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Year : 2020  |  Volume : 21  |  Issue : 1  |  Page : 73-75

A case of netherton syndrome with novel mutation in SPINK5 gene expressing incomplete phenotype

Department of Dermatology, Vernerology, Leprology, Gujarat Cancer Society Medical College, Hospital and Research Centre, Ahmedabd, Gujarat, India

Date of Submission31-Jul-2019
Date of Decision15-Aug-2019
Date of Acceptance03-Sep-2019
Date of Web Publication24-Dec-2019

Correspondence Address:
Dr Jigna Krunal Padhiyar
Department of Dermatology, Vernerology, Leprology, Gujarat Cancer Society Medical College, Hospital and Research Centre, Room No-35, Ahmedabd, Gujarat
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpd.IJPD_76_19

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Netherton syndrome (NS) is characterized by ichthyosis linearis circumflexa, trichorrhexis invaginata, and atopic diathesis. It is also considered a probable primary immunodeficiency as many patients have shown increased tendency for infections and abnormal levels of various immunoglobulins. Primary defect in NS is mutation in SPINK5 (serine protease inhibitor Kazal-type 5) gene which leads to the defective expression and function of lymphoepithelial Kazal-type-related inhibitor. We describe a case of a 7-year-old male born out of first-degree consanguineous marriage with findings of novel mutation, noninvolvement of the hair shaft, and unusual histopathology.

Keywords: Netherton syndrome, novel mutation, phenotype, SPINK5 gene

How to cite this article:
Patel TD, Padhiyar JK, Patel NH, Trivedi NS. A case of netherton syndrome with novel mutation in SPINK5 gene expressing incomplete phenotype. Indian J Paediatr Dermatol 2020;21:73-5

How to cite this URL:
Patel TD, Padhiyar JK, Patel NH, Trivedi NS. A case of netherton syndrome with novel mutation in SPINK5 gene expressing incomplete phenotype. Indian J Paediatr Dermatol [serial online] 2020 [cited 2021 Apr 22];21:73-5. Available from: https://www.ijpd.in/text.asp?2020/21/1/73/273839

  Introduction Top

Netherton syndrome (NS), an autosomal recessive disorder, is primarily considered a triad of ichthyosis linearis circumflexa (ILC), trichorrhexis invaginata (TI), and atopic diathesis (atopic dermatitis, urticaria, angioedema, asthma, rhinitis, and food allergies). These patients might initially express congenital ichthyosiform erythroderma (CIE), which in some of them might improve and evolve into ILC.[1]

Loss of lymphoepithelial Kazal-type-related inhibitor (LEKTI) because of SPINK5 (serine protease inhibitor Kazal-type 5) gene mutation causes overactivity of tissue kallikreins leading to detachment of stratum corneum through degradation of desmoglein-1, skin inflammation, and elastase-induced profilaggrin degradation, resulting in defective skin barrier. The same is also responsible for bamboo-like hair TI. NS has also been proposed to be a primary immune deficiency owing to the findings of reduced memory B-cells, decreased natural killer cell cytotoxicity, and selective deficiency to bacterial antigen. This clinically expresses as recurrent bacterial infections along with findings of elevated serum total immunoglobulin (Ig) E levels, elevated IgG4, and hypereosinophilia.[2]

Nothing specifically has been found to be effective in the treatment of NS. Acitretin and intravenous immunoglobulin (IVIG) have been tried with variable response.

  Case Report Top

A 7-year-old male child born of a first-degree consanguineous marriage presented to us with complaint of generalized skin lesions since infancy. On examination, the averagely built child had multiple, grouped vesicles on the trunk. There were multiple plaques with double-edged scale, which were present on the trunk and limbs. [Figure 1] Face showed diffuse erythema with exfoliation. Mild lichenification was present in flexures. Nail and mucous membrane were normal on examination. Multiple trichogram from the scalp and eyebrows did not show any hair shaft anomalies. All routine investigations were within the normal limits except high serum IgE level (1715 ng/ml) and eosinophilia (746/mm3). Considering the absence of hair shaft abnormality, we considered the differential diagnosis of inflammatory peeling skin syndrome Type B and CIE along with NS without/delayed onset of hair shaft anomalies [Figure 2]. Histopathological examination showed orthokeratotic hyperkeratosis with subcorneal split filled with neutrophils, epidermal spongiosis, and neutrophil exocytosis. In accordance with this histopathology finding, list of differential diagnosis was expanded to include pustular psoriasis, and subcorneal pustular dermatosis. As the diagnosis was not yet conclusive, we asked the patient to undergo genetic testing. As the patient was not affording, only ichthyosis panel for gene mutation was carried out. Genetic report (test methodology used was target gene sequencing – selective capture and sequencing of the protein-coding regions of the gene) is summarized in [Table 1]. A heterozygous single-base-pair deletion in exon 28 of the SPINK5 gene (chr5: G.147504338del; depth: ×30) that results in a frameshift and premature truncation of the protein 49 amino acids downstream to codon 893 (P. Ala893 LecFsTer49; ENST00000359874.3) was detected and considered to be pathogenic variant.
Figure 1: Varied clinical presentations (a) multiple tiny erythematous vesicular lesions with exfoliation and flexural lichenification (b) ruptured superficial blister with mild exfoliation and erythema over the face and normal hair growth (c) diffuse congenital ichthyosiform erythroderma like presentation during flare-ups (d) ichthyosis linearis circumflexa on legs during improvement and evolution

