- Email: [email protected]
Granulomatous disease associated with NOD2 sequence variants and familial camptodactyly: An intermediate form of NOD2-associated diseases?
Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]
Contents lists available at ScienceDirect
Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit
Granulomatous disease associated with NOD2 sequence variants and familial camptodactyly: An intermediate form of NOD2-associated diseases? Min Shen, MDa, Rocio Moran, MDb, Kenneth J. Tomecki, MDc, Qingping Yao, MD, PhDa,d,n a
Department of Rheumatic and Immunologic Disease/A50, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH c Dermatology, Cleveland Clinic, Cleveland, OH d Division of Rheumatology, Allergy and Immunology, Stony Brook University, Stony Brook, NY b
a r t i c l e in fo
Keywords: Nucleotide-binding oligomerization domain-containing protein-2 NOD2-associated autoinflammatory disease Blau syndrome
a b s t r a c t Objective: Nucleotide-binding oligomerization domain-containing protein-2 (NOD2)-associated diseases may be a spectrum of disease. We report two families who exhibited an intermediate form of Blau syndrome and NOD2-associated autoinflammatory disease (NAID). Methods: We identified two families with granulomatous disease. The clinical phenotypes and genotypes of these two families were reviewed and analyzed. Results: The proband in family 1 was a white 57-year-old woman, with camptodactyly (age 6 years), inflammatory polyarthritis and dermatitis (age of 30 years), and cough, dyspnea, dry eyes, parotid gland enlargement, and fever. A computerized tomography showed mediastinal lymphadenopathy without hilar involvement, and a mediastinal lymph node biopsy revealed non-caseating granuloma. Pedigree analysis suggested autosomal dominant inheritance, and genetic testing identified a NOD2 sequence variant IVS8 þ 158. The proband in family 2 was a white 50-year-old woman with inflammatory polyarthritis and periarticular subcutaneous nodules. Skin biopsy showed non-necrotizing granuloma. There was a family history of camptodactyly, and genetic testing identified a NOD2 sequence variant R703C. Conclusions: Both probands had granulomatous disease and autosomal dominant phenotype of familial camptodactyly coupled with the presence of the NOD2 sequence variants, IVS8 þ 158, and R703C. Granulomatous disease associated with NOD2 variants may be an intermediate form between Blau syndrome and NAID. & 2015 Elsevier Inc. All rights reserved.
Introduction Nucleotide-binding oligomerization domain-containing protein-2 (NOD2) is a member of a family of intracellular proteins with N-terminal caspase recruitment domains (CARDs) [1,2]. Since the discovery of NOD2 in 2001, NOD2 sequence variants have been associated with Crohn's disease, Blau syndrome (BS), and most recently NOD2-associated autoinflammatory disease (NAID) [3]. Granulomatous diseases are a group of disorders with granulomatous inflammation on biopsy coupled with either arthritis, uveitis, or rash [4]. BS is a rare autosomal dominant, autoinflammatory granulomatous disorder affecting the skin, eyes, and joints [5], and
n
Correspondence: Division of Rheumatology, Allergy and Immunology, Stony Brook University, Stony Brook, NY 11794. E-mail addresses: [email protected], [email protected] (Q. Yao). http://dx.doi.org/10.1016/j.semarthrit.2015.05.007 0049-0172/& 2015 Elsevier Inc. All rights reserved.
is linked to certain NOD2 sequence variants [6]. NAID is an emerging systemic autoinflammatory disease, characterized by periodic fever, dermatitis, arthritis, gastrointestinal (GI), and sicca-like symptoms, and a genetic association with NOD2 variants, which are distinctly located from BS [7]. NOD2-associated diseases represent a spectrum of diseases. Herein, we report two families with characteristic clinical phenotypes associated with two NOD2 sequence variants and illustrate an intermediate form of NOD2associated diseases.
Patients and methods This research was approved by the Institute Review Board of the Cleveland Clinic and performed according to the Declaration of Helsinki. Informed consent was obtained from all participants, who were observed, treated, and studied by the authors.
