Primary Hyperparathyroidism in Pediatric Patients
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《小儿科》
the Mayo Clinic and Foundation, Rochester, Minnesota
ABSTRACT
Objective. Primary hyperparathyroidism (HPT) is unusual in children. We reviewed our experience with HPT to better characterize these children.
Methods. The retrospective review of patients <19 years old who underwent parathyroid resection for primary HPT from 1970 to 2000 was performed at a single institution..
Results. Fifty-two patients were identified. Median age was 16.8 years (range: 4–18.9) with a female-to-male ratio of 3:2. Eighty-five percent had an elevated parathyroid hormone (PTH) level, and 15% had an inappropriately normal PTH level during hypercalcemia. Serum calcium was elevated in all patients except for 2 with multiple endocrine neoplasma (MEN)-IIA and 1 with familial non-MEN HPT, but both had elevated PTH levels. Alkaline phosphatase levels were significantly higher in children with documented bone involvement. At presentation 41 patients (79%) were symptomatic and end-organ damage (nephrocalcinosis, nephrolithiasis, acute pancreatitis, or bone involvement) occurred in 23 patients (44%). Thirty-four patients (65%) had a single adenoma; hyperplasia was identified in 16 patients (27%), and of these cases, 57% occurred in patients diagnosed with MEN-I. Short-term complications included transient hypocalcemia in 29 patients (56%) and transient vocal cord paralysis in 2 patients (4%). Long-term complications were significant for permanent hypocalcemia in 2 patients (4%) and no recurrent laryngeal nerve injuries. No parathyroid abnormalities were identified during exploration in 4 (8%) children. Long-term follow-up was achieved in 98% of patients for a mean and median of 13 years. Resolution of hypercalcemia was achieved in 94% of cases.
Conclusion. The diagnosis of primary HPT in pediatric patients is frequently delayed, is commonly symptomatic, and has significant morbidity. For children in whom HPT is suspected, evaluation of serum calcium and PTH levels is diagnostic in 100% of children. Parathyroid resection is effective at restoring normal serum calcium, has few complications, and is the treatment of choice for children with primary hyperparathyroidism.
Key Words: children MEN hypercalcemia parathyroid adenoma
Abbreviations: HPT, hyperparathyroidism PTH, parathyroid hormone MEN, multiple endocrine neoplasia
Hyperparathyroidism (HPT) predominantly affects adults (incidence of 1 in 1000) and is very rare in children (incidence of 2–5 in 100000).1–6 Consequently, physicians frequently fail to check serum calcium and parathyroid hormone (PTH) levels when evaluating children with nonspecific complaints such as polyuria, fatigue, poor appetite, weight loss, abdominal pain, nausea, and emesis.7,8 This practice leads to a delay in the recognition and diagnosis of pediatric parathyroid disorders until significant end-organ pathology has already occurred.8 Surgical therapy in almost all of these patients is highly effective in lowering serum calcium but may not reverse end-organ damage that has already occurred.6
All of the conditions that affect the parathyroid glands in children require parathyroid resection for definitive treatment. These conditions include primary, secondary, and tertiary hyperparathyroidism, which may be caused by single (adenoma) or multigland (hyperplasia) disease and rarely by parathyroid carcinoma. HPT is most often sporadic and is usually caused by a parathyroid adenoma. However, HPT may also occur in the setting of multiple endocrine neoplasia (MEN)-I or -II syndromes or familial non-MEN HPT as a result of multigland parathyroid.9 The diagnosis of such conditions in children can be challenging and is based primarily on the results of serum laboratory studies. Advances in serum calcium, PTH determinations, and parathyroid localization with ultrasonography, computed tomography, magnetic resonance imaging, and sestamibi nuclear scans have made the detection and treatment of parathyroid disease more effective.
Primary HPT is a broad classification incorporating sporadic isolated parathyroid adenoma and parathyroid hyperplasia related to MEN and familial non-MEN HPT. Parathyroid adenoma is a benign tumor and is the most common cause of HPT in young patients.5 MEN-I is an endocrinopathy characterized by hyperplasia of parathyroid cells as well as pituitary and pancreatic islet cell neoplasms. Medullary thyroid carcinoma, pheochromocytoma, and occasionally hyperparathyroidism characterize MEN-IIA. Familial non-MEN HPT is a hereditary condition, distinct from MEN-I and -IIA, characterized by a positive family history of HPT, adenomatous changes, and the absence of other MEN features. In all of the above conditions, demonstration of abnormally elevated, or inappropriately normal, serum PTH levels is essential for distinguishing HPT from other etiologies of hypercalcemia. In all instances, surgical resection is the treatment of choice for HPT in children.1,2,5,6,10–12
Most of the literature on HPT in pediatric patients has been limited to case reports and small series. Even larger series of "young patients" have had a preponderance of patients >18 years of age.12 Allo et al5 studied 53 patients, 35 of whom were >19 years of age. The largest series reported on sporadic primary HPT had 33 patients <19 years old (by Harman et al 6). In this study, we report the largest cohort of children and adolescents <19 years of age who have undergone parathyroid resection for primary HPT.
METHODS
Institutional review board approval and patient/parent consent were obtained for all participants in this study. This is a retrospective, consecutive review of the medical records of all patients <19 years of age who underwent parathyroid resection for primary HPT at the Mayo Clinic in Rochester, Minnesota, between 1970 and 2000. After the initial review of 61 patients, 3 children were excluded because normal parathyroid glands were removed during unrelated thyroidectomy. An additional 6 children were also excluded, including 1 with familial hypocalciuric hypercalcemia, 2 with secondary hyperparathyroidism, 2 with parathyroid cysts, and 1 whose final diagnosis was unclear. In total, 52 medical records were reviewed regarding clinical presentation, preoperative biochemical findings, radiographic studies, operative findings, pathology, postoperative course, and postoperative PTH levels and serum calcium levels. Follow-up was determined by chart review of postdischarge appointments with a physician at our institution and, in some cases, by telephone interviews.
