Abstract
Homozygous inactivating pathogenic variants of calcium-sensing receptors cause severe hyperparathyroidism (HPT), typically presenting in early infancy. In the pediatric age group, HPT is uncommon and can be due to parathyroid adenoma or hyperplasia. We describe the case of a 3-year, 10-month-old girl who presented with severe HPT with symptomatic hypercalcemia, skeletal demineralization, and bone pains resulting from a homozygous missense variant p.Gly670Arg in the CaSR gene that was previously reported in association with familial hypocalciuric hypercalcemia in its heterozygous state. Parathyroidectomy with autotransplant of one-fourth of the gland in the forearm did not result in a cure even after the removal of autotransplant. In addition to controlling preoperative hypercalcemia, pamidronate helped alleviate bone pains and improve skeletal remineralization when used postoperatively for a brief period.
Keywords: calcium sensing receptor, hyperparathyroidism, pamidronate, bone pains
Introduction
Hyperparathyroidism (HPT) is uncommon in the pediatric age group and is either sporadic or familial. Sporadic HPT is most commonly caused by solitary adenoma, whereas familial cases result from parathyroid hyperplasia or multinodular adenoma [1]. In neonates and infants, it is almost exclusively caused by the inactivating pathogenic variants of the calcium-sensing receptor (CaSR) gene. Located on chromosome 3, the CaSR gene encodes for a plasma membrane G protein-coupled receptor abundant in parathyroid glands and kidneys and is responsible for calcium homeostasis by regulating PTH production from parathyroid glands and renal calcium excretion. Inactivation of the CaSR gene alters the set point for PTH production causing hypercalcemic syndromes: neonatal severe hyperparathyroidism (NSHPT) and familial hypocalciuric hypercalcemia (FHH). Although FHH is often asymptomatic, NSHPT causes severe hypercalcemia, skeletal demineralization, and debilitating symptoms and can be fatal if left untreated [2]. We report a girl presenting with NSHPT phenotype resulting from a homozygous pathogenic CaSR variant at 3 years, 10 months of age and discuss the difficulties in diagnosis and management.
Case Presentation
A 3-year, 10-month-old girl presented with an 8-month history of progressive body aches and joint pains that rendered her immobile and bedridden. She was born at term (weight: 2.88 kg; length: 48.5 cm) to a third-degree consanguineous couple. She had gastroesophageal reflux and poor weight gain at 6 weeks of life that improved with medical management. At 18 months, she was investigated for global developmental delay, microcephaly, and failure to thrive. Clinical exome sequencing using next-generation sequencing (NGS/CES) reported a homozygous missense pathogenic variant in the RBBP8 gene, on exon 11 of chromosome 18, associated with Jawad syndrome or Seckel syndrome 2. In carrier screening, both parents were heterozygous for the same variant. The child's phenotype partially fits into the literature descriptions of these syndromes (eg, facial dysmorphism, intellectual disability, microcephaly; postnatal growth restriction, skeletal abnormalities) NGS/CES also identified long stretches of copy-neutral loss of heterozygosity in many chromosomes including chromosome 3, indicating the possibility of autosomal recessive conditions, but were attributed to underlying consanguinity.
By her third birthday, the child could walk with support, speak a few words, and was playful and happy. A few weeks later she developed pains in her knees, elbows, hands, and feet. Because a mild COVID-19 illness preceded this, she was diagnosed with postviral arthralgias. Blood work, including liver and renal functions and creatinine kinase, was unremarkable. Over the next couple of months, as symptoms worsened and the child became less mobile, she was referred to a rheumatologist who made a diagnosis of possible atypical juvenile rheumatoid arthritis. X-rays performed at that time were considered unremarkable by the treating clinician. Oral prednisolone was administered unsuccessfully for 5 months and a trial treatment with biologic agents was considered. When parents sought a second opinion, serum calcium (Ca) was checked, which was very high at 20.8 mg/dL (5.19 mmol/L) (reference range: 8.8-10.8 mg/dL; 2.2-2.7 mmol/L). At this juncture, she was referred to our team for further management.
Diagnostic Assessment
On examination, the child weighed only 10.2 kg (−3.34 SD score), was short (length: 87 cm; −3.44 SD score), and had dysmorphic facies. Small and medium joints were tender with mild swelling. The rest of the examination was unremarkable.
