Hypercalcemic Disorders in Children.

Hypercalcemia is defined as a serum calcium concentration that is greater than two standard deviations above the normal mean, which in children may vary with age and sex, reflecting changes in the normal physiology at each developmental stage. Hypercalcemic disorders in children may present with hypotonia, poor feeding, vomiting, constipation, abdominal pain, lethargy, polyuria, dehydration, failure to thrive, and seizures. In severe cases renal failure, pancreatitis and reduced consciousness may also occur and older children and adolescents may present with psychiatric symptoms. The causes of hypercalcemia in children can be classified as parathyroid hormone (PTH)-dependent or PTH-independent, and may be congenital or acquired. PTH-independent hypercalcemia, ie, hypercalcemia associated with a suppressed PTH, is commoner in children than PTH-dependent hypercalcemia. Acquired causes of PTH-independent hypercalcemia in children include hypervitaminosis; granulomatous disorders, and endocrinopathies. Congenital syndromes associated with PTH-independent hypercalcemia include idiopathic infantile hypercalcemia (IIH), William's syndrome, and inborn errors of metabolism. PTH-dependent hypercalcemia is usually caused by parathyroid tumors, which may give rise to primary hyperparathyroidism (PHPT) or tertiary hyperparathyroidism, which usually arises in association with chronic renal failure and in the treatment of hypophosphatemic rickets. Acquired causes of PTH-dependent hypercalcemia in neonates include maternal hypocalcemia and extracorporeal membrane oxygenation. PHPT usually occurs as an isolated nonsyndromic and nonhereditary endocrinopathy, but may also occur as a hereditary hypercalcemic disorder such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated primary hyperparathyroidism, and less commonly, as part of inherited complex syndromic disorders such as multiple endocrine neoplasia (MEN). Advances in identifying the genetic causes have resulted in increased understanding of the underlying biological pathways and improvements in diagnosis. The management of symptomatic hypercalcemia includes interventions such as fluids, antiresorptive medications, and parathyroid surgery. This article presents a clinical, biochemical, and genetic approach to investigating the causes of pediatric hypercalcemia. © 2017 American Society for Bone and Mineral Research.

Classification of Disorders of Bone and Calcium Metabolism.

Classification is a natural human trait that enables us to put what may otherwise be very complex subjects into some order. However, classification should be seen not as an end in itself but rather as a means to help us understand certain topics. In the case of medicine, classification helps to provide information about the causes underlying many of the conditions encountered and, in some cases, provides a rationale for developing new treatments. This chapter aims to provide a helpful (if complex) classification of diseases of bone and calcium and, where known, to describe the underlying genetic mechanisms.

Treatment of chronic hypercalcemia.

Hypercalcemia is a relatively frequent alteration, mostly associated to primary hyperparathyroidism (PHPT) and malignancy-associated hypercalcemia (MAH). Treatment first includes rehydration and loop diuretics, as general measures. Bisphosphonates are considered the drugs of choice due to their long-term management. Calcitonin is preferable in the short-term control of severe hypercalcemia. The antireabsorptive action of bisphosphonates has been considered the most effective in the disorders characterized by an excessive bone resorption. Zoledronate is superior to both clodronate or pamidronate in the treatment of MAH. Calcimimetic agents has been recently introduced to control hypercalcemia in selected cases of PHPT. They are used when surgery is not possible or patients do not meet surgical criteria. Malignancy- associate hypercalcemia is broadly divided into two categories: humoral MAH and osteolytic MAH. The first concerns the paraneoplastic release of humoral factors, mainly parathyroid hormone-related peptide (PTHrP). Recently a humanized monoclonal antibody against human PTHrP has been generated and is still under evaluation. The receptor activator of nuclear factor-κ ligand (RANKL) has a critical role in the etiology of malignancy skeletal complications. The fully humanized anti-RANKL antibody (denosumab) would seem to be even more effective than bisphosphonates to suppress bone resorption, as shown in preliminary results .

[Cytokines in bone diseases. Cytokines and malignancy-associated hypercalcemia].

