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CASE BASED REVIEW
Ahead of print publication  

Autoinflammation with arthritis and dyskeratosis an inflammasomopathy: Case report and review of literature


1 Department of Clinical Immunology and Rheumatology, Nizam's Institute of Medical Sciences; Department of Rheumatology and Clinical Immunology, Star Hospitals, Hyderabad, Telangana, India
2 Department of Clinical Immunology and Rheumatology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India

Date of Submission20-Jan-2021
Date of Acceptance08-Apr-2021
Date of Web Publication18-Nov-2021

Correspondence Address:
Liza Rajasekhar,
Department of Clinical Immunology and Rheumatology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_17_21

  Abstract 


Inherited disorders of the inflammasome pathway causes dysregulated inflammasome activation, which presents with inflammation and other clinical features linked to the defective protein. Eight mutations have been previously described in the NLRP1 inflammasome protein, causing different inflammatory skin disorders. Two of these mutations are associated with “autoinflammation with arthritis and dyskeratosis (AIADK),” a novel Mendelian auto-inflammatory disorder, in the 2017 International Union of Immunological Societies phenotypic classification for primary immunodeficiencies. We report a 22-year-old female, with recurrent generalized urticaria, periodic fever and pain abdomen, inflammatory polyarthritis, cutaneous lesions over the extremities, and persistently elevated inflammatory markers. On next-generation sequencing, a heterozygous missense mutation in exon 4 of the NLRP1 gene (chr17:G.5461839C>T) was detected, which results in the amino acid substitution of glutamine for arginine at codon 726 (c.2177G>A; p.Arg726Gln). A probable diagnosis of AIADK, possibly caused by this mutation was proposed, and patient responded well to colchicine.

Keywords: Autoinflammatory syndrome, inflammasome, inflammasomopathies, NLRP1, primary immunodeficiency diseases



How to cite this URL:
Sureja NP, Rajasekhar L. Autoinflammation with arthritis and dyskeratosis an inflammasomopathy: Case report and review of literature. Indian J Rheumatol [Epub ahead of print] [cited 2021 Dec 9]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=330660




  Introduction Top


Inherited disorders in the Inflammasome pathway are grouped under the umbrella of inflammasomopathies. Inflammasomes are large intracellular multiprotein complexes. They exist in two receptor forms. One of them is the NOD (nucleotide-binding oligomerization domain) like receptor family consisting of proteins NLRP1, NLRP3, NLRP6, NLRP12, and NLRC4; another is interferon inducible protein AIM2. A typical inflammasome consists of a pattern recognition receptor, an adaptor protein and caspase 1. Once a pathogen associated or danger associated molecular pattern is recognized, caspase activation results in maturation of inflammatory cytokine response involving interleukin (IL)-1 and IL-18.[1],[2] Inherited disorders affecting this pathway present with inflammation and other clinical features linked to the defective protein.[3] The NLRP1 protein is coded by the NLRP1 gene, and is organized into the following domains: Amino-terminal pyrin domain (PYD), NACHT, leucine-rich repeats (LRRs), a function-to-find domain (FIIND), and a carboxy-terminal caspase recruitment domain.[2] Dysregulated inflammasome activation due to various NLRP1 gene mutations leads to autoinflammatory disorders with different phenotypes.


  Case Report Top


A 22-year-old female, first child of unrelated healthy parents, with a 17-year-old healthy younger sister, had unremarkable birth events and developmental milestones. She presented with a history of episodic fever and abdominal pain of 6 years duration. Fever recurred every month and lasted for a week. Aching lower abdominal pain accompanied the febrile episodes which lasted for around 6 hours a day, unaccompanied by any other gastrointestinal symptoms. In the initial 3 years she had recurrent generalized urticaria, and in the 8 months before presentation she had developed inflammatory polyarthritis of the small and large joints of the upper and lower extremities. Over the month before presentation, she also experienced a rash over the feet, which started as diffuse erythema and later exfoliated. She was receiving deflazacort 15 mg/day, hydroxychloroquine 200 mg/day, and methotrexate 15 mg/week over the last 6 months. Her arthritis had improved, but all other symptoms were persisting at presentation.

