Primary juvenile hyperparathyroidism. Report of 24 cases

AIM OF THE STUDY: Primary hyperparathyroidism usually affects elderly patients. Juvenile primary hyperparathyroidism is rare, and raises diagnostic and prognostic problems. The aim of this retrospective study on 24 patients is to establish clinical, histological, and therapeutic features of juvenile primary hyperparathyroidism. PATIENTS AND METHODS: From 1986 to 2001, 673 patients were treated for primary hyperparathyroidism in our department. Twenty four patients were younger than 30 years old (3.5%). There were 14 women and 10 men. Mean age was 23 year (14-30). Clinical manifestations, pathologics findings and postoperative results were studied. RESULTS: Sixteen patients presented a sporadic form of primary hyperparathyroidism with a single adenoma. Clinical manifestations were renal symptoms in 11 cases and acute hypercalcemia syndrome in 2 cases. Seven patients had a NEM I syndrome: parathyroid lesions were 6 hyperplasia and one adenoma. A 27 years old woman presented a recurrent familial isolated hyperparathyroidism. She was operated on 10 years before and at reoperation parathyroid carcinoma was found. Nineteen patients were cured after a post operative follow up ranging from 3 to 168 months. One patient had an asymptomatic hypercalcemia recurrence. Two patients presented permanent hypoparathyroidism treated with calcitriol and calcium. CONCLUSION: Sporadic forms represent majority of cases of juvenile hyperparathyroidism. Renal manifestations are usual. Nevertheless, multiple endocrine neoplasia type 1 has to be evocated.     

Long-term follow-up of a patient with Gitelman's syndrome

The long-term follow-up (from age 6 to 20 years) of a girl with Gitelman's syndrome, who had four hypomagnesaemic-tetanic episodes associated with normal plasma calcium, hypokalaemia and hypocalciuria, is presented. During and after puberty, hypomagnesaemia was of the order of 0.41–0.49 mmol/l and plasma potassium was at the lower reference limit. The long-term clinical course and growth of this patient appeared good, but, magnesium supplementation reduces the risk of tetanic crises.     

Familial hypokalemia-hypomagnesemia or Gitelman's syndrome: a further case.

A woman aged 33 years presented hypokalemia and hypomagnesemia associated with renal potassium and magnesium wasting. Her mean 24-hour urinary calcium excretion was strikingly low despite normocalcemia, normal creatinine clearance, normal serum PTH and calcitriol. Normal distal fractional chloride reabsorption [CH2O/(CH2O + CCl)] was noted during water load but was reduced during hypotonic saline infusion. In response to intravenous furosemide (1 mg/kg), the patient showed significant increments in sodium, chloride and magnesium excretion as well as abolition of hypocalciuria. The association of renal calcium transport from magnesium transport together with exaggerated natriuresis after furosemide suggests the presence of a defect in the distal tubule rather than in the loop of Henle. We propose that our patient is affected by the syndrome of primary renotubular hypomagnesemia-hypokalemia with hypocalciuria, known as Gitelman's syndrome.     

Genetic hypercalcemia

A genetic disorder should be suspected in patients with hypercalcemia, notably those who are young; have family members with hypercalcemia; or have had a tumor of the endocrine pancreas, thyroid, pituitary, adrenal gland, or jaw bone. All forms of hypercalcemia should be interpreted according to the serum level of parathyroid hormone (PTH). Genetic forms are thus classified as related or unrelated to a parathyroid gland disorder. When the PTH level is elevated or is not depressed despite the hypercalcemia, findings that suggest family history of hypercalcemia due to a genetic cause include syndromic manifestations in the patient or family members, parathyroid cancer (either suspected before surgery or confirmed during parathyroidectomy), multiple or recurrent parathyroid tumors, a family history of primary hyperparathyroidism, and the onset of primary hyperthyroidism before 50 years of age. In patients with moderate hypercalcemia, a normal PTH level, and relative hypocalciuria, the first hypothesis is a mutation in the calcium-sensing receptor gene, which is often difficult to distinguish from primary hyperparathyroidism, particularly when there is no known family history of hyperparathyroidism, as is often the case. A low PTH level suggests non-parathyroid hypercalcemia due to a genetic defect in patients with no evidence of other conditions associated with hypercalcemia and low PTH levels and in those whose calcitriol levels are elevated or normal (instead of depressed as expected when PTH is elevated). Patients with hypercalciuria but no evidence of conditions such as granulomatous diseases should be evaluated for increased vitamin D sensitivity due to a CYP 4A1 mutation. Other very rare causes include hypophosphatasia due to ALPL mutations, which is characterized by a low alkaline phosphatase level; and renal phosphate wasting due to an NPT2A mutation, in which serum phosphate levels are low. A thorough analysis of the clinical and laboratory data can point toward a genetic disorder in patients with hypercalcemia. The diagnosis is then confirmed by obtaining genetic tests tailored to the clinical and laboratory test abnormalities. The current development of diagnostic genetic testing is shedding new light on the phenotypes, thereby improving their management.     

