4.7 3.

Review

Pediatric Neuroendocrine
Neoplasia of the Parathyroid
Glands: Delving into Primary
Hyperparathyroidism

Mara Carsote, Mihaela Stanciu, Florina Ligia Popa, Ana-Maria Gheorghe, Adrian Ciuche and
Claudiu Nistor

https://doi.org/10.3390/biomedicines11102810
 biomedicines
Review
Pediatric Neuroendocrine Neoplasia of the Parathyroid Glands:
Delving into Primary Hyperparathyroidism
Mara Carsote 1,2 , Mihaela Stanciu 3, *, Florina Ligia Popa 4, * , Ana-Maria Gheorghe 2,5 , Adrian Ciuche 6,7,†
and Claudiu Nistor 6,7,†
Citation: 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
Academic Editor: Shaker A. Mousa
Received: 19 September 2023
Revised: 7 October 2023
Accepted: 13 October 2023
Published: 17 October 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Biomedicines 2023, 11, 2810. https://doi.org/10.3390/biomedicines11102810
1 Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
carsote_m@hotmail.com
2 C.I. Parhon National Institute of Endocrinology, 011863 Bucharest, Romania;
anamaria.gheorghe96@yahoo.com
3 Department of Endocrinology, Faculty of Medicine, “Lucian Blaga” University of Sibiu, Victoriei Blvd.,
550024 Sibiu, Romania
4 Department of Physical Medicine and Rehabilitation, Faculty of Medicine, “Lucian Blaga” University of Sibiu,
Victoriei Blvd., 550024 Sibiu, Romania
5 Ph.D. Doctoral School, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
6 Department 4—Cardio-Thoracic Pathology, Thoracic Surgery II Discipline, Carol Davila University of
Medicine and Pharmacy, 050474 Bucharest, Romania; adrianciuche@gmail.com (A.C.);
ncd58@yahoo.com (C.N.)
7 Thoracic Surgery Department, Dr. Carol Davila Central Emergency University Military Hospital,
010825 Bucharest, Romania
* Correspondence: mihaela.stanciu@yahoo.com (M.S.); florina.popa@yahoo.com (F.L.P.)
† These authors contributed equally to this work.
Abstract: Our objective was to overview the most recent data on primary hyperparathyroidism (PHP)
in children and teenagers from a multidisciplinary perspective. Methods: narrative review based on
full-length, English-language papers (from PubMed, between January 2020 and July 2023). Results:
48 papers (14 studies of ≥10 subjects/study, and 34 case reports/series of <10 patients/study).
Study-sample-based analysis: except for one case–control study, all of the studies were retrospective,
representing both multicenter (n = 5) and single-center (n = 7) studies, and cohort sizes varied
from small (N = 10 to 19), to medium-sized (N = 23 to 36) and large (N = 63 to 83); in total, the
reviewed studies covered 493 individuals with PHP. Case reports/series (n = 34, N = 41): the mean
ages studied varied from 10.2 to 14 years in case reports, and the mean age was 17 years in case
series. No clear female predominance was identified, unlike that observed in the adult population.
Concerning the assessments, there were four major types of endpoints: imaging data collection, such
as ultrasound, 99mTc Sestamibi, or dual-phase computed tomography (CT); gene testing/familial
syndrome identification; preoperative findings; and exposure to surgical outcome/preoperative
drugs, like cinacalcet, over a 2.2-year median (plus two case reports of denosumab used as an off-
label calcium-lowering agent). Single-gland cases (representing 85% of sporadic cases and 19% of
genetic PHP cases) showed 100% sensitivity for neck ultrasounds, with 98% concordance with 99mTc
Sestamibi, as well as a 91% sensitivity for dual-phase CT, with 25% of the lesions being ectopic
parathyroids (mostly mediastinal intra-thymic). Case reports included another 9/41 patients with
ectopic parathyroid adenomas, 3/41 with parathyroid carcinomas, and 8/41 subjects with brown
tumors. Genetic PHP (which has a prevalence of 5–26.9%) mostly involved MEN1, followed by
CDC73, CASR, RET, and CDKN1B, as well as one case of VHL. Symptomatic PHP: 70–100% of all
cases. Asymptomatic PHP: 60% of genetic PHP cases. Renal involvement: 10.5% of a cohort with
genetic PHP, 71% of sporadic PHP cases; 50% (in a cohort with a mean age of 16.7), 29% (in a cohort
with a mean age of 15.2); 0% (in infancy) to 50–62% (in teenagers). Bone anomalies: 83% of the
children in one study and 62% of those in two other studies. Gastrointestinal issues: 40% of one
cohort, but the data are heterogeneous. Cure rate through parathyroidectomy: 97–98%. Recurrent
PHP: 2% of sporadic PHP cases and 38% of familial PHP cases. Hungry bone syndrome: maximum
rate of 34–40%. Case reports identified another 7/41 subjects with the same post-parathyroidectomy
condition; a potential connection with ectopic presentation or brown tumors is suggested, but there
https://www.mdpi.com/journal/biomedicines
Biomedicines 2023, 11, 2810 2 of 25

are limited data. Minimally invasive thoracoscopic approaches for ectopic tumors seemed safe. The
current level of statistical evidence on pediatric PHP qualifies our study- and case-sample-based
analysis (n = 48, N = 534) as one of the largest of its kind. Awareness of PHP is the key factor to
benefit our young patients.

Keywords: neuroendocrine; primary hyperparathyroidism; multiple endocrine neoplasia; surgery;

pediatric; parathyroidectomy; ectopic; calcium; PTH; thoracoscopy

1. Introduction
Pediatric primary hyperparathyroidism (PHP) represents a rare condition that is
usually caused by a parathyroid neuroendocrine tumor, most commonly an adenoma (in
65–95% of cases) of small dimensions. Since clinical evaluation of the tumor itself is rather
irrelevant, the index of suspicion usually comes from acute and chronic hypercalcemia-
related complications [1,2]. Imaging tools are essential to locating the parathyroid tumor,
starting with a traditional anterior cervical ultrasound, up to the use of specific functional
imaging, such as the use of 99 m Technetium (Tc) Sestamibi scintigraphy, SPECT/CT
(single-photon emission computerized tomography/computed tomography), 4D-CT, 4D-
resonance magnetic imaging, etc. [3–6]. Surgical approaches, similar to those seen in adult
populations, are the only methods that provide a disease cure [7–9]. Recently, thoracoscopic
resection of ectopic adenomas (that generally represent 6–16% of all parathyroid tumors)
has been applied in young patients, as well [10–12].
As opposed to cases of adults admitted for the traditional panel of PHP (not the
modern picture of asymptomatic PHP), PHP-associated clues are unusual findings among
infants and teenagers, due to a reduced epidemiological impact (with an incidence of
1 case/300,000 children, or up to 2–5 cases/100,000, still almost 100 times less frequent than
PHP in adults); thus, diagnosis may be delayed, and the presentation may be complicated
by multiple bone, renal, digestive, cardiac, and/or growth disturbances [13–15].
A genetic background is found in 10–30% of juvenile cases, typically involving dele-
tions/duplications or pathogenic variants of the MEN1, which underlines multiple en-
docrine neoplasia type 1 syndrome (MEN1), CDC73 (also known as HRPT2; its germline
pathogenic variant causes hyperparathyroidism (jaw tumor syndrome)), CDKN1B, RET
(MEN2), AIP, CDKN1B, and CASR (calcium-sensing receptor) genes, requiring differential
diagnosis of familial hypocalciuric hypercalcemia, which might be complicated by severe
neonatal PHP with homozygote status [16–19]. In adults, one out of ten subjects confirmed
with PHP has a genetic condition, most commonly MEN1, MEN4, MEN2, hereditary
hyperparathyroidism (jaw tumor syndrome), or isolated familial PHP [20–22].
Overall, pediatric PHP is considered more severe when compared to PHP in adults,
due to its heterogeneous presentation, various complaints that a child cannot entirely
describe, and its rarity, which leads to a more challenging index of suspicion; also, a
complex pathogenic panel, with regard to mineral and bone metabolism changes during
growth and puberty, including the achievement of peak bone mass, could potentially
be affected by the high calcium and/or PTH (parathyroid hormone) levels caused by
the condition. For these reasons, it is mandatory to address this topic from a modern
multidisciplinary perspective, in order to increase awareness around it and to facilitate
its early recognition, thus reducing the disease burden, a result which has proven to be
life-saving in certain patients [2,23–25].

Aim
Our objective was to overview the most recent data concerning neuroendocrine tu-
mors causing PHP in children and teenagers from the multidisciplinary perspectives of
pathogenic traits, clinical presentations, genetic analysis, management, and outcomes.
Biomedicines 2023, 11, 2810 3 of 25

2. Materials and Methods

For this narrative review, we searched for full-length papers, published in the English
language, that were freely accessed via PubMed according to the key words “pediatric
primary hyperparathyroidism”, “child and primary hyperparathyroidism”, and “teenager
and primary hyperparathyroidism” (Table 1).

Table 1. The search criteria according to our methods.

Inclusion Criteria Exclusion Criteria

Studied population: children and teenagers (patients 18 years old
Reviews, editorials
or younger)
PubMed access of the papers Experimental studies
Secondary (vitamin D-associated) hyperparathyroidism
Full-length, English-language articles
and/or rickets
Research keywords within the title and/or abstract:
“pediatric primary hyperparathyroidism”, “child and primary
Secondary or tertiary (renal) hyperparathyroidism
hyperparathyroidism”, or “teenager and primary
hyperparathyroidism”
Original studies (studies, case series, case reports) of any design
Primary hyperparathyroidism in pregnancy
(regardless the level of statistical evidence)
Familial hypocalciuric hypercalcemia
Time frame (by publication date): January 2020–July 2023 Bartter syndrome
Inherited conditions of mineral metabolism
Mixed (adult and pediatric) studies, unless a specific
analysis of the pediatric data was provided

According to the three PubMed search strategies within the mentioned timeframe, we
identified 92, 115, and 95 papers, respectively, then applied the exclusion criteria, removed
duplicates, and ultimately included the following in this 3-year case- and study-sample-
based analysis: 48 original articles (14 studies (≥10 patients/study), 27 individual case
reports without, and 7 case reports and series (<10 patients/article)with, specific genetic
testing (n = 34 case reports/series)) (Figure 1).

Figure 1. The workflow of research according to our methods.

Biomedicines 2023, 11, 2810 4 of 25

3. An Update of Pediatric Primary Hyperparathyroidism: From Admission to Outcome

3.1. Clinical Presentation
The clinical elements may be acute (with recent onset), or there may be a history of
a few months or even years of various complications, including impairment in achieving
normal growth and pubertal development in severe cases; some authors consider the
clinical picture to be more severe than that seen in adults: children with genetic PHP who
come from families with a known mutation may be the subjects of surveillance programs;
thus, the clinical picture may be deficient [24,26]. One study from 2022, on 66 pediatric
patients with sporadic and familial PHP with a mean age of 17 years (studied between
1994 and 2020), showed that the clinical presentations were suggestive for the diagnosis of
PHP in 71% of the subjects (symptomatic PHP) [27]. A retrospective juvenile study (N = 35;
mean age of 15.2 years; male to female ratio of 1 to 1.9) revealed symptomatic PHP in
94% of the cohort; the most frequent clinical presentation was related to bone disturbances
(83%), followed by renal complications in 29% of the children and teenagers. Fractures
were confirmed in 54% of the individuals, while hypercalcemic crisis was identified in 2.8%
of them, and recurrent pancreatitis in 11.4% [28].
Bin Yahib et al. [29], while reporting on a teenager with recurrent abdominal pain as
a dominant feature on admission, performed a sample case analysis between 2007 and
2020 (13 articles regarding a total of 331 individuals diagnosed with PHP, aged 22 years
and younger) and identified the main symptoms of the clinical presentation as being renal
(like kidney stones and polyuria) in 27.41% of the patients, osseous (bone pain, deformities,
and fractures) in 23.49% of the individuals, fatigue-related (and lethargy) in 20.48% of the
cohort, gastrointestinal (for instance, recurrent abdominal pain, anorexia, nausea, vomiting,
weight loss, and jaundice) in 18.67% of the subjects, and neurological (for example, memory
loss, incapacity to concentrate, and depressive mood) in 17.46% of them. On the other hand,
the incidental diagnosis of PHP was established in 5.44% of the cases, and asymptomatic
PHP was confirmed in 3.3% of the 331 patients [29]. Abdominal pain may affect 11–45%
of the pediatric population, while 29% to 87% of juvenile cases with PHP involve this
complaint [29–33]. Of note, abdominal pain may be caused by hypercalcemia-induced
pancreatitis or PHP-related kidney stones (sometimes accompanied by hematuria) [34,35];
these should not be missed due to the fact that a child with PHP might present a certain
level of emotional instability, chronic asthenia, or other aches, such as bone pain [36].
Respiratory complaints are rarely reported; for instance, an 18-year-old female was
admitted for chest pain and dyspnea, and she was diagnosed with non-syndromic PHP,
complicated with an osteolytic rib lesion. She underwent left inferior parathyroidectomy,
which was followed by hungry bone syndrome; the pathological report pointed out a
parathyroid tumor with cystic transformation [15].
Rickets may be coincidental, and sometimes this delays the recognition of PHP. For
example, a 12-year-old boy coming from Sudan presented with a 6-month history of
bone pain, loss of appetite, and fatigue, associated with progressive lower limb deformity
that impaired normal walking. Left inferior parathyroid adenoma-associated PHP was
masked by rickets anomalies, such as genu valgum that required further surgical correction
after successful parathyroid tumor removal. Assessing the status of the vitamin D level
helps with the decision of vitamin D supplementation, including in selective cases, with
PHP-associated hypercalcemia [37]. However, Dikova et al. [38] reported two teenagers
with PHP-associated genu valgum [38]. Another case with PHP-related genu valgum
was published by Lee et al. [39]. A teenager suffering from bilateral genu valgum and
associated short stature was referred for orthopedic correction at the age of 15 (with normal
calcium values at that point); however, 2 years later, he suffered multiple fractures due
to adenoma-associated PHP causing brown tumors. A good outcome was registered
after parathyroidectomy [40]. In 2020, Lee et al. [39] reviewed all the cases with genu
valgum and PHP reported between 1945 and 2019 and found 23 cases. The potential
pathogenic mechanism is represented by PTH over excess and its contributions to the
Biomedicines 2023, 11, 2810 5 of 25

epiphyseal plate and to the bone remodeling amid puberty; however, this knowledge is
still incomplete [39,41].
Giant parathyroid tumors are exceptional in children; they may be associated with a
more severe clinical picture compared to small-sized parathyroid adenomas. A 16-year-old
male was admitted for severe digestive complaints, caused by biochemical and hormonal
issues related to a giant parathyroid adenoma (that was large enough to be palpable) [9].
Interestingly, this patient also displayed cerebral calcification at the level of frontal lobe
(according to a CT scan) that was considered by Muse et al. [9] to be the first reported
case in pediatric PHP (in 2023) complicated with this unusual entity [9]. While central
calcifications are rather signature of hypoparathyroidism, they have been exclusively
reported in adults with PHP, and they do not belong to the classical picture of PHP, as
opposed to nephrolithiasis or renal calcifications of any size [42–44].
Another unusual neurological presentation of PHP was reported by Pal et al. [44],
namely, posterior reversible encephalopathy syndrome due to hypercalcemia (manifested
as generalized seizures and anomalies of the sensorium). These two patients represent the
first of their kind in the pediatric population according to the authors, who identified only
four other cases, all in adults [44] (Table 2).

