Background:Netherton syndrome (NTS) is a rare autosomal recessive multisystem disorder characterized by congenital erythroderma and ichthyosis, hair shaft abnormalities and immune dysregulation. The disorder is caused...Background:Netherton syndrome (NTS) is a rare autosomal recessive multisystem disorder characterized by congenital erythroderma and ichthyosis, hair shaft abnormalities and immune dysregulation. The disorder is caused by deleterious mutations in the SPINK5 gene, encoding the serine protease inhibitor LEKTI. Objective:Our objective was to investigate if the erythrodermic variant of peeling skin syndrome is also caused by SPINK5 mutations and to study the consequences of the disease on infantile brain development. Methods:In an infant with extensive erythroderma, peeling skin and failure to thrive, we analyzed the SPINK5 gene for pathogenic mutations by direct DNA sequencing and performed repeated brain MRI studies with diffusion-weighted imaging. Results:We identified a homozygous 4-base-pair insertion in exon 5 of SPINK5, which introduces a premature termination codon and appears to be a common mutation among West Indies islanders. MRI analyses revealed a persistent diffuse volume loss. Conclusion:Our results confirm that early truncation mutations of the coding sequence of SPINK5 produce a severe phenotype and that generalized peeling skin is one of the manifestations of NTS. We further demonstrate for the first time that NTS may be associated with MRI abnormalities indicative of a permanent tissue injury of the brain.展开更多
Netherton syndrome (NS) is a severe autosomal recessive ichthyosis. It is characterized by congenital ichthyosiform erythroderma, trichorrhexis invaginata, ichthyosis linearis circumflexa, atopic diathesis and frequen...Netherton syndrome (NS) is a severe autosomal recessive ichthyosis. It is characterized by congenital ichthyosiform erythroderma, trichorrhexis invaginata, ichthyosis linearis circumflexa, atopic diathesis and frequent bacterial infections. Pathogenic mutations in SPINKS have recently been identified in NS. SPINKS encodes lymphoepithelial Kazal-type-related inhibitor (LEKTI), a new type of serine protease inhibitor involved in the regulation of skin barrier formation and immunity. We report two Taiwan Residents brothers with NS. The patients had typical manifestations of NS with an atopic diathesis and recurrent staphylococcal infections, including staphylococcal scalded skin syndrome (SSSS) since birth. Horny layers were obtained by skin surface biopsy for electron microscopy from lesional skin of both patients and from normal controls. All 33 exons and flanking intron boundaries of SPINKS were amplified for direct sequencing. The ultrastructure of the stratum corneum (SC) was characterized by premature degradation of corneo desmosomes (CDs) with separation of corneocytes. A homozygous 2260A→ T (K754X) mutation of SPINK5 was found in both patients. Staphylococcal exfoliative toxin A (ETA) is a serine protease capable of cleaving desmoglein 1, an important adhesive molecule of CDs, and can cause separation of the SC, resulting in SSSS. The premature degradation of CDs found in our patients may be attributable to insufficient LEKTI, and possibly also to colonization/infection of ETA-producing Stophylococcus aureus. Mechanisms involved in the pathogenesis of the skin barrier defect in NS are proposed. Further study is needed to prove this hypothesis.展开更多
The congenital erythrodermas represent a heterogeneous group of inherited and acquired disorders often accompanied by systemic infections, impaired epidermal barrier function and concomitant life-threatening fluid and...The congenital erythrodermas represent a heterogeneous group of inherited and acquired disorders often accompanied by systemic infections, impaired epidermal barrier function and concomitant life-threatening fluid and electrolyte imbalance. In the present report, we describe a patient who was considered to have congenital ichthyosiform erythroderma for 26 years until molecular testing led to the correct diagnosis of Netherton syndrome.展开更多
