Autosomal Recessive Congenital Ichthyosis Research Articles

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

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.

High TGM1 Allelic Heterogeneity causing Lamellar ichthyosis in a small geographic area in South Mexico: Another Example of the “Réunion Paradox”

Lamellar ichthyosis (LI) is an autosomal recessive congenital ichthyosis characterized by generalized dry skin and severe scaling. It is caused by biallelic mutations in the TGM1 gene, however molecular data from non-Caucasian populations are limited. Results of genetic-molecular analysis of a group of LI pedigrees originating from two close small populations from south Mexico are presented. LI affected individuals belonging to 9 apparently unrelated families were studied. Exome sequencing or Sanger sequencing in probands from each family was carried out. Furthermore, DNA from 294 unaffected subjects from one of the communities were Sanger sequenced to determine the carrier frequency of the c.427C > T TGM1 variant. Five different TGM1 pathogenic variants, either in homozygous or in compound heterozygous state, were demonstrated in affected subjects. The two most common variants were c.427C > T (p.Arg143Cys) and c.1159+1G > T. A novel c.1645+1G > T TGM1 pathogenic allele was recognized. Carrier frequency analysis identified a total of 23 individuals heterozygous for the c.427C > T variant, predicting a prevalence of 78 carriers per 1000 inhabitants in the community. A high TGM1 allelic heterogeneity with 5 different LI-causing alleles in a limited geographic area was demonstrated. While the occurrence of homozygosity for a founder mutation is expected in small populations with high frequency of a particular autosomal recessive disorder, the occurrence of multiple pathogenic alleles has been previously described, a situation known as the Reúnion paradox. Our results expand the current knowledge of the mutational spectrum of TGM1-linked LI.

Expanding the allelic spectrum of ELOVL4-related autosomal recessive neuro-ichthyosis.

Very long-chain fatty acids (VLCFAs) composed of more than 20 carbon atoms are essential in the biosynthesis of cell membranes in the brain, skin, and retina. VLCFAs are elongated beyond 28 carbon atoms by ELOVL4 enzyme. Variants in ELOVL4 are associated with three Mendelian disorders: autosomal dominant (AD) Stargardt-like macular dystrophy type 3, AD spinocerebellar ataxia, and autosomal recessive disorder congenital ichthyosis, spastic quadriplegia and impaired intellectual development (ISQMR). Only seven subjects from five unrelated families with ISQMR have been described, all of which have biallelic single-nucleotide variants. We performed clinical exome sequencing on probands from four unrelated families with neuro-ichthyosis. We identified three novel homozygous ELOVL4 variants. Two of the families originated from the same Saudi tribe and had the exact homozygous exonic deletion in ELOVL4, while the third and fourth probands had two different novel homozygous missense variants. Seven out of the eight affected subjects had profound developmental delay, epilepsy, axial hypotonia, peripheral hypertonia, and ichthyosis. Delayed myelination and corpus callosum hypoplasia were seen in two of five subjects with brain magnetic rosonance imaging and cerebral atrophy in three. Our study expands the allelic spectrum of ELOVL4-related ISQMR. The detection of the same exonic deletion in two unrelated Saudi family from same tribe suggests a tribal founder mutation.

O13 JAK inhibitors to restore skin barrier function in ARCI

Abstract The autosomal recessive congenital ichthyoses (ARCI) are a group of chronic conditions where there is unmet therapeutic need. Harlequin ichthyosis (HI) is the most severe form of ARCI, with aberrant differentiation of the epidermis leading to a severe barrier defect. It is caused by mutations in ABCA12, a lipid transporter involved in the transport of glucosylceramides from the lamellar body to the lipid lamellae. Lamellar ichthyosis is caused by mutations in TGM1. Several Janus kinase (JAK) inhibitors (JAKi) inhibiting the JAK–STAT pathway are now licensed for atopic dermatitis. Previous work from our group in an in vitro HI model showed that tofacitinib had a restorative effect on the lipid barrier. We hypothesized that JAKi A, B and C could restore the epidermal barrier in both HI three-dimensional (3D) organotypic models (OTs) made using ABCA12 CrispR-Cas9 knockout and wild-type keratinocytes and ARCI 3D OTs generated with short hairpin RNA knock down of TGM1. The JAKi were tested at three concentrations in the 3D models (20, 50 and 500 nmol L–1 for JAKiA; 10, 50 and 250 nmol L–1 for JAKiB; 2, 25 and 125 nmol L–1 for JAKiC) and vehicle only was used as the control. The OTs were stained with haematoxylin and eosin, Nile red and differentiation markers such as K10, K14, transglutaminase 1 (TGM1) and involucrin. All three JAKi had a positive effect on the epidermal barrier. The epidermal structure looked more organized and uniform, with an increase in neutral and polar lipids in the upper epidermis. The differentiation markers showed normalization of the expression of involucrin, K10 and TGM1 at the same drug concentrations. These results suggest that JAKi have a generalized positive effect on the skin barrier and will be further investigated in an in vivo mouse model of HI.

