title: Intrafamily and Interfamilial Phenotype Variation and Immature Immunity in Patients With Netherton Syndrome and Finnish SPINK5 Founder Mutation.
abstract: OBJECTIVE
  Netherton syndrome (NS) is a rare and severe genodermatosis caused by SPINK5 mutations leading to the loss of lymphoepithelial Kazal-type-related inhibitor (LEKTI). Netherton syndrome is characterized by neonatal scaling erythroderma, a bamboolike hair defect, a substantial skin barrier defect, and a profound atopic diathesis. Netherton syndrome has been proposed to be a primary immunodeficiency syndrome because of the high frequency of infections. The precise mechanisms underlying the disease are not fully understood.
  
  
  OBJECTIVE
  To study the association of the SPINK5 mutation with the NS phenotype and the extent of immunologic deficiencies in NS.
  
  
  METHODS
  Relevant tissue samples and follow-up data from 11 patients with NS from 7 families, including 3 multiplex families, were collected, constituting all known patients with NS in Finland. Another patient with NS from a neighboring country was included. Data were collected from August 10, 2011, to February 20, 2015. SPINK5 mutations were sequenced, and thorough clinical evaluation and histopathologic and immunohistochemical evaluations of skin samples were performed. The function of natural killer cells, lymphocyte phenotype, and serum immunoglobulin subclass levels were evaluated. Data analysis was conducted from October 19, 2011, to February 20, 2015.
  
  
  METHODS
  The nature of SPINK5 mutations and their correlation with phenotypes in Finnish patients with NS, intrafamilial phenotype variations, and the type of immunologic defects in NS were evaluated.
  
  
  RESULTS
  Among the 11 Finnish patients with NS (8 male [73%]; 3 female [27%]; mean [SD] age, 30.1 [9.1] years), a Finnish founder mutation c.652C>T (p.Arg218*) in SPINK5 was identified in 10 patients from 6 families who all originated from the same region. Eight patients were homozygotes for this mutation and 2 siblings were compound heterozygotes with a splice site mutation c.1220 + 1G>C (IVS13 + 1 G>C). Phenotypes were comparable, but some intrafamilial and interfamilial variations were noted. Compound heterozygous patients had a milder phenotype and showed residual LEKTI expression. A previously unreported c.1772delT (p.Leu591Glnfs124*) mutation was found in 1 patient with a phenotype similar to the patients homozygous for the founder mutation. The patient from the neighboring country had a distinct phenotype and different mutations. Immunologically, natural killer cells had an immature phenotype and impaired cytotoxicity and degranulation, levels of memory B cells were reduced, and serum IgG4 levels were elevated. Intravenous immunoglobulin treatment has been beneficial in 1 patient with NS.
  
  
  CONCLUSIONS
  This report discloses a prevalent SPINK5 founder mutation in Finland and illustrates NS phenotype variability. Our results also point to a possible role of immature immunity in the frequent infections seen in NS.
authors: Department of Dermatology and Allergology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland2Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland.
authors: Katariina
authors: K
authors: Hannula-Jouppi
authors: Department of Dermatology, Tampere University Hospital, Tampere, Finland.
authors: Satu-Leena
authors: SL
authors: Laasanen
authors: Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors: Mette
authors: M
authors: Ilander
authors: Laboratory of Genetic Skin Diseases, Institut National de la Santé et de la Recherche Medicale, Unité Mixte de Recherche 1163, Paris, France6Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, Paris, France.
authors: Laetitia
authors: L
authors: Furio
authors: Department of Dermatology, Seinäjoki Central Hospital, Seinäjoki, Finland.
authors: Mirja
authors: M
authors: Tuomiranta
authors: Department of Pediatrics, Seinäjoki Central Hospital, Seinäjoki, Finland.
authors: Riitta
authors: R
authors: Marttila
authors: Department of Dermatology and Allergology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Leila
authors: L
authors: Jeskanen
authors: Department of Otorhinolaryngology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Valtteri
authors: V
authors: Häyry
authors: Department of Otorhinolaryngology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Mervi
authors: M
authors: Kanerva
authors: Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Sirpa
authors: S
authors: Kivirikko
authors: Department of Dermatology, Tampere University Hospital, Tampere, Finland.
authors: Marja-Leena
authors: ML
authors: Tuomi
authors: Department of Dermatology and Allergology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Hannele
authors: H
authors: Heikkilä
authors: Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors: Satu
authors: S
authors: Mustjoki
authors: Laboratory of Genetic Skin Diseases, Institut National de la Santé et de la Recherche Medicale, Unité Mixte de Recherche 1163, Paris, France6Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, Paris, France11Department of Genetics, Necker H.
authors: Alain
authors: A
authors: Hovnanian
authors: Department of Dermatology and Allergology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Annamari
authors: A
authors: Ranki
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D005192:Family Health; D005260:Female; D005387:Finland; D005500:Follow-Up Studies; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D009154:Mutation; D056770:Netherton Syndrome / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D010641:Phenotype; D053491:Proteinase Inhibitory Proteins, Secretory / Q000235:genetics*; D000074163:Serine Peptidase Inhibitor Kazal-Type 5
chemical_list: D007074:Immunoglobulin G; D053491:Proteinase Inhibitory Proteins, Secretory; C120650:SPINK5 protein, human; D000074163:Serine Peptidase Inhibitor Kazal-Type 5