A previously healthy 8-year-old boy presents with 2 weeks of poor oral intake, persistently red eyes, intermittent nausea, and 1 day of pallor. His parents report that he fatigues more easily with playing but deny fever, night sweats, weight loss, eye pain, pruritis of eyes, eye discharge, eyelid swelling, vision changes, rhinorrhea, cough, sore throat, vomiting, abdominal pain, diarrhea, or joint pain. He has not recently traveled or been ill, and there are no reported sick contacts, insect bites, or animal exposures.
Vital signs are notable for normal temperature, heart rate of 119 beats/min, respiratory rate of 22 breaths/min, and blood pressure of 125/93 mm Hg. He is in no distress and has normal cardiovascular and respiratory examination findings. Abdominal examination reveals a soft abdomen with normal bowel sounds, no tenderness to palpation, and no hepatosplenomegaly. Eye examination is notable for bilateral conjunctival injection with normal-appearing eyelids, no ocular discharge, round pupils that are equally reactive to light, and full extraocular movements. He has normal joint range of motion without tenderness or deformity, and skin examination reveals a 2 × 2-cm light pinkish-brown, nonscaly ovoid plaque on the right buttock; no other skin lesions are noted. Initial laboratory evaluation is notable for an elevated blood urea nitrogen level (28 mg/dL [10 mmol/L]; reference range, 5–18 mg/dL [1.78–6.43 mmol/L]), elevated creatinine level (2.24 mg/dL [198.02 µmol/L]; reference range, 0.52–0.69 mg/dL [45.97–61.00 µmol/L]), elevated total protein (9.2 g/dL [92 g/L]; reference range, 6.0–8.0 g/dL [60–80 g/L]), anemia (hemoglobin level, 10.8 g/dL [108 g/L]; reference range, 11.5–14.9 g/dL [115–149 g/L]), normal mean corpuscular volume (79.4 µm3 [79.4 fL]; reference range, 75–90 µm3 [75–90 fL]), normal white blood cell (WBC) count with eosinophilia (WBC count, 9,900/µL [9.9 × 109/L]; reference range, 4,500–13,500/µL [4.5–13.5 × 109/L]; differential cell count, 57% neutrophils [reference range, 31%–61%], 26.2% lymphocytes [reference range, 28%–48%], 7.3% monocytes [reference range, 0%–10%], 7.9% eosinophils [reference range, 0%–5%], 1% basophils [reference range, 0%–2%]), thrombocytosis (platelet count, 516 × 103/µL [516 × 109/L]; reference range, 150–475 × 103/µL [150–475 × 109/L]), elevated phosphorus level (6.1 mg/dL [1.97 mmol/L]; reference range, 3.7–5.6 mg/dL [1.20–1.81 mmol/L]), and normal calcium level (10.5 mg/dL [2.63 mmol/L]; reference range, 8.0–11.0 mg/dL [2.0–2.75 mmol/L]). Urinalysis is notable for 1+ protein with a normal specific gravity of 1.010 (reference range, 1.002–1.030). Uric acid level, lactate dehydrogenase level, and the remainder of the complete metabolic panel are normal. After consultation with nephrology, he is given 2.5 mg of isradipine, with improvement in blood pressure to 110/74 mm Hg. Additional laboratory studies reveal a urine sodium level of 64 mEq/L (64 mmol/L; reference range, 15–301 mEq/L [15–301 mmol/L]), urine calcium level of 6.5 mg/dL (1.63 mmol/L; reference range, 1.0–38.0 mg/dL [0.25–9.5 mmol/L]), urine protein-to-creatinine ratio of 1.7 (reference range, <0.2; nephrotic range, >2), and fractional excretion of sodium (FENa) of 2.3% (FENa <1% is often associated with prerenal azotemia or glomerulonephritis, FENa >2% is often associated with acute tubular necrosis, and variable levels of FENa are seen with tubulointerstitial nephritis). (1)(2)(3)(4)(5)(6)(7) Renal ultrasonography is interpreted as bilateral isoechoic to slightly hyperechoic renal parenchyma and mild nephromegaly, suggestive of medical renal disease. Ophthalmologic examination shows bilateral anterior uveitis with optic disc hyperemia and edema. He is admitted to the nephrology service for ongoing evaluation, where additional physical examination, laboratory studies, and biopsy ultimately reveal the diagnosis.
