Primary Sjögren's syndrome in children: is a family approach indicated?

Longhi, Barbara S; Appenzeller, Simone; Centeville, Maraisa; Gusmão, Reinaldo J; Marini, Roberto

doi:10.1590/S1807-59322011001100023

CASE REPORT

Primary Sjögren's syndrome in children: is a family approach indicated?

Barbara S. Longhi^I; Simone Appenzeller^II; Maraisa Centeville^I,III; Reinaldo J. Gusmão^IV; Roberto Marini^I

^IUniversidade Estadual de Campinas (UNICAMP), Faculty of Medical Science State, Department of Pediatrics, Campinas/SP, Brazil

^IIUniversidade Estadual de Campinas (UNICAMP), Department of Medicine, Division of Rheumatology, Campinas/SP, Brazil

^IIIUniversidade Estadual de Campinas (UNICAMP), Faculty of Medical Science, Post-Graduate Program in Child and Adolescent Health, Campinas/SP, Brazil

^IVUniversidade Estadual de Campinas (UNICAMP), Pediatric Otorhinoloaryngology Unit, Campinas/SP, Brazil

INTRODUCTION

Sjögrens syndrome (SS) is a chronic autoimmune disease primarily affecting the lachrymal and salivary glands with varying degrees of systemic involvement. SS can be isolated (p rimary SS or pSS) or associated with other autoimmune diseases, such as rheu matoid arthritis, systemic lupus erythem atosus, or scleroderma (secondary SS). pSS pre dominantly affects middle-aged women and is uncommon in child hood.^1-4 In addition to being underdiagnosed, clinical manifestations are often different in children when compare d to adults. Recurrent parotid swelling is a common feature observed in children with pSS (37, 5- 100%).² Oral and ocular involvement, however, is present in a minority of children, especially at the onset of disease (23- 80%).² Pathologic and laboratory findings are similar to those found in adults and include characteristic lymphocy tic infilt ration of the exocrine glands, the presence of hypergammaglobulinemia, an elevated erythrocyte sedi mentation rate (ESR), and the presence of autoantibodies (such as anti-Ro/SSA, anti-La/SSB, antinuclear antibody (ANA), and rheumatoid factor (RF)^4-6). Although pSS is an autoimmune disease, familial incidence of pSS is infrequently reported.^6-8

We report the occurrence of pSS in two siblings and in their mother and review the literature on multiplex pSS families.

CASE REPORTS

Patient 1 - A 9-year-old girl with a one-year history of bilateral recurrent enlargement of the parotid gland was sent to the rheumatology unit. She denied having dry mouth, dry eyes, or any systemic symptoms. Upon examination, she was healthy with a weight in the 75^th percentile and a height in the 90^th percentile. Her physical examination was unremarkable, except for the presence of a bilateral, painful parotid enlargement. The physician also identified sialadenitis upon sialography and a positive Schirmers test upon ophthalmological evaluation. The patient was negative for RF and antinuclear antibodies (ANA), but positive for anti-Ro. Antibodies against La, double-stranded DNA (anti-dsDNA), and Sm were also negative. Her white blood cell counts (WBCs) and ESR were normal, and no hypergammaglobulinemia was observed. A minor salivary gland biopsy showed diffuse lymphocytic infiltration.

Patient 2 - During medical evaluation, the mother of the patient mentioned that her other 8-year-old daughter also had a two-year history of recurrent parotid gland swelling. The patient denied having dry mouth, dry eyes, or any systemic symptoms. Her physical exam was unremarkable. The patient had a normal Schirmer's test and did not have any evidence of chronic sialadenitis upon sialography. Her laboratory test results revealed that she was positive for RF, ANA, Ro, and La antibodies as well as negative for antidsDNA and anti-Sm. The patient displayed normal WBC and ESR, but exhibited polyclonal hypergammaglobulinemia. A salivary gland biopsy revealed lymphocytic sialadenitis with more than four lymphoid foci (4 mm² in size), which was compatible with SS.

