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| Rev Esp Endocrinol Pediatr 2024;15(2):35-39 | Doi. 10.3266/RevEspEndocrinolPediatr.pre2024.Dec.932 | |||||||||
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| A case of severe neonatal hyperparathyroidism secondary to a de novo heterozygous mutation in the calcium-sensing receptor gene (CaSR) with a favorable response to cinacalcet | |||||||||
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| Caso de hiperparatiroidismo neonatal grave secundario a una mutación heterocigota de novo en el gen del receptor sensor del calcio (CaSR) con adecuada respuesta al cinacalcet | |||||||||
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| Sent for review: 1 Nov. 2024 | Accepted: 7 Dec. 2024 | Published: 30 Jan. 2025 | |||||||||
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| MarÃa Mora Loro1, Ana Ortiz Ortigosa1, Isabel Leiva Gea2, Leo Tapia Ceballos2, José Manuel Jiménez Hinojosa2 | |||||||||
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| 1 PediatrÃÂa. Hospital Materno Infantil Regional de Málaga. Málaga, Málaga (Spain) 2 EndocrinologÃÂa Pediátrica. Hospital Materno Infantil Regional de Málaga. Málaga, Málaga (Spain) | |||||||||
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| Correspondence:MarÃa Mora Loro, PediatrÃÂa, Hospital Materno Infantil Regional de Málaga, Málaga, Málaga, Spain E-mail: mmora0325@gmail.com | |||||||||
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Introduction Severe neonatal hyperparathyroidism (NSHPT) is a rare condition with only about 100 cases described in the literature1. It is a life-threatening disorder that typically manifests in the first weeks of life, characterized by failure to thrive, respiratory distress, hypotonia, and characteristic bone alterations2. The pathophysiology is due to elevated serum parathyroid hormone (PTH) levels and hypercalcemia secondary to a loss of function in the gene that encodes the calcium-sensing receptor (CaSR), located on chromosome 3q13.213. The CaSR is a transmembrane G protein-coupled receptor primarily located in the parathyroid glands and renal tubules. It is responsible for detecting circulating plasma calcium concentrations and regulating PTH secretion and urinary calcium excretion to maintain homeostasis3. Mutations with loss of function in the CaSR gene decrease the receptor's sensitivity to circulating calcium, leading to increased PTH secretion and, consequently, higher serum calcium concentration. Inactivating biallelic mutations, whether homozygous or compound heterozygous, are responsible for the condition, whereas heterozygous mutations result in a milder form of presentation known as familial hypocalciuric hypercalcemia (FHH)4. However, cases of NSHPT related to compound heterozygous mutations do exist, and their clinical severity depends on the residual functionality of the receptor. The treatment consists of managing acute hypercalcemia with intravenous fluid therapy, diuretics, and bisphosphonate infusion5, followed by long-term treatment. Until recently, parathyroidectomy was the definitive treatment. However, despite reducing calcemia levels, parathyroidectomy has adverse effects and can negatively impact patients' quality of life6,7. In recent years, calcimimetic drugs, such as cinacalcet, have emerged as an alternative treatment. Cinacalcet works by binding to the extracellular domain of the CaSR, promoting its activation, increasing sensitivity to calcemia, and normalizing PTH secretion6. However, cases of NSHPT unresponsive to cinacalcet have been reported, particularly in homozygous cases with minimal residual protein function or those with truncated binding sites for cinacalcet on the extracellular domain of the receptor5,7,8,9,10,11. Therefore, the use of cinacalcet should be individualized12.
Clinical case We report the case of a 22-day-old first-born female with adequate weight, length, and head circumference for gestational age, with no prenatal or postnatal concerns. The maternal family history showed no findings of interest, while the paternal history could not be obtained as the mother was the only caregiver. The patient was brought to primary care, showing a 14.6% weight loss from birth. She was bottle-fed, with sucking and swallowing difficulties. Additionally, she presented with constipation, as well as frequent regurgitations and vomiting. Physical examination revealed decreased subcutaneous fat and palpable indurated masses at the rib level. Neurological examination showed marked hypotonia on horizontal and vertical suspension. Blood tests revealed a corrected calcium of 12.9 mg/dL (reference range [RR] 8-11.3 mg/dL), ionic calcium of 1.61 mmol/L (RR 1.08-1.3 mmol/L), and phosphorus of 5.2 mg/dL (RR 4.8-7.4 mg/dL). Parathyroid hormone (PTH) was 195 pg/mL (RR 10-65 pg/mL), with alkaline phosphatase levels of 423 U/L (normal < 1076 U/L) and 25-hydroxy-vitamin D of 36.8 pg/mg (normal > 30 pg/mg). The urinary calcium/creatinine ratio in an isolated urine sample was 0.43 (normal < 0.86). A skeletal survey showed a bell-shaped ribcage and multiple rib fractures. The study also demonstrated diffuse bone demineralization, as well as fractures in the distal humeri and femora with laminar periosteal reaction. Additionally, asymmetry was observed in the epiphyseal ossification of both femurs and humeri, being larger in the right limbs (Figure 1). An electrocardiogram and kidney ultrasound scan performed to rule out complications from hypercalcemia showed no significant findings. Given the suspicion of primary hyperparathyroidism and early onset within the first weeks of life, a genetic study was requested, which detected a heterozygous (c.658C>T; Arg220Trp) mutation in the CaSR gene, corresponding to a previously undescribed nonsense mutation compatible with severe neonatal hyperparathyroidism. The genetic study was extended to the mother, who did not carry the