Download Endocrine Disorders in the Neonatal Period

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Endocrine Disorders in
the Neonatal Period
Karishma A. Datye, MD; and Andrew A. Bremer, MD, PhD
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Abstract
Many endocrine conditions are unique to the perinatal period. In this article, we
review many such conditions, including disorders of the pituitary gland, disorders
of sexual differentiation, disorders of glucose homeostasis, disorders of the thyroid
gland, and disorders of calcium homeostasis. Rather than serving as a comprehensive
resource, the article is meant to serve as a guide for general pediatricians and neonatologists caring for infants with endocrine disorders. Moreover, because the field of
pediatric endocrinology continues to evolve, consultation with a pediatric endocrinologist for any child with an endocrinopathy is recommended.
EDUCATIONAL OBJECTIVES
1. Review common endocrine conditions that often present in the
newborn and perinatal period.
2. Determine the enzymes involved
in steroidogenesis.
3. Discuss the diagnostic evaluation
of hypoglycemia.
Karishma A. Datye, MD, is a PGY-3 Resident in Pediatrics, Vanderbilt University
School of Medicine. Andrew. A. Bremer, MD,
PhD, is Assistant Professor of Pediatrics, Division of Pediatric Endocrinology, Department of Pediatrics, Vanderbilt University
© Shutterstock
School of Medicine.
Address correspondence to: Andrew A.
Bremer, MD, PhD, Department of Pediatrics, 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
PEDIATRIC ANNALS 42:5 | MAY 2013
Healio.com/Pediatrics | 67
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T
he transition from the intrauterine to extrauterine environment
is a “rite of passage” for every
individual. However, the perinatal period is also a time when an infant may
display clinical signs of an underlying
endocrinopathy that may not have been
apparent either in utero or at birth. Herein, we present some common endocrinopathies that may present in the neonatal period. Importantly, the descriptions
are not intended to replace the more
comprehensive information that can be
found in general pediatric or endocrine
texts; rather, they are meant to serve as
a quick guide for general pediatricians
and neonatologists caring for infants
with endocrine disorders. As with most
endocrine conditions in the perinatal
period, consultation with a pediatric endocrinologist is recommended regarding
the most up-to-date treatment.
DISORDERS OF THE PITUITARY
GLAND
The pituitary gland is critical to human development, and secretes many
hormones vital to normal growth and
survival. Importantly, the pituitary gland
is divided into two distinct parts; the
adenohypophysis (composed of the anterior lobe of the pituitary, intermediate
lobe, and pars tuberalis) is derived from
the oral ectoderm,1 whereas the neurohypophysis (or posterior pituitary gland)
is derived from the neural ectoderm
of the forebrain.2 The blood supply to
these embryologically distinct parts of
the pituitary also differ, with that of the
adenohypophysis coming from the hypothalamic-pituitary portal circulation
and that of the neurohypophysis coming
from the inferior hypophyseal artery.1
The adenohypophysis, after receiving myriad signaling factors from the
hypothalamus through the hypothalamic-pituitary portal system, produces
several hormones necessary for growth
and development. Five different cell
types in the anterior pituitary secrete six
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separate hormones: follicle-stimulating
hormone (FSH), leutinizing hormone
(LH), thyroid-stimulating hormone
(TSH), growth hormone (GH), prolactin (PRL), and adrenocorticotropic
hormone (ACTH).2 Alternatively, the
posterior pituitary releases hormones
important in the regulation of blood
volume (arginine vasopressin [AVP])
and reproduction (oxytocin).2
The nonspecific signs and
symptoms of hypopituitarism
in the neonatal period can
make its diagnosis difficult.
Hypopituitarism in the neonatal period can be secondary to genetic or anatomic abnormalities, and can present as
isolated or multiple hormone deficiencies. One genetic cause of combined
pituitary hormone deficiencies is mutations in the PROP1 gene, which regulates the development of several anterior pituitary cell lineages.2 Anatomic
abnormalities that may cause pituitary
dysfunction include midline defects like
septo-optic dysplasia and optic nerve
hypoplasia.2
The nonspecific signs and symptoms
of hypopituitarism in the neonatal period
can make its diagnosis difficult. Infants
may present with poor growth, poor
feeding, temperature instability, or hypoglycemia.2 In males, the combination
of micropenis and hypoglycemia should
always alert the clinician of potential
pituitary dysfunction. Early diagnosis is
important as prolonged hypoglycemia,
hypothyroidism, in addition to other
manifestations of hypopituitarism, have
the potential to cause developmental delays. Central adrenal insufficiency could
also potentially be life-threatening. Hypopituitarism is diagnosed through a
combination of individual hormone testing (eg, evaluating the thyroid axis, ad-
renal axis, growth hormone axis, etc), in
addition to magnetic resonance imaging
(MRI) of the pituitary gland and hypothalamus.2 Treatment varies depending
on the specific hormones affected.
