CASE REPORT
Intraoperative Parathyroid Hormone Monitoring in Neonatal Severe Primary Hyperparathyroidism AUTHORS: Emilio García-García, MD, Inmaculada Domínguez-Pascual, MD, Mercedes Requena-Díaz, MD, Rosa Cabello-Laureano, MD, Israel Fernández-Pineda, MD, and María J. Sánchez-Martín, MD Virgen del Rocío Hospital, Sevilla, Spain KEY WORDS neonatal severe primary hyperparathyroidism, parathyroid hormone, hypercalcemia ABBREVIATIONS CaSR—calcium sensing receptor NSPH—neonatal severe primary hyperparathyroidism PTH—parathyroid hormone
abstract Neonatal severe primary hyperparathyroidism presents in the first days of life with severe life-threatening hypercalcemia. It is associated with an inactivating homozygous mutation of the calcium sensing receptor gene. Total parathyroidectomy is the treatment of choice, so the surgeon must identify all the parathyroid tissue, including supernumerary and ectopic glands. We present the case of an infant who underwent total parathyroidectomy at age 4 months in which intraoperative parathyroid hormone monitoring provided immediate confirmation of surgical cure. Pediatrics 2014;134:e1203–e1205
Dr García-García carried out patient management and drafted the initial manuscript; Drs Domínguez-Pascual, Requena-Díaz, Cabello-Laureano, Fernández-Pineda, and Sánchez-Martín carried out patient management and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted. www.pediatrics.org/cgi/doi/10.1542/peds.2013-3668 doi:10.1542/peds.2013-3668 Accepted for publication Feb 27, 2014 Address correspondence to Emilio García-García, MD, Department of Pediatrics, Virgen del Rocío Hospital, Avenida Manuel Siurot, Sevilla, E-41013, Spain. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2014 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
PEDIATRICS Volume 134, Number 4, October 2014
Downloaded from pediatrics.aappublications.org at Medical School Library on April 10, 2015
e1203
Neonatal severe primary hyperparathyroidism (NSPH) is a life-threatening condition that presents within days of life with marked hypercalcemia, relative hypocalciuria, and serum parathyroid hormone (PTH) concentrations as much as 10-fold higher than normal. It is associated with an inactivating homozygous mutation of the calcium sensing receptor (CaSR) gene.1–3 Total parathyroidectomy is the treatment of choice. Residual or ectopic parathyroid tissue explains persistence of hyperparathyroidism after surgery; any parathyroid remnant quickly becomes hyperplastic.4–6 In other types primary hyperparathyroidism, intraoperative PTH monitoring provides real-time confirmation of surgical cure and indicates to the surgeon when all hyperfunctional parathyroid tissue has been adequately excised.7 To our knowledge, this is the first report of intraoperative PTH assessment in NSPH.
PATIENT PRESENTATION A male infant was referred to our institution for parathyroidectomy at 3.5 months of age. He was admitted to another hospital at 18 days of age with severe global hypotonia, poor feeding, failure to thrive, signs of dehydration, and lethargy. The initial analysis revealed severe hypercalcemia with a total serum calcium level of 5.6 mmol/L (normal values 2.0–2.6 nmol/L) and PTH of 526 pg/mL (normal values 15–70 pg/mL). The parents were cousins. The genetic test revealed a homozygous
mutation in exon 5 in the patient’s CaSR gene, which was heterozygous in both progenitors, so diagnosis of NSPH was confirmed in the infant. Parathyroid gland localization tests including 99mTcsestamibi scintigraphy, as well as ultrasonography, were negative. A total parathyroidectomy was conducted at 4 months of age. Intact PTH was measured by a rapid assay (Elecsys, Roche Diagnostics, Mannheim,Germany; detection limits 1.20–5000 pg/mL) that requires ∼20 minutes to obtain a result. Before the operation, the PTH value was 190.0 pg/mL, and 10 minutes after excision of 4 parathyroid glands, the PTH value fell to 19.8 pg/mL. Thirty-six hours later, he started to require calcium supplements for hypocalcemia. Histology revealed parathyroid chief cell hyperplasia.
