Ichthyosis: case report in a Colombian man with genetic alterations in ABCA12 and HRNR genes.

BACKGROUND: Ichthyosis is a heterogeneous group of diseases caused by genetic disorders related to skin formation. They are characterized by generalized dry skin, scaling, hyperkeratosis and frequently associated with erythroderma. Among its different types, harlequin ichthyosis (HI) stands out due to its severity. HI is caused by mutations in the ABCA12 gene, which encodes essential proteins in epidermal lipid transport, and it helps maintain the homeostasis of the stratum corneum of the epidermis. However, due to the wide spectrum of genetic alterations that can cause ichthyosis, holistic medical care, and genetic studies are required to improve the diagnosis and outcomes of these diseases. CASE PRESENTATION: Here, we presented the case of a 19 years old male patient who was a premature infant and exhibited clinical features consistent with HI, including bright yellow hyperkeratotic plates with erythematous fissures that covered his entire body like a collodion baby. Currently, he exhibited erythroderma, photosensitivity, ectropion, auricular pavilion alterations, and musculoskeletal disorders, such as equinovarus feet, fingers, hands, and hypoplastic feet with contractures in flexion and marked difficulty in fine motor skills. In addition, he presented dyschromatopsia, Achilles reflex hyporeflexia, slight speech, dental alteration and deficient cognitive performance. After the genetic sequencing, variants were found in ABCA12 and HRNR which are related to several skin diseases, including ichthyosis. CONCLUSIONS: Although in clinical practice, ichthyosis is a common entity, a severe type of ichthyosis is presented, highlighting the importance of appropriate genetic diagnosis, given the broad spectrum of genetic alterations with similar phenotypic and clinical characteristics. These pathologies must be known to guarantee initial support measures to prevent complications and offer multidisciplinary management to those patients.

A novel ABCA12 pathologic variant identified in an Ecuadorian harlequin ichthyosis patient: A step forward in genotype-phenotype correlations.

BACKGROUND: Autosomal recessive congenital ichthyoses (ARCI) have been associated with different phenotypes including: harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE), and lamellar ichthyosis (LI). While pathogenic variants in all ARCI genes are associated with LI and CIE phenotypes, the unique gene associated with HI is ABCA12. In HI, the most severe ARCI form, pathogenic variants in both ABCA12 gene alleles usually have a severe impact on protein function. The presence of at least one non-truncating variant frequently causes a less severe congenital ichthyosis phenotype (LI and CIE). METHODS: We report the case of a 4-year-old Ecuadorian boy with a severe skin disease. Genetic diagnosis was performed by NGS. In silico predictions were performed using Alamut software v2.11. A review of the literature was carried out to identify all patients carrying ABCA12 splice-site and missense variants, and to explore their genotype-phenotype correlations. RESULTS: Genetic testing revealed a nonsense substitution, p.(Arg2204*), and a new missense variant, p.(Val1927Leu), in the ABCA12 gene. After performing in silico analysis and a comprehensive review of the literature, we conclude that p.(Val1927Leu) affects a well conserved residue which could either disturb the protein function or alter the splicing process, both alternatives could explain the severe phenotype of our patient. CONCLUSION: This case expands the spectrum of ABCA12 reported disease-causing variants which is important to unravel genotype-phenotype correlations and highlights the importance of missense variants in the development of HI.

Generalized morphea in a child with harlequin ichthyosis: a rare association.