ВРОЖДЕННЫЙ ИХТИОЗ (КОЛЛОДИЙНЫЙ ПЛОД) (КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ)

Intensive research is currently underway on the treatment of congenital ichthyosis in newborns. The paper describes a case of lamellar congenital ichthyosis, manifested by the state of a "colloidal" fetus. Congenital ichthyosis is a serious disease in which the process manifests itself at the time of birth. At the same time, the skin of the child is covered with a thin, dry, yellowish-brown layer resembling a colloid; ectropion and eclabium are often noted. After some time, cracks appear, often deep, the film turns into large scales, a clinical picture of congenital ichthyosis is formed. Lamellar ichthyosis (LI) belongs to the group of autosomal recessive congenital ichthyosis of the skin and is caused by a significant impairment of the skin barrier function due to the inability of differentiated keratinocytes to synthesize and/or secrete lipids necessary for the formation of corneocytes and the extracellular matrix of the stratum corneum. For the first time the disease was described by E. Seligman (1841) under the name "lamellar desquamation of newborns". The term "lamellar ichthyosis" was proposed by L. Gross and L. Torok (1895). The disease is genetically heterogeneous, occurs with a frequency of 1:300,000 of the population, more often in closely related marriages. They are affected with equal frequency by males and females. The described clinical case vividly illustrates the features of the course of congenital ichthyosis, the effectiveness of timely therapy using modern skin care products in a short time without the use of hormonal drugs.

The possibilities of using retinol palmitate in the systemic treatment of generalized hereditary keratinization disorders

Hereditary ichthyosis is a group of generalized hereditary keratinization disorders characterized by general dryness of the skin, peeling, hyperkeratosis and often erythroderma. These manifestations are caused by mutations in genes mainly involved in the formation of the skin barrier. Hereditary ichthyosis is divided into syndromic and non-syndromic. Nonsyndromic ichthyoses include: vulgar ichthyosis, recessive X-linked ichthyosis, autosomal recessive congenital ichthyosis, keratinopathic ichthyosis and other forms. At present, the best result for achieving clinical remission has been established with oral retinoids: retinol palmitate, isotretinoin (1st generation of retinoids) and acitretin (2nd generation of retinoids). The ability of retinol palmitate to regulate keratinization processes, strengthen the epidermal barrier and have an antioxidant effect is used in the treatment of generalized hereditary keratinization disorders. Medium and high therapeutic doses (200010 000 IU/kg/day) are used in the treatment. The prescribed dose of retinol palmitate differs in various nosological forms of ichthyosis, and depends on the severity of the pathological process, the age and weight of the patient, which must be taken into account when prescribing therapy to obtain the best result. It should be noted that clinical manifestations mainly regress at doses that do not lead to the appearance of signs of toxicity of the drug. The methods of retinol palmitate treatment of ichthyosis and ichthyosiform erythroderma are described.

The Cornified Envelope: A Versatile Contributor to the Epidermal Barrier

The Cornified Envelope: A Versatile Contributor to the Epidermal Barrier

A novel homozygous splice site variant in CERS3 causes autosomal recessive congenital ichthyosis.

The authors have no conflicts of interest to declare. Data are available on request from the authors. Figure S1: Pedigree of family segregating autosomal recessive congenital ichthyosis haplotypes of the closely linked locus-specific microsatellite markers under each genotyped member. The cytogenetic position is represented in centimorgan (cM). Black symbols depict affected members whereas blank symbols represent normal members of the family. Table S1: Description and Pathogenicity Prediction of Identified variant (c.466-1G>A) Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Recombinant PNPLA1 catalyzes the synthesis of acylceramides and acyl acids with selective incorporation of linoleic acid