Background: Netherton syndrome (NS) is a severe autosomal recessive disorder characterized by ichthyosiform erythroderma, bamboo hair and atopy. The disease is caused by mutations in the SPINK5 gene, which encodes a p...Background: Netherton syndrome (NS) is a severe autosomal recessive disorder characterized by ichthyosiform erythroderma, bamboo hair and atopy. The disease is caused by mutations in the SPINK5 gene, which encodes a putative serine protease inhibitor, LEKTI (lymphoepithelial Kazal- type- related inhibitor). Previous studies have clearly shown a crucial role for LEKTI in skin barrier formation. Objectives: To identify pathogenic mutations in two Japanese siblings with NS, and further to investigate the consequences of the mutations at the protein level. Methods: To screen for mutations in the SPINK5 gene, all of its exons and splice junctions were amplified by polymerase chain reaction and directly sequenced. In addition, immunohistochemical staining of LEKTI, desmoglein (Dsg) 1 and elafin was performed with their specific antibodies. Results: Mutation analysis resulted in the identification of compound heterozygous mutations, Q713X and R790X, in the SPINK5 gene of both patients. The former one is a novel mutation. Immunohistochemical studies in one patient demonstrated a complete absence of LEKTI and a strong expression of elafin in the patient’ s skin. Dsg1 was normally expressed in our patient. Conclusions: In this report, we describe compound heterozygous mutations in the SPINK5 gene in two Japanese siblings with NS. The result of immunohistochemistry shows LEKTI deficiency and upregulation of elafin in the skin of one patient. Furthermore, our data indicate that degradation of Dsg1 does not always occur in NS.展开更多
We report a 6- month- old Japanese boy showing ichthyosis linearis circumflexa localized on the palms and soles. He showed bamboo hairs and aminoaciduria, and was positive for cow’ s milk and egg IgE antibodies by ra...We report a 6- month- old Japanese boy showing ichthyosis linearis circumflexa localized on the palms and soles. He showed bamboo hairs and aminoaciduria, and was positive for cow’ s milk and egg IgE antibodies by radioallergosorbent tests. Trypsin- like hydrolytic activity in the patient’ s lesional stratum corneum showed an activity seven times higher than that in age- matched controls. DNA analysis showed that the patient harboured the compound heterozygous mutations R790X and 1220+ 1 G → C in the SPINKS gene, compatible with the diagnosis of Netherton syndrome (NS). As the genotype/phenotype correlations in NS have not yet been fully clarified, the position of the premature termination codon in the SPINK5 gene may contribute to explain such a mild form of NS in our patient.展开更多
文摘Background:Netherton syndrome (NTS) is a rare autosomal recessive multisystem disorder characterized by congenital erythroderma and ichthyosis, hair shaft abnormalities and immune dysregulation. The disorder is caused by deleterious mutations in the SPINK5 gene, encoding the serine protease inhibitor LEKTI. Objective:Our objective was to investigate if the erythrodermic variant of peeling skin syndrome is also caused by SPINK5 mutations and to study the consequences of the disease on infantile brain development. Methods:In an infant with extensive erythroderma, peeling skin and failure to thrive, we analyzed the SPINK5 gene for pathogenic mutations by direct DNA sequencing and performed repeated brain MRI studies with diffusion-weighted imaging. Results:We identified a homozygous 4-base-pair insertion in exon 5 of SPINK5, which introduces a premature termination codon and appears to be a common mutation among West Indies islanders. MRI analyses revealed a persistent diffuse volume loss. Conclusion:Our results confirm that early truncation mutations of the coding sequence of SPINK5 produce a severe phenotype and that generalized peeling skin is one of the manifestations of NTS. We further demonstrate for the first time that NTS may be associated with MRI abnormalities indicative of a permanent tissue injury of the brain.