Patient 3 - The mother was 28 years in age and complained of persistent dry mouth, photophobia, and dry eyes after two years of her daughters' follow-up. Her physical exam was unremarkable. She was negative for RF, positive for ANA, and anti-Ro, had a normal WBC and ESR, and presented no hypergammaglobulinemia. Ophthalmological examination revealed positive results both on Schirmer's test and the Rose Bengal test. Her salivary gland scintigraphy revealed deficient drainage of her left parotid gland, and her salivary gland biopsy showed no evidence of diffuse lymphocytic infiltration.

DISCUSSION

pSS is a well-known autoimmune disease that predominantly affects middle-aged women. pSS is diagnosed following the Revised International Classification Criteria for Sjögren's Syndrome from the American-European Group and includes six items: (I) presence of ocular symptoms, (II) presence of oral symptoms, (III) evidence of keratoconjunctivitis sicca, (IV) focal sialadenitis upon minor salivary gland biopsy, (V) instrumental evidence of salivary gland involvement, and (VI) presence of SSA or SSB autoantibodies. Diagnosis of pSS requires 4 of the six criteria.^5,9 As there are no specific diagnostic criteria for pSS in children, and the adult criteria are often used. The diagnosis of childhood SS may be difficult because the classical diagnostic criteria that are successfully used for adults are often not fulfilled by children at disease onset.

The onset of disease may not only be different in children, but also characterized by nonspecific symptoms. Frequently, salivary gland enlargement or recurrent par otitis is observed; sicca symptoms are rarely referred.² Laboratory signs are present early during the course of disease and include hypergammaglobulinemia, positive tests for anti-SS-A and/or anti-SSB, a high titer of speckled antinuclear antibodies, and/or the presence of rheumatoid factor.¹⁰

pSS is rare in children and adolescents.^4,6,11 During a three-ye ar study, Cimaz et al.² collected data on 40 patients from ten different centers worldwide. The most common manifest ation reported in their study was recurrent parotid swelling (72.5%) at the onset of disease, whereas ocular and/or oral symptoms were only found in a minority of children. Other clinical signs and symptoms observed at disease onset were arthritis (10%), fever (10%), fatigue (7.5%), and submandibular swelling (5%). Similar results were observed in other reports.^6,12

The differential diagnosis of recurrent parotitis is broad in children and includes mechanical, infectious, malignant, and inflammatory etiologies. ⁶ It is important to note that in both the children in this case study, recurrent parotitis was the initial clinical manifestation of pSS. Therefore, recurrent parotitis should alert the clinician to the possibility of pSS.^6,12

Familial cases of pSS are rare (Table 1).^6,8,19-27 Lichtenfeld et al. described one patient with SS in whom a primary parotid gland lymphoma subsequently developed. ⁸ Moreover, two of four siblings had evidence of SS, and the authors suggested that genetic influences may facilitate the development of SS. Houghton et al. reported pSS in dizygotic adolescent twins; recurren t parotitis was the initial clinical manifestation in both parents.⁶ The authors proposed that pSS is likely a polygeni c disorder resulting from several genes interacting with environmental factors. Some studies of pSS showed that it has a strong association with HLA-DR3.^6,13,14 However, recent studies have suggested that pSS is a complex, polygenic disorder sharing common genetic determinants with related autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).¹⁴ Recent advance s in SLE and RA provide valuable insights into the potential genetic complexity of SS.¹⁴ Several families with mu ltiplex SS have also been described,^6,15,16 and relatives often have other autoimmune diseases, such as SS (12%), autoimmune thyroid disease (AITD) (14%), RA (14%), and SLE (5%-10%).^17,18

Thumbnail

In conclusion, although pSS is a complex genetic disorder, familial cases of SS are rarely reported. In children, pSS may be underdiagnosed because of the lack of classic sicca symptoms. However, pSS should be included in the differential diagnosis of recurrent parotid swelling, and whe n diagnosed, siblings should be evaluated.

ACKNOWLEDGEMENTS

Fundação Amparo á Pesquisa Estado São Paulo-Brasil (FAPESP 2008/02917-0, Conselho Nacional Pesquisa Desenvolvimento-Brasil CNPq (300447/2009-4).

AUTHOR CONTRIBUTIONS

Longhi BS, Marini R, Appenzeller S, Centeville M, and Gusmão RJ were respo nsible for the revision of the charts and manuscript preparation.

No potential conflict of interest was reported.

