Seminars in Pediatric Surgery 29 (2020) 150923

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Seminars in Pediatric Surgery

journal homepage: www.elsevier.com/locate/sempedsurg

Pediatric parathyroid disease

Ramin Jamshidi a,b,c,d,∗, J. Craig Egan a,b,c,d
a
Institutional affiliation: Phoenix Children’s Hospital
b
Departments of Surgery and Child Health, Univeristy of Arizona, Phoenix, AZ
c
Department of Surgery, Creighton University School of Medicine, Phoenix, AZ
d
Departments of Surgery and Pediatrics, Mayo Clinic Arizona, Phoenix, AZ

a r t i c l e i n f o a b s t r a c t

Keywords: Parathyroid glands are critical for calcium and phosphate homeostasis. Parathyroid disease is relatively
Parathyroid rare in the pediatric population, but there are some important pediatric-specific considerations and con-
Hypoparathyroidism
ditions. This article reviews parathyroid physiology, disorders of hyper- and hypo- function, operative
Hyperparathyroidism
management, and uniquely pediatric diagnoses such as neonatal severe hyperparathyroidism. Advances
Parathyroid Carcinoma
Neonatal Severe Hyperparathyroidism in preoperative imaging, intra-operative gland identification, and management of post-thyroidectomy
Post-thyroidectomy Hypocalcemia hypocalcemia are also presented in detail. This article combines a review of fundamentals with recent
Parathyroid Imaging advances in care, emphasizing pediatric-specific publications.
© 2020 Elsevier Inc. All rights reserved.

Introduction enhances release of calcium from the large reservoir of calcium

phosphate salts. In kidneys, PTH increases calcium reabsorption
The sole functions of the parathyroid glands are calcium and and facilitates the synthesis of active vitamin D, aka calcitriol
phosphate homeostasis. These glands secrete parathyroid hormone (1,25-dihydroxyvitamin D). In conjunction with calcitriol, PTH reg-
(PTH) in response to a calcium-mediated feedback loop which con- ulates calcium and phosphate absorption from the small intestine.
trols calcium and phosphate metabolism in the kidneys, intestine, Increased serum calcium levels exert a negative-feedback signal
and long bones. Survival is possible without the parathyroids, but on the parathyroid glands to stop the release of PTH. The serum
requires intensive medication regimens and close monitoring. Un- half-life of activated PTH is a few minutes and it is cleared from
treated hypoparathyroidism can result in tetany, bronchospasm, serum quickly by the kidneys and liver.1 Calcitonin acts to reduce
seizures, cardiac dysrhythmia, and death. serum calcium, opposing the effects of PTH.
There are usually four parathyroid glands located just posterior
to the thyroid in the central compartment of the neck. Parathyroid PTH Effects on Bones
glands develop from the endoderm of the third and fourth pharyn-
geal pouches. The inferior parathyroid glands arise from the dorsal Calcium is the most abundant mineral in the human body, with
part of the third pouch, and the thymus arises from the ventral approximately 99% contained within the skeleton in the form of
part of the third pouch. The superior parathyroid glands are de- calcium phosphate salts.2 PTH directly stimulates osteoblasts to
rived from the fourth pharyngeal pouch and migrate along with increase their expression of RANKL, a receptor activator for nu-
the ultimobranchial bodies that become the calcitonin-secreting clear factor kappa-B ligand, allowing for the differentiation of os-
parafollicular C cells.1 The inferior parathyroid glands migrate a teoblasts into osteoclasts. PTH also inhibits the secretion of osteo-
longer distance, are more commonly ectopic, and may be found protegerin, allowing for preferential differentiation into osteoclasts.
within the thymus. On the other hand, ectopic superior parathy- Osteoclasts deconstruct bone through the process of resorption,
roid glands are sometimes intrathyroidal. leading to the release of ionized calcium and phosphate into the
The parathyroid glands secrete PTH in response to low serum blood stream. Conversely, calcitonin inhibits osteoclast activity and
calcium levels. PTH increases serum calcium levels through its ef- prevents bone resorption.
fects on bones, kidneys, and small intestine. (Fig. 1) In bones, PTH
PTH Effects on Kidneys

∗
Calcium reabsorption in the nephron takes place mostly in the
Corresponding author: Ramin Jamshidi, MD, FACS. Phoenix Children’s Hospital,
Division of Pediatric Surgery, 1919 E. Thomas Rd., Phoenix, Arizona 85016. proximal convoluted tubule and (to a lesser degree) the ascend-
E-mail addresses: rjamshidi@phoenixchildrens.com (R. Jamshidi), ing loop of Henle. The quantity of calcium ions reabsorbed in the
cegan@phoenixchildrens.com (J.C. Egan).
https://doi.org/10.1016/j.sempedsurg.2020.150923
1055-8586/© 2020 Elsevier Inc. All rights reserved.
2 R. Jamshidi and J.C. Egan / Seminars in Pediatric Surgery 29 (2020) 150923

Fig. 1. The Parathyroid Axis. The synthesis of parathyroid hormone (PTH) and parathyroid hormone–related peptide (PTHrP) is shown on the left, and their target sites of
action are shown on the right. Both act by means of the same receptor (also termed the type 1 PTH receptor). Negative feedback of 1,25-dihydroxyvitamin D (calcitriol) is
not shown. (Marx S. Hyperparathyroid and hypoparathyroid disorders. New England Journal of Medicine 20 0 0; 343: 1863-1875.)

