Dear Editor,
Nonsyndromic epidermal differentiation disorders (nEDDs) are a heterogeneous group of keratinization disorders. NIPAL4 encodes a putative magnesium transporter, and the dehydration lethality in knockout mice suggests the essential role for NIPAL4 in skin barrier formation [1]. NIPAL4‐nEDD phenotypes range from lamellar ichthyosis to congenital ichthyosiform erythroderma [2]. We report a NIPAL4‐nEDD patient with compound heterozygous NIPAL4 variants including a novel p.Ser231Argfs*4 variant.
The patient was a 1‐year‐old Japanese female with generalized xerosis and mild pruritus since birth. No collodion baby phenotype was observed. Examination revealed faint erythema with fine scales on her trunk and lamellar scales on her legs (Figure 1a,b). The patient exhibited hypohidrosis, except on her head. Palmoplantar hyperkeratosis was almost absent. The patient had no ectropion or eclabium. There was no family history of similar symptoms. Skin biopsy demonstrated compact hyperkeratosis and acanthosis (Figure 1c). Electron microscopy revealed a normal‐appearing corneocyte lipid envelope (CLE) and a small number of lipid droplets in the stratum corneum (SC). The lipid lamella structures and the lamellar granules were unclear, and the keratohyalin granules in the granular layer were small (Figure 1d–f). Whole‐exome sequencing identified compound heterozygous variants in NIPAL4 (NM_001099287.1): a paternal c.458G>A (p.Arg153Gln), and a maternal c.692_693insGG (p.Ser231Argfs*4), which was absent from public databases. The patient was diagnosed with NIPAL4‐nEDD. Her skin symptoms remain slightly improved with topical emollients and mild topical steroids.
FIGURE 1.
Clinical, histopathological and ultrastructural findings. (a) Fine, powdery scales with mild erythema on the trunk. (b) Reticulated erythema with some brownish lamellar scales on the lower legs. (c) Histopathology of a skin biopsy from the left abdomen demonstrating compact hyperkeratosis and acanthosis (hematoxylin and eosin stain, original magnification ×200). Scale bar, 100 μm. (d–f) Transmission electron micrographs (TEM) of the upper epidermis after pyridine extraction to visualize the corneocyte lipid envelope (CLE). (d) Granular layer (GL) and stratum corneum (SC) of the upper epidermis. Original magnification, ×18 000. (e) A small number of lipid droplets (yellow arrowheads) are present within the SC. Original magnification, ×31 000. (f) Higher‐magnification view highlighting a well‐preserved CLE (red arrowheads). Original magnification, ×170 000.
Our case showed a milder phenotype than those of the previously reported cases with a homozygous c.223 + 5G>C splice site variant [3] and with a homozygous p.Arg153Gln variant [4]. The latter case, a 41‐year‐old female, presented with ichthyosiform erythroderma, mild ectropion, and significant palmoplantar keratoderma [4].
The novel c.692_693insGG (p.Ser231Argfs*4) variant was a frameshift variant, and it was located in the middle of the fourth transmembrane helix and predicted to introduce a premature stop codon, leading to the loss of more than 40% of the C‐terminal region of the NIPAL4 protein [5]. Such a transcript would likely be degraded by nonsense‐mediated mRNA decay (NMD), resulting in no protein products.
The mechanism of the milder phenotype in the present case than in the p.Arg153Gln homozygous case remains uncertain. However, a nonlinear gene‐dosage‐interaction may be involved. In addition, regulatory variants or post‐zygotic events cannot be excluded. Otherwise, environmental factors may be attributed to the severe phenotypes in past cases. If so, the milder phenotype in the present patient might be maintained in the future through continuous skin management.
In our case, the indistinct lipid lamella and preserved recognizable CLE may reflect some, but not severe, impairment of acylceramide metabolism. Furthermore, the lipid droplets in the SC may indicate defective secretion or intracellular processing of lamellar body contents [1].
The limitations regarding comparisons with previous cases [3, 4] may include the age differences and additional genetic factors. However, the lack of key features, such as ectropion and palmoplantar keratoderma, indicates that the phenotype was unique to the present compound heterozygous variants.
In conclusion, the milder phenotype in the present case challenges conventional predictions and highlights the importance of considering unique allelic combinations in genetic counseling for NIPAL4‐nEDD.
Funding
This research was supported by a Health and Labor Sciences Research Grant for Research on Intractable Diseases (23FC1039) from the Ministry of Health, Labour, and Welfare to M.A. This work was supported by a JST FOREST Program grant (JPMJFR210R) from Japan Science and Technology Agency awarded to T.T. This study was also supported in part by a JSPS KAKENHI grant JP24K02470 from Japan Society for the Promotion of Science to M.A. from the Japan Society for the Promotion of Science.
Disclosure
Masashi Akiyama is an Editorial Board member of Journal of Dermatology and a co‐author of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication.
Ethics Statement
Reviewed and approved by the Institutional Review Board of Nagoya University Graduate School of Medicine; approval #2016‐0412.
Consent
The patients in this manuscript have given written informed consent to the publication of their case details.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
We gratefully thank the family for having participate in this study. We also thank Dr. Seiji Morioka, Morioka Dermatology Clinic, Takamatsu, Kagawa, Japan, for providing clinical information.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.