Endocrine Disorders in the Neonatal Period Karishma A

CM E

Endocrine Disorders in the Neonatal Period Karishma A. Datye, MD; and Andrew A. Bremer, MD, PhD

Abstract CM E EDUCATIONAL OBJECTIVES Many endocrine conditions are unique to the perinatal period. In this article, we 1. Review common endocrine conditions that often present in the review many such conditions, including disorders of the pituitary gland, disorders newborn and perinatal period. of sexual differentiation, disorders of glucose homeostasis, disorders of the thyroid 2. Determine the enzymes involved gland, and disorders of calcium homeostasis. Rather than serving as a comprehensive in steroidogenesis. resource, the article is meant to serve as a guide for general pediatricians and neona- 3. Discuss the diagnostic evaluation tologists caring for infants with endocrine disorders. Moreover, because the field of of hypoglycemia. pediatric endocrinology continues to evolve, consultation with a pediatric endocrinologist for any child with an endocrinopathy is recommended. Karishma A. Datye, MD, is a PGY-3 Resi- dent in Pediatrics, Vanderbilt University School of Medicine. Andrew. A. Bremer, MD, PhD, is Assistant Professor of Pediatrics, Di- vision of Pediatric Endocrinology, Depart- ment of Pediatrics, Vanderbilt University School of Medicine. Address correspondence to: Andrew A. Bremer, MD, PhD, Department of Pediat- rics, Division of Endocrinology, Vanderbilt University, 2200 Children’s Way, 11134-A DOT-9170, Nashville, TN 37232-9170; email: [email protected]. Disclosure: The authors have no relevant financial relationships to disclose. doi: 10.3928/00904481-20130426-08 © Shutterstock

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he transition from the intrauter- separate hormones: follicle-stimulating renal axis, growth hormone axis, etc), in ine to extrauterine environment hormone (FSH), leutinizing hormone addition to magnetic resonance imaging T is a “rite of passage” for every (LH), thyroid-stimulating hormone (MRI) of the pituitary gland and hypo- individual. However, the perinatal pe- (TSH), growth hormone (GH), pro- thalamus.2 Treatment varies depending riod is also a time when an infant may lactin (PRL), and adrenocorticotropic on the specific hormones affected. display clinical signs of an underlying hormone (ACTH).2 Alternatively, the The posterior pituitary gland releases endocrinopathy that may not have been posterior pituitary releases hormones AVP as a mechanism to regulate the vol- apparent either in utero or at birth. Here- important in the regulation of blood ume status of the body. AVP then acts on in, we present some common endocri- volume (arginine vasopressin [AVP]) the kidney to control the amount of wa- nopathies that may present in the neona- and reproduction (oxytocin).2 ter that is excreted from the body.3 Cen- tal period. Importantly, the descriptions tral diabetes insipidus (DI) occurs when are not intended to replace the more defects in vasopressin at the level of the comprehensive information that can be The nonspecific signs and pituitary lead to inappropriate water loss found in general pediatric or endocrine symptoms of hypopituitarism and large quantities of dilute urine.4 texts; rather, they are meant to serve as The etiology of central DI varies by a quick guide for general pediatricians in the neonatal period can age group; in the neonatal period, the and neonatologists caring for infants make its diagnosis difficult. majority of central DI is caused by ana- with endocrine disorders. As with most tomic or genetic defects. Examples of endocrine conditions in the perinatal anatomic abnormalities include septo- period, consultation with a pediatric en- Hypopituitarism in the neonatal pe- optic dysplasia, agenesis of the corpus docrinologist is recommended regarding riod can be secondary to genetic or ana- callosum, and