generally requires no specific treatment.1–3 Total parathyroidectomy is the standard treatment of NSPH1–14 and leads to significantly greater survival than subtotal parathyroidectomy or medical treatment.2 Individual variations of the location and number of glands may pose difficulties because unidentified extra parathyroid tissue will complicate the patient’s course.15 Seven percent of the normal population has supernumerary glands that can be found along the mediastinum, thyroid or thymus, requiring thymectomy or hemithyroidectomy.1,15,16 Preoperative localization tests, including scintigraphy, ultrasonography, and magnetic resonance imaging, are useless, so the parathyroid tissue must be identified during the surgery.8
CaSR regulates calcium homeostasis through its ability to modulate PTH secretion and renal calcium reabsorption. NSPH is most commonly an autosomal recessive condition produced by an inactivating homozygous mutation in CaSR gene. By contrast, more common heterozygous mutations are associated with a benign variant termed familial hypocalciuric hypercalcemia, which
Intraoperative PTH monitoring takes advantage of the short plasma half-life (3–5 minutes) of PTH and a rapid assay technique that allows measurements while the patient is still in the operating room. A relative drop in PTH level into the normal range is suggestive of adequate removal of hyperfunctioning parathyroid tissue. For localization of an occult gland, bilateral jugular venous sampling for PTH can be performed at the time of exploration. A unilateral elevation is suspicious for a missing hyperfunctioning gland on that side.7 We conclude that intraoperative PTH monitoring is useful providing real-time confirmation of surgical cure in NSPH.
3. Roizen J, Levine MA. Primary hyperparathyroidism in children and adolescents. J Chin Med Assoc. 2012;75(9):425–434 4. Fox L, Sadowsky J, Pringle KP, et al. Neonatal hyperparathyroidism and pamidronate therapy in an extremely premature infant. Pediatrics. 2007;120(5). Available at: www.pediatrics.org/cgi/content/full/120/5/e1350
5. Wilhelm-Bals A, Parvex P, Magdelaine C, Girardin E. Successful use of bisphosphonate and calcimimetic in neonatal severe primary hyperparathyroidism. Pediatrics. 2012;129(3). Available at: www.pediatrics.org/cgi/content/ full/129/3/e812 6. Ch’ng JL, Kaiser A, Lynn J, Joplin GF. Postparathyroidectomy restoration of normal
At 30 months of age, the patient was following a normal diet with calcidiol supplements, psychomotor development and growth are appropriate, and serum analysis reveals PTH of 3.1 pg/mL and total calcium of 2.0 mmol/L.
DISCUSSION
REFERENCES 1. Al-Khalaf FA, Ismail A, Soliman AT, Cole DE, Ben-Omran T. Neonatal severe hyperparathyroidism: further clinical and molecular delineation. Eur J Pediatr. 2011;170(5):625– 631 2. Ross AJ III, Cooper A, Attie MF, Bishop HC. Primary hyperparathyroidism in infancy. J Pediatr Surg. 1986;21(6):493–499
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Downloaded from pediatrics.aappublications.org at Medical School Library on April 10, 2015
CASE REPORT
calcium homeostasis in neonatal primary hyperparathyroidism. Acta Endocrinol (Copenh). 1984;105(3):350–353 7. Yamashita H, Gao P, Cantor T, et al. Comparison of parathyroid hormone levels from the intact and whole parathyroid hormone assays after parathyroidectomy for primary and secondary hyperparathyroidism. Surgery. 2004;135(2):149–156 8. Al-Shanafey S, Al-Hosaini R, Al-Ashwal A, AlRabeeah A. Surgical management of severe neonatal hyperparathyroidism: one center’s experience. J Pediatr Surg. 2010;45(4):714–717 9. Fujimoto Y, Hazama H, Oku K. Severe primary hyperparathyroidism in a neonate having a parent with hypercalcemia: treatment by total parathyroidectomy and simultaneous
heterotopic autotransplantation. Surgery. 1990;108(5):933–938 10. Cooper L, Wertheimer J, Levey R, et al. Severe primary hyperparathyroidism in a neonate with two hypercalcemic parents: management with parathyroidectomy and heterotopic autotransplantation. Pediatrics. 1986;78(2):263–268 11. Lutz P, Kane O, Pfersdorff A, Seiller F, Sauvage P, Levy JM. Neonatal primary hyperparathyroidism: total parathyroidectomy with autotransplantation of cryopreserved parathyroid tissue. Acta Paediatr Scand. 1986;75(1):179–182 12. Obermannova B, Banghova K, Sumník Z, et al. Unusually severe phenotype of neonatal primary hyperparathyroidism due to a heterozygous inactivating mutation in the CASR gene. Eur J Pediatr. 2009;168(5):569–573
