POLSKI
Introduction
Primary hyperparathyroidism (PHPT) is a rare endocrine disorder in the pediatric population, characterized by dysregulated parathyroid hormone (PTH) secretion, leading to hypercalcemia. Unlike adults, where the condition is frequently asymptomatic and diagnosed through routine laboratory evaluations, pediatric cases often present with symptomatic hypercalcemia and sometimes significant end-organ damage [1, 2]. The estimated incidence of PHPT in children is approximately 2–5 per 100,000 person-years, which is markedly lower than the adult prevalence of 25 and 66 cases per 100,000 person-years in men and women, respectively [3, 4].
The etiopathogenesis of PHPT in children shows notable differences compared to adults. Hereditary factors play a significant role, accounting for approximately 10–15% of adult cases and up to 30% of pediatric cases [5]. Heritable forms of PHPT can be divided into syndromic and non-syndromic causes. Syndromic cases are most frequently associated with pathogenic variants in genes such as MEN1 (multiple endocrine neoplasia type 1), RET (MEN2A), CDKN1B (MEN4), MAX (MEN5), and CDC73 (hyperparathyroidism-jaw tumor syndrome, HPT-JT). Non-syndromic heritable PHPT includes neonatal severe hyperparathyroidism (NSHPT), a life-threatening condition caused by homozygous mutations in the CASR gene. Additionally, heterozygous CASR mutations and variants in GNA11 and APS1 are associated with familial hypocalciuric hypercalcemia (FHH). Mutations in GCm2 have also been implicated in familial isolated hyperparathyroidism. Among hereditary PHPT cases, more than half are due to MEN1 syndrome [1, 5].
Despite the significant contribution of genetic factors, sporadic solitary parathyroid adenomas remain the most common cause of pediatric PHPT, accounting for 65–80% of cases [5]. The rarity of pediatric PHPT and the absence of comprehensive evidence-based guidelines emphasize the need for detailed case studies and cohort analyses to improve understanding and optimize management. This study presents the clinical characteristics, diagnostic pathways, surgical outcomes, and follow-up of a case series of pediatric PHPT patients managed at a single tertiary center.
Material and methods
Study population
This observational, analytic, retrospective study was conducted at a tertiary care center in the central region of Portugal. Pediatric patients aged 0 to 18 years with a confirmed diagnosis of primary PHPT between 2012 and 2024 were included in the study.
Inclusion and exclusion criteria
Patients were included if they had biochemically confirmed PHPT, defined as elevated serum calcium levels (reference range 8.8–10.6 mg/dl) in conjunction with inappropriately normal or elevated PTH levels. Cases of secondary or tertiary hyperparathyroidism were excluded.
Data collection
Data were retrieved from medical records, including demographic information, clinical presentation, biochemical parameters, imaging findings, surgical outcomes, pathology reports, and follow-up outcomes. All imaging procedures were interpreted by experienced radiologists specializing in pediatric imaging, ensuring diagnostic accuracy. Family history was recorded as positive if one or more first-degree relatives had a diagnosis of PHPT, either linked to a known germline mutation or deemed sporadic. All patients, except one, without a prior known germline mutation underwent genetic testing using a comprehensive multi-gene panel, including CASR, CDC73, CDKN1B, GCm2, MEN1, and RET, performed with Next-Generation Sequencing technology. For one patient, genetic analysis was conducted using a single-gene approach via Sanger sequencing, reflecting standard clinical practice at the time of diagnosis. Genetic variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines, ensuring standardized interpretation.
Definitions and outcomes
Cure from PHPT was defined as achieving normocalcemia 6 months postoperatively. Persistent PHPT was defined as failure to achieve normocalcemia within 6 months of surgery. Recurrent PHPT was defined as the reappearance of hypercalcemia after an initial normocalcemic period of more than 6 months post-surgery.
Statistical analysis
Descriptive statistics were employed to characterize demographic, clinical, and biochemical data. Continuous variables were reported as mean ±standard deviation (SD) for normally distributed data or median with interquartile range (IQR) for non-normally distributed data, as appropriate. All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 27.0 (IBM Corp., Armonk, NY, USA).
