Abstract
Primary hyperparathyroidism in children and adolescents is rare and often symptomatic at presentation. A 15-year-old bo presented with bilateral genu valgum for two years. Biochemical results were consistent with primary hyperparathyroidism Calcium levels normalized two months after removal of a left inferior parathyroid adenoma.
Keywords: primary hyperparathyroidism, adolescent, genu valgum, parathyroid neoplasms
INTRODUCTION
Primary hyperparathyroidism (PHPT) is a disorder of bone and mineral metabolism caused by autonomous secretion of parathyroid hormone (PTH). It is mainly seen in adults between 50 and 60 years of age, with an annual incidence of 30 per 100,000 and a lifetime prevalence of one per 1,000. The female to male ratio is approximately 3:1.1 On the other hand, PHPT in children and adolescents is rare, with a prevalence of two to five cases per 100,000 and no apparent sex predilection.1, 2 In contrast to adults who are often asymptomatic and commonly recognized during routine biochemical screening, children and adolescents with PHPT are mostly clinically symptomatic with endorgan damage. These include skeletal abnormalities and/or nephrolithiasis at presentation.2
Genu valgum is an unusual manifestation of PHPT in children and adolescents. To date, there is a limited number of published reports describing such presentation. We report a young patient who had bilateral genu valgum as a result of a parathyroid adenoma.
CASE
A 15-year-old boy presented in October 2018 with bilateral knock-knee for two years. He had an uneventful antenatal history and normal developmental milestones. He did not have any knee pain, swelling or stiffness. He had no history of injury, fracture or infection to his knees or legs. None of his family members had disorders related to multiple endocrine neoplasia type 1 (MEN 1) or type 2A (MEN 2A), hyperparathyroidism-jaw tumor (HPT-JT) syndrome or familial isolated hyperparathyroidism (FIHPT).
Physical examination revealed short stature (below 5th percentile) and bilateral genu valgum (Figure 1). There were no bony deformities including those typical of rickets. He had no polydactyly, joint laxity or lumbar kyphosis to suggest skeletal dysplasia. The knee joints were not swollen, tender or warm. Laboratory evaluation showed hypophosphatemia and elevated levels of calcium, alkaline phosphatase and intact parathyroid hormone (iPTH), consistent with the diagnosis of primary hyperparathyroidism (Table 1). Neck ultrasonography revealed a well-defined hypoechoic lesion measuring 1.2x1.5x2.7 cm at the inferior pole of left thyroid lobe. Kidney and liver function tests were normal. Unfortunately, serum vitamin D, urinary calcium, kidney ultrasonography and bone mineral density scan were not performed in this case.
Figure 1.
Clinical (A) and radiologic (B) evidence of bilateral genu valgum.
Table 1.
Preoperative and postoperative biochemical profile
| Parameters | Preoperation (October 2018) | Two months post-operation (February 2019) | six months post-operation (June 2019) | Reference range |
|---|---|---|---|---|
| Corrrected calcium, mmol/L | 2.97 | 2.14 | 2.13 | 2.10-2.55 |
| Phosphate, mmol/L | 1.03 | 1.64 | 1.3 | 1.45-2.10 |
| Alkaline phosphatase, U/L | 1354 | 560 | 377 | 116-468 |
| Intact PTHa, pmol/L | 154 | - | - | 1.5-7.6 |
| Creatinine, μmol/L | 33 | 55 | - | 50-77 |
PTH, parathyroid hormone
He subsequently underwent left inferior parathyroidectomy in December 2018. Histopathologic examination of the resected parathyroid gland confirmed a parathyroid adenoma. His immediate postoperative serum calcium was 1.9 mmol/L, for which he received oral calcium and calcitriol for a month. His calcium levels normalized two months after surgery (Table 1). Meanwhile, corrective osteotomy is currently being contemplated by the pediatric orthopedic surgery team.
DISCUSSION
Our adolescent patient presented with bilateral genu valgum as a result of excessive parathyroid hormone secretion from a parathyroid adenoma. His age at presentation corresponds to those with a similar deformity described in literature (Table 2). Majority of reported cases presented during the adolescent period—between 11 to 17 years old— except for one who came for medical attention at the age of 21.3 Out of these 23 patients with PHPT who manifested either unilateral or bilateral genu valgum, 13 were females. The underlying reason for the occurrence of such deformity in this particular age group remains unclear. It has been postulated that the direct effect of elevated parathyroid hormone on the epiphyseal plate and bone remodeling during the pubertal growth spurt could be the main contributing factor.4
Table 2.
