Neonatal severe hyperparathyroidism is a rare life-threatening disorder characterized by very high serum calcium concentrations (> 15 mg/dl). Many cases have occurred in families with familial hypocalciuric hypercalcemia, a benign condition transmitted as a dominant trait. Among several hypothesized relationships between the two syndromes is the suggestion that neonatal severe hyperparathyroidism is the homozygous form of familial hypocalciuric hypercalcemia. To test this hypothesis, we refined the map location of the gene responsible for familial hypocalciuric hypercalcemia on chromosome 3q. Analyses in 11 families defined marker loci closely linked to the gene responsible for familial hypocalciuric hypercalcemia. These loci were then analyzed in four families with parental consanguinity and offspring with neonatal severe hyperparathyroidism. Each individual who was homozygous for loci that are closely linked to the gene responsible for familial hypocalciuric hypercalcemia had neonatal severe hyperparathyroidism. The calculated odds of linkage between these disorders of > 350,000:1 (lod score = 5.56). We conclude that dosage of the gene defect accounts for these widely disparate clinical phenotypes; a single defective allele causes familial hypocalciuric hypercalcemia, while two defective alleles causes neonatal severe hyperparathyroidism.
The hypercalcemias are a common and heterogeneous group of disorders, ranging from the occasional detection of a high level of serum calcium to a life-treating condition. In a patient presenting with hypercalcemia, a differential diagnosis can be established easily by measuring serum calcium and parathyroid hormone (PTH) concentrations. We describe the case of an 83-year-old man presenting with a severe symptomatic hypercalcemia with high-normal PTH level due to the coexistence of primary hyperparathyroidism and malignancy-associated hypercalcemia. The presence of two conditions producing hypercalcemia was revealed only during in-hospital stay and after the administration of an intravenous bisphosphonate, when the PTH concentration increased rapidly after bisphosphonate treatment with a decrease in serum calcium. The occurrence of two conditions producing hypercalcemia is a rare event in the literature, and should be considered in the presence of an abnormally high serum calcium level associated with normal or high-normal PTH, in order to establish a correct diagnosis and appropriate interventions.
Bisphosphonates; Hypercalcemia; Malignancy-associated hypercalcemia; Parathyroid hormone; Primary hyperparathyroidism
Purpose of the review
In this review we define hypercalcemia levels, common etiologies for hypercalcemia in children, and treatment in order to aid the practicing pediatrician.
One rare cause of hypercalcemia in the child is Familial hypocalciuric hypercalcemia (FHH) [also termed familial benign hypercalcemia (FBH)]. Mutations that inactivate the Ca2+-sensing receptor gene FHH have been described as an autosomal dominant disorder, but recently milder mutations in the CASR have been shown to cause hypercalcemia when homozygous.
Normal serum levels of calcium are maintained through the interplay of parathyroid, renal, and skeletal factors. In this review, we have distinguished the neonate and infant from the older child and adolescent because the causes and clinical features of hypercalcemia can differ in these two age groups. However the initial approach to the medical treatment of severe or symptomatic hypercalcemia is to increase the urinary excretion of calcium in both groups. In most cases, hypercalcemia is due osteoclastic bone resorption, and agents that inhibit or destroy osteoclasts are therefore effective treatments. Parathyroid surgery, the conventional treatment for adults with symptomatic primary hyperparathyroidism, is recommended for all children with primary hyperparathyroidism.
hypercalcemia; pediatrics; bisphosphonates; hyperparathyroidism
Clear cell sarcoma of the kidney (CCSK) is a rare renal neoplasm of paediatrics, making up about 3% of all renal tumours in paediatrics, with a high tendency for developing bone metastasis. A seven year-old boy was referred to our clinic with two firm, large masses over the manubrium of the sternum and right frontal area, which pathologically were confirmed as a metastatic CCSK. The patient had a history of a renal mass three years earlier, for which radical nephrectomy had been performed, and histopathologic diagnosis was compatible with mesoblastic nephroma. Thus, no further investigation and therapy had been applied for the patient. CCSK is a rare but malignant and aggressive paediatric renal tumour, with a high tendency for developing distant bone metastases, leading to its poor prognosis. CCSK could be misdiagnosed as several other renal tumours such as mesoblastic nephroma, and thus CCSK should be taken carefully into consideration in the diagnosis of renal tumours.
clear cell sarcoma of the kidney; sternum; frontal bone; mesoblastic nephroma; bone metastasis
Hypercalcemia is a common problem in clinical practice and can be related to endocrine disorders or malignant disease, especially in elderly patients. Although rare, other causes can also be responsible.
