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Original Investigation |

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

Katariina Hannula-Jouppi, MD, PhD, MBA1,2; Satu-Leena Laasanen, MD, PhD3; Mette Ilander, PhD4; Laetitia Furio, PhD5,6; Mirja Tuomiranta, MD, PhD7; Riitta Marttila, MD, PhD8; Leila Jeskanen, MD1; Valtteri Häyry, MD, PhD9; Mervi Kanerva, MD, PhD9; Sirpa Kivirikko, MD, PhD10; Marja-Leena Tuomi, MD3; Hannele Heikkilä, MD, PhD1; Satu Mustjoki, MD, PhD4; Alain Hovnanian, MD, PhD5,6,11; Annamari Ranki, MD, PhD1
[+] 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.
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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.

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Figure 1.
Erythema and Scaling in the Skin in Netherton Syndrome

Patient III:1 had erythroderma and superficial scaling neonatally (left) and as an infant (right). Patient VI:1 had localized facial scaling as a newborn (left) and localized ichthyosis linearis circumflexa as an infant (right). At preschool age, patient I:1 had erythema on the back and patient II:1 had patchy erythema and mild scaling. Patient VIII:1 had large erythematous plaques as a young teenager. Patient VII:1 in her 40s had extensive inflammation and scaling of the skin.

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Figure 2.
Immature Immunophenotype and Decreased Cytolytic Capacity of Natural Killer (NK) Cells in Netherton Syndrome (NS)

The NK cell phenotype and function was studied in 7 patients (I:1, II:1, VIII:1, V:1, V:2, VI:1, and VII:1). A-C, The phenotype of NK cells (patients I:1, II:1, V:1, V:2, VI:1, and VII:1) show decreased CD27 expression and increased CD45RA and CD62L expression. D-E, The cytotoxicity of NK cells against the K562 target cell line was decreased in patients with NS (patients I:1, II:1, V:1, V:2, VI:1, VII:1, and VIII:1) compared with controls. Data points indicate proportion of alive K562 cells; error bars, SD. F, The degranulation responses of NK cells after the stimulation with K562 cells were lower in patients with NS (patients I:1, II:1, V:1, V:2, VI:1, and VIII:1). G, The cytokine secretion by NK cells after stimulation with phorbol myristate acetate and calcium 1 was similar in patients with NS (patients I:1, II:1, V:1, V:2, and VIII:1) to that in healthy controls. INF-γ indicates interferon-γ; TNF, tumor necrosis factor.

aP < .05.

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