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Case Letter
ARTICLE IN PRESS
doi:
10.25259/IJDVL_438_2024

A novel compound heterozygous variant in the ABCA12 gene associated with mild palmoplantar keratoderma

Department of Dermatology, West China Hospital, Wuhou District, Guoxue Alley, Chengdu, Sichuan, China
West China School of Medicine, Sichuan University, West China School of Medicine, Sichuan University, Guoxue Alley, Chengdu City, Chengdu, China

Corresponding author: Dr. Sheng Wang, Department of Dermatology, West China Hospital, Wuhou District, Guoxue Alley, Chengdu, Sichuan, China. wangsheng1892@126.com

Licence
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Song D, Li J, Zhang F, Luo L, Jiang X, Wang S. A novel compound heterozygous variant in the ABCA12 gene associated with mild palmoplantar keratoderma. Indian J Dermatol Venereol Leprol. doi: 10.25259/IJDVL_438_2024

Dear Editor,

Pathogenic variants in ABCA12 are important causative genetic defects for autosomal recessive congenital ichthyoses (ARCI), including congenital ichthyosiform erythroderma, harlequin ichthyosis and lamellar ichthyosis, often accompanied by palmoplantar keratoderma (PPK).1,2 Occasionally, specific ABCA12 mutations have been linked to milder phenotypes, including erythrokeratodermia variabilis et progressiva and pityriasis rubra pilaris.2,3 This report presents a case of isolated PPK resulting from variants in the ABCA12 gene and reviews such reported mild cases associated with ABCA12 variants.

A 31-year-old healthy woman, employed as a teahouse manager, presented with progressive thickening of the palms and soles since seven years of age, without significant discomfort. On examination, she exhibited mild, thick, yellowish plaques on weight-bearing sites of the palmoplantar areas, notably on the finger flexors and calcaneal regions [Figures 1a, 1b and 1c]. There was no evidence of hyperhidrosis, transgradiens, or a sponge-like appearance after water immersion. No cutaneous involvement suggestive of ichthyosis was noted in other areas of the body, and no abnormalities of nails, hair, or teeth were observed. Family history was noncontributary [Supplementary Figure 1]. Histological examination of the keratotic lesion from the right thumb showed orthohyperkeratosis and acanthosis without acantholysis [Figure 1d].

Mild, thick, yellowish plaques of the palms, notably on the finger flexors.
Figure 1a:
Mild, thick, yellowish plaques of the palms, notably on the finger flexors.
Thick, yellowish plaques on weight-bearing sites of the plantar areas.
Figure 1b:
Thick, yellowish plaques on weight-bearing sites of the plantar areas.
Thick, yellowish plaques on the calcaneal regions.
Figure 1c:
Thick, yellowish plaques on the calcaneal regions.
Orthohyperkeratosis and acanthosis without acantholysis (Haematoxylin-eosin, 100×).
Figure 1d:
Orthohyperkeratosis and acanthosis without acantholysis (Haematoxylin-eosin, 100×).

Supplementary Files

After informed consent and approval from the ethics committee of the institute, peripheral blood samples were taken from the patient and her parents. Whole-exome sequencing identified a novel compound heterozygous variant in the ABCA12 gene in the proband, which was confirmed by Sanger sequencing. This included the duplication variant c.7659_7662dupGAGT (p.Q2555Efs*20) in exon 52, and the missense variant c.7386G>C (p.M2462I) in exon 50, inherited from her mother and father, respectively [Figure 2a]. These observed variants have not been reported from the databases of single nucleotide polymorphisms, ExAC, 1000 genomes, gnomAD, and Exome Variant Server (EVS). Both the variants were predicted to be detrimental using Sorting Intolerant From Tolerant PolyPhen-2, MutationTaster, and Genomic Evolutionary Rate Profiling [Supplementary Figure 2-3]. These variants are classified as uncertain significance according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Moreover, any other disease-causing variants associated with PPK were not detected. Given the genetic defects and clinical features, the diagnosis of isolated PPK associated with ABCA12 variants was established.

Genetic analysis (sequence chromatogram) showing compound heterozygous variants in the C-terminus of ABCA12, including c.7659_7662dupGAGT (p.Q2555Efs*20) and c.7386G>C (p.M2462I). (A: Adenosine, C: Cytosine, T: Thymine, G: Guanine).
Figure 2a:
Genetic analysis (sequence chromatogram) showing compound heterozygous variants in the C-terminus of ABCA12, including c.7659_7662dupGAGT (p.Q2555Efs*20) and c.7386G>C (p.M2462I). (A: Adenosine, C: Cytosine, T: Thymine, G: Guanine).

