Answers

  1. 1.

    What are the diagnostic possibilities in a child with hypocalcemia and nephrocalcinosis?

    The differential diagnoses for hypocalcemia with nephrocalcinosis are familial isolated hypoparathyroidism (FIH), syndromic hypoparathyroidism, calcium-sensing receptor (CaSR)-activating mutations (sporadic and autosomal dominant), pseudohypoparathyroidism (insensitivity to PTH), and acquired causes of hypoparathyroidism (HPT). Familial hypoparathyroidism has autosomal recessive (GCM2, PTH gene mutations), autosomal dominant (CaSR gene mutation and some cases of GCM2 mutations), or X-linked (SOX3 gene mutation) inheritance. DiGeorge syndrome type 1 and type 2, CHARGE syndrome, autoimmune polyendocrine syndrome type 1, Kenny-Caffey syndrome type 1 and type 2, Sanjad-Sakati syndrome, Barakat syndrome, Kearns-Sayre syndrome, MELAS syndrome, mitochondrial trifunctional protein deficiency syndrome, Gracile bone dysplasia, and Pearson syndrome are the syndromic causes of hypoparathyroidism. Activating mutations of the CaSR gene cause autosomal dominant hypocalcemia type 1. Pseudohypoparathyroidism is caused by insensitivity to the PTH hormone due to mutations in genes PTHR1, GNAS, PRKAR1A, and hypomagnesemia [1]. The acquired causes of hypoparathyroidism include activating antibodies to the CasR, maternal hyperparathyroidism, post-surgical and radiation-induced damage to the parathyroid glands, deposition of iron or copper (thalassemia, hemochromatosis, Wilson disease), or infiltration (neoplastic invasion, sarcoidosis, amyloidosis) [2].

    Our patient had tetany, convulsions with hypocalcemia, hyperphosphatemia, low serum PTH, nephrocalcinosis, and calcifications in basal ganglia and frontal lobes. Hence, a provisional diagnosis of hypoparathyroidism was considered. Syndromic and acquired causes of hypoparathyroidism were considered unlikely as there were no features or history suggestive of the same. Pseudohypoparathyroidism was ruled out as serum PTH was low. A targeted genetic analysis by clinical exome sequencing was performed in our case which revealed a heterozygous missense variation c.1151C>T in exon 5 of the GCM2 gene (chr 6: 10874598G>A), confirming the diagnosis of familial isolated hypoparathyroidism-type 2 (autosomal dominant inheritance).

  2. 2.

    How should this child be managed?

    Management of such cases includes evaluation, treatment of acute hypocalcemia, and long-term follow-up. The index case presented with seizures to our pediatric emergency unit. At admission, there were no features suggestive of meningitis, and the blood glucose was normal. The index case had hypocalcemia, hyperphosphatemia with low PTH levels, and normal serum creatinine, confirming hypoparathyroidism. Another condition with similar clinical manifestations (tetany, seizures), hypocalcemia, hyperphosphatemia, and ectopic calcifications in brain and kidneys is pseudohypoparathyroidism. However, specific clinical features (short stature, obesity, rounded face, and brachydactyly mostly affecting the 4th and 5th metacarpals and metatarsals in Albright hereditary osteodystrophy) and high serum PTH levels in pseudohypoparathyroidism differentiate it from hypoparathyroidism [3].

    Hypoparathyroidism is associated with ectopic calcifications. Hence, screening for calcifications in the kidney and brain is recommended. This includes urinary calcium/creatinine ratio and renal ultrasonogram to look for nephrocalcinosis and computed tomography (CT) of cranium for basal ganglia and intracerebral calcifications. Ophthalmological evaluation for posterior subcapsular cataract should be done which can occur due to elevated calcium-phosphorus products accumulating in the lens of the eyes [4]. Our index case had elevated urinary calcium/creatinine ratio (0.42) and grade 3 nephrocalcinosis with bilateral symmetrical calcification in basal ganglia and frontal lobes.