Table 2. Studies addressing PHP in children and teenagers (with different types of outcomes, and at
least 10 patients per study) according to our methods; the list starts with the most recent publication
date [5,18,26–28,45–52].

First Author
Study Design
Year of Publication Outcome
Studied Population
Reference Number
Cervical ultrasound: 100% sensitivity for single parathyroid
Single-center study (between 2003 and 2021) tumors (none ectopic)
He
N = 32 patients with PHP 99mTc Sestamibi scintigraphy: concordant with ultrasound results
2023
Age: ≤18 years old≤(mean age of 14.7 ± 2.5 years) in 98% of cases (N1 = 30)
[45]
Parathyroid tumor≤size: 1–5.8 cm (mean size of 2.85 cm) N2 = 2 patients with multi-glandular parathyroid disease
≤ according to 99mTc Sestamibi, but not with ultrasound assessment
Sharma Single-center imaging study
Dual-phase computed tomography provided good sensitivity
2023 N = 23 children and teenagers with PHP (4/23 with germline
(91.3%) and specificity (99.5%) in single-gland disease
[46] mutations: 3 with CDC73 and 1 with CASR)
71% symptomatic PHP
32% known with genetic PHP (mostly MEN1)
Szabo Yamashita
≤
Single-center retrospective study (between 1994 and 2020) 5% of apparently sporadic cases were genetic PHP
2022
≤
N = 66 with PHP (61% females) Sporadic vs. familial PHP:
[27]
≤
Age: ≤21 years old (mean age of 17.3 years)
≤ Single-gland disease: 85% vs. 19% (p < 0.00001)
recurrent PHP: 2% vs. 38% (p = 0.0004)
postoperative recurrence time: 61 vs. 124 months (p = 0.001)
N1: 90% with pathogenic variants: MEN1 gene (8/10), CDC73
(1/10)
Single-center retrospective study (between January 2020 and N2 = 26.9% with pathogenic variants/homozygotes: CDC73
January 2021) (4/26), CASR (3/26)
Sharma
N = 36 patients with PHP (55% males) N1 vs. N2: →
2022
Age < 20 years (median age of 17 years) →
[26]
N1 = 10 genetic/familial PHP asymptomatic PHP: 60% vs. 0% → (p < 0.001)
N2 = 16 apparently sporadic PHP lower baseline PTH: 237 vs. 1369 pg/mL (p = 0.001)
lower maximum tumor diameter (0.9 vs. 2.2 cm, p = 0.01)
renal complications: 10.5% vs. 71.4% (p = 0.01)
Multicenter study Median duration of therapy: 2.2 years
Bernardor N = 18 patients with PHP receiving cinacalcet Dose: 0.7 (0.6–1) mg/kg/day → 1 (0.9–1.4) mg/kg/day
2022 Median age of 10.2 years PTH drop (p = 0.01)
[18] (N1 = 10 genetic PHP involving CASR, CDC73, and Hypercalcemia drop (p = 0.002) →
MEN1 genes) Nephrolithiasis: 1/13 →
→
Single-center (single surgeon) study →
N = 19 patients who underwent parathyroidectomy (as 8/19 patients had unilateral parathyroidectomies
Ramonell
outpatients) for PHP 9/19 patients had trans-cervical thymectomies
2022
Mean age of 14.1 years 1/19 subject had transitory hypocalcemia
[47]
N1 = 1 case with MEN1 1/19 subject had permanent hypoparathyroidism
N2 = 1 case with MEN2
90% (of the patients) had muscle and skeletal complaints
50%: bone deformities
Boro Single-center study 50%: kidney stones
2022 N = 10 patients who underwent parathyroidectomy 30%: fractures
[48] Mean age of 16.7 years 40%: gastrointestinal complaints
30%: pancreatitis
40%: hungry bone syndrome

≤
≤
≤
Biomedicines 2023, 11, 2810 6 of 25

Table 2. Cont.

First Author
Study Design
Year of Publication Outcome
Studied Population
Reference Number
Shariq Retrospective study
80% of the patients had PHP (70% of them underwent a
2021 N = 80 patients with MEN1
parathyroidectomy)
[49] Age: ≤18 years old (median age of 14 years)
52% had genetic PHP
El Allali
Retrospective study Younger group (94%) had CASR mutations
2021
N = 63 patients with PHP who underwent genetic analysis Older group presented other mutations (MEN1, CDC73, RET,
[50]
and CDKN1B)
94% of the patients had symptomatic PHP
83%: skeletal anomalies
Sharanappa Retrospective study (between 1989 and 2019) 29%: renal complications
2020 N = 35 patients with PHP 8%: familial PHP
[28] Mean age of 15.2 years 97%: cure rate via parathyroidectomy
2.8%: hypercalcemic crisis
34%: hungry bone syndrome
≤
≤
Triple-center retrospective study (between 1997 and 2017)
Rampp ≤ PHP who underwent parathyroidectomy 25% of the patients had ectopic adenomas (59% of them
N = 83 patients with
2020 ≤ were intra-thymic)
(64% females)
[5] 98% of the patients had a 6-month cure rate
Age: ≤21 years old (mean age of 17 years)
N1: high frequency of bone disease (42% of the patients from N1)
Jovanovic Case–control, single-center (high-volume surgery) study
N2: high frequency of asymptomatic presentation (39% of the
2020 N1 = 14 patients with PHP (age ≤ 20 years)
patients from N2)
[51] N2 = 28 adults with PHP
Female to male ratio: 1 to 1 (N1); 8 to 1 (N2) (p = 0.005)
Retrospective study N1 vs. N2:
Zivaljevic Out of 1363 patients, N = 14 patients with PHP (age < 20 years male to female ratio: 1 to 1 (N1); 1 to 1.7 (N2)
2020 representing 1% of entire cohort) renal stones: 0% versus 62%
[52] N1 = 6 children with PHP (aged ≤ 15 years) Most frequent complications: bone (62%) vs. renal (50%)
N2 = 8 teenagers with PHP (age: >15 and ≤20 years) 1 case of parathyroid carcinoma (N1)
Abbreviations: N = number of patients; PHP = primary hyperparathyroidism; PTH = parathyroid hormone;
MEN = multiple endocrine neoplasia; Tc = Technetium.
→
→
3.2. Genetic Considerations →
MEN1-associated PHP represents a major part of the genetic →
picture accompanying
PHP affecting both children and adults. Some controversies around the use of total/partial
parathyroidectomy and their timing still exist, as patients may experience other tumors,
such as gastrointestinal, lung, thymic, etc., and pituitary neuroendocrine neoplasia, leading
to a dramatic burden and a reduced quality of life [53,54]. Screening protocols start in
the second decade of life, and MEN1-related pediatric PHP seems the most important
gene-associated form of PHP [55–57]. MEN1, an autosomal dominant condition with a
clinical onset before the age of 20, is not studied across generous published cohorts with
respect to juvenile PHP, and we only have a limited amount of information so far on this
specific matter [58–60].
Shariq et al. [49] published a retrospective study on 80 individuals with MEN1 who
began screenings before the age of 18. Of them, 70% had at least one tumor confirmed by
this cutoff age (at a median age of 14), while PHP was identified in 80% of them (>70%
of this subgroup already had a parathyroidectomy performed); 35% of the patients had
a pancreaticoduodenal neuroendocrine tumor, and 30% had pituitary neuroendocrine
neoplasia≤ [49].
≤
Interestingly, in 2021, Srirangam Nadhamuni et al. [61] reported the first pediatric
≤
case of MEN1-associated
≤ gigantism due to ectopic Growth-Hormone-Releasing Hormone
(GHRH) production, in an 18-year-old female who also underwent parathyroidectomy
for PHP at the age of 15 [61]. Moreover, a new MEN1 germline pathogenic variant was
described in 2020 (heterozygous variant c.105_107dupGCT) starting from a proband who
was a teenager diagnosed with PHP and a pituitary micro-adenoma; further confirmation
of a similar phenotype–genotype combination was conducted in her father [62].
If MEN1-associated PHP is detected in a child (as an index case), first degree relatives
should be tested, as well, and start surveillance protocols if they also harbor the pathogenic
variant [63]. Petriczko et al. [64] reported the case of a 17-year-old male who presented
with a pancreatic tumor in association with MEN1-related PHP; his sister had the same

≤
≤
≤
Biomedicines 2023, 11, 2810 7 of 25

tumors, but also an unusual central ganglioglioma; they inherited the condition from their
father, who was also confirmed with PHP [64].
Blackburn et al. [17] also introduced a case series (N = 2) regarding CDC73 (cell division
cycle) pathogenic variants and pediatric PHP, with patients of 10 and 14 years old having
symptomatic hypercalcemia [17]. On the other hand, Ramonell et al. [47] identified a case
of MEN2–associated PHP harboring RET mutations, which seem rarer than previously
mentioned two, MEN1 and CDC73 [47]. Infants are more likely to be affected by CASR
mutations, which, in heterozygote status, do not present as classical PHP. One study on
63 pediatric patients with PHP (from 1998 to 2018) showed that 52% of them had a genetic
condition; while infants were more likely to be asymptomatic when compared to older
children (15% vs. 54%, p = 0.002), the younger group were associated with pathogenic
variants, particularly (94%) involving CASR, whereas the older group presented other
mutations, such as MEN1, CDC73, RET, and CDKN1, which were associated with higher
PTH levels, but with similar serum calcium values to the infant group [50].
The reclassification from sporadic to genetic (familial) PHP stands out as a pitfall of
juvenile PHP. Szabo Yamashita T. et al. [27] showed that, among 66 pediatric patients with PHP,
approximately one-third of them had a prior-known familial syndrome (mostly MEN1), and
another 5% of the children initially considered as having a sporadic PHP turned out to have a
genetic form. The study also provided insightful information concerning the presentations
and outcomes in sporadic vs. familial PHP; for instance, the rates of single-parathyroid-gland
involvement were 85% vs. 19%, respectively; postoperative recurrent PHP was identified in
2% vs. 38% of patients, respectively, with a time to recurrence higher in sporadic PHP [27].
Similarly, genetic/familial PHP vs. apparently sporadic PHP was studied in a single-center
analysis, published in 2022 by Sharma et al. [26] (N = 36 Asian/Indian patients younger than
20 years; 55% were males; the median age was 17 years). Of the subjects from the first group,
90% mainly carried MEN1 and CDC73 pathogenic variants, while, notably, 26.9% of the second
group harbored pathogenic variants such as CDC73 and CASR. The “genetic” group was
more frequently asymptomatic, while renal complications had the highest prevalence among
other involvements within second group (71%) [26]. These two studies [26,27] pointed out
the importance of genetic awareness in pediatric PHP despite negative family history, noting
that 5–29% of the children that were initially considered sporadic cases actually harbored a
pathogenic variant [26,27].
Of note, in dramatic cases like parathyroid (hypercalcemic) crisis, which is not respon-
sive to standard medical therapy, or even off-label use of calcium-lowering agents such as
denosumab [65], emergency parathyroidectomy should not be postponed in order to find
out the results of the genetic analysis [66] (Table 3).

Table 3. Case reports and series (<10 patients/article) with data concerning genetic profiling in
pediatric PHP, according to our methods (the list starts with the most recent publication date)
[17,53,61,62,64,65,67]; additional studies (≥10 patients/study) that also include genetic analysis are
introduced in Table 2. Data were provided by Sharma [26,46], Szabo Yamashita [27], Bernardor [18],
Ramonell [47], Shariq [49], El Allali [50], Sharanappa [28].

First Author
Pathogenic Variant Year of Publication Index Case
Reference Number
17-year-old male diagnosed with PHP and pancreatic
Petriczko
neuroendocrine tumor
2022
Family data: father with PHP; sister with PHP, pancreatic
[64]
MEN1 neuroendocrine tumor, and central ganglioglioma
At the age of 10: resection of an insulinoma
Srirangam Nadhamuni
At the age of 15: parathyroidectomy for PHP
2021
At the age of 18: gigantism due to ectopic GHRH production
[61]
(pancreatic neuroendocrine tumor)
Biomedicines 2023, 11, 2810 8 of 25

Table 3. Cont.

First Author
Pathogenic Variant Year of Publication Index Case
Reference Number
Cho # 12-year-old female was the daughter of the proband
2021 PHP, prolactinoma, pancreatic neuroendocrine tumor;
[53] Frame-shift mutation: NM_130799.1:c.1546dupC (p.Arg516Profs∗15)
MEN1 16-year-old female diagnosed with PHP and pituitary microadenoma
Stasiak Novel MEN1 germline pathogenic variant
2020 (heterozygous variant c.105_107dupGCT)
[62] Family data: father with the same pathogenic variant
(PHP and pituitary neuroendocrine tumor)
14-year-old male with heterogeneous gene deletion
Blackburn
(symptomatic hypercalcemia due to a single PT adenoma)
2022
10-year-old female with known autosomal dominant mutation
[17]
CDC73 (symptomatic hypercalcemia and bilateral PT adenoma)
Mamedova 16-year-old female admitted for fractures, nausea, vomiting,
2020 weight loss (heterozygote status)
[65] 60 mg denosumab → parathyroidectomy → hypocalcemia
16-year-old female admitted for diabetes mellitus and
Belaid
high blood pressure due to pheochromocytoma
VHL 2020
Ectopic PTH (adrenal) production → remission of PHP
[67]
after bilateral adrenalectomy
Abbreviations: GHRH = Growth-Hormone-Releasing Hormone; MEN = multiple endocrine neoplasia; VHL = von
Hipple–Lindau; PT = parathyroid; PHP = primary hyperparathyroidism; # = in this case, the child was the daughter
of the proband.