holoprosencephaly.4 Both the most up-to-date treatment. tomic abnormalities, and can present as autosomal dominant and recessive ge- isolated or multiple hormone deficien- netic defects have also been identified DISORDERS OF THE PITUITARY cies. One genetic cause of combined that cause central DI.5 Other causes of GLAND pituitary hormone deficiencies is muta- central DI include acquired DI after sur- The pituitary gland is critical to hu- tions in the PROP1 gene, which regu- gery, for example after craniopharyngi- man development, and secretes many lates the development of several ante- oma resection, or direct invasion of the hormones vital to normal growth and rior pituitary cell lineages.2 Anatomic posterior pituitary by tumor.4 survival. Importantly, the pituitary gland abnormalities that may cause pituitary Infants with DI may present with is divided into two distinct parts; the dysfunction include midline defects like polyuria, polydipsia, and poor growth, adenohypophysis (composed of the an- septo-optic dysplasia and optic nerve in addition to other non-specific symp- terior lobe of the pituitary, intermediate hypoplasia.2 toms. Biochemical abnormalities in- lobe, and pars tuberalis) is derived from The nonspecific signs and symptoms clude serum hyperosmolality (typically the oral ectoderm,1 whereas the neuro- of hypopituitarism in the neonatal period with concomitant hypernatremia) in the hypophysis (or posterior pituitary gland) can make its diagnosis difficult. Infants setting of dilute urine. In older patients, is derived from the neural ectoderm may present with poor growth, poor the diagnosis may be made through of the forebrain.2 The blood supply to feeding, temperature instability, or hy- water deprivation testing; however, in these embryologically distinct parts of poglycemia.2 In males, the combination neonates, making the diagnosis can be the pituitary also differ, with that of the of micropenis and hypoglycemia should challenging because water deprivation adenohypophysis coming from the hy- always alert the clinician of potential cannot be easily performed. If central pothalamic-pituitary portal circulation pituitary dysfunction. Early diagnosis is DI is suspected, an MRI of the pituitary and that of the neurohypophysis coming important as prolonged hypoglycemia, should be performed to evaluate for mid- from the inferior hypophyseal artery.1 hypothyroidism, in addition to other line structural defects6 and the posterior The adenohypophysis, after receiv- manifestations of hypopituitarism, have pituitary “bright spot” (signifying the ing myriad signaling factors from the the potential to cause developmental de- anatomic presence of AVP). Central DI hypothalamus through the hypotha- lays. Central adrenal insufficiency could is typically managed by administering lamic-pituitary portal system, produces also potentially be life-threatening. Hy- desmopressin, a vasopressin analog.6 several hormones necessary for growth popituitarism is diagnosed through a In neonates, administration of this ana- and development. Five different cell combination of individual hormone test- log coupled with polydipsia may lead to types in the anterior pituitary secrete six ing (eg, evaluating the thyroid axis, ad- hyponatremia; therefore, in some cases,

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fluid intake (to match urinary losses) is the sole treatment.6 Unlike central DI, nephrogenic DI occurs when the kidney is resistant to the actions of vasopressin. Nephrogenic DI can result from genetic or acquired causes, and since the kidney is typically nonresponsive to vasopressin, desmopressin in most cases is not a therapeutic option. Thus, the main goals of therapy are to ensure the intake of adequate calo- ries for growth and to avoid severe dehy- dration. Thiazide diuretics in combination with amiloride or indomethacin are also often used.

