AP1B1 – KIDAR Syndrome (Ichthyosiform Erythroderma, Corneal Involvement, and Hearing Loss)

AP1B1 encodes the β1-adaptin subunit of the AP-1 clathrin adaptor complex, essential for endosomal and Golgi vesicle trafficking. Biallelic loss-of-function variants cause keratitis-ichthyosis-deafness (KIDAR) syndrome, a rare autosomal recessive disorder characterized by ichthyosiform erythroderma, corneal involvement, and sensorineural deafness. The clinical presentation is highly concordant across reported cases, underscoring the specificity of AP1B1 deficiency in this phenotype.

Genetic analyses have identified homozygous deletions encompassing AP1B1 exons in ten unrelated probands to date (PMID:37657632). These deletions predict protein truncation or absence, consistent with a loss-of-function mechanism under autosomal recessive inheritance. Familial segregation data are limited, with no additional affected relatives reported.

The variant spectrum in KIDAR is currently restricted to copy-number losses, including a recurrent deletion impacting identical exons in multiple individuals (PMID:37657632). No missense or splice variants have been documented, reflecting a requirement for complete loss of AP1B1 function to produce disease. Diagnostic evaluation should incorporate both sequencing and copy-number analysis of AP1B1.

Phenotypic features shared by all reported individuals include congenital ichthyosis with prominent palmoplantar keratoderma, sparse and brittle hair with vertex alopecia, bilateral profound sensorineural deafness, and enteropathy with feeding difficulties and failure to thrive (PMID:37657632). Additional manifestations observed in more than one patient include frontal bossing, short stature, slender build, microdontia, cerebral atrophy, neutropenia, thrombocytopenia, and fetal ascites. These findings expand the KIDAR clinical spectrum beyond ectodermal and sensory involvement.

Functional studies implicate AP1B1 in clathrin-mediated trafficking and lysosomal biogenesis, processes critical for epidermal barrier function and inner ear homeostasis. Loss of AP1B1 likely disrupts keratinocyte desquamation and cochlear hair cell maintenance; however, disease-specific in vitro or in vivo models and rescue experiments have not yet been reported.

In summary, biallelic AP1B1 deletions produce a consistent KIDAR phenotype through loss-of-function. Genetic testing for AP1B1 sequence variants and copy-number alterations is clinically indicated in patients presenting with congenital ichthyosis and deafness. Further functional modeling will solidify mechanistic insights and advance therapeutic strategies.

References

• European Journal of Medical Genetics • 2023 • Severe KIDAR syndrome caused by deletion in the AP1B1 gene: Report of a teenage patient and systematic review of the literature PMID:37657632

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