    Treatment of acute hypocalcemia aims at control of seizures and correction of hypocalcemia to prevent further seizures. Intravenous calcium gluconate (elemental calcium 9.3 mg/mL) 1–2 ml/kg (total dose should not exceed 10 ml) diluted with an equal amount of dextrose should be given slowly at the rate of 0.5 to 1 mL/min under strict cardiac monitoring, followed by infusion of the same solution every 4–6 h until calcium is normalized. Long-term goals in the management of hypoparathyroidism are to achieve a near normal range of serum calcium (8–9 mg/dL) to prevent seizures and tetany and decrease calcium–phosphate products to prevent ectopic calcifications. Targeting higher serum calcium levels and overzealous treatment with oral calcium and calcitriol should be avoided which can result in hypercalciuria and nephrocalcinosis leading to renal impairment or chronic kidney disease in some cases. To achieve this, oral calcium (calcium carbonate or calcium citrate) and active form of vitamin D3 (calcitriol) or vitamin D2 should be supplemented [5]. Severe hyperphosphatemia needs to be treated with phosphate binders such as sevelamer. Thiazide diuretics (hydrochlorothiazide) effectively reduce urinary calcium excretion and are often used in cases where normocalcemia (lower normal) is not achieved with adequate calcium and calcitriol doses; they are also used in cases with nephrocalcinosis [6]. On follow-up, serum calcium and phosphate levels, 6-monthly urinary calcium/creatinine ratio, and renal ultrasonogram (for nephrocalcinosis) should be done to titrate the doses of oral calcium and calcitriol supplementations [7]. The newer treatment regimens for hypoparathyroidism are teriparatide and recombinant human PTH. Recent trials with teriparatide (recombinant human PTH1-34 [rhPTH1-34]) in children with hypoparathyroidism showed promising results with a decrease in the requirement of oral calcium and calcitriol supplementation, steady serum calcium concentration, and decrease in urinary calcium excretion [8,9,10,11,12]. Our patient responded well to calcitriol and calcium supplements, along with hydrochlorothiazide and sevelamer, resulting in an increase in serum calcium levels and decrease in serum phosphorus levels on follow-up. Therefore, teriparatide was not prescribed.

  3. 3.

    What is the mechanism of nephrocalcinosis in this setting?

Individuals affected with hypoparathyroidism have a unique feature of being at risk for hypocalcemia as well as nephrocalcinosis. Nephrocalcinosis refers to an asymptomatic deposition of calcium within the renal parenchyma and can progress to renal insufficiency. Hyperphosphatemia, which occurs in association with hypoparathyroidism, may lead to calcium-phosphate deposition in soft tissues [13]. Vitamin D analogues and calcium supplements have been the cornerstone in the treatment of hypoparathyroidism to maintain calcium at the lower end of the normal range. The fine balance of providing just adequate treatment to treat hypocalcemia and avoiding overtreatment that can result in nephrocalcinosis is often difficult. Additionally, children with hypoparathyroidism due to activating CaSR mutation particularly have disproportionate hypercalciuria at lower serum calcium levels leading to poor response as well as worsening of hypercalciuria with conventional therapy [14, 15]. There are a few studies that have analyzed the long-term outcome of patients with hypoparathyroidism. A retrospective study of adult patients with hypoparathyroidism showed renal calcifications in 31% of patients with 2- to 17-fold increased rates (compared to normal individuals) of chronic kidney disease (stage 3 or higher) over a 7-year follow-up [16]. More recently, a study showed that nephrocalcinosis occurred in 6.7% of hypoparathyroid patients [17]. The predictors for nephrocalcinosis include younger age of onset of symptoms of hypocalcemia and higher serum calcium-phosphorus product at presentation. Levy et al. observed a three-fold higher risk of nephrocalcinosis in children than adults [13].

Commentary

Hypoparathyroidism (HPT) is a condition in which there is a partial or complete abatement of PTH secretion from parathyroid glands. Calcitriol (1,25-dihydroxy vitamin D) is produced by stimulation of 1-α hydroxylase enzyme (in the kidneys) by PTH. Calcitriol promotes active intestinal absorption of oral calcium. PTH also causes bone resorption resulting in the release of calcium into the blood and facilitates excretion of phosphate from the kidneys. Hence, HPT presents with characteristic features of hypocalcemia and hyperphosphatemia [18]. The incidence of HPT among various countries such as the USA, Italy, and Denmark is 23–37 per 1,000,000 population, whereas it was underreported in other countries [1]. Structural (maldevelopment or non-development of parathyroid glands), genetic, and autoimmune causes form predominant etiologies of HPT in the pediatric age group [4]. HPT is usually diagnosed by clinical features of hypocalcemia like tetany, seizures, carpopedal spasms, laryngospasm, stridor, and cardiac arrhythmias. The less common presenting features include dystonia, cognitive or motor delay, and anomalies of the skin, tooth, or nails [19]. Our index case was diagnosed to have familial isolated hypoparathyroidism (FIH), which was confirmed by a heterozygous missense variation of the GCM2 gene (autosomal dominant) on genetic analysis.

