Primary hyperparathyroidism (PHPT), characterized by autonomous parathormone (PTH) secretion from one or more parathyroid glands, is the leading cause of hypercalcemia [1]. Though common in adults, PHPT is rare in children and adolescents [2]. In adolescents, it may be sporadic or have a genetic etiology, occurring either as a part of multiple endocrine neoplasia (MEN types 1, 2 A, 4, 5) and hyperparathyroidism-jaw tumor (HPT-JT) syndromes or an isolated endocrinopathy in familial hypocalciuric hypercalcemia (FHH) or familial isolated hyperparathyroidism (FIHP) [3].

Adolescent PHPT presents distinct clinical features compared to adults, and most have a symptomatic disease affecting target organs [2]. Asymptomatic/normocalcemic forms are primarily detected through MEN, HPT-JT syndrome, or FHH surveillance. Beyond the classical and nonclassical manifestations [4], adolescents may develop rickets, short stature, and slipped capital femoral epiphysis (SCFE) *[5], [6]. Observational studies highlight unique adolescent PHPT phenotypes linked to various genetic causes *[5], *[7].

Surgical excision remains the treatment of choice. Most adolescents have single gland disease, and accurate preoperative localization enables minimally invasive parathyroidectomy [8], [9], [10]. Clinicians should be cognizant of ectopic parathyroid gland in 10–25 % of PHPT cases when interpreting preoperative scans [11]. MEN1 syndrome in adolescents is frequently associated with asymptomatic and asynchronous parathyroid gland involvement, making the optimal timing and extent of surgery debatable [12]. Surgery is not indicated in FHH; mild hypercalcemia does not require treatment, while moderate hypercalcemia can improve with off-label use of cinacalcet [13]. Postoperative hungry bone syndrome, common with skeletal involvement, should be managed similarly to adults.

The epidemiology of adolescent PHPT stands in contrast to its adult counterpart. Pediatric and teenage data come from retrospective observational studies, with nearly all reporting on fewer than 100 patients. The largest study to date comprised 168 pediatric/adolescent surgical cases across three decades [14]. A nationwide study from France estimated the combined incidence of neonatal, childhood, and adolescent PHPT at 1 per 200–300,000 live births- more than 100-fold lower than in adults [15], [16]. The United Kingdom Registry of Endocrine and Thyroid Surgery (UKRETS) further illustrated this disparity, with only 105 of 15,738 parathyroidectomies (0.7 %) between 2016 and 2020 performed in PHPT patients aged 20 years or younger [17]. Adolescent PHPT exhibits gender parity or a female predilection, with female-to-male ratios of 0.8–2, in contrast to adults with a clear female dominance after 45–50 years of age *[5], [6], *[7], [16], [18], [19], [20], [21], [22]. Adolescent PHPT continues to be predominantly symptomatic across the world, like adults in India and China, and in contrast to Western nations where adult PHPT has evolved into a largely asymptomatic disease after implementing routine serum calcium and osteoporosis screening programs and a the reduction in vitamin D deficiency (Table 1)[23], [24].

The greater propensity for symptomatic hypercalcemia, despite much earlier diagnosis than in adults, may be due to yet-unidentified biological factors [37].

A genetic cause is identified in 33–44 % of childhood-adolescent probands from retrospective studies, commonly involving MEN1, cell division cycle 73 (CDC73), and calcium-sensing receptor (CASR) genes *[5], [6], *[7]. The likelihood of detecting a germline mutation varies by clinical presentation. Two studies found deleterious germline variants in about one-fourth of pediatric patients with an apparently sporadic presentation (involving CDC73 and CASR genes), while the yield was significantly higher (66–90 %) in cases with familial inheritance or syndromic manifestations (involving MEN1 and CDC73) *[5], [6]. Although adolescent-specific data is unavailable, genetic testing yields across all age groups for suspected FHH (parathormone -dependent hypercalcemia with a 24-hour urinary calcium/creatinine clearance ratio <0.01) and FIHP are 30–60 % and 20–40 %, respectively [38], [39], [40], [41].

MEN1 syndrome, caused by heterozygous loss-of-function mutations in the MEN1 gene, predisposes individuals to neuroendocrine and nonendocrine neoplasms. These germline variants are found in 8–22 % of pediatric PHPT cohorts *[5], [6], *[7]. PHPT is detected in 50–77 % of pediatric/adolescent MEN1 patients by 18–21 years of age [12], [42], *[43]. Around 50–70 % harbor truncating variants *[5], [12], *[43]. Multiple parathyroid glands are affected asynchronously due to independent loss of heterozygosity events within each gland [44]. Current understanding has led to a proposal to replace 'parathyroid hyperplasia' with multiglandular parathyroid disease or adenomas to signify multiple clonal neoplastic proliferations [45].