Email: appenzellersimone@yahoo.com

Tel.: 55 19 3289-1818

1. Civilibal M, Canpolat N, Yurt A, Kurugoglu S, Erdamar S, Bagci O, et al. A Child With Primary Sjögren Syndrome and a Review of the Literature. Clinical Pediatrics. 2007;46:738-42, doi: 10.1177/0009922807301945.
2. Cimaz R, Casadei A, Rose C, Bartunkova J, Sediva A, Falcini F, et al. Primary Sjögren syndrome in paediatric age: a multicentre survey. Eur J Pediatr. 2003;162:661-5, doi: 10.1007/s00431-003-1277-9.
3. Stiller M, Golder W, Döring E, Biedermann T. Primary and secondary Sjögren' syndrome in children-a comparative study. Clin Oral Invest. 2000;4:176-82, doi: 10.1007/s007840000070.
4. Nikitakis NG, Rivera H, Lariccia C, Papadimitriou JC, Sauk JJ. Primary Sjögren syndrome in childhood: report of a case and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;96:42-7, doi: 10.1016/S1079-2104(03)00159-8.
5. Fox R. Sjögren' syndrome. Lancet. 2005;366:321-31, doi: 10.1016/S0140-6736(05)66990-5.
6. Houghton KM, Cabral DA, Petty RE, Tucker LB. Primary Sjögren syndrome in dizygotic adolescent twins: one case with lymphocytic interstitial pneumonia. J Rheumatol. 2005;32:1603-6.
7. Doni A, Brancato R, Bartolettl L, Berni G. La famlliarita della malattia di Sjbgren. Riv Crit Clln Med. 65:750:1965.
8. Lichtenfeld JL, Kirschner RH, Wiernik PH. Familial Sjogren' syndrome with associated primary salivary gland lymphoma. Am J Med. 1976;60:286-92, doi: 10.1016/0002-9343(76)90439-3.
9. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al. European Study Group on Classification Criteria for Sjögren' Syndrome. Classification criteria for Sjögren' syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;61:554-8, doi: 10.1136/ard.61.6.554.
10. Bartunková J, Sedivá A, Vencovsky J, Tesar V. Primary Sjögren syndrome in Children and adolescents: Proposal for diagnostic criteria. Clin Exp Rheumatol. 1999;17:381-86.
11. Anaya J, Ogawa N, Talal N. Sjögren' syndrome in childhood. J Rheumatol. 1995;22:1152-8.
12. Houghton K, Mah W-L, Maleeson P, Cabral D, Petty R, Tucker L. Primary Sjögren syndrome in Children and adolescents: are current diagnostic criteria applicable? [abstract}. Canadian Rheumatology Association Meeting. Lake Louise, Alberta, Canada, February 25-28. J Rheumatol. 2004;31:1436.
13. Foster H, Stephenson A, Walker D, Cavanagh G, Kelly C, Griffiths I. Linkage studies of HLA and Primary Sjögren syndrome in multicase families. Arthritis Rheum. 1993;36:473-84, doi: 10.1002/art.1780360407.
14. Cobb BL, Lessard CJ, Harley JB,Moser KL. Genes and Sjögren' Syndrome. Rheum Dis Clin N Am. 2008;34:847-868, doi: 10.1016/j.rdc.2008.08.003.
15. Boling EP, Wen J, Reveille JD, Bias WB, Chused TM, Arnett FC. Primary Sjogren' syndrome and autoimmune hemolytic anemia in sisters. A family study. Am J Med. 1983;74:1066-71.
16. Sestak AL, Shaver TS, Moser KL, Neas BR, Harley J B. Familial aggregation of lupus and autoimmunity in an unusual multiplex pedigree. J Rheumatol. 1999;26:1495-9.
17. Reveille JD. The molecular genetics of systemic lupus erythematosus and Sjogren' syndrome. Curr Opin Rheumatol. 1992;4:644-56.
18. Reveille JD, Wilson RW, Provost TT, Bias WB, Arnett FC. Primary Sjogren' syndrome and other autoimmune diseases in families. Prevalence and immunogenetic studies in six kindreds. Ann Intern Med. 1984;101:748-56.
19. Sabio JM, Milla E, Jimenez-Alonso J. A multicase family with primary Sjogren' syndrome. J Rheumatol. 2001;28:1932-4.
20. Coverdale H. Some unusual cases of Sjogren' syndrome. Br J Ophthalmol. 1948;32:669-73, doi: 10.1136/bjo.32.9.669.
21. Bloch KJ, Buchanan WW, Wohl MI, Bunim JJ. Sjogren' syndrome: a clinical pathological and serological study of sixty-two cases. Medicine (Battlmore). 1965;44:187-231, doi: 10.1097/00005792-196505000-00001.
22. Camus JP, Emerit I, Reinhart P, Guillien P, Crouzet J, Fourot J. Sclerodermie familiale avec syndrome de Sjbgren et anomalies lymphocytaires et chromosomiques. Ann Med lnterne (Paris). 1970;121:149.
23. Koivukagas T, Simila S, Heikkinen E, Wasz-Hochert 0. Sjogren' syndrome and achalasia of the cardia in two siblings. Pediatrics. 1973;51:943.
24. Simila S, Kokkonen J, Kaski M. Achalasia sicca - juvenile Sjogren' syndrome with achalasia and gastric hyposecretion. Eur J Pediatr. 1978;129:175-81, doi: 10.1007/BF00442161.
25. Besana C, Salmaggi C, Pellegrino C, Pierro L, Vergani S, Faravelli A, et al. Chronic bilateral dacryo-adenitis in identical twins: a possible incomplete form of Sjogren syndrome. Eur J Pediatr. 1991;150:652-5, doi: 10.1007/BF02072627.
26. Ostuni PA, Ianniello A, Sfriso P, Mazzola G, Andretta M, Gambari PF. Juvenile onset of primary Sjogren' syndrome: report of 10 cases. Clin Exp Rheumatol. 1996;14:689-93.
27. Bolstad AI, Haga HJ, Wassmuth R, Jonsson R. Monozygotic twins with primary Sjogren' syndrome. J Rheumatol. 2000;27:2264-6.

