OBJECTIVE: To explore the clinical characteristics and genetic variant in a premature infant with Netherton syndrome (NS). METHODS: A neonate with NS caused by variants of SPINK5 gene diagnosed at the Children's Hospital Affiliated to Zhejiang University School of Medicine in March 2020 was selected as the study subject. Clinical data and family history were collected. Peripheral blood samples (2 mL each) were obtained from the child and her parents for whole-exome sequencing (WES). Candidate variants were subjected to pathogenicity classification and deleteriousness evaluation. This study has been approved by the Medical Ethics Committee of the Hospital (Ethics No. 2024-IRB-0251-P-01). RESULTS: The infant was born prematurely at 35⁺³ weeks due to "premature rupture of membranes for 4 hours" and exhibited generalized skin peeling, with meconium-stained amniotic fluid resembling bean curd residue. The condition improved with supportive treatments such as anti-infection and moisturizing therapy, though periodic hair loss had persisted. No similar case was reported by family history. WES has revealed a heterozygous c.1130delG (p.G377Efs*127) variant in exon 14 of the SPINK5 gene, which was inherited from her mother, and deletion of exons 1 ~ 33 of the SPINK5 gene, which was inherited from her father. CONCLUSION This case of NS presented with intrauterine onset in a preterm infant, which has not been previously reported. The identification of c.1130delG (p.G377Efs*127) variant has expanded the mutation spectrum of the SPINK5 gene.
Humans ; Serine Peptidase Inhibitor Kazal-Type 5/genetics* ; Netherton Syndrome/genetics* ; Female ; Infant, Newborn ; Infant, Premature ; Mutation ; Exome Sequencing ; Male

OBJECTIVE: To explore the clinical and genetic characteristics of five fetuses with Harlequin ichthyosis (HI). METHODS: Five fetuses with HI diagnosed at Guangdong Women and Children Hospital between 2017 and 2024 were selected as study subjects. Clinical and laboratory data were collected and reviewed. Whole exome sequencing (WES) was carried out, and candidate variants were verified by bioinformatic analysis. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: 202401024). RESULTS: The five fetuses had presented with ectropion, eclabium and contracture and flexion of fingers and toes. WES revealed that all had harbored compound heterozygous or homozygous variants of the ABCA12 gene. Among the eight types of variants, five were unreported previously. CONCLUSION The compound heterozygous or homozygous variants of the ABCA12 gene probably underlay the HI in the five fetuses. Clinicians should be vigilant about the possibility of HI in fetus with ectropion, eclabium, and contracture and flexion of fingers and toes.
Humans ; Ichthyosis, Lamellar/genetics* ; Female ; ATP-Binding Cassette Transporters/genetics* ; Pregnancy ; Genotype ; Phenotype ; Exome Sequencing ; Fetus ; Mutation ; Male ; Adult

OBJECTIVE: To explore the genetic basis of a child with Chanarin-Dorfman syndrome (CDS) manifesting as ichthyosis. METHODS: A child who had presented at Henan Provincial People's Hospital in June 2023 was selected as study subject. Clinical data of the child was collected. Peripheral blood samples were collected from the child and her parents. Following extraction of genomic DNA, whole-exome sequencing (WES) was carried out. Candidate variants were verified by Sanger sequencing. Relevant literature was searched in databases using key words "Chanarin-Dorfman syndrome" and "ABHD5 gene". The clinical manifestations and variant sites of previously reported cases were compiled and analyzed for correlations. This study was approved by the Medical Ethics Committee of Henan Provincial People's Hospital [Ethics No.: (2019) Jun Shen No. (134)]. RESULTS: WES revealed that the child has harbored compound heterozygous variants of the ABHD5 gene, namely c.99_103del (p.H34*) in exon 2 and c.770C>G (p.P257R) in exon 5, which were inherited from her father and mother, respectively. Bioinformatic analysis suggested that both variants were pathogenic. Literature review indicated that the affected organs in CDS are ranked from most to least including liver, eyes, ears, nervous system, muscles, spleen, and kidneys. The c.594insC and c.594dupC variants are most common. CONCLUSION The identification of the two novel ABHD5 gene variants has enriched the mutation spectrum of CDS. c.594insC or c.594dupC are hotspot mutations of this disease, albeit with no definitive correlation between the genotype and phenotype.
Humans ; Female ; Ichthyosiform Erythroderma, Congenital/genetics* ; Lipid Metabolism, Inborn Errors/genetics* ; Phenotype ; 1-Acylglycerol-3-Phosphate O-Acyltransferase/genetics* ; Mutation ; Muscular Diseases/genetics* ; Exome Sequencing ; Child ; Male ; Child, Preschool