kidney is only partially influenced by PTH. Circulating PTH targets PTH Effects on Small Intestine
the distal convoluted tubule and collecting duct, directly increasing
calcium reabsorption. PTH also decreases phosphate reabsorption PTH influences the absorption of calcium in the intestine indi-
at the proximal convoluted tubule. Phosphate ions in the serum rectly through active vitamin D. In the proximal small intestine,
form insoluble salts with calcium, resulting in decreased plasma active vitamin D allows the absorption of calcium through an ac-
calcium. Thus, reduction of serum phosphate ions through urinary tive transcellular pathway and a passive paracellular pathway. The
excretion results in more ionized calcium in the blood. transcellular pathway requires energy, while the paracellular path-
More importantly, the kidney influences serum calcium concen- way allows for the passage of calcium through tight junctions. It
tration through the production of activated vitamin D, which is the has been suggested (based on animal studies) that vitamin D pro-
dihidroxylated form known as calcitriol. PTH stimulates the pro- motes paracellular calcium diffusion throughout the small intestine
duction of 1-alpha-hydroxylase in the proximal convoluted tubule. by increasing ion permeability of those tight junctions.4 , 5
This enzyme is required to catalyze the synthesis of active vita-
min D (1,25-dihydroxycholecalciferol) from the inactive form (25- Parathyroid Evaluation
hydroxycholecalciferol). Although active vitamin D is important for
calcium absorption from the intestine, active vitamin D also plays Parathyroid dysfunction is characterized as under- or over-
a role in calcium reabsorption in the distal convoluted tubule via activity of the glands in relation to serum calcium and phosphate.
calbindin-D, a cytosolic vitamin D-dependent calcium binding pro- Evaluation of serum calcium imbalance begins with laboratory in-
tein.1 , 3 vestigations: PTH, calcium, phosphate, chloride, albumin, vitamin
D, and magnesium.
 R. Jamshidi and J.C. Egan / Seminars in Pediatric Surgery 29 (2020) 150923 3

Hypercalcemia normally suppresses PTH secretion, resulting in children. The most probable explanation for this is that ongoing
lower-than-normal serum levels of PTH. Elevated serum PTH in the bone development results in increased calcium turnover. A meta-
setting of hypercalcemia is suggestive of primary hyperparathy- analysis by Roizen et al found higher values of serum and urinary
roidism (pHPT) and should prompt imaging of the parathyroid calcium in children and adolescents compared to adults with simi-
glands. First-line modalities for imaging of the parathyroid glands lar PTH levels. In the setting of pHPT, most (90%) children and ado-
are ultrasound and/or 99m Tc sestamibi scintigraphy. On ultra- lescents with pHPT are symptomatic at the time of the diagnosis;
sound, a parathyroid adenoma appears hypoechoic and is often in contrast, most adults (80%) are asymptomatic. The predominant
enlarged. On scintigraphy, hyperfunctioning glands demonstrate manifestation is bone disease in children and kidney stones in ado-
greater uptake and retention of the technetium radiotracer (see lescents. The greater morbidity and higher incidence of end-organ
further discussion of imaging below). damage present in children and adolescents may be due to the lack
of routine biochemical analyses in younger patients. Prior to the
Hyperparathyroidism 1970s when routine calcium screening was introduced, almost all
adult pHPT patients presented with symptoms. Moreover, symp-
Although there are various causes of hypercalcemia, hyper- toms of pHPT are often nonspecific, especially in children, which
parathyroidism is of particular interest to endocrine surgeons be- likely results in delay of diagnosis and increased risk of organ in-
cause it is typically cured by an operation.6 , 7 Hyperparathyroidism jury.10
results in hypercalcemia, which can cause constipation, bone pain, Parathyroidectomy is effective – and is the treatment of choice
fatigue, depression and kidney stones. Extreme hypercalcemia can – for pHPT in young patients. A single center study of pediatric
affect the myocardium, resulting in very short QT intervals that pHPT from Mayo Clinic in Rochester, MN included 52 patients
can precipitate fatal arrhythmias such as ventricular tachycardia or younger than 19 years over a 30 year period (1970–20 0 0).10
even ventricular fibrillation. Hyperparathyroidism also drives ab- Female-to-male ratio was 3:2, 79% of patients were symptomatic
normal bone resorption, which can result in early osteoporosis and and 44% had end-organ damage. A single adenoma was present
increased susceptibility to fracture. in 65%, and 65% of these involved a superior gland. Parathyroid
hyperplasia was the next most common pathology, noted in 27%.
Primary Hyperparathyroidism Hyperplasia was attributed to MEN-I (15%), isolated MGD (6%),