Loss-of-function mutations in patatin-like phospholipase domain-containing protein 1 (PNPLA1) cause autosomal recessive congenital ichthyosis, and altered PNPLA1 activity is implicated in the pathogenesis of atopic dermatitis and other common skin diseases. To examine the hypothesis that PNPLA1 catalyzes the synthesis of acylceramides and acyl acids, we expressed and partially purified a soluble, truncated form of PNPLA1 in Escherichia coli, (PNPLA1trun) along with the related protein PNPLA2 (ATGL, adipose triglyceride lipase) and coactivator CGI-58. Liposomal substrates were incubated with recombinant enzymes for 0.5–24 h and products analyzed by HPLC-UV and LC-MS. Using trilinolein or dilinolein substrates, PNPLA1trun, like ATGLtrun, catalyzed lipolysis and acyltransferase reactions with 2–30% conversion into linoleic acid, monolinolein, and trilinolein. CGI-58 enhanced ATGL-catalyzed lipolysis as previously reported, but transacylase activity was not enhanced with ATGL or PNPLA1. In matching the proposed activity in vivo, PNPLA1 catalyzed acyl transfer from trilinolein and dilinolein donors to omega-hydroxy ceramide, omega-hydroxy glucosylceramide, and omega-hydroxy acid acceptors to form acylceramide, glucosyl-acylceramide, and acyl acid, respectively, albeit with only ∼0.05% conversion of the substrates. Notably, in experiments comparing dilinolein vs. diolein acyl donors, PNPLA1 transferred linoleate with 3:1 selectivity over oleate into acylceramide. These results support the role for PNPLA1 in the synthesis of acylceramides and acyl acids in epidermis and suggest that the enrichment of these lipids with linoleic acid could result from the substrate selectivity of PNPLA1.

870 Tofacitinib reduces skin inflammation in a patient with severe autosomal recessive congenital ichthyosis

870 Tofacitinib reduces skin inflammation in a patient with severe autosomal recessive congenital ichthyosis

824 Expanding the spectrum of autosomal recessive congenital ichthyosis caused by variants in NIPAL4 and PNPLA1 and evaluation of biologics interventions

824 Expanding the spectrum of autosomal recessive congenital ichthyosis caused by variants in NIPAL4 and PNPLA1 and evaluation of biologics interventions

Chronic activation of Toll-like receptor 2 induces an ichthyotic skin phenotype.

Ichthyosis defines a group of chronic conditions that manifest phenotypically as a thick layer of scales, often affecting the entire skin. While the gene mutations that lead to ichthyosis are well documented, the actual signalling mechanisms that lead to scaling are poorly characterized; however, recent publications suggest that common mechanisms are active in ichthyotic tissue and in analogous models of ichthyosis. To determine common mechanisms of hyperkeratosis that may be easily targeted with small-molecule inhibitors. We combined gene expression analysis of gene-specific short hairpin RNA (shRNA) knockdowns in rat epidermal keratinocytes (REKs) of two genes mutated in autosomal recessive congenital ichthyosis (ARCI), Tgm1 and Alox12b, and proteomic analysis of skin scale from patients with ARCI, as well as RNA sequencing data from rat epidermal keratinocytes treated with the Toll-like receptor 2 (TLR2) agonist Pam3CSK4. We identified common activation of the TLR2 pathway. Exogenous TLR2 activation led to increased expression of important cornified envelope genes and, in organotypic culture, caused hyperkeratosis. Conversely, blockade of TLR2 signalling in keratinocytes from patients with ichthyosis and our shRNA models reduced the expression of keratin 1, a structural protein overexpressed in ichthyosis scale. A time course of TLR2 activation in REKs revealed that although there was rapid initial activation of innate immune pathways, this was rapidly superseded by widespread upregulation of epidermal differentiation-related proteins. Both nuclear factor kappa B phosphorylation and GATA3 upregulation was associated with this switch, and GATA3 overexpression was sufficient to increase keratin 1 expression. Taken together, these data define a dual role for TLR2 activation during epidermal barrier repair that may be a useful therapeutic modality in treating diseases of epidermal barrier dysfunction.

Mutational Spectrum of the ABCA12 Gene and Genotype–Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis

Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1. The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in ABCA12. Mutations in this gene can also lead to congenital ichthyosiform erythroderma or lamellar ichthyosis. We present a large cohort of 64 patients affected with ARCI carrying biallelic mutations in ABCA12. Our study comprises 34 novel mutations in ABCA12, expanding the mutational spectrum of ABCA12-associated ARCI up to 217 mutations. Within these we found the possible mutational hotspots c.4541G>A, p.(Arg1514His) and c.4139A>G, p.(Asn1380Ser). A correlation of the phenotype with the effect of the genetic mutation on protein function is demonstrated. Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI.

Biallelic mutations in FLG, TGM1, and STS genes segregated with different types of ichthyoses in eight families of Pakistani origin.

