Pediatric Neuroendocrine Neoplasia of the Parathyroid Glands: Delving into Primary Hyperparathyroidism
Abstract
:1. Introduction
Aim
2. Materials and Methods
3. An Update of Pediatric Primary Hyperparathyroidism: From Admission to Outcome
3.1. Clinical Presentation
3.2. Genetic Considerations
3.3. Lab Findings
3.4. Imaging Tools
3.5. Surgical Procedures
3.6. Outcome
4. Discussion
4.1. Changes in Terminology over the Years concerning Parathyroid Tumours
4.2. Neonatal Primary Hyperparathyroidism
4.3. Calcium-Lowering Drugs in Children with PHP
4.4. Paediatric PHP: Osteoporosis and Fracture Issues
4.5. Trans-Pandemic Insights into Paediatric PHP
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AP2S1 | adaptor protein complex 2 subunit sigma |
CASR | Calcium-sensing receptor |
BMD | bone mineral density |
CT | computed tomography |
CDC73 | cell division cycle |
DXA | Dual-Energy X-ray Absorptiometry |
GHRH | Growth-Hormone-Releasing Hormone |
GNA11 | guanine nucleotide-binding protein subunit alpha-11 |
HRpQCT | high-resolution peripheral quantitative computed tomography |
MEN | multiple endocrine neoplasia |
PHP | primary hyperparathyroidism |
PTH | parathyroid hormone |
PHP | primary hyperparathyroidism |
PET/CT | positron emission tomography/computed tomography |
Tc | Technetium |
TBS | trabecular bone score |
SPECT/CT | single-photon emission computerized tomography/computed tomography |
VHL | von Hipple–Lindau |
VATS | Video-Assisted Thoracoscopic Surgery |
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Inclusion Criteria | Exclusion Criteria |
---|---|
Studied population: children and teenagers (patients 18 years old or younger) | Reviews, editorials |
PubMed access of the papers | Experimental studies |
Full-length, English-language articles | Secondary (vitamin D-associated) hyperparathyroidism and/or rickets |
Research keywords within the title and/or abstract: “pediatric primary hyperparathyroidism”, “child and primary hyperparathyroidism”, or “teenager and primary hyperparathyroidism” | Secondary or tertiary (renal) hyperparathyroidism |
Original studies (studies, case series, case reports) of any design (regardless the level of statistical evidence) | Primary hyperparathyroidism in pregnancy |
Time frame (by publication date): January 2020–July 2023 | Familial hypocalciuric hypercalcemia Bartter syndrome Inherited conditions of mineral metabolism |
Mixed (adult and pediatric) studies, unless a specific analysis of the pediatric data was provided |
First Author Year of Publication Reference Number | Study Design Studied Population | Outcome |
---|---|---|
He 2023 [45] | Single-center study (between 2003 and 2021) N = 32 patients with PHP Age: ≤18 years old (mean age of 14.7 ± 2.5 years) Parathyroid tumor size: 1–5.8 cm (mean size of 2.85 cm) | Cervical ultrasound: 100% sensitivity for single parathyroid tumors (none ectopic) 99mTc Sestamibi scintigraphy: concordant with ultrasound results in 98% of cases (N1 = 30) N2 = 2 patients with multi-glandular parathyroid disease according to 99mTc Sestamibi, but not with ultrasound assessment |
Sharma 2023 [46] | Single-center imaging study N = 23 children and teenagers with PHP (4/23 with germline mutations: 3 with CDC73 and 1 with CASR) | Dual-phase computed tomography provided good sensitivity (91.3%) and specificity (99.5%) in single-gland disease |
Szabo Yamashita 2022 [27] | Single-center retrospective study (between 1994 and 2020) N = 66 with PHP (61% females) Age: ≤21 years old (mean age of 17.3 years) | 71% symptomatic PHP 32% known with genetic PHP (mostly MEN1) 5% of apparently sporadic cases were genetic PHP Sporadic vs. familial PHP:
|
Sharma 2022 [26] | Single-center retrospective study (between January 2020 and January 2021) N = 36 patients with PHP (55% males) Age < 20 years (median age of 17 years) N1 = 10 genetic/familial PHP N2 = 16 apparently sporadic PHP | N1: 90% with pathogenic variants: MEN1 gene (8/10), CDC73 (1/10) N2 = 26.9% with pathogenic variants/homozygotes: CDC73 (4/26), CASR (3/26) N1 vs. N2:
|
Bernardor 2022 [18] | Multicenter study N = 18 patients with PHP receiving cinacalcet Median age of 10.2 years (N1 = 10 genetic PHP involving CASR, CDC73, and MEN1 genes) |
