European Journal of Medical Genetics xxx (2016) 1e5
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Review
Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR: A rare cause of life-threatening hypercalcemia ez-Irizarry c, Yves Lacassie d, e, Heidi Murphy a, Jessica Patrick b, Eileen Ba mez c, f, Alfonso Vargas c, f, Brian Barkemeyer b, g, Sohit Kanotra h, i, Ricardo Go Regina M. Zambrano d, e, * a
Department of Pediatrics, Louisiana State University Health Science Center, USA Division of Neonatology, Department of Pediatrics, Louisiana State University Health Science Center, USA Division of Endocrinology, Department of Pediatrics, Louisiana State University Health Science Center, USA d Division of Genetics, Department of Pediatrics, Louisiana State University Health Science Center, USA e Department of Genetics, Children's Hospital of New Orleans, USA f Department of Endocrinology, Children's Hospital of New Orleans, USA g Department of Neonatology, Children's Hospital of New Orleans, USA h Division of Otorlaryngology, Department of Pediatrics, Louisiana State University Health Science Center, USA i Department of Otolaryngology Children's Hospital of New Orleans, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 August 2015 Received in revised form 27 January 2016 Accepted 1 February 2016 Available online xxx
Neonatal severe hyperparathyroidism (NSHPT) is a rare, life-threatening condition that presents with severe hypercalcemia, hyperparathyroidism, and osteopenia in the newborn period. Treatment of NSHPT traditionally includes hydration and bisphosphonates; however newer calcimimetic agents, such as cinacalcet, are now being utilized to prevent or delay parathyroidectomy which is technically difficult in the newborn. Medical treatment success is related to calcium sensing receptor (CaSR) genotype. We report a 4-day-old infant who presented with hyperbilirubinemia, poor feeding, weight loss, severe hypotonia and was ultimately diagnosed with NSHPT. The patient's total serum calcium level of 36.8 mg/ dL (reference range: 8.5e10.4 mg/dL) is, to our knowledge, the highest ever documented in this setting. Exome data previously obtained on the infant's parents was re-analyzed demonstrating bi-parental heterozygosity for a mutation of the CASR gene: c.206G > A, and Sanger sequencing data confirmed the patient was a homozygote for the same mutation. Though a patient with the same CaSR gene mutation described here has responded to cinacalcet, our patient did not respond and required parathyroidectomy. Though this case has previously been published as a surgical case report, a full report of the medical management and underlying genetic etiology is warranted; this case underscores the importance of disclosing bi-parental heterozygosity for a gene causing severe neonatal disease particularly when treatment is available and illustrates the need for further in vitro studies of this CaSR mutation. © 2016 Elsevier Masson SAS. All rights reserved.
Keywords: Neonatal severe hyperparathyroidism CASR Calcimimetic Exome data
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Financial disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
00 00 00 00
Abbreviations: NSHPT, Neonatal severe hyperparathyroidism; CaSR, Calcium-sensing receptor; PTH, Parathyroid hormone; TRPS1, Trichorhinophalangeal syndrome I. * Corresponding author. Division of Clinical Genetics, Department of Pediatrics, Louisiana State University Health Sciences Center, Children's Hospital of New Orleans, 200 Henry Clay Avenue, New Orleans, Louisiana 70118, USA. E-mail address: [email protected] (R.M. Zambrano). http://dx.doi.org/10.1016/j.ejmg.2016.02.001 1769-7212/© 2016 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Murphy, H., et al., Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR: A rare cause of life-threatening hypercalcemia, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.02.001
2
H. Murphy et al. / European Journal of Medical Genetics xxx (2016) 1e5
Funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors' statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Neonatal severe hyperparathyroidism (NSHPT; OMIM 239200) is a rare condition presenting in the first days of life with severe hypercalcemia, hyperparathyroidism, osteopenia, and low fractional excretion of urinary calcium. Patients may also exhibit hypotonia, respiratory distress, bony fractures, and intestinal dysmotility as well as failure to thrive, and if not treated promptly, NSHPT can be fatal (Soblechero et al., 2013). Mutations in the calcium-sensing receptor (CaSR) gene are the most common cause of NSHPT with more than 250 mutations identified (Calcium Sensing Receptor, 2015). The CaSR is a G-protein-coupled receptor found in many tissues throughout the body, but the action is best understood in the parathyroid gland and kidney where parathyroid hormone (PTH) synthesis and secretion and calcium reabsorption and excretion are regulated, respectively (Lu et al., 2009). CaSR gene mutations often decrease the receptor's sensitivity to extracellular calcium. An elevated calcium homeostasis set point (the point at which serum calcium concentration halfmaximally inhibits parathyroid hormone secretion)results, and parathyroid gland stimulation and chief cell proliferation follows (Atay et al., 2014). Increased synthesis and secretion of PTH leads to skeletal demineralization and decreased renal calcium excretion yielding severe hypercalcemia. Medical treatment of NSHPT includes intravenous fluid hydration, diuretics, and bisphosphonates, however, these therapies often fail to control hypercalcemia, hyperparathyroidism, and skeletal demineralization. Parathyroidectomy remains the treatment of choice and is often required though technically difficult in newborns (Garcia-Garcia et al., 2014). Parathyroid gland localization may be challenging and supernumerary parathyroid tissue is not uncommon (Soblechero et al., 2013; GarciaeGarcia et al., 2014). Surgery does not prevent or alleviate prenatal damage nor does it change the impaired calcium sensitivity in other organs (Rus et al., 2008). Recently, calcimimetics specifically cinacalcet, have been utilized to increase the calciumresponsiveness of mutated CaSR genes with some success (Gannon et al., 2014; Reh et al., 2011; Wilhem-Bals et al., 2012). We report a 4-day-old infant with NSHPT who presented with, to our knowledge, the highest total serum calcium level recorded in the setting of NSHPT. The patient failed medical management including cinacalcet, despite having a CaSR mutation previously reported in a patient with NHSPT who responded to bisphosphonates and cinacalcet (Wilhem-Bals et al., 2012).