MEN-IIA (4%), and familial non-MEN HPT (2%). Ectopic glands were
Primary hyperparathyroidism (pHPT) refers to an intrinsic over- observed in 10%: 2 intrathymic adenomas (1 mediastinal), 2 cases
activity of the parathyroid gland itself. pHPT is far less common in of hyperplastic intrathyroidal parathyroids, and 1 patient with 5
pediatric patients than in adults, with an estimated incidence of glands. No cases of multiple adenomas or parathyroid carcinoma
2–5 in 10 0,0 0 0.8 Series show a bimodal age distribution, with an were observed. No parathyroid abnormalities were identified dur-
early peak during the neonatal period and a second peak from the ing exploration in 8% of the patients. Correction of hypercalcemia
age of 6 years to adolescence. pHPT in neonates is typically due was accomplished in 94% of patients following parathyroidectomy
to mutations of the calcium sensing receptor (CaSR) which result in this series. The largest reported series of pediatric pHPT pooled
in severe hypercalcemia (see below). In children and adolescents, 86 children and adolescents from three institutions (Children’s
pHPT is most commonly due to a single parathyroid adenoma (65 - Hospital of Philadelphia, Hospital of University of Pennsylvania,
70%) and less commonly to multiglandular disease (MGD), a broad and the University of Alabama) between 1997 and 2017.9 In this
category that includes hyperplasia, multiple adenomas, and poly- series, the most common pathology was also a single parathyroid
clonal hyperfunction.9 , 10 Adenomas are almost always sporadic. adenoma (71%). MGD was observed in 23%, double adenoma
MGD may be a manifestation of the multiple endocrine neoplasia in 2% (2 patients) and one patient had parathyromatosis. No
syndromes MEN 1 and MEN 2a, or familial isolated hyperparathy- parathyroid carcinoma was identified, although two patients were
roidism syndromes such as hyperparathyroidism jaw tumor syn- missing pathology reports. Ectopic adenomas were noted in 25%:
drome (HPT-JT) and X-linked hypophosphataemia (XLHP). Parathy- 15% intrathymic, 6% tracheoesophageal groove, 2% intrathyroidal,
roid carcinoma (<1%) is a rare cause of hyperparathyroidism which and 2% carotid sheath. The cure rate was 98% (the patient with
is discussed below. Parathyroidectomy in young patients (i.e. age parathyromatosis requires re-operation).
less than 50 years) with pHPT is generally curative and is associ-
ated with increased life expectancy.11 , 12 Secondary and Tertiary Hyperparathyroidism
Patients with pHPT have symptoms of fatigue, weakness and
neuropsychiatric disturbances. A useful mnemonic for recalling Secondary hyperparathyroidism (sHPT) refers to the com-
symptoms of hypercalcemia is “moans (lethargy and fatigue), pensatory over-secretion of PTH in response to abnormally low
stones (nephrolithiasis, nephrocalcinosis), bones (osteopenia and serum calcium due to other pathological processes. Elevated PTH
bone pain), groans (abdominal pain, pancreatitis, gallstones, pep- in the presence of hypocalcemia is most commonly related to
tic ulcer disease, constipation) and psychiatric overtones (depres- renal failure, but may also be caused by vitamin D deficiency or
sion)”. Hypertension is also seen in some patients with pHPT. gastrointestinal malabsorption of calcium.
If there is clinical concern for nephrolithiasis, a renal ultra- As previously described, the kidneys are important sites of
sound should be ordered and 24-hour urine calcium measure- calcium reabsorption, phosphate excretion, and vitamin D activa-
ment can be used to assess the risk of stone formation. The tion. Chronic kidney disease results in abnormalities of mineral
effects of hyperparathyroidism on bone density are assessed by metabolism via several mechanisms, resulting in hypocalcemia,
bone densitometry. When compared to adults, children with hyperphosphatemia and calcitriol deficiency. Continuous stimula-
pHPT more often present with symptomatic disease (79-90%) and tion of the parathyroid glands by a combination of decreased
end organ involvement (44%) (e.g. nephrolithiasis, nephrocalci- extracellular ionized calcium concentration, elevated extracellular
nosis and bone involvement), for which surgery is the definitive phosphate concentration, and markedly reduced serum calcitriol
treatment.6 , 13 leads to increased PTH synthesis and secretion. Simultaneously, el-
Children and adults differ slightly in normal calcium and phos- evated FGF23 expression downregulates 25(OH)-1-hydroxylase in
phorus homeostasis and manifestation of pHPT. Serum calcium and the residual kidney, further exacerbating the calcitriol deficiency
phosphorus levels are higher in healthy children than in healthy and acting as an additional driver of sHPT. In the early stages
adults. Additionally, 24-hour urinary calcium is higher in healthy of hyperparathyroidism, there is downregulation of the calcium-
4 R. Jamshidi and J.C. Egan / Seminars in Pediatric Surgery 29 (2020) 150923