Neonatal hypercalcemia

The causes of hypercalcemia during the neonatal period are varied. Diagnosis is based on the plasma levels of parathyroid hormone (PTH). (a) PTH in plasma is diminished; exogenous o r endogenous calcium overloading is suspected. (b) PTH in plasma is increased; hyperparathyroidism caused by homozygous or heterozygousloss-of-function mutations in the CaR gene is suspected. (c) PTH i n plasma is normal; low or normal urinary calcium excretion (i.e.relative hypocalciuria) and normal PTH plasma levelsare relevant findings of familial hypocalciuric hypercalcemia (FHH) syndrome.     

A case of theophylline induced hypercalcemia

We report a case of theophylline-induced hypercalcemia. The patient, a 51 year old women, had been administered theophylline for about five years because of bronchial asthma. She was referred to us in March 2003 for the treatment of renal failure and hypercalcemia(15.2 mg/dL), which had been increasing since 2001. Clinical and laboratory findings were not consistent with any endocrinopathy. We suspected drug induced hypercalcemia. Three months after discontinuation of theophylline therapy, the hypercalcemia was completely cured. When admitted to our hospital, the patient was diagnosed as also having Hashimoto's disease. Hyperthyroidism might enhance the effect of theophylline on parathyroid hormone action. Therefore, theophylline induced hypercalcemia even though she was taking the therapeutic level. Moreover, her calcium excretion did not increase despite hypercalcemia. We concluded that her hypercalcemia was induced by theophylline and hyperthyroidism, and that hypocalciuria might have enhanced these conditions.     

Hypokalemic alkalosis with hypocalciuria and normomagnesemia: A subgroup of Gitelman's syndrome?

We report a normomagnesemic patient with low normal blood pressure, hypokalemic alkalosis, hyperreninemia, hyperaldosteronism, and hypocalciuria. In renal clearance studies, distal delivery increased well and fractional distal solute reabsorption was dramatically diminished after the administration of furosemide, whereas thiazide produced no change in distal delivery and a moderate decrease in fractional distal solute reabsorption. These findings suggested that there may have been a defective locus in some part of the thiazide-sensitive segment of the distal convoluted tubule. As the features in this patient appear to be similar to those in Gitelman's syndrome, it is appropriate to designate this case, characterized by lack of hypomagnesemia, as a subgroup of Gitelman's syndrome. Received: February 12, 1998 / Accepted: June 30, 1998     

A case of lung cancer with hypercalcemia which was incidentally complicated with primary hyperparathyroidism due to parathyroid adenoma.

