BLAU SYNDROME: AN UNUSUAL CAUSE OF HYPERCALCEMIA IN A CHILD

Blau Syndrome: An Unusual Cause of Hypercalcemia in a Childe278 AACE CLINICAL CASE REPORTS Vol 4 No. 4 July/August 2018
Copyright © 2018 AACE
BLAU SYNDROME: AN UNUSUAL CAUSE OF HYPERCALCEMIA IN A CHILD
Hana Barbra Lo, MD1; Theresa Wampler Muskardin, MD1,2; Peter J. Tebben, MD1,3
Submitted for publication October 17, 2017 Accepted for publication November 21, 2017 From the Department of Pediatric and Adolescent Medicine, 1Division of Endocrinology, 2Division of Rheumatology, and 3Department of Internal Medicine, Division of Endocrinology, Diabetes, Nutrition, and Metabolism, Mayo College of Medicine, Mayo Clinic, Rochester, Minnesota. Address correspondence to Dr. Peter J. Tebben, Division of Pediatric Endocrinology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. E-mail: [email protected]. DOI:10.4158/ACCR-2017-0041 To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright © 2018 AACE.
ABSTRACT
Objective: To report a case of symptomatic vitamin D-mediated hypercalcemia in a girl with Blau syndrome, a rare granulomatous inflammatory disease occurring in early childhood. Methods: Clinical, laboratory, imaging, and genetic findings are presented along with response to therapy. Results: A 5-year-old girl with a history of surgically treated Graves disease presented with a serum calcium of 13.5 mg/dL (reference range is 9.6 to 10.6 mg/dL), phos- phorus of 5.3 mg/dL (reference range is 3.7 to 5.4 mg/dL), parathyroid hormone of 6 pg/mL (reference range is 15 to 65 pg/mL), and an inappropriate 1,25-dihydroxyvitamin D3 of 64 pg/mL (reference range is 24 to 86 pg/mL). Her hypercalcemia was accompanied by painless, boggy joint effusions and hypertension. Additional testing revealed an elevated angiotensin-converting enzyme concentration and negative fungal and tuberculosis tests. Genetic test- ing revealed a mutation in the NOD2 gene, confirming the diagnosis of Blau syndrome. Hypercalcemia resolved with treatment of Blau syndrome. Conclusion: Endogenous vitamin D-mediated hyper- calcemia is uncommon in children and can be resolved
with treatment of the underlying granulomatous disorder. Blau syndrome should be considered in children with vita- min D-mediated hypercalcemia who present with inflam- matory joint, skin, and/or eye diseases. (AACE Clinical Case Rep. 2018;4:e278-e281)
Abbreviations: 1,25(OH)2D3 = 1,25-dihydroxyvitamin D3; 25(OH)D3 = 25-hydroxyvitamin D3; PTH = parathyroid hormone
INTRODUCTION
The importance of calcium homeostasis in bone metabolism, neuromuscular function, and cellular signal- ing is well established. Under normal conditions, serum calcium concentrations are tightly regulated by parathy- roid hormone (PTH) and vitamin D. Hypercalcemia is an uncommon finding in the pediatric setting and can lead to organ dysfunction such as renal, skeletal, cardiac, and neurologic impairment. Appropriate treatment requires establishing the underlying cause of hypercalcemia (Table 1), which has previously been reviewed (1,2). Endogenous vitamin D-mediated hypercalcemia results from increased production or reduced degrada- tion of the active metabolite, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) resulting in increased calcium absorption from the small intestine as well as mobilization from bone (3-5). Granulomatous disease is an uncommon cause of hypercalcemia and has rarely been described in children. Blau syndrome is a familial granulomatous inflamma- tory condition with an autosomal dominant inheritance pattern resulting from mutations in the NOD2 gene and is phenotypically characterized by granulomatous arthri- tis, dermatitis, and uveitis. We describe a 5-year-old girl with Blau syndrome whose principal manifestation was hypercalcemia.
