Sicca Syndrome and Total Lipodystrophy A Case in a Fifteen-Year-Old Female Patient MOSHE M. IPP, M.B., B.Ch.; NEVILLE J. HOWARD, F.R.C.P.(C); RAYMOND C. TERVO, M.D.; and ERWIN W. GELFAND, M.D.; Toronto, Ontario, Canada

A 15-year-old girl is described with the sicca syndrome of keratoconjunctivitis and xerostomia. There was no associated rheumatoid arthritis or other connective tissue disorder, but total lipodystrophy had been present since the age of 9 years. Marked hyperreactivity of the humoral immune system and suppression of cell-mediated immunity was shown. The association of sicca syndrome with total lipodystrophy has not previously been reported.

prominent and easily palpable and the other peripheral lymph nodes were generally enlarged. The abdomen was protuberant with the edge of the liver palpable 8 cm below the right costal margin and the spleen palpable 7 cm below the left costal margin. The skin about both ankles showed hemosiderotic pigmentation from previous purpuric lesions and a skin biopsy showed a mononuclear perivascular infiltrate. Special Studies IMMUNOLOGIC STUDIES

S J O G R E N ' S SYNDROME consists of the triad of keratocon-

junctivitis sicca, xerostomia, and a connective tissue disorder, usually rheumatoid arthritis ( 1 ) . In the absence of a connective tissue disorder the term "sicca syndrome" has been applied ( 2 ) . The condition is extremely rare in children and there are only a few case reports in the literature (7-9). Lipodystrophy is also an extremely rare condition and is characterised by the partial or total loss of subcutaneous adipose tissue and variable metabolic abnormalities. A number of conditions have been described in association with the sicca syndrome ( 1 , 3-6), but to our knowledge it has not previously been described in association with lipodystrophy. Case Report

A 15-year-old girl was one of seven children and the product of a nonconsanguineous marriage. The other six siblings are alive and well, and the mother is known to have thyrotoxicosis and pernicious anemia. The patient remained well until the age of 9 years, when she was first admitted to hospital and the diagnosis of total lipodystrophy was made. At the age of 12 the patient was readmitted to hospital with a history of polyuria and polydipsia, and diabetes mellitus was diagnosed. She then developed recurrent tender bilateral parotitis, and recurrent nonthrombocytopenic purpura on the lower extremities, and began to require medical attention for frequent sore throats, otitis media, and epistaxis. At the age of 15 the patient was again admitted to hospital. On physical examination she was a gaunt female patient without subcutaneous fat (Figure 1) with prominent musculature and deeply pigmented skin. She had thick dark curly brown hair and superficial veins appeared prominent. Her teeth were carious, the tongue was deeply furrowed, and the saliva appeared tacky. The parotid glands were slightly enlarged and felt firm and diffusely irregular. The cervical lymph nodes were • From the Department of Immunology and the Division of Endocrinology, The Hospital for Sick Children; Toronto, Ontario, Canada.

Immunoglobulins: Immunoglobulins were measured as previously described (10). Salivary immunoglobulin A (IgA) was estimated by Immunoelectrophoresis. Autoantibodies: Antibodies to nuclear antigens, mitochondria, smooth muscle, glomerular basement membrane, and gastric and salivary ducts were assayed by standard immunofluorescent techniques. Thyroglobulin antibodies were tested by tanned erythrocyte passive hemagglutination. Rheumatoid factor in serum and parotid juice were assayed using the Hyland RA Latex Kit (Hyland Laboratories; Costa Mesa, California). Platelet antibodies were looked for by the method of platelet serotonin release (11). Polio and Tetanus Antibodies: Tetanus antibodies were assayed by standard hemagglutination techniques (12). Polio antibodies were measured using a microneutralisation technique showing inhibition of the cytopathogenic effect by polio enterovirus on continuous monkey kidney cell monolayers. Rosette Formation: E (erythrocyte) (13) and EAC (Erythrocyte-antibody-complement) (14) rosettes were done as previously described. Lymphocyte Transformation: Phytohemagglutinin, concanavalin A, and pokeweed mitogen stimulation of blood lymphocytes were measured by 3H-thymidine incorporation in 72-h lymphocyte cultures (15). Delayed Hypersensitivity: This was assessed by intradermal tests with PPD (Merck Sharp & Dohme; West Point, Pennsylvania); Candida albicans, 1/10 (Hollister-Stier; Mississauga, Ontario); Streptokinase-streptodornase, 500 U/ml (SK/SDLederle Laboratories; Pearl River, New York); and dermatophytin, 1/30 (Hollister-Stier Laboratories; Spokane, Washington). Complement Studies: /?iC globulin was measured by radial immunodiffusion. Total hemolytic complement activity was measured as previously described (16). ENDOCRINE STUDIES

Prolonged Glucose Tolerance Test: This test was done in the conventional manner using 1.75 g/kg body weight of glucose (17). Insulin Tolerance Test: This test required the intravenous administration of 0.1 U/kg body weight of regular insulin (17). ACTH Stimulation Test: This test was done by giving 0.25 mg of /?i24 corticotrophin (Cortrosyn®; Organon, Inc.; West Hill, Ontario, Canada) by intramuscular injection (18).