MEN2A syndrome, due to heterozygous gain-of-function rearranged during transfection (RET) gene mutations, is characterized by medullary thyroid carcinoma, pheochromocytoma, and PHPT. These variants are identified in 0–6 % of pediatric/adolescent PHPT cohorts *[7], [20]. RET mutations in exons 10 and 11 most commonly predispose to PHPT [46]. Patients harboring exon 10-variants do not usually develop PHPT during adolescence, with an estimated 0 % penetrance by age 20 years [47]. PHPT is rarely reported in adolescents harboring exon 11 codon 634 missense variants, typically due to a single adenoma, though multiple glands may be involved asynchronously [46], [48].

MEN4 syndrome, resulting from monoallelic loss-of-function cyclin-dependent kinase inhibitor 1B (CDKN1B) mutations, represents approximately 3 % of MEN1 phenocopies in adults- patients clinically diagnosed with MEN1 syndrome but lacking MEN1 mutations [49]. PHPT, the most common manifestation, usually occurs from the fifth decade onward, affecting one or more parathyroid glands [50]. Adolescent cases are rare, with the youngest documented at age 15 years *[7], [51].

MEN5 syndrome results from loss-of-function MYC-associated factor X (MAX) mutations. It is linked to paraganglioma, pheochromocytoma, pituitary adenoma, and rarely, ganglioneuroma/neuroblastoma, pancreatic neuroendocrine tumor, and parathyroid adenoma. Limited cases are reported, and further research is required to understand its phenotype [19].

HPT-JT syndrome, arising from heterozygous loss-of-function CDC73 mutations, predisposes to PHPT, ossifying jaw tumors, uterine and renal cysts/tumors. These mutations account for 13–25 % of germline variants in childhood/adolescent PHPT studies *[5], [6], *[7]. While 15 % of adults harbor missense CDC73 variants, pediatric patients only have truncating mutations, suggesting higher adolescent penetrance with these variants [52], [53], *[54]. About 8 % of patients with CDC73 mutations develop PHPT by 25 years of age [54]. Single adenomas predominate, though multi-glandular disease (MGD) and carcinoma (15–20 % of adults, unknown risk in adolescents) may occur.

FHH results from monoallelic inactivating mutations in CASR (FHH1), G-protein subunit alpha 11 (GNA11, FHH2), or adaptor-related protein complex 2, sigma 1 subunit (AP2S1, FHH3), with near-complete penetrance [55]. These mutations elevate the serum calcium set point, causing hypercalcemia with relative hypocalciuria due to renal CaSR inactivation. The parathyroid glands appear normal or slightly enlarged.

Heterozygous missense CASR mutations are identified retrospectively in some adolescent probands with apparently sporadic single parathyroid adenoma/carcinoma *[5], [56]. Although biallelic CASR inactivation typically presents as neonatal severe hyperparathyroidism (NSHPT), low-grade homozygous missense variants rarely manifest as adolescent PHPT *[5], *[57]. These atypical presentations are discussed further in the subsequent section.

FIHP presents as familial PHPT without sufficient clinical, biochemical, or radiological evidence of other genetic causes. FIHP kindreds harbor germline variants in MEN1, CASR, and CDC73 [38]. A study found that one-fifth of kindreds without mutations in the other three genes carried activating glial cells missing transcription factor 2 (GCM2) gene variants. Among these, only one patient with a GCM2 mutation exhibited PHPT during adolescence [58]. Over half the kindreds lack an identified genetic etiology, suggesting the possibility of unidentified genes or deep intronic/promoter region mutations. Patients may develop single or multiple parathyroid neoplasms.

Due to limited routine biochemical screening, most adolescent cases present symptomatically. Asymptomatic/normocalcemic forms are mainly identified during the surveillance of patients with known genetic conditions. Retrospective studies show that 70–98 % of children and adolescents exhibit hypercalcemia-related symptoms, including both classical and non-classical manifestations. Renal stones, nephrocalcinosis, and pancreatitis occur in 10–40 %, 10–20 %, and 5–15 %, respectively *[5], [6], *[7], [16], [18], [20], [21], [22], [25]. In our cohort, 14 % of adolescents had an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m². While the prevalence of symptomatic cases and renal or gastrointestinal involvement shows no geographical variation, skeletal involvement differs by region.