3.3. Lab Findings

Serum calcium and PTH values represent useful diagnostic and follow-up tools;
sometimes, PHP is unexpectedly identified due to a high calcium value at the moment
when the patient is admitted for an apparently unrelated complaint, such as an infec-
tion [68]. Increased values of calcium require prompt medical intervention, including the
decision of administering bisphosphonates and cinacalcet or, in refractory cases, emergency
parathyroid tumor removal [66]. For example, Hayashi et al. [66] described the case of
an 11-year-old male with parathyroid (hypercalcemic) crisis, which mostly manifested as
severe digestive complaints in association with a total serum calcium of 14.3 mg/dL, as well
as a PTH value of 405 pg/mL. Despite standard care (intravenous fluids, furosemide, and
calcitonin), the hypercalcemia rose to 16.5 mg/dL; pamidronate administration induced a
drop to 14 mg/dL, which was followed by emergency parathyroidectomy that achieved
control of the PTH excess [66].
A reduced, yet higher-than-normal value of PTH may be found after surgery, even
after successful parathyroidectomies (for up to a 1-year duration), most probably in relation
to a vitamin D deficiency or to a certain latency of PTH correction, which is currently less
understood, as pointed out in the case of a 11-year-old patient with an ectopic parathyroid
tumor resection (if genetic PHP is excluded) [68].
On the contrary, postoperative hypocalcemia associated with normal (or high, but
lower than the preoperative level) PTH, as described in hungry bone syndrome, was
reported in a few cases/series [15,36,69,70]. For instance, a 14-year-old male who was ad-
mitted for digestive complaints and lethargy was detected to have a PTH excess-associated
brown pelvic tumor, with remission following parathyroidectomy, accompanied by tran-
sitory starvation bone syndrome [71]. Sharanappa et al. [28] reported on a cohort of
35 pediatric subjects with PHP, showing a prevalence of hungry bone syndrome of 34% [28].
Boro et al. [48] showed, in a series of 10 consecutive patients with PHP (a mean age of 16.7),
a prevalence of 40% [48].
Biomedicines 2023, 11, 2810 9 of 25

As expected from the data on adults diagnosed with a parathyroid carcinoma, this
exceptional histological entity (that is described in less than 1% of pediatric cases with
PHP) is associated with very high PTH values [72,73]. For instance, Rahimi et al. [73]
reported on a 15-year-old female who initially presented with a PTH level of 2876 pg/mL
(the immunohistochemistry report showed a Ki67 of 2–3%, and positive CK and CD31
reactions) [73]. The same authors [73] performed an analysis of published cases (from 1972
to 2020) and found 17 reports of parathyroid carcinoma in the pediatric population; total
serum calcium varied between 12 and 20.7 mg/dL, and PTH levels were between 300 and
8638 pg/mL (the ages reported were between 8 and 16 years; the male to female ratio
was 0.6; 60% of these children had palpable neck tumors; 50% of them displayed various
bone complications; one out of five subjects had distant metastases, particularly pulmonary
and lymphatic) [73]. Of note, a similar review from 2020 identified 12 published cases of
parathyroid carcinomas in children, in addition to a new report of a 13-year-old male (with
a baseline total serum calcium of 15.43 mg/dL and PTH of 980 pg/mL) [72].
Collaterally, we mention the assessment of vitamin D level status; some authors sug-
gested that hypovitaminosis D is prone to be associated with postoperative hypocalcemia
or hungry bone syndrome, or it impairs the remission of brown tumors while the correction
of serum 25-hydroxyvitamin D through vitamin D replacement remits the component of
secondary hyperparathyroidism that may be additional to PHP [74].

3.4. Imaging Tools

Cervical ultrasound is the basic imaging assessment used, as seen in the adult pop-
ulation. A recent study concerning the present topic focused on preoperative imaging
techniques, namely, cervical ultrasound and 99mTc Sestamibi scintigraphy. This was a
single-center experiment in 32 subjects, 18 years old or younger (between 2003 and 2021),
with an average age of 14.7 years, that were diagnosed with single parathyroid tumors
(no ectopic adenomas were included; the median diameter of the adenomas was 2.85 cm).
He et al. [45] found that echography had a sensitivity of 100%, while 99mTc Sestamibi
scintigraphy was concordant in 93% of cases [45].
Ectopic (extra-cervical) parathyroid tumors are less likely to be detected through
neck echography; thus, functional imaging to address the parathyroid glands is useful,
with the most practical imagining technique being a 99mTc Sestamibi scan. For example,
Sahu et al. [11] reported, in 2023, a 12-year-old female who was admitted for severe
bone anomalies (limb deformities in association with a history of multiple fractures) and
kidney stones. She had an intra-thymic parathyroid tumor, confirmed though Sestamibi
scintigraphy, that required a thoracoscopic left thymectomy (using a Sestamibi-guided
gamma camera during the procedure in order to locate the ectopic adenoma), with a good
postoperative outcome [11]. On the other hand, Lenschow et al. [75] showed, in a large
study of 628 patients with PHP (only a few females were younger than 18, and most of the
studied population included adults, with an overall median age of 58), that, in cases with
negative cervical ultrasound results, 99mTc Sestamibi identified the parathyroid tumors
in only 25.4% of them, while 11 C-methionine or 11 C-choline PET/CT (positron emission
tomography/CT) identified the lesions in 79% of this subgroup [75]. One case of a teenager
with PHP showed a positive Lincoln sign (“black beard sign”), due to mandibular uptake
of the tracer during 8 F-fluorocholine PET/CT [76].
Another report of an ectopic parathyroid adenoma showed the utility of 99mTc Ses-
tamibi (SPECT/CT) in association with 4-dimensional CT [68]. Similarly, SPECT/CT was
used to identify an intra-thymic adenoma in a 15-year-old male [10]. Moreover, a study on
23 children and teenagers (4/23 with germline pathogenic variants: 3/4 with CDC73 and
1/4 with CASR) with PHP showed that dual-phase CT provided good sensitivity (91.3%)
and specificity (99.5%) in single-gland disease; 95% of the patients with single adenoma
showed post-operative remission within the first 18 months after the initial use of CT
data [46].
Biomedicines 2023, 11, 2810 10 of 25

Another aspect of imaging assessment in PHP includes the diagnosis of brown tumors,
either as incidental findings, or due to local bone pain, deformities, or walking dysfunction-
ality. They are expected to remit after successful parathyroid tumor removal; thus, serial
scans, for instance, with X-ray, CT or magnetic resonance imaging, are mandatory [38,74,77].
Omi et al. [78] reported an impressive case of parathyroid carcinoma, operated on in a
patient at the age of 13, who then survived without recurrence for more than 40 years,
due to multimodal management in terms of diagnosis and therapy; notably, the current
recurrence was identified through 11 C-methionine-positive features of the tumor (i.e.,
99mTc-methoxy-isobutyl-isonitrile- and 18 F-fluorodeoxyglucose-negative) [78].
Overall, imaging analysis is mandatory in order to choose the type of surgical ap-
proach; however, high-volume surgical teams are expected to provide the highest success
rates, due to intraoperative localization and the use of intraoperative PTH assays. As
mentioned, the importance of evaluating the genetic background of a child with PHP is
reflected in the methods of addressing the sites of the tumors (such as multi-glandular
disease of ectopic lesions in genetic PHP) and the type of parathyroidectomy.

3.5. Surgical Procedures

Parathyroidectomy represents the single curative option for PHP, regardless of whether
it occurs in the pediatric or adult populations, with a general cure rate of 95–99%, the excep-
tions being persistent PHP due to inefficient location of the tumor before and during surgery,
multi-glandular parathyroid disease (typically present in genetic PHP), and synchronous
ectopic adenomas [79].
Thoracoscopic parathyroidectomies, including those conducted through minimally
invasive techniques, such as video-assisted thoracoscopic surgery (VATS), that are facil-
itated by having a precise preoperative location of the adenoma, have been safely used
in selected adult cases of ectopic or extremely large orthotopic parathyroid tumors; the
similar pediatric application also seems safe, according to current knowledge, despite
a low level of statistical evidence [11,80–82]. For example, Vitale et al. [69] reported, in
2022, the first pediatric case of PHP-associated ectopic (intra-thymic) mediastinal adenoma
complicated by bilateral slipped capital femoral epiphysis (the same team analyzed similar,
previously published, cases and identified 13 reports with unilateral epiphysis lesions).
The parathyroid tumor (which was confirmed, preoperative, with 99Tc-Sestamibi and CT
scans) was successfully removed via a thoracoscopic resection. The 12-year-old male de-
veloped post-surgery hungry bone syndrome and vitamin D deficiency–related secondary
hyperparathyroidism [69]. Another case of bilateral slipped capital femoral epiphysis was
reported in a 15-year-old male, who also suffered from other complications of PHP (such
as polydipsia, polyuria, and weight loss); however, the patient first underwent orthopedic
correction (due to pathological report confirming brown tumors) and, further on, parathy-
roidectomy of the single adenoma was performed [77]. Moreover, another unilateral case
was reported, in relation to an ectopic adenoma, by Badhe et al. [83]; Seo et al. [10] added a
case of a teenager who underwent VATS–based removal of an intra-thymic adenoma [10].
Alternatively, an ectopic site within the piriform sinus of a 9-year-old child required a
reperformed parathyroidectomy [84]. Overwhelmingly, most recent reports include thora-
coscopic resection of ectopic adenomas [11,29,68,69]. Additionally, a robot-assisted surgical
procedure for an ectopic (thymic) parathyroid adenoma resection was successful, not
only to control the biochemical findings, but also, to control the associated psychiatric
manifestations in the affected teenager [85].
In 2021, Flokas et al. [68] published a review of ectopic parathyroid adenomas in
patients 18 years and younger and identified 33 cases (published between 1982 and 2019).
Prior reports suggested that ectopic forms are identified in 5–26% of the children confirmed
with PHP. In this analysis, there was relatively equal sex distribution; 2 out of the 33 tumors
were carcinomas; half of the ectopic adenomas were located at the thymus level and 17%
of all tumors were unexpectedly detected. Other comorbidities included bone and kidney
complications in addition to a MEN1-associated panel (1/33) [68].
Biomedicines 2023, 11, 2810 11 of 25

The high frequency of mediastinal (intra-thymic) site occurrence among ectopic tumors
suggests that the thoracoscopic approach and minimally invasive techniques are stepping
stones in modern parathyroid pediatric surgery, which is otherwise challenging, not only in
relation to the adenoma site, but also with the patients’ ages and preoperative complications.
For example, the analysis by Sharanappa et al. [28], performed between 1989 and 2019,
pointed out that, among 35 pediatric subjects with PHP (8.5% of whom were diagnosed with
familial PHP), 91% had a parathyroid adenoma; minimally invasive parathyroidectomies
were performed in 40% of all cases, and the cure rate was 97%, which was consistent with
prior reported data [28]. One retrospective study from 2022 analyzed a single (high-volume)
surgeon’s experience from 2002 to 2020 and showed a safe profile of the parathyroidectomy
in 19 pediatric outpatients (with a mean age of 14.1). The surgical procedure varied, from
8/19 unilateral parathyroidectomies to 9/19 trans-cervical thymectomies. Preoperative
findings showed that fatigue was the most frequent clinical element (affecting 62% of the
subjects); lab assays showed a mean total serum calcium of 11.7 mg/dL and an average
PTH of 102.3 pg/mL. The cohort included two genetic PHPs (MEN1 and MEN2). A
postoperative calcium correction was identified (a mean value of 9.6 mg/dL was found
at 6 months following the procedure; 1/19 subjects experienced transitory hypocalcemia),
as well as normalization of elevated PTH (a mean of 29 pg/mL at 6 months after surgery;
1/19 of the subjects was confirmed with permanent hypoparathyroidism) [47].

3.6. Outcome
While parathyroidectomy is recognized worldwide to provide the cure for hyper-
parathyroidism in most cases, the management of PHP-associated hypercalcemia represents
a heterogeneous domain. Calcimimetics are approved for selected cases of adult primary
PHP (not only renal hyperparathyroidism), depending on country protocols; their off-label
use in infants and teenagers with PHP seems to be a new area that remains a matter of
debate. The drug may induce severe hypocalcemia, as well as cardiac rhythm anomalies
such as prolonged QT interval; however, some data showed its efficacy, being seemingly
safe when offered to young patients for a limited period of time [86,87]. A multicenter
French study on 18 patients (with a median age of 10.2; range between 2 and 14.4 years)
included 13 individuals with primary PHP (10 of them with known genetic PHP-carrying
pathogenic variants with respect to the CASR, CDC73, and MEN1 genes). Overall, under
a progressively increased dose over a median of 2.2 years, cinacalcet decreased PTH and
serum calcium levels, with stable alkaline phosphatase and no significant side effects [18].
The overall outcome in PHP has been analyzed in a few studies, according to our
3-year analysis, as previously mentioned. Additionally, another retrospective, tri-center
study from 2020 outlined the outcomes after parathyroidectomy on 86 patients, with a
median age of 17 (64% were females); the 6-month cure rate was 98%. Of note, 25% of the
tumors were ectopic (and half of them were thymic), while preoperative identification of
adenoma was conducted with 99mTc Sestamibi in 58% of cases, and with neck ultrasound
in 43% of the patients [5].
We identified a singular study of its kind, a case–control analysis in pediatric vs. adult
subjects, who were referred to surgery at a single (high-volume) center of surgery (between
2004 and 2017). The juvenile group (N = 14) demonstrated a more severe clinical picture vs.
the adult group (N = 28); the most frequent complication was bone disease (affecting 42%
of the subgroup), while the adults were mostly asymptomatic (39%) [51]. Moreover, the
authors published a second (retrospective) study comparing children (≤15 years, N = 6,
male-to-female ratio of 2) with teenagers (>15 and ≤20 years, N = 8, male-to-female ratio of
1 to 1.7) who had renal stones in 0% vs. 62% of subjects, and statistically significant higher
calcium and PTH levels in the younger vs. older group [52].
A mostly unexpected resolution of PHP was detected after a bilateral adrenalec-
tomy for Von Hippel–Lindau Disease-related bilateral pheochromocytoma with ectopic
(intra-adrenal) PTH expression; this was the case of a 17-year-old teenager admitted for
pheochromocytoma-related diabetes mellitus and high blood pressure. This represents
Biomedicines 2023, 11, 2810 12 of 25

the only patient harboring the VHL pathogenic variant that we could identify within the
mentioned timeframe of our research [67] (Table 4).