In lung cancer patients, hypercalcemia is a fairly common metabolic problem associated with malignancy. However, the occurrence of hypercalcemia in lung cancer patients means an ominous prognostic sign. As hypercalcemia often causes early death, quick diagnosis and treatment for hypercalcemia are required. A 69-year-old woman was admitted to our hospital with anorexia caused by hypercalcemia. On admission, serum level of PTH was elevated and PTHrP was normal. From the results of CT findings and transbronchial lung biopsy, the cause of the hypercalcemia was determined as lung cancer incidentally complicated with primary hyperparathyroidism. First, serum calcium level was returned to normal through hydration with saline and bisphosphonates. Next, left hemithyroidectomy for primary hyperparathyroidism was performed. Histologically, the tumor was diagnosed as parathyroid adenoma. Fifteen days later, left lower lobectomy for primary lung cancer was performed under a video-assisted thoracoscopic approach. Histologically, the tumor was diagnosed as a moderately differentiated adenocarcinoma. Four years and three months after the operation, the patient is alive and well with no sign of recurrence. When a lung cancer patient is complicated with hypercalcemia, we need to consider that primary hyperparathyroidism is a possible cause of the hypercalcemia.     

Genetic renal disorders with hypomagnesemia and hypocalciuria

The combination of hypomagnesemia and hypocalciuria is the phenotypic signature of two distinct genetic renal tubular transport disorders: Gitelman's syndrome and autosomal dominant isolated renal magnesium wasting. In the past 5 years the genetic defects underlying these disorders have been elucidated through positional candidate cloning approaches. The defective proteins involved in both diseases are located within the distal convoluted tubule (DCT), a segment of the nephron known to play an important role in active magnesium reabsorption in the nephron. The introduction outlines the magnesium handling in the body in general and, in particular, in the kidney, followed by a detailed discussion of Gitelman's syndrome and isolated renal magnesium wasting, including the clinical and biochemical symptoms, genetic aspects and pathophysiology.     

Increased fracture risk in hypercalcemia. Bone mineral content measured in hyperparathyroidism

In the present study, 39 women with mild hypercalcemia, which had been detected 18 years earlier during a health survey, and presumably caused by primary hyperparathyroidism (HPT), were investigated together with 34 age-matched controls. The bone mineral content (BMC) of the nondominant distal forearm was measured by single-photon absorptiometry, and the occurrence of fractures was recorded. Among women up to the age of 70 years, those with hypercalcemia had lower BMC than the controls (P less than 0.05), whereas among the older women, there was no difference. Twelve of the women with probable primary HPT had suffered a distal radius fracture as compared with 3 of the controls (P less than 0.05). Thus, also mild hypercalcemia is a risk factor for bone loss and distal forearm fractures. The findings constitute arguments in favor of early detection and treatment of primary HPT.     

Milk alkali syndrome. Does it exist and can it be differentiated from primary hyperparathyroidism?

Four patients with milk-alkali syndrome (MAS) presented with many of the characteristics of primary hyperparathyroidism including hypercalcemia, low or normal serum phosphorus levels, normal or increased urinary calcium levels, and inappropriately high or elevated serum parathyroid hormone levels. These laboratory findings differ from those classically described in MAS, i.e., hypercalcemia without hypercalciuria and a normal or high plasma phosphate level. Because the serum calcium level failed to return to normal after two weeks of hydration and a low calcium diet, and because of the inability to distinguish this syndrome from primary hyperparathyroidism, two of the four patients underwent neck exploration. Four normal parathyroid glands were histologically proven in each, and at autopsy in a third patient, there was no evidence of parathyroid hyperplasia or adenoma. Hypercalcemia eventually resolved in all patients with a low-calcium diet for as long as six months. Of the several features of MAS, hypercalcemia, alkalosis in the presence of azotemia, a history of increased calcium and alkali intake, and a response to dietary calcium restriction are helpful in differentiating this syndrome from primary hyperparathyroidism. Laboratory tests in patients with MAS may be confusing and the return to normocalcemia in response to a calcium deficient diet may be delayed.     

Unusually prolonged vitamin D intoxication after discontinuation of vitamin D: possible role of primary hyperparathyroidism

A 77-year-old woman had taken 50,000 IU of vitamin D2 daily, instead of once weekly, for over 2 years. She developed severe hypercalcemia, and after stopping vitamin D, her serum 25-hydroxyvitamin D (25(OH)D) remained higher than 250 nmol/l for almost 2(1/2) years. Inappropriately high parathyroid (PTH) concentrations were particularly evident after serum calcium was suppressed to slightly above the reference range by the administration of intravenous pamidronate and prednisone. It seems that an underlying primary hyperparathyroidism that was masked initially by the hypercalcemia of vitamin D intoxication was responsible for the unusually prolonged half-life of 25(OH)D in the blood. After vitamin D2 had been stopped, the decline in serum 25(OH)D was unusually slow. In this unusual case, primary hyperparathyroidism probably prevented an appropriate increase in the vitamin D-catabolizing enzyme, 25(OH)D-24-hydroxylase, thereby slowing metabolic clearance of 25(OH) vitamin D.     