Skeletal manifestations (bone pain, fractures, rickets, short stature, proximal myopathy, and osteitis fibrosa cystica) (Fig. 1) are less frequent in children/adolescents from Western countries (13–34 %) compared to India and China (71–86 %), mirroring adult patterns (Table 1) *[5], [6], *[7], [16], [18], [20], [21], [22], [25]. This disparity likely arises from endemic vitamin D deficiency and inadequate dietary calcium intake in Asian countries [59], [60]. Studies in adults show that vitamin D levels correlate inversely with adenoma weight, PTH and alkaline phosphatase (ALP) [61]. Vitamin D deficiency may accelerate adenoma growth, increasing PTH secretion, bone turnover, and bone loss, leading to severe skeletal manifestations. Corroborative differences in the vitamin D status and intact PTH (iPTH) levels in pediatric cohorts support this further. In France (1984–2004), 39/42 pediatric PHPT patients had a normal 25-hydroxyvitamin D (25D), with a subsequent study showing a median of 21 ng/mL *[7], [16]. In Asian cohorts, median levels were lower and ranged from 9.5 to 13 ng/mL *[5], [6], [22]. The median iPTH varied from 1.5 to 2 times the upper limit in the USA/Europe to 8–16 times in India/China *[5], [6], *[7], [16], [18], [20], [21], [22], [25], [62].

Rickets, a distinctive skeletal manifestation, occurs in 14–45 % of Asian pediatric PHPT cases *[5], [6], [18], [22]. Severe PHPT in late adolescence is occasionally associated with slipped capital femoral epiphysis (SCFE) [63]. 25(OH)D deficiency and PTH-induced hypophosphatemia can impair growth plate mineralization, especially during the adolescent growth spurt, leading to rickets or SCFE [64]. Chinese children/adolescents with PHPT-related rickets were younger, had higher ALP, and were more prone to postoperative hungry bone syndrome (HBS), suggesting that early disease onset affects bone mineralization more severely [6].

Short stature is observed in 10–40 % of cases, though effects on puberty are undocumented *[5], [6], *[7], [22]. Growth and puberty may be affected by rickets, chronic renal disease, nutritional deficits, and weight loss arising due to hypercalcemia-related symptoms like nausea, vomiting, peptic ulcer disease, or pancreatitis.

Among the nonclassical complications, psychiatric symptoms occur in 8–14 % of children/adolescents, with no data on quality-of-life scores, cognitive function, and cardiovascular manifestations *[7], [16], [20], [21], [22].

An observational study from our center found that adolescents without an evident family history or syndromic cause (the apparently sporadic group) have severe disease with target organ manifestations. In contrast, probands with familial or syndromic PHPT (F/S group) exhibited milder disease- more frequent asymptomatic presentation, reduced musculoskeletal involvement, lower iPTH, and parathyroid lesion size, attributed mainly to MEN1 syndrome [5].

The genetic forms of PHPT exhibit distinct clinical patterns in adolescence.

MEN1-associated PHPT, the most common MEN1 neoplasm in adolescence, presents with a familial/syndromic pattern and mild phenotype. In our cohort, all adolescent MEN1-PHPT cases were detected through serum calcium screening in asymptomatic individuals from MEN1 families or those presenting with entero-pancreatic or pituitary neoplasms. These patients demonstrated lower renal and musculoskeletal involvement, iPTH, and lesion dimensions (Fig. 2) compared to CDC73, CASR, and mutation-negative groups [5]. Previous studies corroborate these findings, with symptomatic MEN1-PHPT in 9–20 % by 18–21 years of age [12], [42], *[43].

Adolescent probands with CDC73-associated PHPT predominantly present as apparently sporadic cases, followed by HPT-JT syndrome and FIHP. In our cohort, probands harboring CDC73 variants exhibited severe phenotype, with renal and musculoskeletal manifestations in 4/5 patients, pancreatitis in one, PTH elevated > 10 times the upper reference level (URL), and median lesion size 2.7 cm. Limited data exists on the frequency of other HPT-JT manifestations in adolescence, with jaw tumors in 0–33 %, uterine tumors in 20–66 %, and renal lesions in 0–20 % *[5], [6], [52], [53], *[54], [65]. Jaw tumors mimic OFCs, and radiology, histopathology, and nonresolution after curative parathyroidectomy may help distinguish them [3].