Granulomatous inflammation of the skin and lymph nodes induced by intravenous or injectable silicone is a rare condition of hypercalcemia that is usually not within the scope of differential diagnosis. Here, we report a 72-year-old woman with symptomatic hypercalcemia related to cosmetic treatment of the neck. Topical applied liquid silicone by means of a focal ultrasound device induced extensive granulomatous inflammation of the skin and local lymph nodes, being the underlying cause for hypercalcemia in this case.
In rare cases, symptomatic hypercalcemia can be caused by silicone due to a severe granulomatous tissue reaction. This is the first time that a transdermal silicone treatment has been reported to cause severe granulomatous tissue inflammation.
hypercalcemia; granulomatous inflammation; silicone; ultrasound treatment
Hypercalcemia has been widely associated with granulomatous processes. This is due to enhanced extra-renal conversion of calcidiol to calcitriol by activated macrophages within the granuloma. Symptomatic hypercalcemia due to granulomatous disorders is not common, with the incidence in sarcoidosis ranging from 10–20%. Large aggregates of monosodium urate crystals in patients with longstanding chronic tophaceous gout can serve as the inciting antigen for the development of granuloma, but hypercalcemia has not been described in this context. We report a case of symptomatic hypercalcemia due to gouty tophi induced granulomatous inflammation. Long term treatment with immunosuppressants, in addition to bisphosphonates and uric acid lowering therapy, has led to stabilization of serum calcium levels and other lab parameters indicative of granulomatous burden.
Hypercalcemia is well described in various granulomatous disorders, such as sarcoidosis, tuberculosis, berylliosis, leprosy and fungal infections. However, the association of Paracoccidioides brasiliensis and hypercalcemia is rare: to the best of our knowledge, only two cases have previously been reported, and neither had a clear documentation of the etiology of the hypercalcemia.
We report the case of a 22-year-old man in whom disseminated infection with paracoccidioidomycosis was associated with hypercalcemia. The patient had a high normal serum level of 1,25-dihydroxyvitamin D and a suppressed parathyroid hormone value, an indication that the hypercalcemia was not mediated by parathyroid hormone and might be associated with 1,25-dihydroxyvitamin D.
The episode resolved readily with administration of corticosteroids, an outcome suggesting that this is an effective treatment of hypercalcemia of this origin. On follow-up, while receiving antifungal therapy for P. brasiliensis the patient's calcium values remained normal.
The most common cause of hypercalcemia in hospitalized patients is malignancy. Primary hyperparathyroidism most commonly causes hypercalcemia in the outpatient setting. These two account for over 90% of all cases of hypercalcemia. Hypercalcemia can be divided into PTH-mediated and PTH-independent variants. Primary hyperparathyroidism, familial hypocalciuric hypercalcemia, familial hyperparathyroidism, and secondary hyperparathyroidism are PTH mediated. The most common PTH-independent type of hypercalcemia is malignancy related. Several mechanisms lead to hypercalcemia in malignancy-direct osteolysis by metastatic disease or, more commonly, production of humoral factors by the primary tumor also known as humoral hypercalcemia of malignancy that accounts for about 80% of malignancy-related hypercalcemia. The majority of HHM is caused by tumor-produced parathyroid hormone-related protein and less frequently production of 1,25-dihydroxyvitamin D or parathyroid hormone by the tumor. We report the rare case of a patient with hypercalcemia and diagnosed primary hyperparathyroidism. The patient had persistent hypercalcemia after surgical removal of parathyroid adenoma with recorded significant decrease in PTH level. After continued investigation it was found that the patient also had elevated 1,25-dihydroxyvitamin D and further studies confirmed a large spleen mass that was later confirmed to be a lymphoma. This is a rare example of two concomitant causes of hypercalcemia requiring therapy.