The differential diagnosis for a child presenting with evidence of renal disease, anemia, eosinophilia, and uveitis is broad. However, these findings, in conjunction with a normal blood urea nitrogen–to-creatinine ratio, abnormal renal ultrasonography findings, and the absence of hematuria, are suggestive of intrinsic renal disease such as tubulointerstitial nephritis. (2)(3)(8) Infectious etiologies of tubulointerstitial nephritis include bacteria such as streptococcus, leptospirosis, and typical causative agents of pyelonephritis such as Escherichia coli; viruses such as hepatitis B, Epstein-Barr virus, cytomegalovirus, adenovirus, and human immunodeficiency virus; fungi such as Histoplasma capsulatum; and protozoa such as Toxoplasma gondii. (8) Neoplastic considerations include leukemia and lymphoma. (9) Intrinsic renal disorders include glomerulonephritis and tubulointerstitial nephritis and uveitis syndrome. (8) Systemic disorders such as systemic lupus erythematosus, vasculitides, Crohn disease, antitubular basement disease, and sarcoidosis can have similar manifestations. (8)(10) Drug/toxin-mediated causes of renal disease, and specifically interstitial nephritis, are numerous, but specific agents to consider include nonsteroidal anti-inflammatory medications; antibiotics such as penicillins, sulfonamides, gentamicin, and trimethoprim-sulfamethoxazole; anticonvulsants such as phenobarbital, phenytoin, and sodium valproate; and heavy metals. (8)(11)
After admission, an extensive laboratory evaluation ensues. Inflammatory markers are notable for normal C-reactive protein (CRP) and an elevated erythrocyte sedimentation rate (84 mm/hr; reference range, 0–15 mm/hr). Studies for infectious diseases are notable for negative hepatitis B surface antigen, positive hepatitis B surface antibody, negative hepatitis C antibody, nonreactive human immunodeficiency virus antibody screen, negative Toxoplasma gondii antibodies, a negative tuberculin purified protein derivative test result, and indeterminate results of QuantiFERON®-TB Gold Plus (Qiagen, Germantown, MD) testing. The patient is subsequently noted to have bogginess and decreased range of motion of the right elbow and wrist concerning for arthritis; rheumatologic studies are notable for elevated antinuclear antibody IgG titers of 1:160, negative anti-Smith and anti–double-stranded DNA antibodies, normal antineutrophil cytoplasmic antibodies, elevated C3 complement level (181 mg/dL [1.81 g/L]; reference range, 80.0–150.0 mg/dL [0.8–1.50 g/L]), and elevated C4 complement level (59 mg/dL [0.59 g/L]; reference range, 13.0–38.0 mg/dL [0.13–0.38 g/L]). Results of thyroid studies are normal, 25-hydroxyvitamin D level is normal, and 1,25-dihydroxyvitamin D level is elevated at 125 pg/mL (300 pmol/L; reference range, 19.9–79.3 pg/mL [47.8–190.3 pmol/L]). In the setting of a normal serum calcium level and an elevated phosphorus level, the patient’s low parathyroid hormone (PTH) level (<6.3 pg/mL [<6.3 ng/L]; reference range, 10.0–65.0 pg/mL [10.0–65.0 ng/L]) is unexpected; it is likely that this low value is related to the negative feedback of the elevated 1,25-dihydroxyvitamin D level on transcription of the PTH gene. (12)(13) His angiotensin-1-converting enzyme (ACE) and chest radiograph are normal. Renal biopsy reveals granulomatous acute and chronic tubulointerstitial nephritis with numerous eosinophils, severe acute tubular injury, and severe interstitial fibrosis and tubular atrophy (Figs 1 and 2); stains for fungi and acid-fast bacilli are negative. Given the constellation of physical examination, laboratory, and pathology findings, the patient is diagnosed as having sarcoidosis.
Sarcoidosis is a granulomatous inflammatory disorder with the potential to affect every organ system. (10)(14) Pediatric sarcoidosis is rare, with an estimated incidence of 0.22 to 0.8 per 100,000 children based on available literature; peak pediatric incidence is seen in the early teenage years. (14)(15)(16) Although the underlying etiology of sarcoidosis has yet to be determined, development of this disorder is thought to arise from a combination of genetic predisposition and environmental contact with a particular, albeit also unknown, antigen. (9)(10)(14) Sarcoidosis is characterized by the presence of noncaseating, epithelioid granulomas composed of a central follicle containing activated macrophages and CD4+ T lymphocytes surrounded by an external ring of monocytes, fibroblasts, and CD4+ and CD8+ lymphocytes. (10)(14) Granulomatous inflammation is driven by cellular secretion of inflammatory mediators, including tumor necrosis factor α, interferon-γ, and interleukin-2. (10)(16) Although approximately 20% of granulomas are associated with fibrosis and cause organ damage, these lesions can heal spontaneously without scarring or long-term effects. (10)