2. Case report We report a 4-day-old, full term infant born to a 29-year-old father and a 32-year old multigravida mother via spontaneous vaginal delivery following a pregnancy complicated by preterm labor and polyhydramnios. On day of life 2, the infant appeared well and was discharged from the delivery hospital. Two days later, the patient presented with hyperbilirubinemia, poor feeding, weight loss, lethargy, hypotonia, hypercapnea, and hypoxia. Initial laboratory evaluation revealed hypercalcemia, serum calcium level of
00 00 00 00 00
9.2 mmol/L (reference range: 2.10e2.55 mmol/L) and hyperparathyroidism, PTH of 91.99 pmol/L (reference range: 1.59e6.9 pmol/ L), hyperbilirubinemia 19.4 mg/dL (reference range: 0e12 mg/dL), and hypophosphatemia 3.2 mg/dL (reference range: 4.5e9.0 mg/ dL). The patient was transferred to Children's Hospital of New Orleans neonatal intensive care unit (NICU) for suspected hyperparathyroidism. Family history is significant for consanguineous parents (fifth cousins), and the patient's older sibling has a de novo mutation in the TRPS1 (Trichorhinophalangeal syndrome I) gene, detected on exome sequencing prior to the patient's birth (Casci et al., 2014). The paternal grandfather had a female sibling with parathyroid glands removed in her fifth decade, and the paternal great-grandfather had a female offspring with hyperparathyroidism requiring parathyroidectomy in her second decade of life. Physical examination of the infant demonstrated lethargy and mild jaundice with severe hypotonia and absent deep tendon reflexes but no dysmorphic features. Hypercalcemia persisted with total serum calcium of 5.725 mmol/L and a serum ionized calcium level of >5 mmol/L (exceeding the instrument's ability to quantify; reference range: 1.075e1.475 mmol/L). Other laboratories included: intact PTH 115.54 pmol/L, 25-hydroxyvitamin D level of 21 ng/mL (reference range: 30e100 ng/mL) 1,25-dihydroxy vitamin D 41 pg/ mL (reference range: A. Sanger sequencing in the proband confirmed homozygosity for the same c.206G > A mutation. Parathyroidectomy was deferred as medical management appeared to be successful initially. However, the patient ultimately failed to maintain normocalcemia and PTH levels never normalized. Repeated doses of pamidronate were given (days of life 28, 31, and 33), however the patient's calcium levels suggested pamidronate's duration of effect was approximately two weeks. This short duration of effect coupled with the lack of evidence regarding long-term effects of pamidronate prompted discontinuation of this therapeutic agent. After obtaining informed consent from the parents, cinacalcet therapy was initiated (0.4 mg/kg/day; 6 mg/m2/day) on day of life
Please cite this article in press as: Murphy, H., et al., Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR: A rare cause of life-threatening hypercalcemia, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.02.001
H. Murphy et al. / European Journal of Medical Genetics xxx (2016) 1e5
3
Calcium and PTH under bisphosphonate and cinacalcet
9
Normal Calcium Range
Normal Intact PTH Range
Cinacalcet give
Calcium (mmol/L)
Intact PTH (pmol/L)
Pamidronate given
Parathyroidectomy 180
8
160 7
120 5 100 4
80
3
60
51
50
35 36 37 38 40 42 44 46 48 49
33
30
0 28 29
0 26
20
19 20 21 22 24
1
12 14 16
40
7
2
Intact PTH range (pmol/L)
6
4
Calcium Range (mmol/L)
140
Days of Life Fig. 1. Calcium and parathyroid hormone (PTH) levels over time from day of life 4 through the immediate post-operative period. Pamidronate administration, cinacalcet administration and parathyroidectomy are all indicated with corresponding responses in calcium and PTH levels.
18. The patient was discharged on day of life 23 to continue cinacalcet (0.6 mg/kg/day; 9 mg/m2/day), vitamin D, and phosphorous supplementation. Calcium levels continued to rise and normalization of PTH was never achieved despite increasing dosages of cinacalcet (highest dose: 8.5 mg/kg/day; 143 mg/m2/day). The patient was re-admitted on day of life 25 with persistent hypercalcemia (total serum calcium: 3.68 mmol/L; ionized calcium: 2.43 mmol/L), hyperparathyroidism (PTH: 111.19 pmol/L), and poor feeding (see Fig. 1). Intravenous saline, furosemide, pamidronate infusions, and high-dose cinacalcet only achieved partial control of the patient's hypercalcemia, and the infant underwent a total parathyroidectomy on day of life 50 (Fig. 1). Cure and complete resection of all parathyroid tissue was confirmed intraoperatively with PTHmonitoring (Garcia-Garcia et al., 2014). Postoperatively, the patient experienced hypocalcemia requiring intravenous calcium. The infant was discharged on day of life 55 with calcitriol and calcium supplements.