GCM2 (Glial cell missing-2) gene plays a vital regulatory role in the organogenesis of the parathyroid glands and the active function of parathyroid cells. GCM2 modulates the differentiation of parathyroid cells and the expression of functional genes such as the PTH gene. GCM2 with MAFB (transcriptional factor) modulates the expression of the PTH gene. The absence of GCM2 upregulation causes premature apoptosis of parathyroid cells [20]. Mutations in GCM2 genes were previously reported to be associated with hypoparathyroidism (loss-of-function mutations) and hyperparathyroidism (gain-of-function mutations) [21, 22].

Familial isolated hypoparathyroidism (FIH) is of two types—FIH-1 and FIH-2—caused by mutations in PTH and GCM2 genes, respectively. Homozygous, heterozygous, and compound heterozygous mutations of the PTH gene on chromosome 11p15 result in FIH-1 (OMIM 146200). Whereas the majority of cases are homozygous, few cases of heterozygous mutations of GCM2 gene on chromosome 6p24 leading to FIH-2 have been reported (OMIM 618883). Both autosomal recessive and autosomal dominant types of inheritance of FIH-2 have been described [21, 23,24,25,26].

Children with FIH-2 can present with hypocalcemia and seizures at an early age (infancy). These children who were adequately treated with calcium and vitamin D analogues had normal development [23]. The absence of parathyroid glands was detected in some FIH-2 patients [25].

Management of HPT consists of acute treatment of hypocalcemia (by intravenous calcium gluconate) and standard therapy with oral calcium carbonate or calcium citrate and vitamin D analogues (calcitriol or alfacalcidol) targeting near normal serum calcium levels (8–9 mg/dL) with prevention of hypercalciuria. Sevelamer is used to treat severe hyperphosphatemia. Thiazide diuretics are used to decrease hypercalciuria if present. However, some patients may not show significant improvement in their serum calcium levels even at higher doses of oral calcium and calcitriol, keeping them at risk of hypocalcemia as well hypercalciuria and nephrocalcinosis [27]. This can result in frequent hospital admissions for intravenous calcium gluconate (for acute symptomatic hypocalcemia). In a long-term retrospective follow-up study performed by Levy et al on children with HPT on standard therapy for 7.4 years, around 38% had nephrocalcinosis and 45% had low eGFR [13]. Another study performed by Saha et al with 165 patients who received conventional therapy reported nephrocalcinosis in 6.7% and kidney dysfunction in 14% of the patients. Among these patients, 9% had developed nephrocalcinosis over a follow-up period of 10 years on conventional therapy [17].

High doses of cholecalciferol (vitamin D) in some cases can cause hypercalcemia as it gets stored in fat, leading to protracted PTH-independent hypercalcemia when these fat stores are released. Children receiving vitamin D doses of more than 1,000,000 units/day are at high risk of hypercalcemia. Vitamin D intoxication causes hypercalcemia by augmented absorption of calcium from the intestine as well as intensified bone resorption [28].

Some patients with HPT, especially with activating mutations of CaSR and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy were earlier reported to have a poor response to conventional therapy [6]. Previous studies on teriparatide (rhPTH1-34) in children with HPT showed better results with twice a day dose compared to once a day dose in terms of serum calcium levels and reduced urinary excretion of calcium [8]. Another study showed efficacy and safety of rhPTH1-34 up to 3 years with adequate linear growth, weight gain, bone accretion, and high normal bone turnover markers [9]. Studies on pump delivery of rhPTH1-34 twice a day injection in children with HPT reported normal serum and urinary calcium [10]. A recent study performed by Winer et al observed that twice daily or thrice daily subcutaneous rhPTH1-34 injections are safe and efficacious replacement therapy up to 10 years in HPT patients [11]

Conclusions

To summarize, we have presented a child with recurrent episodes of tetany and seizures, in association with grade 3 nephrocalcinosis, who was confirmed to have hypoparathyroidism due to heterozygous missense variation in the GCM2 gene (autosomal dominant inheritance). Nephrocalcinosis can complicate hypoparathyroidism in a significant proportion of cases. It is important for pediatric nephrologists to be aware that in any child with hypocalcemia, hyperphosphatemia, hypercalciuria, and nephrocalcinosis, workup for hypoparathyroidism should be initiated to ensure prompt management strategies.