Statistical analysis included a 2 or Fisher's exact test, used when appropriate, to test the association of single and multiple operations on calcium supplementation and transient and permanent hypocalcemia. Because of the non-Gaussian nature of the data, nonparametric tests of significance were used to assess continuous factors. A Wilcoxon rank-sum test was used to assess differences in the age at diagnosis by gender, alkaline phosphatase by the presence of bone involvement, and alkaline phosphatase by the presence of calcium supplementation. The Kruskal-Wallis test was used in assessing effect of diagnosis type on age at diagnosis. P values .05 were considered statistically significant.
RESULTS
Patient Demographics
Review yielded 52 patients with a median age of 16.8 years at presentation (range: 4.9–18.9). Most patients presented between 15 and 18 years of age. No significant age differences were observed between males and females (Fig 1). There were no significant differences in the ages of patients at the time of surgery based on diagnosis; although MEN-IIA patients did present slightly earlier (mean: 11.7 years compared with 16 years for all others). There were 31 female and 21 male patients for a female-to-male ratio of 3:2. There were no statistically significant differences in the pathologic conditions between male and female patients (Table 1). However, parathyroid adenoma and MEN syndromes occurred more commonly in female patients. In total, 36 patients had an adenoma, 10 patients had MEN-I, 3 patients had MEN-IIA, and 3 patients had familial non-MEN HPT.
Presentation
Of our 52 patients, 41 (79%) children were symptomatic at presentation. The most common presenting symptoms included fatigue and lethargy (35%), headache (35%), nephrolithiasis (33%), nausea (29%), abdominal pain (25%), vomiting (23%), and polydipsia (21%) (Table 2). Patients with MEN-I and adenoma had the highest frequency of symptoms (Table 3). We found it was common for a delay in the diagnosis of HPT to occur. For 19 patients in whom we were able to determine a specific time of onset for symptoms, the median time until diagnosis was 24 months (range: 1-60 months).
In our series, a family history of parathyroid dysfunction was identified in 16 patients (31%). A positive family history was identified in only 1 patient with adenoma (1.8%) but was identified in all 10 patients with MEN-I, all 3 with familial HPT, and in 2 of 3 patients with MEN-IIA. Children with MEN either presented with a positive family history of MEN or as symptomatic HPT, later determined to be MEN. Parathyroid disease was the first presenting symptom for all MEN patients. There were no patients with a history of prior radiation exposure.
Physical examination was largely unremarkable. Only 4 patients had a palpable parathyroid mass. This was most commonly a 1-cm, mobile, nontender, solitary mass. Cervical adenopathy was present in 5 patients and 1 patient had supraclavicular adenopathy. It is interesting to note that none of the children with adenopathy had a palpable parathyroid mass. There were no other significant physical findings noted.
Laboratory and Radiologic Studies
Several laboratory and radiologic studies were notable. Median values for serum PTH were 60 μLeq/mL (n = 39; range: 19–1700) by radioimmunoassay (normal: <40 μLeq/mL) and 8.1 pmol/L (n = 14; range: 3.1–34) by immunochemiluminometric assay (normal = 1.0–5.2 pmol/L). Serum PTH level was elevated in 44 children (85%), whereas the other 8 (15%) had inappropriately normal PTH levels. Other abnormal laboratory studies included serum calcium (elevated in 89% of all patients and 100% of adenoma and MEN-I patients), phosphorus (low in 50% of cases), chloride/phosphate ratio (elevated in 61%), and alkaline phosphatase (elevated for age in 29%) (Table 4). In addition, alkaline phosphatase levels were significantly higher in patients with documented bone involvement (median: 654 U/L; range: 156–6256; n = 9) compared with patients documented to be without bone involvement (median: 240 U/L; range: 70–1470; n = 19) (P < .01). Patients with symptomatic hypocalcemia postoperatively had a higher preoperative alkaline phosphatase level (median: 360; range: 59–6256; n = 21), compared with patients without symptomatic hypocalcemia (median: 275; range: 38–1470; n = 23), but this did not reach statistical significance given the large variation in values.
Studies used in preoperative localization included ultrasonography (used in 42% of patients), magnetic resonance imaging (14%), computed tomography (8%), nuclear scans (6%), and selective angiography (2%). Ultrasonography was the most common procedure performed with a sensitivity of 86%, specificity of 67%, and a positive predictive value of 95%. Four out of 24 cases were incorrectly read, with 1 false positive and 3 false negatives.
End-Organ Damage
Our patients had a substantial incidence (44%) of end-organ damage from HPT including nephrocalcinosis, nephrolithiasis, and bone involvement (Table 3). Of the 11 children with documented bone involvement, 5 had fractures and the rest had radiographic evidence of osteopenia or osteolysis. Bone involvement was more common in younger patients (median: 15.3 vs 17.3 years; P = .02), although the clinical significance of this difference is not appreciable. However, the broad category of end-organ damage was not more common in younger patients. Eighty-three percent of patients with end organ disease had a parathyroid adenoma. Six patients had multiple end organs effected, and all of these children had a parathyroid adenoma; 5 presented with nephrolithiasis and bone involvement, and 1 had both nephrolithiasis and nephrocalcinosis. However, given the small sample size and the parameter variability, this did not reach statistical significance. None of the patients had documented band keratopathy or subcutaneous calcinosis.
Operative Findings and Pathology
Operative treatment consisted of cervical exploration with single-gland parathyroidectomy for isolated adenoma and subtotal parathyroidectomy or total parathyroidectomy with autotransplantation for multiple-gland disease or hyperplasia. Operative and pathologic findings included ectopic glands identified in 5 patients (9.6%), including 1 intrathymic adenoma, 1 intrathymic mediastinal adenoma, and 2 cases of hyperplastic glands located within the thyroid gland. In 1 patient, 5 glands were identified. Thirty-four children (65%) had a single adenoma, and of these, 22 (65%) involved a superior gland. Median weight of resected adenomas was 450 mg (range: 90–9760 mg). Parathyroid hyperplasia was the next most common type of pathology identified in 14 patients (27%), and 8 (57%) of these cases occurred in MEN-I patients. Hyperplasia was also identified in 3 patients with isolated primary HPT, 2 with MEN-IIA, and 1 with familial non-MEN HPT. No cases of multiple adenomas or parathyroid carcinoma occurred. No parathyroid abnormalities were identified during exploration in 4 (8%) of the children. Two of these patients were symptomatic, had normal calcium but elevated PTH levels, and subsequently remained normocalcemic. One other child had hypercalcemia; however, biopsy of all 4 glands demonstrated normal tissue. A later cervical and upper thoracic exploration still did not identify any pathology, and the patient remains hypercalcemic. The last patient had familial HPT with hypercalcemia, had 3.5 glands removed, and now requires calcium supplementation.