3. Discussion Though this case has previously been published as a surgical case report, a full report of the medical management and underlying genetic etiology is warranted (Brickman et al., 2015). NSHPT remains a rare disorder; however research into treatment strategies and the consequence of CaSR gene mutations is ongoing. The mutation noted in our patient, c.206G > A, was first described in 2009 by Rodrigues et al. in a family including three generations affected
with hypocalciuric hypercalcemia (Calcium Sensing Receptor, 2015; Rodrigues et al., 2009). This missense mutation is found in the third exon of the CaSR gene in the extracellular domain of the receptor, and though the chemical characteristics of this region should not be altered, the steric shape may be affected leading to calcium-binding difficulties (Wilhem-Bals et al., 2012). Successful use of bisphosphonates and cinacalcet following surgical failure in a patient with NSHPT secondary to the same homozygous mutation we describe here has been reported (Wilhem-Bals et al., 2012). Following parathyroidectomy, the patient was found to have residual, miliary parathyroid tissue, and hypercalcemia with hyperparathyroidism persisted. This patient remains on cinacalcet and has maintained near-eucalcemia though our patient, with the same genotype, failed to respond. The mechanism underlying the variability in response is incompletely understood. Bisphosphonates are often utilized in patients with NSHPT and were initially used in the patient reported by Wilhelm-Bals et al (Wilhem-Bals et al., 2012). The initial improvement in hypercalcemia seen in this patient may be attributed to the effect of pamidronate rather than of cinacalcet. However, the near normal calcium levels noted more than 6 years following the last pamidronate infusion suggest bisphosphonate effect is not solely responsible. Progression to a more benign hypocalciuric hypercalcemia disease state may be the natural evolution in some patients with NSHPT and explains the improvement in hypercalcemia observed over time (Fox et al., 2007). Reduction in serum calcium in patients
Please cite this article in press as: Murphy, H., et al., Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR: A rare cause of life-threatening hypercalcemia, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.02.001
4
H. Murphy et al. / European Journal of Medical Genetics xxx (2016) 1e5
with heterozygous CaSR mutations may be attributable to the calcimimetic acting on the normal CaSR protein encoded by the wildtype allele rather than effect on mutated CaSR protein (Atay et al., 2014); however, both our patient and the patient presented by Wilhelm-Bals et al. had homozygous mutations (Wilhem-Bals et al., 2012). Unidentified genetic modifiers may exist that influence phenotype, and environmental factors, gestational age, nutritional status, metabolism, intestinal absorption, maternal serum calcium levels, and maternal vitamin D levels may all impact presentation (Reh et al., 2011; Fox et al., 2007; Hannan and Thakker, 2013). Dose effect must also be considered. We initiated cinacalcet therapy at 0.4 mg/kg/day (6 mg/m2/day) and titrated to 8.5 mg/kg/ day (143 mg/m2/day) without achieving normocalcemia. Twice a day dosing was used throughout therapy. Successful management of a patient with NSHPT using cinacalcet monotherapy and a similar regimen (0.4e9.6 mg/kg/day; 6 mg/m2/day-202 mg/m (Calcium Sensing Receptor, 2015)/day) was described by Gannon et al., but three times a day dosing was required.7Historically, alternating daily doses of 90 mg/60 mg was used and currently 90 mg daily is employed by Wilhelm-Bals et al. to achieve near-normal calcium levels (Wilhem-Bals et al., 2012). Reh et al. describe regimens utilizing a 4 mg (20 mg/m2/day) dose first daily then in two divided doses (Reh et al., 2011). In all three cases of successful treatment, eucalcemia was not achieved. In cases of cinacalcet failure, dosing ranges from 15 mg/m (Calcium Sensing Receptor, 2015)/day up to 90 mg/m2/day administered as daily oral doses were used (Soblechero et al., 2013; Atay et al., 2014). Together these suggest high doses of cinacalcet are required with multiple doses administered each day. Cinacalcet may be trialed in an effort to delay or prevent surgical intervention, but careful consideration and close monitoring must be undertaken throughout therapy. Clinical trials in pediatric patients are currently on hold pending United States Food and Drug Administration investigation of the death of a 14year-old patient in a cinacalcet study, and further studies are required to determine best use of this medication in the setting of NSHPT (United States Food and Drug Administration). Parental exome sequencing data obtained during the sibling's prior genetic workup was available and proved indispensable in establishing a prompt diagnosis of NSHPT. This case underscores the importance of reporting bi-parental heterozygosity for a recessive gene causing severe neonatal disease particularly when treatment is available (Zambrano and Lacassie, 2014). Disclosing this finding would have allowed for genetic counseling, prenatal testing, and prompt therapy perhaps preventing the infant's precarious neonatal course. Heterozygosity for the c.206G > A mutation is an important point for discussion. Few reports of this mutation exist in the literature, and the effects of heterozygosity are unclear. Once biparental heterozygosity for this mutation was established, parents both underwent evaluation for hyperparathyroidism. They were both found to have mild hypercalcemia (2.62 mmol/L in both parents) and normal PTH levels (2.8 pmol/L in both parents); a tendency to borderline low normal urinary calcium in the father (0.11 mg/mg) and normal urinary calcium in the mother (0.14 mg/ mg) were noted. The data reported by Rodrigues et al. suggests heterozygotes may experience hypocalciuric hypercalcemia (Calcium Sensing Receptor, 2015; Rodrigues et al., 2009). The case presented by Wilhelm-Bals et al., does not mention parental studies (Wilhem-Bals et al., 2012). Together, these sparse data lead us to predict heterozygosity may lead to mild elevations in calcium with normal PTH levels and perhaps in some cases hypocalciuric hypercalcemia. To our knowledge, this is the highest total serum calcium level documented in the setting of NSHPT. Our patient survived and is thriving, achieving normal growth and neurodevelopmental