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Figure 2: (a) ×10 view showing orthokeratotic hyperkeratosis, subepidermal split, and psoriasiform hyperplasia along with spongiosis with neutrophilic exocytosis (b) ×40 view showing subepidermal split with neutrophils in the cavity

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Table 1: Genetic analysis

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  Discussion Top

Hair abnormality usually starts after the 1st year of life, but it may be delayed up to 8 years of age. The most characteristic and specific hair abnormality is TI. Hannula-Jouppi et al.[2] have studied phenotype variation among patients of NS. They also found that of 11 patients, 2 patients had an absence of any hair abnormality. They also observed two siblings who were compound heterozygous for the founder mutation and had much milder phenotype than homozygous patients. Of these two siblings, one had not developed TI. Our patient also had heterozygous type of mutation which may explain incomplete phenotype (absence of TI) or phenotype variation. They also studied along with immature immunity in patients of NS and found out that these patients also exhibit recurrent infections along with immature B-cell function. Our patient did not have any associated systemic findings and recurrent infections as a manifestation of immunodeficiency though eosinophilia and increased IgE levels were found.

Our patient did not show other features of atopy except for mild atopic dermatitis. This also may be attributable to heterozygous mutation expressing milder phenotype.

Histopathology showed subcorneal split with neutrophils and psoriasiform hyperplasia. Usually, the biopsy shows psoriasiform hyperplasia with associated spongiosis and adherent parakeratotic scale along with oval dark granules in stratum granulosum.[3] Hence, this further added to the confusion in diagnosis, as ILC sometimes may not always be a part of NS.[4]

To our best of knowledge and after thorough literature search, we were unable to find an article that reports heterozygous mutation in exon 28 of SPINK5 gene. A study by Bitoun et al.[5] observed that different mutations in SPINK5 gene have variable effects on messenger ribonucleic acid stability, which, in turn, may be responsible for structurally abnormal and nonfunctional LEKTI polypeptide. Expression of LEKTI might help in effects of SPINK5 mutations. They also observed that homozygous mutations were lethal and severe in five patients. They attributed interfamily phenotype variation to environmental factors.

We were not able to do LEKTI expression in our patient because of its unavailability at our center.

  Conclusion Top

This case is being reported for its novel mutation as there are not much data of genetic analysis in cases of NS in Indian patients. Although trichogram may not show any hair shaft abnormality, if the suspicion is high, genetic analysis may help to diagnose the condition as well as to counsel the parents about future siblings. Genotype and phenotype correlation studies in Indian patients are also needed to derive further conclusive data.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal patient identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Raghunath M, Tontsidou L, Oji V, Aufenvenne K, Schürmeyer-Horst F, Jayakumar A et al. SPINK5 and Netherton syndrome: Novel mutations, demonstration of missing LEKTI, and differential expression of transglutaminases. J Invest Dermatol 2004;123:474-83.  Back to cited text no. 1
Hannula-Jouppi K, Laasanen SL, Ilander M, Furio L, Tuomiranta M, Marttila R et al. Intrafamily and interfamilial phenotype variation and immature immunity in patients with Netherton syndrome and finnish SPINK5 founder mutation. JAMA Dermatol 2016;152:435-42.  Back to cited text no. 2
Metze D. Disorders of keratinization. In: Calonnje E, Brenn T, Lazar A, Mckee PH, Mckee's Pathology of Skin. editors. China: Saunders Elsevier; 2012. p. 61-3.  Back to cited text no. 3
Bilgili SG, Karadag AS, Calka O, Onder S, Bayram I. Ichthyosis linearis circumflexa: Not always a part of Netherton syndrome. Genet Couns 2016;27:353-6.  Back to cited text no. 4
Bitoun E, Chavanas S, Irvine AD, Lonie L, Bodemer C, Paradisi M, et al. Netherton Syndrome: Disease Expression and Spectrum of SPINK5 Mutations in 21 families. J Invest Dermatol 2002;118(2):352-61.  Back to cited text no. 5


  [Figure 1], [Figure 2]

  [Table 1]

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