DISORDERS OF SEXUAL DIFFERENTIATION Normal sexual development consists Figure 1. Integrated view of steroidogenesis. ACTH = adrenocorticotropic hormone; b5 = cytochrome of three related and sequential process- b5; CMO = corticosterone methyloxidase; DHEA = dehydroepiandrosterone; DHT = dihydrotestoster- es: 1) the establishment of the chromo- one; DOC = deoxycorticosterone; HSD = hydroxysteroid dehydrogenase; POR = P450 oxidoreductase; somal (genetic) sex (XX as female, XY StAR = steroidogenic acute regulatory protein. (Adapted from Oberfield et al29) as male); 2) the determination of the gonadal sex; and 3) the development of the sure (either endogenous or exogenous). cy.5 Treatment includes prompt initiation sexual phenotypes. For the first 2 months The most common cause of overviril- of glucocorticoid therapy (with possible after fertilization, the 2 sexes develop in ized 46,XX fetuses is congenital adrenal mineralocorticoid therapy as well) and an identical fashion. Then, around the hyperplasia (CAH), which is typically referral to a pediatric endocrinologist. 8th week of gestation, the indifferent due to defects in the gene encoding the Another cause of virilization of the gonad develops into an ovary or testis, 21-hydroxylase enzyme (P450c21). In 46,XX fetus is decreased androgen me- with subsequent hormone production in this condition, defects in 21-hydroxy- tabolism, an example being placental- the case of testicular development. The lase (and less commonly 11beta-hy- fetal aromatase deficiency. Normally, hormonal profile then directs the devel- droxylase [encoded by P450c11b]) lead the testosterone that is derived from opment of the indifferent anlagen of the to decreased cortisol synthesis (see Fig- both the fetal and maternal production urogenital tract into characteristic male ure 1),7 which causes oversecretion of of dehydroepiandrosterone (DHEA) is or female structures, a process which is ACTH from the pituitary and ultimately converted to estradiol by the aromatase largely completed by the 12th week of increased androgen production and vir- enzyme, “protecting” the female fe- gestation. Although an extensive review ilization of the external genitalia. A defi- tus from excessive androgen exposure. of all the disorders of sexual develop- ciency in 21-hydroxylase can also cause However, a deficiency in aromatase in- ment (DSDs) is beyond the scope of this potentially life-threatening salt wasting creases circulating testosterone levels article, DSDs are often broken down and adrenal insufficiency, while 11beta- and can cause virilization in both the into 3 categories: overvirilized 46,XX hydroxylase deficiency can cause fluid mother and fetus.8 females, undervirilized 46,XY males, retention and hypertension secondary to A further cause of virilization of and ovotesticular DSDs. deoxycorticosterone (DOC) production. the 46,XX fetus is increased maternal Importantly, the internal genitalia androgen exposure. Both endogenous Overvirilized 46,XX Infants (Mullerian structures) of these patients (androgen-secreting adrenal or ovarian Overvirilization of 46,XX fetuses develop appropriately.5 Diagnosis of tumors)9 or exogenous androgens can can occur by three main mechanisms: these disorders is based on build up of cause virilization.10 However, since ex- 1) increased androgen production, 2) de- 17-hydroxyprogesterone in 21-hydroxy- posure to these androgens ceases after creased androgen metabolism (ie, clear- lase deficiency7 and DOC and 11-deoxy- delivery, virilization of the infant will ance), and 3) maternal androgen expo- cortisol in 11beta-hydroxylase deficien- not continue to progress after birth.

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Undervirilized 46,XY Infants the androgen receptor (AR) gene, which mixture of Mullerian and Wolffian struc- Undervirilization of 46,XY fetuses, causes androgen insensitivity syndrome tures internally, and ambiguous genitalia formerly called male pseudohermaph- (AIS). Infants who are 46,XY with the externally, although some patients have roditism, is caused by myriad factors complete form of AIS have female ex- entirely female external genitalia. Di- resulting in errors of testosterone pro- ternal genitalia and typically do not have agnosis is guided by biopsy identifying duction, testosterone metabolism, and/ Wolffian or Mullerian structures. Par- ovarian and testicular tissues.15 