13. Doria AS, Huang C, Makitie O, et al. Neonatal, severe primary hyperparathyroidism: a 7-year clinical and radiological follow-up of one patient. Pediatr Radiol. 2002;32(9):684–689 14. Cakmak O, Agis¸ ER, Teziç T, Ates¸ G. Primary hyperparathyroidism in infancy: a case report. J Pediatr Surg. 1996;31(3):437–438 15. Topaloglu AK, Yuksel B, Tuncer R, Mungan NO, Ozer G. Primary hyperparathyroidism in an infant with three parathyroid glands and pulmonary calcinosis. J Pediatr Endocrinol Metab. 2001;14(8):1173–1175 16. Janik JE, Bloch CA, Janik JS. Intrathyroid parathyroid gland and neonatal primary hyperparathyroidism. J Pediatr Surg. 2000; 35(10):1517–1519
PEDIATRICS Volume 134, Number 4, October 2014
Downloaded from pediatrics.aappublications.org at Medical School Library on April 10, 2015
e1205
Intraoperative Parathyroid Hormone Monitoring in Neonatal Severe Primary Hyperparathyroidism Emilio García-García, Inmaculada Domínguez-Pascual, Mercedes Requena-Díaz, Rosa Cabello-Laureano, Israel Fernández-Pineda and María J. Sánchez-Martín Pediatrics 2014;134;e1203; originally published online September 1, 2014; DOI: 10.1542/peds.2013-3668 Updated Information & Services
including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/134/4/e1203.full. html
References
This article cites 16 articles, 4 of which can be accessed free at: http://pediatrics.aappublications.org/content/134/4/e1203.full. html#ref-list-1
Permissions & Licensing
Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xh tml
Reprints
Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org at Medical School Library on April 10, 2015
Intraoperative Parathyroid Hormone Monitoring in Neonatal Severe Primary Hyperparathyroidism Emilio García-García, Inmaculada Domínguez-Pascual, Mercedes Requena-Díaz, Rosa Cabello-Laureano, Israel Fernández-Pineda and María J. Sánchez-Martín Pediatrics 2014;134;e1203; originally published online September 1, 2014; DOI: 10.1542/peds.2013-3668
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/134/4/e1203.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org at Medical School Library on April 10, 2015
Intraoperative Parathyroid Hormone Monitoring in Neonatal Severe Primary Hyperparathyroidism AUTHORS: Emilio García-García, MD, Inmaculada Domínguez-Pascual, MD, Mercedes Requena-Díaz, MD, Rosa Cabello-Laureano, MD, Israel Fernández-Pineda, MD, and María J. Sánchez-Martín, MD Virgen del Rocío Hospital, Sevilla, Spain KEY WORDS neonatal severe primary hyperparathyroidism, parathyroid hormone, hypercalcemia ABBREVIATIONS CaSR—calcium sensing receptor NSPH—neonatal severe primary hyperparathyroidism PTH—parathyroid hormone
abstract Neonatal severe primary hyperparathyroidism presents in the first days of life with severe life-threatening hypercalcemia. It is associated with an inactivating homozygous mutation of the calcium sensing receptor gene. Total parathyroidectomy is the treatment of choice, so the surgeon must identify all the parathyroid tissue, including supernumerary and ectopic glands. We present the case of an infant who underwent total parathyroidectomy at age 4 months in which intraoperative parathyroid hormone monitoring provided immediate confirmation of surgical cure. Pediatrics 2014;134:e1203–e1205
Dr García-García carried out patient management and drafted the initial manuscript; Drs Domínguez-Pascual, Requena-Díaz, Cabello-Laureano, Fernández-Pineda, and Sánchez-Martín carried out patient management and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted. www.pediatrics.org/cgi/doi/10.1542/peds.2013-3668 doi:10.1542/peds.2013-3668 Accepted for publication Feb 27, 2014 Address correspondence to Emilio García-García, MD, Department of Pediatrics, Virgen del Rocío Hospital, Avenida Manuel Siurot, Sevilla, E-41013, Spain. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2014 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
PEDIATRICS Volume 134, Number 4, October 2014
Downloaded from pediatrics.aappublications.org at Medical School Library on April 10, 2015
e1203
Neonatal severe primary hyperparathyroidism (NSPH) is a life-threatening condition that presents within days of life with marked hypercalcemia, relative hypocalciuria, and serum parathyroid hormone (PTH) concentrations as much as 10-fold higher than normal. It is associated with an inactivating homozygous mutation of the calcium sensing receptor (CaSR) gene.1–3 Total parathyroidectomy is the treatment of choice. Residual or ectopic parathyroid tissue explains persistence of hyperparathyroidism after surgery; any parathyroid remnant quickly becomes hyperplastic.4–6 In other types primary hyperparathyroidism, intraoperative PTH monitoring provides real-time confirmation of surgical cure and indicates to the surgeon when all hyperfunctional parathyroid tissue has been adequately excised.7 To our knowledge, this is the first report of intraoperative PTH assessment in NSPH.