The ABCA12 protein, consisting of 2595 amino acids encoded by 53 exons, plays a crucial role in skin metabolism and keratinisation.1,2 This ATP-binding cassette transporter facilitates the transport of lipid glucosylceramides, crucial for forming the extracellular lamellar membrane.1,2 Disturbances in ABCA12 function can lead to impaired lamellar granules, disrupting intercellular lipid deposition and skin barrier function.1,2 Consequently, hyperkeratosis occurs due to compensatory hyperproliferation of keratinocytes.1

The clinical severity often correlates with the nature of mutations affecting ABCA12 function. For example, potentially fatal harlequin ichthyosis often results from loss-of-function truncating mutations, while biallelic missense mutations typically lead to milder phenotypes like congenital ichthyosiform erythroderma or lamellar ichthyosis.1,2

Recent reports have linked ABCA12 mutations to relatively milder keratinisation disorders2-7 [Table 1]. Several ABCA12 variants have been identified in erythrokeratodermia variabilis, an otherwise dominant disorder resulting from connexin gene defects.2,3 Terrinoni et al. also identified a compound heterozygous mutation in ABCA12 (exon 30 and exon 31) in a family displaying an variabilis et progressiva phenotype.4 Their evaluation of glucosyl-ceramides in the upper epidermal layers suggested a partial depletion of ABCA12 function in the mild phenotype, characterised by reduced and patchy hydroxy ceramide deposition.4 ABCA12 variants also cause a blaschkoid form of congenital ichthyosiform erythroderma due to recessive mosaicism.5 Additionally, cases resembling pityriasis rubra pilaris have been described in association with ABCA12 variants.6 These mild cases often involve unique missense changes in ABCA12, not leading to complete loss of function.6

Table 1: ABCA12-associated mild keratinisation disorders
Clinical phenotype Genetic basis Reference/PMID
EKV or EKVP

Compound heterozygous: p.N678Rfs*10; c.2866-8T>A

Compound heterozygous: p.D844G;p.P1938S

Compound heterozygous: p.Y1929*; p.E2284D

Sun Q, et al. 2

PMID: 34851365

Compound heterozygous: H1471R; T1534M

Terrinoni A, et al.4

PMID: 37762265

Compound heterozygous: p.P2416L; p.Y1218C

Liu Y, et al.3

PMID: 38085035

PRP

Homozygous: p.T1534M

Homozygous: p.R2426W

Takeichi T, et al.6

PMID: 37752865

Nevoid form of CIE

Recessive mosaicism:

p.l1257Nfs*4; p.E1227K

van Leersum FS, et al.5

PMID: 31206590

Mild CIE with periodic exacerbation Compound heterozygous: p.N2184I; p.I2307Rfs*14

Wada Y, et al.7

PMID: 28771802

Isolated PPK Compound heterozygous: p.Q2555Efs*20; p.M2462I Our case

EKV, erythrokeratodermia variabilis; EKVP, erythrokeratodermia variabilis et progressive; PRP, pityriasis rubra pilaris; PPK, palmoplantar keratoderma; CIE, congenital ichthyosiform erythroderma.

In our case, isolated PPK without generalised ichthyosis was noted. The identified causal mutations, located in exon 50 and 52, might cause a potential mild loss of protein function in the C-terminus of ABCA12 [Figure 2b], offering a plausible explanation for the observed mild phenotypes. Given that lesions are localised in weight-bearing and friction areas, environmental factors like pressure might contribute to hyperkeratotic lesions in individuals with a genetic background of hypomorphic ABCA12 variants. However, further functional studies are necessary to validate this hypothesis.

Schematic representation of the ABCA12 structure showing the identified variants located in the C-terminus. (COOH: carboxylic acid).
Figure 2b:
Schematic representation of the ABCA12 structure showing the identified variants located in the C-terminus. (COOH: carboxylic acid).

In conclusion, we identified a novel compound heterozygous variant in the ABCA12 gene in a patient presenting with a mild form of isolated PPK. Our study expands the phenotypic spectrum associated with ABCA12 variants and underscores the genetic heterogeneity of isolated PPK. Further research is crucial for elucidating precise genotype–phenotype correlations for ABCA12 mutations, particularly in cases with mild phenotypes.

Ethical approval statement

The research/study was approved by the Institutional Review Board at Ethics Committee Biomedical Research, West China Hospital of Sichuan University, number IRB No. 202304705, dated 2023.12.05.

Declaration patient consent

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

References

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