|Year : 2021 | Volume
| Issue : 3 | Page : 267-270
A heterozygous missense mutation of CARD14 gene in a case of Netherton-Like syndrome
Surya Ravindran1, Sebastian Criton1, Divya Surendran2
1 Department of Dermatology, Amala Institute of Medical Sciences, Thrissur, Kerala, India
2 Department of Pathology, Amala Institute of Medical Sciences, Thrissur, Kerala, India
|Date of Submission||29-Apr-2020|
|Date of Decision||12-May-2020|
|Date of Acceptance||30-Mar-2021|
|Date of Web Publication||30-Jun-2021|
Department of Dermatology, Amala Institution of Medical Sciences, Thrissur, Kerala
Source of Support: None, Conflict of Interest: None
Netherton syndrome (NS) is a multi-domain genodermatoses with hair, skin, and immunological abnormalities caused by a monogenic serine protease inhibitor of Kazal type 5 mutation. As it presents with a myriad of overlapping clinical features, it often creates a diagnostic confusion from other congenital erythroderma causes. The molecular basis of NS was investigated in a 7-month-old male child using next-generation sequencing. Sequencing identified an A-to-G transition at producing the missense mutation p.Met238Val in exon 5 of the CARD14 gene. This study suggests the occurrence of the CARD14 gene as a novel missense mutation in NS and suggests that it may be a recurrent abnormality and the probable reason for the atypical features of this genodermatosis presenting as congenital erythroderma.
Keywords: Congenital erythoderma, Netherton, CARD14
|How to cite this article:|
Ravindran S, Criton S, Surendran D. A heterozygous missense mutation of CARD14 gene in a case of Netherton-Like syndrome. Indian J Paediatr Dermatol 2021;22:267-70
|How to cite this URL:|
Ravindran S, Criton S, Surendran D. A heterozygous missense mutation of CARD14 gene in a case of Netherton-Like syndrome. Indian J Paediatr Dermatol [serial online] 2021 [cited 2021 Jul 24];22:267-70. Available from: https://www.ijpd.in/text.asp?2021/22/3/267/319952
| Introduction|| |
The incidence of Netherton syndrome (NS) is 1 per 200,000 births, and it accounts for 18% of congenital erythrodermas. NS is characterized by the triad of ichthyosis linearis circumflexa, trichorrhexis invaginata, and atopic diathesis. The classical NS is characterized by a germline mutation in the serine protease inhibitor of Kazal type 5 (SPINK5) genes located on chromosome 5q31-32. Its mutation leads to dysfunctional or nonfunctional LEKT1 that stimulates unrestricted proteolytic activity in the stratum corneum, causing corneodesmosome cleavage leading to altered epidermal barrier and desquamation, respectively. This activity further perpetuates a cascade of infections secondary to loss of antimicrobial peptides and inflammatory defenses.
Even though most case reports are from Caucasian populations, it is under-reported in the Indian population due to a lack of diagnostic facilities such as genetic analysis and confusion with severe atopic dermatitis. The condition is often challenging to diagnose because of the rare nature of the genetic disease (fewer than 100 published cases), its clinical overlap with various congenital erythrodermas.
| Case Report|| |
A 7-month-old male child born to nonconsanguineous parents normal at birth developed erythema and scaling over the cheeks that progressed over time to diffuse erythema, induration, and scaling all over the body at the time of presentation [Figure 1] and [Figure 2]. The mother gave a history of atopy with recurrent respiratory tract infections. Examination revealed generalized erythema with fine, double-edged scales on the trunk and extremities with sparse eyebrows and eyelashes. His hair was dry and lusterless with alopecia. Hair microscopic examination revealed trichorrhexis invaginata [Figure 3]. He had finger and toenail dystrophy. Skin biopsy showed focal parakeratosis and moderate psoriasiform elongation of the rete ridges with spongiform pustules in the upper layers of the epidermis. Dermis showed a moderate lymphohistiocytic infiltrate [Figure 4]. During admission, he had multiple diarrheal episodes and progressively developed hypotension, hypoalbuminemia, and thrombocytopenia. After admission into the pediatric intensive care unit, he was managed with injectable antibiotics, oral steroids, albumin infusion, fresh frozen plasma infusion, inotropes and emollients, electrolyte supplementation, and a modified diet. The patient improved symptomatically. After 1 month, there was a marked improvement in scaling, induration, and erythema with increased weight gain [Figure 5] and [Figure 6]. The patient is under monthly follow-up.
