Mutations in CERS3 Gene Underlies a Case of Autosomal Recessive Congenital Ichthyosis / 罕见病研究

Autosomal recessive congenital ichthyosis caused by CERS3 mutations is extremely rare in clinical practice. We recently identified a family of autosomal recessive congenital ichthyosis and performed multigene exome sequencing for hereditary skin diseases to identify causative genes. Mutation analysis revealed compound heterozygous mutations of c.746A>G(from the mother) and exon12 deletion(from the father)in CERS3 were detected in the proband, which were verified by Sanger sequencing and co-segregated with the ichthyosis phenotype in the proband and her parents. These mutations were both reported for the first time. For the treatment, the proband received an oral acitretin capsules of 20 mg once daily. After 3-month follow up, the patient's lesion improved significantly.

Ictiosis Laminar. Un caso familiar recurrente

Introducción: Las ictiosis hereditarias pueden ser sindrómicas y no sindrómicas, estas últimas, de acuerdo con la expresión fenotípica cutánea, incluyen, ictiosis comunes, ictiosis recesiva ligada al cromosoma X, ictiosis congénita autosómica recesiva, ictiosis queratinopática y otras formas. La ictiosis congénita autosómica recesiva, incluye tres fenotipos principales: La ictiosis arlequín, ictiosis laminar y eritrodermia ictiosiforme congénita. Comunicamos un caso clínico de ictiosis laminar recurrente en una familia. Reporte de caso: Recién nacido pretérmino, tiene hermana de 6 años, con diagnóstico de ictiosis lamelar. Madre niega consanguinidad con esposo, y parientes con esta enfermedad. Al nacer se observa cubierto de membrana colodión en toda la piel, ectropión y eclabio. El manejo inicial, fue gasa vaselinada, lagrimas artificiales, gasas húmedas en los ojos. Actualmente baños con crema de ducha, Shampoo y Aceite mineral, cremas y loción hidratantes y Acitretina, está en franca mejoría. Conclusiones: Con la historia clínica y los antecedentes familiares es posible diagnosticar ictiosis laminar. El manejo es multidisciplinario.

Introduction: Hereditary ichthyosis can be syndromic and non-syndromic, the latter, according to the cutaneous phenotypic expression, include common ichthyosis, X-linked recessive ichthyosis, autosomal recessive congenital ichthyosis, keratinopathic ichthyosis and other forms. Autosomal recessive congenital ichthyosis includes three main phenotypes: harlequin ichthyosis, lamellar ichthyosis, and congenital ichthyosiform erythroderma. We report a clinical case of recurrent lamellar ichthyosis in a family. Case Report: Preterm newborn, has a 6-year-old sister, diagnosed with lamellar ichthyosis. Mother denies consanguinity with husband, and relatives with this disease. At birth, it is observed covered with collodion membrane throughout the skin, ectropion and eclabio. The initial management was Vaseline gauze, artificial tears, wet gauze in the eyes. Currently baths with shower cream, Shampoo and mineral oil, moisturizing creams and lotions and Acitretin, is clearly improving. Conclusions: With the medical history and family history it is possible to diagnose lamellar ichthyosis. Management is multidisciplinary.

Mutation Analysis of the CYP4F22 Gene in a Family with Autosomal Recessive Congenital Ichthyosis / 罕见病研究

Autosomal recessive congenital ichthyosis (ARCI) is a rare hereditary cornification disorder presented with abnormal skin scaling. In this paper, we used next-generation sequencing to determine the variants in a Chinese ARCI patient. We used sanger sequencing to verify bidirectionally the DNA from the proband and her parents. Results showes that two compound heterozygous variants (c.235G > T and c.641delG) in CYP4F22 gene, and both of the mutations are novel. The parents were heterozygous carriers. The two variants are classified as pathogenic variants based on interpretation guidelines. The compound heterozygous mutations in CYP4F22 gene were the causative mutations responsible for ARCI in proband.