Physical examination revealed features of Cushing's syndrome. Multiple skin lesions were present; exfoliation over medial and dorsal aspect of both feet, macular lesions posteriorly over the right leg and a plaque over the right forearm. Asymmetrical muscle tenderness was noted in all extremities. Assessment of muscle power was limited due to myalgia. There was no arthritis. Rest of the physical examination was normal.

Laboratory studies revealed elevated acute-phase reactants (erythrocyte sedimentation rate [ESR]: 105 mm/h, C-reactive protein [CRP]: 12 mg/L). Serum aspartate aminotransferase and serum alanine aminotransferase were elevated 1.5 and 2 times upper normal limit, respectively. Creatine phosphokinase was normal, antinuclear antibodies (ANA), rheumatoid factor, and anti-cyclic citrullinated peptide antibodies were absent.

Considering a possibility of autoinflammatory syndrome, a panel of genes associated with primary immunodeficiency diseases and autoinflammatory syndromes were analyzed by next-generation sequencing. A heterozygous missense mutation in exon 4 of the NLRP1 gene (chr17:G.5461839C>T) that results in the amino acid substitution of glutamine for arginine at codon 726 (c.2177G>A; p.Arg726Gln) was detected. With a diagnosis of autoinflammation with arthritis and dyskeratosis (AIADK) (OMIM#617388), possibly caused by mutation in NLRP1 gene (OMIM*606636), colchicine was started at 1 mg/day in divided doses, later increased to 1.5 mg/day. In view of exogenous Cushing's syndrome, steroid was gradually tapered and stopped. After 4 months of treatment, fever, rash, myalgia and arthritis subsided, ESR decreased to 15 mm/h, CRP, serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase normalized, but episodes of pain abdomen continued.


  Discussion Top


AIADK is categorized as an auto-inflammatory disorder in the 2019 update of the International Union of Immunological Societies phenotypic classification for primary immunodeficiencies.[4] Mutations in NLRP1 gene causing a novel disease were first described in 2016, in three cases reported by Grandemange et al.[2] Two of these patients (a 16-year-old boy, and an 8-year-old girl) were double first cousins born to consanguineous parents originating from Algeria, and the third patient was a 10-year-old girl, the second child of unrelated healthy Dutch parents. Clinical features of these patients are described in [Table 1]. In all three patients, CRP was repeatedly elevated, and Vitamin-A levels were persistently below the normal range. ANA was positive in patients 2 and 3. Skeletal radiographs of patients 2 and 3 showed abnormal metaphysis of knees and abnormal lower femoral epiphysis. Histology of vocal cords of patient 1, and skin biopsy of patients 2 and 3 showed acanthosis, scattered to confluent dyskeratotic keratinocytes affecting all the layers of epidermis except the basal layers. Lesions were covered by dense orthokeratosis with focal parakeratosis. Serum levels of caspase-1 and IL-18 were elevated in all the three patients and in two heterozygous parents of patients 1 and 2, suggesting involvement of NLRP1 inflammasome. Serum IL-1β level was elevated only in patient 3. Genetic analysis of these 3 patients revealed two distinct mutations in NLRP1 gene. In the cousins, a homozygous mutation (c.2176C>T; p.Arg726Trp) located between the NACHT domain and the LRR domain was seen. In patient 3, a de novo heterozygous mutation (c.3641C>G; p.Pro1214Arg) located in the FIIND domain was seen. The mutation in our patient is also located similar to patient 1 and 2, in the same linker region between the NACHT domain and the LRR domain [Figure 1].
Table 1: Previously described pathogenic NLRP1 mutations with their phenotypes

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Figure 1: Schematic representation of NLRP1 protein showing location of mutations in our patient A726G (*) and previously described patients.[2],[5],[6],[7] CARD: Caspase recruitment domain, FIIND: Function to find domain, LRR: Leucine-rich repeat domain, PYD: Pyrin domain