Median duration of therapy: 2.2 years Dose: 0.7 (0.6–1) mg/kg/day → 1 (0.9–1.4) mg/kg/day PTH drop (p = 0.01) Hypercalcemia drop (p = 0.002) Nephrolithiasis: 1/13 |
Ramonell 2022 [47] | Single-center (single surgeon) study N = 19 patients who underwent parathyroidectomy (as outpatients) for PHP Mean age of 14.1 years N1 = 1 case with MEN1 N2 = 1 case with MEN2 | 8/19 patients had unilateral parathyroidectomies 9/19 patients had trans-cervical thymectomies 1/19 subject had transitory hypocalcemia 1/19 subject had permanent hypoparathyroidism |
Boro 2022 [48] | Single-center study N = 10 patients who underwent parathyroidectomy Mean age of 16.7 years | 90% (of the patients) had muscle and skeletal complaints 50%: bone deformities 50%: kidney stones 30%: fractures 40%: gastrointestinal complaints 30%: pancreatitis 40%: hungry bone syndrome |
Shariq 2021 [49] | Retrospective study N = 80 patients with MEN1 Age: ≤18 years old (median age of 14 years) | 80% of the patients had PHP (70% of them underwent a parathyroidectomy) |
El Allali 2021 [50] | Retrospective study N = 63 patients with PHP who underwent genetic analysis | 52% had genetic PHP Younger group (94%) had CASR mutations Older group presented other mutations (MEN1, CDC73, RET, and CDKN1B) |
Sharanappa 2020 [28] | Retrospective study (between 1989 and 2019) N = 35 patients with PHP Mean age of 15.2 years | 94% of the patients had symptomatic PHP 83%: skeletal anomalies 29%: renal complications 8%: familial PHP 97%: cure rate via parathyroidectomy 2.8%: hypercalcemic crisis 34%: hungry bone syndrome |
Rampp 2020 [5] | Triple-center retrospective study (between 1997 and 2017) N = 83 patients with PHP who underwent parathyroidectomy (64% females) Age: ≤21 years old (mean age of 17 years) | 25% of the patients had ectopic adenomas (59% of them were intra-thymic) 98% of the patients had a 6-month cure rate |
Jovanovic 2020 [51] | Case–control, single-center (high-volume surgery) study N1 = 14 patients with PHP (age ≤ 20 years) N2 = 28 adults with PHP | N1: high frequency of bone disease (42% of the patients from N1) N2: high frequency of asymptomatic presentation (39% of the patients from N2) Female to male ratio: 1 to 1 (N1); 8 to 1 (N2) (p = 0.005) |
Zivaljevic 2020 [52] | Retrospective study Out of 1363 patients, N = 14 patients with PHP (age < 20 years representing 1% of entire cohort) N1 = 6 children with PHP (aged ≤ 15 years) N2 = 8 teenagers with PHP (age: >15 and ≤20 years) | N1 vs. N2:
|
Pathogenic Variant | First Author Year of Publication Reference Number | Index Case |
---|---|---|
MEN1 | Petriczko 2022 [64] | 17-year-old male diagnosed with PHP and pancreatic neuroendocrine tumor Family data: father with PHP; sister with PHP, pancreatic neuroendocrine tumor, and central ganglioglioma |
Srirangam Nadhamuni 2021 [61] | At the age of 10: resection of an insulinoma At the age of 15: parathyroidectomy for PHP At the age of 18: gigantism due to ectopic GHRH production (pancreatic neuroendocrine tumor) | |
Cho # 2021 [53] | 12-year-old female was the daughter of the proband PHP, prolactinoma, pancreatic neuroendocrine tumor; Frame-shift mutation: NM_130799.1:c.1546dupC (p.Arg516Profs∗15) | |
Stasiak 2020 [62] | 16-year-old female diagnosed with PHP and pituitary microadenoma Novel MEN1 germline pathogenic variant (heterozygous variant c.105_107dupGCT) Family data: father with the same pathogenic variant (PHP and pituitary neuroendocrine tumor) | |
CDC73 | Blackburn 2022 [17] | 14-year-old male with heterogeneous gene deletion (symptomatic hypercalcemia due to a single PT adenoma) 10-year-old female with known autosomal dominant mutation (symptomatic hypercalcemia and bilateral PT adenoma) |
Mamedova 2020 [65] | 16-year-old female admitted for fractures, nausea, vomiting, weight loss (heterozygote status) 60 mg denosumab → parathyroidectomy → hypocalcemia | |
VHL | Belaid 2020 [67] | 16-year-old female admitted for diabetes mellitus and high blood pressure due to pheochromocytoma Ectopic PTH (adrenal) production → remission of PHP after bilateral adrenalectomy |
First Authors Reference Number | Year of Publication | Patient | Preoperative Findings | Postoperative Findings and Outcome |
---|---|---|---|---|