Primary hyperparathyroidism presenting as genu valgum: A summary of case reports and case series from published literature
| Publication | Year | Age, yr | Gender | end-organ damage | etiology | Outcome after parathyroidectomy |
|---|---|---|---|---|---|---|
| McClure RD et al6 | 1945 | 14 | Female | Skeletal abnormalities | Left inferior parathyroid adenoma | Biochemical normalization and spontaneous correction of genu valgum |
| Balch HE et al3 | 1953 | 21 | Female | Skeletal abnormalities | Left inferior parathyroid adenoma | Hungry bone syndrome in immediate post-operative period, followed by biochemical normalization and recalcification of demineralized bones |
| Lloyd HM et al7 | 1965 | 14 | Male | Skeletal abnormalities | Left inferior parathyroid adenoma | Biochemical normalization and skeletal improvement |
| Rapaport D et al4 | 1986 | 15 | Female | Skeletal abnormalities, nephrolithiasis | Right inferior parathyroid adenoma | Clinical and biochemical resolution |
| 15 | Male | Skeletal abnormalities, nephrolithiasis | Right inferior parathyroid adenoma | Clinical and biochemical resolution | ||
| Kauffmann C et al8 | 1993 | 13 | Female | Skeletal abnormalities | Left inferior parathyroid adenoma | Biochemical normalization and resolution of bone demineralization |
| Menon PS et al9 | 1994 | 14 | Female | Skeletal abnormalities, nephrolithiasis | Left superior parathyroid adenoma | Normalization of calcium and phosphate |
| Harman CR et al10 | 1999 | 14 | Female | Skeletal abnormalities | - | - |
| Walczyk A et al11 | 2011 | 15 | Male | Skeletal abnormalities | Right inferior parathyroid adenoma | Biochemical resolution and improvement of BMDa |
| Dutta D et al21 | 2013 | 12 | Female | Skeletal abnormalities | Right inferior parathyroid adenoma | Clinical and biochemical resolution |
| Ratnasingam J et al12 | 2013 | 15 | Female | Skeletal abnormalities | Right parathyroid adenoma | Biochemical resolution |
| Ramkumar S et al13 | 2014 | 16 | Male | Skeletal abnormalities | Left inferior parathyroid adenoma | Biochemical resolution |
| 13 | Male | Skeletal abnormalities | Right inferior parathyroid adenoma | Biochemical resolution | ||
| Sharma S et al14 | 2016 | 15 | Female | Skeletal abnormalities | Left inferior parathyroid adenoma | Biochemical resolution |
| Zil-E-Ali A et al15 | 2016 | 14 | Female | Skeletal abnormalities | Right inferior parathyroid adenoma | Biochemical resolution |
| Arambewela MH et al16 | 2017 | 12 | Female | Skeletal abnormalities | Right inferior parathyroid adenoma | Resolution of primary hyperparathyroidism |
| Kamath SP et al17 | 2018 | 11 | Female | Skeletal abnormalities | Left superior parathyroid adenoma | Normalization of iPTHb |
| 12 | Male | Skeletal abnormalities, nephrolithiasis | Left superior parathyroid adenoma | Normalization of iPTHb | ||
| Khan KA et al22 | 2019 | 17 | Male | Skeletal abnormalities | Left inferior parathyroid adenoma | Biochemical resolution |
| Paruk IM et al18 | 2019 | 17 | Male | Skeletal abnormalities | Left inferior parathyroid adenoma | Clinical and biochemical resolution |
| 13 | Male | Skeletal abnormalities | Right superior parathyroid adenoma | Clinical and biochemical resolution | ||
| Rao KS et al19 | 2019 | 12 | Female | Skeletal abnormalities, nephrolithiasis | Right inferior parathyroid adenoma | Hungry bone syndrome in immediate post-operative period, long term outcome not reported |
| Yanrismet Y et al20 | 2019 | 13 | Male | Skeletal abnormalities | Right inferior parathyroid adenoma | Hungry bone syndrome in immediate post-operative period, long term outcome not reported |
BMD, bone mineral density
iPTH, intact parathyroid hormone
Primary hyperparathyroidism in children and adolescents is caused by either parathyroid adenoma (solitary or multiple) or hyperplasia, which may be sporadic or familial. Parathyroid carcinoma in this age group is rarely reported.2 Familial causes encompass MEN 1 or MEN 2A, HPT-JT and FIHPT. Our patient most likely has sporadic PHPT due to the absence of a family history of the aforementioned disorders. Moreover, additional screening revealed a normal prolactin level and a normal pituitary gland on magnetic resonance imaging. Solitary parathyroid adenoma appears to be the etiology in all the reported cases, including our patient (Table 2).