Osteoporosis that is by far the most common metabolic bone disease, has been defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Anabolic therapy with teriparatide, recombinant human parathyroid hormone (PTH 1-34), stimulates bone formation and resorption and improves trabecular and cortical microarchitecture. Teriparatide is indicated for the treatment of men and postmenopausal women with osteoporosis who are at high risk for fracture, including those who have failed or are intolerant of previous osteoporosis therapy. In conclusion, although teriparatide seems quite effective in the treatment of osteoporosis, it may cause life-threatening hypercalcemia. Therefore, patients should be closely monitored if symptoms of hypercalcemia are present during teriparatide treatment. Sustained hypercalcemia due to teriparatide treatment can not be seen in literature so we wanted to emphasize that severe hypercalcemia may develop due to teriperatide.
Hypercalcemia; osteoporosis; teriparatide
Congenital mesoblastic nephroma (CMN) is a rare renal tumor. It can be detected antenatally especially with judicious use of ultrasonography.
A premature female neonate 28 weeks’ gestation, complicated by polyhydramnios, was born to a 28-year-old woman. An abdominal mass was detected antenatally. At the end of the first week of life, the newborn had hypertension that was controlled by hydralazine. Ultrasonography and CT scan showed a right-sided renal heterogeneous solid mass. Right nephrectomy was performed and the histology showed CMN.
Congenital mesoblastic nephroma; Polyhydramnios; Neonatal hypertension
While paraneoplastic syndromes in patients with malignant and metastasizing tumors are common, they are rarely associated with skin tumors showing predominantly local growth patterns. This case report relates to a patient with giant condyloma acuminatum, also called Buschke-Löwenstein tumor, with paraneoplastic hypercalcemia, who was successfully treated with conservative treatment.
The patient in question is a 48-year-old German man with a giant periscrotal tumor. Before and during the therapy, two episodes of symptomatic hypercalcemia occurred, which were successfully treated by bisphosphonates, intravenous fluids and diuretics. No evidence of lytic bone affection was found.
Paraneoplastic hypercalcemia may occur in patients who have a Buschke-Löwenstein tumor. For patients, where surgery is not an option, established medical therapies like bisphosphonates may be useful in addition to diuretics and infusions.
Paraneoplastic hypercalcemia; Buschke-Löwenstein tumor; Giant condyloma acuminatum
Cystic nephroma is a rare benign renal neoplasm that is purely cystic and is lined by an epithelium. Bilateral cystic nephromas are even rarer with only a handful cases reported in the literature. A case of a 2-year-old male child who presented with bilateral renal cystic masses later diagnosed as cystic nephromas is presented here. Ultrasound, CT scan and histopathological investigations aided in arriving at the correct diagnosis. The most concerning feature was the presence of a fluid filled cystic mass in the lungs, most probably a pleuropulmonary blastoma which is a rare malignant neoplasm known to be associated with bilateral cystic nephromas. The most common presenting symptoms of cystic nephroma are painless abdominal mass, abdominal or flank pain and haematuria. These tumours usually follow a benign course and nephrectomy alone is curative. A close surveillance of such patients is recommended because of elevated risk of other tumours.
Hypophosphatasia (HPP) is an inborn error of metabolism characterized by defective bone mineralization caused by a deficiency in alkaline phosphatase (ALP) activity due to mutations in the tissue-nonspecific ALP (TNALP) gene. The clinical expression of the disease is variable. Six forms of HPP are identified according to age at presentation and clinical features. Patients with the infantile form are normal at birth. First symptoms appear within the first 6 months of life. Along with skeletal findings, HPP patients may present with hypercalcemia, seizures, pseudotumor cerebri, and pulmonary insufficiency. Seizures in HPP are refractory to conventional antiepileptic drugs, but are responsive to pyridoxine. Herein, we report a case of HPP who presented with pyridoxine-responsive seizures in the early neonatal period and was found to have hypercalcemia, skeletal demineralization and increased intracranial pressure. Key words: Hypophosphatasia, pyridoxine-responsive seizures, bisphosphonates, alkaline phosphatase, bone resorption, hypercalcemia
Conflict of interest:None declared.