PATIENT PRESENTATION A male infant was referred to our institution for parathyroidectomy at 3.5 months of age. He was admitted to another hospital at 18 days of age with severe global hypotonia, poor feeding, failure to thrive, signs of dehydration, and lethargy. The initial analysis revealed severe hypercalcemia with a total serum calcium level of 5.6 mmol/L (normal values 2.0–2.6 nmol/L) and PTH of 526 pg/mL (normal values 15–70 pg/mL). The parents were cousins. The genetic test revealed a homozygous
mutation in exon 5 in the patient’s CaSR gene, which was heterozygous in both progenitors, so diagnosis of NSPH was confirmed in the infant. Parathyroid gland localization tests including 99mTcsestamibi scintigraphy, as well as ultrasonography, were negative. A total parathyroidectomy was conducted at 4 months of age. Intact PTH was measured by a rapid assay (Elecsys, Roche Diagnostics, Mannheim,Germany; detection limits 1.20–5000 pg/mL) that requires ∼20 minutes to obtain a result. Before the operation, the PTH value was 190.0 pg/mL, and 10 minutes after excision of 4 parathyroid glands, the PTH value fell to 19.8 pg/mL. Thirty-six hours later, he started to require calcium supplements for hypocalcemia. Histology revealed parathyroid chief cell hyperplasia.
generally requires no specific treatment.1–3 Total parathyroidectomy is the standard treatment of NSPH1–14 and leads to significantly greater survival than subtotal parathyroidectomy or medical treatment.2 Individual variations of the location and number of glands may pose difficulties because unidentified extra parathyroid tissue will complicate the patient’s course.15 Seven percent of the normal population has supernumerary glands that can be found along the mediastinum, thyroid or thymus, requiring thymectomy or hemithyroidectomy.1,15,16 Preoperative localization tests, including scintigraphy, ultrasonography, and magnetic resonance imaging, are useless, so the parathyroid tissue must be identified during the surgery.8
CaSR regulates calcium homeostasis through its ability to modulate PTH secretion and renal calcium reabsorption. NSPH is most commonly an autosomal recessive condition produced by an inactivating homozygous mutation in CaSR gene. By contrast, more common heterozygous mutations are associated with a benign variant termed familial hypocalciuric hypercalcemia, which
Intraoperative PTH monitoring takes advantage of the short plasma half-life (3–5 minutes) of PTH and a rapid assay technique that allows measurements while the patient is still in the operating room. A relative drop in PTH level into the normal range is suggestive of adequate removal of hyperfunctioning parathyroid tissue. For localization of an occult gland, bilateral jugular venous sampling for PTH can be performed at the time of exploration. A unilateral elevation is suspicious for a missing hyperfunctioning gland on that side.7 We conclude that intraoperative PTH monitoring is useful providing real-time confirmation of surgical cure in NSPH.
3. Roizen J, Levine MA. Primary hyperparathyroidism in children and adolescents. J Chin Med Assoc. 2012;75(9):425–434 4. Fox L, Sadowsky J, Pringle KP, et al. Neonatal hyperparathyroidism and pamidronate therapy in an extremely premature infant. Pediatrics. 2007;120(5). Available at: www.pediatrics.org/cgi/content/full/120/5/e1350
5. Wilhelm-Bals A, Parvex P, Magdelaine C, Girardin E. Successful use of bisphosphonate and calcimimetic in neonatal severe primary hyperparathyroidism. Pediatrics. 2012;129(3). Available at: www.pediatrics.org/cgi/content/ full/129/3/e812 6. Ch’ng JL, Kaiser A, Lynn J, Joplin GF. Postparathyroidectomy restoration of normal
At 30 months of age, the patient was following a normal diet with calcidiol supplements, psychomotor development and growth are appropriate, and serum analysis reveals PTH of 3.1 pg/mL and total calcium of 2.0 mmol/L.