Mutation analysis of the PNPLA1 gene in three families with congenital ichthyosiform erythroderma / 中华皮肤科杂志

Objective:To detect gene mutations in 3 Chinese families with congenital ichthyosiform erythroderma.Methods:Exome sequencing of peripheral blood DNA was performed for 3 probands clinically diagnosed with congenital ichthyosiform erythroderma by using a gene panel targeting hereditary skin diseases to identify mutation sites. Primers were designed according to the mutation sites for PCR amplification, and Sanger sequencing was performed to verify the mutations in probands and other family members in order to identify the cause of the disease.Results:The probands 1 and 2 presented with generalized skin dryness and scaling, and polygonal dark brown scales on the extensor aspect of the lower limbs; the proband 3 mainly presented with well-circumscribed erythema, papules and scales scattered on the trunk and extremities. All probands denied family history of similar diseases. Genetic testing showed that the proband 1 carried compound heterozygous mutations c.100G>A and c.377G>A in the PNPLA1 gene, which were inherited from her mother and father respectively; the proband 2 carried compound heterozygous mutations c.320T>A and c.434T>C in the PNPLA1 gene, which were inherited from her mother and father respectively; a homozygous mutation c.1300delG was identified in the PNPLA1 gene in the proband 3. The mutations co-segregated with the disease phenotypes in the two families with compound heterozygous mutations. Among the 5 identified mutations, the two missense mutations (c.377G>A and c.320T>A) were firstly reported.Conclusion:Biallelic mutations in the PNPLA1 gene are the causative mutations responsible for autosomal recessive congenital ichthyosis in the three probands, and the newly reported mutations expand the mutation spectrum in the disease.

Novel Pathogenic Mutation of PNPLA1 Identified in Autosomal Recessive Congenital Ichthyosis: A Case Report / 中国医学科学杂志(英文版)

Autosomal recessive congenital ichthyosis (ARCI) is characterized by being born as collodion babies, hyperkeratosis, and skin scaling. We described a collodion baby at birth with mild ectropion, eclabium, and syndactyly. Whole exome sequencing showed a compound heterozygous variant c.[56C>A], p.(Ser19X) and c.[100G>A], p.(Ala34Thr) in the PNPLA1 gene [NM_001145717; exon 1]. The protein encoded by PNPLA1 acts as a unique transacylase that specifically transfers linoleic acid from triglyceride to ω-hydroxy fatty acid in ceramide, thus giving rise to ω-O-acylceramide, a particular class of sphingolipids that is essential for skin barrier function. The variant was located in the patatin core domain of PNPLA1 and resulted in a truncated protein which could disrupt the function of the protein. This case report highlights a novel compound heterozygous mutation in PNPLA1 identified in a Chinese child.

Ictiosis Lamelar autosómica recesiva: revisión de la literatura y caso clínico / Autosomal recessive lamellar ichthyosis: review of the literature and clinical case

Resumen Las ictiosis congénitas autosómicas recesivas (ICAR) son poco frecuentes a nivel mundial con una incidencia de 1:300,000 nacimientos, se caracterizan por trastornos de la queratinización, entre sus variantes engloban las formas no sindrómicas de ictiosis, como la ictiosis laminar (IL), la eritrodermiaictiosiforme congénita (EIC) y actualmente se incluyen la ictiosis arlequín, el bebé colodión autorresolutivo, el bebé colodión autorresolutivoacral y la ictiosis en traje de baño. Desde el punto de vista genético son heterogéneas, originadas por una mutación en el gen de la transglutaminasa 1 y se las haasociado a TGM1, ALOXE3, ALOX12B, NIPAL4, CYP4F22 y ABCA12. Clínicamente, la ictiosis se caracteriza principalmente por piel gruesa, escamas laminares adherentes con hendiduras profundas. En este trabajo pretende revisar los conocimientos actuales en el campo de las ICAR, incluyendo aspectos clínicos, histológicos, ultraestructurales, genético-moleculares, tratamiento,y también su manejo clínico.

Abstract The autosomal recessive congenital ichthyosis (ARCI) is a rare worldwide condition with an incidence of (1: 300,000 births), characterized by disorders of keratinization, among its variants encompass the non-syndromic forms of ichthyosis, such as laminar ichthyosis (IL) , congenital ichthyosiform erythroderma (EIC) and currently include harlequin ichthyosis, self-healing colodion baby, acral self-healing colodion baby and ichthyosis in swimsuits. From a genetic point of view, they're heterogeneous, originated by a mutation in the gene of transglutaminase 1 and associated with TGM1, ALOXE3, ALOX12B, NIPAL4, CYP4F22 and ABCA12. Clinically, ichthyosis is mainly characterized by thick skin, adherent lamellar scales with deep clefts. The aim of this work is to review the current knowledge in the field of ICAR, including clinical, histological, ultrastructural, genetic-molecular and therapeutic aspects as well as its clinical management.