Fig. 2. Schematic representation of the interactions between the different PTH-regulating factors. Normal state (upper panel), and renal failure (lower panel).14

sensing receptor, CaSR, and vitamin D receptor, VDR, expression on tributes to a vicious cycle of dysregulated calcium and phosphate
parathyroid cells, rendering the parathyroid cells less responsive to homeostasis.14
calcium and/or calcitriol. The resulting increase in proliferative ac- Treating the underlying cause of hypocalcemia will resolve most
tivity of the parathyroid glands leads to parathyroid hyperplasia. cases of sHPT. For example, approximately 80% of cases of sHPT
(Fig. 2) The net result is increased production of PTH which con- due to renal failure resolve with successful kidney transplantation.
 R. Jamshidi and J.C. Egan / Seminars in Pediatric Surgery 29 (2020) 150923 5

Spontaneous regression of glandular hyperplasia may take 6–12 accuracy of 69-92%. Concordant US and sestamibi results allow
months, so it is prudent to wait 12 months post-transplant before the surgeon to proceed with MIP with confidence and allows for
considering parathyroidectomy.15 First-line management of sHPT exploration of the single abnormal gland. US and sestamibi scan
includes dietary restriction of phosphorous, phosphate binders to co-localize adenomas in 44% of cases.12 , 13 The ability of US and
limit intestinal absorption of phosphate and dietary supplemen- sestamibi imaging to distinguish single gland from multiple gland
tation of calcium and activated vitamin D. Newer vitamin D ana- disease and to accurately predict the laterality of the abnormal
logues and cacimimetics are being trialed. Bisphosphonates, by solitary gland was 100%. (Fig. 3) In the setting of discordant find-
limiting the high rate of bone resorption, may have a role in severe ings or findings supportive of MGD, four gland exploration may
sHPT, if only as a bridge to more definitive treatment. However, the be necessary. Furthermore, Rampp et al observed a high incidence
use of bisphosphonates, because of their very slow removal from (25%) of ectopic parathyroid adenomas in patients <21 years of
bone, carries the risk of inducing low-turnover bone disease, espe- age with pHPT. Location of the ectopic gland was most commonly
cially in patients who ultimately undergo parathyroidectomy. intrathymic, followed by tracheoesophageal groove, carotid sheath
Total or subtotal parathyroidectomy is generally only consid- and intrathyroid.9
ered when pharmacologic intervention has failed. Approximately MIP is further facilitated by the use of intraoperative PTH
1% to 10% of patients with renal failure require parathyroidec- (ioPTH) measurements, resulting in shorter procedure times and
tomy for sHPT. Although there are no well-defined criteria for lower failure rates. The short plasma half-life of intact PTH, and
parathyroidectomy in children with sHPT, parathyroidectomy is suppression of the uninvolved, normal parathyroid glands by hy-
considered in adults with sHPT refractory to medical therapy with percalcemia induced by the adenoma, lead to a rapid decrease in
PTH >10 0 0 pg/ml and at least one hyperplastic gland with a vol- circulating levels of intact PTH soon after excision of a solitary
ume >500 mm3 . Parathyroidectomy dramatically improves sHPT, parathyroid adenoma. Utilizing ioPTH, Mancilla et al showed 14/15
increasing survival rates and patient quality of life in suitable pediatric patients with pHPT had a >50% decrease in PTH levels
candidates. Firor et al published a series of 6 children who had 10 min post-resection of a single parathyroid adenoma, suggesting
subtotal parathyroidectomy for sPTH. In all six, bone pain resolved, cure (Fig. 4). Most patients had another level measured 30 minutes
fractures healed, and bone re-calcification was evident on follow- post-resection and it remained low in all except the one patient
up x-rays. Another small series reported total parathyroidectomy who did not show an initial decrease. ioPTH facilitated the use of
and autotransplantation of 10-20, 1 mm3 fragments of parathy- MIP in 2 patients who had non-focal preoperative imaging studies.
roid tissue into the brachioradialis muscle, resulting in complete One was an intrathymic adenoma and the other was a small ade-
healing of renal osteodystrophy. Serum PTH and biopsies done 3 noma in the neck. No side effects were described except for mild,
months after autotransplant demonstrated functioning parathyroid transient hypocalcemia on the first postoperative day in 75% of
autotransplants at 19 and 20 months postoperatively in these two cases, which resolved with calcium and calcitriol supplementation.
patients. Interestingly, serum PTH was consistently higher in draws There were no recurrent laryngeal nerve injuries, bleeding requir-
from the ipsilateral antecubital vein (vs contralateral arm), reflect- ing reoperation, or surgical site infections. Post-operative serum
ing secretion from the transplanted gland. sHPT may persist or calcium and phosphate levels were normal in all patients (Ca range
recur because of hyperfunction of the remnant or autotransplanted 8.8–10.4). PTH levels were available for 10 patients at 6–12 months
parathyroid tissue. In adults, 5-9% of patients develop recurrent post-parathyroidectomy and were normal. These findings utilizing
sHPT and require removal of autotransplanted grafts. 16–19 ioPTH to guide MIP in children recapitulate those seen in large se-
Tertiary hyperparathyroidism (tHPT) occurs when autonomous ries of adults undergoing MIP.
PTH secretion continues despite resolution of the cause of sHPT. Following the Miami criteria, Mancilla et al showed that ioPTH
Following renal transplantation, tHPT has been estimated to oc- levels in children predicted postoperative normocalcemia in 93%
cur in approximately 20 – 40% of adult patients and 25-35% of of cases, with one false negative result. The Miami criteria re-
pediatric patients.20–23 While it is recognized that most of these quire serial measurement of ioPTH during the course of the op-
cases will resolve with time and medication management, the like- eration; if ioPTH measured 10 min after resection of the suspicious
lihood of persistent tHPT is not clear. Parathyroidectomy with or gland drops by ≥50% of the highest pre-incision or pre-excision
without autotransplantation should be considered in patients with PTH level, pHPT is cured in 96% of cases.25 Durkin showed an 89%
persistent tHPT. Moazam et al first reported 2 patients, 24 and 28 cure rate (8/9 patients) using MIP and ioPTH in children <19 years
months of age, who were successfully treated with total parathy- of age without a family history of pHPT. Alagaratnam showed 100%
roidectomy with autotransplantation into the brachioradialis mus- cure rate using MIP in 9 children, using a small lateral neck inci-
cle. Saafan et al performed 3-gland parathyroidectomy on 17 pa- sion to remove a single parathyroid gland without visualization of
tients, ages 6 to 16 years. 15 of these had hyperplasia and 2 had other glands. Mancilla et al’s approach was a 2 cm transverse cen-
single adenomas. 2 of these patients required reoperation for re- tral neck incision. Whichever the approach, the data support mini-
current hyperparathyroidism. Recurrence rates vary from 0% to mally invasive parathyroidectomy as a suitable alternative to stan-
80%, with 8-14% of patients requiring reoperation.13 , 17 , 24 dard neck exploration for pHPT in children. Preoperative US and
sestamibi scans are complementary studies that are useful in di-
Surgery for Hyperparathyroidism recting the surgeon to the abnormal gland. ioPTH predicts post-
operative normocalcemia and is especially useful to confirm cure
Removal of abnormal parathyroid glands is the best treatment and limit operative exploration when imaging studies are incon-
in the majority of children diagnosed with pHPT. Distinguishing clusive.11
between a single gland adenoma and MGD, such as four gland Surgery for multigland disease (MGD) involves removal of 3 or
hyperplasia, allows for a more directed operative approach. Bio- 4 glands. In children with familial HPT, it is reasonable to proceed
chemical, genetic, and radiological testing help distinguish single with surgery without preoperative imaging, as familial HPT is most
gland from multigland disease and allow for the introduction of commonly caused by hyperplasia of multiple glands, which shows
minimally invasive parathyroidectomy (MIP) via smaller incisions. poorly on imaging. Localization of abnormal glands in familial HPT
MIP results in less pain, shorter hospital stay and improved cos- is also not essential, as the recommended operation is direct vi-
metic results. US has a sensitivity of 60-93% and a specificity of sualization of all glands and the removal of abnormal glands. Ala-
98% for detecting a parathyroid adenoma. For sestamibi scans, the garatnam et al demonstrated that familial HPT can be caused by
sensitivity and specificity are 92% and 97%, respectively, with an multi-gland hyperplasia, multi-gland adenomas or a combination
6 R. Jamshidi and J.C. Egan / Seminars in Pediatric Surgery 29 (2020) 150923