DISCUSSION
REFERENCES 1. Al-Khalaf FA, Ismail A, Soliman AT, Cole DE, Ben-Omran T. Neonatal severe hyperparathyroidism: further clinical and molecular delineation. Eur J Pediatr. 2011;170(5):625– 631 2. Ross AJ III, Cooper A, Attie MF, Bishop HC. Primary hyperparathyroidism in infancy. J Pediatr Surg. 1986;21(6):493–499
e1204
GARCÍA-GARCÍA et al
Downloaded from pediatrics.aappublications.org at Medical School Library on April 10, 2015
CASE REPORT
calcium homeostasis in neonatal primary hyperparathyroidism. Acta Endocrinol (Copenh). 1984;105(3):350–353 7. Yamashita H, Gao P, Cantor T, et al. Comparison of parathyroid hormone levels from the intact and whole parathyroid hormone assays after parathyroidectomy for primary and secondary hyperparathyroidism. Surgery. 2004;135(2):149–156 8. Al-Shanafey S, Al-Hosaini R, Al-Ashwal A, AlRabeeah A. Surgical management of severe neonatal hyperparathyroidism: one center’s experience. J Pediatr Surg. 2010;45(4):714–717 9. Fujimoto Y, Hazama H, Oku K. Severe primary hyperparathyroidism in a neonate having a parent with hypercalcemia: treatment by total parathyroidectomy and simultaneous
heterotopic autotransplantation. Surgery. 1990;108(5):933–938 10. Cooper L, Wertheimer J, Levey R, et al. Severe primary hyperparathyroidism in a neonate with two hypercalcemic parents: management with parathyroidectomy and heterotopic autotransplantation. Pediatrics. 1986;78(2):263–268 11. Lutz P, Kane O, Pfersdorff A, Seiller F, Sauvage P, Levy JM. Neonatal primary hyperparathyroidism: total parathyroidectomy with autotransplantation of cryopreserved parathyroid tissue. Acta Paediatr Scand. 1986;75(1):179–182 12. Obermannova B, Banghova K, Sumník Z, et al. Unusually severe phenotype of neonatal primary hyperparathyroidism due to a heterozygous inactivating mutation in the CASR gene. Eur J Pediatr. 2009;168(5):569–573
13. Doria AS, Huang C, Makitie O, et al. Neonatal, severe primary hyperparathyroidism: a 7-year clinical and radiological follow-up of one patient. Pediatr Radiol. 2002;32(9):684–689 14. Cakmak O, Agis¸ ER, Teziç T, Ates¸ G. Primary hyperparathyroidism in infancy: a case report. J Pediatr Surg. 1996;31(3):437–438 15. Topaloglu AK, Yuksel B, Tuncer R, Mungan NO, Ozer G. Primary hyperparathyroidism in an infant with three parathyroid glands and pulmonary calcinosis. J Pediatr Endocrinol Metab. 2001;14(8):1173–1175 16. Janik JE, Bloch CA, Janik JS. Intrathyroid parathyroid gland and neonatal primary hyperparathyroidism. J Pediatr Surg. 2000; 35(10):1517–1519
PEDIATRICS Volume 134, Number 4, October 2014
Downloaded from pediatrics.aappublications.org at Medical School Library on April 10, 2015
e1205
Intraoperative Parathyroid Hormone Monitoring in Neonatal Severe Primary Hyperparathyroidism Emilio García-García, Inmaculada Domínguez-Pascual, Mercedes Requena-Díaz, Rosa Cabello-Laureano, Israel Fernández-Pineda and María J. Sánchez-Martín Pediatrics 2014;134;e1203; originally published online September 1, 2014; DOI: 10.1542/peds.2013-3668 Updated Information & Services
including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/134/4/e1203.full. html
References
This article cites 16 articles, 4 of which can be accessed free at: http://pediatrics.aappublications.org/content/134/4/e1203.full. html#ref-list-1
Permissions & Licensing
Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xh tml
Reprints
Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org at Medical School Library on April 10, 2015
Intraoperative Parathyroid Hormone Monitoring in Neonatal Severe Primary Hyperparathyroidism Emilio García-García, Inmaculada Domínguez-Pascual, Mercedes Requena-Díaz, Rosa Cabello-Laureano, Israel Fernández-Pineda and María J. Sánchez-Martín Pediatrics 2014;134;e1203; originally published online September 1, 2014; DOI: 10.1542/peds.2013-3668
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/134/4/e1203.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org at Medical School Library on April 10, 2015
