A 13 year old boy Sick for 3 Months

A 13-year-old boy presents to the emergency department (ED) with a history of epigastric pain, vomiting, malaise, polyuria, and a 12-pound weight loss during the past 3 months. The parents report no history of hematuria, hematemesis, fever, chills, or any other associated symptoms, prior surgeries, or medical problems. The patient has previously been seen by his pediatrician and is undergoing a workup. An upper gastroendoscopy performed at a nearby hospital 2 weeks ago had revealed chronic gastritis with erosive changes in the antral region. Triple treatment for Helicobacter pylori, however, did not lead to any improvement. Abdominal ultrasonography also performed at that time showed mild nephrocalcinosis. The parents have brought the patient to the ED today because his pain and vomiting are worsening.

On physical examination, the child is thin and mildly ill-appearing. His temperature is 98.6°F (37.0°C), his pulse has a regular rhythm, with a rate of 80 bpm, and his blood pressure is 120/70 mm Hg. The patient's respirations are regular and unlabored at 14 breaths/min. The child is in mild distress secondary to his epigastric discomfort. The examination of the head and neck is normal except that the oropharynx appears slightly dry. He has no dysmorphic facial features. His lungs are clear to auscultation, and normal respiratory effort is noted. The S1 and S2 heart sounds are normal, and no murmurs are detected. The abdomen is soft but tender to deep palpation in the epigastric region. The patient's extremities show no edema and there is brisk capillary refill. His skin is clear except for in the gluteal region, where a nodular eczematous lesion is present.

The patient is hospitalized. During the hospital course, additional laboratory tests are performed. The thyroid hormone levels are in the normal range, but the parathyroid hormone level is low at 10.91 pg/mL (10.91 ng/L; normal range, 15-65 pg/mL). Vitamin D metabolites are not measured. The serum angiotensin-converting enzyme (ACE) level is normal at 32.7 Units/L (547.7 nkat/L; normal range, 12-42 Units/L). The results of a purified protein derivative test are negative.

A urinalysis performed on several occasions shows a specific gravity of 1.003 and a pH of 5, with normal urinary sediment. Urinary cultures are negative. On several occasions, there is marked hypercalciuria, with a level of 14 mg/kg and a urinary calcium:creatinine ratio (mmol/mmol) ranging from 2.5 to 3.5. There is no glycosuria or aminoaciduria.

Ultrasonography is performed. The parathyroid glands appear normal. Renal ultrasonography confirms mild nephrocalcinosis around the renal calices. A renal biopsy is performed. The specimen exhibits tubulointerstitial nephritis associated with tubular calcium deposits (see Figure 3). There is also interstitial infiltration by mononuclear cells, interstitial fibrosis, tubular necrosis, and atrophy. Dystrophic calcifications are present in some of the tubules. Negative results are obtained for IgA, IgG, IgM, and C3 on immunofluorescent analysis. Immunohistochemical analysis reveals inflammatory cellular substrate CD 68, macrophages, and lymphoid population. No glomerular abnormalities are evident.

The clinical picture of this patient was dominated by nonspecific constitutional symptoms, such as fatigue, malaise, vomiting, abdominal cramps, and weight loss. He had no history of maculopapular rashes, erythema nodosum, arthritis, chronic lymphocytopenia, hepatomegaly, splenomegaly, lymphadenopathy, or uveitis. He also did not have any coughing or exertional dyspnea. The child did have vomiting and polyuria, which were caused by his hypercalcemia. The renal biopsy specimen exhibited acute tubulointerstitial nephritis associated with tubular calcium deposits without glomerular abnormalities. In addition, the chest radiograph demonstrated combined hilar lymphadenopathy and reticulonodular interstitial infiltrates in the upper lung zone (see Figure 2). The chest radiograph findings, when considered along with the hypercalcemia, rash, and renal biopsy results, were consistent with stage 2 radiographic sarcoidosis.

