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Original Investigation
April 2016

Intrafamily and Interfamilial Phenotype Variation and Immature Immunity in Patients With Netherton Syndrome and Finnish SPINK5 Founder Mutation

Author Affiliations
  • 1Department of Dermatology and Allergology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • 2Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland
  • 3Department of Dermatology, Tampere University Hospital, Tampere, Finland
  • 4Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
  • 5Laboratory of Genetic Skin Diseases, Institut National de la Santé et de la Recherche Medicale, Unité Mixte de Recherche 1163, Paris, France
  • 6Imagine Institute, Paris Descartes University–Sorbonne Paris Cité, Paris, France
  • 7Department of Dermatology, Seinäjoki Central Hospital, Seinäjoki, Finland
  • 8Department of Pediatrics, Seinäjoki Central Hospital, Seinäjoki, Finland
  • 9Department of Otorhinolaryngology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • 10Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • 11Department of Genetics, Necker Hospital for Sick Children, Paris, France
JAMA Dermatol. 2016;152(4):435-442. doi:10.1001/jamadermatol.2015.5827

Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 and Relevance  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.