Bioethical standards
As this study was retrospective in nature and involved analysis of anonymized data, formal ethics committee approval was waived according to our local institutional guidelines. The study was conducted in compliance with institutional policies regarding data privacy and confidentiality. All patient data were anonymized before analysis.
Results
The study group comprised 6 pediatric patients diagnosed with PHTP, with a male predominance of 66.6% (n = 4). The median age at diagnosis was 16 years (range: 9–17 years). A family history of PHPT was documented in 50% of cases, involving 2 patients with MEN1 mutations and one with a CDC73 mutation. Two patients were prepubertal at the time of diagnosis.
At presentation, 50% (n = 3) of the patients were symptomatic: recurrent abdominal pain (1/6), nephrolithiasis (2/6), and recurrent bone pain (1/6), as detailed in Table I. None of the patients reported classic symptoms of hypercalcemia such as polyuria, polydipsia, or weight loss, despite active inquiry during clinical evaluation. Retrospectively, only one patient (case 1) described symptoms consistent with polyuria that resolved following surgery. All asymptomatic patients in this series carried known germline mutations. Notably, case 4 was diagnosed 3 years prior with a pancreatic insulinoma following recurrent hypoglycemia. Surgical excision resolved the condition without recurrence. Case 1 was notable due to persistent pain in the right leg bone. An MRI identified a primary epiphyseal tibial lesion consistent with chondroblastoma, along with multiple nodular lesions. Bone scintigraphy also suggested the presence of a chondroblastoma, and an X-ray imaging revealed multiple lytic lesions. Further work up with laboratory tests showed corrected serum calcium at 13.1 mg/dl, markedly elevated PTH at 2,597 pg/ml, and alkaline phosphatase (ALP) at 1,662 U/l. Genetic testing was negative, and the lytic lesions were identified as brown tumors secondary to poorly controlled PHPT.
Table I
Characteristics of patients
Laboratory results at diagnosis and during follow-up are detailed in Table II and Table III. At presentation, the median highest recorded serum total calcium was 11.4 ±0.9 mg/dl (range: 10.7–13.1 mg/dl). The mean parathyroid hormone (PTH) level was 140 ±38 pg/ml, excluding an extreme outlier (Case 1) with a markedly elevated PTH of 2,597 pg/ml. Similarly, the mean alkaline phosphatase (ALP) level was 194 ±107 U/l, excluding the same outlier with a value of 1,662 U/l. The median 25-hydroxyvitamin D [25(OH)D] concentration was notably low at 16.0 ng/ml, reflecting common vitamin D insufficiency in this population. Mean serum phosphate was within the normal range at 3.5 ±0.2 mg/dl.
Table II
Summary of biochemical findings at diagnosis (6 patients) and 6 months post-surgery (4 patients)
Table III
Individual biochemical parameters before and after treatment; Vitamin D = 25-hydroxycholecalciferol; - not available; Calciuria is expressed as total urinary calcium and calculated per kg of body weight; hypercalciuria was defined as > 4 mg/kg/24 h
End-organ manifestations of PHPT were evident in several patients within the cohort. Nephrolithiasis was identified in 50% (n = 3) of the patients, with one case complicated by nephrocalcinosis, reflecting significant renal involvement. Hypercalciuria, defined as 24-hour urinary calcium excretion of > 4 mg/kg, was present in half of the patients for whom data were available (n = 5). Additionally, all patients in this subgroup exhibited an elevated calcium-to-creatinine clearance ratio (UCCR) greater than 0.02. Skeletal involvement was less prominent, with bone mineral density (BMD) assessment available for only one patient, revealing reduced bone density. Notably, no patient in this series experienced pathological fractures.