M. Shen et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]
2
Examination of the NOD2 gene for sequence variants by DNA polymerase chain reaction and DNA sequencing of all 12 exons were performed (Center for Genetics, St. Francis, OK).
Family 1 The proband was a 57-year-old white woman with asymptomatic flexion contractures of her 3rd, 4th, and 5th proximal interphalangeal joints (PIPs) of both hands since 6 years of age. As an adult, she later developed inflammatory polyarthritis and erythematous facial plaques and patches. A skin biopsy showed non-specific dermatitis. As a result of cough and dyspnea, chest radiograph and computerized tomography demonstrated multiple pulmonary nodules and lymphadenopathy in the mediastinum without hilar involvement. Mediastinal lymph node biopsy revealed non-caseating granuloma. Treatment with prednisone (40 mg daily with taper) resulted in marked clinical improvement. Ophthalmic examination showed xerophthalmia without uveitis. She had right parotid gland swelling histologically consistent with pleomorphic adenoma at the age of 26 years, and left parotid enlargement with scanty granuloma composed of lymphocytes and mixed with debris and rare collections of histiocytes at the age of 53 years. She had intermittent low-grade fever, fatigue, night sweats, myalgia, neck pain, and low back pain. Pedigree analysis (Fig. 1) identified her mother with hand deformities and limb ichthyosis who died at the age of 84 years reportedly. Her brother had flexion contractures of the 2nd through 5th fingers. Her 15-year-old son had bilateral flexion of the 4th and 5th PIPs (Fig. 1C) at the age of 6 years, rash on the face and ichthyosis on leg, intermittent fever at childhood, and intermittent painful red and dry eyes, without uveitis. Her 28-year-old daughter had finger flexion deformities of 3rd and 4th and eczema at the age of 2 years, intermittent abdominal pain/diarrhea, and dry eyes without uveitis. On physical examination, the proband
was afebrile, had camptodactyly of the 3rd, 4th, and 5th fingers of both hands (Fig. 1B), and ichthyosis on all her limbs (Fig. 1A). Laboratory investigation showed normal complete blood count (CBC), complete metabolic panel (CMP), erythrocyte sedimentation rate (ESR), and serum angiotensin-converting enzyme (ACE). Serological testings for autoimmune diseases, including antinuclear antibody, anti-double-stranded DNA, anti-neutrophil cytoplasmic antibodies, and rheumatoid factor, were all negative. Blood CD4, CD8, and NK cell counts were normal, as were blood vascular endothelial growth factor and TNFα levels. Genetic testing for the known periodic fever syndrome genes (ELA2, LPIN2, MEFV, MVK, NLRP3, PSTPIP1, and TNFRSF1A) was negative (GeneDx, MD). Sequencing of NOD2 revealed a heterozygous NOD2 sequence variant IVS8 þ 158 in the proband, her daughter, and son.
Family 2 The proband was a 50-year-old white woman with inflammatory polyarthritis for 5 months and “aching skin” and subcutaneous nodules on the elbows, wrists, and knees, which resolved after 2 months of treatment with sulfasalazine 1 g, twice daily. She had dry eyes/mouth but without uveitis or parotid gland enlargement and reported fatigue and myalgia, but without fever, weight loss, abdominal pain, or diarrhea. She had family history of earlyonset flexion contracture deformities of the 5th PIPs in several family members (Fig. 2B and C). On physical examination, she had tender, mobile subcutaneous nodules ranging from 0.5 to 1.5 cm on the elbows and wrists (Fig. 2A). Laboratory work was normal, including CBC, CMP, ESR, urine analysis, and serum ACE. Serologic testing was negative for systemic autoimmune disorders. Biopsy of skin nodule showed non-necrotizing granulomatous inflammation consisting of histiocytes with some well-formed granulomas. Genetic testing identified the heterozygous sequence variant in NOD2, R703C.