Hypophosphatasia; pyridoxine-responsive seizures; bisphosphonates; Alkaline phosphatase; bone resorption; hypercalcemia
Familial Hypocalciuric Hypercalcemia (FHH) is a generally benign disorder caused by heterozygous inactivating mutations in the Calcium-Sensing Receptor (CaSR) gene resulting in altered calcium metabolism.
We report a case of unusually severe neonatal FHH due to a novel CaSR gene mutation that presented with perinatal fractures and moderate hypercalcemia.
A female infant was admitted at 2 weeks of age for suspected non-accidental trauma (NAT). Laboratory testing revealed hypercalcemia (3.08 mmol/L), elevated iPTH (20.4 pmol/L) and low urinary calcium clearance (0.0004). Radiographs demonstrated multiple healing metaphyseal and rib fractures and bilateral femoral bowing. The femoral deformity and stage of healing were consistent with prenatal injuries rather than non-accidental trauma (NAT). Treatment was initiated with cholecalciferol, 400 IU/day, and by 6 weeks of age, iPTH levels had decreased into the high-normal range. Follow up radiographs demonstrated marked improvement of bone lesions by 3 months. A CaSR gene mutation study showed heterozygosity for a T>C nucleotide substitution at c.1664 in exon 6, resulting in amino acid change I555T in the extracellular domain consistent with a missense mutation. Her mother does not carry the mutation and the father is unknown. At 18 months of age, the child continues to have relative hyperparathyroidism and moderate hypercalcemia but is otherwise normal.
This neonate with intrauterine fractures and demineralization, moderate hypercalcemia and hyperparathyroidism was found to have a novel inactivating missense mutation of the CaSR not detected in her mother. Resolution of bone lesions and reduction of hyperparathyroidism was likely attributable to the natural evolution of the disorder in infancy as well as the mitigating effect of cholecalciferol treatment.
FHH; Neonatal hyperparathyroidism; Hypercalcemia; NHPT; CaSR; Vit D
Primary hyperparathyroidism (PHPT) is a common endocrine disorder in adults in whom the typical presentation is incidentally discovered as asymptomatic hypercalcemia. PHPT is much less common in children and adolescents, but has greater morbidity in this age group, as most young patients with PHPT will have symptomatic hypercalcemia or complications such as kidney stones, abdominal pain, and skeletal fragility. An important feature of PHPT in younger patients is the relatively high prevalence of germline inactivating mutations of the CASR gene, which encodes the calcium-sensing receptor. Biallelic CASR mutations cause neonatal severe hyperparathyroidism, a life-threatening condition that presents within days of life with marked hypercalcemia, respiratory distress, failure to thrive, and skeletal demineralization. By contrast, more common heterozygous CASR mutations are generally associated with a benign variant of PHPT termed familial hypocalciuric hypercalcemia. Appropriate management of PHPT in children and adolescents requires distinction between familial hypocalciuric hypercalcemia, which generally requires no specific treatment, and other forms of PHPT that are best treated by parathyroidectomy.
calcium sensing receptor; hypercalcemia; MEN1; osteoporosis; parathyroid; primary hyperparathyroidism; PTH
Hot packs (instant hot compresses) are frequently used to relieve pain. We report a patient who had significant complications from ingestion of a hot pack containing calcium salts. A 35-year-old male swallowed three hot packs, and developed hematemesis, severe abdominal pain, and hypercalcemia (21.1 mg/dl). He developed diffuse gastric necrosis requiring gastrectomy and colonic interposition. Hypercalcemia was treated with intravenous fluids, pamidronate, and calcitonin. A Medline search revealed no prior report on hot pack ingestion though ingestion of calcium salts has been reported. Hot packs can potentially cause significant injury both from an exothermic reaction and hypercalcemia. Ingestions of calcium salts can result in necrosis of the stomach. Management includes aggressive treatment of hypercalcemia, supportive care and upper gastrointestinal endoscopy.