INTRODUCTION

Lamellar ichthyosis (LI) is an inherited rare disorder characterized by generalized scaling presenting at birth and persisting throughout life. It presents at birth with a collodion membrane, later developing into large, brown scales across the skin. LI requires ongoing treatment and monitoring due to physical and psychosocial impacts. This study highlights siblings who showed substantial quality-of-life improvements with oral retinoid therapy.

To present and discuss a detailed case summary, explore management options, and evaluate the treatment outcomes.

We report on a pair of siblings, a 24-year-old male and a 19-year-old female, who were born encased in a collodion membrane, and later presented with large, brown, plate-like scales all over the body. Skin changes were accompanied by intermittent heat intolerance and mild ectropion, which subsequently caused impaired quality of life while growing up. Histopathology results were consistent with lamellar ichthyosis. Both siblings responded well to oral Acitretin at 0.5 mglkglday, showing significant shedding of thick scales and a reduction of ectropion within the first two weeks of therapy.

Lamellar ichthyosis, a severe, lifelong disorder with psychosocial repercussions, requires long-standing, continual therapy. Maximizing treatment options with oral acitretin, addressing the psychosocial implications of the disease and getting patients actively involved in its management results in better treatment outcomes.

A 4-year-old female with Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects (CHILD) syndrome, with a pathogenic variant of the NSDHL gene, c.130G>A (p.Gly44Ser), and unilateral right-sided erythematous verrucous plaques with scaling and ipsilateral limb defects, was started on 5% simvastatin ointment. It was applied twice daily for four months, with improvement already seen starting week 2. Monotherapy with 5% simvastatin ointment was able to decrease the thickness of the verrucous plaques seen in our patient, highlighting that the accumulation of toxic metabolites may play a more crucial role in its disease pathogenesis.

Lamellar Ichthyosis (LI) is a rare autosomal recessive disorder caused by mutations in genes, primarily TGM1, that affect skin barrier formation. It results in large, hyperpigmented, plate-like scales covering the entire body and persists throughout life. This case illustrates the chronic and debilitating nature of LI, highlights therapeutic approaches that improve quality of life, and emphasizes the importance of genetic testing in managing the condition.

Patient A, a 25-year-old female, and Patient B, a 22-year-old male, are Filipino siblings from non-consanguineous parents with no notable family history. Both were born encased in a collodion membrane that later revealed generalized erythema with large scales and deep fissures. As they aged, symptoms worsened, including reduced sweating, heat intolerance, ectropion, eclabium, cicatricial alopecia, palmoplantar hyperkeratosis, limited finger movement, and blurred vision from corneal scarring. Whole exome sequencing identified a homozygous pathogenic variant in the TGM1 gene (Arg396Cys). Their parents are carriers, giving future offspring a 25% risk of inheriting the condition. Acitretin therapy at 0.2 mg/kg/day, combined with topical keratolytics, led to significant improvement in symptoms and quality of life within four weeks.

Accurate diagnosis of ichthyosiform disorders requires thorough clinical documentation, family history, physical examination, and genetic findings. Effective management of lamellar ichthyosis needs a multidisciplinary approach, focusing on improving quality of life by addressing physical discomfort and social challenges. Genetic testing, especially Whole Exome Sequencing (WES), is crucial for precise diagnosis, genetic counseling, and informed family planning.

Netherton Syndrome (NS) is characterized by a triad of congenital ichthyosiform erythroderma, trichorrhexis invaginata, and atopic diathesis. Diagnosis of NS poses a challenge due to its variable presentation and overlap with other dermatological conditions. Herein, we report a case of NS in a sibling pair, underscoring the challenges in diagnosis and genetic implications of this condition.

We present a case of an 8-year-old female and a 7-year-old male sibling pair, with Netherton Syndrome, who initially presented with atopic dermatitis and erythroderma without hair shaft abnormalities. Further investigation and genetic testing revealed homogeneous SPINK5 gene mutations in both patients, leading to the diagnosis of NS.