The posterior pituitary gland releases
AVP as a mechanism to regulate the volume status of the body. AVP then acts on
the kidney to control the amount of water that is excreted from the body.3 Central diabetes insipidus (DI) occurs when
defects in vasopressin at the level of the
pituitary lead to inappropriate water loss
and large quantities of dilute urine.4
The etiology of central DI varies by
age group; in the neonatal period, the
majority of central DI is caused by anatomic or genetic defects. Examples of
anatomic abnormalities include septooptic dysplasia, agenesis of the corpus
callosum, and holoprosencephaly.4 Both
autosomal dominant and recessive genetic defects have also been identified
that cause central DI.5 Other causes of
central DI include acquired DI after surgery, for example after craniopharyngioma resection, or direct invasion of the
posterior pituitary by tumor.4
Infants with DI may present with
polyuria, polydipsia, and poor growth,
in addition to other non-specific symptoms. Biochemical abnormalities include serum hyperosmolality (typically
with concomitant hypernatremia) in the
setting of dilute urine. In older patients,
the diagnosis may be made through
water deprivation testing; however, in
neonates, making the diagnosis can be
challenging because water deprivation
cannot be easily performed. If central
DI is suspected, an MRI of the pituitary
should be performed to evaluate for midline structural defects6 and the posterior
pituitary “bright spot” (signifying the
anatomic presence of AVP). Central DI
is typically managed by administering
desmopressin, a vasopressin analog.6
In neonates, administration of this analog coupled with polydipsia may lead to
hyponatremia; therefore, in some cases,
PEDIATRIC ANNALS 42:5 | MAY 2013
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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 calories for growth and to avoid severe dehydration. Thiazide diuretics in combination with amiloride or indomethacin are
also often used.
DISORDERS OF SEXUAL
DIFFERENTIATION
Normal sexual development consists
of three related and sequential processes: 1) the establishment of the chromosomal (genetic) sex (XX as female, XY
as male); 2) the determination of the gonadal sex; and 3) the development of the
sexual phenotypes. For the first 2 months
after fertilization, the 2 sexes develop in
an identical fashion. Then, around the
8th week of gestation, the indifferent
gonad develops into an ovary or testis,
with subsequent hormone production in
the case of testicular development. The
hormonal profile then directs the development of the indifferent anlagen of the
urogenital tract into characteristic male
or female structures, a process which is
largely completed by the 12th week of
gestation. Although an extensive review
of all the disorders of sexual development (DSDs) is beyond the scope of this
article, DSDs are often broken down
into 3 categories: overvirilized 46,XX
females, undervirilized 46,XY males,
and ovotesticular DSDs.
Overvirilized 46,XX Infants
Overvirilization of 46,XX fetuses
can occur by three main mechanisms:
1) increased androgen production, 2) decreased androgen metabolism (ie, clearance), and 3) maternal androgen expo-
PEDIATRIC ANNALS 42:5 | MAY 2013
Figure 1. Integrated view of steroidogenesis. ACTH = adrenocorticotropic hormone; b5 = cytochrome
b5; CMO = corticosterone methyloxidase; DHEA = dehydroepiandrosterone; DHT = dihydrotestosterone; DOC = deoxycorticosterone; HSD = hydroxysteroid dehydrogenase; POR = P450 oxidoreductase;
StAR = steroidogenic acute regulatory protein. (Adapted from Oberfield et al29)
sure (either endogenous or exogenous).
The most common cause of overvirilized 46,XX fetuses is congenital adrenal
hyperplasia (CAH), which is typically
due to defects in the gene encoding the
21-hydroxylase enzyme (P450c21). In
this condition, defects in 21-hydroxylase (and less commonly 11beta-hydroxylase [encoded by P450c11b]) lead
to decreased cortisol synthesis (see Figure 1),7 which causes oversecretion of
ACTH from the pituitary and ultimately
increased androgen production and virilization of the external genitalia. A deficiency in 21-hydroxylase can also cause
potentially life-threatening salt wasting
and adrenal insufficiency, while 11betahydroxylase deficiency can cause fluid
retention and hypertension secondary to
deoxycorticosterone (DOC) production.