Postoperative Complications
Short-term complications (within 90 days) occurred in a number of patients after parathyroid resection. Postoperative transient hypocalcemia diagnosed biochemically was observed in 29 (56%) of the patients. Twenty-four patients (46%) experienced symptomatic hypocalcemia postoperatively, consisting of paresthesias (36%), positive Chvostek sign (31%), or positive Trousseau sign (7%) within 3 days postoperatively. Sixteen of the 24 symptomatic hypocalcemic patients received calcium supplementation. Central nervous system or musculoskeletal symptoms, including migraine headaches, "spells," slurred speech, tetany, fatigue, or chronic arthralgias, were also identified in 2 children (4%). Other complications included transient vocal cord paralysis in 4% of the patients, diagnosed by vocal cord examination.
Multiple operations were necessary in 9 patients (17%), for a total of 61 operations among the 52 study subjects. Of these 9 patients, 4 had their initial procedure at an outside institution but remained hypercalcemic. After reoperation at this institution, 1 patient became hypocalcemic and the others had resolution of their HPT. The other 5 patients who required a second operation had their initial procedure performed at this institution. Three patients had a good initial result but developed a second adenoma years later (range: 5–16 years). One of these patients continues to have problems with mild hypercalcemia; the others are normocalcemic. The other 2 patients had a persistence of their hypercalcemia immediately after their first procedure. One of these patients had an exploration during which 3 normal glands were identified. A subsequent reexploration identified the adenomatous gland in the thymus, and excision resulted in resolution of the hypercalcemia. The other patient had all 4 gland biopsied, with normal parathyroid gland identified by the pathologist for all 4 glands. The patient remained hypercalcemic, and a subsequent cervical and thoracic exploration failed to identify any etiology for the child's HPT. Therefore, for patients whose first operation was performed at this institution, 96% (46 of 48) were initially successful. This success rate is much better compared with those children referred from outside institutions or from this institution with immediate persistent hypercalcemia or later development of a new adenoma who required second operations. Of 9 patients, only 7 (78%) had resolution of their hypercalcemia, and 1 of these developed hypocalcemia.
Transient hypocalcemia and calcium supplementation rates were not significantly different for multiple-surgery versus single-surgery patients. There were no transient vocal cord injuries among the patients who underwent multiple operations. Long-term complications (after 90 days) occurred in few patients. Overall, hypocalcemia lasting at least 6 months occurred in 2 (4%) patients. No permanent recurrent laryngeal nerve injuries occurred. No deaths occurred as a result of parathyroidectomy or its complications.
Follow-up
Follow-up in this study was achieved in 98% of patients, for a mean and median of 13 years (range: 3–23). Laboratory studies obtained at patient follow-up included serum Ca2+ levels, with a median value of 9.25 mg/dL (range: 6.1–13). Three patients (6%) continue to have persistent problems with hypercalcemia. One patient has MEN-I, and during exploration only 3 glands were identified, with 2.5 removed. The patient has declined additional exploration. One child had 4 glands biopsied, all with normal pathology. A later reexploration still has not identified any pathology. The last patient had 1 gland removed and remained hypercalcemic. At later reexploration all glands were removed with 1 gland implanted into the arm.
DISCUSSION
Diseases of the parathyroid glands in pediatric patients constitute a rare group of conditions that have significant morbidity. Consequently, further study is necessary to advance our understanding of HPT in children, to lower our threshold for screening, and allow intervention before serious and permanent sequelae occur. Given the results of our study, we suggest that children with symptoms of fatigue, headache, nausea, abdominal pain, emesis, polydipsia, diarrhea, depression, or joint pain that is not directly attributable to some other process or that does not resolve should have a screening serum calcium and PTH level obtained.
Our study found HPT to be slightly more common in young females compared with males, most notably in children with adenoma. Previous studies have reported that primary HPT is more common in young males compared with females.2,12,13 However, other studies have shown an equal distribution or slight preponderance of females.1,6,14 Our results are most similar to Lawson et al1 and Loh et al14 for whom the female-to-male ratio was 6:5 and 7:4,respectively. These differences in gender rates between studies may be the result of referral patterns or the high variability in patient demographics that can occur in uncommon diseases with small sample sizes. This ambiguity is not present for adult patients in whom fourfold more common in women than men.15 In this study pediatric HPT occurred most commonly during adolescence, consistent with previous reports. Studies evaluating parathyroid adenoma in children describe 74% to 88% of cases occurring during adolescence and cases in children <10 years old to be unusual.1,4 In our series, when we looked at patients with different etiologies for primary HPT, the same distribution held true.
There are many etiologies for hypercalcemia in pediatric patients.16 The most common pathology for our patients was parathyroid adenoma consistent with other studies.2,12 Others have documented that MEN and familial non-MEN HPT can constitute as much as 30% to 50% of pediatric HPT disease compared with 5% in adults.17 Our own results support these numbers, with 31% of our patients having a diagnosis other than parathyroid adenoma.
A family history of parathyroid disease or hypercalcemia was present in a significant portion of patients. However, it frequently indicated the presence of MEN or familial non-MEN HPT. This is expected because familial forms of HPT (MEN or familial non-MEN HPT) can make up 10% to 50% of children with hypercalcemia.17 In contrast, a positive family history was not readily associated with parathyroid adenoma. Loh et al14 described this same observation: a family history of HPT was present in only 2 out of 22 patients with adenoma. However, we do recommend genetic evaluation for all patients and family members diagnosed with multigland hyperplasia but with no previous family history of MEN or familial non-MEN disease.