Muse [9] | 2023 | 16-year-old male | Nausea, vomiting, headache | Giant PT adenoma This is the first report of a PHP-related brain calcification at the frontal lobe in a child |
Sahu [11] | 2023 | 12-year-old female | History of limb deformities, multiple fragility fractures, kidney stones | Ectopic PT adenoma (intra-thymus) Sestamibi-guided thoracoscopic left thymectomy (CT with radioisotope scans) |
Boggs [15] | 2023 | 12-year-old female | Chest pain and dyspnea (complication: one osteolytic rib lesion) | Cystic left inferior PT adenoma Hungry bone syndrome following parathyroidectomy |
Badhe [83] | 2023 | 13-year-old male | Unilateral slipped capital femoral epiphysis | Ectopic mediastinal PT adenoma |
Zenno [84] | 2023 | 9-year-old female | Symptomatic hypercalcemia | Ectopic PT adenoma (pyriform sinus) → reperformed parathyroidectomy |
de Silva [40] | 2023 | 17-year-old male | Multiple fractures (brown tumors) | Good outcome after parathyroidectomy |
Prakash [76] | 2023 | 14-year-old female | PHP | Lincoln sign (“black beard sign”) due to mandibular uptake of the tracer during 8 F-fluorocholine PE/CT |
Gafar [37] | 2022 | 12-year-old male | A 6-year history of bone pain, loss of appetite, fatigue, progressive lower limb deformity | Removal of inferior parathyroid adenoma → postoperative hypocalcemia → calcium and alfacalcidol replacements Association with genu valgum due to rickets |
Hayashi [66] | 2022 | 11-year-old male | Hypercalcemic crisis | Poor response to standard care (including calcitonine → pamidronate) → successful emergency parathyroidectomy |
Vitale [69] | 2022 | 12-year-old male | Bilateral slipped capital femoral epiphysis | Ectopic PT adenoma (intra-thymus) Thoracoscopic resection → post-parathyroidectomy hungry bone syndrome |
Boro [70] | 2022 | 16-year-old female | Severe clinical picture | Atypical PT adenoma → postoperative hungry bone disease |
Oh [34] | 2022 | 9-year-old female (C1) 14-year-old male (C2) 14-year-old female (C3) | Abdominal pain due to pancreatitis (C1) Abdominal pain due to ureter stone (C2) Gait disturbance, weakness (C3) | Postoperative PTH normalization (C3: ectopic PT adenoma) |
Bin Yahib [29] | 2021 | 13-year-old female | 8-month history of recurrent abdominal pain, nausea, vomiting, bone pain | Ectopic PT adenoma (intra-thymus) Thoracoscopic resection |
Dikova [38] | 2021 | 12-year-old female (C1) 15-year-old female (C2) | Admission for genu valgum (orthopedic assessment) | C1 associated a local brown tumor C2 associated a local bone cyst |
Tuli [36] | 2021 | 16-year-old female (C1) 14-year-old female (C1) | Brown tumor at the heel (C1) Recurrent abdominal pain, emotional lability, asymptomatic nephrolithiasis (C2) | Preoperative cinacalcet (3 months) use (C2) Successful conventional parathyroidectomy in both cases (hungry bone syndrome in C2 that required calcitriol for 2 years) |
Flokas [68] | 2021 | 11-year-old female | Unexpected detection of hypercalcemia during admission for peritonsillar cellulitis | Ectopic PT adenoma (intra-thymic) Thoracoscopic thymectomy (5 months after initial presentation) |
Fukaya [35] | 2021 | 12-year-old female | Recurrent abdominal pain, macroscopic hematuria | Parathyroidectomy of a large PT adenoma (1.8 g) |
Rahimi [73] | 2021 | 15-year-old female | 8-year history of bone pain and progressive limping | Parathyroid carcinoma |
Roztoczyńska [77] | 2020 | 15-year-old male | Bilateral slipped capital femoral epiphysis, polydipsia, polyuria, weight loss | Orthopedic correction (brown tumors) → medical therapy for hypercalcemia (including pamidronate) → left inferior parathyroidectomy |
Legault [71] | 2020 | 14-year-old male | Abdominal pain, vomiting, constipation, pelvic brown tumor | Parathyroidectomy → hungry bone syndrome Postoperative brown tumor remission |
Minelli [85] | 2020 | 17-year-old female | Psychiatric manifestations | Ectopic PT adenoma (intra-thymus) Robot-assisted surgery for tumor removal |
Seo [10] | 2020 | 15-year-old male | Adenoma localization required SPECT/CT | Ectopic PT adenoma (intra-thymus) → VATS |
Lenherr-Taube [72] | 2020 | 13-year-old male | Muscle and bone pain, brown tumors | Parathyroid carcinoma (loss of parafibromin) Therapy with pamidronate, denosumab → parathyroidectomy → hungry bone syndrome (intravenous calcium for 3 weeks) → no relapse for 18 months Postoperative brown tumor remission |