Importantly, the internal genitalia
(Mullerian structures) of these patients
develop appropriately.5 Diagnosis of
these disorders is based on build up of
17-hydroxyprogesterone in 21-hydroxylase deficiency7 and DOC and 11-deoxycortisol in 11beta-hydroxylase deficien-
cy.5 Treatment includes prompt initiation
of glucocorticoid therapy (with possible
mineralocorticoid therapy as well) and
referral to a pediatric endocrinologist.
Another cause of virilization of the
46,XX fetus is decreased androgen metabolism, an example being placentalfetal aromatase deficiency. Normally,
the testosterone that is derived from
both the fetal and maternal production
of dehydroepiandrosterone (DHEA) is
converted to estradiol by the aromatase
enzyme, “protecting” the female fetus from excessive androgen exposure.
However, a deficiency in aromatase increases circulating testosterone levels
and can cause virilization in both the
mother and fetus.8
A further cause of virilization of
the 46,XX fetus is increased maternal
androgen exposure. Both endogenous
(androgen-secreting adrenal or ovarian
tumors)9 or exogenous androgens can
cause virilization.10 However, since exposure to these androgens ceases after
delivery, virilization of the infant will
not continue to progress after birth.
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Undervirilized 46,XY Infants
Undervirilization of 46,XY fetuses,
formerly called male pseudohermaphroditism, is caused by myriad factors
resulting in errors of testosterone production, testosterone metabolism, and/
or end-organ action of testosterone. As
early as 10 weeks gestation, testosterone is released from the Leydig cells
in the testes to help form (along with
dihydrotestosterone [DHT]) the male
reproductive tissues and external genitalia. Early during gestation, human
chorionic gonadotropin (hCG) from the
placenta is responsible for testosterone
secretion; later, LH from the developing
fetal pituitary takes over. Both LH and
hCG bind to the same receptor, and thus
defects in this receptor can ultimately
cause problems with testosterone secretion and abnormalities in external genitalia formation.11
As would be expected, defects in any
enzyme associated with testosterone biosynthesis (see Figure 1) will result in undervirilization of 46,XY fetuses. Moreover, defects in gonadal and adrenal
steroidogenesis (which occurs in congenital lipoid adrenal hyperplasia and is
characterized by the impaired ability to
convert cholesterol to pregnenolone12)
also result in undervirilization of the
46,XY infant. A deficiency in 17alphahydroxylase/17,20-lyase also yields poor
production of cortisol and testosterone
(causing cortisol deficiency and undervirilization), as well as overstimulation
of the mineralocorticoid pathway due
to excess ACTH release from the pituitary (causing hypertension). Diagnosis
of these conditions involves identifying
elevated precursors in the steroiodogenesis pathway, and therapy involves treating salt wasting and cortisol deficiency
(if present).
Other causes of undervirilization of
46,XY fetuses include a deficiency in
5alpha-reductase, the enzyme that converts testosterone to the more potent
androgen, DHT,13 as well as defects in
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the androgen receptor (AR) gene, which
causes androgen insensitivity syndrome
(AIS). Infants who are 46,XY with the
complete form of AIS have female external genitalia and typically do not have
Wolffian or Mullerian structures. Par-
There is considerable debate
regarding what glucose
concentrations define
hypoglycemia in the neonate.
tial AIS in 46,XY infants causes variable degrees of undervirilization, and
patients may have ambiguous external
genitalia with Wolffian structures internally.14 Diagnosis is made by sequencing the AR gene, and by examining LH
and testosterone levels. In complete AIS,
sex assignment is female, whereas sex
assignment in incomplete AIS is more
challenging.5
Ovotesticular DSD
Ovotesticular DSD, previously called
true hermaphroditism, refers to individuals with ovarian and testicular tissues.
The majority of these patients are 46,XX,
although 46,XY and 45,X/46,XY patients are also seen.5 Gonads in these
patients may be ovotestis, containing
both ovarian and testicular tissue, or patients may have an ovary on one side and
testis on the other. Infants may have a
mixture of Mullerian and Wolffian structures internally, and ambiguous genitalia
externally, although some patients have
entirely female external genitalia. Diagnosis is guided by biopsy identifying
ovarian and testicular tissues.15 Treatment of these individuals is complicated
and involves removing dysgenetic testicular tissue, and ultimately proceeding
with gender assignment.5
DISORDERS OF GLUCOSE
HOMEOSTASIS
Hypoglycemia of the newborn is a
common problem, and its symptoms in
neonates range from irritability to hypothermia to seizures. One of the clinical
challenges is determining the circumstances under which a neonate may be
hypoglycemic, when to check a blood
glucose level, and what level is concerning. There is considerable debate
regarding what glucose concentrations
define hypoglycemia in the neonate; for
practical purposes, we use ≤45 mg/dL.16
When infants present with recurrent hypoglycemia, blood work obtained while
the infant is hypoglycemic is crucial to
making the diagnosis (see Figure 2).