milestones on calcitriol and calcium supplementation. Financial disclosure The authors have no financial relationships relevant to this case report to disclose. Funding source The authors report no external funding source for this manuscript. Conflicts of interest The authors declare they have no potential conflicts of interest to disclose. Contributors' statement Dr. Murphy provided care to this patient throughout her initial hospitalization, drafted the. initial manuscript, and approved the final manuscript as submitted. Dr. Patrick provided care to this patient throughout her initial hospitalization, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. B aez-Irizarry provided care to this patient throughout her initial hospitalization, organized data sets for figures, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. Lacassie provided care to this patient's family, reviewed and revised the manuscript, and approved the final manuscript as submitted. mez provided care to this patient throughout her course, Dr. Go reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. Vargas provided care to this patient throughout her course, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. Barkemeyer provided care to this patient throughout her initial hospitalization, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. Kanotra provided care to this patient throughout her initial hospitalization, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. Zambrano provided care to this patient, collected genetic data for this patient, conceptualized the case report, reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Acknowledgments We thank the family for their cooperation. We also thank Ms. Dima El-Khechen and Dr. Sha Tang at Ambry Genetics for their quick review of the Exome data in this family which allowed molecular confirmation. Dr. Todd Brickman and Dr. Anita Jeyakumar for their contribution to the surgical management of this patient. References Atay, Z., Bereket, A., Haliloglu, B., Abali, S., Ozdogan, T., Altuncu, E., Canaff, L., Vilaça, T., Wong, B.Y.L., Cole, D.E.C., Hendy, G.N., Turan, S., 2014. Novel homozygous inactivating mutation of the calcium-sensing receptor gene (CASR) in
Please cite this article in press as: Murphy, H., et al., Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR: A rare cause of life-threatening hypercalcemia, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.02.001
H. Murphy et al. / European Journal of Medical Genetics xxx (2016) 1e5 neonatal severe hyperparathyroidism-lack of effect of cinacalcet. Bone 64, 102e107. Brickman, T.M., Stark, M.W., Jayakumar, A., 2015. Unusual case of neonatal hypoercalcemia. Int. J. Pediatr. Otorhinolaryngol. 79 (5), 758e759. Calcium Sensing Receptor Database. http://www.casrdb.mcgill.ca/. Accessed May 26, 2015. Casci, I., Accousti, W., Lacassie, Y., 2014. Unexpected exome sequencing result: de novo TRPS1 mutation in an infant with infantile scoliosis, mild developmental delay, and history of consanguinity. Am. J. Med. Genet. Part A 2013 (164A), 1334e1337. Fox, L., Sadowsky, J., Pringle, K.P., Kidd, A., Murdoch, J., Cole, D.E.C., Wiltshire, E., Pamidronate, 2007. Neonatal Hyperparathyroidism Therapy in an extremely premature infant. Pediatrics 120 (5) e1350ee1254. Gannon, A.W., Monk, H.M., Levine, M.A., 2014. Cinacalcet monotherapy in neonatal severe hyperparathyroidism: a case study and review. J. Clin. Endocrinol. Metab. 99 (1), 7e11. Garcia-Garcia, E., Dominguez-Pascual, I., Requena-Diaz, M., Cabello-Laureano, R., ndez-Pineda, I., S Ferna anchez-Martin, M.J., 2014. Intraoperative parathyroid hormone monitoring in neonatal severe primary hyperparathyroidism. Pediatrics 134, e1203ee1205. Hannan, F.M., Thakker, R.V., 2013. Calcium-sensing receptor (CaSR) mutations and disorders of calcium, electrolyte, and water metabolism. Best. Pract. Res. Clin. Endocrinol. Metab. 27, 359e371. Lu, J.Y.L., Yang, Y., Gnacadja, G., Christopoulos, A., Reagan, J.D., 2009. Effect of the calcimimetic R-568 [3-(2 chlorophenyl)-N-((1R)-1-(3-methoxyphenyl) ethyl)1- propanamine] on correcting inactivating mutations in the human calciumsensing receptor. J. Pharmacol. Exp. Ther. 331 (3), 775e786.
5
Reh, C.M.S., Hendy, G.N., Cole, D.E.C., Jeandron, D.D., 2011. Neonatal hyperparathyroidism with a heterozygous calcium-sensing receptor (CASR) R185Q mutation: clinical benefit from cinacalcet. J. Clin. Endocrinol. Metab. 96 (4), E707eE712. Rodrigues, L.S., Bussmann, L.Z., Correa, P.H.S., Martin, R.M., 2009. New mutation in the CaSR involving three generations in a family with hypocalciuric hypercalcemia. Endocr. Soc. Congr. P2eP204. €hr, V., Mayr, B., Mo €hlig, M., Schulze, E., FrankRus, R., Haag, C., Bumke-Vogt, C., Ba €ft, C., 2008. Novel inactivating mutations of the calciumRaue, K., Raue, F., Scho sensing receptor: the calcimimetic NPS R-568 improves signal transduction of mutant receptors. J. Clin. Endocrinol. Metab. 93 (12), 4797e4803. Soblechero, E.G., Castillo, M.T.F., Crespo, B.J., Quintero, M.L.D., Fuentes, C.G., 2013. Neonatal hypercalcemia due to a homozygous mutation in the calcium-sensing receptor: failure of cinacalcet. Neonatology 104, 104e108. United States Food and Drug Administration. Sensipar (cinacalcet hydrochloride): Drug Safety Communication. FDA suspends pediatric clinical trials after report of death. http://www.fda.gov/safety/MedWatch/SafetyInformation/ SafetyAlertsforHumanMedicalProducts/ucm341255.htm. Published February 26, 2013. Accessed May 21, 2015. Wilhem-Bals, A., Parvex, P., Magdelaine, C., Girardin, E., 2012. Successful use of bisphosphonate and calcimimetic in neonatal severe primary hyperparathyroidism. Pediatrics 129 (3), e812e816. Zambrano, R.M., Lacassie, Y., 2014. Should the American college of medical genetics expand the required reportable disorders or findings on exome sequencing? reporting a recent experience; (2588S). In: Presented at the 64th Annual Meeting of the American Society of Human Genetics, October, 19 2014 in San Diego, California. http://abstracts.ashg.org/cgibin/2014/ashg14s.pl?author ¼zambrano&sort¼ptimes&sbutton¼Detail&absno¼140120043&sid¼212532.