Parathyroid ultrasound (US) and technetium-99m sestamibi (99mTc-MIBI) scintigraphy were performed in all but one patient. US detected abnormal parathyroid glands in 80% (4/5) of cases, with imaging concordance in all but one (case 2). In this discordant case, US suggested bilateral inferior adenomas, but 99mTc-MIBI scintigraphy localized only the left-sided adenoma. Surgical exploration confirmed a solitary adenoma of the left inferior parathyroid, with the right-sided lesion being a thymic remnant. Additional imaging modalities were employed to improve lesion localization. Cervical magnetic resonance imaging (MRI) with contrast was conducted in 3 patients (cases 3, 5, and 6). In case 3, MRI detected 3 potential parathyroid adenomas. However, 99mTc-MIBI scintigraphy and US only revealed a single hyperfunctioning focus in the left inferior parathyroid. In contrast, no adenomas were visualized on MRI in cases 5 and 6.
Treatment and follow-up
Of the 6 patients included in this study, four underwent focused parathyroidectomy (PTX), while 2 did not. Case 5 underwent extensive diagnostic evaluation, including a 4D-dynamic contrast-enhanced MRI and an 18F-Choline PET/CT scan, both of which failed to localize a parathyroid lesion. Genetic testing was negative for known hereditary PHPT syndromes. Following a multidisciplinary team discussion, bilateral neck exploration was deemed inappropriate. The patient’s arthralgias improved over time, and her nephrolithiasis remained stable. She continues to be managed conservatively with hydration, vitamin D supplementation and regular clinical follow-up. Case 6, the most recently diagnosed patient, is a 10-year-old boy with autism spectrum disorder and a confirmed MEN1 germline mutation, inherited from his father and uncle. Due to his sensory sensitivities, standard imaging procedures such as parathyroid ultrasound and 99mTc-MIBI scintigraphy could not be performed without sedation. However, during a scheduled abdominal MRI under sedation for MEN1 surveillance, a 4D–dynamic contrast-enhanced neck MRI was conducted, which did not reveal any parathyroid abnormalities. The patient remains under close surveillance and managed conservatively with hydration and vitamin D supplementation.
The four patients who underwent PTX (cases 1–4) had solitary parathyroid adenomas localized to the left inferior pole. Tumor sizes ranged from 15 to 38 mm (median: 18 mm), and none exhibited atypical histological features. None of the 6 patients received bisphosphonates, cinacalcet, or loop diuretics preoperatively. All patients were advised to increase oral fluid intake and to correct vitamin D deficiency, when present. Case 1 additionally required intravenous hydration and was started on low-dose cholecalciferol supplementation (667 IU/day) one week prior to surgery.
Six months postoperatively, the mean corrected calcium level decreased to 9.6 ±0.5 mg/dl, and the median PTH level dropped to 48 pg/ml (range: 40–51 pg/ml), indicating biochemical cure.
Postoperative complications were minimal. Two patients experienced transient hypocalcemia, which resolved promptly with oral calcium supplementation. Case 1 developed hungry bone syndrome (HBS), presenting with profound hypocalcemia (ionized calcium of 1.02 mmol/l), hypophosphatemia, and hypomagnesemia, along with suppressed PTH levels (nadir: 23 pg/ml). Management included intravenous calcium and active vitamin D analogs. Due to persistent hypocalcemia, teriparatide (20 µg every 12 hours) was initiated, resulting in significant clinical improvement. There were no reports of recurrent laryngeal nerve injury or permanent postoperative hypoparathyroidism. All four surgically treated patients were followed for a median duration of 103 months (range: 17–134 months). No cases of persistent or recurrent PHPT were identified during the follow-up period, and all patients achieved sustained biochemical remission. End-organ manifestations significantly improved after surgery: bone pain resolved completely with healing of lytic lesions; abdominal pain, fatigue, and arthralgias fully resolved; nephrolithiasis stabilized without recurrence; and nephrocalcinosis demonstrated radiological improvement during follow-up.
Discussion
To the best of our knowledge, this study represents the largest single-center cohort of Portuguese patients under 18 years old diagnosed with primary hyperparathyroidism (PHPT). Although PHPT is a rare endocrine disorder in children and adolescents, our findings highlight its clinical heterogeneity and some of the challenges associated with its diagnosis and management.