Congenital ichthyosis is a diverse group of keratinization disorders associated with generalized scaling of skin of varying severity. The non-syndromic forms of congenital ichthyosis are further grouped into common ichthyosis (ichthyosis vulgaris and X-linked ichthyosis), autosomal recessive congenital ichthyosis, and keratopathic ichthyosis. To identify sequence variants involved in different forms of hereditary ichthyoses. We studied eight families with different types of ichthyosis including four families with autosomal recessive congenital ichthyosis and four families with common ichthyosis. Whole exome sequencing and PCR based genotyping was carried out to find out the molecular basis of disease. In one family, a novel duplication sequence variant NM_002016.2:c.2767dupT; NP_002007.1:p.Ser923PhefsTer2 was identified in FLG gene; in four families a previously reported nonsense sequence variant NM_000359.3:c.232C>T; NP_002007.1:p.Arg78Ter was identified in TGM1 gene, while, in three families of X-linked recessive ichthyosis, the whole STS gene (NM_001320752.2; NP_001307681.2) regions were deleted. Gene expression studies have not been performed that would have strengthened the findings of computational analysis. This study highlights the significance of the c.232C>T variant in the TGM1 gene as a possible founder mutation, complete STS gene deletion as reported previously in Pakistani population, while novel sequence variant in the FLG gene expands the spectrum of variations in this gene. These findings may be used for genetic counseling of the studied families.

Familial Lamellar Ichthyosis in 6 Years Old and 2 Years Old Children: A Rare Case Report

Background: Lamellar ichthyosis (LI) is a rare non-syndromic congenital ichthyosis and is autosomal recessive. LI patients are generally born with abnormalities of keratinization, then develop into lamellar scales and persist into adulthood. This study aimed to describe cases of lamellar ichthyosis and provide appropriate management to prevent worsening patient prognosis.
 Case presentation: A 6-year-old girl and her younger brother, 2-year-old have been complaining of scaly skin all over their bodies since birth. Both patients were born with a history of being covered by a collodion membrane. On physical examination, thick and wide lamellar scales were seen with an erythematous base and palmoplantar hyperkeratosis. Ectropion of the eyelids, eclabium in the mouth area, and microtia in the ears were seen. The results of the dermoscopy examination showed brownish quadrilateral structures with white scales forming a lamellar pattern. Laboratory examination showed vitamin D insufficiency. Both patients were referred to the Pediatric Polyclinic regarding insufficiency and developmental complaints. Patients received therapy in the form of moisturizers, artificial eye drops, topical urea as a keratolytic, and oral vitamin D 2,000 IU per day. There was a clinical improvement after 3 months of treatment.
 Conclusion: Lamellar ichthyosis is an autosomal recessive congenital ichthyosis with clinical manifestations limited to the skin. In a minority of cases, LI can be inherited in an autosomal dominant manner. Thorough management is necessary to prevent a poor prognosis in patients.

276 CLDN1 is associated with autosomal recessive congenital ichthyosis

Autosomal recessive congenital recessive (ARCI) refers to a large and genetically heterogeneous group of non-syndromic disorders of cornification featuring diffuse scaling. Ichthyosis, leukocyte vacuoles, alopecia and sclerosing cholangitis (ILVASC) syndrome is a rare autosomal recessive syndromic form of ichthyosis. The disease usually results from premature termination codon-causing pathogenic variants in CLDN1 encoding CLAUDIN-1 (CLDN1). Here, we aimed at delineating the genetic basis of autosomal recessive congenital ichthyosis in two adult siblings.

273 Serum interleukin-18 as a disease-specific marker of epidermolytic ichthyosis: a potential therapeutic target

Epidermolytic ichthyosis (EI) is a major form of congenital ichthyosis and characterized by erythroderma, marked scales, bulla, and erosions at birth. EI is recently classified as keratinopathic ichthyoses and caused mainly by heterozygous mutations in the KRT1 or KRT10 genes, encoding keratin (K) 1 or K10, respectively. No effective treatment strategy for EI has been established yet. To investigate disease-specific markers and novel therapeutic targets in EI, we examined serum samples for 9 patients with congenital ichthyoses including five EI patients, one ichthyosis with confetti patient, one Netherton syndrome patient, and two autosomal recessive congenital ichthyosis patients.