Please cite this article in press as: Murphy, H., et al., Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR: A rare cause of life-threatening hypercalcemia, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.02.001
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Review
Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR: A rare cause of life-threatening hypercalcemia ez-Irizarry c, Yves Lacassie d, e, Heidi Murphy a, Jessica Patrick b, Eileen Ba mez c, f, Alfonso Vargas c, f, Brian Barkemeyer b, g, Sohit Kanotra h, i, Ricardo Go Regina M. Zambrano d, e, * a
Department of Pediatrics, Louisiana State University Health Science Center, USA Division of Neonatology, Department of Pediatrics, Louisiana State University Health Science Center, USA Division of Endocrinology, Department of Pediatrics, Louisiana State University Health Science Center, USA d Division of Genetics, Department of Pediatrics, Louisiana State University Health Science Center, USA e Department of Genetics, Children's Hospital of New Orleans, USA f Department of Endocrinology, Children's Hospital of New Orleans, USA g Department of Neonatology, Children's Hospital of New Orleans, USA h Division of Otorlaryngology, Department of Pediatrics, Louisiana State University Health Science Center, USA i Department of Otolaryngology Children's Hospital of New Orleans, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 August 2015 Received in revised form 27 January 2016 Accepted 1 February 2016 Available online xxx
Neonatal severe hyperparathyroidism (NSHPT) is a rare, life-threatening condition that presents with severe hypercalcemia, hyperparathyroidism, and osteopenia in the newborn period. Treatment of NSHPT traditionally includes hydration and bisphosphonates; however newer calcimimetic agents, such as cinacalcet, are now being utilized to prevent or delay parathyroidectomy which is technically difficult in the newborn. Medical treatment success is related to calcium sensing receptor (CaSR) genotype. We report a 4-day-old infant who presented with hyperbilirubinemia, poor feeding, weight loss, severe hypotonia and was ultimately diagnosed with NSHPT. The patient's total serum calcium level of 36.8 mg/ dL (reference range: 8.5e10.4 mg/dL) is, to our knowledge, the highest ever documented in this setting. Exome data previously obtained on the infant's parents was re-analyzed demonstrating bi-parental heterozygosity for a mutation of the CASR gene: c.206G > A, and Sanger sequencing data confirmed the patient was a homozygote for the same mutation. Though a patient with the same CaSR gene mutation described here has responded to cinacalcet, our patient did not respond and required parathyroidectomy. Though this case has previously been published as a surgical case report, a full report of the medical management and underlying genetic etiology is warranted; this case underscores the importance of disclosing bi-parental heterozygosity for a gene causing severe neonatal disease particularly when treatment is available and illustrates the need for further in vitro studies of this CaSR mutation. © 2016 Elsevier Masson SAS. All rights reserved.
Keywords: Neonatal severe hyperparathyroidism CASR Calcimimetic Exome data
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Financial disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
00 00 00 00
Abbreviations: NSHPT, Neonatal severe hyperparathyroidism; CaSR, Calcium-sensing receptor; PTH, Parathyroid hormone; TRPS1, Trichorhinophalangeal syndrome I. * Corresponding author. Division of Clinical Genetics, Department of Pediatrics, Louisiana State University Health Sciences Center, Children's Hospital of New Orleans, 200 Henry Clay Avenue, New Orleans, Louisiana 70118, USA. E-mail address: [email protected] (R.M. Zambrano). http://dx.doi.org/10.1016/j.ejmg.2016.02.001 1769-7212/© 2016 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Murphy, H., et al., Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR: A rare cause of life-threatening hypercalcemia, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.02.001
2
H. Murphy et al. / European Journal of Medical Genetics xxx (2016) 1e5
Funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors' statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Neonatal severe hyperparathyroidism (NSHPT; OMIM 239200) is a rare condition presenting in the first days of life with severe hypercalcemia, hyperparathyroidism, osteopenia, and low fractional excretion of urinary calcium. Patients may also exhibit hypotonia, respiratory distress, bony fractures, and intestinal dysmotility as well as failure to thrive, and if not treated promptly, NSHPT can be fatal (Soblechero et al., 2013). Mutations in the calcium-sensing receptor (CaSR) gene are the most common cause of NSHPT with more than 250 mutations identified (Calcium Sensing Receptor, 2015). The CaSR is a G-protein-coupled receptor found in many tissues throughout the body, but the action is best understood in the parathyroid gland and kidney where parathyroid hormone (PTH) synthesis and secretion and calcium reabsorption and excretion are regulated, respectively (Lu et al., 2009). CaSR gene mutations often decrease the receptor's sensitivity to extracellular calcium. An elevated calcium homeostasis set point (the point at which serum calcium concentration halfmaximally inhibits parathyroid hormone secretion)results, and parathyroid gland stimulation and chief cell proliferation follows (Atay et al., 2014). Increased synthesis and secretion of PTH leads to skeletal demineralization and decreased renal calcium excretion yielding severe hypercalcemia. Medical treatment of NSHPT includes intravenous fluid hydration, diuretics, and bisphosphonates, however, these therapies often fail to control hypercalcemia, hyperparathyroidism, and skeletal demineralization. Parathyroidectomy remains the treatment of choice and is often required though technically difficult in newborns (Garcia-Garcia et al., 2014). Parathyroid gland localization may be challenging and supernumerary parathyroid tissue is not uncommon (Soblechero et al., 2013; GarciaeGarcia et al., 2014). Surgery does not prevent or alleviate prenatal damage nor does it change the impaired calcium sensitivity in other organs (Rus et al., 2008). Recently, calcimimetics specifically cinacalcet, have been utilized to increase the calciumresponsiveness of mutated CaSR genes with some success (Gannon et al., 2014; Reh et al., 2011; Wilhem-Bals et al., 2012). We report a 4-day-old infant with NSHPT who presented with, to our knowledge, the highest total serum calcium level recorded in the setting of NSHPT. The patient failed medical management including cinacalcet, despite having a CaSR mutation previously reported in a patient with NHSPT who responded to bisphosphonates and cinacalcet (Wilhem-Bals et al., 2012).
