1Department of Paediatrics, Klatovy Hospital, Klatovy, Czech Republic; Departments of 2Paediatrics and 3Otorhinolaryngology, Pardubice Hospital, Pardubice, Czech Republic *Corresponding Author’s e-mail: kutilek@nemkt.cz سببان خمتلفان لفرط كالسيوم الدم عند األطفال ستيفان كوتليك، اإيفانا فال�شيلوفا، فيكتور �رسوبوك abstract: Paediatric hypercalcaemia is a rare condition which can be easily overlooked or misdiagnosed. We report two paediatric patients who presented to the Department of Paediatrics, Pardubice Hospital, Pardubice, Czech Republic, in 2009 and 2010, respectively. Each patient was diagnosed with hypercalcaemia due to a different cause. The first case involved a seven-month-old infant who presented with failure to thrive, vomiting and psychomotor retardation. Fluorescent in situ hybridisation revealed Williams-Beuren syndrome. The second patient was a 16-year-old girl with abdominal pain and renal colic due to hypercalcaemia-induced urolithiasis. High parathyroid hormone serum levels suggested primary hyperparathyroidism. An adenoma of the left upper parathyroid gland was diagnosed via technetium-99m-labelled methoxyisobutyl isonitrile single photon emission computed tomography and removed surgically. Hypercalcaemia should be considered in the differential diagnosis of various disease states, particularly among infants who fail to thrive or children with abdominal pain. Keywords: Hypercalcemia; Williams-Beuren Syndrome; Hyperparathyroidism; Parathyroid Adenoma; Case Report; Czech Republic. امللخ�ص: يعد فرط الكال�شيوم يف دماء الأطفال حالة نادرة، ميكن اأن ُتغفل اأو ُيغلط يف ت�شخي�شها. ونعر�ص هنا حلالتي طفلني مري�شني ِجيَء بهما لق�شم الأطفال يف م�شت�شفى باردوب�ص بجمهورية الت�شيك يف عامي 2009 و 2010، على التوايل. ومت ت�شخي�ص كل من احلالتني على اأنهما فرط كال�شيوم الدم ل�شببني خمتلفني. وكانت احلالة الأوىل لر�شيع عمره �شبعة اأ�شهر توقف منوه، وكان م�شابا بقيء وتخلف حركي نف�شي. وثبت من التهجني الفلوري املو�شعي اأن هذا املري�ص م�شاب مبتالزمة ويليام-بيورين. اأما احلالة الثانية فكانت لفتاة يف ال�شاد�ص ع�رس من عمرها م�شابة باأمل بطني ومغ�ص كلوي نتيجة حت�شي احلالب الذي �شببه فرط كال�شيوم الدم. وُوجد لدى هذه املري�شة اأي�شا ارتفاع يف تركيز هرمون الدريقات يف م�شل الدم. واكت�شف عن طريق الت�شوير املقطعي بالنبعاث الفوتوين املنفرد وجود ورم غدي يف اجلزء ال�شمايل الأعلى من الدريقة، ومتت اإزالته جراحيا. ينبغي اأن يو�شع احتمال وجود فرط الكال�شيوم يف الت�شخي�ص التفريقي بني خمتلف الأمرا�ص، خا�شة عند الر�شع الذين توقف منوهم، اأو امل�شابني باأمل يف البطن. الكلمات املفتاحية: فرط كال�شيوم الدم؛ مبتالزمة ويليام-بيورين؛ ارتفاع تركيز هرمون الدريقات؛ ورم الدريقات الغدي؛ تقرير حالة؛ جمهورية الت�شيك. Two Different Causes of Paediatric Hypercalcaemia *Stepan Kutilek,1 Ivana Plasilova,2 Viktor Chrobok3 online case report Sultan Qaboos University Med J, August 2018, Vol. 18, Iss. 3, pp. e389–392, Epub. 19 Dec 18 Submitted 29 Nov 17 Revision Req. 23 Jan 18; Revision Recd. 21 Feb 18 Accepted 15 Mar 18 doi: 10.18295/squmj.2018.18.03.022 Hypercalcaemia is defined as serumcalcium (S-Ca) levels of >2.7 mmol/L, with S-Ca levels of >3.0 mmol/L requiring thera- peutic intervention and those of >3.5 mmol/L consid- ered life-threatening and requiring immediate action.1–4 Treatment consists of ensuring adequate hydration and administering glucocorticoids, diuretics (i.e. furosemide) and bisphosphonates (e.g. pamidronate or zoledronate). Vitamin D and calcium supplementation should be avoided, as well as exposure to sunshine.1–3 Hypercalcaemia in childhood is rare and may have different origins, including vitamin D intoxication, hyper- parathyroidism, hyperthyroidism, granulomatous disease, Williams-Beuren syndrome, calcium-sensing receptor mutations, Jansen’s metaphyseal chondrodysplasia, hypo- phosphatasia, subcutaneous fat necrosis and humoral or osteolytic malignancy.1–3 A complete evaluation of blood minerals together with assessments of serum alkaline phosphatase (S-ALP) activity and parathyroid hormone (S-PTH) levels usually helps to ensure