Further investigation revealed hypophosphatemia, normal alkaline phosphatase, normal magnesium, normal 25 (OH) vitamin D, and significantly elevated PTH (769 pg/mL, 81.5 pmol/L) (reference range: 15-60 pg/mL; 1.6-6.3 pmol/L) leading to a diagnosis of hyperparathyroidism. Her initial urine calcium creatinine ratio was slightly high (Table 1). A review of radiographs showed severe generalized osteopenia, joint capsule calcification, and acro-osteolysis (Fig. 1). Renal ultrasonogram revealed no nephrocalcinosis. Tc99m sestamibi scan was negative for parathyroid adenoma or focal hyperplasia. Neck ultrasonogram under anesthesia and a 4-dimensional computed tomography scan were negative for any parathyroid abnormality. Repeat urine calcium creatinine ratio results were lower than 0.1 mg/mg (<0.28 mmol/mol). Genetic reanalysis reported a homozygous novel missense variant c.G2038A/p.Gly680Arg in the CaSR gene on exon 7 of chromosome 3. Biochemical screening confirmed FHH phenotype in both parents and the younger sibling (Table 2).
Table 1.
Biochemical parameters pre- and postparathyroidectomy
| At admission | Immediate pre-PTE |
Immediate post-PTE | 2-weeks post-PTE | 18 months post-PTE | Reference ranges | |
|---|---|---|---|---|---|---|
| Serum calcium | 20.8 mg/dL (5.19 mmol/L) |
16.7 mg/dL (4.2 mmol/L) |
11.9 mg/dL (3.0 mmol/L) |
19.3 mg/dL (4.8 mmol/L) |
13.6 mg/dL (3.4 mmol/L) |
8.8-10.8 mg/dL (2.2-2.7 mmol/L) |
| Serum phosphate | 1.7 mg/dL (0.55 mmol/L) |
2.8 mg/dL (0.9 mmol/L) |
NA | 3.7 mg/dL (1.2 mmol/L) |
3.5 mg/dL (1.13 mmol/L) |
4-5.4 mg/dL (1.3-1.74 mmol/L) |
| PTH | 769 pg/mL (81.5 pmol/L) |
940 pg/mL (99.7 pmol/L) | 70 pg/mL (7.4 pmol/L) |
120 pg/mL (12.7 pmol/L) | 114 pg/mL (12.1 pmol/L) | 15-60 pg/mL (1.6-6.3 pmol/L) |
| Serum magnesium | 2.7 mg/dL (1.11 mmol/L) |
NA | NA | NA | NA | 1.5-2.4 mg/dL (0.63-1 mmol/L) |
| ALP | 228 U/L | NA | NA | 254 U/L | 224 U/L | 90-180 U/L |
| 25(OH) Vitamin D | 31.6 ng/mL (78.8 nmol/L) |
NA | NA | 26 ng/mL (65 nmol/L) |
29 ng/mL (72.4 nmol/L) |
20-40 ng/mL (60-100 nmol/L) |
| UCCR | 0.5 mg/mg (1.4 mmol/mol) |
<0.1 mg/mg (<0.28 mmol/mol) | NA | NA | NA | <0.4 mg/mg (<1.1 mmol/mol) |
Values in parentheses are International System of Units (SI).
Abbreviations: ALP, alkaline phosphatase; NA, not available; PTE, parathyroidectomy; UCCR, urine calcium creatinine ratio.
Figure 1.
Initial radiographs of the right hand and right foot showing severe osteopenia, acro-osteolysis (arrow chevrons), and joint capsule calcification (arrows).
Table 2.
Investigations of first-degree relatives
| Father | Mother | Younger sibling (aged 18 months) |
Reference ranges | |
|---|---|---|---|---|
| Serum calcium | 10.8 mg/dL (2.7 mmol/L) |
10.4 mg/dL (2.6 mmol/L) |
11.6 mg/dL (2.9 mmol/L) |
8.8-10.8 mg/dL (2.2-2.7 mmol/L) |
| Serum phosphate | 3.8 mg/dL (1.2 mmol/L) |
3.6 mg/dL (1.1 mmol/L) |
4.6 mg/dL (1.5 mmol/L) |
4-5.4 mg/dL (1.3-1.74 mmol/L) |
| PTH | 88.3 pg/mL (9.3 pmol/L) |
83.8 pg/mL (8.9 pmol/L) |
59.5 pg/mL (6.3 pmol/L) |
15-60 pg/mL (1.6-6.3 pmol/L) |
| UCCR | 0.03 mg/mg (0.08 mmol/mol) |
0.025 mg/mg (0.07 mmol/mol) |
0.02 mg/mg (0.05 mmol/mol) |
<0.4 mg/mg (<1.1 mmol/mol) |
Values in parentheses are International System of Units (SI).
Abbreviations: NA, not available; UCCR, urine calcium creatinine ratio.