Fig. 3. Images of parathyroid adenoma on US and Tc-99 sestamibi scan with SPECT. A, Anterior initial images post Tc-99m sestamibi. B, Anterior delay 2 h post Tc-99m
sestamibi. C, Thyroid US showing a 1.2 cm hypoechoic nodule inferior to the left thyroid lobe.11

Fig. 4. ioPTH was performed in 15 of 16 patients, 14/15 patients showed >50% decrease in PTH levels 10–30 min postresection of a PA. PTH decreased from 170 to <5 pg/mL
after resection in one patient with an intrathymic adenoma that had not been localized by preoperative imaging.11

thereof. This small series reported on a total of 7 children with fa- cases of pediatric parathyroid carcinoma have been reported in the
milial HPT undergoing 3 or 4 gland parathyroidectomy. Histology literature.27 Parathyroid carcinoma uniformly presents as primary
among the children with MEN1 showed: one child had 4 gland hy- hyperparathyroidism, and definitive differentiation between carci-
perplasia, one child had 3 gland hyperplasia, one child had 2 gland noma and benign adenoma is made on histology.28–30
hyperplasia and 2 adenomas, and one child had 2 gland nodular Severe hypercalcemia and marked gland enlargement are classic
hyperplasia and 1 normal gland. The child with X linked HP had manifestations of parathyroid carcinoma. In one series of parathy-
4 hyperplastic glands, while the child with MEN2a and the child roid carcinoma patients, calcium at presentation was over 12
with HPT-JT each had a solitary adenoma.12 mg/dL in 85% of patients and size was over 3 cm in 80%.31 There
Preserving some parathyroid function in patients with four is evidence that serum levels of the hyperglycosylated isoform of
gland hyperplasia, especially in younger children, is an attractive human chorionic gonadotropin may differentiate between benign
option. Parathyroid gland preservation is achieved by either re- and malignant parathyroid disease but no specific circulating tu-
moving 3½ glands or performing total parathyroidectomy with mor markers have yet been identified.32 Parathyroid cancer has re-
autotransplantation of a portion of parathyroid tissue into the ster- currence rates as high as 50% and can metastasize to the lungs, cer-
nocleidomastoid or brachioradialis. These approaches can cure hy- vical lymph nodes, bones and mediastinum, thus thorough excision
perparathyroidism and maintain normocalcaemia without calcium and careful post-operative surveillance are important.32 , 33 Overall
supplementation, but carry a risk of recurrent HPT. Recurrent hy- 5- and 10- year survival are reported at 85% and 49%.34
percalcemia occurs in 6%–12% of children after parathyroidectomy The relevance of a preoperative diagnosis or suspicion of carci-
and is most often associated with familial hyperparathyroidism. noma is to anticipate wider excision margins and possible lymph
Removing all four glands, in Alagaratnam’s series, was always node dissection. Parathyroid glands can be intimately associated
curative and children remained normocalcemic with appropriate with the thyroid and in the setting of suspected parathyroid car-
supplementationon (median 5 year follow-up).10 , 12 , 26 cinoma, en bloc thyroid lobectomy may be required, along with
any adherent lymph nodes. Formal lymph node dissection is an
Parathyroid Carcinoma important consideration, though not an established standard. In
a 12-year review of the Surveillance, Epidemiology, and End Re-
Parathyroid carcinoma is an uncommon cause of primary hy- sult (SEER) database including 405 patients with parathyroid carci-
perparathyroidism and is particularly rare in pediatric patients: noma, 114 had lymph nodes evaluated at operation, and only 10%
less than 1% of all primary hyperparathyroidism is due to carci- of them had positive lymph nodes. Tumors ≥ 3 cm were over 7
noma, and the majority of cases occur in adults. Approximately 20 times more likely to have lymph node metastases. However, lymph
 R. Jamshidi and J.C. Egan / Seminars in Pediatric Surgery 29 (2020) 150923 7

surveillance of serum calcium and PTH levels because of the risk of

persistent or recurrent hyperparathyroidism and the need for fur-
ther resection.46 , 47
We advocate for a parathyroid-preserving approach, but prefer
total parathyroidectomy with autotransplantation. Half a parathy-
roid gland is minced into 1 mm3 fragments and autotransplanted
into the brachioradialis, thus avoiding the need for cervical re-
exploration in the event of persistent disease. The site of muscu-
lar implantation is labeled with a small titanium clip for ease of
detection by ultrasound as well as several permanent sutures to
facilitate operative exploration.

