Mar 31, 2009 - adenoma in all cases. Post-operative hungry bone syndrome occurred in 33.3%. Conclusion. PHPT is more common in females. Presentation ...
Original Article
Primary Hyperparathyroidism in Children and Adolescents Joe George, Shrikrishna V Acharya, Tushar R Bandgar, Padma S Menon and Nalini S Shah Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, India
ABSTRACT Objective. Primary hyperparathyroidism (PHPT) in children and adolescents is a rare condition. Awareness should improve in order to lower threshold for screening and allow intervention before serious and permanent sequelac occur. Methods. A retrospective analysis of 15 children and adolescents with PHPT (age 20 yr) with PHPT from our own institution. Statistical analysis was done using SPSS 14 175
Joe George et al software. All results are expressed as mean ± SD (standard deviation of the mean) and median. A value of P < 0.05 was considered significant.
RESULTS The 18 patients analyzed included 14 females and 4 males (ratio: 7:2) ranging in age from 13 to 20 (mean 17.73) yr. Average duration of symptoms were 18.87 (median: 12, range 0-48) mo. Clinical presentation: Major presenting symptom was skeletal involvement in 16 (88.9%) patients; fracture in 11, swelling and deformity in five. One patient was diagnosed during evaluation of acute pancreatitis. The remaining patient was admitted with restrictive cardiomyopathy and cardiac failure and was found to have PHPT on evaluation of accidentally detected hypercalcemia. Table 1 displays the clinical features and complications that were present at the time of diagnosis. It plays true to the classical pattern of “bones, stones and groans” but without psychic moans. Skeletal involvement was evidenced as bone pain in 14 (78%) patients in addition to the 17 fractures seen among 11 patients. Bony deformities and swellings were present T ABLE 1. Comparison of Clinical Characteristics with Adult Patients Age < 20 years (%)
Clinical Features and complications
Age > 20 P value years (%)
Number of subjects 1 8 Male: Female 2:7 Median duration of 1 2 symptoms (mo) Asymptomatic 0 Normocalcemia 1 (5.6)
70 2:5 30
Proximal myopathy 9 (50) Bone pain 1 4 (78) Fracture 1 1 (61.1) Renal calculi 6 (40) Renal failure 0 Pancreatitis 1 (5.5) Palpable Gland 2 (11)
33 52 37 25 8 13 7
Osteopenia Subperiosteal Radiology resorption Osteitis Fibrosa Cystica (OFC )
0 5 (7.1)
1.0
(47.1) (74.3) (52.9) (35.7) (11.4) (18.6) (10)
0.97 0.50 0.61 0.75
1 6 (88.9) 1 6 (88.9)
6 0 (85.7) 4 8 (68.6)
1.0 0.06
1 2 (66.7)
2 5 (35.7)
0.75
Right Superior Site of Right Inferior adenoma Left Superior left Inferior
2 7 1 8
Post Hungry bone operative Transient compli- Hypoparathyroidism cations
5 (27.7)
1 8 (28.1)
0.75
8 (44.4)
4 2 (65.6)
0.51
Histopa- Adenoma thology Hyperplasia ( HP) Carcinoma (HP)
176
(11.1) (38.9) (5.5) (44.4)
1 8 (100) 0 0
7 22 7 25
0.45 0.66
(11.5) (36.1) (11.5) (41)
5 4 (84.4) 8 (12.5) 2 (3.1)
in 9 (50%) patients that included palpable osteitis fibrosa cystica (OFC) in 5(27.8%) and genu valgum in 5(27.8%) in addition to residual deformities produced by healed fractures. Renal calculi including nephrocalcinosis were present in 7 (38.9%) patients. Psychiatric symptoms and hypertension were not present in any patient. Symptoms directly attributable to hypercalcemia also were conspicuous by their absence. Gastro intestinal symptoms of nausea, vomiting and constipation were not seen except in a few who volunteered on direct questioning. None had family history or features suggestive of multiple endocrine neoplasia (MEN). Parathyroid adenoma was palpable in one patient. Investigation and Localisation: Serum biochemistry followed the standard pattern of elevated total corrected calcium (13.43 ± 1.95 mg/dl) with a low inorganic phosphorus (1.96 ± 0.56 mg/dl) and an elevated total alkaline phosphatase (median: 609, range 105-4873 IU/L) in all except one. There was a normocalcemic PHPT with corrected calcium value of 9.2 mg/dl. Parathyroid hormone (PTH) was elevated (801.87±660.89 pg/ml) in all by radioimmunoassay. Renal function was normal in all cases. Skeletal involvement studied using radiography revealed subperiosteal resorption in 16(88.9%), osteopenia in 16 (88.9%), OFC in 12(66.7%), pseudo fracture in 9 (50%) and slipped capital femoral epiphysis in 3 (16.7%). Preoperative localization was done using ultrasonography (used in 95% of patients, sensitivity: 55.5%), computed tomography (in 83.3%, sensitivity: 80%) and nuclear scans (in 66.7%, sensitivity: 90%). There was no false localization. Peri-operative management: After localization, all the patients were subjected to parathyroidectomy. Five patients (27.8%) required treatment with IV pamidronate at a dose 60 -90 mg to control their calcium level below 14 mg/dl prior to surgery. A single experienced surgeon did all surgeries. Operative procedure consisted of unilateral neck exploration directed by the preoperative localization, with removal of the abnormal looking gland and biopsy of the other gland of the same side if visualized. Single adenoma was localised in all cases at the site of preoperative localisation. The mean tumor weight was 3.84 (range1.1-6.5) gm 83% of the tumors were from inferior glands with equal distribution between right and left side. All patients were put on oral calcium carbonate with first oral feed. Six lakh units of vit D were also given to all. Serum calcium and phosphorous were estimated on the 2nd day or earlier if the patient became symptomatic with hypocalcemia. Post-operative nadir of calcium was 7.75 ± 1.70 mg/dl and was reached after a median of 36 hr of surgery (range- 24 – 96 hr). Hungry bone syndrome characterised by severe hypocalcemia, hypophosphatemia, tetany, peri-oral tingling and Indian Journal of Pediatrics, Volume 77—February, 2010