Treat- or end-organ action of testosterone. As ment of these individuals is complicated early as 10 weeks gestation, testoster- and involves removing dysgenetic tes- one is released from the Leydig cells ticular tissue, and ultimately proceeding in the testes to help form (along with with gender assignment.5 dihydrotestosterone [DHT]) the male reproductive tissues and external geni- DISORDERS OF GLUCOSE talia. Early during gestation, human HOMEOSTASIS chorionic gonadotropin (hCG) from the Hypoglycemia of the newborn is a placenta is responsible for testosterone common problem, and its symptoms in secretion; later, LH from the developing neonates range from irritability to hypo- fetal pituitary takes over. Both LH and thermia to seizures. One of the clinical hCG bind to the same receptor, and thus challenges is determining the circum- defects in this receptor can ultimately stances under which a neonate may be cause problems with testosterone secre- hypoglycemic, when to check a blood tion and abnormalities in external geni- There is considerable debate glucose level, and what level is con- talia formation.11 cerning. There is considerable debate As would be expected, defects in any regarding what glucose regarding what glucose concentrations enzyme associated with testosterone bio- define hypoglycemia in the neonate; for synthesis (see Figure 1) will result in un- concentrations define practical purposes, we use ≤45 mg/dL.16 dervirilization of 46,XY fetuses. More- hypoglycemia in the neonate. When infants present with recurrent hy- over, defects in gonadal and adrenal poglycemia, blood work obtained while steroidogenesis (which occurs in con- the infant is hypoglycemic is crucial to genital lipoid adrenal hyperplasia and is tial AIS in 46,XY infants causes vari- making the diagnosis (see Figure 2). characterized by the impaired ability to able degrees of undervirilization, and There are many different causes of hy- convert cholesterol to pregnenolone12) patients may have ambiguous external poglycemia, ranging from transient self- also result in undervirilization of the genitalia with Wolffian structures inter- resolving processes to severe lifelong 46,XY infant. A deficiency in 17alpha- nally.14 Diagnosis is made by sequenc- conditions. hydroxylase/17,20-lyase also yields poor ing the AR gene, and by examining LH Transient hypoglycemia may be production of cortisol and testosterone and testosterone levels. In complete AIS, seen in children born to diabetic moth- (causing cortisol deficiency and under- sex assignment is female, whereas sex ers or mothers using beta-blockers, and virilization), as well as overstimulation assignment in incomplete AIS is more in children born small for gestational of the mineralocorticoid pathway due challenging.5 age (SGA). More persistent hypoglyce- to excess ACTH release from the pitu- mia may be caused by hypopituitarism itary (causing hypertension). Diagnosis Ovotesticular DSD and disorders of glycogenolysis, glu- of these conditions involves identifying Ovotesticular DSD, previously called ceoneogensis, lipolysis, and fatty acid elevated precursors in the steroiodogen- true hermaphroditism, refers to individ- oxidation.1 The most common cause of esis pathway, and therapy involves treat- uals with ovarian and testicular tissues. persistent neonatal hypoglycemia is con- ing salt wasting and cortisol deficiency The majority of these patients are 46,XX, genital hyperinsulinism (estimated inci- (if present). although 46,XY and 45,X/46,XY pa- dence of 1:50,000 live births), which can Other causes of undervirilization of tients are also seen.5 Gonads in these cause severe neurologic sequelae if not 46,XY fetuses include a deficiency in patients may be ovotestis, containing managed appropriately. The diagnosis 5alpha-reductase, the enzyme that con- both ovarian and testicular tissue, or pa- is based on blood work obtained while verts testosterone to the more potent tients may have an ovary on one side and the child is hypoglycemic, and includes androgen, DHT,13 as well as defects in testis on the other. Infants may have a the findings of low fatty acid levels, low

