Endocrinology and Metabolism

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Chapter 8

Endocrinology and Metabolism

Hypocalcemia

In newborn infants there is a physiologic decline in serum total and ionized calcium during the first 48 hours of life. This decline is exaggerated in preterm infants compared with term infants, with a direct correlation between serum calcium and gestational age ( Fig. 8-1). Because no symptoms are specific for early hypocalcemia in preterm infants, the diagnosis is made by demonstrating a serum calcium level below 7 mg/dL (1.75 mmol/L).

Calcium therapy may block the normal physiologic adaptation to hypocalcemia, which includes increasing serum levels of parathyroid hormone (PTH) and 1,25(OH)2 vitamin D in the first few days of life.

Further arguments against the need for the treatment of incidentally noted hypocalcemia in the preterm infant are the following:

In the absence of additional data, it is conventional to treat all serum calcium levels below 6 mg/dL, even in asymptomatic neonates. The addition of 200 mg/kg/day of 10% calcium gluconate to standard IV solutions provides 20 mg/kg/day of elemental calcium. If symptoms are present (especially cardiac arrhythmia or seizures), a bolus of 100 mg/kg of 10% calcium gluconate (10 mg/kg elemental calcium) may be given intravenously over 10 minutes with careful cardiac monitoring. One should be cautious using a peripheral IV means to administer calcium because calcium can be very irritating to tissues.

image KEY POINTS: HYPOCALCEMIA

Recent studies in premature infants using stable isotopes of calcium showed a true calcium absorption rate of 50% to 90%. Thus to meet an accretion rate of 100 mg/kg/day with an absorption rate of 75% and an assumed retention rate of 75% (which may be on the high side), oral intake of calcium for growing premature infants should be about 200 mg/kg/day. This large intake in infants with very low birth weight can be achieved only with special formulas for low-birth-weight infants or mineral fortifiers for breast milk–fed preterm infants. ∗

This problem is much more difficult to address, although intestinal absorption is not a factor. In the early weeks of life with fluid intakes of 150 mg/kg/day, it is difficult to exceed an IV calcium intake of 60 mg/kg/day in the smallest premature infants (weight <1000 g) with standard total parenteral nutrition (TPN) solutions. When the concentration of calcium exceeds 60 mg/dL (3 mEq/dL) in TPN solutions, precipitation with phosphate may occur, depending on variables such as temperature, pH, amino acid content, and even the method by which the nutrients are added to the solution.

Clinical rickets develops in preterm infants with very low birth weight who are fed human milk not fortified with minerals and vitamins. Typically, the disease presents after 8 weeks of life with severe hypophosphatemia, “relative hypercalcemia,” and hypercalciuria. The x-ray findings mimic those of rickets resulting from vitamin D deficiency. The biochemical findings are the result of low mineral intake. Because human milk is low in both calcium and phosphorus, the very low phosphorus intake (about 50% of calcium intake) severely limits deposition of calcium in bone.

Caution: Because treatment with phosphorus alone can result in severe hypocalcemia, supplements of both minerals are imperative.

Seizures secondary to hypocalcemia are very unlikely in a previously healthy term infant at 2 weeks of age. The differential diagnosis includes late infantile tetany associated with high phosphate load (e.g., feedings with cow milk), acid–base disturbances caused by diarrhea treated with alkali therapy, and congenital hypomagnesemia (rare).

Treatment of hypocalcemic seizures is the same for both premature and term infants. In general, 10% calcium gluconate containing 9.4 mg/mL of elemental calcium is the drug of choice. The usual dose of 2 mL/kg body weight (18 mg/kg of elemental calcium). Infusion should occur slowly over the course of 10 minutes with heart rate monitoring. Make sure the line is patent before infusing calcium.

Hypercalcemia

There are three fractions of calcium in serum: ionized calcium (50%), calcium bound to serum proteins (40%), and calcium complexed to serum anions (10%). Ionized calcium and total calcium can be measured in most hospital laboratories.