Hypercalcemia; Hot pack; Thermal injury; Gastrointestinal necrosis; Gastric ulcers
Milk-alkali syndrome is a rare cause of hypercalcemia characterized by the triad of hypercalcemia, renal insufficiency, and metabolic alkalosis that results from the overconsumption of calcium containing products. In the setting of pregnancy where there is a physiologic increase in calcium absorption, milk-alkali syndrome can be potentially life threatening. We report a case of a 26-year-old woman in her second trimester of pregnancy who presented with 2 weeks of flank pain, nausea, vomiting, anorexia, headache, and lightheadedness. The history revealed consumption of a large quantity of milk, calcium carbonate antacid, and calcium-containing prenatal vitamins. Her symptoms and hypercalcemia resolved with intravenous fluids and a loop diuretic. With the increased use of calcium carbonate for peptic ulcer disease, gastroesophageal reflux disease, and osteoporosis, milk-alkali syndrome has experienced a resurgence and must be considered in the differential diagnosis of hypercalcemia. In this clinical vignette we review the literature on milk-alkali syndrome in pregnancy and discuss important diagnostic and therapeutic considerations when managing the pregnant patient with hypercalcemia.
hypercalcemia; milk-alkali syndrome; pregnancy
Humoral hypercalcemia of malignancy is rarely associated with cholangiocarcinoma (CC).
A 77-year-old man was admitted with confusion. Computer tomography showed a large multinodular mass in the right lobe of the liver and smaller lesions in the right lung. Liver histology confirmed the diagnosis of CC. Elevated calcium levels and suppressed intact parathyroid hormone in the absence of skeletal metastases or parathyroid gland pathology suggested the diagnosis of humoral hypercalcemia of malignancy (HHM). Treatment of hypercalcemia with saline infusion, loop diuretics, biphosphonate and calcitonin was effective in normalizing calcium levels and consciousness state within 48 hours, but a relapse occurred 4 weeks later and the patient succumbed to his disease.
Clinicians should be aware of this rare manifestation of CC as prompt and aggressive correction of hypercalcemia alleviates symptoms and improves patient's quality of life, despite the poor overall prognosis.
Although congenital renal tumors are rare, congenital mesoblastic nephroma (CMN) is the most common renal tumor in early infancy. It is non-metastatic, well differentiated, amenable to surgical removal, and carries a good prognosis. Polyhydramnios has been detected in most of the published cases of CMN. However, we experienced a rare case of fetal CMN associated with oligohydramnios. A 28-yr old woman at 34 weeks of gestation was referred to our hospital for oligohydramnios and a fetal abdominal mass. An ultrasonography revealed a huge, well-encapsulated mass arising from the right kidney. An emergency cesarean section was performed due to fetal distress. After birth, despite intensive neonatal care, the baby died because of renal failure, disseminated intravascular coagulopathy, pulmonary edema, together with other problems
Oligohydramnios; Congenital Mesoblastic Nephroma; Renal Failure
We report the case of a female patient with severe acute necrotizing pancreatitis associated with hypercalcemia as first manifestation of primary hyperparathyroidism caused by a benign parathyroid adenoma. Initially the acute pancreatitis was treated conservatively. The patient subsequently underwent surgical resection of the parathyroid adenoma and surgical clearance of a large infected pancreatic pseudocyst. Although the association of parathyroid adenoma-induced hypercalcemia and acute pancreatitis is a known medical entity, it is very uncommon. The pathophysiology of hypercalcemia-induced acute pancreatitis is therefore not well known, although some mechanisms have been proposed. It is important to treat the provoking factor. Therefore, the cause of hypercalcemia should be identified early. Surgical resection of the parathyroid adenoma is the ultimate therapy.
Acute necrotizing pancreatitis; Hypercalcemia; Primary hyperparathyroidism; Parathyroid adenoma
We report a case of a 62-year-old woman with renal cell carcinoma (RCC) presenting with a hypercalcemia-induced coma. A laboratory evaluation indicated nonparathyroid-mediated hypercalcemia with an initial serum calcium level of 18.6 mg/dL. Our patient’s parathyroid hormone (PTH)-related peptide level was undetectable. Initial imaging was negative, but PET scan identified a mass in the upper pole of the left kidney. Our patient underwent partial nephrectomy, and the mass was identified as RCC on final pathology. After surgery, her hypercalcemia resolved and PTH returned to normal limits. This case report describes a patient with RCC with the unusual presentation of hypercalcemic coma. We review the differential diagnosis of malignant hypercalcemia and the evaluation of hypercalcemia occurring with RCC. This case illustrates the need to carefully review and interpret all available data, especially when conventional testing in the work-up of hypercalcemia is unrevealing.
hypercalcemia; renal cell carcinoma; interleukin-6; parathyroid hormone; PTHrP
To present a case of hypercalcemia associated with thyrotoxicosis in a patient with vitamin D deficiency and review biochemical changes during the course of treatment.