Pal [44] | 2020 | 12-year-old male 16-year-old male | Posterior reversible encephalopathy syndrome | Neurological symptom remission after parathyroidectomy |
David [74] | 2020 | 15-year-old female | Brown tumors | Parathyroidectomy → hungry bone syndrome |
Lee [39] | 2020 | 15-year-old male | Bilateral genu valgum | Parathyroidectomy → calcium normalization within 2 months |
Omi [78] | 2020 | 13-year-old female | Fibular fracture | Parathyroidectomy (confirmation of parathyroid carcinoma) → at age of 22: femoral fracture → resection of bilateral lung metastases → at age of 33: re-resection of pulmonary metastases → at age of 57 → suspected neck recurrence → en bloc resection of parathyroid adenoma → 11C-methionine-positive tumor recurrence → removal → relapse 8 months later → denosumab for hypercalcemia + radiotherapy to control the recurrence |
First Author Reference Number | Year of Publication | Patient | Clinical Presentation | Management |
---|---|---|---|---|
Shaukat [102] | 2022 | 6-month-old male | Lethargy, bradycardia, hyperreflexia (his sibling died of the same condition) | CASR pathogenic variant Poor control of hypercalcemia through pamidronate, cinacalcet → parathyroidectomy+ self-transplantation of half of the left inferior PT gland → calcium and alfacalcidol supplements |
Özgüç Çömlek [103] | 2022 | 6-day-old male | Hypotonia, poor feeding → weight loss | Therapy with cinacalcet for 13 months → hypercalcemia after 2 months since stopping cinacalcet→ parathyroidectomy |
Gupta [104] | 2022 | 20-day-old female | Growth and developmental delays | Parathyroidectomy at 7 months |
Hassan [105] | 2022 | 3 infant siblings | Polyuria, failure to thrive, fractures | 2/3 patients (a 7-month-old female and an 8-month-old male) were tested and found positive for homozygous missense CASR pathogenic variant: c 2038 C T p (Arg680Cys) Patients underwent parathyroidectomies |
Höppner [101] | 2021 | 2 infant siblings | Hypercalcemia + preterm (C1) Hypercalcemia + severe muscular hypotonia + thrombocytopenia + multiple fractures (C2) | Heterozygous CASR pathogenic variant: c.554G>A; p. (Arg185Gln) Both patients were stabilized under medical therapy (C2: therapy with cinacalcet was used for 3 months) |
Gulcan-Kersin [108] | 2020 | 2-day-old female | Severe hypercalcemia during the first day of life | Homozygous CASR pathogenic variant: c.1836G>A (p.G613E) Therapy with cinacalcet since day 2 → 18 months (heterozygote status of her father and sister) |
Abdullayev [106] | 2020 | 7-month-old male | Multiple episodes of hypercalcemia early after birth | Therapy with calcitonin, cinacalcet, pamidronate → parathyroidectomy twice at 7 months (first removal of all 4 PT glands → persistent high PTH → thymectomy) |
Sorapipatcharoen [107] | 2020 | 10-day-old female | Severe hypercalcemia early after birth | Homozygous CASR pathogenic variant 1630 (c.1630C > T) Therapy with calcitonin, cinacalcet, pamidronate, zoledronate → parathyroidectomy (day 70) → hungry bone syndrome |
Sadacharan [99] | 2020 | 4 cases (mean age of 28.7 days) | Severe hypercalcemia early after birth (hypotonia, respiratory insufficiency, failure to thrive) | Medical therapy → parathyroidectomy + trans-cervical thymectomy (+hemi-thyroidectomy in one case) |
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Carsote, M.; Stanciu, M.; Popa, F.L.; Gheorghe, A.-M.; Ciuche, A.; Nistor, C. Pediatric Neuroendocrine Neoplasia of the Parathyroid Glands: Delving into Primary Hyperparathyroidism. Biomedicines 2023, 11, 2810. https://doi.org/10.3390/biomedicines11102810
Carsote M, Stanciu M, Popa FL, Gheorghe A-M, Ciuche A, Nistor C. Pediatric Neuroendocrine Neoplasia of the Parathyroid Glands: Delving into Primary Hyperparathyroidism. Biomedicines. 2023; 11(10):2810. https://doi.org/10.3390/biomedicines11102810
Chicago/Turabian StyleCarsote, Mara, Mihaela Stanciu, Florina Ligia Popa, Ana-Maria Gheorghe, Adrian Ciuche, and Claudiu Nistor. 2023. "Pediatric Neuroendocrine Neoplasia of the Parathyroid Glands: Delving into Primary Hyperparathyroidism" Biomedicines 11, no. 10: 2810. https://doi.org/10.3390/biomedicines11102810