There are many different causes of hypoglycemia, ranging from transient selfresolving processes to severe lifelong
conditions.
Transient hypoglycemia may be
seen in children born to diabetic mothers or mothers using beta-blockers, and
in children born small for gestational
age (SGA). More persistent hypoglycemia may be caused by hypopituitarism
and disorders of glycogenolysis, gluceoneogensis, lipolysis, and fatty acid
oxidation.1 The most common cause of
persistent neonatal hypoglycemia is congenital hyperinsulinism (estimated incidence of 1:50,000 live births), which can
cause severe neurologic sequelae if not
managed appropriately. The diagnosis
is based on blood work obtained while
the child is hypoglycemic, and includes
the findings of low fatty acid levels, low
PEDIATRIC ANNALS 42:5 | MAY 2013
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plasma ketone levels, and an increase in
blood glucose levels in response to glucagon.17 Immediate treatment involves
stabilizing glucose levels, frequently
with high dextrose-containing intravenous 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 appear to be different, but the clinical presentation of these two disorders is similar. Neonates present with intrauterine
growth restriction, likely secondary to
decreased levels of the growth factor insulin. They also have polyuria, failure to
thrive, and can present with diabetic ketoacidosis.1 Treatment varies depending
on the cause, but is typically with subcutaneous insulin. However, some forms
of neonatal diabetes are amenable to oral
sulfonylurea therapy.20
DISORDERS OF THE
THYROID GLAND
Thyroid dysfunction in the neonate
can be broken down into hypothyroidism and hyperthyroidism. These categories can be further divided into transient
versus permanent dysfunction.
Transient hypothyroidism is defined
by low thyroxine (T4) and elevated TSH
concentrations that ultimately return
to normal.21 Transient hypothyroidism
can occur secondary to iodine deficiency, excess maternal anti-thyroid drugs
reaching the fetus in utero, and transplacental passage of maternal thyrotropin
receptor-blocking antibodies.22 In North
America, transient hypothyroidism is
rare, about 1 in 50,000, but is increased
in countries with iodine deficiency. It
PEDIATRIC ANNALS 42:5 | MAY 2013
Figure 2. Hypoglycemia evaluation in an infant. 3-OHB = 3-hydroxybutyrate; AA = acetoacetate; FFA =
free fatty acid. *The physical examination or diagnostic imaging studies should demonstrate hepatomegaly. (Adapted from Fuhrman30)
also appears to be increased in preterm
infants as compared to term infants.21,23
Congenital hypothyroidism can be divided into two categories, primary (due
to defects of the thyroid gland itself) or
secondary (due to defects in the central
nervous system), with primary being
much more common. Thyroid dysgenesis (1:4,000) accounts for about 85% of
primary congenital hypothyroidism, and
is most commonly due to an ectopic thyroid gland, followed by thyroid aplasia
and hypoplastic thyroid.24 The majority
of cases of thyroid dysgenesis are sporadic.24 The remaining causes of primary congenital hypothyroidism are mostly
secondary to thyroid dyshormonogenesis (1:40,000).1 Even rarer causes of
primary hypothyroidism include errors
in metabolism and transport of thyroid
hormone, and defects in the thyroid hormone receptor. The most common cause
of secondary hypothyroidism is hypopituitarism (1:100,000).1
Newborn screening has greatly aided
in the prompt diagnosis of congenital
hypothyroidism. If an infant is found
to have an abnormal newborn screen,
they should be immediately referred to
a pediatric endocrinologist, as the goal
is to treat as soon as possible due to the
known importance of thyroid hormone
on brain development.21 Importantly,
the newborn screen in most states is designed to identify primary hypothyroidism; as such, cases of hypothyroidism
due to hypopituitarism may not be identified. The American Academy of Pediatrics has created screening and treatment
guidelines to facilitate the identification
and treatment of these infants. Alternatively, hyperthyroidism in
the neonatal period is rare, with the
most common etiology being maternal
Graves’ disease.25 Neonatal hyperthyroidism secondary to maternal Graves’
disease is due to the transplacental passage of maternal TSH receptor-stimulating antibodies (TSA) to the fetus.