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features of established cirrhosis with moderate fatty infiltration, some ductular proliferation, and a focal chronic mononuclear inflammatory infiltrate. RENAL FUNCTION STUDIES

A routine urinalysis showed 2 g/dl of glucose and 100 mg/dl of protein. A 24-h urine specimen contained 2 g of protein. The blood urea nitrogen and creatinine were normal. Creatinine clearance was 29 ml/min/ 1 • 73m2. No impairment of renal acid excretion was seen after an acid-loading test with ammonium chloride (19). A kidney biopsy showed a focal segmental glomerulopathy with some tubular atrophy and a mild interstitial infiltrate of lymphocytes. Immunofluorescence showed immunoglobulin M (IgM) and /^C glomerular basement membrane deposition in a focal and segmental distribution. BIOCHEMICAL STUDIES

Serum triglycerides measured 880 mg/dl and cholesterol, 137 mg/dl. Endocrine studies showed abnormal glucosetolerance and insulin-tolerance tests, indicative of hyperinsulinism and (insulin-resistant) hyperglycemia. A lownormal adrenal response was shown to ACTH stimulation. Plasma viscosity using a Wells-Brookfield viscometer* (21) was increased. SICCA SYNDROME

Salivary gland scintography using 99m Tc pertechnetate showed normal uptake and concentration of the radioisotope by the parotid glands but complete failure of excretion into the oral cavity at 40 min. Sialography of the left parotid gland showed punctate sialectasis. Parotid saliva was collected with a Kirby cup and showed a reduced salivary flow rate of 2 ml/10 min. Lower lip biopsy (Figure 2) showed diffuse lymphocytic infiltration of the minor salivary glands, atrophy of the acinar tissue, and follicle formation with germinal centre activity. Immunofluorescence showed strong IgM staining along the atrophic ducts. Keratoconjunctivitis sicca was shown by the Schirmer test, which showed less than 2 mm of lacrimal Figure 1. Patient showing total absence of subcutaneous adipose tissue.

* Brookfield Engineering; Stoughton, Massachusetts.

Results HEMATOLOGICAL STUDIES

Hemoglobin measured 11.9 g/dl. The leukocyte count was 2900/mm3 and the platelet count 85 000/mm3. The erythrocyte sedimentation rate was consistently above 100 mm in the first hour (Westergren). Bone-marrow examination showed hypercellularity with prominent plasma cells and absent stainable iron. Serum iron was 45 /xg/100 ml and iron-binding capacity, 440 fig/100 ml. LIVER FUNCTION STUDIES

Serum bilirubin, serum glutamic oxalacetic transaminase, and alkaline phosphatase were essentially normal. Serum albumin measured 2.4 g/dl and gammaglobulin was 5.4 g/dl. A liver-spleen scan showed marked hepatosplenomegaly and a needle biopsy of the liver showed 444

Figure 2. Lower lip biopsy from patient. (Original magnification, X 115.) A germinal follicle is present amidst an extensive lymphoid infiltrate.

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wetting after 5 min (normal, 15 mm) and rose bengal staining of the conjunctiva and cornea showed bilateral islands of damaged epithelium. Slit lamp examination showed typical filamentary keratitis. IMMUNOLOGIC STUDIES

Humoral Immunity: Serum immunoglobulin determinations showed the following: IgG, 4130 mg/dl; IgA, 290 mg/dl; IgM, 320 mg/dl; and IgE, 90 ng/ml. On Immunoelectrophoresis there was an increased precipitin band of IgG. Cellulose acetate protein electrophoresis showed a diffuse and polyclonal hypergammaglobulinemia. The IgA content of parotid saliva was increased. Brisk antibody synthesis was seen in response to a booster injection of polio and tetanus. The EAC rosettes were normal. Autoantibodies were found to a number of nonorgan and organ-specific antigens (Table 1). Cell Mediated Immunity: The patient was completely unresponsive to intradermal skin tests with PPD, monilia, streptokinase/streptodornase, and dermatophytin. Lymphocyte cultures showed a reduced mitogenic response, and no evidence for a serum inhibitor was found. The E-rosette formation was decreased at 24% E-rosetting cells (normal, 4 5 % to 6 0 % ) . Complement: Total hemolytic complement was normal and the f3xC globulin was elevated at 200 mg/dl. Immunologic studies on the mother's serum showed antibodies to thyroid microsomal antigens but not to thyroglobulin or gastric antigens. Antinuclear factor was positive to a titre of 1/80 with a speckled pattern. Discussion