Malignancy-associated hypercalcemia is one of the commonest causes of hypercalcemia. Clinically, it has been subdivided into HHM (humoral hypercelcemia of malignancy) and LOH (local osteolytic hypercalcemia) . PTHrP (PTH related protein) , which has high homology with PTH in its N-terminus and binds to a common receptor (PTH1R) with PTH, plays a central role in the development of hypercalcemia in HHM. Although most features of HHM can be explained by excessive action of circulating PTHrP, decreased serum level of 1,25 (OH) (2)D and markedly suppressed bone formation found in HHM cannot be explained by the action of N-terminus of PTHrP. Fragments of PTHrP that do not bind to PTH1R, found in the circulation of HHM patients, or some other cytokines secreted by cancer cells may modify the clinical features of HHM. PTHrP also plays important roles in the development of LOH in some cancers, such as breast cancer. In this article, the role of cytokines, mainly PTHrP, in MAH will be reviewed.

Aspectos clínicos da hipocalcemia e da hipercalcemia

O cálcio é um íon divalente que participa de importantes funções no organismo. Entre elas pode-se citar: o metabolismo ósseo, a coagulação sanguínea, a adesão plaquetária, o potencial de ação das células neurológicas, a contração muscular e a sinalização celular como segundo mensageiro. Esta última função é fundamental para a realização dos diversos processos tanto fisiológicos quanto os patológicos. Nos processos fisiológicos, podem-se citar: a secreção dos diversos hormônios, a fertilização e a divisão celular. Nos processos patológicos, a morte celular e a apoptose são os principais exemplos

Primary liver lymphoma with hypercalcemia: a case report.

Primary liver lymphoma is extremely rare. The diagnosis depends on the physician's suspicions and histological examination. We report the case of a man aged 38 years who suffered from abdominal discomfort and hypercalcemia. Sonography showed a huge, solid liver tumor, and magnetic resonance imaging showed the tumor had characteristics of hypointensity on T1-weighted and hyperintensity on T2-weighted imaging. Primary liver lymphoma was diagnosed by histological examination from biopsy. We report this rare type of liver tumor and review the clinical presentation and treatment of the disease.

[Usefulness of Pak's test in Stapleton's modification in diagnosis of hypercalciuria in children]. / Przydatnosc testu Paka w modyfikacji Stapletona w diagnostyce hiperkalciuri u dzieci.

UNLABELLED: Recognition of the type of hypercalciuria in children in Pak's test in Stapleton's modification was performed. 26 children with hypercalciuria was enrolled to the study. 15/26 had positive family history. In all Pak's test in Stapleton's modification was done, blond tests of renal function (urea, creatinine), calcium-phosphate balance (Ca, P, ALP, PTH, Vit D3 metabolites) and in 24 hr urine collection: promoters and inhibitors of crystallization, 24 hr urine pH measurement was performed. RESULTS: In 18 children--absorptive hipercalciuria: type II, in 1--type I, renal in 4; complex mechanism in 3, hypocitraturia was recognized in 4. Normalization of calciuria was obtained in 16 out of 26. In 3 others new formation of kidney stones was observed. CONCLUSIONS: Performation of Pak's test in Stapleton's modification allows to establish a type of hypercalciuria in children and recognize a pathomechanism of disease.

Idiopathic hypercalciuria in children. Classification, clinical manifestations and outcome.

Between 1981 and 1983, 49 children aged 2 to 15 years were diagnosed as having idiopathic hypercalciuria (IH). They were divided into 3 groups based on their response to dietary manipulation: group I (32/49) had absorptive hypercalciuria; group II (8/49) had renal hypercalciuria and group III (6/49) had sodium-dependent hypercalciuria. Response to diet was more reliable than Pak's test in differentiating between the three groups. A control group (CG) of 45 healthy, age matched children determined baseline levels for all metabolic parameters. At the time of presentation IH children did not differ from the CG in height or weight. Fifty percent of IH children had first degree relatives with urolithiasis. Yet, only 16% of the IH children had urolithiasis, the majority presenting with gross hematuria and urinary tract infections (UTI). With few exceptions the clinical symptoms resolved when urine calcium excretion was controlled. Severe calcium restriction in a few patients produced osteoporosis and delayed bone age although growth velocity was unaffected. Thiazide therapy in a few patients produced some metabolic derangements. The authors conclude that IH in childhood is a benign disease which may present with UTI or hematuria. They further propose a new classification method based on response to dietary manipulation.