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plasma ketone levels, and an increase in blood glucose levels in response to glu- cagon.17 Immediate treatment involves stabilizing glucose levels, frequently with high dextrose-containing intrave- nous fluids, while long-term management may include various medications like diazoxide, octreotide, or ultimately a partial or total pancreatic resection.18 Alternatively, hyperglycemia in the newborn period can be caused by neonatal diabetes (estimated incidence of 1 in 100,000 newborns).19 There are transient forms of neonatal diabetes, which typically resolve within 3 to 6 months of life, and permanent lifelong forms. The cellular defects noted in transient versus permanent neonatal diabetes ap- pear to be different, but the clinical presentation of these two disorders is simi- Figure 2. Hypoglycemia evaluation in an infant. 3-OHB = 3-hydroxybutyrate; AA = acetoacetate; FFA = lar. Neonates present with intrauterine free fatty acid. *The physical examination or diagnostic imaging studies should demonstrate hepato- growth restriction, likely secondary to megaly. (Adapted from Fuhrman30) decreased levels of the growth factor insulin. They also have polyuria, failure to also appears to be increased in preterm to have an abnormal newborn screen, thrive, and can present with diabetic ke- infants as compared to term infants.21,23 they should be immediately referred to toacidosis.1 Treatment varies depending Congenital hypothyroidism can be di- a pediatric endocrinologist, as the goal on the cause, but is typically with sub- vided into two categories, primary (due is to treat as soon as possible due to the cutaneous insulin. However, some forms to defects of the thyroid gland itself) or known importance of thyroid hormone of neonatal diabetes are amenable to oral secondary (due to defects in the central on brain development.21 Importantly, sulfonylurea therapy.20 nervous system), with primary being the newborn screen in most states is de- much more common. Thyroid dysgen- signed to identify primary hypothyroid- DISORDERS OF THE esis (1:4,000) accounts for about 85% of ism; as such, cases of hypothyroidism THYROID GLAND primary congenital hypothyroidism, and due to hypopituitarism may not be iden- Thyroid dysfunction in the neonate is most commonly due to an ectopic thy- tified. The American Academy of Pediat- can be broken down into hypothyroid- roid gland, followed by thyroid aplasia rics has created screening and treatment ism and hyperthyroidism. These catego- and hypoplastic thyroid.24 The majority guidelines to facilitate the identification ries can be further divided into transient of cases of thyroid dysgenesis are spo- and treatment of these infants. versus permanent dysfunction. radic.24 The remaining causes of prima- Alternatively, hyperthyroidism in Transient hypothyroidism is defined ry congenital hypothyroidism are mostly the neonatal period is rare, with the by low thyroxine (T4) and elevated TSH secondary to thyroid dyshormonogen- most common etiology being maternal concentrations that ultimately return esis (1:40,000).1 Even rarer causes of Graves’ disease.25 Neonatal hyperthy- to normal.21 Transient hypothyroidism primary hypothyroidism include errors roidism secondary to maternal Graves’ can occur secondary to iodine deficien- in metabolism and transport of thyroid disease is due to the transplacental pas- cy, excess maternal anti-thyroid drugs hormone, and defects in the thyroid hor- sage of maternal TSH receptor-stim- reaching the fetus in utero, and transpla- mone receptor. The most common cause ulating antibodies (TSA) to the fetus. cental passage of maternal thyrotropin of secondary hypothyroidism is hypopi- The most common symptom seen in the receptor-blocking antibodies.22 In North tuitarism (1:100,000).1 neonate is tachycardia, which can aid in America, transient hypothyroidism is Newborn screening has greatly aided diagnosis of this condition. The at-risk rare, about 1 in 50,000, but is increased in the prompt diagnosis of congenital fetus can be monitored with maternal in countries with iodine deficiency. It hypothyroidism. If an infant is found blood testing (TSA levels), fetal ultra-