Recent evidence suggests that symptoms in children with primary HPT are more severe and more common than in their adult counterparts.6,12 The high incidence of patients who where symptomatic at diagnosis in our series (79%) is similar to the report by Lawson et al1 in which 91% of patients were symptomatic. This observation is in contrast to adult patients in whom only 20% to 50% of primary HPT patients are symptomatic at diagnosis.6,18 This discrepancy between children and adult HPT patients may be due to the rarity of routinely checking serum laboratory values in children presenting with nonspecific complaints.
End-organ damage is common in pediatric patients with HPT, and some studies have documented end-organ damage in all symptomatic patients.1 Our incidence of nephrolithiasis was slightly lower than other series studying pediatric parathyroid adenoma.12 Rates of nephrocalcinosis in children with parathyroid adenoma have been reported to be between 30% and 70%.19 Our rate of nephrocalcinosis was somewhat lower, documented in only 1 (8%) of the 13 patients in whom it was specifically evaluated. Our incidence of bone involvement was also lower (34%) than what has been quoted previously for parathyroid adenoma (80%).1 The high incidence of bone involvement in children is not surprising considering the high rate of bone turnover in children compared with adults. This would explain why bone involvement is common in children but occurs in only 10% of adults.20,21 Our lower rates of symptoms and end organ damage may be due to the number of patients with familial disorders included in this study who were diagnosed through screening programs before the patient became symptomatic. Also, because end-organ damage is related to the severity and duration of hypercalcemia, commonly worse with parathyroid adenoma (which constitutes the majority of the literature on pediatric HPT), our inclusion of other HPT disease states may have accounted for our lower prevalence of end-organ damage. Last, the small number of patients who were evaluated by radiographic studies may have influenced the rate of nephrocalcinosis observed.
Another finding of this study is the significant delay that often occurs between onset of symptoms and the time of diagnosis. This delay has been observed not only in this study, in which the average time to diagnosis was almost 2 years, but also by Rapaport et al, 4 who demonstrated a mean duration of symptoms of 4.7 years. However, a shorter time to diagnosis (7.2 months) was observed in a series of patients with parathyroid adenoma.1 This delay is probably related to the infrequency of screening lab tests in pediatrics compared with adults. This unfortunate delay may be associated with irreversible end-organ damage most notably renal dysfunction.4,22,23 Laboratory studies including serum calcium and PTH levels remain the primary tests for the diagnosis of HPT.24,25
In adult patients, elevated alkaline phosphatase has been a good predictor of bone involvement and the requirement for postoperative calcium supplementation due to the "hungry-bone syndrome."26 However, given the wide range of normal alkaline phosphatase levels in children and its age dependence, this relationship has been difficult to substantiate in children.1 Our results show that the serum alkaline phosphatase was elevated in a significant percentage of patients, especially those with bone involvement. Although case reports have suggested the relationship between elevated alkaline phosphatase, bone involvement, and postoperative hypocalcemia,27 ours is the first study large enough to show this difference statistically.
Additional tests to confirm the diagnosis and localize the abnormal gland are generally thought to be unnecessary for adult patients without a prior history of cervical exploration.28 The exception to this occurs when a limited surgical exploration, with only visualization and removal of 1 gland, is planned. However, in children it has been argued that there is a higher rate of failed primary operations (20%) compared with adults (1%), most commonly due to ectopic parathyroid glands.6 For example, an ectopic fifth parathyroid gland was found in the thymus for 13% of children.29 Therefore, some have recommended routine ultrasonography in children, possibly combined with sestamibi scanning.6 Our results with a positive predictive value of 95% are consistent with previously published data regarding the efficacy of ultrasound in diagnosing parathyroid pathology.30 Ultrasonography is therefore a reliable noninvasive method for confirming parathyroid pathology in children preoperatively. Other reliable studies include 99mTc and sestamibi scans, which have been reported to have a sensitivity of 67% to 80% for localizing adenomas and a sensitivity of 45% to 60% for hyperplasia; however, data in children are not well established.31,32 In this study, nuclear medicine accurately localized the pathology in 2 of 3 children.
Operative treatment for HPT in children was individualized but consisted of single gland parathyroidectomy for isolated adenoma, subtotal parathyroidectomy or total parathyroidectomy with autotransplantation. The last 2 options are used in hereditary and multigland hyperplastic diseases such as MEN or familial hyperplasia.33 The use of preoperative localization imaging with sestamibi scintigraphy or high-resolution ultrasonography coupled with intraoperative rapid PTH assay has made more minimally invasive unilateral image-guided explorations possible in highly selected patients. Reported advantages include smaller incisions, less pain, shorter operative time, and a decreased length of hospital stay.33 In appropriate patients, this has been our preferred approach. However, traditional bilateral neck exploration remains the standard approach, especially for reoperative cases and suspected multigland disease.
Few patients had any serious long-term effects from parathyroidectomy at our institution; 2 patients (4%) experienced permanent hypocalcemia, 3 patients (6%) had persistent hypercalcemia, and no patients had permanent recurrent laryngeal nerve injuries. This complication rate for parathyroidectomy in children is comparable to the 3% permanent hypocalcemia usually sited in the literature for adults.34 Complication rates were similar for the children who underwent multiple operations for persistent or recurrent hypercalcemia. This is a lower complication rate than what is usually quoted in other series for adult parathyroid reoperation, which can have an incidence of 8% permanent vocal cord paralysis.35–37 The overall success rate for operative treatment of HPT in pediatric patients is excellent, and operative therapy has p been shown to be more effective than medical therapy for infants and neonates.11 We achieved successful restoration of normal serum calcium by operative intervention in 94% of cases, which compares to previous reports of 95%.19
CONCLUSIONS
Primary hyperparathyroid disease among pediatric patients is more common in females, more common in adolescents than in younger children, is frequently symptomatic is most commonly due to a single adenoma, and is associated with significant morbidity. Despite the high frequency of symptoms in pediatric hyperparathyroid patients compared with their adult counterparts, definitive diagnosis is often significantly delayed after the onset of symptoms. Children that are suspected of having HPT should be screened by using serum calcium and PTH levels. Additional laboratory and radiographic studies are often helpful for verifying the diagnosis, evaluating for complications of HPT and preparing for surgical treatment. Parathyroidectomy has few complications, is effective at restoring normal serum calcium, and is the treatment of choice in children with HPT.