2. Case report We report a 4-day-old, full term infant born to a 29-year-old father and a 32-year old multigravida mother via spontaneous vaginal delivery following a pregnancy complicated by preterm labor and polyhydramnios. On day of life 2, the infant appeared well and was discharged from the delivery hospital. Two days later, the patient presented with hyperbilirubinemia, poor feeding, weight loss, lethargy, hypotonia, hypercapnea, and hypoxia. Initial laboratory evaluation revealed hypercalcemia, serum calcium level of
00 00 00 00 00
9.2 mmol/L (reference range: 2.10e2.55 mmol/L) and hyperparathyroidism, PTH of 91.99 pmol/L (reference range: 1.59e6.9 pmol/ L), hyperbilirubinemia 19.4 mg/dL (reference range: 0e12 mg/dL), and hypophosphatemia 3.2 mg/dL (reference range: 4.5e9.0 mg/ dL). The patient was transferred to Children's Hospital of New Orleans neonatal intensive care unit (NICU) for suspected hyperparathyroidism. Family history is significant for consanguineous parents (fifth cousins), and the patient's older sibling has a de novo mutation in the TRPS1 (Trichorhinophalangeal syndrome I) gene, detected on exome sequencing prior to the patient's birth (Casci et al., 2014). The paternal grandfather had a female sibling with parathyroid glands removed in her fifth decade, and the paternal great-grandfather had a female offspring with hyperparathyroidism requiring parathyroidectomy in her second decade of life. Physical examination of the infant demonstrated lethargy and mild jaundice with severe hypotonia and absent deep tendon reflexes but no dysmorphic features. Hypercalcemia persisted with total serum calcium of 5.725 mmol/L and a serum ionized calcium level of >5 mmol/L (exceeding the instrument's ability to quantify; reference range: 1.075e1.475 mmol/L). Other laboratories included: intact PTH 115.54 pmol/L, 25-hydroxyvitamin D level of 21 ng/mL (reference range: 30e100 ng/mL) 1,25-dihydroxy vitamin D 41 pg/ mL (reference range: A. Sanger sequencing in the proband confirmed homozygosity for the same c.206G > A mutation. Parathyroidectomy was deferred as medical management appeared to be successful initially. However, the patient ultimately failed to maintain normocalcemia and PTH levels never normalized. Repeated doses of pamidronate were given (days of life 28, 31, and 33), however the patient's calcium levels suggested pamidronate's duration of effect was approximately two weeks. This short duration of effect coupled with the lack of evidence regarding long-term effects of pamidronate prompted discontinuation of this therapeutic agent. After obtaining informed consent from the parents, cinacalcet therapy was initiated (0.4 mg/kg/day; 6 mg/m2/day) on day of life
Please cite this article in press as: Murphy, H., et al., Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR: A rare cause of life-threatening hypercalcemia, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.02.001
H. Murphy et al. / European Journal of Medical Genetics xxx (2016) 1e5
3
Calcium and PTH under bisphosphonate and cinacalcet
9
Normal Calcium Range
Normal Intact PTH Range
Cinacalcet give
Calcium (mmol/L)
Intact PTH (pmol/L)
Pamidronate given
Parathyroidectomy 180
8
160 7
120 5 100 4
80
3
60
51
50
35 36 37 38 40 42 44 46 48 49
33
30
0 28 29
0 26
20
19 20 21 22 24
1
12 14 16
40
7
2
Intact PTH range (pmol/L)
6
4
Calcium Range (mmol/L)
140
Days of Life Fig. 1. Calcium and parathyroid hormone (PTH) levels over time from day of life 4 through the immediate post-operative period. Pamidronate administration, cinacalcet administration and parathyroidectomy are all indicated with corresponding responses in calcium and PTH levels.
18. The patient was discharged on day of life 23 to continue cinacalcet (0.6 mg/kg/day; 9 mg/m2/day), vitamin D, and phosphorous supplementation. Calcium levels continued to rise and normalization of PTH was never achieved despite increasing dosages of cinacalcet (highest dose: 8.5 mg/kg/day; 143 mg/m2/day). The patient was re-admitted on day of life 25 with persistent hypercalcemia (total serum calcium: 3.68 mmol/L; ionized calcium: 2.43 mmol/L), hyperparathyroidism (PTH: 111.19 pmol/L), and poor feeding (see Fig. 1). Intravenous saline, furosemide, pamidronate infusions, and high-dose cinacalcet only achieved partial control of the patient's hypercalcemia, and the infant underwent a total parathyroidectomy on day of life 50 (Fig. 1). Cure and complete resection of all parathyroid tissue was confirmed intraoperatively with PTHmonitoring (Garcia-Garcia et al., 2014). Postoperatively, the patient experienced hypocalcemia requiring intravenous calcium. The infant was discharged on day of life 55 with calcitriol and calcium supplements.