Primary Hyperparathyroidism in Children and Adolescents numbness occurred in 5 (27.7%). Eight patients (44.4%) developed hypoparathyroidism, which was transient in all cases. There were no surgical complications including vocal cord palsy. Histopathology revealed adenoma in all cases. Post-operative follow up is available for all but one patient for 2 (range: 0 to 7) yr. All were cured except one. Unfortunately, the one patient with persistent hypercalcemia at discharge was lost for follow up. There was no case of hypoparathyroidism. None developed additional features suggestive of MEN. Differences from adult patients: When it comes to manifestation of a disease, it has been shown repeatedly that children are not just miniature adults. The disease may have different etiology, pathophysiology and clinical presentation in children as compared to adults. This was looked at in PHPT by comparing the above data with unpublished data of 70 adult (age>20 yr) patients from the same institute. The duration of symptoms prior to diagnosis was slightly shorter in pediatric population (12 mo) as compared to adults (30 mo). Apart from this, the major manifestations of the disease including complications were comparable between the two groups except for absence of renal failure in pediatric population (11.43 % in adults). Another difference noticed between the groups was the occurrence of cases of hyperplasia (13.8%) and carcinoma (3.1%) in adult patients. DISCUSSION PHPT in children is a rare disease and not well characterized in literature. Present study found it to be more common in young females compared with males. Some of previous studies have reported similar findings, while others have shown an equal distribution or slight preponderance of males. 2,3,8,9 However, the present study results show a more skewed female-to-male ratio (7:2) as compared to Lawson et al2 and Kollars et al3 for where the ratio was 6:5 and 3:2 respectively. In the present study pediatric HPT occurred most commonly during adolescence, consistent with previous reports.2,7 Studies evaluating parathyroid adenoma in children describe 74% to 88% of cases occurring during adolescence.2,3 Studies have quoted MEN and familial non-MEN HPT to constitute as much as 30% to 50% of pediatric PHPT. 2,10 In the present series, we had no case belonging to present category. None of the cases had suggestive features of MEN nor did they have family history. Only long term follow up would reveal whether they were the first manifestation of MEN. We have a mean follow up of 2 yr (range- 0 to 7 yr) which failed to show any other emerging features and our own department data during previous 25 yr show that MEN Indian Journal of Pediatrics, Volume 77—February, 2010
as a disease entity is rarely encountered. One of the striking features in this study was the severity of the patient’s symptoms. Eighty nine percent of the patients had bone disease and all demonstrated severe changes on radiology. There were 17 fractures in between 11 patients. In addition 5 patients had features of rickets and 5 had clinically palpable OFC. This is considerably higher as compared to some studies which quote skeletal involvement at 27- 34% with fracture incidence of around 10% but comparable to study by Lawson et al2 which quote bone involvement at 80%. 3,9 This high incidence in children may not be surprising considering the high bone turnover rate in them. Lower skeletal involvement in some studies was probably due to the large number of familial cases (upto 30%) which were diagnosed through screening programs in the asymptomatic stage. Although renal involvement in the present study, patients (38.9%) were comparable to other studies (33% - 40% ), all of them were asymptomatic as against previous studies where upto 15.1 % had to undergo surgical intervention for nephrolithiasis. 