Fig. 1. Pedigree and phenotypes of family 1. Ichthyosis plaques on the leg (A) and camptodactyly (B) in the proband and camptodactyly (C) in her son.
M. Shen et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]
3
Fig. 2. Pedigree and phenotypes of family 2. Periarticular subcutaneous nodules in the proband (A) and camptodactyly in the family members (B and C).
Discussion NOD2-associated diseases currently include Crohn's disease, Blau syndrome (BS), and most recently NOD2-associated autoinflammatory disease (NAID) [3]. BS is an autosomal dominant disease synonymous with early-onset sarcoidosis [4], and typically characterized by granulomatous dermatitis, inflammatory arthritis, and uveitis. The clinical manifestations of the proband in family 1 included polyarthritis with camptodactyly, dermatitis, and non-caseating granuloma of lymph nodes, with a positive family history of camptodactyly and rash. These phenotypic features, along with a family history of autosomal dominant inheritance, are suggestive of BS even without uveitis in this case. BS has been linked to specific NOD2 sequence variants, including R334W, R334Q, E383K, E383G, G464W, L469F, W490L, ELL (498500)V, M513R, R587C, T605N, H496L, M513T, C495Y, and N670K [6]. These NOD2 sequence variants are primarily located in the nucleotide-binding domain (NBD) region, and some of these mutants have “gain of function” in vitro studies [8]. The presence of the NOD2 sequence variant IVS8 þ 158 in the proband and her two children in family 1 suggests its potential association with BS. To our knowledge, only one single case of pediatric BS (9-month old) was associated with the presence of the NOD2 variant IVS8 þ 158 [9]. Given the lack of uveitis and presence of atypical NOD2 variant in this case and her family members, we would argue against the diagnosis of typical BS. The NOD2 sequence variant IVS8 þ 158 is located in-between the NBD and leucine-rich repeat (LRR) regions of the NOD2 gene [3]. This particular NOD2 variant was initially thought to be related to Ashkenazi Jewish patients with Crohn's disease but unconfirmed in later studies [10,11]. This NOD2 sequence variant has been recently identified by our group as the most common genotype of NAID [7,12]. The function of the variant in NAID is unclear, but it could be a marker in linkage disequilibrium. The proband in family 2 had polyarthritis, cutaneous/subcutaneous nodules with pathological evidence of non-necrotizing granuloma, and the presence of the rare NOD2 sequence variant R703C.
These clinical phenotypic and genotypic findings were consistent with NAID and BS. NAID patients typically have recurrent fever, dermatitis, polyarthritis with characteristic distal extremity swelling, and sicca and GI symptoms, all commonly associated with the NOD2 sequence variants IVS8 þ 158 and R702W [7]. Patients with NAID have occasional granulomatous disease, but this patient did not have classic findings of NAID. Without uveitis and granulomatous dermatitis in this case, we could argue against the diagnosis of typical BS. Intriguingly, the proband had a family history of camptodactyly compatible with an autosomal dominant pattern of inheritance, though she did not have finger flexion deformities. These findings suggest that family members might have NOD2associated diseases. Unfortunately, family members were unavailable for assessment. In addition, there was no evidence of uveitis or hilar adenopathy in the proband to suggest a diagnosis of adult sarcoidosis, or GI symptoms to suggest inflammatory bowel disease. Our previous case report [13] supports the diagnosis of Blau-like disease in this adult proband; the patient had dermatitis, inflammatory arthritis, and granulomatous pneumonitis as an adult. Interestingly, these two patients shared similar phenotypes and identical genotype R703C, which is located in-between the NBD and LRR regions [3]. R703C was initially linked to Crohn's disease susceptibility [14], yet it is absent in healthy control population and causes “gain of function” like the common BS-associated gene sequence variants [8]. These data together may support the presence of an adult-onset BS-like presentation. While these two proband cases were not typical for BS or NAID, they lacked evidence of adult sarcoidosis and Crohn's disease. This study of two patients and their families may suggest the presence of an intermediate form of disease between BS and NAID, i.e., NAID and BS may share similarities, but they have distinct phenotypic and genotypic features as summarized in the Table. Briefly, camptodactyly and uveitis are absent, and granulomatous changes rarely occur in NAID, where most cases are sporadic with little familial aggregation [7]. NAID is distinct from adult-onset
M. Shen et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]
4
Table Differentiating features among Blau syndrome, NAID, and adult-onset sarcoidosis
Age at onset Fever Serositis Joints Skin Uveitits Hilar adenopathy GI symptoms Sicca-like Kidney and CNS damage Inheritance Gene sequence variants Therapy
Blau syndrome
NAID
Adult-onset sarcoidosis
o 5years Rare No Polyarthritis, granulomatous, and camptodactyly Granulomatous dermatitis, papules and nodules, and subcutaneous plaques Yes No
Adult Periodic, lasting several days Yes Oligo and polyarthritis/arthralgia, more common in lower extremities Spongiotic dermatitis, and erythematous patches/plaques No No
Adult Yes No Polyarthritis/arthralgia, periarticular nodular
No Yes Rare
Yes Yes Rare
No Yes Yes
Dominant NOD2: NBD
Mostly sporadic NOD2: in between LRR and NBD
Mostly sporadic No association with NOD2
NSAIDS, GC, and infliximab
GC and sulfasalazine
GC, immunosuppressive agents, and TNFα antagonists
Noncaseating granulomas, erythematous papules, and plaques or nodules; erythema nodosum Yes (25%) Yes (90%)
NAID: NOD2-associated autoinflammatory disease; GI: gastrointestinal; CNS: central nervous system; NOD2: nucleotide-binding oligomerization domain-containing protein2; LRR: leucine-rich repeat; NBD: nucleotide-binding domain; GC: glucocorticoid; NSAID: non-steroidal anti-inflammatory drugs.
sarcoidosis in that hilar lymphadenopathy accounts for 90%, camptodactyly is generally absent, and no association with NOD2 sequence variants has been found in adult sarcoidosis [15]. Conclusion In conclusion, this study suggests that the granulomatous disease associated with NOD2 mutations may be an intermediate form between BS and NAID. Further study of a larger series of cases is warranted. Acknowledgment We are thankful to the patients for providing the data. References [1] Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G. Nod2, a Nod1/ Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 2001;276:4812–8. [2] McGovern DP, van Heel DA, Ahmad T, Jewell DP. NOD2 (CARD15), the first susceptibility gene for Crohn's disease. Gut 2001;49:752–4. [3] Yao Q. Nucleotide-binding oligomerization domain containing 2: structure, function, and diseases. Semin Arthritis Rheum 2013;43:125–30. [4] Rosé CD, Wouters CH, Meiorin S, Doyle TM, Davey MP, Rosenbaum JT, et al. Pediatric granulomatous arthritis: an international registry. Arthritis Rheum 2006;54:3337–44.