3. Discussion Though this case has previously been published as a surgical case report, a full report of the medical management and underlying genetic etiology is warranted (Brickman et al., 2015). NSHPT remains a rare disorder; however research into treatment strategies and the consequence of CaSR gene mutations is ongoing. The mutation noted in our patient, c.206G > A, was first described in 2009 by Rodrigues et al. in a family including three generations affected
with hypocalciuric hypercalcemia (Calcium Sensing Receptor, 2015; Rodrigues et al., 2009). This missense mutation is found in the third exon of the CaSR gene in the extracellular domain of the receptor, and though the chemical characteristics of this region should not be altered, the steric shape may be affected leading to calcium-binding difficulties (Wilhem-Bals et al., 2012). Successful use of bisphosphonates and cinacalcet following surgical failure in a patient with NSHPT secondary to the same homozygous mutation we describe here has been reported (Wilhem-Bals et al., 2012). Following parathyroidectomy, the patient was found to have residual, miliary parathyroid tissue, and hypercalcemia with hyperparathyroidism persisted. This patient remains on cinacalcet and has maintained near-eucalcemia though our patient, with the same genotype, failed to respond. The mechanism underlying the variability in response is incompletely understood. Bisphosphonates are often utilized in patients with NSHPT and were initially used in the patient reported by Wilhelm-Bals et al (Wilhem-Bals et al., 2012). The initial improvement in hypercalcemia seen in this patient may be attributed to the effect of pamidronate rather than of cinacalcet. However, the near normal calcium levels noted more than 6 years following the last pamidronate infusion suggest bisphosphonate effect is not solely responsible. Progression to a more benign hypocalciuric hypercalcemia disease state may be the natural evolution in some patients with NSHPT and explains the improvement in hypercalcemia observed over time (Fox et al., 2007). Reduction in serum calcium in patients
Please cite this article in press as: Murphy, H., et al., Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR: A rare cause of life-threatening hypercalcemia, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.02.001
4
H. Murphy et al. / European Journal of Medical Genetics xxx (2016) 1e5
with heterozygous CaSR mutations may be attributable to the calcimimetic acting on the normal CaSR protein encoded by the wildtype allele rather than effect on mutated CaSR protein (Atay et al., 2014); however, both our patient and the patient presented by Wilhelm-Bals et al. had homozygous mutations (Wilhem-Bals et al., 2012). Unidentified genetic modifiers may exist that influence phenotype, and environmental factors, gestational age, nutritional status, metabolism, intestinal absorption, maternal serum calcium levels, and maternal vitamin D levels may all impact presentation (Reh et al., 2011; Fox et al., 2007; Hannan and Thakker, 2013). Dose effect must also be considered. We initiated cinacalcet therapy at 0.4 mg/kg/day (6 mg/m2/day) and titrated to 8.5 mg/kg/ day (143 mg/m2/day) without achieving normocalcemia. Twice a day dosing was used throughout therapy. Successful management of a patient with NSHPT using cinacalcet monotherapy and a similar regimen (0.4e9.6 mg/kg/day; 6 mg/m2/day-202 mg/m (Calcium Sensing Receptor, 2015)/day) was described by Gannon et al., but three times a day dosing was required.7Historically, alternating daily doses of 90 mg/60 mg was used and currently 90 mg daily is employed by Wilhelm-Bals et al. to achieve near-normal calcium levels (Wilhem-Bals et al., 2012). Reh et al. describe regimens utilizing a 4 mg (20 mg/m2/day) dose first daily then in two divided doses (Reh et al., 2011). In all three cases of successful treatment, eucalcemia was not achieved. In cases of cinacalcet failure, dosing ranges from 15 mg/m (Calcium Sensing Receptor, 2015)/day up to 90 mg/m2/day administered as daily oral doses were used (Soblechero et al., 2013; Atay et al., 2014). Together these suggest high doses of cinacalcet are required with multiple doses administered each day. Cinacalcet may be trialed in an effort to delay or prevent surgical intervention, but careful consideration and close monitoring must be undertaken throughout therapy. Clinical trials in pediatric patients are currently on hold pending United States Food and Drug Administration investigation of the death of a 14year-old patient in a cinacalcet study, and further studies are required to determine best use of this medication in the setting of NSHPT (United States Food and Drug Administration). Parental exome sequencing data obtained during the sibling's prior genetic workup was available and proved indispensable in establishing a prompt diagnosis of NSHPT. This case underscores the importance of reporting bi-parental heterozygosity for a recessive gene causing severe neonatal disease particularly when treatment is available (Zambrano and Lacassie, 2014). Disclosing this finding would have allowed for genetic counseling, prenatal testing, and prompt therapy perhaps preventing the infant's precarious neonatal course. Heterozygosity for the c.206G > A mutation is an important point for discussion. Few reports of this mutation exist in the literature, and the effects of heterozygosity are unclear. Once biparental heterozygosity for this mutation was established, parents both underwent evaluation for hyperparathyroidism. They were both found to have mild hypercalcemia (2.62 mmol/L in both parents) and normal PTH levels (2.8 pmol/L in both parents); a tendency to borderline low normal urinary calcium in the father (0.11 mg/mg) and normal urinary calcium in the mother (0.14 mg/ mg) were noted. The data reported by Rodrigues et al. suggests heterozygotes may experience hypocalciuric hypercalcemia (Calcium Sensing Receptor, 2015; Rodrigues et al., 2009). The case presented by Wilhelm-Bals et al., does not mention parental studies (Wilhem-Bals et al., 2012). Together, these sparse data lead us to predict heterozygosity may lead to mild elevations in calcium with normal PTH levels and perhaps in some cases hypocalciuric hypercalcemia. To our knowledge, this is the highest total serum calcium level documented in the setting of NSHPT. Our patient survived and is thriving, achieving normal growth and neurodevelopmental