FOOTNOTES
Accepted Aug 16, 2004.
No conflict of interest declared.
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ABSTRACT
Objective. Primary hyperparathyroidism (HPT) is unusual in children. We reviewed our experience with HPT to better characterize these children.
Methods. The retrospective review of patients <19 years old who underwent parathyroid resection for primary HPT from 1970 to 2000 was performed at a single institution..
Results. Fifty-two patients were identified. Median age was 16.8 years (range: 4–18.9) with a female-to-male ratio of 3:2. Eighty-five percent had an elevated parathyroid hormone (PTH) level, and 15% had an inappropriately normal PTH level during hypercalcemia. Serum calcium was elevated in all patients except for 2 with multiple endocrine neoplasma (MEN)-IIA and 1 with familial non-MEN HPT, but both had elevated PTH levels. Alkaline phosphatase levels were significantly higher in children with documented bone involvement. At presentation 41 patients (79%) were symptomatic and end-organ damage (nephrocalcinosis, nephrolithiasis, acute pancreatitis, or bone involvement) occurred in 23 patients (44%). Thirty-four patients (65%) had a single adenoma; hyperplasia was identified in 16 patients (27%), and of these cases, 57% occurred in patients diagnosed with MEN-I. Short-term complications included transient hypocalcemia in 29 patients (56%) and transient vocal cord paralysis in 2 patients (4%). Long-term complications were significant for permanent hypocalcemia in 2 patients (4%) and no recurrent laryngeal nerve injuries. No parathyroid abnormalities were identified during exploration in 4 (8%) children. Long-term follow-up was achieved in 98% of patients for a mean and median of 13 years. Resolution of hypercalcemia was achieved in 94% of cases.
Conclusion. The diagnosis of primary HPT in pediatric patients is frequently delayed, is commonly symptomatic, and has significant morbidity. For children in whom HPT is suspected, evaluation of serum calcium and PTH levels is diagnostic in 100% of children. Parathyroid resection is effective at restoring normal serum calcium, has few complications, and is the treatment of choice for children with primary hyperparathyroidism.
Key Words: children MEN hypercalcemia parathyroid adenoma
Abbreviations: HPT, hyperparathyroidism PTH, parathyroid hormone MEN, multiple endocrine neoplasia
Hyperparathyroidism (HPT) predominantly affects adults (incidence of 1 in 1000) and is very rare in children (incidence of 2–5 in 100000).1–6 Consequently, physicians frequently fail to check serum calcium and parathyroid hormone (PTH) levels when evaluating children with nonspecific complaints such as polyuria, fatigue, poor appetite, weight loss, abdominal pain, nausea, and emesis.7,8 This practice leads to a delay in the recognition and diagnosis of pediatric parathyroid disorders until significant end-organ pathology has already occurred.8 Surgical therapy in almost all of these patients is highly effective in lowering serum calcium but may not reverse end-organ damage that has already occurred.6
All of the conditions that affect the parathyroid glands in children require parathyroid resection for definitive treatment. These conditions include primary, secondary, and tertiary hyperparathyroidism, which may be caused by single (adenoma) or multigland (hyperplasia) disease and rarely by parathyroid carcinoma. HPT is most often sporadic and is usually caused by a parathyroid adenoma. However, HPT may also occur in the setting of multiple endocrine neoplasia (MEN)-I or -II syndromes or familial non-MEN HPT as a result of multigland parathyroid.9 The diagnosis of such conditions in children can be challenging and is based primarily on the results of serum laboratory studies. Advances in serum calcium, PTH determinations, and parathyroid localization with ultrasonography, computed tomography, magnetic resonance imaging, and sestamibi nuclear scans have made the detection and treatment of parathyroid disease more effective.
Primary HPT is a broad classification incorporating sporadic isolated parathyroid adenoma and parathyroid hyperplasia related to MEN and familial non-MEN HPT. Parathyroid adenoma is a benign tumor and is the most common cause of HPT in young patients.5 MEN-I is an endocrinopathy characterized by hyperplasia of parathyroid cells as well as pituitary and pancreatic islet cell neoplasms. Medullary thyroid carcinoma, pheochromocytoma, and occasionally hyperparathyroidism characterize MEN-IIA. Familial non-MEN HPT is a hereditary condition, distinct from MEN-I and -IIA, characterized by a positive family history of HPT, adenomatous changes, and the absence of other MEN features. In all of the above conditions, demonstration of abnormally elevated, or inappropriately normal, serum PTH levels is essential for distinguishing HPT from other etiologies of hypercalcemia. In all instances, surgical resection is the treatment of choice for HPT in children.1,2,5,6,10–12
Most of the literature on HPT in pediatric patients has been limited to case reports and small series. Even larger series of "young patients" have had a preponderance of patients >18 years of age.12 Allo et al5 studied 53 patients, 35 of whom were >19 years of age. The largest series reported on sporadic primary HPT had 33 patients <19 years old (by Harman et al 6). In this study, we report the largest cohort of children and adolescents <19 years of age who have undergone parathyroid resection for primary HPT.
METHODS
Institutional review board approval and patient/parent consent were obtained for all participants in this study. This is a retrospective, consecutive review of the medical records of all patients <19 years of age who underwent parathyroid resection for primary HPT at the Mayo Clinic in Rochester, Minnesota, between 1970 and 2000. After the initial review of 61 patients, 3 children were excluded because normal parathyroid glands were removed during unrelated thyroidectomy. An additional 6 children were also excluded, including 1 with familial hypocalciuric hypercalcemia, 2 with secondary hyperparathyroidism, 2 with parathyroid cysts, and 1 whose final diagnosis was unclear. In total, 52 medical records were reviewed regarding clinical presentation, preoperative biochemical findings, radiographic studies, operative findings, pathology, postoperative course, and postoperative PTH levels and serum calcium levels. Follow-up was determined by chart review of postdischarge appointments with a physician at our institution and, in some cases, by telephone interviews.