Table 4. Case reports and series (<10 patients per article) of pediatric PHP (the list starts with the
most recent publications) [9–11,15,29,34–40,44,66,68–74,77,78,83–85]; the published cases with specific
genetic testing were already introduced in Table 3 [17,53,61,62,64,65,67].

First Authors
Year of Publication Patient Preoperative Findings Postoperative Findings and Outcome
Reference Number
Giant PT adenoma
Muse
2023 16-year-old male Nausea, vomiting, headache This is the first report of a PHP-related brain
[9]
calcification at the frontal lobe in a child
History of limb deformities, Ectopic PT adenoma (intra-thymus)
Sahu
2023 12-year-old female multiple fragility fractures, Sestamibi-guided thoracoscopic left thymectomy
[11]
kidney stones (CT with radioisotope scans)
Chest pain and dyspnea Cystic left inferior PT adenoma
Boggs
2023 12-year-old female (complication: one osteolytic Hungry bone syndrome following
[15]
rib lesion) parathyroidectomy
Badhe Unilateral slipped capital
2023 13-year-old male Ectopic mediastinal PT adenoma
[83] femoral epiphysis
Zenno Ectopic PT adenoma (pyriform sinus) →
2023 9-year-old female Symptomatic hypercalcemia
[84] reperformed parathyroidectomy
de Silva Multiple fractures
2023 17-year-old male Good outcome after parathyroidectomy
[40] (brown tumors)
Lincoln sign (“black beard sign”) due to
Prakash
2023 14-year-old female PHP mandibular uptake of the tracer during 8
[76]
F-fluorocholine PE/CT
A 6-year history of bone pain, Removal of inferior parathyroid adenoma →
Gafar loss of appetite, fatigue, postoperative hypocalcemia → calcium and
2022 12-year-old male
[37] progressive lower limb alfacalcidol replacements
deformity Association with genu valgum due to rickets
Poor response to standard care (including
Hayashi
2022 11-year-old male Hypercalcemic crisis calcitonine → pamidronate) → successful
[66]
emergency parathyroidectomy
Ectopic PT adenoma (intra-thymus)
Vitale Bilateral slipped capital femoral
2022 12-year-old male Thoracoscopic resection →
[69] epiphysis
post-parathyroidectomy hungry bone syndrome
Boro Atypical PT adenoma → postoperative hungry
2022 16-year-old female Severe clinical picture
[70] bone disease
Abdominal pain due to
9-year-old female (C1)
pancreatitis (C1)
Oh 14-year-old male (C2) Postoperative PTH normalization (C3: ectopic
2022 Abdominal pain due to ureter
[34] 14-year-old female PT adenoma)
stone (C2)
(C3)
Gait disturbance, weakness (C3)
8-month history of recurrent
Bin Yahib abdominal pain, nausea, Ectopic PT adenoma (intra-thymus)
2021 13-year-old female
[29] vomiting, Thoracoscopic resection
bone pain
12-year-old female
Dikova (C1) Admission for genu valgum C1 associated a local brown tumor
2021
[38] 15-year-old female (orthopedic assessment) C2 associated a local bone cyst
(C2)
Brown tumor at the heel (C1)
16-year-old female Preoperative cinacalcet (3 months) use (C2)
Recurrent abdominal pain,
Tuli (C1) Successful conventional parathyroidectomy in
2021 emotional lability,
[36] 14-year-old female both cases (hungry bone syndrome in C2 that
asymptomatic nephrolithiasis
(C1) required calcitriol for 2 years)
(C2)
Unexpected detection of
Ectopic PT adenoma (intra-thymic)
Flokas hypercalcemia during
2021 11-year-old female Thoracoscopic thymectomy (5 months after initial
[68] admission for peritonsillar
presentation)
cellulitis
Fukaya Recurrent abdominal pain,
2021 12-year-old female Parathyroidectomy of a large PT adenoma (1.8 g)
[35] macroscopic hematuria
Rahimi 8-year history of bone pain and
2021 15-year-old female Parathyroid carcinoma
[73] progressive limping
Bilateral slipped capital femoral Orthopedic correction (brown tumors) → medical
Roztoczyńska
2020 15-year-old male epiphysis, polydipsia, polyuria, therapy for hypercalcemia (including
[77]
weight loss pamidronate) → left inferior parathyroidectomy
Biomedicines 2023, 11, 2810 13 of 25

Table 4. Cont.

First Authors
Year of Publication Patient Preoperative Findings Postoperative Findings and Outcome
Reference Number
Abdominal pain, vomiting,
Legault Parathyroidectomy → hungry bone syndrome
2020 14-year-old male constipation, pelvic
[71] Postoperative brown tumor remission
brown tumor
Minelli Ectopic PT adenoma (intra-thymus)
2020 17-year-old female Psychiatric manifestations
[85] Robot-assisted surgery for tumor removal
Seo Adenoma localization required
2020 15-year-old male Ectopic PT adenoma (intra-thymus) → VATS
[10] SPECT/CT
Parathyroid carcinoma (loss of parafibromin)
Therapy with pamidronate, denosumab →
Lenherr-Taube Muscle and bone pain, parathyroidectomy → hungry bone syndrome
2020 13-year-old male
[72] brown tumors (intravenous calcium for 3 weeks) → no relapse for
18 months
Postoperative brown tumor remission
Pal 12-year-old male Posterior reversible Neurological symptom remission after
2020
[44] 16-year-old male encephalopathy syndrome parathyroidectomy
David
2020 15-year-old female Brown tumors Parathyroidectomy → hungry bone syndrome
[74]
Lee Parathyroidectomy → calcium normalization
2020 15-year-old male Bilateral genu valgum
[39] within 2 months
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
Omi of 57 → suspected neck recurrence → en bloc
2020 13-year-old female Fibular fracture
[78] resection of parathyroid adenoma →
11
C-methionine-positive tumor recurrence →
removal → relapse 8 months later → denosumab
for hypercalcemia + radiotherapy to control
the recurrence
Abbreviations: C = case; CT = computed tomography; PT = parathyroid; PHP = primary hyperparathyroidism;
SPECT/CT = single-photon emission computerized tomography/computed tomography; VATS = video-assisted
thoracic surgery.

4. Discussion
PHP in children and teenagers is associated with a heterogeneous spectrum, from
baseline picture to long-term follow-up. Our 42-month sample-based study was related to
several major points, as follows.

4.1. Changes in Terminology over the Years concerning Parathyroid Tumours

The last 3 years brought forth new terminologies, such as those included in the WHO
2022 classification; for example, “multi-glandular” is now used instead of the prior “hyper-
plasia”, there are new definitions for carcinomas and atypical tumors (previously described
as “adenomas”), including the distinct subgroup of “parafibromin-deficient neoplasms”,
in association with the increasing importance of genetics, immunohistochemistry, and
molecular biology assessments in parathyroid tumors [88]. Nevertheless, gathering data
from different publications might help to share common ground, in order to achieve a
certain level of understanding and knowledge.
We restricted our research to PHP in order to avoid conditions with different pathogenic
traits; that is why we did not include children diagnosed with acute or chronic kidney
damage-related hyperparathyroidism, involving the parathyroid glands as a secondary
event following kidney lesions, regardless of their type (including post-transplant PTH
status); for the same reason, we also did not include Bartter syndrome, which can be asso-
ciated with nephrocalcinosis and increased PTH values [89–92]. We also did not include
studies that specifically addressed hypovitaminosis D-associated secondary PTH value
increase; however, the importance of vitamin D supplementation to correct its deficiency
was also found in the pediatric population co-diagnosed with PHP, as similarly seen in
adults with the same conditions [93].
PHP remains a challenging topic that concerns a multidisciplinary perspective. The
index of clinical suspicion is far from being generous, but awareness is essential in order to
Biomedicines 2023, 11, 2810 14 of 25

avoid a hypercalcemia-associated life-threatening event or progressive skeletal and renal

anomalies due to long-term uncorrected PTH and high calcium values.

4.2. Neonatal Primary Hyperparathyroidism

Alternatively, we conducted a second analysis with respect to severe neonatal hyper-
parathyroidism. We applied the same research strategy and utilized an additional term,
“neonatal”; thus, we identified 49 papers and selected 9 of them (including original case
reports and series, for a total of 15 patients). This represents a dramatic condition diagnosed
within the first six months after birth, usually in relation to a genetic background involving
CASR. Familial hypocalciuric hypercalcemia of types 1 to 3 underline CASR anomalies
that induce a mild elevation in serum calcium and PTH, starting from childhood and
continuing into adulthood (which is distinct from PHP, with parathyroidectomy being un-
necessary) [94–96]. Associated pathogenic variants involve the CASR gene on chromosome
3q 13.3–21 (loss of mutation), with more than 300 mutations described so far (60% of all
familial cases), but also involving the GNA11 (guanine nucleotide-binding protein subunit
alpha-11) gene, as well as the AP2S1 (adaptor protein complex 2 subunit sigma) gene,
affecting 5% and 20%, respectively, of all individuals confirmed with familial hypocalciuric
hypercalcemia [97–99]. However, the inheritance of the condition (homozygote status)
may lead to dramatic consequences in terms of neonatal presentation, with a high mor-
bidity (due to metabolic, bone, nutritional, and neurodevelopmental consequences) and
mortality [100].
Extremely rare heterozygous mutations may manifest with a dramatic depiction of
hypercalcemia at birth (these cases are prone to be transitory, as opposed to homozy-
gous) [101]. For example, a new case was reported in 2022, in a boy who inherited the
mutation from his father, who was an asymptomatic heterozygous carrier of the same gene.
His admission was based on a severe clinical picture of hypercalcemia (with lethargy and
bradycardia) that was particularly managed with pamidronate and cinacalcet, with poor
response; thus, parathyroidectomy was mandatory. Of note, the subject had a sibling who
died of the same condition at the same age, which suggests dramatic consequences for this
genetic type of PHP at the newborn stage [102].
Another dramatic case was reported in a newborn with abnormally high calcium and
PTH values (of 12 mg/dL and 1120 ng/dL, respectively); he was treated for 13 months
with cinacalcet and a parathyroidectomy was finally performed at the age of 17 months.
Calcimimetic drugs delayed the need for surgery, thus representing a valuable treatment
solution, even for cases with a modest response to this medication [103]. Another 7-month-
old girl, who underwent parathyroidectomy for the same condition, was reported [104].
The first such report from Sudan included three siblings carrying a pathogenic homozygous
missense variant of CASR and, since medical alternatives were not available, a parathy-
roidectomy was performed [105]. A 7-month-old male infant received a parathyroidectomy
twice, since the (thymus) ectopic parathyroid tissue could not be located before surgery,
and the decision to conduct a total thymectomy was made following persistent PTH values
after the initial removal of all four parathyroid glands [106]. The use of an intraoperative
PTH assay may serve to confirm the success of the surgical procedure [107]. Of note, the
youngest patient receiving cinacalcet for homozygote status of the CASR gene—c.1836G>A
(p.G613E)—was a 2-day-old newborn (in a report from 2020). The child was started on
the medication due to very high calcium and PTH levels (14.4 mg/dL and 1493 pg/mL,
respectively) during her first day of life; this case introduced the longest period of medical
therapy with cinacalcet to avoid parathyroidectomy (18 months) [108].
Awareness of this particular type of PTH excess-related condition is essential, and it
should be taken into consideration when addressing the larger frame of infancy-associated
parathyroid neuroendocrine neoplasia (Table 5).
Biomedicines 2023, 11, 2810 15 of 25

Table 5. Case reports and series of neonatal hyperparathyroidism due to inheritance of CASR
pathogenic variants; PubMed access (between January 2020 and July 2023) [99,101–108].

First Author
Year of Publication Patient Clinical Presentation Management
Reference Number
CASR pathogenic variant
Lethargy, bradycardia, Poor control of hypercalcemia through
Shaukat
2022 6-month-old male hyperreflexia (his sibling died of pamidronate, cinacalcet → parathyroidectomy+
[102]
the same condition) self-transplantation of half of the left inferior PT
gland → calcium and alfacalcidol supplements
Therapy with cinacalcet for 13 months →
Özgüç Çömlek Hypotonia, poor feeding →
2022 6-day-old male hypercalcemia after 2 months since stopping
[103] weight loss
cinacalcet→ parathyroidectomy
Gupta
2022 20-day-old female Growth and developmental delays Parathyroidectomy at 7 months
[104]
2/3 patients (a 7-month-old female and an
8-month-old male) were tested and found
Hassan Polyuria, failure to thrive,
2022 3 infant siblings positive for homozygous missense CASR
[105] fractures
pathogenic variant: c 2038 C T p (Arg680Cys)
Patients underwent parathyroidectomies
Heterozygous CASR pathogenic variant:
Hypercalcemia + preterm (C1)
c.554G>A; p. (Arg185Gln)
Höppner Hypercalcemia + severe muscular
2021 2 infant siblings Both patients were stabilized under medical
[101] hypotonia + thrombocytopenia +
therapy (C2: therapy with cinacalcet was used
multiple fractures (C2)
for 3 months)
Homozygous CASR pathogenic variant:
c.1836G>A (p.G613E)
Gulcan-Kersin Severe hypercalcemia during the
2020 2-day-old female Therapy with cinacalcet since day 2 → 18
[108] first day of life
months
(heterozygote status of her father and sister)
Therapy with calcitonin, cinacalcet, pamidronate
Abdullayev Multiple episodes of → parathyroidectomy twice at 7 months (first
2020 7-month-old male
[106] hypercalcemia early after birth removal of all 4 PT glands → persistent high
PTH → thymectomy)
Homozygous CASR pathogenic variant 1630
(c.1630C > T)
Sorapipatcharoen Severe hypercalcemia early after
2020 10-day-old female Therapy with calcitonin, cinacalcet,
[107] birth
pamidronate, zoledronate → parathyroidectomy
(day 70) → hungry bone syndrome
Severe hypercalcemia early after Medical therapy → parathyroidectomy +
Sadacharan 4 cases (mean age of
2020 birth (hypotonia, respiratory trans-cervical thymectomy
[99] 28.7 days)
insufficiency, failure to thrive) (+hemi-thyroidectomy in one case)
Abbreviations: CASR = calcium-sensing receptor, PTH = parathyroid hormone; PT = parathyroid.