milestones on calcitriol and calcium supplementation. Financial disclosure The authors have no financial relationships relevant to this case report to disclose. Funding source The authors report no external funding source for this manuscript. Conflicts of interest The authors declare they have no potential conflicts of interest to disclose. Contributors' statement Dr. Murphy provided care to this patient throughout her initial hospitalization, drafted the. initial manuscript, and approved the final manuscript as submitted. Dr. Patrick provided care to this patient throughout her initial hospitalization, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. B aez-Irizarry provided care to this patient throughout her initial hospitalization, organized data sets for figures, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. Lacassie provided care to this patient's family, reviewed and revised the manuscript, and approved the final manuscript as submitted. mez provided care to this patient throughout her course, Dr. Go reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. Vargas provided care to this patient throughout her course, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. Barkemeyer provided care to this patient throughout her initial hospitalization, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. Kanotra provided care to this patient throughout her initial hospitalization, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. Zambrano provided care to this patient, collected genetic data for this patient, conceptualized the case report, reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Acknowledgments We thank the family for their cooperation. We also thank Ms. Dima El-Khechen and Dr. Sha Tang at Ambry Genetics for their quick review of the Exome data in this family which allowed molecular confirmation. Dr. Todd Brickman and Dr. Anita Jeyakumar for their contribution to the surgical management of this patient. References Atay, Z., Bereket, A., Haliloglu, B., Abali, S., Ozdogan, T., Altuncu, E., Canaff, L., Vilaça, T., Wong, B.Y.L., Cole, D.E.C., Hendy, G.N., Turan, S., 2014. Novel homozygous inactivating mutation of the calcium-sensing receptor gene (CASR) in
Please cite this article in press as: Murphy, H., et al., Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR: A rare cause of life-threatening hypercalcemia, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.02.001
H. Murphy et al. / European Journal of Medical Genetics xxx (2016) 1e5 neonatal severe hyperparathyroidism-lack of effect of cinacalcet. Bone 64, 102e107. Brickman, T.M., Stark, M.W., Jayakumar, A., 2015. Unusual case of neonatal hypoercalcemia. Int. J. Pediatr. Otorhinolaryngol. 79 (5), 758e759. Calcium Sensing Receptor Database. http://www.casrdb.mcgill.ca/. Accessed May 26, 2015. Casci, I., Accousti, W., Lacassie, Y., 2014. Unexpected exome sequencing result: de novo TRPS1 mutation in an infant with infantile scoliosis, mild developmental delay, and history of consanguinity. Am. J. Med. Genet. Part A 2013 (164A), 1334e1337. Fox, L., Sadowsky, J., Pringle, K.P., Kidd, A., Murdoch, J., Cole, D.E.C., Wiltshire, E., Pamidronate, 2007. Neonatal Hyperparathyroidism Therapy in an extremely premature infant. Pediatrics 120 (5) e1350ee1254. Gannon, A.W., Monk, H.M., Levine, M.A., 2014. Cinacalcet monotherapy in neonatal severe hyperparathyroidism: a case study and review. J. Clin. Endocrinol. Metab. 99 (1), 7e11. Garcia-Garcia, E., Dominguez-Pascual, I., Requena-Diaz, M., Cabello-Laureano, R., ndez-Pineda, I., S Ferna anchez-Martin, M.J., 2014. Intraoperative parathyroid hormone monitoring in neonatal severe primary hyperparathyroidism. Pediatrics 134, e1203ee1205. Hannan, F.M., Thakker, R.V., 2013. Calcium-sensing receptor (CaSR) mutations and disorders of calcium, electrolyte, and water metabolism. Best. Pract. Res. Clin. Endocrinol. Metab. 27, 359e371. Lu, J.Y.L., Yang, Y., Gnacadja, G., Christopoulos, A., Reagan, J.D., 2009. Effect of the calcimimetic R-568 [3-(2 chlorophenyl)-N-((1R)-1-(3-methoxyphenyl) ethyl)1- propanamine] on correcting inactivating mutations in the human calciumsensing receptor. J. Pharmacol. Exp. Ther. 331 (3), 775e786.
5
Reh, C.M.S., Hendy, G.N., Cole, D.E.C., Jeandron, D.D., 2011. Neonatal hyperparathyroidism with a heterozygous calcium-sensing receptor (CASR) R185Q mutation: clinical benefit from cinacalcet. J. Clin. Endocrinol. Metab. 96 (4), E707eE712. Rodrigues, L.S., Bussmann, L.Z., Correa, P.H.S., Martin, R.M., 2009. New mutation in the CaSR involving three generations in a family with hypocalciuric hypercalcemia. Endocr. Soc. Congr. P2eP204. €hr, V., Mayr, B., Mo €hlig, M., Schulze, E., FrankRus, R., Haag, C., Bumke-Vogt, C., Ba €ft, C., 2008. Novel inactivating mutations of the calciumRaue, K., Raue, F., Scho sensing receptor: the calcimimetic NPS R-568 improves signal transduction of mutant receptors. J. Clin. Endocrinol. Metab. 93 (12), 4797e4803. Soblechero, E.G., Castillo, M.T.F., Crespo, B.J., Quintero, M.L.D., Fuentes, C.G., 2013. Neonatal hypercalcemia due to a homozygous mutation in the calcium-sensing receptor: failure of cinacalcet. Neonatology 104, 104e108. United States Food and Drug Administration. Sensipar (cinacalcet hydrochloride): Drug Safety Communication. FDA suspends pediatric clinical trials after report of death. http://www.fda.gov/safety/MedWatch/SafetyInformation/ SafetyAlertsforHumanMedicalProducts/ucm341255.htm. Published February 26, 2013. Accessed May 21, 2015. Wilhem-Bals, A., Parvex, P., Magdelaine, C., Girardin, E., 2012. Successful use of bisphosphonate and calcimimetic in neonatal severe primary hyperparathyroidism. Pediatrics 129 (3), e812e816. Zambrano, R.M., Lacassie, Y., 2014. Should the American college of medical genetics expand the required reportable disorders or findings on exome sequencing? reporting a recent experience; (2588S). In: Presented at the 64th Annual Meeting of the American Society of Human Genetics, October, 19 2014 in San Diego, California. http://abstracts.ashg.org/cgibin/2014/ashg14s.pl?author ¼zambrano&sort¼ptimes&sbutton¼Detail&absno¼140120043&sid¼212532.
Please cite this article in press as: Murphy, H., et al., Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR: A rare cause of life-threatening hypercalcemia, European Journal of Medical Genetics (2016), http://dx.doi.org/10.1016/j.ejmg.2016.02.001