Publication Dates

Publication in this collection
11 Nov 2011
Date of issue
2011

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Civilibal M, Canpolat N, Yurt A, Kurugoglu S, Erdamar S, Bagci O, et al. A Child With Primary Sjögren Syndrome and a Review of the Literature. Clinical Pediatrics. 2007;46:738-42, doi: 10.1177/0009922807301945.

[2] 2. Cimaz R, Casadei A, Rose C, Bartunkova J, Sediva A, Falcini F, et al. Primary Sjögren syndrome in paediatric age: a multicentre survey. Eur J Pediatr. 2003;162:661-5, doi: 10.1007/s00431-003-1277-9.

[3] 3. Stiller M, Golder W, Döring E, Biedermann T. Primary and secondary Sjögren' syndrome in children-a comparative study. Clin Oral Invest. 2000;4:176-82, doi: 10.1007/s007840000070.

[4] 4. Nikitakis NG, Rivera H, Lariccia C, Papadimitriou JC, Sauk JJ. Primary Sjögren syndrome in childhood: report of a case and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;96:42-7, doi: 10.1016/S1079-2104(03)00159-8.

[5] 5. Fox R. Sjögren' syndrome. Lancet. 2005;366:321-31, doi: 10.1016/S0140-6736(05)66990-5.

[6] 6. Houghton KM, Cabral DA, Petty RE, Tucker LB. Primary Sjögren syndrome in dizygotic adolescent twins: one case with lymphocytic interstitial pneumonia. J Rheumatol. 2005;32:1603-6.

[7] 7. Doni A, Brancato R, Bartolettl L, Berni G. La famlliarita della malattia di Sjbgren. Riv Crit Clln Med. 65:750:1965.

[8] 8. Lichtenfeld JL, Kirschner RH, Wiernik PH. Familial Sjogren' syndrome with associated primary salivary gland lymphoma. Am J Med. 1976;60:286-92, doi: 10.1016/0002-9343(76)90439-3.

[9] 9. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al. European Study Group on Classification Criteria for Sjögren' Syndrome. Classification criteria for Sjögren' syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;61:554-8, doi: 10.1136/ard.61.6.554.