4.3. Calcium-Lowering Drugs in Children with PHP

As previously mentioned, cinacalcet was studied in one study (N = 18 patients with
a median age of 10.2 years) [18], and for the case of one 14-year-old teenager [36]. The
duration of therapy varied, from 3 months to a median of 2.2 years [18,36]. It has been
suggested that its preoperative use may increase the risk of post-parathyroidectomy hungry
bone syndrome that requires prompt calcium and calcitriol intervention, but the level of
pediatric evidence remains low [36].
We identified two single case reports of denosumab administration in order to control
unexpectedly high hypercalcemia [65]. One teenager was diagnosed with a parathyroid
adenoma; he was first admitted for fractures and digestive complaints. The subject’s
very high values of total calcium (16.71 mg/dL) and PTH (2151 pg/mL) required prompt
intervention; 60 mg of denosumab was administered (in addition to standard care), and
his hypercalcemia rapidly reduced within 12 h. Mamoedova et al. [65] considered that
controlling hypercalcemia via medical therapy allowed for a useful timeframe in which to
obtain the results of the genetic analysis (in this case, it revealed a heterozygote status of
the CDC73 gene). A genetic condition might require a multi-glandular resection and/or
a distinct surgical approach. The 16-year-old patient underwent parathyroidectomy on
day 22 after denosumab injection, with tumor removal being followed by hypocalcemia. A
potential role of the drug in inducing prolonged low serum calcium values might therefore
be incriminated in subjects diagnosed with PHP and renal hyperparathyroidism [109,110].
Biomedicines 2023, 11, 2810 16 of 25

However, the adequate administration of calcium and alfacalcidol controlled the tetany in
this case [65].
The second case of juvenile denosumab use was in a 13-year-old boy diagnosed
with a PHP-associated parathyroid carcinoma, complicated with brown tumors and post-
parathyroidectomy hungry bone syndrome. In this situation, after standard care of preoper-
ative hypercalcemia with intravenous fluids, two doses of subcutaneous calcitonin (4 U/kg)
were followed by two consecutive doses of pamidronate (0.5/kg) that were not efficient;
thus, 60 mg subcutaneous denosumab was offered to the young patient (on the fourth
day since first admission), resulting in a normal calcemic value after another 4 days [72].
Generally, off-label use of calcium-lowering agents that are only approved for adults (in-
cluding denosumab) requires distinct ethical precautions, such as Local Committee of
Ethics approval and informed consent from the patients (depending on their age) and
their parents.

4.4. Paediatric PHP: Osteoporosis and Fracture Issues

Neuroendocrine tumors of the parathyroid gland might be associated with bone
involvement, such as fragility fractures, reduced bone mineral density (BMD) (implicitly,
of Z-scores in children), deterioration of bone microarchitecture, and even impairment of
peak bone mass achievement during the teenage years. However, the decision of therapy
against osteoporosis is controversial, since successful parathyroidectomy might restore
the normal bone–skeletal dynamics, depending on the patient’s age, sex, and pubertal
stage [2,111,112]. Fukaya et al. [35] presented the case of a 12-year-old girl with non-
syndromic PHP who was confirmed with low BMD according to a Z-score of −2.7 SD (on
admission, total serum calcium was 13.7 mg/dL and PTH level was 321 pg/mL). After
successful parathyroidectomy of an adenoma, of 2.5 cm at its largest diameter, the PTH
level decreased to a value of 10 pg/mL without associated symptomatic hypocalcemia.
Good clinical and lab parameter evolutions were associated with an increase in BMD,
according to a lumbar Z-score of −1.9 SD 6 months after parathyroid removal, with a
further measurement of −1.2 SD recorded after another 10 months [35].
The correct timing of performing and repeating DXA (Dual-Energy X-ray Absorp-
tiometry) in these young patients is still a matter of debate, unless a clinical fracture or
osteoporosis diagnosis is difficult to confirm. Moreover, the interpretation of DXA assess-
ments should take into consideration physiological changes during growth and puberty,
including the achievement of peak bone mass [113]. A recovery of prior weight loss due
to hypercalcemia-associated appetite loss, recurrent abdominal pain, and even depressive
mood might be correlated with an increase in DXA-BMD. However, the decision of using
bisphosphonates should be cautiously considered in cases with fractures, since parathyroid
tumor removal will most likely improve the bone status in a matter of months [114–116].
On the other hand, very low Z-scores were reported in patients with multiple fractures and
those with brown tumors; for instance, de Silva et al. [40] reported on a 17-year-old male
teenager with a Z-score of −5.8 who had a severe presentation, with multiple fractures that
required the use of a wheelchair [40].
As an alternative to a DXA scan (which turned out to be normal), Lenherr-Taube et al. [72]
assessed microarchitecture and strength via high-resolution peripheral quantitative CT
(HRpQCT) at the levels of the distal tibia and distal radius in a 13-year-old patient with
PHP; the scans, performed 1.5 years after successful parathyroid surgery, showed a good
outcome in terms of osteolytic lesion resolution, an increased volumetric density, an increased
number of trabeculae, as well as improved cortical thickness and density (within healthy con-
trol ranges) [72]. HRpQCT might represent an alternative for skeletal assessment in pediatric
PHP; there are a few similar studies in adults with PHP, as well. However, currently, the
level of overall statistical significance remains low; also, routine use of HRpQCT is limited
by access to the device. Moreover, normal (healthy) reference population parameters (nor-
mative data) according to biological age, sex, pubertal stage and geographic area must be
provided [117,118]. Lately, the lumbar DXA-based trabecular bone score (TBS), as a practical
Biomedicines 2023, 11, 2810 17 of 25

tool for bone microarchitecture assessment, was applied in individuals younger than 18 years
old to a lesser extent than in adults, but the topic continues to expand, and we anticipate
valuable pediatric studies in PHP, as well [119,120]. As seen in other malignancies of both
children and adults, the overall bone status should be regarded in relation to the primary
tumor (such as a parathyroid carcinoma) and in relation to the changes resulting from surgery.

4.5. Trans-Pandemic Insights into Paediatric PHP

Our analysis covered the COVID-19 pandemic era; during this period of time, many
medical and surgical conditions were reshaped or associated with new entities, due to
coronavirus infection or to new COVID-related regulations [121–123]. With respect to
PHP, a delay in hospital admission and, potentially, a more frequent indication of using
calcium-lowering agents, such as cinacalcet or denosumab to function as a bridge to the
surgical procedure (if it was not considered an emergency), were registered amid the
first waves [124,125]. However, we found no pediatric studies on this specific matter.
Moreover, compressive neck symptoms should prompt consideration of not only thyroid
and parathyroid tumors, but also infection-associated clinical pictures [126–128].
Overall, after reviewing almost 350 papers, we included the following in our final analysis:
48 original studies with different levels of statistical significance (which included 14 studies of
at least 10 subjects per study and 34 case reports and series of fewer than 10 patients per study)
and a collateral checkup of neonatal cases (thus identifying another 9 case reports and series),
which is a distinct subgroup that we previously mentioned [99,101–108].
The main study-sample-based analysis showed that, except for a case–control study, all
of the studies were retrospective with multicenter (N = 5) or single-center (some including
a single-surgeon experience) studies (N = 7). Sample size data identified small cohorts
of 10 to 19 patients (10, with cohorts of 14, 18, and 19 subjects per study); medium-sized
studies, including between 23 and 36 individuals (with cohorts of 23, 32, 35, and 36 subjects
per study); and large studies, enrolling between 63 and 83 children and teenagers (with
cohorts of 63, 66, 80, and 83 subjects per study); thus, these studies included a total of
493 individuals with PHP. Some case reports included articles with specific genetic testing:
five reports with one case, and two reports with two cases (N = 7, N = 9). Non-genetic
information was included in 27 papers (23 with a single patient per report, 3 with 2 patients
per series, and 1 with 3 subjects per series; N = 27, N = 32). Thus, a total of 41 patients from
isolated reports were included (N = 534 total subjects with PHP in childhood and teenage
years, according to our methods).
The admissions of the patients within the mentioned study designs occurred between
1989 and 2021 (different timeframe combinations). The mean ages of the patients were
as follows: 10.2 (the lowest mean value) in some studies, and around 14 years (for ex-
ample, 14, 14.1, 14.7, and 15.2 years) in other studies and case reports, as well as around
the age of 17 (for instance, 16.7, 17, and 17.3) in case series [5,18,26–28,45–52]. We ex-
ceptionally included four studies that applied a (maximum) cutoff age of 20–21 (rather
than 18), but for which the average and median ages of the entire studied populations
were below 18 [5,26,27,52]. Case reports included patients within an age range of 9 to
17 years [9–11,15,29,34–40,44,66,68–74,77,78,83–85]. Overall, no clear female predominance
was registered, as is seen in the adult population with PHP [51,52].
Most studies were descriptive. A single study compared adults (N = 28) with children
(N = 14) [51], while another showcased infants vs. teenagers [51]. Genetic PHP and
apparently sporadic PHP were compared in four studies [18,26,27,50]. Concerning the
assessments within the studies, we identified four major types of endpoints, as follows:
particular imaging data, such as ultrasound, 99mTc Sestamibi scintigraphy, and dual-
phase computed tomography [45,46]; a second cluster included meticulous gene testing, or
patients with familial syndromes such as MEN1, etc. [18,26,27,46,47,49]; a third point related
to preoperative findings in terms of clinical presentation [5,26–28,48,51,52]; meanwhile,
the fourth type of evaluation provided surgical outcomes, postoperative issues, and an
Biomedicines 2023, 11, 2810 18 of 25

alternative to surgical approach in the form of a study on preoperative cinacalcet exposure

with a 2.2-year median duration [18].
Analyzing the type of gland involvement showed involvement of a single gland in
85% of sporadic cases, and in 19% in genetic PHP cases [27]; localization studies found
100% sensitivity for neck ultrasound in cases with single, non-ectopic tumors, with a
98% concordance with 99mTc Sestamibi [45]. A 91% sensitivity for dual-phase CT for
single-gland tumors was revealed in one study [46], in which 25% of the lesions were
ectopic parathyroid tumors (mostly intra-thymus, representing one-half of the ectopic
presentations) [5]. Case reports included another 9 out of the 41 patients with ectopic
parathyroid adenomas [10,11,29,34,68,69,83–85], and 3 parathyroid carcinomas [72,73,78];
moreover, 8 subjects (N = 8/41) had brown tumors [15,36,38,40,71,72,74,77].
Genetic PHP mostly involved the MEN1 gene, followed by CDC73, CASR, RET, and
CDKN1B; a maximum prevalence of 32–52% with respect to genetic PHP was reported, and
an additional subgroup representing 5–26.9% of the patients was reclassified from appar-
ently sporadic to genetic PHP [26,27,50]. Gene assays from isolated reports included MEN1
pathogenic variants in four papers [53,61,62,64], CDC73 variants in two articles [17,65],
and a VHL mutation in one subject [67]. Novel findings in the genetic field included a
germline MEN1 mutation heterozygous variant c.105_107dupGCT [62] and a new pediatric
phenotype with ectopic GHRH pancreatic overproduction in MEN1 [61].
Symptomatic PHP was reported in 71% of all cases (with a mean age of 17.3) [27],
while asymptomatic PHP was found in 60% of genetic PHP cases, and in 0% for sporadic
PHP cases [26]. Renal involvement (including kidney stones) was recorded to affect the
following: 10.5% of a cohort with genetic PHP, 71% of the cases diagnosed with sporadic
PHP [26], 50% of a cohort with a mean age of 16.7 [48], and 29% of another cohort with
a mean age of 15.2 [28], from 0% (in infancy) to 50–62% (teenagers) [52]. Bone anomalies
affected 50% of a cohort with deformities, while 30% of the patients had fractures [48]; 83%
of the children were affected by some type of skeletal involvement [28], while 62% of the
studied population was affected in another study [52]. Gastrointestinal issues affected 40%
of one cohort [48], but the data in this domain are heterogeneous.
The cure rate through parathyroidectomy was 97% [28] to 98% [5]. Recurrent PHP
was reported in 2% of sporadic PHP cases, and in 38% of familial PHP cases [27]. Hungry
bone syndrome was found with a maximum rate in 34% of the cases in one study [28], and
in 40% of another [48]. Case reports identified another seven subjects with the same post-
parathyroidectomy hypocalcemia-based syndrome; a potential connection with ectopic
presentation or brown tumors was suggested, but there are limited data from a strictly
statistical perspective [15,36,69–72,74]. Minimally invasive thoracoscopic approaches seem
safe, and they should be used for ectopic tumors when possible [11,80–82].
We are aware of the limitations of a narrative review mainly focused on PubMed–
based research for sample-based analysis, but this allowed us to have a more flexible
approach than a systematic review/meta-analysis would allow, due to the heterogeneity of
the studied parameters. Within the timeframe of our research, we identified a few reviews
with different objectives in pediatric PHP, as mentioned. For instance, Bin Yahib et al. [29]
analyzed 13 previously published papers (N = 331 children, teenagers and young adults)
studying recurrent abdominal pain as feature of PHP [29]. Lee et al. [39] studied prior
reports of young patients with genu valgum and PHP and identified 23 such cases [39].
Rahimi et al. [73] analyzed 17 previously published studies with regard to pediatric parathy-
roid carcinoma [73], while another review identified 12 individuals confirmed with the
same histological diagnosis and added 1 new report (N = 13) [72]. In 2021, Flokas et al. [68]
published a review of 33 ectopic parathyroid juvenile adenomas [68].
Due the level of statistical evidence concerning the area of pediatric PHP publications,
our study- and case-sample-based analysis, which included 48 articles and a total of
534 published cases of PHP, represents one of the largest of its kind.
Biomedicines 2023, 11, 2810 19 of 25

5. Conclusions
PHP in children and teenagers represents a challenging and dynamic field with a nec-
essarily multidisciplinary approach. Recent data suggest that infants and patients with an
already-known genetic/familial condition are prone to asymptomatic PHP. An infant with
PHP may be the index case in their family for genetic conditions such MEN1. The panel of
bone, renal, and digestive complications varied, and an index of suspicion should be kept in
mind. One out of four patients had ectopic parathyroid tumors, most probably mediastinal.
The importance of preoperative imaging assessment, such as 99mTc Sestamibi scintigraphy,
was closely related to the usefulness of genetic testing before parathyroidectomy in provid-
ing adequate information that influenced the surgical technique. Thoracoscopic procedures
showed good results, as seen in adults nowadays, but the level of evidence remains low
in this particular instance. Awareness of pediatric PHP is the key factor to benefiting our
young patients.