We report a case, describe the changes in serum calcium, phosphorus, parathyroid hormone in Graves’ disease and concomitant Vitamin D deficiency. We compare our findings to those reported in literature.
Our patient had hypercalcemia secondary to thyrotoxicosis alone, which was confirmed by low parathyroid hormone level and resolution of hypercalcemia with treatment of thyrotoxicosis. The case was complicated by a concomitant vitamin D deficiency. Serum calcium elevation in patients with thyrotoxicosis occurs secondary to hyperthyroidism alone or due to concurrent hyperparathyroidism. Hypercalcemia from thyrotoxicosis is usually asymptomatic and is related to bone resorption. Vitamin D deficiency can be seen in patients with thyrotoxicosis because of accelerated metabolism, poor intestinal absorption and increased demand during bone restoration phase. Coexistence of hypercalcemia and Vitamin D deficiency in patients with thyrotoxicosis is rare, but possible, and 25-hydroxyvitamin D levels should be checked. The definite treatment for hypercalcemia in thyrotoxicosis is correction of thyroid function.
Hypercalcemia in thyrotoxicosis should be distinguished from concomitant hyperparathyroidism and confirmed by resolution of hypercalcemia with control of thyrotoxicosis. Patients with hypercalcemia and thyrotoxicosis may also have vitamin D deficiency and 25-OH Vitamin D levels should be checked.
hypercalcemia; thyrotoxicosis; vitamin D deficiency
Although hypercalcemia is a known metabolic complication of sarcoidosis, it is rarely a presenting manifestation. Long-standing hypercalcemia and hypercalciuria can cause nephrocalcinosis and chronic renal failure. Acute renal failure, although described, is also a rare presentation of patients with sarcoidosis. We describe two patients with sarcoidosis, who presented with severe hypercalcemia and worsening renal function. Parathyroid hormone levels were appropriately suppressed. This led to an extensive search for the cause of hypercalcemia. Finally, after a lymph node biopsy in both cases, a diagnosis of sarcoidosis was established, hypercalcemia resolved, and renal function improved in both cases after administration of prednisone.
Subcutaneous fat necrosis of the newborn (ScFN) is an uncommon condition caused by generalized and/or local tissue hypoperfusion. The skin lesions of ScFN tend to improve spontaneously. However, ScFN may also lead to complications which cause serious problems. The severity of the etiologic factors contributing to the development of the disease determines the severity of complications. Therefore, these patients should be closely monitored for complications, especially for hypercalcemia which may be life-threatening. The severity and duration of hypercalcemia are associated with the extensity of skin lesions.
We present a newborn who developed ScFN as a result of systemic hypotension. The ScFN resolved after the first few weeks of life, but the patient developed mild hypercalcemia during the 4-month follow-up period. The infant was breast-fed during follow-up, and vitamin D prophylaxis was not initiated. The hypercalcemia resolved within four months without any complications. We would like to draw attention to the need to monitor serum calcium levels in these infants and to refrain from initiating vitamin D prophylaxis in the first months of life.
Conflict of interest:None declared.
Subcutaneous fat necrosis; hypercalcemia; follow-up
Vitamin A intoxication secondary to over-the-counter nutritional supplements and from its use in acne treatment has been described. However, there have been very few case reports of chronic hypervitaminosis A leading to hypercalcemia in the pediatric population. This paper describes a boy with hypercalcemia secondary to chronic vitamin A intoxication in the context of vitamin A usage for therapy of autism. In addition to discontinuation of vitamin A, hyperhydration, and furosemide, the hypercalcemia in this patient required the use of prednisone and pamidronate to normalize the calcium.