Our patient presented with isolated bilateral genu valgum with no other symptoms attributable to hypercalcemia. This piece of information has to be taken with a pinch of salt because it is well-known that children and adolescents with PHPT may have vague and non-specific symptoms involving the gastrointestinal, renal, musculoskeletal and neurological systems.1, 2 These non-specific complaints may potentially be dismissed as trivial and hence fail to raise the alarm unless a calcium level, which is often not part of routine blood tests in children, is checked. As a consequence, delayed diagnosis of PHPT and end-organ damage at presentation are common in this age group.
Interestingly, the lack of routine biochemical screening in children and adolescents may not exclusively justify the more severe presentations of PHPT in this juvenile population compared to their adult counterparts. This is because symptomatic PHPT remains uncommon at the fourth and fifth decades of life, as it is detected mainly by routine biochemical tests.1 The question of whether juvenile PHPT and adult PHPT represent two separate entities remains unanswered. A meta-analysis of 16 studies that included 268 juvenile and 2,405 adult patients with PHPT demonstrated that the former had greater hypercalcemia and hypercalciuria, despite similar serum iPTH levels. Decreased parathyroid adenoma sensitivity to negative feedback by calcium and increased target tissue responsiveness to the effects of parathyroid hormone in juvenile PHPT were suggested to be the key differences between these two age groups, providing the basis for future research.5
In addition to genu valgum, most patients reported in literature also manifested with other radiologic changes typical of primary hyperparathyroidism.3,6-20 These include subperiosteal bone resorption especially over the phalanges, acro-osteolysis, subchondral resorption around specific joints, brown tumors, salt-and-pepper radiologic appearance of the skull and osteopenia. It is noteworthy that three patients were initially treated as vitamin D deficiency rickets before the final diagnosis of PHPT was made.20-22 In fact, genu valgum is one of the known clinical features of nutritional rickets.23 In these patients, the lack of clinical improvement and new onset of hypercalcemia coupled with persistent elevation of parathyroid hormone following vitamin D repletion eventually unveiled the diagnosis of PHPT. On a different note, concomitant nephrolithiasis seems infrequent, as only four out of twenty-three total cases in literature exhibited the said complication.4,9,17
Parathyroidectomy is the mainstay of treatment in children with PHPT.1 Treatment goals include immediate and permanent cure of excessive calcium and parathyroid hormone secretion, mitigation of symptoms as well as reversal of end-organ damage.2 All reported cases including ours underwent successful parathyroidectomy. Hungry bone syndrome during the immediate postoperative period, which constituted a significant risk in this age group due to the greater disease severity, was reported in a handful of cases.3,19,20 Long-term outcomes postparathyroidectomy are favorable as evidenced by clinical and/or biochemical resolution in majority of patients. Our patient’s calcium levels remained within normal range six months after surgery without any calcium or vitamin D supplement (Table 1). However, he will still require osteotomy to correct his bilateral genu valgum.
In conclusion, primary hyperparathyroidism in children and adolescents is rare and often diagnosed late, with genu valgum being an unusual manifestation of this disorder. Nevertheless, a high index of suspicion is warranted, as prompt parathyroidectomy may lead to cure and reversal of debilitating complications.
Acknowledgment
The authors would like to thank the Director General of Health Malaysia for the permission to publish this case report.
Ethical Consideration
Patient consent was obtained before submission of the manuscript.
Statement of Authorship
All authors certified fulfillment of ICMJE authorship criteria.
Author Disclosure
All authors declared no conflicts of interest.
Funding Source
None.
References
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