This is an Open Access article under the CC-BY-NC license.-ND
CASE REPORT
A 5-year-old girl with a history of Graves disease treated surgically and maintained on levothyroxine was referred to our institution for evaluation of hypercalcemia. She had experienced intermittent abdominal pain which did not respond to proton pump inhibitor therapy. She also developed constipation for which she was given poly- ethylene glycol. At the time of presentation, she was not taking calcium or vitamin D supplementation. Her dietary calcium intake was restricted only after she was noted to have hypercalcemia. Her symptoms were accompanied by boggy, painless joint effusions involving the left knee and both wrists. Beta blocker therapy was initiated due to hypertension. Her initial laboratory studies revealed hyper- calcemia, low PTH, undetectable PTH-related peptide, and an elevated ratio of urine calcium to creatinine (Table 2). Her 1,25(OH)2D3 concentration was 64 pg/mL (refer- ence range is 15 to 75 pg/mL) and 25-hydroxyvitamin D3 (25(OH)D3) concentration was 13 ng/mL (reference range is 20 to 50 ng/mL). Her most recent thyroid function tests were normal. Intravenous fluid administration and calcito- nin only transiently normalized her serum calcium. Laboratory findings at the time of referral are outlined in Table 2. Examination identified effusions on the dorsum of bilateral wrists and synovial thickening of the left knee. Skeletal survey and renal ultrasound were unremarkable. Because laboratory studies were most suggestive of a vitamin D-mediated process, tests for tuberculosis, fungal infection, and sarcoidosis were undertaken. The tuberculo- sis test and fungal serologies were negative. Serum angio- tensin-converting enzyme concentration was elevated at 126 U/L (reference range is 8 to 53 U/L). Additional imag- ing with positron emission tomography identified inflam- matory changes in the shoulders and hips involving the joints and surrounding muscle. A clinical diagnosis of Blau syndrome was made, which was later confirmed with the identification of
a mutation in the NOD2/CARD15 gene (c2123G>A). Prednisolone therapy was initiated at a dose of 1 mg/kg/ day and methotrexate at 11 mg/m2/week which resulted in improvement, but not resolution of her joint disease. Within 2 months, her serum calcium normalized and PTH became detectable. Her blood pressure was maintained in the normal range and she was eventually weaned off anti- hypertensive medications within a year of starting treat- ment. Because of persistent disease activity, adalimumab was initiated. Methotrexate was continued and prednisolone was tapered and eventually discontinued after 12 months (Fig. 1). After 16 months of treatment, her joint effusion and synovitis has resolved. Her serum calcium remains normal with normal angiotensin-converting enzyme and 1,25(OH)2D3 concentrations.
DISCUSSION
Hypercalcemia in infants and children may occur as an incidental finding or may cause a constellation of nonspe- cific symptoms including lethargy, hypotonia, anorexia, polyuria, polydipsia, vomiting, abdominal pain, failure to gain weight, constipation, and bone pain (2). Severe or prolonged hypercalcemia can result in fractures, nephroli- thiasis, nephrocalcinosis, and renal insufficiency in addition to low bone density. Appropriate management of patients with hypercalcemia requires establishment of the underly- ing cause and reduction of serum calcium to prevent organ damage. It is important to consider the age of the patient, the principal factors that regulate calcium concentrations (namely PTH and vitamin D metabolites), and their roles in the physiology of calcium homeostasis (1,2). Among older children with hypercalcemia, the principal causes to be considered are primary hyperparathyroidism, immobili- zation, and malignancy (2). However, our patient presented with an elevated serum calcium accompanied by undetect- able PTH and PTH-related peptide and an inappropriate 1,25(OH)2D3 concentration. These laboratory features are
Table 1 Differential Diagnoses of Children With Hypercalcemia
Parathyroid hormone mediated Non-parathyroid hormone mediated • Primary hyperparathyroidism
- Sporadic - Familial - Multiple endocrine neoplasia type I - Multiple endocrine neoplasia type IIa - Hyperparathyroidism-jaw tumor
• Inactivating mutations in calcium-sensing receptor gene - Familial hypocalciuric hypercalcemia - Neonatal severe hyperparathyroidism
• Premature infants on human milk or standard formula
• Excessive exogenous calcium intake • Hypervitaminosis D
- Excessive intake - Granulomatous diseases - CYP24A1 mutation
• Subcutaneous fat necrosis • Williams syndrome • Immobilization • Malignancies (parathyroid hormone-related
peptide, lytic lesions) • Hyperthyroidism • Renal tubular acidosis • Drugs (e.g. thiazide diuretics, lithium)
e280 Blau Syndrome and Hypercalcemia, AACE Clinical Case Rep. 2018;4(No. 4) Copyright © 2018 AACE
most consistent with vitamin D-mediated hypercalcemia and the patient was evaluated accordingly. Among non-PTH-mediated causes of hypercalcemia in older children and adolescents, hypervitaminosis D caused by excessive ingestion of vitamin D leads to eleva- tion of serum 25(OH)D3 but not 1,25(OH)2D3. Our patient was not receiving exogenous vitamin D supplementation and her serum 25(OH)D3 concentration was not elevated.