INTRODUCTION: Harlequin ichthyosis (HI) is a severe and rare hereditary congenital skin disorder characterized by excessive dryness, ectropion and eclabion. The association of ichthyosis with systemic sclerosis has been described in only three children. No patient with generalized morphea (GM) associated with harlequin ichthyosis was described. CASE REPORT: A 4-years and 6-months girl, diagnosed with harlequin ichthyosis based on diffuse cutaneous thickening, scaling, erythema, ectropion and eclabium since the first hours of birth was described. She was treated with acitretin (1.0mg/kg/day) and emollient cream. At 3 years and 9 months, she developed muscle contractures with pain on motion and limitation in elbows and knees, and diffuse sclerodermic plaques on the abdomen, back, suprapubic area and lower limbs. Skin biopsy showed rectified epidermis and mild hyperorthokeratosis, reticular dermis with perivascular and periadnexal infiltrates of lymphocytes and mononuclear cells, and reticular dermis and sweat gland sclerosis surrounded by a dense collagen tissue, compatible with scleroderma. The patient fulfilled the GM subtype criteria. Methotrexate and prednisone were introduced. At 4 years and 3 months, new scleroderma lesions occurred and azathioprine was associated with previous therapy, with no apparent changes after two months. DISCUSSION: A case of harlequin ichthyosis associated with a GM was reported. The treatment of these two conditions is a challenge and requires a multidisciplinary team.

Morfeia generalizada em uma criança com ictiose arlequim, uma associação rara / Generalized morphea in a child with harlequin ichthyosis: a rare association

Resumo Introdução Ictiose arlequim é uma doença cutânea congênita grave, autossômica e rara, caracterizada por ressecamento excessivo da pele e hiperqueratose. A associação de ictiose com esclerose sistêmica foi descrita em apenas três crianças. Ainda não foi descrito nenhum paciente com morfeia generalizada (MG) associada à ictiose arlequim. Relato de caso: Menina de quatro anos e seis meses de idade com diagnóstico de ictiose arlequim baseado em espessamento cutâneo difuso, com fissuras, descamação, eritema e sangramento da lesão desde as primeiras horas de vida. A paciente foi tratada com acitretina (1,0 mg/kg/dia) e creme emoliente. Aos três anos e nove meses, desenvolveu contraturas musculares com dor à movimentação e limitação nos cotovelos e joelhos e placas esclerodérmicas difusas no abdômen, nas costas, na região suprapúbica e nas extremidades inferiores. A biópsia de pele mostrou epiderme retificada e hiperqueratose leve, derme reticular com linfócitos, infiltrado mononuclear perivascular e perianexial e esclerose da derme reticular e glândula sudorípara rodeada por um tecido colágeno denso, compatível com esclerodermia. A paciente preencheu os critérios para o subtipo MG. Metotrexato e prednisona foram introduzidos. Aos quatro anos e três meses, apresentou novas lesões esclerodérmicas, associando-se azatioprina à terapêutica anterior, sem resposta após dois meses. Discussão: Um caso de ictiose arlequim associada à MG foi descrito. O tratamento dessas duas condições é um desafio e requer uma equipe multidisciplinar.

Abstract Introduction: Harlequin ichthyosis (HI) is a severe and rare hereditary congenital skin disorder characterized by excessive dryness, ectropion and eclabion. The association of ichthyosis with systemic sclerosis has been described in only three children. No patient with generalized morphea (GM) associated with harlequin ichthyosis was described. Case report: A 4-years and 6-months girl, diagnosed with harlequin ichthyosis based on diffuse cutaneous thickening, scaling, erythema, ectropion and eclabium since the first hours of birth was described. She was treated with acitretin (1.0 mg/kg/day) and emollient cream. At 3 years and 9 months, she developed muscle contractures with pain on motion and limitation in elbows and knees, and diffuse sclerodermic plaques on the abdomen, back, suprapubic area and lower limbs. Skin biopsy showed rectified epidermis and mild hyperorthokeratosis, reticular dermis with perivascular and periadnexal infiltrates of lymphocytes and mononuclear cells, and reticular dermis and sweat gland sclerosis surrounded by a dense collagen tissue, compatible with scleroderma. The patient fulfilled the GM subtype criteria. Methotrexate and prednisone were introduced. At 4 years and 3 months, new scleroderma lesions occurred and azathioprine was associated with previous therapy, with no apparent changes after two months. Discussion: A case of harlequin ichthyosis associated with a GM was reported. The treatment of these two conditions is a challenge and requires a multidisciplinary team.