pathogenic variant. Since she was the only caregiver of the child, paternal genetic testing could not be obtained. Intravenous fluid therapy was initiated (intravenous 0.9% saline/5% glucose; total 200 cc/kg/day) along with furosemide (3 mg/kg/day), achieving an initial decrease in calcemia to 11.7 mg/dL (RR 8-11.3 mg/dL). The patient also required nasogastric tube feeding due to suction-swallowing incoordination and low weight. A subsequent rise in calcemia occurred a few days later, leading to the initiation of subcutaneous calcitonin (4 mg/kg/day). After 10 days of treatment with subcutaneous calcitonin and discontinuation of diuretic therapy, the patient showed stable serum calcium levels around 12 mg/dL (RR 8-11.3 mg/dL) and phosphoremia of 4.9 mg/dL (RR 4.8-7.4 mg/dL), and oral phosphorus solution was introduced. Following a literature review that revealed several cases of heterozygosis successfully treated with cinacalcet, and given the limitations of parathyroidectomy in managing this condition, off-label treatment was proposed and approved by the mother. Treatment was initiated with diluted oral cinacalcet (1.5 mg tablet diluted in 5 mL of water) at the minimum dose according to the literature (0.2 mg/kg/day), with progressive dose increases based on response and weight gain. Patient tolerance was monitored, and serum calcium and phosphorus concentrations were measured regularly. PTH levels were measured monthly and at the third and sixth months of treatment. After initiation of calcitonin and cinacalcet treatment, calcium levels stabilized at the upper limit of normal range during the first 6 months, along with normalization of PTH levels (Figure 2). Optimal calcium control was achieved from the sixth month onwards with a cinacalcet dose of 2.7 mg/kg/day. Subsequently, the dose was adjusted according to weight, up to a maximum dose of 4 mg/kg/day at the ninth month of treatment.
Discussion and conclusions We report a case of neonatal severe hyperparathyroidism with a heterozygous C>T point mutation at nucleotide c.658 in exon 4 (c.658C>T) which results in the replacement of arginine by tryptophan at codon 220 (Arg220Trp) of CaSR gene successfully managed with cinacalcet. To date, only nine cases have been successfully treated, six of which involved compound heterozygous mutations2,12,13,14,15,16 and three with homozygous CaSR mutations17,18,19. The remaining reported cases showed no favorable response to cinacalcet, requiring long-term treatment with parathyroidectomy or bisphosphonates5,7,8,9,10,11. NSHPT is a potentially lethal disease that usually occurs in the first months of life, and delayed diagnosis can result in a mortality rate exceeding 50%20. Its prevalence is unknown, with no published studies of its worldwide distribution to date21. It should be suspected in neonates with symptoms compatible with hypercalcemia and underlying biochemical alterations, such as increased calcium, PTH, and serum alkaline phosphatase, along with decreased phosphorus levels. The presence of bone fractures and skeletal demineralization supports the diagnosis. However, definitive diagnosis requires genetic testing. Initial treatment aims to control calcium levels to prevent acute complications and achieve hemodynamic stabilization through fluid therapy and hypocalcemic drugs, such as diuretics, calcitonin, or intravenous bisphosphonates5. In recent decades, long-term management has consisted of curative parathyroidectomy, with total parathyroidectomy without autotransplantation showing the lowest failure and recurrence rates reported to date7. Nevertheless, this technique reduces PTH to undetectable levels, leading to secondary hypoparathyroidism and requiring lifelong calcium and calcitriol administration6. Cinacalcet is a calcimimetic drug that acts by binding to the extracellular domain of CaSR and inducing a conformational change that promotes its activation6. In this regard, its mechanism of action is similar to that of physiological calcium increase in healthy individuals, avoiding undesirable effects derived from parathyroidectomy. Currently, its use in pediatric patients is restricted to children older than 3 years with advanced chronic kidney disease, to reduce bone remodeling secondary to 1,25-dihydroxyvitamin D deficiency. Its approval in the management of neonatal hyperparathyroidism remains to be defined. This article presents a case of NSHPT with a heterozygous mutation showing adequate response to long-term cinacalcet treatment, achieving normalization of calcium levels at the sixth month of treatment with a dose of 2.7 mg/kg/day, consistent with maximum doses reported in other articles13. The maximum dose reached was 4 mg/kg/day at the ninth month of treatment, compared to the maximum reported dose in the literature of 9.6 mg/kg/day14. However, not all cases of hyperparathyroidism treated with cinacalcet show an adequate response. Initially, it was postulated that the main factor determining response to cinacalcet was the severity of the genetic mutation and, consequently, the residual functionality of the encoded receptor. Thus, individuals with homozygous mutations resulting in truncated proteins with minimal functionality were expected to have little or no response to cinacalcet13,22. Nonetheless, in recent years, cases with homozygous mutations showing response to treatment have been reported17,18,19, suggesting that additional factors must be involved. Recent reviews indicate that the integrity of the cinacalcet binding site in the extracellular domain is another determining factor12, potentially expanding the number of individuals with hyperparathyroidism who could be candidates for cinacalcet treatment. However, many questions remain unanswered, and further studies on calcium-sensing receptor functionality are needed to establish definitive conclusions. | |||||||||
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