Statistical analysis included a 2 or Fisher's exact test, used when appropriate, to test the association of single and multiple operations on calcium supplementation and transient and permanent hypocalcemia. Because of the non-Gaussian nature of the data, nonparametric tests of significance were used to assess continuous factors. A Wilcoxon rank-sum test was used to assess differences in the age at diagnosis by gender, alkaline phosphatase by the presence of bone involvement, and alkaline phosphatase by the presence of calcium supplementation. The Kruskal-Wallis test was used in assessing effect of diagnosis type on age at diagnosis. P values .05 were considered statistically significant.
RESULTS
Patient Demographics
Review yielded 52 patients with a median age of 16.8 years at presentation (range: 4.9–18.9). Most patients presented between 15 and 18 years of age. No significant age differences were observed between males and females (Fig 1). There were no significant differences in the ages of patients at the time of surgery based on diagnosis; although MEN-IIA patients did present slightly earlier (mean: 11.7 years compared with 16 years for all others). There were 31 female and 21 male patients for a female-to-male ratio of 3:2. There were no statistically significant differences in the pathologic conditions between male and female patients (Table 1). However, parathyroid adenoma and MEN syndromes occurred more commonly in female patients. In total, 36 patients had an adenoma, 10 patients had MEN-I, 3 patients had MEN-IIA, and 3 patients had familial non-MEN HPT.
Presentation
Of our 52 patients, 41 (79%) children were symptomatic at presentation. The most common presenting symptoms included fatigue and lethargy (35%), headache (35%), nephrolithiasis (33%), nausea (29%), abdominal pain (25%), vomiting (23%), and polydipsia (21%) (Table 2). Patients with MEN-I and adenoma had the highest frequency of symptoms (Table 3). We found it was common for a delay in the diagnosis of HPT to occur. For 19 patients in whom we were able to determine a specific time of onset for symptoms, the median time until diagnosis was 24 months (range: 1-60 months).
In our series, a family history of parathyroid dysfunction was identified in 16 patients (31%). A positive family history was identified in only 1 patient with adenoma (1.8%) but was identified in all 10 patients with MEN-I, all 3 with familial HPT, and in 2 of 3 patients with MEN-IIA. Children with MEN either presented with a positive family history of MEN or as symptomatic HPT, later determined to be MEN. Parathyroid disease was the first presenting symptom for all MEN patients. There were no patients with a history of prior radiation exposure.
Physical examination was largely unremarkable. Only 4 patients had a palpable parathyroid mass. This was most commonly a 1-cm, mobile, nontender, solitary mass. Cervical adenopathy was present in 5 patients and 1 patient had supraclavicular adenopathy. It is interesting to note that none of the children with adenopathy had a palpable parathyroid mass. There were no other significant physical findings noted.
Laboratory and Radiologic Studies
Several laboratory and radiologic studies were notable. Median values for serum PTH were 60 μLeq/mL (n = 39; range: 19–1700) by radioimmunoassay (normal: <40 μLeq/mL) and 8.1 pmol/L (n = 14; range: 3.1–34) by immunochemiluminometric assay (normal = 1.0–5.2 pmol/L). Serum PTH level was elevated in 44 children (85%), whereas the other 8 (15%) had inappropriately normal PTH levels. Other abnormal laboratory studies included serum calcium (elevated in 89% of all patients and 100% of adenoma and MEN-I patients), phosphorus (low in 50% of cases), chloride/phosphate ratio (elevated in 61%), and alkaline phosphatase (elevated for age in 29%) (Table 4). In addition, alkaline phosphatase levels were significantly higher in patients with documented bone involvement (median: 654 U/L; range: 156–6256; n = 9) compared with patients documented to be without bone involvement (median: 240 U/L; range: 70–1470; n = 19) (P < .01). Patients with symptomatic hypocalcemia postoperatively had a higher preoperative alkaline phosphatase level (median: 360; range: 59–6256; n = 21), compared with patients without symptomatic hypocalcemia (median: 275; range: 38–1470; n = 23), but this did not reach statistical significance given the large variation in values.
Studies used in preoperative localization included ultrasonography (used in 42% of patients), magnetic resonance imaging (14%), computed tomography (8%), nuclear scans (6%), and selective angiography (2%). Ultrasonography was the most common procedure performed with a sensitivity of 86%, specificity of 67%, and a positive predictive value of 95%. Four out of 24 cases were incorrectly read, with 1 false positive and 3 false negatives.
End-Organ Damage
Our patients had a substantial incidence (44%) of end-organ damage from HPT including nephrocalcinosis, nephrolithiasis, and bone involvement (Table 3). Of the 11 children with documented bone involvement, 5 had fractures and the rest had radiographic evidence of osteopenia or osteolysis. Bone involvement was more common in younger patients (median: 15.3 vs 17.3 years; P = .02), although the clinical significance of this difference is not appreciable. However, the broad category of end-organ damage was not more common in younger patients. Eighty-three percent of patients with end organ disease had a parathyroid adenoma. Six patients had multiple end organs effected, and all of these children had a parathyroid adenoma; 5 presented with nephrolithiasis and bone involvement, and 1 had both nephrolithiasis and nephrocalcinosis. However, given the small sample size and the parameter variability, this did not reach statistical significance. None of the patients had documented band keratopathy or subcutaneous calcinosis.
Operative Findings and Pathology
Operative treatment consisted of cervical exploration with single-gland parathyroidectomy for isolated adenoma and subtotal parathyroidectomy or total parathyroidectomy with autotransplantation for multiple-gland disease or hyperplasia. Operative and pathologic findings included ectopic glands identified in 5 patients (9.6%), including 1 intrathymic adenoma, 1 intrathymic mediastinal adenoma, and 2 cases of hyperplastic glands located within the thyroid gland. In 1 patient, 5 glands were identified. Thirty-four children (65%) had a single adenoma, and of these, 22 (65%) involved a superior gland. Median weight of resected adenomas was 450 mg (range: 90–9760 mg). Parathyroid hyperplasia was the next most common type of pathology identified in 14 patients (27%), and 8 (57%) of these cases occurred in MEN-I patients. Hyperplasia was also identified in 3 patients with isolated primary HPT, 2 with MEN-IIA, and 1 with familial non-MEN HPT. No cases of multiple adenomas or parathyroid carcinoma occurred. No parathyroid abnormalities were identified during exploration in 4 (8%) of the children. Two of these patients were symptomatic, had normal calcium but elevated PTH levels, and subsequently remained normocalcemic. One other child had hypercalcemia; however, biopsy of all 4 glands demonstrated normal tissue. A later cervical and upper thoracic exploration still did not identify any pathology, and the patient remains hypercalcemic. The last patient had familial HPT with hypercalcemia, had 3.5 glands removed, and now requires calcium supplementation.