Author Contributions: Conceptualization, M.C., M.S., F.L.P., A.C. and C.N.; methodology, A.C.,
A.-M.G. and C.N.; software, M.C., M.S., F.L.P., A.-M.G. and C.N.; validation, M.C., M.S., F.L.P. and
A.-M.G.; formal analysis, M.C., A.C., M.S., F.L.P., A.-M.G. and C.N.; investigation, M.C., M.S., F.L.P.
and C.N.; resources, M.S., F.L.P., A.-M.G. and C.N.; data curation, M.C., M.S., F.L.P., A.-M.G., A.C.
and C.N.; writing—original draft preparation, M.C.; writing—review and editing, M.C., M.S., F.L.P.
and A.-M.G.; visualization, M.C., M.S., F.L.P., A.C. and C.N.; supervision, M.C., M.S., F.L.P., A.C. and
C.N.; project administration, M.C., M.S., A.C. and C.N.; funding acquisition, M.S. All authors have
read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict 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
Biomedicines 2023, 11, 2810 20 of 25

References
1. Motlaghzadeh, Y.; Bilezikian, J.P.; Sellmeyer, D.E. Rare Causes of Hypercalcemia: 2021 Update. J. Clin. Endocrinol. Metab. 2021,
106, 3113–3128. [CrossRef] [PubMed]
2. Zanocco, K.A.; Yeh, M.W. Primary Hyperparathyroidism: Effects on Bone Health. Endocrinol. Metab. Clin. N. Am. 2017, 46, 87–104.
[CrossRef] [PubMed]
3. Khalatbari, H.; Cheeney, S.H.E.; Manning, S.C.; Parisi, M.T. Pediatric hyperparathyroidism: Review and imaging update. Pediatr.
Radiol. 2021, 51, 1106–1120. [CrossRef]
4. Stanciu, M.; Boicean, L.C.; Popa, F.L. The role of combined techniques of scintigraphy and SPECT/CT in the diagnosis of primary
hyperparathyroidism: A case report. Medicine 2019, 98, e14154. [CrossRef] [PubMed]
5. Rampp, R.D.; Mancilla, E.E.; Adzick, N.S.; Levine, M.A.; Kelz, R.R.; Fraker, D.L.; Iyer, P.; Lindeman, B.M.; Mejia, V.A.;
Chen, H.; et al. Single Gland, Ectopic Location: Adenomas are Common Causes of Primary Hyperparathyroidism in Children
and Adolescents. World J. Surg. 2020, 44, 1518–1525. [CrossRef] [PubMed]
6. Dumitru, N.; Ghemigian, A.; Carsote, M.; Albu, S.E.; Terzea, D.; Valea, A. Thyroid nodules after initial evaluation by primary
health care practitioners: An ultrasound pictorial essay. Arch. Balk. Med. Union 2016, 51, 434–438.
7. Murugan, N.; Kandasamy, D.; Sharma, R.; Goyal, A.; Gupta, A.K.; Tandon, N.; Gupta, N.; Goswami, R.; Vurthaluru, S.;
Damle, N.; et al. Comparison of 4DMRI and 4DCT for the preoperative evaluation of patients with primary hyperparathyroidism.
Eur. J. Radiol. 2021, 138, 109625. [CrossRef] [PubMed]
8. Bunch, P.M.; Randolph, G.W.; Brooks, J.A.; George, V.; Cannon, J.; Kelly, H.R. Parathyroid 4D CT: What the Surgeon Wants to
Know. Radiographics 2020, 40, 1383–1394. [CrossRef]
9. Muse, J.; Palmer, R.; Auriemma, J. A Giant Parathyroid Adenoma Presenting as Nausea, Vomiting, and Headaches in an
Adolescent Male. Case Rep. Pediatr. 2023, 2023, 5530269. [CrossRef]
10. Seo, Y.; Song, K.; Choi, H.S.; Suh, J.; Kwon, A.; Chae, H.W.; Kim, H.S. A case of primary hyperparathyroidism due to an
intrathymic ectopic parathyroid adenoma in a 15-year-old boy. Ann. Pediatr. Endocrinol. Metab. 2020, 25, 187–191. [CrossRef]
11. Sahu, A.; Zameer, M.M.; Rao, S.; D’Cruz, A. Sestamibi-guided thoracoscopic excision of functional mediastinal parathyroid
adenoma in a child: A case report and review of literature. J. Minim. Access. Surg. 2023. [CrossRef] [PubMed]
12. Liu, X.; Sun, L.; Shao, M.; Li, P.; Liu, W.; Zhang, X.; Zhang, L.; Ma, Y.; Li, W. Primary hyperparathyroidism due to ectopic
parathyroid adenoma in an adolescent: A case report and review of the literature. Endocrine 2019, 64, 38–42. [CrossRef] [PubMed]
13. Kollars, J.; Zarroug, A.E.; van Heerden, J.; Lteif, A.; Stavlo, P.; Suarez, L.; Moir, C.; Ishitani, M.; Rodeberg, D. Primary hyper-
parathyroidism in pediatric patients. Pediatrics 2005, 115, 974–980. [CrossRef] [PubMed]
14. Root, A.W.; Levine, M.A. One half-century of advances in the evaluation and management of disorders of bone and mineral
metabolism in children and adolescents. J. Pediatr. Endocrinol. Metab. 2023, 36, 105–118. [CrossRef] [PubMed]
15. Boggs, E.; Szymusiak, J. Common in Adults and Often Overlooked in Pediatrics: A Case Report of Primary Hyperparathyroidism
in an Adolescent Patient. Cureus 2023, 15, e38112. [CrossRef]
16. Duval, M.; Haissaguerre, M. MEN for multiple endocrin neoplasms: When evokate MEN? Update 2022. Rev. Med. Int. 2023,
44, 12–18. [CrossRef]
17. Blackburn, J.; Mulvey, I.; Nadar, R.; Dias, R.P.; Saraff, V.; Senniappan, S. Heterozygous CDC73 mutation causing hyperparathy-
roidism in children and adolescents: A report of 2 cases. J. Pediatr. Endocrinol. Metab. 2022, 35, 1547–1551. [CrossRef]
18. Bernardor, J.; Flammier, S.; Salles, J.P.; Amouroux, C.; Castanet, M.; Lienhardt, A.; Martinerie, L.; Damgov, I.; Linglart, A.;
Bacchetta, J. Off-label use of cinacalcet in pediatric primary hyperparathyroidism: A French multicenter experience. Front. Pediatr.
2022, 10, 926986. [CrossRef]
19. Vierimaa, O.; Villablanca, A.; Alimov, A.; Georgitsi, M.; Raitila, A.; Vahteristo, P.; Larsson, C.; Ruokonen, A.; Eloranta, E.;
Ebeling, T.M.; et al. Mutation analysis of MEN1, HRPT2, CASR, CDKN1B, and AIP genes in primary hyperparathyroidism
patients with features of genetic predisposition. J. Endocrinol. Investig. 2009, 32, 512–528. [CrossRef]
20. Machens, A.; Elwerr, M.; Lorenz, K.; Weber, F.; Dralle, H. 100-Year evolution of precision medicine and surgery for multiple
endocrine neoplasia type 2A. Endocrine 2020, 68, 368–376. [CrossRef]
21. Cetani, F.; Pardi, E.; Aretini, P.; Saponaro, F.; Borsari, S.; Mazoni, L.; Apicella, M.; Civita, P.; La Ferla, M.; Caligo, M.A.; et al. Whole
exome sequencing in familial isolated primary hyperparathyroidism. J. Endocrinol. Investig. 2020, 43, 231–245. [CrossRef]
22. Mariathasan, S.; Andrews, K.A.; Thompson, E.; Challis, B.G.; Wilcox, S.; Pierce, H.; Hale, J.; Spiden, S.; Fuller, G.;
Simpson, H.L.; et al. Genetic testing for hereditary hyperparathyroidism and familial hypocalciuric hypercalcaemia in a
large UK cohort. Clin. Endocrinol. 2020, 93, 409–418. [CrossRef]
23. Masi, L. Primary Hyperparathyroidism. In Frontiers of Hormone Research; Karger: Basel, Switzerland, 2019; Volume 51, pp. 1–12.
[CrossRef]
24. McKenna, K.; Dunbar, N.S.; Parham, K. Why is primary hyperparathyroidism more severe in children? Med. Hypotheses 2021,
147, 110482. [CrossRef] [PubMed]
25. Shah, V.N.; Bhadada, S.K.; Bhansali, A.; Behera, A.; Mittal, B.R.; Bhavin, V. Influence of age and gender on presentation of
symptomatic primary hyperparathyroidism. J. Postgrad. Med. 2012, 58, 107–111. [CrossRef] [PubMed]
26. Sharma, A.; Memon, S.; Lila, A.R.; Sarathi, V.; Arya, S.; Jadhav, S.S.; Hira, P.; Garale, M.; Gosavi, V.; Karlekar, M.; et al. Genotype-
Phenotype Correlations in Asian Indian Children and Adolescents with Primary Hyperparathyroidism. Calcif. Tissue Int. 2022,
111, 229–241. [CrossRef] [PubMed]
Biomedicines 2023, 11, 2810 21 of 25

27. Szabo Yamashita, T.; Gudmundsdottir, H.; Foster, T.R.; Lyden, M.L.; Dy, B.M.; Tebben, P.J.; McKenzie, T. Pediatric primary
hyperparathyroidism: Surgical pathology and long-term outcomes in sporadic and familial cases. Am. J. Surg. 2023, 225, 699–702.
[CrossRef]
28. Sharanappa, V.; Mishra, A.; Bhatia, V.; Mayilvagnan, S.; Chand, G.; Agarwal, G.; Agarwal, A.; Mishra, S.K. Pediatric Primary
Hyperparathyroidism: Experience in a Tertiary Care Referral Center in a Developing Country Over Three Decades. World J. Surg.
2021, 45, 488–495. [CrossRef]
29. Bin Yahib, S.M.; Algarni, B.; Alghamdi, A.; Nassan, S. Primary Hyperparathyroidism as a Rare Cause of Unexplained Recurrent
Abdominal Pain: Case Presentation and Literature Review. Cureus 2021, 13, e19155. [CrossRef]
30. Stokes, V.J.; Nielsen, M.F.; Hannan, F.M.; Thakker, R.V. Hypercalcemic Disorders in Children. J. Bone Miner. Res. 2017, 32, 2157–2170.
[CrossRef]
31. George, J.; Acharya, S.V.; Bandgar, T.R.; Menon, P.S.; Shah, N.S. Primary hyperparathyroidism in children and adolescents. Indian
J. Pediatr. 2010, 77, 175–178. [CrossRef]
32. Plunkett, A.; Beattie, R.M. Recurrent abdominal pain in childhood. J. R. Soc. Med. 2005, 98, 101–106. [CrossRef] [PubMed]
33. Belcher, R.; Metrailer, A.M.; Bodenner, D.L.; Stack, B.C., Jr. Characterization of hyperparathyroidism in youth and adolescents: A
literature review. Int. J. Pediatr. Otorhinolaryngol. 2013, 77, 318–322. [CrossRef] [PubMed]
34. Oh, A.; Lee, Y.; Yoo, H.W.; Choi, J.H. Three pediatric patients with primary hyperparathyroidism caused by parathyroid adenoma.
Ann. Pediatr. Endocrinol. Metab. 2022, 27, 142–147. [CrossRef]
35. Fukaya, Y.; Oto, Y.; Inoue, T.; Itabashi, H.; Shiraishi, M.; Nitta, A.; Murakami, N.; Soh, S.; Ogawa, T.; Matsubara, T. Primary
hyperparathyroidism in a child with abdominal pain and hematuria. Clin. Pediatr. Endocrinol. 2021, 30, 111–113. [CrossRef]
36. Tuli, G.; Munarin, J.; Tessaris, D.; Buganza, R.; Matarazzo, P.; De Sanctis, L. Primary Hyperparathyroidism (PHPT) in Children:
Two Case Reports and Review of the Literature. Case Rep. Endocrinol. 2021, 2021, 5539349. [CrossRef] [PubMed]
37. Gafar, S.M.; Fadlalbari, G.F.; Abdalla, A.T.; Mohammed, S.A.R.; Alrasheed, M.K.; Taha, I.A.; Abdullah, M.A. Pitfalls in the
Diagnosis of Primary Hyperparathyroidism in a Sudanese Adolescent Boy; a case disguised as rickets. BMC Endocr. Disord. 2022,
22, 322. [CrossRef]
38. Dikova, M.I.; Petkova, B.; Alexiev, V. Skeletal Deformity in Children with Primary Hyperparathyroidism. Acta Chir. Orthop.
Traumatol. Cech. 2021, 88, 375–378. [CrossRef]
39. Lee, S.P.; Chai, S.T.; Loh, L.T.; Ali, N.M. Bilateral Genu Valgum in an Adolescent with Primary Hyperparathyroidism: A Case
Report and Review of Literature. J. ASEAN Fed. Endocr. Soc. 2020, 35, 220–223. [CrossRef]
40. de Silva, N.L.; Jayalath, M.D.; Sampath, W.K.C.; Perera, R.; Karunathilake, C. Primary hyperparathyroidism in an adolescent
presenting with genu valgus progressing to extensive bone disease; a case report. BMC Endocr. Disord. 2023, 23, 71. [CrossRef]
41. Chuang, T.J.; Tang, W.H.; Hung, Y.J.; Kuo, F.C. Aggressive gyriform calcifications and seizures after ischemia stroke in a patient
with primary hyperparathyroidism. QJM 2014, 107, 567–569. [CrossRef]
42. de la Plaza, L.R.; Ramia Ángel, J.M.; Arteaga Peralta, V.; Hernández Cristóbal, J.; López Marcano, A.J. Brain calcifications and
primary hyperparathyroidism. Cir. Esp. 2016, 94, e5–e7. [CrossRef]
43. Landais, A.; Mallet, G.; Bourgeois-Beauvais, Q.; Parisi, J.; Mecharles, S.; Lannuzel, A. Gyriform calcifications after ischemic stroke
in a patient with primary hyperparathyroidism. Press. Med. 2018, 47 Pt 1, 690–692. [CrossRef] [PubMed]
44. Pal, R.; Dutta, A.; Agrawal, K.; Jain, N.; Dutta, P.; Bhansali, A.; Behera, A.; Bhadada, S.K. Primary Hyperparathyroidism Presenting
as Posterior Reversible Encephalopathy Syndrome: A Report of Two Cases. J. Clin. Res. Pediatr. Endocrinol. 2020, 12, 432–438.
[CrossRef] [PubMed]
45. He, Y.; Luo, Y.; Jin, S.; Wang, O.; Liao, Q.; Zhu, Q.; Liu, H. Can we skip technetium-99 m sestamibi scintigraphy in pediatric
primary hyperparathyroidism patients with positive neck ultrasound results? Pediatr. Radiol. 2023, 53, 2253–2259. [CrossRef]
46. Sharma, A.; Patil, V.; Sarathi, V.; Purandare, N.; Hira, P.; Memon, S.; Jadhav, S.S.; Karlekar, M.; Lila, A.R.; Bandgar, T. Dual-phase
computed tomography for localization of parathyroid lesions in children and adolescents with primary hyperparathyroidism.
Ann. Endocrinol. 2023, 84, 446–453. [CrossRef]
47. Ramonell, K.M.; Fazendin, J.; Lovell, K.; Iyer, P.; Chen, H.; Lindeman, B.; Dream, S. Outpatient parathyroidectomy in the pediatric
population: An 18-year experience. J. Pediatr. Surg. 2022, 57, 410–413. [CrossRef]
48. Boro, H.; Khatiwada, S.; Alam, S.; Kubihal, S.; Dogra, V.; Malla, S.; Kumar, C. The spectrum of manifestations of primary
hyperparathyroidism in children and adolescents. Pediatr. Endocrinol. Diabetes Metab. 2022, 28, 178–187. [CrossRef]
49. Shariq, O.A.; Lines, K.E.; English, K.A.; Jafar-Mohammadi, B.; Prentice, P.; Casey, R.; Challis, B.G.; Selberherr, A.; Boon, H.;
Cranston, T.; et al. Multiple endocrine neoplasia type 1 in children and adolescents: Clinical features and treatment outcomes.
Surgery 2022, 171, 77–87. [CrossRef]
50. El Allali, Y.; Hermetet, C.; Bacchetta, J.; Amouroux, C.; Rothenbuhler, A.; Porquet-Bordes, V.; Champigny, M.A.; Baron, S.;
Barat, P.; Bony-Trifunovic, H.; et al. Presenting features and molecular genetics of primary hyperparathyroidism in the paediatric
population. Eur. J. Endocrinol. 2021, 184, 347–355. [CrossRef]
51. Jovanovic, M.; Paunovic, I.; Zdravkovic, V.; Djordjevic, M.; Rovcanin, B.; Tausanovic, K.; Slijepcevic, N.; Zivaljevic, V. Case-control
study of primary hyperparathyroidism in juvenile vs. adult patients. Int. J. Pediatr. Otorhinolaryngol. 2020, 131, 109895. [CrossRef]
52. Zivaljevic, V.; Jovanovic, M.; Diklic, A.; Zdravkovic, V.; Djordjevic, M.; Paunovic, I. Differences in primary hyperparathyroidism
characteristics between children and adolescents. J. Pediatr. Surg. 2020, 55, 1660–1662. [CrossRef] [PubMed]
Biomedicines 2023, 11, 2810 22 of 25