Mutation analysis of the ABCA12 gene in two families with autosomal recessive congenital ichthyosis / 中华皮肤科杂志

Objective To detect mutations of the ABCA12 gene in 2 Chinese families with autosomal recessive congenital ichthyosis (ARCI).Methods According to the typical clinical manifestations,two probands were diagnosed with ARCI.DNA was extracted from the peripheral blood samples collected from the patients and their parents.High-throughput sequencing was conducted by using multi-gene array for genetic skin disorders to determine mutation sites in the probands,and then DNA isolated from the probands and their parents were bidirectionally verified by Sanger sequencing.Results Two compound heterozygous mutations (c.2759A＞G and c.7004A＞G) in the ABCA12 gene were found in the proband 1,and another two compound heterozygous mutations (c.6163_6164insT and c.7406G＞A) were identified in the proband 2.The parents of the two probands were heterozygous carriers of one of the two mutations in the ABCA12 gene.Function prediction for the 4 mutations showed that all of the 3 missense mutations (c.2759A＞G,c.7004A＞G and c.7406G＞A) may exert pathogenic effect,and fragnin encoded by the frameshift mutation c.6163_6164insT may also affect protein function,c.2759A＞G and c.6163_6164insT were newly identified mutation sites.Conclusion The compound heterozygous mutations in the ABCA 12 gene are the causative mutations responsible for ARCI in the two probands of the two pedigrees.

Mutation analysis of the PNPLA1 gene in a family with autosomal recessive congenital ichthyosis / 中华皮肤科杂志

Objective To identify a causative gene of autosomal recessive congenital ichthyosis (ARCI) in a Chinese family,and to analyze the genotype-phenotype correlation.Methods Peripheral blood samples were collected from the proband,his elder brother and parents,and genomic DNA was extracted from these blood samples.Genome-wide exome sequencing was conducted to determine the mutation site in the proband,and then allele-specific oligonucleotide primers were designed based on the mutation site.PCR was performed to detect the mutation site to further identify the causative gene of ARCI in the family.Results A new homozygous missense mutation was identified in exon 4 in 1 allele of the PNPLA1 gene in the proband,which led to a codon change from cytosine (C) to thymine (T) at position 700 (c.700C ＞ T) and resulted in the substitution of proline by serine (p.pro234ser).The same mutation was also detected in the proband's brother,and his parents were the mutation carriers.No mutations were found in unrelated healthy Chinese individuals.Conclusion The missense mutation in the PNPLA1 gene (p.pro234ser) is associated with clinical symptoms of the patient with ARCI.

A Novel Transglutaminase-1 Missense Mutation in a Palestinian Family with Autosomal Recessive Congenital Ichthyosis: A Case Report.

This work presents the molecular genetics investigation of a male neonate referred to our genetics laboratory with the diagnosis of classical lamellar ichthyosis (one form of autosomal recessive congenital ichthyosis). The neonate was born as a "collodion-baby" and he is the product of a maternal first cousin marriage. DNA sequencing of the coding exons of transglutiminase-1 (TGM1) gene revealed a novel missense (c.A1621C) mutation in exon 11. The mutation altered codon 541 from ACC into CCC thus changing the amino acid threonine into proline (p.T541P) and was predicted to be pathogenic. The presence of the mutation in both parents in heterozygous form and in the patient in homozygous form was further confirmed by PCR-restriction fragment length polymorphism (PCR-RFLP) designed specifically for the identified mutation. It is concluded that the T541P mutation is the cause of the congenital ichthyosis in the presented case and the parents were advised to undergo a PGD-IVF for embryo selection prior to their next pregnancy.

Lamellar ichthyosis

Lamellar ichthyosis is an inherited autosomal recessive disorder characterized by non-bullous erythroderma and scaling at birth. We report a patient born encased in a collodion membrane, who later developed generalized, brownish, plate-like scales, anhidrotic skin, scarring alopecia, bilateral ectropion, with a family history of similar-looking skin condition. Skin biopsy demonstrated marked lamellated orthohyperkeratosis and areas of hypergranulosis. Therapeutic trial of four topical agents (extravirgin coconut oil, urea lotion, mineral oil and petroleum jelly) was done which gave minimal improvement of scaling and dryness. Oral retinoids (Acitretin) was then initiated and yielded better results.