Many pediatric patients initially demonstrate constitutional symptoms such as fever, weight loss, and fatigue. (10)(14) The most commonly implicated organs include the lungs (often manifesting as dry cough, dyspnea, chest pain, or interstitial infiltrates on radiographs), reticuloendothelial system (often manifesting as isolated bilateral hilar adenopathy, peripheral lymphadenopathy, or hepatosplenomegaly), eyes (often manifesting as uveitis, iritis, or conjunctival granulomas), skin (often manifesting as maculopapular lesions, nodules, plaques, or lupus pernio), and joints (often manifesting as joint effusions or pain). (9)(10)(14) The renal system is not commonly affected by sarcoidosis in children, with a recent literature review documenting only 22 reported cases of sarcoidosis-associated renal disease in pediatric patients. (15) Most of these patients presented with acute kidney injury and had evidence of granulomatous interstitial nephritis on biopsy. (15) Renal effects of sarcoidosis may also be associated with hypercalcemia and/or hypercalciuria, metabolic abnormalities that are mediated by the release of 1,25-dihydroxyvitamin D from activated follicular macrophages. (9)(10) However, renal involvement can have a variety of presentations, including proteinuria, hematuria, nephrolithiasis, hypertension, and renal insufficiency. (9)(10) Involvement of the heart and the parotid gland, as well as the central nervous, gastrointestinal, hematologic, and other organ systems, are also infrequent. (10)(14)
Although previously considered a distinctive presentation of sarcoidosis in very young children, early-onset sarcoidosis, which often manifests in infants with dermatitis, uveitis, and arthritis, is now considered to be a separate entity associated with sporadic mutations in the nucleotide-binding oligomerization domain 2 (NOD2) or caspase recruitment domain family member 15 (CARD15) gene on chromosome 16q12. (9)(10)(14)(16)(17) Blau syndrome is the name given to this condition when it is caused by autosomal dominant mutations in the NOD2/CARD15 gene. (17)
Sarcoidosis can be definitively diagnosed in pediatric patients with a biopsy of involved tissue that reveals a typical noncaseating granuloma, after exclusion of etiologies such as tuberculosis, fungal infections, and toxoplasmosis. (9)(10)(14) Laboratory abnormalities are nonspecific and varied; patients may demonstrate an elevated erythrocyte sedimentation rate, leukopenia, anemia, eosinophilia, hypergammaglobulinemia, hypercalcemia, and an elevated serum ACE level. (9)(10)(14) ACE levels are neither sensitive nor specific for the diagnosis of sarcoidosis but may be used to monitor disease activity when elevated. (9)(10) Whereas 1,25-dihydroxyvitamin D level is frequently elevated in sarcoidosis due to overproduction by follicular macrophages, serum calcium levels are only infrequently elevated. (10)(12)(18) Patients with sarcoidosis have been documented to demonstrate unmeasurably low levels of PTH, which is independent of the serum calcium value; a significantly elevated 1,25-dihydroxyvitamin D level, often seen in sarcoidosis, downregulates production of PTH and likely leads to a decrease in this laboratory value. (12)(13)(19)(20) Chest radiography or high-resolution chest computed tomography may reveal mediastinal lymphadenopathy or pulmonary disease. (9)(14) Bronchoalveolar lavage can demonstrate lymphocytosis with an elevated CD4+:CD8+ ratio. (10)(14)
The initial treatment of sarcoidosis usually consists of either oral or intravenous corticosteroids, with induction dosing (1–2 mg/kg per day of prednisone; maximum, 40 mg/day) continued for 4 to 12 weeks before a taper over months. (9)(10)(14) Patients may be maintained on a low dose of corticosteroids to repress disease activity, taken off corticosteroids if asymptomatic, or transitioned to a corticosteroid-sparing agent such as methotrexate, mycophenolate mofetil, hydroxychloroquine, or tumor necrosis factor α inhibitor. (9)(10)(14) Regular monitoring of organ involvement with laboratory, pulmonary function, and/or imaging testing is crucial to evaluating treatment response. (10) After the diagnosis of sarcoidosis, periodic ophthalmologic examination is also required to evaluate for associated ocular disease. (10)
Because pediatric sarcoidosis remains a rare disorder, its prognosis is not completely elucidated. (9)(10) Pediatric patients with sarcoidosis may experience full recovery, with rates of 45% to 78% reported in the literature, or they may experience a relapsing or progressive disease course. (10)(14) Although mortality from pediatric sarcoidosis may be uncommon, morbidity from this disease, particularly from ocular, pulmonary, and joint involvement, can be substantial and varied depending on organ involvement and response to treatment. (10)
The patient was treated with 5 days of intravenous methylprednisolone and discharged to continue prednisolone 30 mg daily. His creatinine level slowly decreased during hospitalization and was 1.32 mg/dL [116.69 µmol/L] on discharge. His skin lesion was considered consistent with ringworm and resolved with ketoconazole cream. His uveitis was treated with prednisolone acetate and cyclopentolate drops; after discharge his eye redness resolved, but he has yet to follow up with ophthalmology due to insurance concerns. His hypertension was managed with amlodipine. Per rheumatology recommendations, he was started on infliximab infusion every 2 weeks. Genetic testing for NOD2 mutation was negative. Follow-up visits revealed normalizing creatinine levels and ongoing hypertension requiring adjustment of amlodipine dosage; his prednisolone is being tapered, infliximab infusions have been spaced to every 4 weeks, and he was started on methotrexate to prevent the development of anti-infliximab antibodies.
Lessons for the Clinician
Sarcoidosis can present with a myriad of symptoms, ranging from constitutional symptoms to those reflecting specific organ system involvement; typically involved organ systems include the lungs, reticuloendothelial system, eyes, skin, and joints. (9)(10)(14)
Drs Bolt, Bansal, and Hendricks have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.