Treatment
After initial hydration and furosemide, IV pamidronate (0.5 mg/kg/dose × once daily for 2 days) improved hypercalcemia and pain symptoms over the next 2 weeks. While awaiting further localizing investigations, hypercalcemia worsened and a trial of cinacalcet was started at 0.4 mg/kg/day, increased to 0.75 mg/kg/day over the next 4 weeks with no benefit. When genetic reanalysis revealed a homozygous pathogenic CaSR variant we proceeded with total parathyroidectomy (PTE) and cervical thymectomy with autotransplantation of 1/4 of the gland in the left forearm. Additional pamidronate (0.5 mg/kg/dose × once daily for 2 days) was given to control hypercalcemia preoperatively. Histopathology of all 4 removed glands confirmed hyperplastic parathyroid tissue with most of the capsule intact. The left inferior parathyroid measured 8 × 6 × 3 mm, whereas the other 3 measured 6 × 4 × 3 mm each. Within 10 minutes after PTE, her PTH level decreased from 940 pg/mL (99.7 pmol/L) to 70 pg/mL (7.4 pmol/L) and Ca level from 16.7 mg/dL (4.2 mmol/L) to 11.9 mg/dL (3.0 mmol/L). This correlated clinically with symptomatic improvement that lasted a few days. However, over the next 2 weeks, PTH steadily increased, though to a much lesser extent than the pre-PTE values, accompanied by worsening hypercalcemia and clinical deterioration (Table 2). Persistent HPT from either the autotransplant or an ectopic gland was considered.
As the child became immobile because of pain, a clinical decision was made to continue pamidronate for pain relief and to aid skeletal remineralization. A pamidronate dose of 0.75 mg/kg gave significant symptomatic relief lasting 3 to 4 weeks. Monthly pamidronate was continued for another 6 months. The child became increasingly mobile and pain-free, with noticeable improvement in bone mineralization on the X-rays, even as a milder degree of HPT persisted (Fig. 2). A later attempt at the removal of forearm autotransplant did not alter calcium or PTH levels.
Figure 2.
Comparative radiographs of the left hand at diagnosis (A) and 6 months after parathyroidectomy and pamidronate (B) show improved cortical thickness (arrow chevrons) and resolving joint capsule calcifications (arrows).
Outcome and Follow-up
Over the next 2 years, PTH fluctuated between 73 and 114 pg/mL, (7.7-12.1 pmol/L) (reference range: 15-60 pg/mL; 1.6-6.3 pmol/L) and calcium settled at 13.2 to 13.6 mg/dL (3.3-3.4 mmol/L), even after reintroducing a moderate amount of dairy in the diet. Cinacalcet was stopped. The child remains symptom-free on conservative management.
Discussion
Homozygous loss of function CaSR gene variants cause NSHPT and can be lethal in infancy without treatment [2]. The delayed presentation of our case beyond 3 years of age and a previous NGS/CES report without a mention of any CaSR variant posed an initial diagnostic challenge. Persistent HPT after PTE presented a significant therapeutic dilemma.
At 18 months, the NGS/CES in our case reported only Jawad syndrome/Seckel syndrome 2, based on a clinical phenotype that did not include hypercalcemia. Although NGS/CES has become the standard technique for genetic diagnosis, data sequencing bias can result in false-negative results. Data analysis can sometimes discard potential variants based on quality criteria, which can be avoided if a distinct clinical phenotype is available to help sequence specific variants [3]. Clinicians need to be cognizant of these limitations. When standard and advanced imaging did not find parathyroid adenoma or hyperplasia, we did a genetic reanalysis that revealed a homozygous missense variant c.G2038A/p.Gly680Arg in the CaSR gene on exon 7 of chromosome 3. The CASR gene has 2 mRNA transcripts: NM_001178065.2 (isoform 1) and NM_000388.4 (isoform 2). Using isoform 1, which is 10 amino acids longer than isoform 2, as the reference transcript, our genetics laboratory reported this finding as a novel variant of unknown significance. However, this variant corresponds to Gly670Arg when isoform 2 is used as a reference [4]. Gly670Arg has already been reported as a pathogenic variant and causes FHH in the heterozygous state [5-9]. To our knowledge, ours is the first report where a homozygous Gly670Arg variant resulted in severe HPT albeit with a presentation delayed beyond infancy.
The human CaSR gene encodes the CaSR which has a large extracellular domain, and 7 transmembrane hexahelical domains (TM/HH) with intra- and extracellular loops. Most pathogenic variants causing NSHPT are homozygous, whereas a few heterozygous variants with dominant negative effect have been described [10]. Conversely, FHH is asymptomatic and is typically caused by heterozygous inactivating variants, with a few reports of homozygous cases presenting with mild or no symptoms [11-13]. Late childhood, even adult-onset, severe symptomatic HPT was reported previously with pathogenic mutations in the extracellular domain, near the N terminal, leading the authors to postulate that the N-terminus location of the variant might be responsible for the late-onset phenotype [14, 15]. However, in our case, the mutant variant was located on exon 7, which encodes the TM/HH domain, implying that the position of the mutation alone cannot explain the CaSR residual activity. The loss of function CaSR gene variants are increasingly recognized as contributing to a spectrum of hypercalcemic disorders with marked phenotypic heterogeneity, rather than the strict binary classification of NSHPT and FHH. In homozygous inactivating pathogenic variants, the residual signaling capacity of the CaSR determines the severity of HPT. As a result, some survive into childhood and adulthood, and some may even present only as asymptomatic FHH [11, 16].