Hypoparathyroidism

Naturally-occurring hypoparathyroidism is generally caused by

autoimmune disease, metabolic derangements, genetic conditions,
infiltrative conditions, and congenital absence of parathyroid
Fig. 5. Chest radiograph of a 4 week old boy with neonatal severe hyperparathy-
glands. However, the most common cause of hypoparathyroidism
roidism. Notable findings include the narrow chest, and multiple lytic lesions of the
ribs, clavicles, and humeri. (Image courtesy of Ramin Jamshidi, MD)
is iatrogenic, due to parathyroid removal or devascularization
during anterior neck operations.48 Central compartment lymph
node dissection is a well-recognized risk factor for hypoparathy-
node status did not correlate with disease-specific survival.35 Sim- roidism.49 , 50 As the American Thyroid Association 2015 consen-
ilarly, a 10-year review of the National Cancer Database (NCDB) sus guidelines recommend central compartment lymphadenectomy
found lymph node status was not a significant predictor of sur- for all pediatric differentiated thyroid carcinomas, the incidence of
vival.35 Although there is no consensus on the indication for cen- post-thyroidectomy hypoparathyroidism may be increasing.51
tral neck lymph node dissection at the time of parathyroidectomy, The incidence of temporary post-thyroidectomy hypoparathy-
data suggest that it should at least be pursued in the setting of a roidism is higher in pediatric patients than in adults. The pedi-
markedly enlarged parathyroid gland and/or concerning-appearing atric center at University of Texas MD Anderson recently reported
lymph nodes.36 their experience over 2 decades, noting temporary post-operative
hypoparathyroidism in 35% of cases, which remained permanent
Neonatal Severe Hyperparathyroidism in 3%.51 Children’s Hospital of Philadelphia similarly reported their
nearly 2-decade experience in patients aged 2-24 years; temporary
Neonatal severe hyperparathyroidism (NSHPT) is a rare and dis- post-operative hypoparathyroidism occurred in 37% of cases, and
tinct condition characterized by profound primary hyperparathy- permanent hypoparathyroidism in 0.6%.52 The association of sur-
roidism beginning in the neonatal period. NSHPT is caused by geon volume with thyroidectomy outcomes is well established.53
dysfunction of the calcium-sensing receptor (CaSR) due to an in- Younger patients have smaller, more delicate anatomy which in-
activating mutation, resulting in unchecked PTH secretion.37 The creases technical demands of operation. It is believed that pedi-
severity of hyperparathyroidism is variable and correlates with atric parathyroid glands are more susceptible to transient dysfunc-
the specific mutation and inheritance pattern; it is worst when tion (“stun”) from manipulation / dissection because the vascular
the patient carries homozygous mutations. Heterozygous muta- pedicles are finer and the glands are more adherent to the thyroid
tions result in familial hypocalciuric hypercalcemia (FHH), which is than in adult patients.
a milder clinical entity.38 In addition to the inherited forms, there True hypoparathyroidism is characterized not just by low PTH,
are reports of de novo CaSR mutations.39 but also low serum calcium and high serum phosphate. Hypocal-
NSHPT manifests as severe calcium elevation (>14 mg/dL) with cemia may result from other conditions without hypoparathy-
marked PTH elevation. The resulting metabolic bone disease man- roidism, including medications (e.g. steroids, loop diuretics, pro-
ifests as severe generalized osteopenia, short ribs with irregular ton pump inhibitors, antiepileptics), hypomagnesemia, vitamin D
ends, metaphyseal sclerosis, and a bell-shaped chest. (Fig. 5) Un- deficiency, and hypoalbuminemia. Pseudohypoparathyroidism re-
treated, NHSPT can cause catastrophic neurodevelopmental deficits sults from tissue insensitivity to PTH; PTH levels are elevated,
or even death. 38 , 40 Although homozygous CaSR mutations are usu- but calcium remains low and phosphate remains elevated. The
ally associated with disease of this severity, specific heterozygous phenotypic appearance is that of Albright hereditary osteodystro-
mutations have been identified which resulted in the same dra- phy: obesity, short stature, subcutaneous ossifications, and brachy-
matic phenotype.41 , 42 FHH is far less likely to be symptomatic or dactyly. Pseudopseudohypoparathyroidism is so named because
have as marked elevations of calcium and PTH. patients present with the same phenotype as pseudohypoparathy-
Treatment of NSHPT is aimed at stabilizing calcium levels and roidism, but the tissues are not PTH-insensitive and PTH, calcium,
minimizing bone resorption, as these cause osteopenia, polyuria, and phosphate levels are all normal.
dehydration, hypotonia, and respiratory distress within days or
weeks of birth. The mainstays of pharmacologic management are Management of Hypoparathyroidism
bisphosphonates and the calcimimetic cinacalcet, an allosteric ago-
nist for CaSR. Multiple case reports have established the success of Aside from meticulous operative technique in the atraumatic
this approach.43–45 However, medically refractory disease requires preservation of the parathyroids, there are preoperative measures
parathyroidectomy. Genetic testing can aid in operative planning, which reduce the incidence of post-thyroidectomy hypoparathy-
as certain genetic mutations - particularly when inherited in a ho- roidism. Multiple studies have shown that routine post-operative
mozygous pattern - are unlikely to respond to pharmacologic man- supplementation with calcium and vitamin D reduces the inci-
agement.38 Total parathyroidectomy is curative but results in life- dence of post-operative hypocalcemia.54–56 A 2019 meta-analysis
long hypoparathyroidism; thus, some authors advocate for subto- of 10 randomized controlled studies combined 1620 patients and
tal parathyroidectomy. Subtotal parathyroidectomy requires lifelong observed that post-operative hypocalcemia was roughly half as
8 R. Jamshidi and J.C. Egan / Seminars in Pediatric Surgery 29 (2020) 150923

Fig. 6. Calcium management pathway for thyroidectomy patients at Phoenix Children’s Hospital.

