Erythrokeratodermia Variabilis due to a Compound Heterozygous Variants in the NIPAL4 Gene

ABSTRACT

We report on a novel pathogenic genetic variant in compound heterozygosis of the NIPAL4 gene c.396C>Gp.(Ile132Met); additionally, we comment on key clinical findings that contribute to the expansion of the EKVP phenotype in childhood.

To the Editors,

1.

Erythrokeratodermia variabilis progressiva (EKVP) is a rare genodermatosis characterized by abnormal keratinization caused by mutations in the GJB3, GJB4, and occasionally GJA1 genes, affecting connexin proteins involved in transmembrane regulation, intercellular channels, and keratinocyte differentiation [1, 2, 3]. It has also been linked to a novel mutation in the NIPAL4 gene [4], the second most common mutation in non‐syndromic autosomal recessive congenital ichthyosis (ARCI). Moreover, EKV‐like phenotypes have been reported in ABCA12 pathogenic variant carriers [5].

We present a 4‐year‐old girl of Venezuelan origin, the youngest of three daughters of non‐consanguineous parents. Since birth, the patient has presented with migratory, red, and dry patches and plaques over the trunk and extremities, managed with emollients and corticosteroids with partial response. Past medical history was notable for a preterm delivery at 28 weeks.

Physical examination showed well‐demarcated, erythematous, hyperkeratotic, and desquamative plaques involving the flexures and extending medially over islands of spared skin (Figures 1 and 2). Histopathologic examination via 4‐mm skin punch biopsy showed epidermal acanthosis, granular‐layer thickening, and compact orthokeratosis, compatible with an ichthyosiform pattern. An initial presumptive diagnosis of EKVP was made based on the phenotypic features.

FIGURE 1.

Clinical photographs displaying the face, intertriginous spaces, arms, legs, and dorsum of the hands and feet of the patient. Notable corrugated hyperpigmentation and hyperkeratosis were most evident in the flexural areas of the armpits and antecubital fossae (A) with discrete involvement of the forehead (B).

FIGURE 2.

The dorsum of the hands, and extensor surfaces of the arms and legs (A). Notable islands of spared skin with well‐demarcated desquamative plaques in the dorsum of both feet (B).

Whole exome sequencing (WES) showed compound heterozygosis of the NIPAL4 gene. The first variant (NM_001099287.1):c.527C>A (Ala176Asp) is known to be pathogenic. The second variant (NM_001099287.1):c.396C>G (Ile132Met), a variant of unknown significance (VUS), is suspected to be pathogenic based on the updated ACMG guidelines.

Segregation studies showed that the proband inherited one variant from each unaffected parent (father as a carrier of c.210C>G and mother as a carrier of c.341C>A), confirming compound heterozygosity in an autosomal recessive inheritance pattern. This led to a definite diagnosis of EKVP, and genetic and reproductive counseling was provided to the family.

EKVP, formerly known as Mendes Da Costa syndrome, manifests as migratory erythematous patches and fixed to generalized hyperkeratotic plaques affecting the face, buttocks, and limbs, typically appearing shortly after birth and stabilizing during adolescence.

Genetically heterogeneous EKVP phenotypes have been described with mutations in other ichthyosis genes such as ABHD5, ELOVL4, PNPLA1, and more recently, the NIPAL4 gene. The analysis of the latest findings suggests that compromised Mg+transportation affects lipid traffic signaling, impaired intracellular lipid layers, and keratinocyte differentiation, which ultimately compromise the skin barrier [4, 5].

Our patient was identified as compound heterozygous for two distinct missense variants (p.Ala176Asp and p.Ile132Met), consistent with an autosomal recessive inheritance pattern. Notably, the p.Ile132Met variant has not been previously reported in association with EKVP. Previously reported EKV phenotypes in children are summarized in a Table S1.

We hypothesize that compound heterozygosity may allow the wild‐type allele to exert a compensatory effect during keratinization, potentially leading to subtler clinical signs. However, this remains speculative without functional assays to evaluate mutation effects on protein structure and functionality. Additionally, documented intrafamilial phenotypic variability in EKV suggests that other genetic and epigenetic factors may also contribute and should be considered.

NIPAL4 variant carriers can present with either non‐syndromic ARCI or EKVP, making differentiation difficult due to overlapping histopathologic features. This underscores the importance of genotype/phenotype correlation. The variation in disease presentation suggests that NIPAL4 variants may link cornification disorders and connexinopathies, warranting further research into the relationship between ARCI and EKVP in NIPAL4 mutations.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1. Summarizes key patient characteristics from published research on pediatric erythrokeratodermia variabilis (EKV). It includes patient age and sex, age at presentation, evolving clinical features, EKV phenotypes observed, reported genetic variants, and references to cited articles.

Sánchez‐Espino L. F., Ivars M., Vicente‐López A., Prat‐Torres C., Armstrong‐Morón J., and Baselga E., “Erythrokeratodermia Variabilis due to a Compound Heterozygous Variants in the NIPAL4 Gene,” Pediatric Dermatology 42, no. 6 (2025): 1297–1298, 10.1111/pde.15959.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.