53. Cho, Y.Y.; Chung, Y.J. A germline c.1546dupC MEN1 mutation in an MEN1 family: A case report. Medicine 2021, 100, e26382.
[CrossRef]
54. Al-Salameh, A.; Cadiot, G.; Calender, A.; Goudet, P.; Chanson, P. Clinical aspects of multiple endocrine neoplasia type 1. Nat. Rev.
Endocrinol. 2021, 17, 207–224. [CrossRef] [PubMed]
55. Pieterman, C.R.C.; Valk, G.D. Update on the clinical management of multiple endocrine neoplasia type 1. Clin. Endocrinol. 2022,
97, 409–423. [CrossRef] [PubMed]
56. van den Broek, M.F.M.; van Nesselrooij, B.P.M.; Pieterman, C.R.C.; Verrijn Stuart, A.A.; van de Ven, A.C.; de Herder, W.W.;
Dekkers, O.M.; Drent, M.L.; Havekes, B.; Kerstens, M.N.; et al. Clues for Genetic Anticipation in Multiple Endocrine Neoplasia
Type 1. J. Clin. Endocrinol. Metab. 2020, 105, dgaa257. [CrossRef] [PubMed]
57. Marini, F.; Giusti, F.; Cioppi, F.; Maraghelli, D.; Cavalli, T.; Tonelli, F.; Brandi, M.L. Bone and Mineral Metabolism Phenotypes in
MEN1-Related and Sporadic Primary Hyperparathyroidism, before and after Parathyroidectomy. Cells 2021, 10, 1895. [CrossRef]
58. Wang, W.; Kong, J.; Nie, M.; Jiang, Y.; Li, M.; Xia, W.; Meng, X.; Xing, X.; Wang, O. Primary hyperparathyroidism in Chinese
children and adolescents: A single-centre experience at Peking Union Medical College Hospital. Clin. Endocrinol. 2017, 87, 865–873.
[CrossRef]
59. Roizen, J.; Levine, M.A. Primary hyperparathyroidism in children and adolescents. J. Chin. Med. Assoc. 2012, 75, 425–434.
[CrossRef]
60. Marx, S.J.; Lourenço, D.M., Jr. Familial Hyperparathyroidism–Disorders of Growth and Secretion in Hormone-Secretory Tissue.
Horm. Metab. Res. 2017, 49, 805–815. [CrossRef]
61. Srirangam Nadhamuni, V.; Iacovazzo, D.; Evanson, J.; Sahdev, A.; Trouillas, J.; McAndrew, L.R.; Kurzawinski, T.; Bryant, D.;
Hussain, K.; Bhattacharya, S.; et al. GHRH secretion from a pancreatic neuroendocrine tumor causing gigantism in a patient with
MEN1. Endocrinol. Diabetes Metab. Case Rep. 2021, 2021, 1–8. [CrossRef]
62. Stasiak, M.; Dedecjus, M.; Zawadzka-Starczewska, K.; Adamska, E.; Tomaszewska, M.; Lewiński, A. Novel Germline
c.105_107dupGCT MEN1 Mutation in a Family with Newly Diagnosed Multiple Endocrine Neoplasia Type 1. Genes 2020, 11, 986.
[CrossRef] [PubMed]
63. Pilarski, R.; Nagy, R. Genetic testing by cancer site: Endocrine system. Cancer J. 2012, 18, 364–371. [CrossRef] [PubMed]
64. Petriczko, E.; Marcinkiewicz, K.; Prokurat, A.; Sagan, L.; Malkowski, B.; Biczysko-Mokosa, A.; Horodnicka-Jozwa, A.; Andrysiak-
Mamos, E.; Syrenicz, A.; Kostrzeba, E.; et al. Rare clinical manifestation of multiple endocrine neoplasia type 1. Neuro Endocrinol.
Lett. 2022, 43, 199–207. [PubMed]
65. Mamedova, E.; Kolodkina, A.; Vasilyev, E.V.; Petrov, V.; Belaya, Z.; Tiulpakov, A. Successful Use of Denosumab for Life-
Threatening Hypercalcemia in a Pediatric Patient with Primary Hyperparathyroidism. Horm. Res. Paediatr. 2020, 93, 272–278.
[CrossRef] [PubMed]
66. Hayashi, S.; Oba, T.; Ichikawa, K.; Nakamura, C.; Hara, Y.; Kanai, T.; Sato, Y.; Uehara, T.; Ito, K.I. Hypercalcemic crisis caused by
primary hyperparathyroidism in a 11-year-old boy: A rare case report and review of the literature. Gland Surg. 2022, 11, 1279–1286.
[CrossRef]
67. Belaid, R.; Oueslati, I.; Chihaoui, M.; Yazidi, M.; Grira, W.; Chaker, F. A Case of Von Hippel-Lindau Disease with Bilateral
Pheochromocytoma and Ectopic Hypersecretion of Intact Parathyroid Hormone in an Adolescent Girl. Case Rep. Endocrinol. 2020,
2020, 8824640. [CrossRef]
68. Flokas, M.E.; Ganieva, G.; Grieco, A.; Agdere, L. Ectopic Parathyroid Adenoma in an 11-Year-Old Girl: Case Report and Literature
Review. AACE Clin. Case Rep. 2020, 7, 51–56. [CrossRef]
69. Vitale, R.J.; Shieh, H.F.; Modi, B.P.; Gordon, R.J. Primary Hyperparathyroidism from Ectopic Parathyroid Adenoma in a 12-Year-
Old With Slipped Capital Femoral Epiphysis. J. Endocr. Soc. 2022, 6, bvac071. [CrossRef]
70. Boro, H.; Alam, S.; Kubihal, V.; Khatiwada, S.; Kubihal, S.; Agarwal, S.; Khadgawat, R. Atypical parathyroid adenoma: Severe
manifestations in an adolescent girl. Pediatr. Endocrinol. Diabetes Metab. 2022, 28, 91–100. [CrossRef]
71. Legault, O.; Inman, M.; Moolman, N.; Wiebe, S.; Poulin, A.; Nour, M.A. Severe hypercalcemia and a pelvic brown tumor in an
adolescent with primary hyperparathyroidism: A case report. BMC Pediatr. 2020, 20, 547. [CrossRef]
72. Lenherr-Taube, N.; Lam, C.K.; Vali, R.; Shammas, A.; Campisi, P.; Zawawi, F.; Somers, G.R.; Stimec, J.; Mete, O.; Wong, A.K.; et al.
Severe Primary Hyperparathyroidism Caused by Parathyroid Carcinoma in a 13-Year-Old Child; Novel Findings from HRpQCT.
JBMR Plus 2020, 4, e10324. [CrossRef] [PubMed]
73. Rahimi, A.; Shahbazi, R.; Nikuei, P.; Soleimani, S.; Moradkhani, A.; Atashabparvar, A.; Khajehrahimi, F.; Zoghi, G.;
Kheirandish, M. A Pediatric Parathyroid Carcinoma: An Unusual Clinical Presentation and Mini-review. Int. J. Endocrinol. Metab.
2021, 19, e110234. [CrossRef] [PubMed]
74. David, O.; Loewenthal, N.; Haim, A.; Makarov, V.; Hershkovitz, E. Diagnosis, Management, and Possible Prevention of Hungry
Bone Syndrome in an Adolescent with Primary Hyperparathyroidism and Vitamin D Deficiency. Isr. Med. Assoc. J. 2020,
22, 122–124. [PubMed]
75. Lenschow, C.; Wennmann, A.; Hendricks, A.; Germer, C.T.; Fassnacht, M.; Buck, A.; Werner, R.A.; Plassmeier, L.; Schlegel, N.
Questionable value of [99m Tc]-sestamibi scintigraphy in patients with pHPT and negative ultrasound. Langenbecks Arch. Surg.
2022, 407, 3661–3669. [CrossRef]
76. Prakash, S.; Damle, N.A.; Kumar, P.; Dharmashaktu, Y.; Bal, C.S. Lincoln Sign in a Case of Primary Hyperparathyroidism on
18 F-Fluorocholine PET/CT. Clin. Nucl. Med. 2023, 48, e343–e344. [CrossRef]
Biomedicines 2023, 11, 2810 23 of 25