SARCOIDOSIS:

Hypercalcemia associated with hypercalciuria and nephrocalcinosis are rare in childhood and may have many causes.  The most common cause is iatrogenic. This is followed by idiopathic infantile hypercalcemia (IIH) in its mild or severe form (Williams syndrome). Intoxication with vitamin D is a rare cause of clinically manifested hypercalcemia, but it is associated with significant morbidity. 

Measurement of an intact parathyroid hormone (PTH) level at the time of hypercalcemia is pivotal in narrowing the differential diagnosis. If the PTH level is high, the child must be thoroughly investigated for the cause of hyperparathyroidism and may require urgent surgical intervention. If the PTH level is low (as it was in this patient), additional calciotropic hormones may be assayed if appropriate testing is available. Identifying the abnormal calciotropic hormone might allow for the diagnosis of the specific cause, elucidation of the mechanism for the hypercalcemia, and optimal treatment.

Sarcoidosis is a multisystem disorder characterized by an increased cellular immune response to an unknown antigen and the formation of noncaseating granulomas in affected tissues. Although the lungs and lymph nodes are the predominant sites affected by sarcoidosis (75-90%), other organs, such as the eyes, bone marrow, kidneys, liver, and spleen, may also be involved. Cases of extrapulmonary sarcoidosis affecting the kidneys are rare; most such cases present with nephrocalcinosis or nephrolithiasis (3.6%). Renal failure is an extremely uncommon manifestation.

Hypercalcemia in sarcoidosis is uncommon, only occurring in approximately 10% of cases. It is usually caused by the autonomous production of 1,25-dihydroxyvitamin D (calcitriol) by macrophages within the granuloma. These macrophages can convert 25-hydroxyvitamin D, produced by the liver, into calcitriol by possessing the 1alpha-hydroxylase enzyme. Calcitriol then travels to the intestinal cells and promotes luminal absorption of calcium and phosphate into the circulation. Hypercalcemia is accompanied by hypercalciuria and, eventually, nephrocalcinosis (as seen in this case). Hypercalcemia may also eventually cause renal failure both by causing dehydration and by inducing renal vasoconstriction, thereby reducing the glomerular filtration rate. Systemic corticosteroids can be used to treat hypercalcemia associated with sarcoidosis because they inhibit the production of calcitriol within the macrophages.

The true incidence and prevalence in children are unknown because of the rarity of the disease and the small number of reported cases in childhood. Most reported childhood cases have occurred in patients aged 13-15 years, but the disease has also been reported in very young children. Two distinct forms of childhood sarcoidosis appear to exist. Older children usually present with a multisystem disease similar to the adult manifestation, with frequent lymphadenopathy and pulmonary involvement. They also show generalized signs and symptoms, such as fever and malaise. In contrast, early-onset childhood sarcoidosis is a unique form of the disease characterized by the triad of rash, uveitis, and arthritis, usually in patients who are younger than 4 years of age.

Pulmonary disease and abnormal findings on chest radiography are more common in children with sarcoidosis who are aged 8- 15 years; these findings occur in 94-100% of patients in that age group compared with 22% in those who are younger than 4 years of age. Bilateral hilar adenopathy is the most common finding on chest radiography in children, and it occurs in almost all cases. It is typically symmetrical, although it may appear unilateral in rare instances. Pulmonary parenchymal involvement is common and predominantly appears radiographically as an interstitial pattern; however, nodular, alveolar, and fibrotic patterns have also been described. Other uncommon manifestations include pleural effusion, pneumothorax, pleural thickening, calcification, atelectasis, and cor pulmonale. Nearly half of all children with sarcoidosis demonstrate restrictive lung disease on static and dynamic pulmonary function tests, including a reduction in total lung capacity, forced vital capacity, functional residual capacity, and transfer factor. These changes are believed to be secondary to early alveolitis progressing to fibrosis. An obstructive ventilatory pattern has been reported in approximately 15% of children with sarcoidosis. Airway obstruction may be secondary to airway hyperactivity, intrabronchial sarcoid granuloma, hilar or mediastinal lymph node compression of the airways, or bronchiectasis.