[5] Wouters CH, Maes A, Foley KP, Bertin J, Rosé CD. Blau syndrome, the prototypic auto-inflammatory granulomatous disease. Pediatr Rheumatol Oline J 2014;12:33. [6] Sfriso P, Caso F, Tognon S, Galozzi P, Gava A, Punzi L. Blau syndrome, clinical and genetic aspects. Autoimmun Rev 2012;12:44–51. [7] Yao Q, Shen M, McDonald C, Lacbawan F, Moran R, Shen B. NOD2-associated autoinflammatory disease: a large cohort study. Rheumatology (Oxford) 2015 [Epub ahead of print]. [8] Chamaillard M, Philpott D, Girardin SE, Zouali H, Lesage S, Chareyre F, et al. Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases. Proc Natl Acad Sci U S A 2003;100:3455–60. [9] Borzutzky A, Fried A, Chou J, Bonilla FA, Kim S, Dedeoglu F. NOD2-associated diseases: bridging innate immunity and autoinflammation. Clin Immunol 2010;134:251–61. [10] Sugimura K, Taylor KD, Lin YC, Hang T, Wang D, Tang YM, et al. A novel NOD2/ CARD15 haplotype conferring risk for Crohn disease in Ashkenazi Jews. Am J Hum Genet 2003;72:509–18. [11] Karban A, Eliakim R. Failure to replicate the association of the novel NOD2/ CARD15 haplotype (S268P-JW1) to Crohn's disease in the Jewish Israeli population. Gastroenterology 2004;126:624–5. [12] Yao Q, Zhou L, Cusumano P, Bose N, Piliang M, Jayakar B, et al. A new category of autoinflammatory disease associated with NOD2 gene mutation. Arthritis Res Ther 2011;13:R148. [13] Yao Q, Piliang M, Nicolacakis K, Arrossi A. Granulomatous pneumonitis associated with adult-onset Blau-like syndrome. Am J Respir Crit Care Med 2012;186:465–6. [14] Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001;411:599–603. [15] Pabst S, Golebiewski M, Herms S, Karpushova A, Díaz-Lacava A, Walier M, et al. Caspase recruitment domain 15 gene haplotypes in sarcoidosis. Tissue Antigens 2011;77:333–7.
Contents lists available at ScienceDirect
Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit
Granulomatous disease associated with NOD2 sequence variants and familial camptodactyly: An intermediate form of NOD2-associated diseases? Min Shen, MDa, Rocio Moran, MDb, Kenneth J. Tomecki, MDc, Qingping Yao, MD, PhDa,d,n a
Department of Rheumatic and Immunologic Disease/A50, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH c Dermatology, Cleveland Clinic, Cleveland, OH d Division of Rheumatology, Allergy and Immunology, Stony Brook University, Stony Brook, NY b
a r t i c l e in fo
Keywords: Nucleotide-binding oligomerization domain-containing protein-2 NOD2-associated autoinflammatory disease Blau syndrome
a b s t r a c t Objective: Nucleotide-binding oligomerization domain-containing protein-2 (NOD2)-associated diseases may be a spectrum of disease. We report two families who exhibited an intermediate form of Blau syndrome and NOD2-associated autoinflammatory disease (NAID). Methods: We identified two families with granulomatous disease. The clinical phenotypes and genotypes of these two families were reviewed and analyzed. Results: The proband in family 1 was a white 57-year-old woman, with camptodactyly (age 6 years), inflammatory polyarthritis and dermatitis (age of 30 years), and cough, dyspnea, dry eyes, parotid gland enlargement, and fever. A computerized tomography showed mediastinal lymphadenopathy without hilar involvement, and a mediastinal lymph node biopsy revealed non-caseating granuloma. Pedigree analysis suggested autosomal dominant inheritance, and genetic testing identified a NOD2 sequence variant IVS8 þ 158. The proband in family 2 was a white 50-year-old woman with inflammatory polyarthritis and periarticular subcutaneous nodules. Skin biopsy showed non-necrotizing granuloma. There was a family history of camptodactyly, and genetic testing identified a NOD2 sequence variant R703C. Conclusions: Both probands had granulomatous disease and autosomal dominant phenotype of familial camptodactyly coupled with the presence of the NOD2 sequence variants, IVS8 þ 158, and R703C. Granulomatous disease associated with NOD2 variants may be an intermediate form between Blau syndrome and NAID. & 2015 Elsevier Inc. All rights reserved.