Early recognition and diagnosis of Netherton Syndrome are essential for proper management. In patients with early-onset atopic dermatitis resistant to treatment and recurrent erythroderma, further investigation is needed to exclude other diagnoses like Netherton Syndrome.

Objective: To present a rare case of Netherton Syndrome (NS) in a Filipino child. Case: This is a case of an 11-year-old girl with elevated immunoglobulin E, trichorrhexis nodosa, and ichthyosis linearis circumflexa. She had dry skin with fine scaling at birth with recurrent pruritic, erythematous papules coalescing to plaques mainly on the face and extensors. The skin dryness turned to generalized redness with fine scaling, and the skin started getting tight. She could no longer completely extend both knees, but she was still able to walk. She also started having difficulty closing both eyes. She developed migratory serpiginous erythematous plaques with peripheral double-edged scaling. At six years old, she developed ulcers in the scalp, trunk, and extremities, which resulted in admission to our institution. She was managed for multiple skin infections, pneumonia, sepsis, seizure, severe malnutrition, joint contracture, atopy, and bilateral cicatricial ectropion. Conclusion Management of NS remains challenging. Common management options include emollients, topical corticosteroids, calcineurin, and protease inhibitor, and phototherapy while newer ones that need further validation include intravenous immunoglobulins and biologics such as infliximab. However, until specific recommendations are made, overall management for NS remains challenging. Regular multidisciplinary monitoring of the manifestations of NS is central to its management.
Netherton syndrome ; ichthyosis ; trichorrhexis nodosa ; atopy

Netherton syndrome (NS) is an autosomal recessive genodermatosis characterized by cutaneous and systemic complications (recurrent infections, dehydration, and sepsis). This highlights the urgency of making an accurate diagnosis, especially in infants and children. However, it is important to note that the recognition of NS is usually delayed due to its rarity and similarity to cutaneous disorders with atopiform, erythrodermic, and ichthyosiform presentations. We report a case of a 1-year-old female who was previously diagnosed with a case of infantile psoriasis and was subsequently treated with topical emollients. However, after months of surveillance, the patient developed feeding problems, failure to thrive, recurrent diarrhea, upper respiratory tract, and gastrointestinal infection, leading to repeated hospitalizations. The patient then underwent further clinical examinations and laboratory analysis, which revealed abnormal hair shaft findings, elevated immunoglobulin (Ig) E levels, and normal chromosomal analysis. Multispecialty referrals with other services were done to address the current problems and ensure holistic care for the patient. On her last admission, the patient was given three doses of intravenous Ig therapy with noted improvement in lesion presentation without any systemic symptoms.
Netherton Syndrome

OBJECTIVE: To explore the clinical and genetic characteristics of a pediatric patient suspected for Autosomal Recessive Congenital Ichthyosis (ARCI). METHODS: Clinical data of the patient was analyzed. Peripheral blood samples were collected from the patient and his parents for the extraction of genomic DNA. Next-generation sequencing (NGS) was then carried out. Candidate variants were confirmed by Sanger sequencing. A variety of bioinformatic tools including Mutation Taster, PROVEAN, and PolyPhen2 were used to predict the pathogenicity of the variants based on guidelines from the American College of Medical Genetics and Genomics (ACMG). RESULTS: The patient, a 1-month-and-7-day-old male, had presented with cutaneous erythema and fine scaling of the whole body. NGS revealed that he has harbored compound heterozygous variants c.1579G>A (p.Val527Met) (paternal) and c.923T>C (p.Leu308Pro) (maternal) of the ALOX12B gene. The former was known to be likely pathogenic, while the latter was unreported previously and categorized as "likely pathogenic" based on the ACMG guidelines. Based on the clinical and genetic findings, the patient was diagnosed with ARCI. CONCLUSION The c.1579G>A and c.923T>C variants of the ALOX12B genes probably underlay the ARCI in this patient. Above finding has enriched the spectrum of ALOX12B mutations and enabled molecular diagnosis of the patient, based on which genetic counseling and prenatal diagnosis may be provided.
Arachidonate 12-Lipoxygenase/genetics* ; Child ; Female ; Genes, Recessive ; Genetic Testing ; High-Throughput Nucleotide Sequencing ; Humans ; Ichthyosis, Lamellar/genetics* ; Male ; Mutation ; Pregnancy