[10] 10. Bartunková J, Sedivá A, Vencovsky J, Tesar V. Primary Sjögren syndrome in Children and adolescents: Proposal for diagnostic criteria. Clin Exp Rheumatol. 1999;17:381-86.

[11] 11. Anaya J, Ogawa N, Talal N. Sjögren' syndrome in childhood. J Rheumatol. 1995;22:1152-8.

[12] 12. Houghton K, Mah W-L, Maleeson P, Cabral D, Petty R, Tucker L. Primary Sjögren syndrome in Children and adolescents: are current diagnostic criteria applicable? [abstract}. Canadian Rheumatology Association Meeting. Lake Louise, Alberta, Canada, February 25-28. J Rheumatol. 2004;31:1436.

[13] 13. Foster H, Stephenson A, Walker D, Cavanagh G, Kelly C, Griffiths I. Linkage studies of HLA and Primary Sjögren syndrome in multicase families. Arthritis Rheum. 1993;36:473-84, doi: 10.1002/art.1780360407.

[14] 14. Cobb BL, Lessard CJ, Harley JB,Moser KL. Genes and Sjögren' Syndrome. Rheum Dis Clin N Am. 2008;34:847-868, doi: 10.1016/j.rdc.2008.08.003.

[15] 15. Boling EP, Wen J, Reveille JD, Bias WB, Chused TM, Arnett FC. Primary Sjogren' syndrome and autoimmune hemolytic anemia in sisters. A family study. Am J Med. 1983;74:1066-71.

[16] 16. Sestak AL, Shaver TS, Moser KL, Neas BR, Harley J B. Familial aggregation of lupus and autoimmunity in an unusual multiplex pedigree. J Rheumatol. 1999;26:1495-9.

[17] 17. Reveille JD. The molecular genetics of systemic lupus erythematosus and Sjogren' syndrome. Curr Opin Rheumatol. 1992;4:644-56.

[18] 18. Reveille JD, Wilson RW, Provost TT, Bias WB, Arnett FC. Primary Sjogren' syndrome and other autoimmune diseases in families. Prevalence and immunogenetic studies in six kindreds. Ann Intern Med. 1984;101:748-56.

[19] 19. Sabio JM, Milla E, Jimenez-Alonso J. A multicase family with primary Sjogren' syndrome. J Rheumatol. 2001;28:1932-4.

[20] 20. Coverdale H. Some unusual cases of Sjogren' syndrome. Br J Ophthalmol. 1948;32:669-73, doi: 10.1136/bjo.32.9.669.

[21] 21. Bloch KJ, Buchanan WW, Wohl MI, Bunim JJ. Sjogren' syndrome: a clinical pathological and serological study of sixty-two cases. Medicine (Battlmore). 1965;44:187-231, doi: 10.1097/00005792-196505000-00001.

[22] 22. Camus JP, Emerit I, Reinhart P, Guillien P, Crouzet J, Fourot J. Sclerodermie familiale avec syndrome de Sjbgren et anomalies lymphocytaires et chromosomiques. Ann Med lnterne (Paris). 1970;121:149.

[23] 23. Koivukagas T, Simila S, Heikkinen E, Wasz-Hochert 0. Sjogren' syndrome and achalasia of the cardia in two siblings. Pediatrics. 1973;51:943.

[24] 24. Simila S, Kokkonen J, Kaski M. Achalasia sicca - juvenile Sjogren' syndrome with achalasia and gastric hyposecretion. Eur J Pediatr. 1978;129:175-81, doi: 10.1007/BF00442161.

[25] 25. Besana C, Salmaggi C, Pellegrino C, Pierro L, Vergani S, Faravelli A, et al. Chronic bilateral dacryo-adenitis in identical twins: a possible incomplete form of Sjogren syndrome. Eur J Pediatr. 1991;150:652-5, doi: 10.1007/BF02072627.

[26] 26. Ostuni PA, Ianniello A, Sfriso P, Mazzola G, Andretta M, Gambari PF. Juvenile onset of primary Sjogren' syndrome: report of 10 cases. Clin Exp Rheumatol. 1996;14:689-93.

[27] 27. Bolstad AI, Haga HJ, Wassmuth R, Jonsson R. Monozygotic twins with primary Sjogren' syndrome. J Rheumatol. 2000;27:2264-6.