The immediate goal of medical management in severe HPT is to control hypercalcemia and alleviate symptoms before surgery. This involves hydration, a low-calcium diet, bisphosphonates (BP), and cinacalcet. French data show that milder forms of NSHPT can be treated conservatively with long-term medical management alone [17]. Cinacalcet, an allosteric CaSR modulator, can restore normal function in most pathogenic TM/HH domain mutations by increasing the receptors' binding affinity, signaling capacity, and cell surface expression. Long-term cinacalcet treatment has a significant dose-dependent effect on lowering serum calcium and causing symptom relief in patients with FHH1. However, the response to cinacalcet in NSHPT is quite variable and depends on the type of mutation [18]. An in vitro study showed that the Gly670Arg variant significantly reduced cinacalcet's binding affinity to the CaSR [7]. This could explain the lack of response to cinacalcet in our case and underscores the importance of genotyping in therapeutics.
For NSHPT, total PTE is usually curative with or without autotransplantation of parathyroid tissue in the forearm. In our case, HPT persisted at a milder degree post-PTE and did not improve with the removal of the forearm autotransplant, which could be due to the fragments of the parathyroid gland in the left forearm that could not be removed completely or from an unidentified ectopic gland [1, 19]. The prevalence of supranumerary parathyroids can be as high as 30%, most ectopic, with 80% located in the thymus and the rest ranging from carotid bifurcation to superior mediastinum [20, 21]. In NSHPT, preoperative localization studies including ultrasonogram, and Tc99m sestamibi scan, are often not helpful [1, 19]. Extensive exploration of the mediastinum and carotid sheath during the first surgery is not recommended because it is associated with significant morbidity. Moreover, in the kidneys, CaSR counteracts PTH-mediated calcium reabsorption via the cAMP signaling pathway. CaSR inactivation can persist in the kidneys even after PTE, leading to unopposed PTH-mediated renal calcium retention and aggravated hypercalcemia [11]. Pamidronate has been effectively used in HPT as rescue therapy to stabilize severe hypercalcemia and associated respiratory failure preoperatively [16, 22]. The skeletal demineralization and postoperative pain symptoms in our child improved with ongoing pamidronate infusions even after surgery. BPs have been used to mitigate bone pain in a variety of pediatric bone disorders associated with chronic pain, including osteogenesis imperfecta, idiopathic and secondary osteoporosis, unresectable benign bone tumors, and cancer-associated bone pain. In a systematic review, IV BPs were found to help alleviate pain in 20 of the 24 studies even with significant heterogeneity in the dose and duration of treatment [23]. Data from adult primary HPT studies suggest long-term therapy with BP as an option to improve bone mineral density in those with surgical contraindications or delays. However, as BPs increase PTH, which can contribute to adverse cardiovascular effects, their long-term safety is unclear [24].
Learning Points
Pathogenic loss of function CaSR variants cause a spectrum of hypercalcemic disorders and must be considered in severe HPT even beyond infancy.
Clinicians must be aware of the limitations of NGS/CES, and the importance of reanalysis when a new clinical situation arises.
Genetic laboratories searching for previously reported pathogenic variants should ensure they use the same isoform references.
An extended course of pamidronate can potentially offer symptom relief and aid in skeletal remineralization when parathyroid surgery fails to be curative in severe HPT.
Acknowledgments
We acknowledge the contribution of Leanne Ward in guiding the postoperative management and Rachel Gafni in helping to clarify the genetic diagnosis.
Contributor Information
Sirisha Kusuma Boddu, Department of Pediatric Endocrinology & Diabetes, Rainbow Children’s Hospital, Hyderabad, TS 500084, India.
Rabindera Nath Mehrotra, Department of Endocrinology, Apollo Hospitals, Hyderabad, TS 500033, India.
Siddhartha Chakravarthy, Department of Endocrine Surgery, Apollo Hospitals, Hyderabad, TS 500033, India.
Contributors
All authors made individual contributions to authorship. S.K.B. and R.N.M. were involved in the diagnosis and management of the patient. S.K.B. drafted the manuscript for submission. S.C. was responsible for the patient's surgeries. All authors reviewed and approved the final draft.
Funding
No public or commercial funding
Disclosures
None declared.
Informed Patient Consent for Publication
Signed informed consent was obtained directly from the patient's relatives or guardians.
Data Availability Statement
Original data generated and analyzed during this study are included in this published article.
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Associated Data
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Data Availability Statement
Original data generated and analyzed during this study are included in this published article.