the correct diagn- osis. This case report describes two cases of paediatric hypercalcaemia arising from different causes, one case in an infant and the other in an adolescent girl. Case One A seven-month-old girl was referred to the Department of Paediatrics, Pardubice Hospital, Pardubice, Czech Republic, in 2009 due to lethargy, psychomotor retard- ation, muscle hypotonia, anorexia, vomiting, constipation and failure to thrive. Her family and perinatal history was normal, with a 41-week gestational period, birthweight of 3,670 g, birth length of 50 cm and Apgar scores of 6–9. Up until the age of five months, her rate of weekly weight gain had been normal at 150–200 g; however, between months five and six, she gained only 100 g (from 7,200 g to 7,300 g) and between months six and seven, she lost 460 g (from 7,300 g to 6,840 g). She was being Two Different Causes of Paediatric Hypercalcaemia e390 | SQU Medical Journal, August 2018, Volume 18, Issue 3 S-Ca levels (from 3.54 to 3.02 mmol/L and 2.4 mmol/L, respectively) within 48 hours. One week after admission, the patient was discharged with a bodyweight of 7,300 g. She continued receiving a low-calcium milk-free diet (≤200 mg of calcium/day), primarily consisting of vegetable soup, poultry, mixed fruit and pastries, with no vitamin D supplementation. Her S-Ca levels remained between 2.25–2.6 mmol/L; however, after an isolated attempt to reintroduce milk at the age of eight months, her S-Ca levels increased transiently to 3.5 mmol/L [Figure 1A]. Despite the normalisation in her S-Ca levels, the patient’s psychomotor development remained slow and the muscle hypotonia persisted. Furthermore, her weight gain rate remained inappropriately low. She had no apparent dysmorphic facial features. Accordingly, at the age of 11 months, the patient underwent fluorescent in situ hybridisation (FISH) which revealed a chromosome 7q11.23 deletion indicative of Williams- Beuren syndrome. This was confirmed when ‘elfin’ facial features became apparent at the age of one year (i.e. a broad forehead, stellate iris pattern, flat nasal bridge, full cheeks and lips, long smooth philtrum and wide mouth). In the following years, she displayed behaviour characteristic of Williams-Beuren syndrome (i.e. over friendliness, empathy, generalised anxiety, specific phobias and attention deficit disorder).5–8 From the age of 10 months, her blood S-Ca levels rem-ained normal. At the time of writing, the patient was nine years old and under close surveillance. Although mildly to moderately developmentally delayed, her anthro- pometric data were within normal reference ranges for the syndrome.8 Case Two A 16-year old girl was admitted to the Department of Paediatrics, Pardubice Hospital, in 2010 with complaints of recurrent abdominal pain. Her family and personal breastfed, administered infant formula and vegetable soup and was receiving regular antirachitic prophylaxis (oral cholecalciferol at 500 IU/day). Upon admission, blood biochemistry tests revealed high levels of S-Ca (3.8 mmol/L), low levels of S-ALP (1.5 µkat/L), mildly elevated serum creatinine levels (52 µmol/L) and low S-PTH levels (4.8 ng/L). Other biochemistry results were normal [Table 1]. Echocardiography revealed very mild pulmonary artery stenosis (gradient of 10–15 mmHg) and nephro- calcinosis was apparent on a renal ultrasound. However, a wrist X-ray was normal, without any osteolytic signs. The combination of hypercalcaemia, normophosphat- aemia and low S-PTH and S-ALP levels ruled out primary hyperparathyroidism (HPT); additionally, vitamin D intox- ication was excluded by the low-to-normal 25-hydroxy- vitamin D levels. Accordingly, idiopathic infantile hyper- calcaemia was suspected and, on the second day of admission, the patient received an intravenous infusion of 0.9% sodium chloride with 5% dextrose together with methylprednisolone and furosemide (2 mg/kg/day each). This resulted in a gradual decrease in Table 1: Blood