Pseudogout as a clue and complication in primary hyperparathyroidism

The pseudogout syndrome has been suggested to be a diagnostic clue of hyperparathyroidism or a complication after parathyroidectomy that abruptly relieves hypercalcemia. In this report of 20 patients who had pseudogout, eight had intermittent attacks of arthritis associated with chondrocalcinosis that led through the pseudogout syndrome to a confirmed diagnosis of primary hyperparathyroidism. In an additional 12 patients, the diagnosis of pseudogout was made in patients who suffered from acute arthritis after parathyroidectomy that relieved the primary hyperparathyroidism. The postoperative attacks were seen most commonly on or after the second day after surgery and were associated with the lowest point in serum calcium levels. Pseudogout occurred in one or more joints, often involving the knee. The diagnosis was proved by aspiration of joint synovial fluid in many of the patients and identification of calcium pyrophosphate dihydrate crystals. To estimate the incidence of pseudogout in the population of patients with primary hyperparathyroidism, these 20 patients were distinguished in 531 patients undergoing parathyroidectomy, for a 3.8% incidence of the pseudogout feature. No other markers of higher risk for this complication were apparent, including age, sex, biochemistry, or prior history. This collected experience suggests that (1) pseudogout is a biochemical entity associated with primary hyperparathyroidism and may offer a useful clue to the recognition of the disease in screening; (2) acute arthritis after parathyroidectomy is most likely pseudogout, and this complication occurs more frequently than has been recognized previously; (3) patients with hypercalcemia have a high incidence of calcium pyrophosphate dihydrate crystal deposition in articular cartilage (chondrocalcinosis); and (4) relative hypocalcemia after parathyroidectomy is a stimulus for crystal shedding into synovial fluid, which may precipitate acute attacks of pseudogout.     

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 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

Successful treatment by cyclooxyenase-2 inhibitor of refractory hypokalemia in a patient with Gitelman's syndrome

Gitelman's syndrome is manifested by hypokalemic alkalosis, hypomagnesemia, hypocalciuria, normotensive hyperreninemia and hyperaldosteronism. Hypokalemia can at times be refractory to treatment. We present a patient refractory to a variety of drugs including indomethacin, the nonspecific COX inhibitor. Rofecoxib, a specific COX 2 inhibitor, promptly elevated serum potassium concentration with normalization of plasma aldosterone and near normalization of renin without a change in serum magnesium. Our patient also had rhabdomyolysis, a rarely reported complication, which was also ameliorated by COX 2 inhibition.     

Subtotal parathyroidectomy for primary chief cell hyperplasia of the multiple endocrine neoplasia type I syndrome.

To evaluate the efficacy of subtotal parathyroidectomy (STP) in the treatment of primary hyperparathyroidism due to multiple gland disease, 12 patients with multiple endocrine neoplasia (MEN) type I syndrome were reviewed out of 132 patients undergoing parathyroidectomy. Each patient had yearly follow-up examinations and calcium determinations for a minimum of four years except for one patient who died one year after S.T.P. Permanent hypoparathyroidism occurred in three patients. Two patients remained persistently hypercalcemic, and two patients developed recurrent hypercalcemia. One patient required oral administration of calcium and vitamin D for ten years following STP before recurrent hypercalcemia developed. Another patient was normocalcemic for three years before recurrent hypercalcemia was noted. Only five of these 12 patients remain normocalcemic without need of calcium and vitamin D therapy. In patients with MEN type I, the long-term results of STP are less than satisfactory. Not only is it difficult to gauge how viable parathyroid tissue must be left to prevent both permanent hypoparathyroidism and persistent hyperparathyroidism but there is also a long-term risk of recurrence.     

