B1 or AP1S1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the AP1B1 or AP1S1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.