biochemistry results of case one Serum levels Result Normal range* Calcium in mmol/L 3.8 2.2–2.6 Sodium in mmol/L 134 135–145 Potassium in mmol/L 3.7 3.5–5.0 Phosphorus in mmol/L 1.13 1.1–2.2 Magnesium in mmol/L 0.7 0.6–1.1 ALP in µkat/L 1.5 2.2–9.3 Creatinine in µmol/L 52 20–40 PTH in ng/L 4.8 15–65 25-OH vitamin D in nmol/L 72 75–125 ALP = alkaline phosphatase; PTH = parathyroid hormone; OH = hydroxy. *Age-specific reference range. Figure 1: Serum calcium changes over time for (A) case one and (B) case two. The dotted lines represent the upper and lower reference values. S-Ca = serum calcium. Stepan Kutilek, Ivana Plasilova and Viktor Chrobok Online Case Report | e391 Histological evaluation confirmed the diagnosis of an adenoma. Subsequently, her S-PTH levels dropped to 15 ng/L and thereafter remained between 10–20 ng/L. The postoperative course was uneventful over the next three days; however, on the fourth day, the patient developed hungry bone syndrome with a drop in S-Ca levels (1.9 mmol/L) [Figure 1B]. Accordingly, she received calcium (3,000 mg/day) and cholecalciferol (5,000–7,500 IU/day) supplementation for four months. At the time of writing, the patient was 24 years old, in a good state of health with normal S-Ca levels and was being monitored by an endocrinologist. Discussion Hypercalcaemia should be considered in infants and children with failure to thrive, constipation, hypotonia and psychomotor retardation. In the current case report, the two presented cases of paediatric hypercalcaemia serve as an important clinical reminder of the complex differential diagnosis of mineral metabolism disorders. In the first patient, the underlying cause of hypercal- caemia was Williams-Beuren syndrome, while the second was caused by primary HPT due to an adenoma of the parathyroid gland. Williams-Beuren syndrome is caused by a 7q11.23 contiguous gene deletion of the Williams-Beuren synd- rome critical region that encompasses the elastin gene.5 It is transmitted in an autosomal dominant manner and occurs in one in 10,000 live births, of which most cases are de novo. Hypercalcaemia occurs in 15–50% of affected children, although the specific causative mechanism by which this occurs is currently unknown.5 Apart from hypercalcaemia, typical manifestations include congenital heart defects (especially supravalvular aortic and periph- eral pulmonary artery stenosis), hypercalciuria with nephrocalcinosis/urolithiasis, endocrine abnormalities (i.e. thyroid hypoplasia, impaired glucose tolerance and growth hormone deficiency), feeding problems, failure to thrive, hypertension, dental anomalies and distinctive facial features and behavioural characteristics, such as irritability, anxiety, overfriendliness and hypersensit- ivity to noise.6–8 However, not all of these are present among affected infants, with certain manifestations only becoming apparent later, usually in early childhood.6 While the prognosis is generally good, there is an incr- eased risk of cardiovascular morbidities and patients require periodic monitoring by specialists (i.e. an endocr- inologist, cardiologist, neurologist, psychologist, psychi- atrist, stomatologist and orthopaedic surgeon).5,8 Generally, primary HPT is rare in children and adolescents, constituting less than 5% of all cases.9–12 At the Johns Hopkins Children’s Center in Baltimore, Mary- land, USA, only 16 paediatric and adolescent patients history was normal. One week prior, a urinalysis had revealed proteinuria and microscopic haematuria and she had been provisionally diagnosed with a urinary tract infection and prescribed painkillers and amoxicillin/cla- vulanate by a general practitioner. This resulted in temp- orary cessation of the pain. However, the abdominal pain and microscopic haematuria recurred and she was admit- ted to hospital. Upon admission, her blood pressure was normal (120/80 mmHg) and an abdominal X-ray and ultrasound examination failed to show any concrements, although