|Figure 4: 10X view showing parakeratosis, psoriasiform elongation of the rete ridges, lymphocytic infiltrate in the epidermis, and lymphohistiocytic infiltrate in the dermis|
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To identify the molecular basis of NS, we employed next-generation sequencing (NGS), including 95 dominant keratinization genes. After obtaining informed consent, genomic DNA was extracted from a peripheral blood sample obtained from the affected individual, and sequencing was performed using a standard kit on Illumina MiSeq/NextSeq with the expected data output of ~3 GB per sample. The parents were not consenting for venesection and testing due to financial constraints. Written informed consent was sought, and the study was conducted in compliance with the Declaration of Helsinki principles. The probands genomic DNA was submitted for exome sequencing, and the reads were aligned against the whole genome build hg19 using STRAND® NGS [Figure 7].
|Figure 7: Identified heterozygous missense substitution (p.Met238Val) lies in exon 5 of the CARD14 gene on next-generation sequencing|
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| Discussion|| |
NS is a challenging diagnosis, but it is also easily misdiagnosed as atopic dermatitis due to its variable clinical presentation. Leung et al. reported a similar misdiagnosis where the diagnosis was delayed until 8 years. It was the pathognomonic appearance of trichorrhexis invaginata that clinched the diagnosis later. The diagnosis is often missed as the characteristic ichthyosis linearis circumflexa does not manifest early or develops gradually at 2 years of age. Hair shaft abnormalities, characteristically trichorrhexis invaginata, are predominantly found in infancy or early childhood and need to be examined on suspicion. The eyebrow examination is more sensitive than scalp hair, especially for patients first seen in late childhood. Pili torti and trichorrhexis nodosa have also been reported in association with NS attributing to probable kazalk5/KLK5 expression. SPINK5 and filaggrin mutations have both been associated with atopic dermatitis and with NS. However, there were no pathogenic alterations in the patient's FLG or SPINK5 gene.
The CARD14 gene provides instructions for making a protein that turns on (activates) a group of interacting proteins known as nuclear factor kappa-B. Germline pathogenic variations in the CARD14 gene are associated with familial pityriasis rubra pilaris, and psoriasis. After a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration, leading to hyperkeratosis and scaling. Craiglow et al. proposed a spectrum of CARD14-associated papulosquamous eruption (CAPE) that showed features of both psoriasis and pityriasis rubra pilaris. Our case is similar to CAPE as the child has sparing of the infralabial region but distinct with hair shaft abnormalities, double-edged scales, and atopic diathesis. The identified variant (chr17:78162212A>G c.712A>G p.Met238Val) seems to be a novel variant in our report, as it has not been previously reported in the literature. To identify the variant impact on the gene, the StrandOmics Variant Annotation engine was used which includes algorithms using both public content (HGMD, ClinVar, OMIM, HPO, links to dbSNP, 1000 Genomes, Exome Variant Server, and six in silico predictors – SIFT, PolyPhen-2, Mutation Taster, FATHMM, Mutation Assessor, and LRT). Of note, missense variants in the CARD14 gene, such as p.Leu124Pro and p.Leu156Pro, have been reported in the past in patients affected with pityriasis rubra pilaris. The identified missense variant alters a conserved residue in the protein; however, the exact role of the variant in the disease could not be ascertained. This variant was predicted to be damaging by one (Mutation Taster) out of six in silico missense prediction tools. In summary, we have elucidated NS molecular basis in an Indian participant using NGS. Although SPINK5 is the known mutation in NS, our findings identified a missense variant in the CARD14 gene (chr17:78162212A>G c.712A>G p.Met238Val), in our case, seems to be a novel variant, more studies are required to confirm its role in the pathogenesis of this disorder of cornification.
The limitation of our case is that it is a single case report, and it would have been ideal if the genomic DNA of both the parents was analyzed with NGS as a trio. Such observations may be further confirmed by polymerase chain reaction, or the probable undercovered parts of genes may be sequenced with Sanger sequencing with chromatogram analysis.
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 identity, but anonymity cannot be guaranteed.
We acknowledge the help of Strand Life Sciences Pvt., Ltd., Bangalore, for the genetic analysis and Dr. Manjunath M Madathil and Dr. Shruthi Rathish for their help.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]