Identification of a novel R642C mutation in Na/Cl cotransporter with Gitelman's syndrome.

Gitelman's syndrome, a variant of Bartter's syndrome, is an inherited disorder characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria, and these abnormalities have recently been linked to the thiazide-sensitive Na/Cl cotransporter (TSC) gene. We evaluated three unrelated patients affected with this syndrome whose diagnosis was made based on clinical and biochemical features. The data of clearance studies in these patients were compatible with Gitelman's syndrome. We then investigated possible mutations of the TSC gene. In one patient whose parents are consanguineous, we identified a novel missense mutation in the TSC gene, which causes alteration of arginine to cysteine at codon 642 (R642C mutation) located in the cytoplasmic tail of the product. This mutation results in the loss of an MspI site in exon 15 of the TSC gene. MspI digestion analysis of genomic DNA fragments from the family was consistent with the autosomal recessive inheritance of the disorder, and presence of this mutation correlated with the clinical manifestations. Such mutation was not detected in 47 normal healthy subjects. In the second patient, we found another missense mutation in one allele of the TSC gene, which results in alteration of arginine to glutamine at codon 955. In the third patient, no mutation causing amino acid substitution was found in the TSC gene. These results indicate that the R642C mutation in TSC is critically important for impairment of this cotransporter function and also suggest the necessity of further investigations in the genetic background of Gitelman's syndrome.     

Gitelman's syndrome (familial hypokalemia-hypomagnesemia)

Gitelman's syndrome (GS) is a heritable renal disorder characterized by hypomagnesemia, hypokalemia and hypocalciuria, and distinct from Bartter's syndrome (BS). As compared to those with BS, patients with GS present at an older age, and they have a milder clinical picture, normal or slightly decreased concentrating ability, reduced urinary excretion of calcium, and permanently decreased serum magnesium level. GS is caused by defective NaCl transport in the distal convoluted tubule, and linked to the gene encoding the thiazide sensitive Na-Cl-cotransporter located on chromosome 16q. Patients with BS, on the other hand, have mutations in the transporters in the thick ascending loop of Henle (NKCC2, ROMK, and C1C-Kb). Treatment of GS consists of magnesium salt replacement. Long term prognosis in terms of maintaining growth, preserving renal function and life expectancy is excellent.     

Renal magnesium wasting, hypomagnesemic hypocalcemia, hypocalciuria and osteopenia in a patient with glycogenosis type II

We describe a patient with late-onset glycogenosis type II with renal magnesium wasting, hypomagnesemic hypocalcemia, hypocalciuria and osteopenia. He was admitted to our hospital for evaluation of lower limb weakness and mild deterioration of liver function. Serum magnesium and calcium were low with low-to-normal levels of PTH in the patient. Echocardiogram revealed marked concentric hypertrophy of the left ventricle. An X-ray film of his spine showed a thoracic (Th12) vertebral compression fracture. Bone mineral density of the lumbar spine L2-L4 showed a reduced value. Kidney, liver and muscle biopsies were performed. These were found to have histologic features consistent with glycogenosis type II. In addition, accumulation of PAS-positive material in the cytoplasmic vacuoles of the tubular epithelium was present only in the distal tubules. An oral magnesium supplement was useful in helping to correct the hypomagnesemia, despite the presence of renal magnesium wasting in our patient. Magnesium supplement was also sufficient to maintain normal serum calcium concentrations. However, the hypocalciuria persisted in our patient despite correction of hypomagnesemia. In conclusion, the consistent association between the glycogen accumulation in distal tubules, renal magnesium wasting, hypomagnesemic hypocalcemia and hypocalciuria, in the absence of other identifiable reasons, suggests a cause-and-result relationship. Also, the combination of renal magnesium wasting, hypomagnesemia and hypocalciuria is a picture similar to that of Gitelman's syndrome in our patient. The glycogen accumulation in distal tubules may cause renal magnesium wasting and hypocalciuria through tubular injury. Therefore, we may speculate that the present case has glycogenosis type II-associated Gitelman's-like syndrome.