dilation of the left renal pelvis and ureter was apparent. Laboratory results revealed high S-Ca levels of 3.2 mmol/L, normal phosphorus levels of 0.9 mmol/L (normal age-specific range: 0.7–1.5 mmol/L), normal S- ALP levels of 1.5 µkat/L (normal age-specific range: 0.7–2.5 µkat/L) and high S-PTH levels of 126.0 ng/L (normal age-specific range: 15.0–65.0 ng/L). A helical computed tomography (CT) scan revealed a 3-mm urolithiasis which was voided spontaneously. Multiple endocrine neoplasia (MEN) types I and II and a jaw tumour were ruled out as the patient’s thy- rotropin and free thyroxin levels were normal, along with magnetic resonance imaging (MRI) of the brain, skull and abdomen. A diagnosis of primary HPT was established. As a technetium-99m (99Tc)-labelled metho- xyisobutyl isonitrile (MIBI) scan showed only mild accum- ulation at the upper left parathyroid gland, 99Tc-MIBI single photon emission CT (SPECT) was performed; this confirmed left upper parathyroid enlargement, most probably due to an adenoma. This was also corroborated by MRI and a neck ultrasound. As measured by dual X-ray absorptiometry, her bone mineral density was within normal limits for her age. She was prescribed 20 mg/day of furosemide and her S-Ca levels dropped below 3 mmol/L within one week. Two months later, the patient underwent a parathy- roidectomy of the left upper parathyroid gland [Figure 2]. Figure 2: Gross photograph of a parathyroid adenoma excised from a 16-year-old girl with recurrent abdominal pain and hypercalcaemia. Two Different Causes of Paediatric Hypercalcaemia e392 | SQU Medical Journal, August 2018, Volume 18, Issue 3 References 1. Lietman SA, Germain-Lee EL, Levine MA. Hypercalcemia in children and adolescents. Curr Opin Pediatr 2010; 22:508–15. doi: 10.1097/MOP.0b013e32833b7c23. 2. Davies JH. Approach to the child with hypercalcaemia. Endocr Dev 2015; 28:101–18. doi: 10.1159/000380998. 3. McNeilly JD, Boal R, Shaikh MG, Ahmed SF. Frequency and aetiology of hypercalcaemia. Arch Dis Child 2016;101:344–7. doi: 10.1136/archdischild-2015-309029. 4. Elshafie OT, Woodhouse NJ. The diagnosis and management of severe hypercalcaemia: A simplified approach - Report of five cases. Sultan Qaboos Univ Med J 2010; 10:388–95. 5. Morris CA. Williams syndrome. In: Adam MP, Ardinger HH, Pagon RA, Eds. GeneReviews®. From: www.ncbi.nlm.nih.gov/ books/NBK1249/ Accessed: Feb 2018. 6. Sindhar S, Lugo M, Levin MD, Danback JR, Brink BD, Yu E, et al. Hypercalcemia in patients with Williams-Beuren syndr- ome. J Pediatr 2016; 178:254–60.e4. doi: 10.1016/j.jpeds.2016. 08.027. 7. Güven A. Seven cases with Williams-Beuren syndrome: Endocrine evaluation and long-term follow-up. J Pediatr Endocrinol Metab 2017; 30:159–65. doi: 10.1515/jpem-2016-0039. 8. Committee on Genetics. American Academy of Pediatrics: Health- care supervision for children with Williams syndrome. Pediatrics 2001; 107:1192–204. 9. 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:N44–50. 10. Paunovic I, Zivaljevic V, Stojanic R, Kalezic N, Kazic M, Diklic A. Primary hyperparathyroidism in children and young adults: A single institution experience. Acta Chir Belg 2013; 113:35–9. doi: 10.1080/00015458.2013.11680882. 11. Libánský P, Astl J, Adámek S, Nanka O, Pafko P, Spacková J, et al. Surgical treatment of primary hyperparathyroidism in children: Report of 10 cases. Int J Pediatr Otorhinolaryngol 2008; 72:1177–82. doi: 10.1016/j.ijporl.2008.04.005. 12. Lou I, Schneider DF, Sippel RS, Chen H, Elfenbein DM. The changing pattern of diagnosing primary hyperparathyroidism in young patients. Am J Surg 2017; 213:146–50. doi: 10.1016/j.amj surg.2016.03.019. 13. Wei WJ, Shen CT, Song HJ, Qiu ZL, Luo QY. Comparison of SPET/CT, SPET and planar imaging using 99mTc-MIBI as independent techniques to support minimally invasive parathy- roidectomy in primary hyperparathyroidism: A meta-analysis. Hell J Nucl Med 2015; 18:127–35. doi: 10.1967/s002449910207. 