Palmoplantar keratodermas

Gene: AP1B1

Green List (high evidence)

Comment on list classification: At least 6 unrelated individuals harbouring biallelic variants in AP1B1, diagnosed with Keratitis-ichthyosis-deafness syndrome, presented with syndromic palmoplantar hyperkeratosis. Based on the available evidence, this gene should be rated Green for Palmoplantar hyperkeratosis.

Created: 17 Oct 2025, 4:37 p.m. | Last Modified: 17 Oct 2025, 4:37 p.m.

Panel Version: 4.3

PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 31630788 Boyden et al., 2019
Individual 424, adult male, born with normal skin; diagnosed with ichthyosis at 2 months old; developmental delay, growth delay, partial hearing loss, tooth loss, profound photophobia, and
corneal scarring leading to near complete vision loss. At age 33 had erythroderma with thin palmoplantar
keratoderma, and a fissured tongue; noted thickening of his palms and soles since childhood.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, palmoplantar keratoderma, moderate motor & mental retardation, failed the auditory brainstem response test bilaterally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, erythroderma, palmoplantar keratoderma, hearing loss, ichthyosis. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Sources: Literature

Created: 17 Oct 2025, 4:29 p.m. | Last Modified: 17 Oct 2025, 4:34 p.m.

Panel Version: 4.3

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150; KID syndrome, MONDO:0018781

Publications

• 31630791
• 31630788
• 33452671
• 33349978
• 32969855
• 35144013