Normal values (in milligrams per deciliter, expressed as mean± standard deviation and range) depend on chronologic age and laboratory variation (to a lesser degree):

Normal values (in milligrams per deciliter, expressed as mean ± standard deviation and range) depend on gestational age:

Total serum calcium above 10.8 mg/dL or ionized serum calcium above 5.4 mg/dL.

15. What are some of the causes of hypercalcemia in neonates?

16. How is acute hypercalcemia managed in newborn infants?

Williams syndrome is the likely diagnosis in an infant with hypercalcemia and supravalvular stenosis who was born small for gestational age. It results from a deletion of the elastin gene on 7q11.23. Affected infants are often described as having “elfin” faces. ∗

The most likely diagnosis is an autosomal dominant mutation of the calcium-sensing receptor, or “hypocalciuric hypercalcemia.” The infant’s urinary calcium level will be inappropriately low for the serum calcium. In the heterozygous state this is generally thought to be a benign condition, and treatment is not indicated. Rare cases of homozygous mutations result in severe neonatal hyperparathyroidism, which is a life-threatening disorder. ∗

A defect in the intestinal transport of tryptophan causes excretion of blue, water-insoluble tryptophan metabolites. The reason that these children have high calcium levels is not well understood.

Hypomagnesemia and Hypermagnesemia

image

Intracellular and extracellular types of magnesium reactions are important.

Magnesium is the second most abundant intracellular cation after potassium and helps to regulate cellular metabolism. As part of the magnesium-adenosine triphosphate complex, it is essential for all biosynthetic processes, including glycolysis, formation of cyclic adenosine monophosphate, and transmission of the genetic code. In addition, any reaction that uses or produces energy requires magnesium.

Only 1% of magnesium is contained in extracellular fluid. However, extracellular concentrations are critical for maintenance of electric potentials of nerve and muscle membranes and for the transmission of impulses across the neuromuscular junction. Magnesium and calcium may act synergistically or antagonistically in many of these processes.

Most infants are asymptomatic. On rare occasions the following signs and symptoms may be seen:

Hypomagnesemia usually increases the secretion of PTH, thereby increasing calcium levels. In chronic magnesium-deficient states, however, secretion of PTH is reduced. In such circumstances hypomagnesemia may induce hypocalcemia. ∗

In extreme cases cardiorespiratory function ceases, and death ensues.

Thyroid Disorders

Congenital hypothyroidism occurs in 1 in 4000 liveborn infants.

32. What are the embryonic stages of development of the fetal hypothalamic–pituitary–thyroid axis?

The hypothalamic–pituitary–thyroid axis is in place by the end of the first trimester. The thyroid and pituitary glands reach mature secretory capacity by 30 to 35 weeks of gestation. The feedback interrelationship among the units is fully established when hypothalamic TRH maturation is completed by 1 to 2 months after birth. ∗

The amount of T4 secreted by the fetal thyroid gland increases slowly until midgestation (20 to 24 weeks) when, stimulated by increasing amounts of TSH from the fetal pituitary, T4 levels begin to increase more rapidly, reaching a normal adult level by approximately 30 weeks’ gestation. Thereafter T4 increases slowly to high normal levels at term gestation. ∗

The amount of circulating TSH begins to increase in midgestation (20 weeks) and reaches a peak level of approximately 15 μU/mL by 30 weeks’ gestation. The TSH level then declines gradually to about 10 μU/mL at term.

Maternal TSH does not cross the placenta, but maternal iodine crosses the placenta freely and is essential for the synthesis of thyroid hormones by the fetus.

The placenta is a barrier to the passages of thyroid hormones and contains enzymes that break down maternal T4 and T3 into inactive metabolites. Only a small percentage of circulating maternal T4 and very little (if any) T3 reaches the fetus. However, the amount of maternal T4 that does cross the placenta is significant. During the first 10 to 12 weeks of gestation, all of the circulating T4 in the fetus is from maternal sources; thus early brain development depends on maternal hormone. Even after the fetus synthesizes its own T4 in the second and third trimesters, maternal T4 is essential for normal neurologic development, including neuronal proliferation and maturation, dendritic arborization, and synapse formation. It accounts for approximately 30% of fetal T4 levels at term. ∗†

Within 15 to 20 minutes after birth, the fetal pituitary releases a surge of TSH, probably in response to cooling. TSH reaches a peak of about 80 μU/mL in approximately 30 minutes, decreases rapidly over the first 24 hours of life, and then drops more gradually to levels comparable to normal adult levels by the end of the first 1 to 2 weeks of life.