文摘Netherton syndrome (NS) is a severe autosomal recessive ichthyosis. It is characterized by congenital ichthyosiform erythroderma, trichorrhexis invaginata, ichthyosis linearis circumflexa, atopic diathesis and frequent bacterial infections. Pathogenic mutations in SPINKS have recently been identified in NS. SPINKS encodes lymphoepithelial Kazal-type-related inhibitor (LEKTI), a new type of serine protease inhibitor involved in the regulation of skin barrier formation and immunity. We report two Taiwan Residents brothers with NS. The patients had typical manifestations of NS with an atopic diathesis and recurrent staphylococcal infections, including staphylococcal scalded skin syndrome (SSSS) since birth. Horny layers were obtained by skin surface biopsy for electron microscopy from lesional skin of both patients and from normal controls. All 33 exons and flanking intron boundaries of SPINKS were amplified for direct sequencing. The ultrastructure of the stratum corneum (SC) was characterized by premature degradation of corneo desmosomes (CDs) with separation of corneocytes. A homozygous 2260A→ T (K754X) mutation of SPINK5 was found in both patients. Staphylococcal exfoliative toxin A (ETA) is a serine protease capable of cleaving desmoglein 1, an important adhesive molecule of CDs, and can cause separation of the SC, resulting in SSSS. The premature degradation of CDs found in our patients may be attributable to insufficient LEKTI, and possibly also to colonization/infection of ETA-producing Stophylococcus aureus. Mechanisms involved in the pathogenesis of the skin barrier defect in NS are proposed. Further study is needed to prove this hypothesis.
文摘The congenital erythrodermas represent a heterogeneous group of inherited and acquired disorders often accompanied by systemic infections, impaired epidermal barrier function and concomitant life-threatening fluid and electrolyte imbalance. In the present report, we describe a patient who was considered to have congenital ichthyosiform erythroderma for 26 years until molecular testing led to the correct diagnosis of Netherton syndrome.
文摘Background: Netherton syndrome (NS) is a severe autosomal recessive disorder characterized by ichthyosiform erythroderma, bamboo hair and atopy. The disease is caused by mutations in the SPINK5 gene, which encodes a putative serine protease inhibitor, LEKTI (lymphoepithelial Kazal- type- related inhibitor). Previous studies have clearly shown a crucial role for LEKTI in skin barrier formation. Objectives: To identify pathogenic mutations in two Japanese siblings with NS, and further to investigate the consequences of the mutations at the protein level. Methods: To screen for mutations in the SPINK5 gene, all of its exons and splice junctions were amplified by polymerase chain reaction and directly sequenced. In addition, immunohistochemical staining of LEKTI, desmoglein (Dsg) 1 and elafin was performed with their specific antibodies. Results: Mutation analysis resulted in the identification of compound heterozygous mutations, Q713X and R790X, in the SPINK5 gene of both patients. The former one is a novel mutation. Immunohistochemical studies in one patient demonstrated a complete absence of LEKTI and a strong expression of elafin in the patient’ s skin. Dsg1 was normally expressed in our patient. Conclusions: In this report, we describe compound heterozygous mutations in the SPINK5 gene in two Japanese siblings with NS. The result of immunohistochemistry shows LEKTI deficiency and upregulation of elafin in the skin of one patient. Furthermore, our data indicate that degradation of Dsg1 does not always occur in NS.
文摘We report a 6- month- old Japanese boy showing ichthyosis linearis circumflexa localized on the palms and soles. He showed bamboo hairs and aminoaciduria, and was positive for cow’ s milk and egg IgE antibodies by radioallergosorbent tests. Trypsin- like hydrolytic activity in the patient’ s lesional stratum corneum showed an activity seven times higher than that in age- matched controls. DNA analysis showed that the patient harboured the compound heterozygous mutations R790X and 1220+ 1 G → C in the SPINKS gene, compatible with the diagnosis of Netherton syndrome (NS). As the genotype/phenotype correlations in NS have not yet been fully clarified, the position of the premature termination codon in the SPINK5 gene may contribute to explain such a mild form of NS in our patient.