Postoperative Complications
Short-term complications (within 90 days) occurred in a number of patients after parathyroid resection. Postoperative transient hypocalcemia diagnosed biochemically was observed in 29 (56%) of the patients. Twenty-four patients (46%) experienced symptomatic hypocalcemia postoperatively, consisting of paresthesias (36%), positive Chvostek sign (31%), or positive Trousseau sign (7%) within 3 days postoperatively. Sixteen of the 24 symptomatic hypocalcemic patients received calcium supplementation. Central nervous system or musculoskeletal symptoms, including migraine headaches, "spells," slurred speech, tetany, fatigue, or chronic arthralgias, were also identified in 2 children (4%). Other complications included transient vocal cord paralysis in 4% of the patients, diagnosed by vocal cord examination.
Multiple operations were necessary in 9 patients (17%), for a total of 61 operations among the 52 study subjects. Of these 9 patients, 4 had their initial procedure at an outside institution but remained hypercalcemic. After reoperation at this institution, 1 patient became hypocalcemic and the others had resolution of their HPT. The other 5 patients who required a second operation had their initial procedure performed at this institution. Three patients had a good initial result but developed a second adenoma years later (range: 5–16 years). One of these patients continues to have problems with mild hypercalcemia; the others are normocalcemic. The other 2 patients had a persistence of their hypercalcemia immediately after their first procedure. One of these patients had an exploration during which 3 normal glands were identified. A subsequent reexploration identified the adenomatous gland in the thymus, and excision resulted in resolution of the hypercalcemia. The other patient had all 4 gland biopsied, with normal parathyroid gland identified by the pathologist for all 4 glands. The patient remained hypercalcemic, and a subsequent cervical and thoracic exploration failed to identify any etiology for the child's HPT. Therefore, for patients whose first operation was performed at this institution, 96% (46 of 48) were initially successful. This success rate is much better compared with those children referred from outside institutions or from this institution with immediate persistent hypercalcemia or later development of a new adenoma who required second operations. Of 9 patients, only 7 (78%) had resolution of their hypercalcemia, and 1 of these developed hypocalcemia.
Transient hypocalcemia and calcium supplementation rates were not significantly different for multiple-surgery versus single-surgery patients. There were no transient vocal cord injuries among the patients who underwent multiple operations. Long-term complications (after 90 days) occurred in few patients. Overall, hypocalcemia lasting at least 6 months occurred in 2 (4%) patients. No permanent recurrent laryngeal nerve injuries occurred. No deaths occurred as a result of parathyroidectomy or its complications.
Follow-up
Follow-up in this study was achieved in 98% of patients, for a mean and median of 13 years (range: 3–23). Laboratory studies obtained at patient follow-up included serum Ca2+ levels, with a median value of 9.25 mg/dL (range: 6.1–13). Three patients (6%) continue to have persistent problems with hypercalcemia. One patient has MEN-I, and during exploration only 3 glands were identified, with 2.5 removed. The patient has declined additional exploration. One child had 4 glands biopsied, all with normal pathology. A later reexploration still has not identified any pathology. The last patient had 1 gland removed and remained hypercalcemic. At later reexploration all glands were removed with 1 gland implanted into the arm.
DISCUSSION
Diseases of the parathyroid glands in pediatric patients constitute a rare group of conditions that have significant morbidity. Consequently, further study is necessary to advance our understanding of HPT in children, to lower our threshold for screening, and allow intervention before serious and permanent sequelae occur. Given the results of our study, we suggest that children with symptoms of fatigue, headache, nausea, abdominal pain, emesis, polydipsia, diarrhea, depression, or joint pain that is not directly attributable to some other process or that does not resolve should have a screening serum calcium and PTH level obtained.
Our study found HPT to be slightly more common in young females compared with males, most notably in children with adenoma. Previous studies have reported that primary HPT is more common in young males compared with females.2,12,13 However, other studies have shown an equal distribution or slight preponderance of females.1,6,14 Our results are most similar to Lawson et al1 and Loh et al14 for whom the female-to-male ratio was 6:5 and 7:4,respectively. These differences in gender rates between studies may be the result of referral patterns or the high variability in patient demographics that can occur in uncommon diseases with small sample sizes. This ambiguity is not present for adult patients in whom fourfold more common in women than men.15 In this study pediatric HPT occurred most commonly during adolescence, consistent with previous reports. Studies evaluating parathyroid adenoma in children describe 74% to 88% of cases occurring during adolescence and cases in children <10 years old to be unusual.1,4 In our series, when we looked at patients with different etiologies for primary HPT, the same distribution held true.
There are many etiologies for hypercalcemia in pediatric patients.16 The most common pathology for our patients was parathyroid adenoma consistent with other studies.2,12 Others have documented that MEN and familial non-MEN HPT can constitute as much as 30% to 50% of pediatric HPT disease compared with 5% in adults.17 Our own results support these numbers, with 31% of our patients having a diagnosis other than parathyroid adenoma.
A family history of parathyroid disease or hypercalcemia was present in a significant portion of patients. However, it frequently indicated the presence of MEN or familial non-MEN HPT. This is expected because familial forms of HPT (MEN or familial non-MEN HPT) can make up 10% to 50% of children with hypercalcemia.17 In contrast, a positive family history was not readily associated with parathyroid adenoma. Loh et al14 described this same observation: a family history of HPT was present in only 2 out of 22 patients with adenoma. However, we do recommend genetic evaluation for all patients and family members diagnosed with multigland hyperplasia but with no previous family history of MEN or familial non-MEN disease.
Recent evidence suggests that symptoms in children with primary HPT are more severe and more common than in their adult counterparts.6,12 The high incidence of patients who where symptomatic at diagnosis in our series (79%) is similar to the report by Lawson et al1 in which 91% of patients were symptomatic. This observation is in contrast to adult patients in whom only 20% to 50% of primary HPT patients are symptomatic at diagnosis.6,18 This discrepancy between children and adult HPT patients may be due to the rarity of routinely checking serum laboratory values in children presenting with nonspecific complaints.
