Deficient stratum corneum intercellular lipid in a Japanese patient with lamellar ichthyosis with a homozygous deletion mutation in SDR 9C7

Dear Editor, Autosomal recessive congenital ichthyosis (ARCI) is an umbrella term for inherited nonsyndromic ichthyosis, which includes harlequin ichthyosis, lamellar ichthyosis (LI), congenital ichthyosiform erythroderma and pleomorphic ichthyosis (also called self‐healing/self‐improving collodion baby).1 The clinical diversity is matched by genetic heterogeneity, with 11 genes currently implicated in the pathobiology of ARCI,2,3 including the most recent discovery of two missense mutations in SDR9C7 in three consanguineous Lebanese families.4 Here we describe a case of ARCI (LI phenotype) with a previously unreported homozygous deletion mutation in SDR9C7. We extend the spectrum of clinical features associated with SDR9C7 mutations and identify deficient intercellular lipid and malformation of intercellular lipid layers in the stratum corneum. The patient is a 72‐year‐old Japanese woman, the youngest of 11 siblings born to nonrelated parents. At birth she was noticed to have collodion membrane and presented with symptoms of ichthyosis after birth. She was treated with systemic retinoid; however, it was ineffective and her scales got worse. Her other medical history included diabetes mellitus and hypertension. On examination, she had large, whitish to light brown scales without erythroderma on her trunk and extremities (Fig. 1a, b). There was palmoplantar keratoderma. She had no hair, nail, dental or mucosal abnormalities, and vision and hearing were normal. There was no family history of any skin disorder. Clinical and morphological features of the patient. (a, b) Large light brown to whitish shiny scales on the trunk (a) and the right upper arm (b). (c) A skin biopsy sample shows compact hyperkeratosis with a slightly thin granular layer. No inflammatory cell infiltration was seen in the dermis or the epidermis. Haematoxylin and eosin stain, scale bar = 50 μm. (d) Ultrastructurally, remarkably compact, thick stratum corneum is seen and almost no lipid droplets are observed in the cornified cells. (e) Lamellar contents of the lamellar granules (arrows) are deficient in the granular layer cells. Only a small amount of lipid material is secreted from the lamellar granules, and the stratum corneum intercellular lipid layers are absent or extremely thin. Scale bars = 1 μm. Following ethical approval, informed written consent was obtained in compliance with the Declaration of Helsinki guidelines. A skin biopsy specimen obtained from the left lower leg showed compact hyperkeratosis with a normal‐appearing granular layer (Fig. 1c). Neither parakeratosis nor dyskeratosis was observed and no inflammatory cell infiltration was present; these features are compatible with LI. Electron microscopy revealed markedly compact hyperkeratosis (Fig. 1d, e), a minimal amount of lipid was observed between the cornified cells, and only very thin or absent intercellular lipid layers were seen within the cornified cell layers. Of note, almost no lipid droplets were found in the cornified cells. Lamellar materials (lipid contents) were markedly reduced in the lamellar granules, although the lamellar granules seemed to fuse normally with the cell membrane. Genomic DNA from the patient was used for whole‐exome sequencing analysis, using methodology described elsewhere.5 No potentially pathogenic mutations were noted in known ARCI genes. In total, 472 previously unreported mutations were identified by whole‐exome sequencing, 44 homozygous and 428 heterozygous. Within these variants, there was a previously unreported homozygous deletion mutation in SDR9C7, c.897delT, which was then confirmed by Sanger sequencing. Further details of the mutation detection and immunohistochemical analyses are available on request. SDR9C7 encodes short‐chain dehydrogenase/reductase family 9C, member 7. SDR9C7 is known to display weak conversion of all‐trans‐retinal to all‐trans‐retinol in the presence of reduced nicotinamide‐adenine dinucleotide (NADH), but has not been shown to have retinoid or dehydrogenase activities.6 However, it is uncertain how mutations in SDR9C7 lead to the clinical phenotypes of ARCI. In cultured cells, expression of both the mutant SDR9C7 proteins (missense mutations) was markedly reduced compared with that of the wild‐type protein, suggesting possible instability of the protein.4 The present mutation, c.897delT (p.Phe300Serfs*3), is different and causes a slightly truncated SDR9C7 protein that lacks 12 residues at the C‐terminus, potentially underscoring the functional importance of the highly conserved C‐terminus. Our ultrastructural findings also provide some insight into disease pathogenesis. Of note, compact hyperkeratosis with a normal granular layer was seen in the patient's skin, and we observed markedly reduced intercellular lipid and defective intercellular lipid layers within the stratum corneum; the lipid contents of the lamellar granules in the granular layer cells were also defective. From these findings we infer that, rather than the vitamin A metabolic pathway abnormality proposed by Shigehara et al.,4 based on SDR9C7 converting retinal into retinol,6 the pathomechanism of LI caused by SDR9C7 deficiency probably involves abnormal metabolism and defective synthesis of lamellar granule lipid contents in keratinocytes, resulting in malformation of the intercellular lipid layers in the stratum corneum. With regard to genotype–phenotype correlation, our patient showed light brown to shiny whitish scales, which were somewhat different from the large erythematous scales reported in the Lebanese patients.4 In addition, our case lacks the palmoplantar keratoderma seen in those cases. These differences might be explained by the nature of the mutations (missense vs. frameshift). However, clinically all patients with ARCI with SDR9C7 mutations have experienced recurrent fungal infections, and it is possible that the defective intercellular lipid layers in the stratum corneum might generate a dysfunctional epidermal barrier that facilitates this type of infection. In summary, our findings expand the molecular basis of ARCI in identifying a patient with LI with a homozygous frameshift mutation in SDR9C7. This provides evidence for defective intercellular lipid layers in the stratum corneum contributing to the clinical phenotype. Funding sources: the authors acknowledge financial support from Japan Society for the Promotion of Science KAKENHI, grant numbers 15K15415, 15H06280 and 16K19717. This work was supported by funding from Advanced Research and Development Programs for Medical Innovation (AMED‐CREST) to M.A. from Japan Agency for Medical Research and Development (AMED), and by a Grant‐in‐Aid for Scientific Research (B) 15H04887 to M.A. from the Japan Society for the Promotion of Science (JSPS). The work was also supported by the Japan Intractable Diseases Research Foundation. Conflicts of interest: none declared.