On the other hand, endogenous vitamin D overproduction can occur in patients with granulomatous diseases such as sarcoidosis, tuberculosis, histoplasmosis, and cat-scratch fever as well as other fungal infections (2). Granulomas are organized inflammatory infiltrates composed of macrophages, epitheloid cells, multinucleated giant cells, lymphocytes, and fibroblasts (6). The unregulated endog- enous production of 1,25(OH)2D3 by activated macro-
Table 2 Laboratory Findings
Reference range*
Calcium (mg/dL) 13.5 11.7 9.9 9.6-10.6 Phosphorus (mg/dL) 5.3 3.9 4.2 3.7-5.4 Parathyroid hormone (pg/mL) 6 <6.0 14 15-65 1,25-dihydroxyvitamin D3 (pg/mL) 64 54 49 24-86 25-hydroxyvitamin D3 (ng/mL) 13 24 36 20-50 Parathyroid hormone-related peptide (pmol/L) <1.6 3.5 N/A <2.0 Calcitonin (pg/mL) <5.0 N/A N/A <8.0 Urine calcium to creatinine ratio (mg/g) 850 N/A 153 <200 Angiotensin-converting enzyme (U/L)** N/A 126 41 8-53 Erythrocyte sedimentation rate (mm/hour) N/A 17 2 C-reactive protein (mg/L) N/A <3.0 <3.0 ≤8.0 Abbreviation: N/A = not assessed. *Mayo Medical Labs reference ranges. **The reference range for pediatric patients may be up to 50% higher than that of adults.
Fig. 1. Changes in serum calcium, 1,25(OH)2D3, and PTH concentrations during treatment of Blau syndrome. 1,25(OH)2D3 = 1,25-dihydroxyvitamin D3; Ca = calcium; MTX = methotrexate; PTH = parathyroid hormone.
Blau Syndrome and Hypercalcemia, AACE Clinical Case Rep. 2018;4(No. 4) e281 Copyright © 2018 AACE
phages within granulomas is responsible for the hypercal- cemia (1,7). Excess vitamin D acts in the small intestine to increase calcium absorption and in the bone to mobilize calcium, subsequently leading to hypercalcemia and hyper- calciuria, as was seen in our patient (3-5). Having eliminat- ed tuberculosis and fungal infections as possible etiologies in our patient and given her other presenting features (such as arthritis and elevated angiotensin-converting enzyme concentration) a clinical diagnosis of pediatric granulo- matous arthritis was made, which was later confirmed by genetic studies. Blau syndrome was first described in 1985 as an autosomal dominant familial granulomatous inflamma- tory disease. The disease is caused by a mutation in the NOD2/CARD15 gene in 50 to 90% of cases (6,8-10) with similar phenotypic features to patients with sarcoidosis, its sporadic counterpart. An international registry established in 2005 was able to identify 61 affected individuals from 22 pedigrees (9). This series has defined a wide phenotypic spectrum among patients with Blau syndrome as well as the mutation frequency and variants among patients (9). The classical clinical features of Blau syndrome consist of granulomatous arthritis, dermatitis, and uveitis. The particular arthritis seen in Blau syndrome is described as polyarticular “boggy” synovitis and tenosyno- vitis, which typically affects peripheral joints and particu- larly the wrists, knees, ankles, and proximal interphalange- al joints of the hands (6). The most frequent appearance of dermatitis is that of an erythematous maculo-micropapular fine scaly rash on the trunk and extremities. In fact, skin rash is often the first symptom to appear in Blau syndrome and it is the most common manifestation (6,9). Uveitis develops in 60 to 80% of patients. It is usually bilateral and presents insidiously as granulomatous iridocyclitis with posterior uveitis, potentially evolving to a severe panuve- itis with multifocal choroiditis, leading to increased risk of visual morbidity (6). Our patient, on evaluation, did not manifest with any sign of uveitis. However, periodic ophthalmologic monitoring is necessary. More recently, an expanded phenotype of Blau syndrome has been found in several studies due to increas- ing availability of genetic testing. Some patients do not present with the usual clinical triad but rather several non-triad systemic, vascular, and visceral organ presenta- tions have been reported such as fever, lymphadenopathy, hepatosplenomegaly, hypertension, and renal impairment (9,11,12). Our patient presented with profound and symp- tomatic hypercalcemia. Although hypercalcemia or hyper- calciuria may be found in up to 30% of sarcoidosis cases in older children (8), to our knowledge there are few reports of hypercalcemia or nephrocalcinosis (a possible indicator of hypercalcemia) in patients with early-onset sarcoidosis or Blau syndrome (11-14). Treatment of Blau syndrome has proven to be quite challenging and the majority of patients are managed with a combination of immunosuppressive and biologic thera-
pies as well as systemic corticosteroids. However, despite combination therapy, some patients continue to have active disease (12). The addition of adalimumab, a tumor necrosis factor alpha inhibitor, has controlled our patient’s disease and her serum calcium concentration remains in the normal range.
CONCLUSION Hypercalcemia, if left untreated, can lead to serious symptoms and organ damage. Vitamin D-mediated hyper- calcemia is an uncommon finding in children and can resolve with treatment of the underlying granulomatous disorder. We have presented a case of Blau syndrome, a rare autoinflammatory granulomatous disease, who presented with symptomatic hypercalcemia. Blau syndrome should be considered in children with vitamin D-mediated hyper- calcemia who present with inflammatory joint, skin, or eye disease.
DISCLOSURE
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