Click here to view


Mutations in other domains of the NLRP1 gene have also been described. Zhong et al.[5] described two overlapping Mendelian monogenic inflammatory skin disorders. Multiple self-healing palmoplantar carcinoma was described in three families with mutations in the PYD (A54T, A66V, and M77T). These patients had palmar and plantar hyperkeratotic nodular growths, resembling rapidly growing benign proliferative epithelial skin lesions known as keratoacanthomas. Histologically, these lesions displayed features of well-differentiated squamous cell carcinoma. A subset of these patients also had conjunctival or corneal dyskeratosis. Another disorder is familial keratosis lichenoides chronica, which was described in two siblings, with a mutation (F787_R843del) immediately N terminal to the LRR domain. These patients had multiple discrete lichenoid papules on the arms, legs, and lower trunks. Herlin et al.[6] described corneal and mucosal dyskeratosis in a 5-year-old boy with A59P mutation in the PYD. Drutman et al.[7] reported a syndromic form of juvenile-onset recurrent respiratory papillomatosis in two siblings with T755N mutation N-terminal to LRR domain. Mutations and phenotypes of all these patients including our patient are summarized in [Table 1].

The pathogenesis of dysregulated activation of the inflammasome in these patients is not clearly known. It is postulated that the NLRP1 inflammasome is maintained in an auto inhibitory state by action of the pyrin and the LRR domains. A recessive loss of function mutation in these regions and in the linker region between the NACHT domain and the LRR domain, releases this auto inhibition and causes inflammasome activation. Alternatively a dominant mutation in the FIIND domain may act as gain-of-function mutations leading to excessive activation of the inflammasome.[2],[5],[8]

Although typical hyperkeratotic lesions were not seen in our patient, and dyskeratosis was not proven by histopathology, a probable diagnosis of AIADK is being proposed based on presence of systemic inflammation, cutaneous involvement and identified genetic mutation. The cutaneous lesions in our patient are thought to be a relatively milder form of dyskeratosis. As the parents did not agree for genetic testing in themselves, the possibility of identified mutation being a benign variant cannot be excluded.

We report a mutation in NLRP1 gene possibly linked to AIADK, an extremely rare and novel Mendelian autoinflammatory disorder.

Consent for publication

Informed consent could not obtained as we lost contact with the patient. However, the report does not contain patient photographs and identity of the patient has not been revealed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Broz P, Dixit VM. Inflammasomes: Mechanism of assembly, regulation and signalling. Nat Rev Immunol 2016;16:407-20.  Back to cited text no. 1
    
2.
Grandemange S, Sanchez E, Louis-Plence P, Tran Mau-Them F, Bessis D, Coubes C, et al. A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis). Ann Rheum Dis 2017;76:1191-8.  Back to cited text no. 2
    
3.
Sönmez HE, Özen S. A clinical update on inflammasomopathies. Int Immunol 2017;29:393-400.  Back to cited text no. 3
    
4.
Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, et al. Human inborn errors of immunity: 2019 update of the IUIS phenotypical classification. J Clin Immunol 2020;40:66-81.  Back to cited text no. 4
    
5.
Zhong FL, Mamaï O, Sborgi L, Boussofara L, Hopkins R, Robinson K, et al. Germline NLRP1 mutations cause skin inflammatory and cancer susceptibility syndromes via inflammasome activation. Cell 2016;167:187-2.02E+19.  Back to cited text no. 5
    
6.
Herlin T, Jørgensen SE, Høst C, Mitchell PS, Christensen MH, Laustsen M, et al. Autoinflammatory disease with corneal and mucosal dyskeratosis caused by a novel NLRP1 variant. Rheumatology (Oxford) 2020;59:2334-9.  Back to cited text no. 6
    
7.
Drutman SB, Haerynck F, Zhong FL, Hum D, Hernandez NJ, Belkaya S, et al. Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis. Proc Natl Acad Sci U S A 2019;116:19055-63.  Back to cited text no. 7
    
8.
Yu CH, Moecking J, Geyer M, Masters SL. Mechanisms of NLRP1-mediated autoinflammatory disease in humans and mice. J Mol Biol 2018;430:142-52.  Back to cited text no. 8
    


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