Introduction Nucleotide-binding oligomerization domain-containing protein-2 (NOD2) is a member of a family of intracellular proteins with N-terminal caspase recruitment domains (CARDs) [1,2]. Since the discovery of NOD2 in 2001, NOD2 sequence variants have been associated with Crohn's disease, Blau syndrome (BS), and most recently NOD2-associated autoinflammatory disease (NAID) [3]. Granulomatous diseases are a group of disorders with granulomatous inflammation on biopsy coupled with either arthritis, uveitis, or rash [4]. BS is a rare autosomal dominant, autoinflammatory granulomatous disorder affecting the skin, eyes, and joints [5], and
n
Correspondence: Division of Rheumatology, Allergy and Immunology, Stony Brook University, Stony Brook, NY 11794. E-mail addresses: [email protected], [email protected] (Q. Yao). http://dx.doi.org/10.1016/j.semarthrit.2015.05.007 0049-0172/& 2015 Elsevier Inc. All rights reserved.
is linked to certain NOD2 sequence variants [6]. NAID is an emerging systemic autoinflammatory disease, characterized by periodic fever, dermatitis, arthritis, gastrointestinal (GI), and sicca-like symptoms, and a genetic association with NOD2 variants, which are distinctly located from BS [7]. NOD2-associated diseases represent a spectrum of diseases. Herein, we report two families with characteristic clinical phenotypes associated with two NOD2 sequence variants and illustrate an intermediate form of NOD2associated diseases.
Patients and methods This research was approved by the Institute Review Board of the Cleveland Clinic and performed according to the Declaration of Helsinki. Informed consent was obtained from all participants, who were observed, treated, and studied by the authors.
M. Shen et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]
2
Examination of the NOD2 gene for sequence variants by DNA polymerase chain reaction and DNA sequencing of all 12 exons were performed (Center for Genetics, St. Francis, OK).
Family 1 The proband was a 57-year-old white woman with asymptomatic flexion contractures of her 3rd, 4th, and 5th proximal interphalangeal joints (PIPs) of both hands since 6 years of age. As an adult, she later developed inflammatory polyarthritis and erythematous facial plaques and patches. A skin biopsy showed non-specific dermatitis. As a result of cough and dyspnea, chest radiograph and computerized tomography demonstrated multiple pulmonary nodules and lymphadenopathy in the mediastinum without hilar involvement. Mediastinal lymph node biopsy revealed non-caseating granuloma. Treatment with prednisone (40 mg daily with taper) resulted in marked clinical improvement. Ophthalmic examination showed xerophthalmia without uveitis. She had right parotid gland swelling histologically consistent with pleomorphic adenoma at the age of 26 years, and left parotid enlargement with scanty granuloma composed of lymphocytes and mixed with debris and rare collections of histiocytes at the age of 53 years. She had intermittent low-grade fever, fatigue, night sweats, myalgia, neck pain, and low back pain. Pedigree analysis (Fig. 1) identified her mother with hand deformities and limb ichthyosis who died at the age of 84 years reportedly. Her brother had flexion contractures of the 2nd through 5th fingers. Her 15-year-old son had bilateral flexion of the 4th and 5th PIPs (Fig. 1C) at the age of 6 years, rash on the face and ichthyosis on leg, intermittent fever at childhood, and intermittent painful red and dry eyes, without uveitis. Her 28-year-old daughter had finger flexion deformities of 3rd and 4th and eczema at the age of 2 years, intermittent abdominal pain/diarrhea, and dry eyes without uveitis. On physical examination, the proband
was afebrile, had camptodactyly of the 3rd, 4th, and 5th fingers of both hands (Fig. 1B), and ichthyosis on all her limbs (Fig. 1A). Laboratory investigation showed normal complete blood count (CBC), complete metabolic panel (CMP), erythrocyte sedimentation rate (ESR), and serum angiotensin-converting enzyme (ACE). Serological testings for autoimmune diseases, including antinuclear antibody, anti-double-stranded DNA, anti-neutrophil cytoplasmic antibodies, and rheumatoid factor, were all negative. Blood CD4, CD8, and NK cell counts were normal, as were blood vascular endothelial growth factor and TNFα levels. Genetic testing for the known periodic fever syndrome genes (ELA2, LPIN2, MEFV, MVK, NLRP3, PSTPIP1, and TNFRSF1A) was negative (GeneDx, MD). Sequencing of NOD2 revealed a heterozygous NOD2 sequence variant IVS8 þ 158 in the proband, her daughter, and son.