9 Acute pancreatitis was present in 5.5% which shows that it is an uncommon complication of the disease as described previously both in pediatric (7% ) and adult population. Tests to confirm the diagnosis and localize the abnormal gland are not analyzed as the sophistication of machine and expertise of personnel have undergone a sea of change for the better in the last decade to make any comparison redundant. This sensitivity of all these modalities has improved over the years with improvement in equipment and expertise and stands at 100% for nuclear scan and 80% for USG and CT since year 2000. Surgical outcomes and post operative complications at our institute were comparable to that of Mayo Clinic. Incidence of post operative hungry bone syndrome was also similar (27.7 % vs 56%).3 As in the present study, surgery was limited to the single diseased gland, absence of post operative hypoparathyroidism was expected. Lack of hyperplasia on histopathology is a significant difference in the present cohort of patients. Parthy it may be due to absence of MEN and familial cases. Results from the study by Harman et al 9 which excluded patients with MEN and familial cases support this, with all patients having a diagnosis of parathyroid adenoma with no hyperplasia. But the study by Kollars et al 3 , where 27% cases were hyperplasia, 11.5% had odenoma still among sporadic cases of PHPT. Contrary to the often quoted argument, children behave as miniature adults in manifestations of PHPT in the present study. One reason for this could be the clustering of disease in early adulthood with more than one third of cases (35.29%) occurring between 15 and 25 yr of age. The disease occurred with a median age at 177
Joe George et al onset of 33 yr with more than three quarter of patients below the age of 40 yr. Literature suggests the symptoms in children with PHPT to be more severe and more common than their adult counterparts.8 The high incidence of patients who were symptomatic at diagnosis in the present series (100 %) is similar to earlier reports of 79% - 91% patients being symptomatic. 1,2 The difference lies in the adult counterparts where only 20% to 50% are symptomatic in western population contrary to rarity of asymptomatic disease in the present study adult population. 4 The authors also could not obtain any difference in skeletal manifestations among the two groups. But early and severe skeletal manifestations may be inferred from the fact that severe and comparable skeletal involvement was present in the present study pediatric population at diagnosis despite the shorter duration of symptoms (12 mo) compared to adults (30 mo). The absence of renal failure in pediatric population (10.7% in adult) may also be due to skeletal involvement leading on to earlier diagnosis before onset of renal failure. This assumption is corroborated by the fact that asymptomatic renal disease in the present pediatric cohort (renal calculus disease: 40% vs 35.7%) was similar to that of adult. CONCLUSION The present study demonstrates the similarities and differences in PHPT in children and adolescents as compared with available literature. It is more common in females compared with males. Presentation of the disease in children is similar to their adult counterparts except for more severe bone disease and less severe renal disease. MEN and familial non-MEN PHPT do not constitute a major cause of pediatric PHPT as against worldwide data. The incidence of hyperplasia as a cause of PHPT is very rare in the present study pediatric population compared with available
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literature and also the present study adult patients. Thus unilateral neck exploration directed by the preoperative localization, with removal of the abnormal looking gland and biopsy of the other gland of the same side if visualized will be the best approach to treatment. Contributions: All authors have contributed in clinical diagnosis and management of these patients. Conflict of Interest: None. Role of Funding Source: None.
REFERENCES 1. Heath H, Hodgson SF, Kennedy MA. Primary hyperparathyroidism: incidence, morbidity and potential economic impact in a community. N Eng J Med 1980; 302: 189 -193. 2. Lawson ML, Miller SF, Ellis G, Filler RM, Kooh SW. Primary hyperparathyroidism in a paediatric hospital. QJM 1996; 89:921–932 3. Kollars J, Zarroug AE, van Heerden J et al. Primary hyperparathyroidism in pediatric patients. Pediatrics 2005; 115: 974–980. 4. Makhdoomi KR, Chalmers J, Campbell IW, Browning GG. Delayed diagnosis of juvenile primary hyperparathyroidism. J R Coll Surg Edinb 1996; 41: 351–353 5. Allo M, Thompson NW, Harness JK, Nishiyama RH. Primary hyperparathyroidism in children, adolescents, and young adults. World J Surg 1982; 6: 771–776 6. Girard RM, Belanger A, Hazel B. Primary hyperparathyroidism in children. Can J Surg 1982; 25: 11–13, 32 7. Rapaport D, Ziv Y, Rubin M, Huminer D, Dintsman M. Primary hyperparathyroidism in children. J Pediatr Surg 1986; 21: 395–397 8. Hsu SC, Levine MA. Primary hyperparathyroidism in children and adolescents: the Johns Hopkins Children’s Center experience 1984–2001. J Bone Miner Res 2002; 17(suppl 2): N44–N50 9. Harman CR, van Heerden JA, Farley DR, Grant CS, Thompson GB, Curlee K. Sporadic primary hyperparathyroidism in young patients: a separate disease entity? Arch Surg 1999; 134: 651– 656. 10. Marx SJ. New insights into primary hyperparathyroidism. Hosp Pract (Off Ed) 1984; 19: 55–63.
Indian Journal of Pediatrics, Volume 77—February, 2010