Our group series exhibited a slight male predominance, contrasting with the female predominance typically observed in adult PHPT cases, where the disease is often asymptomatic and diagnosed incidentally during routine screening [6, 7]. In contrast, our patients presented with a broad clinical spectrum, ranging from asymptomatic individuals identified through familial screening, to symptomatic cases with bone pain and nephrolithiasis. The frequent presence of vitamin D deficiency in our patients is noteworthy, as it can exacerbate PTH overproduction by inducing secondary hyperparathyroidism, further contributing to bone resorption and calcium imbalance [4]. Skeletal manifestations, such as brown tumors observed in case 1, although uncommon, underscore the potential severity of untreated PHPT in pediatric patients.
Consistent with previous literature, sporadic solitary parathyroid adenomas are the most common cause of PHPT in our cohort and due to our limited sample size is the only diagnosis we found [3]. However, the high proportion of patients with hereditary forms of PHPT (50% in our series) is noteworthy and reinforces the importance of genetic screening in younger populations [6]. In particular, MEN1 and CDC73 mutations were predominant, consistent with prior reports indicating that MEN1 is the most frequent hereditary cause of PHPT in children. Due to the extended 12-year study period, comprehensive genetic panels for PHPT were not consistently available, as demonstrated in case 3.
Preoperative localization of hyperfunctioning parathyroid tissue is essential to optimize surgical outcomes. However, available data on imaging modalities in pediatric PHPT remain limited, and imaging strategies should be tailored according to institutional expertise and resource availability [8, 9]. Ideally, 2 concordant preoperative imaging studies – one anatomical and one functional – are recommended to allow for focused parathyroidectomy. Ultrasonography and 99mTc-sestamibi scintigraphy represent the first-line modalities. In cases of negative or discordant findings, additional imaging techniques such as magnetic resonance imaging (which offers the advantage of avoiding radiation exposure), multiphase computed tomography, or choline positron emission tomography (PET)/CT may be considered. Among these, choline PET/CT has demonstrated the highest reported sensitivity, though at the expense of a higher radiation dose [10]. In our group, parathyroid ultrasound and 99mTc-MIBI scintigraphy were concordant in most cases, supporting their combined use in surgical planning. The absence of multiglandular or ectopic disease in our series may explain this high concordance rate.
Surgical management remains the definitive treatment for PHPT and focused PTX may be even viable for appropriately selected patients with MEN-1 [6]. All surgically treated patients in our cohort achieved biochemical cure, with a median follow-up of 92 months. Importantly, no cases of permanent hypoparathyroidism or recurrent laryngeal nerve injury were observed.
In the preoperative setting, severe hypercalcemia (serum calcium > 14 mg/dl) or symptomatic hypercalcemia (calcium 12–14 mg/dl with symptoms) requires prompt treatment. In addition to standard interventions – such as intravenous hydration with normal saline, loop diuretics, and calcitonin – intravenous bisphosphonates can be considered for sustained reduction of serum calcium levels [11]. Short-term use in pediatric patients has been shown to be generally safe and effective, particularly in cases of severe or symptomatic hypercalcemia. Reported side effects may include transient flu-like symptoms. While long-term safety data remain limited in growing children, available evidence supports the cautious use of bisphosphonates in selected cases where initial measures are insufficient [12].
Cinacalcet, a calcimimetic agent, was not used in our series; however, its off-label use in pediatric PHPT has been increasingly reported. Recent multicenter data suggest that cinacalcet can be considered in selected cases, particularly when surgery is contraindicated or a parathyroid lesion cannot be localized. Its indications mirror those of severe and/or symptomatic hypercalcemia. Although not formally approved for this indication in children, growing clinical experience indicates that cinacalcet is generally safe and effective in lowering serum calcium and PTH levels when appropriately monitored [13].
Postoperative complications were minimal, limited to transient hypocalcemia and a single case of hungry bone syndrome (HBS). Although rare and frequently underdiagnosed in children, HBS can occur in severe or prolonged disease and requires diligent postoperative monitoring and management. Data on the prevention and predictors of pediatric PHPT are limited and mainly extrapolated from adult studies. Some risk factors include vitamin D deficiency, increased adenoma size, evidence of bone disease and high PTH. High-risk patients should initiate an intensive phosphocalcium monitoring as was the case of patient 1. Vitamin D supplementation needs to be balanced with increased risk of aggravating hypercalcemia. [14]. The high cure rate and low rate of complication underscores the importance of a dedicated team.