Family 2 The proband was a 50-year-old white woman with inflammatory polyarthritis for 5 months and “aching skin” and subcutaneous nodules on the elbows, wrists, and knees, which resolved after 2 months of treatment with sulfasalazine 1 g, twice daily. She had dry eyes/mouth but without uveitis or parotid gland enlargement and reported fatigue and myalgia, but without fever, weight loss, abdominal pain, or diarrhea. She had family history of earlyonset flexion contracture deformities of the 5th PIPs in several family members (Fig. 2B and C). On physical examination, she had tender, mobile subcutaneous nodules ranging from 0.5 to 1.5 cm on the elbows and wrists (Fig. 2A). Laboratory work was normal, including CBC, CMP, ESR, urine analysis, and serum ACE. Serologic testing was negative for systemic autoimmune disorders. Biopsy of skin nodule showed non-necrotizing granulomatous inflammation consisting of histiocytes with some well-formed granulomas. Genetic testing identified the heterozygous sequence variant in NOD2, R703C.
Fig. 1. Pedigree and phenotypes of family 1. Ichthyosis plaques on the leg (A) and camptodactyly (B) in the proband and camptodactyly (C) in her son.
M. Shen et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]
3
Fig. 2. Pedigree and phenotypes of family 2. Periarticular subcutaneous nodules in the proband (A) and camptodactyly in the family members (B and C).
Discussion NOD2-associated diseases currently include Crohn's disease, Blau syndrome (BS), and most recently NOD2-associated autoinflammatory disease (NAID) [3]. BS is an autosomal dominant disease synonymous with early-onset sarcoidosis [4], and typically characterized by granulomatous dermatitis, inflammatory arthritis, and uveitis. The clinical manifestations of the proband in family 1 included polyarthritis with camptodactyly, dermatitis, and non-caseating granuloma of lymph nodes, with a positive family history of camptodactyly and rash. These phenotypic features, along with a family history of autosomal dominant inheritance, are suggestive of BS even without uveitis in this case. BS has been linked to specific NOD2 sequence variants, including R334W, R334Q, E383K, E383G, G464W, L469F, W490L, ELL (498500)V, M513R, R587C, T605N, H496L, M513T, C495Y, and N670K [6]. These NOD2 sequence variants are primarily located in the nucleotide-binding domain (NBD) region, and some of these mutants have “gain of function” in vitro studies [8]. The presence of the NOD2 sequence variant IVS8 þ 158 in the proband and her two children in family 1 suggests its potential association with BS. To our knowledge, only one single case of pediatric BS (9-month old) was associated with the presence of the NOD2 variant IVS8 þ 158 [9]. Given the lack of uveitis and presence of atypical NOD2 variant in this case and her family members, we would argue against the diagnosis of typical BS. The NOD2 sequence variant IVS8 þ 158 is located in-between the NBD and leucine-rich repeat (LRR) regions of the NOD2 gene [3]. This particular NOD2 variant was initially thought to be related to Ashkenazi Jewish patients with Crohn's disease but unconfirmed in later studies [10,11]. This NOD2 sequence variant has been recently identified by our group as the most common genotype of NAID [7,12]. The function of the variant in NAID is unclear, but it could be a marker in linkage disequilibrium. The proband in family 2 had polyarthritis, cutaneous/subcutaneous nodules with pathological evidence of non-necrotizing granuloma, and the presence of the rare NOD2 sequence variant R703C.