This patient shows the classic features of sicca syndrome and total lipodystrophy, both rare conditions in children. The sicca syndrome in our patient was characterised by keratoconjunctivitis sicca, xerostomia, as well as dryness of the nose and pharynx. In addition, she suffers from recurrent episodes of parotid enlargement, has marked serologic hyperreactivity and has evidence of multisystem involvement. The total lipodystrophy was characterised by the total absence of subcutaneous adipose tissue, hypertriglyceridemia, hyperinsulinism, and insulin-resistant diabetes. It has become quite clear that the sicca syndrome is a multisystem disorder in which dysfunction of the exocrine glands in many areas of the body is the predominant feature (22). In total lipodystrophy, the metabolic disorder tends to affect a number of organs as well, and, in the case presented, the systemic manifestations were clearly related to both underlying conditions, and included hepatic, renal, hematologic, and cutaneous abnormalities. The liver cirrhosis, hypersplenism, and renal findings were likely primarily related to the lipodystrophy whereas the sicca syndrome accounted for the cutaneous manifestations of purpura and a mononuclear perivascular infiltrate. Taken together with the accelerated erythrocyte sedimentation rate, increased concentration of gammaglobulin, increased serum viscosity and leukopenia, these cutaneous findings are classic of benign purpura hyperglobulinemia, as described by Waldenstrom (23).

Table 1. Tests for Antibodies to Nonorgan and Organ-Specific Antigens

Test

Result

Antinuclear factor Latex Coombs' test Antigamma Anti-C3 Antismooth muscle Antiglomerular basement membrane Antisalivary duct Antithyroid Antigastric Antiplatelet Antimitochondrial Lupus erythematosus cells

1/320, speckled pattern 1/60 Positive Negative Positive Positive Positive Negative Negative Negative Negative Negative

The immunologic findings in our patient are similar to those described previously in Sjogren's syndrome (6) and include both cellular and humoral abnormalities. There is hyperreactivity of the humoral immune system resulting in serum hyperglobulinemia, elevated salivary IgA, an extremely brisk antibody response to polio and tetanus booster injections, and numerous autoantibodies. The cellular immune system is suppressed in most patients with Sjogren's syndrome (24) and we showed reduced E rosettes, absent delayed hypersensitivity skin-test reactivity, and impaired in-vitro lymphocyte transformation. The etiology of both sicca syndrome and lipodystrophy is unknown and the relation of these two rare conditions occuring together is intriguing and perhaps not coincidental. Indeed, the classic definition of lipodystrophy described by Lawrence (26) occurred in a young woman who appeared to have features consistent with the diagnosis of sicca syndrome although they were not interpreted as such at that time. She was described as having stony hard enlarged parotid glands, hepatosplenomegaly, and generalised lymphadenopathy; biopsy and postmortem findings of parotid and thyroid tissue showed lymphocytic infiltration with areas of lymphoid follicle formation. These features, thought to be diagnostic of sicca syndrome coexisting in a young female patient with total lipodystrophy, support the contention that these rare conditions occuring together may not be coincidental, and it is likely that the link between these two conditions is in fact multifactorial including genetic, immunologic, and possible viral factors. The finding of similar such cases, and the elucidation of the pathogenesis of lipodystrophy and sicca syndrome in the future would be helpful in understanding how two such rare and enigmatic disorders might occur together in the same individual. ACKNOWLEDGMENTS: Received 2 February 1976; revision accepted 17 May 1976. • Requests for reprints should be addressed to Erwin W. Gelfand, M.D.; Department of Immunology, The Hospital for Sick Children; 555 University Avenue; Toronto, ON, Canada, M5G 1X8. References 1. BLOCH KJ, BUCHANAN WW, WOHL MJ, et al: Sjogren's syn-

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Sicca syndrome and total lipodystrophy: a case in a fifteen-year-old female patient.

Sicca Syndrome and Total Lipodystrophy A Case in a Fifteen-Year-Old Female Patient MOSHE M. IPP, M.B., B.Ch.; NEVILLE J. HOWARD, F.R.C.P.(C); RAYMOND...
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