End-organ damage is common in pediatric patients with HPT, and some studies have documented end-organ damage in all symptomatic patients.1 Our incidence of nephrolithiasis was slightly lower than other series studying pediatric parathyroid adenoma.12 Rates of nephrocalcinosis in children with parathyroid adenoma have been reported to be between 30% and 70%.19 Our rate of nephrocalcinosis was somewhat lower, documented in only 1 (8%) of the 13 patients in whom it was specifically evaluated. Our incidence of bone involvement was also lower (34%) than what has been quoted previously for parathyroid adenoma (80%).1 The high incidence of bone involvement in children is not surprising considering the high rate of bone turnover in children compared with adults. This would explain why bone involvement is common in children but occurs in only 10% of adults.20,21 Our lower rates of symptoms and end organ damage may be due to the number of patients with familial disorders included in this study who were diagnosed through screening programs before the patient became symptomatic. Also, because end-organ damage is related to the severity and duration of hypercalcemia, commonly worse with parathyroid adenoma (which constitutes the majority of the literature on pediatric HPT), our inclusion of other HPT disease states may have accounted for our lower prevalence of end-organ damage. Last, the small number of patients who were evaluated by radiographic studies may have influenced the rate of nephrocalcinosis observed.
Another finding of this study is the significant delay that often occurs between onset of symptoms and the time of diagnosis. This delay has been observed not only in this study, in which the average time to diagnosis was almost 2 years, but also by Rapaport et al, 4 who demonstrated a mean duration of symptoms of 4.7 years. However, a shorter time to diagnosis (7.2 months) was observed in a series of patients with parathyroid adenoma.1 This delay is probably related to the infrequency of screening lab tests in pediatrics compared with adults. This unfortunate delay may be associated with irreversible end-organ damage most notably renal dysfunction.4,22,23 Laboratory studies including serum calcium and PTH levels remain the primary tests for the diagnosis of HPT.24,25
In adult patients, elevated alkaline phosphatase has been a good predictor of bone involvement and the requirement for postoperative calcium supplementation due to the "hungry-bone syndrome."26 However, given the wide range of normal alkaline phosphatase levels in children and its age dependence, this relationship has been difficult to substantiate in children.1 Our results show that the serum alkaline phosphatase was elevated in a significant percentage of patients, especially those with bone involvement. Although case reports have suggested the relationship between elevated alkaline phosphatase, bone involvement, and postoperative hypocalcemia,27 ours is the first study large enough to show this difference statistically.
Additional tests to confirm the diagnosis and localize the abnormal gland are generally thought to be unnecessary for adult patients without a prior history of cervical exploration.28 The exception to this occurs when a limited surgical exploration, with only visualization and removal of 1 gland, is planned. However, in children it has been argued that there is a higher rate of failed primary operations (20%) compared with adults (1%), most commonly due to ectopic parathyroid glands.6 For example, an ectopic fifth parathyroid gland was found in the thymus for 13% of children.29 Therefore, some have recommended routine ultrasonography in children, possibly combined with sestamibi scanning.6 Our results with a positive predictive value of 95% are consistent with previously published data regarding the efficacy of ultrasound in diagnosing parathyroid pathology.30 Ultrasonography is therefore a reliable noninvasive method for confirming parathyroid pathology in children preoperatively. Other reliable studies include 99mTc and sestamibi scans, which have been reported to have a sensitivity of 67% to 80% for localizing adenomas and a sensitivity of 45% to 60% for hyperplasia; however, data in children are not well established.31,32 In this study, nuclear medicine accurately localized the pathology in 2 of 3 children.
Operative treatment for HPT in children was individualized but consisted of single gland parathyroidectomy for isolated adenoma, subtotal parathyroidectomy or total parathyroidectomy with autotransplantation. The last 2 options are used in hereditary and multigland hyperplastic diseases such as MEN or familial hyperplasia.33 The use of preoperative localization imaging with sestamibi scintigraphy or high-resolution ultrasonography coupled with intraoperative rapid PTH assay has made more minimally invasive unilateral image-guided explorations possible in highly selected patients. Reported advantages include smaller incisions, less pain, shorter operative time, and a decreased length of hospital stay.33 In appropriate patients, this has been our preferred approach. However, traditional bilateral neck exploration remains the standard approach, especially for reoperative cases and suspected multigland disease.
Few patients had any serious long-term effects from parathyroidectomy at our institution; 2 patients (4%) experienced permanent hypocalcemia, 3 patients (6%) had persistent hypercalcemia, and no patients had permanent recurrent laryngeal nerve injuries. This complication rate for parathyroidectomy in children is comparable to the 3% permanent hypocalcemia usually sited in the literature for adults.34 Complication rates were similar for the children who underwent multiple operations for persistent or recurrent hypercalcemia. This is a lower complication rate than what is usually quoted in other series for adult parathyroid reoperation, which can have an incidence of 8% permanent vocal cord paralysis.35–37 The overall success rate for operative treatment of HPT in pediatric patients is excellent, and operative therapy has p been shown to be more effective than medical therapy for infants and neonates.11 We achieved successful restoration of normal serum calcium by operative intervention in 94% of cases, which compares to previous reports of 95%.19
CONCLUSIONS
Primary hyperparathyroid disease among pediatric patients is more common in females, more common in adolescents than in younger children, is frequently symptomatic is most commonly due to a single adenoma, and is associated with significant morbidity. Despite the high frequency of symptoms in pediatric hyperparathyroid patients compared with their adult counterparts, definitive diagnosis is often significantly delayed after the onset of symptoms. Children that are suspected of having HPT should be screened by using serum calcium and PTH levels. Additional laboratory and radiographic studies are often helpful for verifying the diagnosis, evaluating for complications of HPT and preparing for surgical treatment. Parathyroidectomy has few complications, is effective at restoring normal serum calcium, and is the treatment of choice in children with HPT.
FOOTNOTES
Accepted Aug 16, 2004.
No conflict of interest declared.
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