The conservative management of case 5 reflects the complexity of balancing surgical risks against potential benefits, particularly when imaging studies, including advanced modalities, fail to localize the lesion. Similarly, in case 6, clinical decisions were influenced by comorbid autism spectrum disorder, underscoring the need for individualized management strategies in pediatric PHPT.
Regarding hypercalcemia, none of the patients, except case 1, received additional measures besides increased hydration due to mild hypercalcemia. In the two non-operated patients, a conservative strategy was adopted given the very mild hypercalcemia, absence of severe symptoms and the lack of definitive lesion localization.
In the literature, a significant portion of published case series includes patients older than 18 years. The most comprehensive and recent review by Carsote et al. [15] included 493 cases under the age of 18 years, compiled from multiple pediatric cohorts of studies between 2020–2023. Their findings are largely consistent with ours: the mean age across series was 17 years, with no clear female predominance. Genetic causes of PHPT accounted for 5–27% of cases. Asymptomatic presentation was more frequent in hereditary PHPT, whereas sporadic forms were symptomatic in approximately 70% of patients. In contrast to our series, gastrointestinal symptoms (such as abdominal pain, weight loss, constipation, and nausea) and renal manifestations (including nephrolithiasis and polyuria) were reported in 40% and 28% of cases, respectively. Solitary adenomas were identified in 85% of sporadic PHPT cases and in 19% of hereditary cases. Imaging with neck ultrasound demonstrated 100% sensitivity in single-gland disease, with 98% concordance with Tc99m-sestamibi scans. The reported surgical cure rate following parathyroidectomy was 98%.
Another recent UK study [Z3] – one of the largest to date – included 168 pediatric PHPT cases over a 25-year period. The cohort was predominantly composed of sporadic cases (85%). In contrast to our series, this study reported a female predominance (69%) and a lower mean age at diagnosis (10 years). Clinical symptoms were not recorded. Although more than 60% of patients underwent bilateral neck exploration, focused parathyroidectomy was shown to be both safe and effective. Solitary adenomas were more frequent in sporadic cases, while familial PHPT was more commonly associated with multiglandular disease. An overall cure rate of 96.9% was achieved.
The primary limitation of this study is the small sample size, inherent to the rarity of pediatric PHPT. With only 6 patients over a 12-year period, statistical analyses are limited, and findings may not be generalizable to larger, more diverse populations. The retrospective design introduces potential biases, including incomplete data collection and variability in diagnostic and management approaches over the study period. For instance, comprehensive genetic testing was not consistently available throughout the study, as seen in case 3, which may have led to underdiagnosis of hereditary forms of PHPT. Despite these limitations, this study offers valuable insights into the clinical spectrum, management strategies, and outcomes of pediatric PHPT. Larger, multicenter studies are necessary to validate these findings and guide evidence-based diagnostic and therapeutic protocols for this rare condition.
Conclusions
Pediatric primary hyperparathyroidism (PHPT) is a rare but clinically significant disorder that often presents with symptomatic hypercalcemia and end-organ complications. In this single-center cohort, solitary parathyroid adenoma emerged as the most common cause, while hereditary syndromes, particularly MEN1 and CDC73 mutations, accounted for a substantial proportion of cases. Surgical management through parathyroidectomy was effective, resulting in biochemical cure and minimal postoperative complications. However, the complexity of managing asymptomatic or genetically predisposed patients highlights the need for individualized approaches. Given the high prevalence of genetic mutations in pediatric PHPT, routine genetic screening should be considered standard practice to guide clinical management and long-term follow-up. Multidisciplinary care and timely intervention are essential to prevent severe complications and optimize outcomes. Future multicenter studies are warranted to establish evidence-based guidelines for the diagnosis, treatment, and follow-up of pediatric PHPT.