The most common symptom seen in the
neonate is tachycardia, which can aid in
diagnosis of this condition. The at-risk
fetus can be monitored with maternal
blood testing (TSA levels), fetal ultraHealio.com/Pediatrics | 71
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sound assessing for presence of goiter,
and fetal heart rate monitoring if necessary.1,25 Treatment involves medical
management of the symptoms and antithyroid drugs if needed. The disease
course is self-limited (3 weeks to 12
weeks) and improves as the maternal antibodies are cleared.1
DISORDERS OF CALCIUM
HOMEOSTASIS
Calcium, phosphorous, and magnesium are carefully regulated in the human body. During pregnancy, the mother provides calcium and phosphorous
to the fetus, which promotes skeletal
development and tissue growth. After
birth, the neonate is responsible for independent calcium homeostasis through
a combination of calcium intake, the
mobilization of calcium stores within
the body, parathyroid hormone (PTH),
vitamin D, and calcitonin. In the first
few days of life, there is a drop in calcium concentrations followed by an acute
compensatory increase in PTH, which
then increases calcium levels.1,26 Calcium and phosphorus concentrations then
gradually decline through 18 months of
age. There are several systems in place
to regulate calcium homeostasis, and errors in these mechanisms can cause both
hypo- and hypercalcemia.
Hypocalcemia in the neonate is often defined as a total calcium level <
7.5 mg/dL or an ionized calcium level
< 1.20 mmol/L. Hypocalcemia may be
asymptomatic, but may also present
with multiple symptoms including, but
not limited to, seizures, apnea, cyanosis, and arrhythmias. In the neonatal period, hypocalcemia is typically divided
into early-onset (within the first 4 days
of life) and late-onset (5-10 days after
birth).27 Early-onset hypocalcemia may
be attributed to prematurity and is also
common in SGA infants. It is also seen
in infants whose mothers have hyperparathyroidism or diabetes mellitus, as
well as in infants with low birth weight,
72 | Healio.com/Pediatrics
respiratory distress, and/or sepsis. From
a mechanistic standpoint, early-onset
hypocalcemia may be due to suppression of PTH, continued release of calcitonin, or hypomagnesemia.1 Alternatively, late-onset hypocalcemia can be
caused by hypoparathyroidism (eg, DiGeorge syndrome and gain-of-function
Hypocalcemia may present
with multiple symptoms
including, but not limited
to, seizures, apnea, cyanosis,
and arrhythmias.
mutations in the calcium sensing receptor gene), pseudohypoparathyroidism,
vitamin D deficiency, and the ingestion
of high phosphorous formula.27
Evaluation includes a careful history
and physical examination, initial laboratory studies determining total and ionized calcium, PTH level, vitamin D level, electrolytes, complete blood count,
and urinary calcium, while treatment
is aimed at symptom management and
normalization of the serum calcium.1
Hypercalcemia in the neonate is
defined as a total calcium level > 10.8
mg/dL; however significant symptoms
are often not seen until a total calcium
level of >12 mg/dL or an ionized calcium level >1.50 mmol/L is reached.28
Symptoms of hypercalcemia vary, and
include anorexia, gastrointestinal reflux, nephrocalcinosis, lethargy, and
seizures.1,28 There are numerous causes
of hypercalcemia in the neonate, ranging from increased calcium absorption,
to idiopathic hypercalcemia, to potentially life-threatening neonatal severe
hyperparathyroidism.28 Infants born to
mothers with hypocalcemia due to hypoparathyroidism or pseudohypoparathyroidism are also at risk. In general,
hypercalcemia with normal PTH and
low urine calcium levels is likely secondary to familial hypercalciuric hypercalcemia. Etiologies of elevated calcium
and low PTH concentrations include
increased calcium absorption, hypervitaminosis D, William’s syndrome, and
subcutaneous fat necrosis. Alternatively,
high PTH levels with hypercalemia indicates neonatal hyperparathyroidism.28
Evaluation of the etiology of hypercalcemia can be detailed, but should start
with electrolytes (including calcium,
magnesium, and phosphorus), calcitriol,
vitamin D, and PTH levels. Treatment is
aimed at normalizing calcium levels and
managing symptoms.1
CONCLUSION
The number of endocrine disorders
that exist is vast, but many are uniquely
relevant just to the newborn or to infants
in the perinatal period. As such, the purpose of this review is to highlight some
of the more common endocrinopathies
that general pediatricians or neonatologists may encounter. Moreover, since
the field of pediatric endocrinology continues to evolve and our understanding
of the pathogenesis of certain endocrine
disorders and their treatment continues
to improve, consultation with a pediatric
endocrinologist for any child with an endocrinopathy is always recommended.
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