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sound assessing for presence of goiter, respiratory distress, and/or sepsis. From low urine calcium levels is likely sec- and fetal heart rate monitoring if nec- a mechanistic standpoint, early-onset ondary to familial hypercalciuric hyper- essary.1,25 Treatment involves medical hypocalcemia may be due to suppres- calcemia. Etiologies of elevated calcium management of the symptoms and an- sion of PTH, continued release of cal- and low PTH concentrations include tithyroid drugs if needed. The disease citonin, or hypomagnesemia.1 Alterna- increased calcium absorption, hypervi- course is self-limited (3 weeks to 12 tively, late-onset hypocalcemia can be taminosis D, William’s syndrome, and weeks) and improves as the maternal an- caused by hypoparathyroidism (eg, Di- subcutaneous fat necrosis. Alternatively, tibodies are cleared.1 George syndrome and gain-of-function high PTH levels with hypercalemia in- dicates neonatal hyperparathyroidism.28 DISORDERS OF CALCIUM Evaluation of the etiology of hypercal- HOMEOSTASIS Hypocalcemia may present cemia can be detailed, but should start Calcium, phosphorous, and magne- with electrolytes (including calcium, sium are carefully regulated in the hu- with multiple symptoms magnesium, and phosphorus), calcitriol, man body. During pregnancy, the moth- including, but not limited vitamin D, and PTH levels. Treatment is er provides calcium and phosphorous aimed at normalizing calcium levels and to the fetus, which promotes skeletal to, seizures, apnea, cyanosis, managing symptoms.1 development and tissue growth. After and arrhythmias. birth, the neonate is responsible for in- CONCLUSION dependent calcium homeostasis through The number of endocrine disorders a combination of calcium intake, the mutations in the calcium sensing recep- that exist is vast, but many are uniquely mobilization of calcium stores within tor gene), pseudohypoparathyroidism, relevant just to the newborn or to infants the body, parathyroid hormone (PTH), vitamin D deficiency, and the ingestion in the perinatal period. As such, the pur- vitamin D, and calcitonin. In the first of high phosphorous formula.27 pose of this review is to highlight some few days of life, there is a drop in calci- Evaluation includes a careful history of the more common endocrinopathies um concentrations followed by an acute and physical examination, initial labora- that general pediatricians or neonatolo- compensatory increase in PTH, which tory studies determining total and ion- gists may encounter. Moreover, since then increases calcium levels.1,26 Calci- ized calcium, PTH level, vitamin D lev- the field of pediatric endocrinology con- um and phosphorus concentrations then el, electrolytes, complete blood count, tinues to evolve and our understanding gradually decline through 18 months of and urinary calcium, while treatment of the pathogenesis of certain endocrine age. There are several systems in place is aimed at symptom management and disorders and their treatment continues to regulate calcium homeostasis, and er- normalization of the serum calcium.1 to improve, consultation with a pediatric rors in these mechanisms can cause both Hypercalcemia in the neonate is endocrinologist for any child with an en- hypo- and hypercalcemia. defined as a total calcium level > 10.8 docrinopathy is always recommended. Hypocalcemia in the neonate is of- mg/dL; however significant symptoms ten defined as a total calcium level < are often not seen until a total calcium REFERENCES 7.5 mg/dL or an ionized calcium level level of >12 mg/dL or an ionized cal- 1. Sperling M. Pediatric Endocrinology, 3rd ed. 28 Philadelphia, PA: WB Saunders; 2008. < 1.20 mmol/L. Hypocalcemia may be cium level >1.50 mmol/L is reached. 2. Mehta A, Dattani M. Developmental disor- asymptomatic, but may also present Symptoms of hypercalcemia vary, and ders of the hypothalamus and pituitary gland with multiple symptoms including, but include anorexia, gastrointestinal re- associated with congenital hypopituitarism. not limited to, seizures, apnea, cyano- flux, nephrocalcinosis, lethargy, and Best Pract Res Clin Endocrinol Metab. 2008;22(1):191-206. 1,28 sis, and arrhythmias. In the neonatal pe- seizures. There are numerous causes 3. Knepper MA. Molecular physiology of uri- riod, hypocalcemia is typically divided of hypercalcemia in the neonate, rang- nary concentrating mechanism: regulation of into early-onset (within the first 4 days ing from increased calcium absorption, aquaporin water channels by vasopressin. Am J Physiol. 1997;272(1 Pt 2):F3-F12. of life) and late-onset (5-10 days after to idiopathic hypercalcemia, to poten- 4. Wang LC, Cohen ME, Duffner PK. Etiologies birth).27 Early-onset hypocalcemia may tially life-threatening neonatal severe of central diabetes insipidus in children. Pedi- be attributed to prematurity and is also hyperparathyroidism.28 Infants born to atr Neurol. 1194;11(4):273-277. 5. Pescovitz O, Eugster E, eds. Pediatric Endo- common in SGA infants. It is also seen mothers with hypocalcemia due to hy- crinology: Mechanisms, Manifestations, and in infants whose mothers have hyper- poparathyroidism or pseudohypopara- Management. Philadelphia, PA: Lippincott parathyroidism or diabetes mellitus, as thyroidism are also at risk. In general, Williams & Wilkins; 2004. well as in infants with low birth weight, hypercalcemia with normal PTH and 6. Ranadive S, Rosenthal S. Pediatric endo-