Ceramide Analysis in Combination With Genetic Testing May Provide a Precise Diagnosis for Self-Healing Collodion Babies

Self-healing collodion baby (SHCB), also called “self-improving collodion baby”, is a rare mild variant of autosomal recessive congenital ichthyosis and is defined as a collodion baby who shows the nearly complete resolution of scaling within the first 3 months to 1 year of life. However, during the neonatal period, it is not easy to distinguish SHCB from other inflammatory forms of autosomal recessive congenital ichthyosis, such as congenital ichthyosiform erythroderma. Here, we report a case study of two Japanese SHCB patients with compound heterozygous mutations, c.235G>T (p.(Glu79∗))/ c.1189C>T (p.(Arg397Cys)) and c.1295A>G (p.(Tyr432Cys))/ c.1138delG (p.(Asp380Thrfs∗3)), in CYP4F22, which encodes cytochrome P450, family 4, subfamily F, polypeptide 22 (CYP4F22). Immunohistochemically, inflammation with the strong expression of IL-17C, IL-36γ, and TNF-α was seen in the skin at birth. CYP4F22 is an ultra-long-chain FA ω-hydroxylase responsible for ω-O-acylceramide (acylceramide) production. Among the epidermal ceramides, acylceramide is a key lipid in maintaining the epidermal permeability barrier function. We found that the levels of ceramides with ω-hydroxy FAs including acylceramides and the levels of protein-bound ceramides were much lower in stratum corneum samples obtained by tape stripping from SHCB patients than in those from their unaffected parents and individuals without SHCB. Additionally, our cell-based enzyme assay revealed that two mutants, p.(Glu79∗) and p.(Arg397Cys), had no enzyme activity. Our findings suggest that genetic testing coupled with noninvasive ceramide analyses using tape-stripped stratum corneum samples might be useful for the early and precise diagnosis of congenital ichthyoses, including SHCB.

Clinical and molecular characteristics of autosomal recessive congenital ichthyosis in Thailand.

Autosomal recessive congenital ichthyosis (ARCI) is a heterogenous group of rare keratinization disorders. To date, more than 13 causative genes have been identified. However, data on clinical and molecular characteristics including genotype-phenotype correlation are lacking in Thailand. We collected cases diagnosed with non-syndromic ARCI and syndromic recessive congenital ichthyosis at the Institute of Dermatology from 2011 to 2021 and performed genetic testing with next-generation sequencing and assessed clinical details. Baseline demographic data, birth history, family history, skin manifestations at birth, current cutaneous manifestations, comorbidities, and response to treatments were assessed. DNA was screened for mutations using targeted gene sequencing of 45 genes related to congenital ichthyosis. A total of 33 patients were analyzed with an average age of 23.8± 13.9 years. Congenital ichthyosiform erythroderma (CIE) was most common (60.6%), followed by lamellar ichthyosis (18.2%), self-improving congenital ichthyosis (6.1%), Netherton syndrome (6.1%), ichthyosis prematurity syndrome (3%), Sjögren-Larsson syndrome (3%) and bathing suit ichthyosis (3%). Eight genes were found with pathogenic variants in our cohort as follows: ABCA12 42.4% (14/33), NIPAL4 24.2% (8/33), TGM1 15.2% (5/33), SPINK5 6.1% (2/33), ALDH3A2 3% (1/33), SLC27A4 3% (1/33), CYP4F22 3% (1/33), and ST14 3% (1/33). Clinically, 79% of patients with ABCA12 pathogenic variants in this study had CIE, 79% of w had novel biallelic pathogenic compound heterozygous variants, whereas 21% had homozygous missense variants. This is the first study to describe clinical and molecular findings of ARCI in a cohort from Thailand. Our findings demonstrate the clinical spectrum of the diseases and expand the molecular findings in a Southeast Asian population.

A Newborn in Western Nepal with Harlequin Ichthyosis: A Case Report

Harlequin ichthyosis (HI) is a rare autosomal recessive congenital ichthyosis with an incidence of 1 in 300,000 live births. It is lethal in 44% of cases and the baby is usually prematurely born. These babies have thick, highly keratinized armor-like skin, which forms large diamond, trapezoid or rectangular plates separated by deep fissures. These affect the shapes of eyelids, nose, mouth and ears, and also limit movement of the arms, legs and chest. This condition is linked with a nonsense or frameshift mutation in the ABCA12 gene, which is responsible for lipid transport in the keratinocytes. This gene synthesizes a protein that transports a lipid, epidermoside, a glucosylceramide, out of stratum corneum cells in the epidermis. To our knowledge, this is the first case report on Harlequin ichthyosis from Nepal, which makes this case unique. The take away lesson from this case is that couples with consanguineous marriages should undergo screening of ABCA12 gene if they plan to conceive.