14. Ozkan ZG, Unal SN, Kuyumcu S, Sanli Y, Gecer MF, Ozcinar B, et al. Clinical utility of Tc-99m MIBI SPECT/CT for preop- erative localization of parathyroid lesions. Indian J Surg 2017; 79:312–18. doi: 10.1007/s12262-016-1489-7. 15. Kundel A, Thompson GB, Richards ML, Qiu LX, Cai Y, Schwenk FW, et al. Pediatric endocrine surgery: A 20-year experience at the Mayo Clinic. J Clin Endocrinol Metab 2014; 99:399–406. doi: 10.1210/jc.2013-2617. 16. Ajmi S, Sfar R, Trimeche S, Ben Ali K, Nouira M. Scinti- graphic findings in hungry bone syndrome following parathy- roidectomy. Rev Esp Med Nucl 2010; 29:81–3. doi: 10.1016/j.re mn.2009.10.003. 17. Witteveen JE, van Thiel S, Romijn JA, Hamdy NA. Hungry bone syndrome: Still a challenge in the post-operative management of primary hyperparathyroidism - A systematic review of the litera- ture. Eur J Endocrinol 2013; 168:R45–53. doi: 10.1530/EJE-12-0528. with primary HPT (mean age: 16.3 ± 2.9 years) were reported between 1984 and 2001.9 In another study from Belgrade, Serbia, there were seven paediatric cases (mean age: 15.7 years) out of 522 patients with primary HPT seen between 2004 and 2010.10 Libánský et al. analysed 10 primary HPT patients between 10–17 years old between 1996 and 2007.11 Currently, the diagnosis of primary HPT in children and adolescents is mostly incidental.11,12 The most frequent manifestation of paed- iatric primary HPT is urolithiasis in 64% of cases, with other symptoms including limb pain, fractures, hyper- tension, fatigue and constipation.1,9–12 In the current case report, the second patient presented with renal colic and hypercalcaemia due to a single parathyroid adenoma. Among children, prim- ary HPT is mostly due to a parathyroid adenoma; how- ever, it can also occur within the context of other syndr- omes, such as parathyroid hyperplasia in MEN types I and II and HPT with jaw tumours.9–12 While a 99Tc-MIBI scan, neck ultrasound and MRI scan can help to localise a parathyroid adenoma, 99Tc-MIBI SPECT is the most reliable method in this regard.13,14 In cases of paediatric parathyroid adenomas, surgical removal is the only effective treatment for primary HPT.11,15 However, hungry bone syndrome is a frequent post- operative complication and usually lasts for 3–4 months, with the duration reflecting the time span of bone remodelling.16,17 Conclusion Hypercalcaemia should be considered in the differential diagnosis for various disease states, especially among infants with psychomotor retardation and failure to thrive and children with abdominal pain, renal colic and urolithiasis. a c k n o w l e d g e m e n t s The authors wish to thank Dr Vladimir Nemec, Dr Hana Teterova-Cerna, Dr Olga Machacova, Dr Kristyna Machata-Hanulikova, Dr Katerina Sachova, Dr Iva Lebedova and Dr Petr Munzar who took care of the patients during their stay in hospital as well as Dr Vera Jüttnerova and Dr Jozef Kubinyi who performed the FISH procedure and 99Tc-MIBI SPECT scan, respect- ively, in the second case. A poster of the preliminary version of the first case in this case report was presented at the 7th International Conference on Children’s Bone Health from 27–30 June 2015 in Salzburg, Austria. An abstract of this poster presentation was subsequently published in Bone Abstracts in 2015 (Volume 4, Issue S3, P. 84). https://doi.org/10.1097/MOP.0b013e32833b7c23 https://doi.org/10.1159/000380998 https://doi.org/10.1136/archdischild-2015-309029 https://doi.org/10.1016/j.jpeds.2016.08.027 https://doi.org/10.1016/j.jpeds.2016.08.027 https://doi.org/10.1515/jpem-2016-0039 https://doi.org/10.1080/00015458.2013.11680882 https://doi.org/10.1016/j.ijporl.2008.04.005 https://doi.org/10.1016/j.amjsurg.2016.03.019 https://doi.org/10.1016/j.amjsurg.2016.03.019 https://doi.org/10.1967/s002449910207 https://doi.org/10.1007/s12262-016-1489-7 https://doi.org/10.1210/jc.2013-2617 https://doi.org/10.1016/j.remn.2009.10.003 https://doi.org/10.1016/j.remn.2009.10.003 https://doi.org/10.1530/EJE-12-0528