Adolescents with CASR variants typically have FHH, characterized by familial presentation and a mild phenotype. While the phenotype of FHH is not described separately in adolescents, adult studies reveal familial presentation in 60 %, renal calculi in 5–30 %, occasional pancreatitis, chondrocalcinosis in approximately 20 %, and lack of other skeletal manifestations [56]. The patients have stable mild-moderate hypercalcemia with iPTH elevated in 20 %, while the rest have normal iPTH [66]. Although urinary calcium is generally low or normal, hypercalciuria is documented in up to 10 % [56]. Among FHH subtypes, FHH3 demonstrates a higher serum calcium and renal calcium reabsorption than FHH1 [67].

Our study identified missense CASR variants retrospectively in three adolescent probands operated for apparently sporadic severe PHPT. These patients showed symptomatic renal, gastrointestinal, or musculoskeletal damage with PTH elevated > 10 times URL and consistent hypercalciuria. Two patients achieved remission following a single adenoma/carcinoma resection [5]. Similarly, CASR variants have been retrospectively identified in operated adolescents and adults with symptomatic single parathyroid neoplasms [56].

One of the three adolescents in our cohort harbored a biallelic homozygous missense CASR variant with normocalcemic heterozygous parents (only proband data is published). Such post-infancy presentation in association with homozygous missense variants is only documented in nine probands (five, including ours diagnosed at <20 years of age), suggesting modest impairment of CaSR activity with delayed PHPT onset. Four of five pediatric presentations with homozygous variants were symptomatic, while one was asymptomatic *[5], [68], [69], [70], [71]. Given the broad phenotypic spectrum of CASR variants, some experts classify FHH as an atypical form of PHPT rather than a separate entity [72].

The clinical phenotype of adolescent PHPT associated with MEN type 2A, 4, 5, or GCM2 variants remains poorly characterized due to their rarity.

Adolescents without germline mutations usually have apparently sporadic disease with a severe PHPT phenotype *[5], [6], *[7], [16], [20], [21], [22], [25], [62].

A low index of suspicion often delays the diagnosis [2]. Diagnosis requires demonstrating hypercalcemia with elevated or inappropriately normal iPTH levels (>20–25 pg/mL). Biotin intake exceeding 1.5 mg/day can falsely lower iPTH in assays using the biotin-streptavidin interaction, requiring a minimum 3-day washout [1]. In suspected FHH, CCCR< 0.01 supports the diagnosis, though studies in young adults show over one-third of values overlap between FHH and PHPT [41]. Vitamin D deficiency, limited dietary calcium intake, renal insufficiency, thiazide diuretics, and errors in urine collection can falsely lower the urinary calcium in PHPT. A ‘pro-FHH’ score factoring plasma calcium, PTH, osteocalcin, and CCCR has also been proposed to differentiate FHH from PHPT in adults [73]. Some experts advocate a two-step diagnostic approach with genetic testing for all patients with CCCR< 0.02 [66]. As previously discussed, a germline variant may not be detected in a significant proportion of suspected FHH, and clinicians must integrate biochemical findings with patient and family data for accurate diagnosis.

After establishing PHPT, biochemical tests (serum phosphate, ALP, 25(OH)D, creatinine, spot or 24-hour urinary calcium/creatinine) and radiological assessments (abdominal ultrasonography, skeletal survey, dual energy X-ray absorptiometry ) are indicated to assess disease severity. Serum phosphate and ALP should be interpreted using age and gender-specific reference intervals [74]. Hypophosphatemia may be an index of disease severity and occurs in about half to three-fourths of Indian and French adolescent patients *[5], *[7], [20], [36]. eGFR estimation uses the revised Schwartz equation (≤18 years) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation (>18 years). Adolescent hypercalciuria is defined by spot urinary calcium/creatinine ratio > 0.25 mg/mg and correlates with 24-hour measurements [75], [76].

Abdominal ultrasonography can help detect silent nephrolithiasis/nephrocalcinosis. A skeletal survey may reveal osteitis fibrosa cystica comprising brown tumors, subperiosteal bone resorption, cortical thinning, ‘salt and pepper’ skull, acro-osteolysis, or rickets (Fig. 1). While there is limited data on the DXA areal bone mineral density (aBMD) in adolescent PHPT, patterns may resemble adults (Table 1) [32], *[33]. In MEN1 syndrome, aBMD measurements may be confounded by comorbid neoplasms rather than reflect PHPT severity. DXA vertebral fracture assessment (VFA) can be an alternative to spine radiography. High-resolution peripheral quantitative computed tomography (HR-pQCT) is not routinely employed and remains primarily investigational in adolescents [77].

In addition, adolescents with syndromic PHPT require age-appropriate clinical, biochemical, and radiological surveillance for other neoplasms.