The serum ACE level is increased in 30-80% of patients with sarcoidosis and may be a surrogate marker of the total granuloma burden. False-positive findings are noted in fewer than 20% of patients with other pulmonary disorders; however, the serum

About 40-70% of children with sarcoidosis have palpable peripheral lymph glands. The lymph nodes typically are firm, nontender, discrete, and freely movable. They do not ulcerate and do not form draining sinuses. The most frequently involved glands are the cervical, axillary, epitrochlear, and inguinal glands. In the neck, the posterior triangle nodes are affected more commonly than the nodes in the anterior triangle. The enlarged peripheral lymph nodes are the most accessible tissue for biopsy, providing a high diagnostic yield.

Hepatosplenomegaly occurs in up to 43% of children with sarcoidosis at some point in their clinical course; however, clinically significant hepatic dysfunction is rare. Mild elevation in biochemical liver function test values is common (as it was in this patient), but severe liver involvement is unusual in children.

Ocular involvement is extremely common in children with sarcoidosis, and a complete ophthalmologic evaluation, including a slit-lamp examination, is crucial (particularly in young children). Any part of the eye or orbit may be affected. Anterior uveitis (also known as iritis or iridocyclitis) is the most frequently observed lesion, occurring in about 58-90% of early-onset sarcoidoses, as compared with 24-54% of sarcoidosis cases in older children. Sarcoid-associated uveitis can be acute or chronic and may vary from an isolated iridocyclitis to a bilateral panuveitis syndrome. If left untreated, the disease may result in synechiae, corneal opacities, glaucoma, and, eventually, blindness. Conjunctival granulomas are the second most common ocular manifestation in sarcoidosis. Other forms of ocular lesions include interstitial keratitis, band keratopathy (from calcium deposition), dacryocystitis, retinal vasculitis, lacrimal gland enlargement, choroiditis, and orbital infiltration, which may result in proptosis.

Cutaneous involvement occurs in about 24-40% of older children with sarcoidosis and in 77% of young children with sarcoidosis. A variety of cutaneous eruptions are frequently found on the face, but the trunk, extremities, and buttocks may also be involved. Skin lesions of sarcoidosis may include macules, papules, nodules, hyperpigmented lesions, hypopigmented lesions, ulcers, subcutaneous tumors, and erythema nodosum. Rarely, "scar sarcoidosis", the infiltration of old scars with granuloma, may present in children.

Renal involvement is not well characterized in published series of childhood sarcoidosis. Actually, only 32 isolated cases of sarcoidosis with renal involvement have been reported in children since 1941. Histopathologic studies have revealed epithelioid granuloma formation, interstitial infiltration by mononuclear cells, interstitial fibrosis, tubulitis, tubular atrophy, mesangial hyperplasia, glomerular fibrosis, membranous nephropathy, and vascular involvement.

The treatment of sarcoidosis remains controversial. Corticosteroids remain the cornerstone of therapy, but immunosuppressive, cytotoxic, and immunomodulatory agents have emerged as viable therapeutic options for patients who do not respond to or experience adverse effects from corticosteroids. Published data most extensively documents treatment with methotrexate, but favorable responses have been noted with leflunomide, azathioprine, and antimalarial and antimicrobial agents, as well as with tumor necrosis factor–alpha inhibitors. The dosage and the duration of corticosteroid therapy must often be individualized. The treatment is continued until the clinical manifestations of the disease resolve or show significant improvement.

The patient in this case received prednisone, 1.5 mg/kg per day for 1 month, with gradual tapering of the dose over the following 4-5 months. Hypercalcemia and renal failure reversed completely, as did the pulmonary changes seen on radiography (see Figure 4). No recurrence was observed at a 1-year follow-up. Renal nephrocalcinosis persisted, however, despite symptomatic and biochemical improvement. During the corticosteroid therapy, measurement of the urinary beta-2-microglobulin concentration by sodium dodecyl sulfate polyacrylamide gel electrophoresis proved a valuable monitoring tool for assessing the recovery of the tubular impairment.

This case is from a recent Medscape Issue.