Patients with keratinization disorders due to ABCA12 variants showing pityriasis rubra pilaris phenotypes

Abstract

Pathogenic variants in ABCA12 are important causative genetic defects for autosomal recessive congenital ichthyoses (ARCI), which include congenital ichthyosiform erythroderma (CIE), harlequin ichthyosis, and lamellar ichthyosis. In addition, pathogenic variants in ABCA12 are known to cause a localized nevoid form of CIE due to recessive mosaicism. We previously reported siblings who carried an ABCA12 variant but did not show a “congenital” phenotype. They were considered to have pityriasis rubra pilaris (PRP). Here, we present a further patient with ABCA12 variants whose phenotype was not congenital ichthyosis, in an independent family. Notably, these three patients had geographic unaffected areas. Such areas are not usually found in patients with ARCI who have ABCA12 variants, suggesting mild phenotypes for these patients. Interestingly, the histological features of the ichthyotic lesions in these patients resembled those of PRP. All three patients had homozygous pathogenic missense variants in ABCA12. Our findings expand the phenotypic spectrum of patients with ABCA12 variants.

Updated mutational spectrum and genotype–phenotype correlations in ichthyosis patients with ABCA12 pathogenic variants

“…They concluded that the mild phenotype resembling EKVP of their patients was due to a partial loss of function of ABCA12, leading to a partial depletion of GlcCer deposition in the stratum corneum 22 . In these two papers by Takeichi et al 21 . and Terrinoni et al., 22 the identical pathogenic missense variant, c.4601C>T p.(Thr1534Met), located within the first ATP‐binding cassette, was identified both in patients with the PRP‐like phenotype and in patients with the EKVP‐like phenotype.…”

“…and Terrinoni et al., 22 the identical pathogenic missense variant, c.4601C>T p.(Thr1534Met), located within the first ATP‐binding cassette, was identified both in patients with the PRP‐like phenotype and in patients with the EKVP‐like phenotype. The other causative ABCA12 variant in a patient with the PRP‐like phenotype was located within the second ATP‐binding cassette 21 . The siblings with the EKVP‐like phenotype were compound heterozygous for c.4601C>T p.(Thr1534Met) and a missense variant in the first ATP‐binding cassette 22 .…”

“…Recently, we reported three patients with non‐congenital ichthyosis similar to pityriasis rubra pilaris (PRP), caused by pathogenic variants in ABCA12 21 . Terrinoni et al 22 .…”

“…They concluded that the mild phenotype resembling EKVP of their patients was due to a partial loss of function of ABCA12, leading to a partial depletion of GlcCer deposition in the stratum corneum. 22 In these two papers by Takeichi et al 21 and Terrinoni et al, 22 is located upstream of the first ATP-binding cassette. 18 Thus, these missense variants are speculated to only mildly impair the function of ABCA12.…”

“…Recently, we reported three patients with non-congenital ichthyosis similar to pityriasis rubra pilaris (PRP), caused by pathogenic variants in ABCA12. 21 Terrinoni et al 22 reported a family with patients showing patchy ichthyosis and erythrodermia resembling clinical features of erythrokeratodermia variabilis et progressiva (EKVP). They concluded that the mild phenotype resembling EKVP of their patients was due to a partial loss of function of ABCA12, leading to a partial depletion of GlcCer deposition in the stratum corneum.…”