likely (OR 0.48) with routine post-operative calcium supplementa- imals.68 , 69 In 2015, the full recombinant human PTH (all 84 amino
tion, and even less likely with routine post-operative calcium and acids) was approved by the FDA for management of hypoparathy-
vitamin D supplementation (OR 0.2).57 This data has shifted prac- roidism. This form has demonstrated different biochemical ac-
tice from supplementation based on symptoms or lab results to a tivity than teriparatide (particularly a much longer half-life) and
strategy of pre-emptive post-operative supplementation. long-term safety has been demonstrated in adult patients.70 , 71 The
The benefit of routine post-operative calcium and vitamin D medication was withdrawn from the US market in late 2019 due to
supplementation has led to the investigation of preoperative sup- a packaging issue but remains available in Europe.72 Recombinant
plementation as well. A group from the University of Virginia PTH represents a major step forward in hypoparathyroidism man-
demonstrated that starting calcium and calcitriol 5 days prior to agement, but standards for its use in the management of pediatric
operation reduced symptomatic hypocalcemia from 16% to 6% and hypoparathyroidism have not been developed, nor are there con-
reduced hospital stay by a day.58 Additionally, a single day of pre- sensus guidelines for management of pediatric hypoparathyroidism
operative calcium and vitamin D supplementation has been shown in general.73
to reduce post-operative hypocalcemia from 26% to 6%.59 There
is an ongoing randomized trial further examining the benefits of Recent Advances in Parathyroid Imaging
calcium and vitamin D supplementation prior to thyroidectomy.60
We have incorporated preoperative calcium carbonate supplemen- Preoperative Imaging
tation into our thyroidectomy management algorithm at Phoenix
Children’s Hospital, and are collecting data on outcomes while we Preoperative parathyroid imaging is important for localizing ab-
consider incorporating preoperative vitamin D. (Fig. 6) normal glands to direct operative exploration and has classically
Postoperative management of hypoparathyroidism is ap- relied on ultrasound and sestamibi scintigraphy scans. In 2006, the
proached variably among different institutions. Routine monitoring concept of a “4-dimensional CT” (4DCT) scan was introduced.74 The
of calcium levels is standard, but some centers also use post- name refers to the standard 3 spatial dimensions plus time, repeat-
operative parathyroid hormone levels as an early signal to begin ing CT scans in rapid succession to image physiologic dynamics.
more aggressive medication regimens, aiming for being proactive With respect to the parathyroid, this means optimal visualization
rather than reactive. The timing of using PTH for predicting post- of contrast uptake and clearance (“washout”). Parathyroid adeno-
operative hypoparathyroidism varies widely in published reports. mas exhibit peak contrast enhancement in the arterial phase, with
There is no standard protocol for implementing PTH assays into rapid washout and subsequent low attenuation. Exact imaging pro-
post-operative calcium management.61–65 tocols vary between institutions, but generally 2-4 points in time
For chronic / severe hypoparathyroidism, the mainstays of treat- (phases) are imaged with 1mm thick planes.75 In the adult popu-
ment remain supplemental calcium, vitamin D, and calcitriol, but lation, 4DCT has become widely adopted in the last 5 years, par-
PTH analogs are gradually changing the treatment landscape. Teri- ticularly when ultrasound and sestamibi scans fail to localize the
paratide is a PTH analog (first 34 amino acids of PTH) which was lesion or are discordant.
FDA-approved in 2002, but safety and efficacy have not been es- Studies have demonstrated the superior performance of 4DCT
tablished for chronic (> 3 years) administration.66 , 67 While some over other methods of parathyroid localization. In the original
use has been reported in pediatric patients, enthusiasm for long- 2006 report by Rodgers et al, laterality of the hyperfunctioning
term use has been tempered by osteosarcoma development in an- parathyroid was correctly identified in 88% of 4DCT, 65% of ses-
 R. Jamshidi and J.C. Egan / Seminars in Pediatric Surgery 29 (2020) 150923 9