77. Roztoczyńska, D.; Wójcik, M.; Konturek, A.; Nogieć, A.; Hubalewska-Dydejczyk, A.; Starzyk, J. Bilateral slipped capital femoral
epiphysis as first manifestation of primary hyperparathyroidism in a 15-year-old boy. Pediatr. Endocrinol. Diabetes Metab. 2020,
26, 220–224. [CrossRef]
78. Omi, Y.; Yamamoto, T.; Nagashima, Y.; Abe, K.; Karasawa, K.; Tanaka, Y.; Okamoto, T. Parathyroid carcinoma in a 13-year-old girl
with a long-term survival. Surg. Case Rep. 2020, 6, 145. [CrossRef]
79. Hendricks, A.; Lenschow, C.; Kroiss, M.; Buck, A.; Kickuth, R.; Germer, C.T.; Schlegel, N. Evaluation of diagnostic efficacy for
localization of parathyroid adenoma in patients with primary hyperparathyroidism undergoing repeat surgery. Langenbecks Arch.
Surg. 2021, 406, 1615–1624. [CrossRef]
80. Kim, R.C.; Roch, A.M.; Birdas, T.J.; Ritter, H.E.; McDow, A.D. Hypercalcemic Crisis Caused by a Parathyroid Mass Requiring
Thoracoscopic Resection. AACE Clin. Case Rep. 2021, 7, 264–267. [CrossRef]
81. Abdulsalam, M.S.; Devanayagam, S.; Santosham, R.; Ganapathy, V.; Menon, M.; Simon, S. Mediastinal parathyroid adenoma
removal by video-assisted thoracoscopic surgery. Ann. Afr. Med. 2021, 20, 150–153. [CrossRef]
82. España, M.; Sastre, I.; Ceballos, R.J.; Bustos, M.E.F. VATS parathyroidectomy for primary hyperparathyroidism. Multimed. Man.
Cardiothorac. Surg. 2020, 2020. [CrossRef]
83. Badhe, P.V.; Patil, S.; Vikram Reddy, G.; Sheshadri, H.; Jain, S.; Nikumbh, T. Slipped capital femoral epiphysis as primary
presentation in an adolescent with primary hyperparathyroidism due to ectopic mediastinal parathyroid adenoma. Clin. Case
Rep. 2023, 11, e7498. [CrossRef] [PubMed]
84. Zenno, A.; Ramamoorthy, B.; Hammoud, D.A.; Quezado, M.; Zeiger, M.A.; Jha, S. Case Report: Nine-year-old with parathyroid
adenoma within the piriform sinus. Front. Endocrinol. 2023, 14, 1171052. [CrossRef]
85. Minelli, R.; Meoli, A.; Tiri, A.; Fanelli, U.; Iannarella, R.; Gismondi, P.; Esposito, S. An Atypical Presentation of Primary
Hyperparathyroidism in an Adolescent: A Case Report of Hypercalcaemia and Neuropsychiatric Symptoms Due to a Mediastinal
Parathyroid Adenoma. Front. Endocrinol. 2020, 11, 581765. [CrossRef] [PubMed]
86. Dillon, M.L.; Frazee, L.A. Cinacalcet for the treatment of primary hyperparathyroidism. Am. J. Ther. 2011, 18, 313–322. [CrossRef]
87. Peacock, M.; Bilezikian, J.P.; Bolognese, M.A.; Borofsky, M.; Scumpia, S.; Sterling, L.R.; Cheng, S.; Shoback, D. Cinacalcet HCl
reduces hypercalcemia in primary hyperparathyroidism across a wide spectrum of disease severity. J. Clin. Endocrinol. Metab.
2011, 96, E9–E18. [CrossRef]
88. Erickson, L.A.; Mete, O.; Juhlin, C.C.; Perren, A.; Gill, A.J. Overview of the 2022 WHO Classification of Parathyroid Tumors.
Endocr. Pathol. 2022, 33, 64–89. [CrossRef]
89. Batte, A.; Kasirye, P.; Baluku, R.; Kiguli, S.; Kalyesubula, R.; John, C.C.; Schwaderer, A.L.; Imel, E.A.; Conroy, A.L. Mineral bone
disorders and kidney disease in hospitalized children with sickle cell anemia. Front. Pediatr. 2023, 10, 1078853. [CrossRef]
90. Prytula, A.; Shroff, R.; Krupka, K.; Deschepper, E.; Bacchetta, J.; Ariceta, G.; Awan, A.; Benetti, E.; Büscher, A.; Berta, L.; et al.
Hyperparathyroidism Is an Independent Risk Factor for Allograft Dysfunction in Pediatric Kidney Transplantation. Kidney Int.
Rep. 2022, 8, 81–90. [CrossRef]
91. Middelkoop, K.; Walker, N.; Stewart, J.; Delport, C.; Jolliffe, D.A.; Nuttall, J.; Coussens, A.K.; Naude, C.E.; Tang, J.C.Y.; Fraser,
W.D.; et al. Prevalence and Determinants of Vitamin D Deficiency in 1825 Cape Town Primary Schoolchildren: A Cross-Sectional
Study. Nutrients 2022, 14, 1263. [CrossRef]
92. Yıldız, G.; Torun Bayram, M.; Çinleti, T.; Koç, A.; Soylu, A.; Kavukçu, S. Late onset Bartter syndrome: Bartter syndrome type
2 presenting with isolated nephrocalcinosis and high parathyroid hormone levels mimicking primary hyperparathyroidism.
J. Pediatr. Endocrinol. Metab. 2022, 35, 1298–1301. [CrossRef] [PubMed]
93. Carsote, M.; Paduraru, D.N.; Nica, A.E.; Valea, A. Parathyroidectomy: Is vitamin D a player for a good outcome? J. Med. Life 2016,
9, 348–352. [PubMed]
94. Mouly, C.; Vargas-Poussou, R.; Lienhardt, A.; Silve, C.; Hureaux, M.; Magdelaine, C.; Buffet, A.; Grunenwald, S.; Kuhn, J.M.;
Brue, T.; et al. Reference Centre for Rare Diseases of Calcium, Phosphate Metabolism. Clinical characteristics of familial
hypocalciuric hypercalcaemia type 1: A multicentre study of 77 adult patients. Clin. Endocrinol. 2020, 93, 248–260. [CrossRef]
[PubMed]
95. Gorvin, C.M. Genetic causes of neonatal and infantile hypercalcaemia. Pediatr. Nephrol. 2022, 37, 289–301. [CrossRef]
96. Arshad, M.F.; McAllister, J.; Merchant, A.; Rab, E.; Cook, J.; Eastell, R.; Balasubramanian, S. Urinary calcium indices in primary
hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcaemia (FHH): Which test performs best? Postgrad. Med. J. 2021,
97, 577–582. [CrossRef]
97. Bollerslev, J.; Rejnmark, L.; Zahn, A.; Heck, A.; Appelman-Dijkstra, N.M.; Cardoso, L.; Hannan, F.M.; Cetani, F.; Sikjær, T.;
Formenti, A.M.; et al. European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in
Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders. Eur. J. Endocrinol. 2022,
186, R33–R63. [CrossRef]
98. Appelman-Dijkstra, N.M.; Ertl, D.A.; Zillikens, M.C.; Rjenmark, L.; Winter, E.M. Hypercalcemia during pregnancy: Management
and outcomes for mother and child. Endocrine 2021, 71, 604–610. [CrossRef]
99. Sadacharan, D.; Mahadevan, S.; Rao, S.S.; Kumar, A.P.; Swathi, S.; Kumar, S.; Kannan, S. Neonatal Severe Primary Hyper-
parathyroidism: A Series of Four Cases and their Long-term Management in India. Indian J. Endocrinol. Metab. 2020, 24, 196–201.
[CrossRef]
Biomedicines 2023, 11, 2810 24 of 25

100. Höppner, J.; Sinningen, K.; Raimann, A.; Obermayer-Pietsch, B.; Grasemann, C. Disorders of the Calcium Sensing Signaling
Pathway: From Familial Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy. J. Clin. Med. 2022,
11, 2595. [CrossRef]
101. Höppner, J.; Lais, S.; Roll, C.; Wegener-Panzer, A.; Wieczorek, D.; Högler, W.; Grasemann, C. Case Report: Severe Neonatal Course
in Paternally Derived Familial Hypocalciuric Hypercalcemia. Front. Endocrinol. 2021, 12, 700612. [CrossRef]
102. Shaukat, M.; Ahmad, H.M.; Shafiq, M.U. Neonatal severe hyperparathyroidism: A case report. J. Pak. Med. Assoc. 2022,
72, 2538–2541. [CrossRef] [PubMed]
103. Özgüç Çömlek, F.; Demir, S.; Gürkan, H.; İnan, M.; Sezer, A.; Dilek, E.; Kökenli, F. The efficiency of cinacalcet treatment in
delaying parathyroidectomy in a case with neonatal severe hyperparathyroidism caused by homozygous mutation in the CASR
gene. Pediatr. Endocrinol. Diabetes Metab. 2022, 28, 168–174. [CrossRef] [PubMed]
104. Gupta, P.; Tak, S.A.; Misgar, R.A.; Agarwala, S.; Jain, V.; Sharma, R. A Case of Neonatal Severe Hyperparathyroidism: Challenges
in Management. Indian J. Pediatr. 2022, 89, 1025–1027. [CrossRef] [PubMed]
105. Hassan, S.S.; Kempers, M.; Lugtenberg, D.; Abdallah, A.T.; Musa, S.A.; Ibrahim, A.A.; Abdullah, M.A. Challenges in diagnosis
and management of neonatal hyperparathyroidism in a resource-limited country: A case series from a Sudanese family. Pan. Afr.
Med. J. 2021, 40, 105. [CrossRef] [PubMed]
106. Abdullayev, T.; Korkmaz, M.; Kul, M.; Koray, N. A rare cause of neonatal hypercalcemia: Neonatal severe primary hyperparathy-
roidism: A case report and review of the literature. Int. J. Surg. Case Rep. 2020, 66, 365–369. [CrossRef]
107. Sorapipatcharoen, K.; Mahachoklertwattana, P.; Tim-Aroon, T.; Wattanasirichaigoon, D.; Karanes, S.; Molagool, S.;
Poomthavorn, P. Successful parathyroidectomy with intra-operative parathyroid hormone monitoring in a neonate with
severe primary hyperparathyroidism caused by homozygous mutation in CASR gene. J. Paediatr. Child Health 2020, 56, 1144–1146.
[CrossRef]
108. Gulcan-Kersin, S.; Kirkgoz, T.; Eltan, M.; Rzayev, T.; Ata, P.; Bilgen, H.; Ozek, E.; Bereket, A.; Turan, S. Cinacalcet as a First-Line
Treatment in Neonatal Severe Hyperparathyroidism Secondary to Calcium Sensing Receptor (CaSR) Mutation. Horm. Res.
Paediatr. 2020, 93, 313–321. [CrossRef]
109. Eremkina, A.; Krupinova, J.; Dobreva, E.; Gorbacheva, A.; Bibik, E.; Samsonova, M.; Ajnetdinova, A.; Mokrysheva, N. Denosumab
for management of severe hypercalcemia in primary hyperparathyroidism. Endocr. Connect 2020, 9, 1019–1027. [CrossRef]
110. Jalleh, R.; Basu, G.; Le Leu, R.; Jesudason, S. Denosumab-Induced Severe Hypocalcaemia in Chronic Kidney Disease. Case Rep.
Nephrol. 2018, 2018, 7384763. [CrossRef]
111. Morimoto, H.; Nakajima, H.; Mori, J.; Fukuhara, S.; Shigehara, K.; Adachi, S.; Hosoi, H. Decrement in bone mineral density after
parathyroidectomy in a pediatric patient with primary hyperparathyroidism. Clin. Pediatr. Endocrinol. 2018, 27, 81–86. [CrossRef]
112. Sankaran, S.; Gamble, G.; Bolland, M.; Reid, I.R.; Grey, A. Skeletal effects of interventions in mild primary hyperparathyroidism:
A meta-analysis. J. Clin. Endocrinol. Metab. 2010, 95, 1653–1662. [CrossRef]
113. Rozenberg, S.; Bruyère, O.; Bergmann, P.; Cavalier, E.; Gielen, E.; Goemaere, S.; Kaufman, J.M.; Lapauw, B.; Laurent, M.R.; De
Schepper, J.; et al. How to manage osteoporosis before the age of 50. Maturitas 2020, 138, 14–25. [CrossRef] [PubMed]
114. Madhuchani, D.; Seneviratne, S.N.; Ward, L.M. Bone health in childhood and adolescence: An overview on dual-energy X-ray
absorptiometry scanning, fracture surveillance and bisphosphonate therapy for low-middle-income countries. Front. Endocrinol.
2023, 14, 1082413. [CrossRef] [PubMed]
115. Ciancia, S.; Högler, W.; Sakkers, R.J.B.; Appelman-Dijkstra, N.M.; Boot, A.M.; Sas, T.C.J.; Renes, J.S. Osteoporosis in children and
adolescents: How to treat and monitor? Eur. J. Pediatr. 2023, 182, 501–511. [CrossRef] [PubMed]
116. Sakka, S.D. Osteoporosis in children and young adults. Best Pract. Res. Clin. Rheumatol. 2022, 36, 101776. [CrossRef] [PubMed]
117. Wang, W.; Nie, M.; Jiang, Y.; Li, M.; Meng, X.; Xing, X.; Wang, O.; Xia, W. Impaired geometry, volumetric density, and microstruc-
ture of cortical and trabecular bone assessed by HR-pQCT in both sporadic and MEN1-related primary hyperparathyroidism.
Osteoporos. Int. 2020, 31, 165–173. [CrossRef]
118. Cusano, N.E.; Rubin, M.R.; Silva, B.C.; Tay, Y.D.; Williams, J.M.; Agarwal, S.; Omeragic, B.; Guo, X.E.; Bilezikian, J.P. Skeletal
Microstructure and Estimated Bone Strength Improve Following Parathyroidectomy in Primary Hyperparathyroidism. J. Clin.
Endocrinol. Metab. 2018, 103, 196–205. [CrossRef]
119. Fraga, M.M.; de Sousa, F.P.; Szejnfeld, V.L.; de Moura Castro, C.H.; de Medeiros Pinheiro, M.; Terreri, M.T. Trabecular bone
score (TBS) and bone mineral density (BMD) analysis by dual X-ray absorptiometry (DXA) in healthy Brazilian children and
adolescents: Normative data. Arch. Osteoporos. 2023, 18, 82. [CrossRef]
120. Valenzuela Riveros, L.F.; Long, J.; Bachrach, L.K.; Leonard, M.B.; Kent, K. Trabecular Bone Score (TBS) Varies with Correction
for Tissue Thickness Versus Body Mass Index: Implications When Using Pediatric Reference Norms. J. Bone Miner. Res. 2023,
38, 493–498. [CrossRef]
121. Nistor, C.E.; Pantile, D.; Stanciu-Gavan, C.; Ciuche, A.; Moldovan, H. Diagnostic and Therapeutic Characteristics in Patients with
Pneumotorax Associated with COVID-19 versus Non-COVID-19 Pneumotorax. Medicina 2022, 58, 1242. [CrossRef]
122. Alfadhli, E.M. Management of Primary Hyperparathyroidism with Severe Hypercalcemia During the COVID-19 Pandemic. Clin.
Ther. 2021, 43, 711–719. [CrossRef] [PubMed]
123. Nistor, C.E.; Gavan, C.S.; Pantile, D.; Tanase, N.V.; Ciuche, A. Cervico-Thoracic Air Collections in COVID-19 Pneumonia
Patients–Our Experience and Brief Review. Chirurgia 2022, 117, 317–327. [CrossRef]
Biomedicines 2023, 11, 2810 25 of 25

124. Kuchay, M.S.; Mathew, A.; Kaur, P.; Mishra, S.K. Denosumab can be used successfully as a bridge to surgery in patients with
severe hypercalcemia due to primary hyperparathyroidism. Arch. Endocrinol. Metab. 2021, 65, 669–673. [CrossRef] [PubMed]
125. Aojula, N.; Ready, A.; Gittoes, N.; Hassan-Smith, Z. Management of Parathyroid Disease during the COVID-19 Pandemic. J. Clin.
Med. 2021, 10, 920. [CrossRef] [PubMed]
126. Stanciu, M.; Ristea, R.P.; Popescu, M.; Vasile, C.M.; Popa, F.L. Thyroid Carcinoma Showing Thymus-like Differentiation (CASTLE):
A Case Report. Life 2022, 12, 1314. [CrossRef]
127. Linquest, L.; Ackerman, K.; Dewan, K. Implications of COVID-19 in Airway and Swallowing Function. OTO Open 2023, 7, e74.
[CrossRef]
128. Gao, Y.; Chen, Z.; Chen, S.; Wang, S.; Lin, J. Risk factors for neck pain in college students: A systematic review and meta-analysis.
BMC Public Health 2023, 23, 1502. [CrossRef]

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.