These clinical phenotypic and genotypic findings were consistent with NAID and BS. NAID patients typically have recurrent fever, dermatitis, polyarthritis with characteristic distal extremity swelling, and sicca and GI symptoms, all commonly associated with the NOD2 sequence variants IVS8 þ 158 and R702W [7]. Patients with NAID have occasional granulomatous disease, but this patient did not have classic findings of NAID. Without uveitis and granulomatous dermatitis in this case, we could argue against the diagnosis of typical BS. Intriguingly, the proband had a family history of camptodactyly compatible with an autosomal dominant pattern of inheritance, though she did not have finger flexion deformities. These findings suggest that family members might have NOD2associated diseases. Unfortunately, family members were unavailable for assessment. In addition, there was no evidence of uveitis or hilar adenopathy in the proband to suggest a diagnosis of adult sarcoidosis, or GI symptoms to suggest inflammatory bowel disease. Our previous case report [13] supports the diagnosis of Blau-like disease in this adult proband; the patient had dermatitis, inflammatory arthritis, and granulomatous pneumonitis as an adult. Interestingly, these two patients shared similar phenotypes and identical genotype R703C, which is located in-between the NBD and LRR regions [3]. R703C was initially linked to Crohn's disease susceptibility [14], yet it is absent in healthy control population and causes “gain of function” like the common BS-associated gene sequence variants [8]. These data together may support the presence of an adult-onset BS-like presentation. While these two proband cases were not typical for BS or NAID, they lacked evidence of adult sarcoidosis and Crohn's disease. This study of two patients and their families may suggest the presence of an intermediate form of disease between BS and NAID, i.e., NAID and BS may share similarities, but they have distinct phenotypic and genotypic features as summarized in the Table. Briefly, camptodactyly and uveitis are absent, and granulomatous changes rarely occur in NAID, where most cases are sporadic with little familial aggregation [7]. NAID is distinct from adult-onset
M. Shen et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]
4
Table Differentiating features among Blau syndrome, NAID, and adult-onset sarcoidosis
Age at onset Fever Serositis Joints Skin Uveitits Hilar adenopathy GI symptoms Sicca-like Kidney and CNS damage Inheritance Gene sequence variants Therapy
Blau syndrome
NAID
Adult-onset sarcoidosis
o 5years Rare No Polyarthritis, granulomatous, and camptodactyly Granulomatous dermatitis, papules and nodules, and subcutaneous plaques Yes No
Adult Periodic, lasting several days Yes Oligo and polyarthritis/arthralgia, more common in lower extremities Spongiotic dermatitis, and erythematous patches/plaques No No
Adult Yes No Polyarthritis/arthralgia, periarticular nodular
No Yes Rare
Yes Yes Rare
No Yes Yes
Dominant NOD2: NBD
Mostly sporadic NOD2: in between LRR and NBD
Mostly sporadic No association with NOD2
NSAIDS, GC, and infliximab
GC and sulfasalazine
GC, immunosuppressive agents, and TNFα antagonists
Noncaseating granulomas, erythematous papules, and plaques or nodules; erythema nodosum Yes (25%) Yes (90%)
NAID: NOD2-associated autoinflammatory disease; GI: gastrointestinal; CNS: central nervous system; NOD2: nucleotide-binding oligomerization domain-containing protein2; LRR: leucine-rich repeat; NBD: nucleotide-binding domain; GC: glucocorticoid; NSAID: non-steroidal anti-inflammatory drugs.
sarcoidosis in that hilar lymphadenopathy accounts for 90%, camptodactyly is generally absent, and no association with NOD2 sequence variants has been found in adult sarcoidosis [15]. Conclusion In conclusion, this study suggests that the granulomatous disease associated with NOD2 mutations may be an intermediate form between BS and NAID. Further study of a larger series of cases is warranted. Acknowledgment We are thankful to the patients for providing the data. References [1] Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G. Nod2, a Nod1/ Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 2001;276:4812–8. [2] McGovern DP, van Heel DA, Ahmad T, Jewell DP. NOD2 (CARD15), the first susceptibility gene for Crohn's disease. Gut 2001;49:752–4. [3] Yao Q. Nucleotide-binding oligomerization domain containing 2: structure, function, and diseases. Semin Arthritis Rheum 2013;43:125–30. [4] Rosé CD, Wouters CH, Meiorin S, Doyle TM, Davey MP, Rosenbaum JT, et al. Pediatric granulomatous arthritis: an international registry. Arthritis Rheum 2006;54:3337–44.
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