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crinology pediatric disorders of water bal- Awady MK, Wilson EM, French FS. Androgen thyroidism. Pediatrics. 2006;117(60):2290- ance. Endocrinol Metab Clin North Am. receptor defects: historical, clinical, and molecular 2303. 2011;58(5):1271-1280. perspectives. Endocr Rev. 1995;16(3):271-321. 22. Parks JS, Lin M, Grosse SD, et al. The impact 7. Speiser P, White P. Congenital adrenal hyper- 15. Kousta E, Papathanasiou A, Skordis N. Sex of transient hypothyroidism on the increas- plasia. N Engl J Med. 2003;349(8):776-788. determination and disorders of sex developing rate of congenital hypothyroidism in the 8. Shozu M, Akasofu K, Harada T, Kubota Y. A ment according to the revised nomenclature United States. Pediatrics. 2010;125(Suppl new cause of female pseudohermaphroditism: and classification in 46,XX individuals.Hor - 2):S54-S63. placental aromatase deficiency.J Clin Endo- mones (Athens). 2010;9(3):218-231. 23. Delange F, Dalhem A, Bourdoux P, et al. In- crinol Metab. 1191;72(3):560-566. 16. Cornblath M, Hawdon JM, Williams AF, et al. creased risk of primary hypothyroidism in per- 9. Kirk JM, Perry LA, Shand WS, Kirby RS, Controversies regarding definition of neonatal term infants. J Pediatr. 1984;105(30:462-469. Besser GM, Savage MO. Female pseudo- hypoglycemia: suggested operational thresh- 24. LaFranchi SH. Approach to the diagnosis and hermaphroditism due to a maternal adre- olds. Pediatrics. 2000;105(5):1141-1145. treatment of neonatal hypothyroidism. J Clin nocortical tumor. J Clin Endocrinol Metab. 17. Huopio H, Shyng SL, Otonkoski T, Nich- Endocrinol Metab. 2011;96(10):2959-2967. 1990;70(5):1280-1284. ols CG. K(ATP) channels and insulin dis- 25. Zimmerman D. Fetal and neonatal hyperthy- 10. Grumbach MM, Ducharme JR, Moloshok orders. Am J Physiol Endocrinol Metab. roidism. Thyroid. 1999;9(7):727-733. RE. On the fetal masculinizing action of cer- 2002;283(2):E207-E216. 26. Kovacs CS, Kronenberg HM. Maternal-fetal tain oral progestins. J Clin Endocrinol Metab. 18. Thornton PS, Alter CA, Katz LE, Baker L, calcium and bone metabolism during preg- 1959;19(11):1369-1380. Stanely CA. Short- and long-term use of oct- nancy, puerperium, and lactation. Endocr Rev. 11. Piersma D, Verhoef-Post M, Berns E, Them- rotide in the treatment of congenital hyperin- 1997;18(6):832-872. men A. LH receptor gene mutations and poly- sulinism. J Pediatr. 1993;123(4):637-643. 27. Thomas TC, Smith JM, White PC, Ad- morphisms: an overview. Mol Cell Endocri- 19. Sperling MA. ATP-sensitive potassium chan- hikari S. Transient neonatal hypocalcemia: nol. 2007;260-262:282-286. nels — neonatal diabetes mellitus and be- presentation and outcomes. Pediatrics. 12. Bose HS, Sugawara T, Strauss JF 3rd, Miller yond. N Engl J Med. 2006;355(5):507-510. 2012;129(6):e1461-e1467. WL. The pathophysiology and genetics of 20. Pearson ER, Flechtner I, Njolstad PR, et al. 28. Soriano JR. Neonatal hypercalcemia. J congenial lipoid adrenal hyperplasia. N Engl Switching from insulin to oral sulfonylureas Nephrol. 2003;16(4):606-608. J Med. 1996;335(25):1870-1878. in patients with diabetes due to Kir6.2 muta- 29. Oberfield SE, Sopher AB, Gerken AT. Approach 13. Wilson JD, Griffin JE, Russell DW. Steroid tions. N Engl J Med. 2006;355(5):467-477. to the girl with early onset pubic hair. J Clin En- 5 alpha-reductase 2 deficiency. Endocr Rev. 21. AAP, Rose SR, Section on Endocrinology and docrinol Metab. 2011;96(6):1610-1622. 1993;14(5):577-593. Committee on Genetics. Update of newborn 30. Fuhrman BP. Pediatric Critical Care. 4th Ed. 14. Quigley CA, De Bellis A, Marschke KB, el- screening and therapy for congenital hypo- Philadelphia, PA: WB Saunders; 2011.

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