tamibi scans, and 57% of ultrasounds. When determining the cervi- MRI is an area of ongoing investigation which is expected to
cal quadrant of the hyperfunctioning parathyroid gland, 4DCT was evolve considerably in the next few years.91
accurate 70% of the time, while sestamibi accuracy was 33% and
ultrasound was 29%. It is worth noting that this study did not com- Intraoperative Imaging
pare to the combination of sestamibi and ultrasound. Other inves-
tigators have reported variable comparative performance, which is Excision or injury of a healthy parathyroid gland during total
not surprising given the inherent user-dependence of ultrasound thyroidectomy can result in permanent hypoparathyroidism in up
performance and scintigraphy interpretation as well as variation in to 3% of the patients. On the other hand, failed parathyroidec-
protocols for 4DCT.76–78 Almost uniformly, 4DCT has demonstrated tomies occur in 5% to 10% of patients due to the inability to iden-
superior sensitivity for identifying and localizing hyperfunctioning tify the diseased gland. US, sestamibi scintigraphy, and CT are vari-
parathyroids, though at least one group has reported similar local- ably effective at localizing diseased parathyroid glands preopera-
ization accuracy of about 80% for 4DCT, SPECT, and ultrasound.79 tively. Consequently, surgical skill and experience are important
Multi-gland disease, parathyroid size less than 1cm, and inferior for identifying and distinguishing healthy and diseased parathy-
position have been identified as risk factors for discordance of roid glands. When in doubt, the surgeon can confirm the identity
4DCT impression with operative findings.80 of parathyroid tissue by sending the specimen for frozen-section
A notable drawback to 4DCT is the increased radiation expo- analysis. Intraoperative biopsy typically requires a wait time of 20
sure, which is potentially more harmful to pediatric patients. As a to 30 minutes per sample and carries the risk of injury to a healthy
point of reference for consideration of radiation exposure, annual parathyroid gland.
background radiation dose exposure is approximately 3mSv at sea Near infrared autofluorescence (NIRAF) is an emerging technol-
level in the United States.81 , 82 Some portion of this radiation is an ogy which can be applied to intraoperative parathyroid evaluation.
absorbed dose, which then translates to an equivalent dose (bio- Noninvasive optical detectors are used to identify healthy and dis-
logical effect) and effective dose (tissue-specific biological effect). eased parathyroid glands with an accuracy as high as 97%. NIRAF
When sestamibi scintigraphy was compared with 3-phase and 4- detection devices are broadly categorized into imaging systems
phase 4DCTs done for parathyroid localization, the mean patient (held 5-20 cm from the tissues) and fiber probe systems (held in
effective doses were 5.6, 16, and 20 mSv, respectively. The thyroid- direct contact with the tissue). Thomas et al performed a prospec-
specific absorbed doses were 1.4, 136, and 182 mGy, respectively.83 tive study comparing the PDE-Neo II imaging system (Mitaka USA,
In another study, 4DCT was compared to sestamibi with single- Denver, CO) with the PTeye fiber probe (AIBiomed Inc, Santa Bar-
photon emission CT (SPECT) imaging, and calculated effective doses bara, CA). These NIRAF devices were utilized in 20 adult patients
were 10.4 and 7.8 mSv, respectively. Notably, the dose to the thy- undergoing parathyroidectomy. Both performed well, but in this
roid was approximately 60 times higher with 4DCT.84 While vari- series the fiber probe device more accurately identified parathyroid
ation exists in the techniques of performing 4DCT and there is tissue (92.3%) compared to the imaging system (78.8-84.6%).92
inherent uncertainty in medical radiation calculations, it is clear Another NIRAF imaging system (Fluobeam, Fluoptics, Grenoble,
that ultrasound causes no radiation, and that sestamibi scintigra- France) was used to study 50 patients, in whom 199 parathy-
phy (and even SPECT) lead to considerably lower effective radiation roid glands were identified. Hyperfunctioning parathyroid glands
doses than 4DCT. were observed to emit lower mean normalized autofluorescence
Increased radiation exposure is particularly critical because of intensity than normofunctioning parathyroid glands (1.8, and 2.6,
the markedly increased sensitivity of pediatric patients to radia- respectively, P < .001). Moreover, hyperfunctioning parathyroid
tion, and that the thyroid gland is inherently particularly sensi- glands more often exhibited a heterogeneous pattern of autoflu-
tive to ionizing radiation.85 , 86 Aside from greater susceptibility to orescence (75% and 5%, respectively, P < .001). These results indi-
radiation-induced malignancy, the longer life that a pediatric pa- cate that NIRAF has the potential for distinguishing normal from
tient lives after the ionizing exposure increases risk of subsequent diseased parathyroid glands based on the pattern of autofluores-
malignancy. This longevity issue is underscored by the fact that cence.93
the relationship between risk of malignancy and time since ex- NIRAF may also help with parathyroid preservation during thy-
posure is not linear – it is logarithmic with much greater risk roidectomy. In 170 patients undergoing total thyroidectomy with
in younger years. Calculations predict that lifetime attributable and without NIRAF, NIRAF increased the number of glands de-
risk of thyroid cancer caused by 3 or 4 phase CT to be ap- tected from 2.6 to 3.5 (p < 0.001) compared to white light alone
proximately 15-30 per million if the patient is in their 50s, but and revealed at least 1 previously missed gland in 67.1% of pa-
around 10-30 times higher for patients 10-20 years old, and 20- tients. Calcium levels ≤7.5 mg/dL were one-tenth as common in
40 times higher for patients under 10 years of age.85 Thus, 4DCT the NIRAF group (p = 0.005). Using NIRAF during thyroidectomy
is not a suitable primary modality for localization of parathy- increased intraoperative identification of parathyroid glands, en-
roids in pediatric patients. However, for patients with complex hanced their detection before thyroid dissection, and decreased the
cervical anatomy due to large tumors, those who have under- incidence of postoperative hypocalcemia.94 In sum, near infrared
gone multiple prior operations, and those in whom neither ultra- autofluorescence detection devices show great promise as intra-
sound nor sestamibi have provided localization, 4DCT is worthy of operative adjuncts for parathyroid identification and preservation
consideration. as well as differentiation between healthy and diseased glands. As
Magnetic resonance imaging (MRI) may prove to be a means further research emerges and clinical experience with these de-
of providing similar cross-sectional imaging without radiation. vices expands, their use may become more widespread.
Recent technological advances have allowed faster MR imaging
such that “4D MRI” can be reasonably explored for localization Conclusion
of parathyroid glands. One multi-institutional group in 2015
characterized the MRI features of parathyroids in comparison Parathyroid disease is relatively rare in the pediatric popula-
to lymph nodes and optimized technique to allow distinction tion. Much of the knowledge guiding management of these dis-
between those structures.87 Others are exploring the potential of ease processes is extrapolated from the adult experience. How-
4D MRI for parathyroid localization, with early studies revealing ever, there is a limited body of pediatric-specific literature and
approximately 80% - 90% reliability in parathyroid localization, some important considerations specific to young patients with
with reduced performance in the setting of MGD.88–90 Parathyroid which pediatric endocrine surgeons should be familiar. Parathyroid
10 R. Jamshidi and J.C. Egan / Seminars in Pediatric Surgery 29 (2020) 150923

imaging, intra-operative identification, and management of iatro- 30. Howell VM, Gill A, Clarkson A, Nelson AE, Dunne R, Delbridge LW, Robinson BG,
genic (post-operative) hypocalcemia continue to evolve. Collabora- Teh BT, Gimm O, Marsh DJ. Accuracy of combined protein gene product 9.5
and parafibromin markers for immunohistochemical diagnosis of parathyroid
tive multi-institutional research is expected to expand pediatric- carcinoma. J Clin Endocrinol Metab. 2009;94(2):434–441.
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parathyroid cancer. Ann Surg Oncol. 2010;17(8):2156–2174.
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