Serum T4 levels increase rapidly, reaching a peak level of about 17 μg/dL at 24 hours. T4 then gradually decreases to levels at the upper limit of normal adult values over the first 4 to 5 weeks of life. Free T4 levels follow the same pattern, reaching a peak of 3.5 ng/dL at 24 to 36 hours.

The levels of TRH, TSH, T4, free T4, and T3 are lower in premature infants than in term infants, and the postnatal surges of TSH and T4, although qualitatively similar, are blunted. These differences are related directly to gestational age: the lower the gestational age, the lower the levels and responses of thyroid-related hormones ( Table 8-1).

TABLE 8-1

SERUM THYROXINE (µg/dL) AT DIFFERENT GESTATIONAL AGES ∗

image

∗Mean (standard deviation).

Adapted from Cuestas RA. Thyroid function in healthy premature infants. J Pediatr 1978;92:963–7.

The term refers to infants with low birth weight (30 to 35 weeks’ gestation) or very low birth weight (<30 weeks’ gestation), who have an even more attenuated rise in T4, after which T4 levels drop below cord levels in the first week of life. Then they rise gradually over 3 to 6 weeks to approach levels of term infants ( Table 8-2).

The premature infant with low T4 and persistently elevated TSH has either transient or permanent hypothyroidism and should be treated with T4 until the nature of the condition becomes clear. However, whether premature infants with low T4 and normal TSH levels should be treated remains controversial. ∗†

This question has not yet been answered. There are some case reports in the literature suggesting that breastfeeding delays the onset of hypothyroidism, but others argue against that finding.

Signs and symptoms of hypothyroidism are subtle at birth, and the characteristic appearance of cretinism may not be apparent for 3 to 4 months. The brain requires thyroid hormone for normal development until approximately 2 to 3 years of age, and deficiency of thyroid hormone during this period causes irreversible brain damage to an extent related directly to the length of time of the hypothyroidism. Thus it is of vital importance to identify a hypothyroid infant as quickly as possible, even before clinical signs appear.

A heel-stick blood sample is taken at discharge or 3 days of life, whichever is earlier. In most parts of the United States, T4 is measured first, then TSH is measured in samples with the lowest 10% to 29% of T4 results. ∗†

See Table 8-3.

TABLE 8-3

CAUSES OF CONGENITAL HYPOTHYROIDISM AND INCIDENCE OF EACH

image

From Fisher FA. Disorders of the thyroid in the newborn and infant. In: Sperling MA, editor. Pediatric endocrinology. Philadelphia: Saunders; 1996. p. 57.

The thyroid-stimulating immunoglobulins (TSIs) cross the placenta and may cause fetal thyrotoxicosis, resulting in goiter, tachycardia, rapid skeletal maturation, premature birth, and congestive heart failure. Long-term neurologic deficits may result because excessive T4 reduces neuronal proliferation.

Only approximately 1 in 70 neonates born to thyrotoxic mothers exhibit clinical thyrotoxicosis. Such infants may show a phase of transient hypothyroidism caused by antithyroid drugs (half-life, 2 to 3 days), then thyrotoxicosis resulting from maternal TSIs. Transient congenital hypothyroidism can result from transplacental transfer of maternal thyrotopin-blocking antibodies. ∗

Methimazole and carbamazole are excreted into breast milk in quantities that may affect the infant adversely. If breastfeeding cannot be avoided, the infant should undergo thyroid function tests at weekly intervals to avoid potential hypothyroidism. PTU is not a contraindication to breastfeeding because only approximately 0.1% is excreted in breast milk.

image KEY POINTS: THYROID-RELATED DISORDERS

1. Hypothyroxinemia of prematurity is associated with a developmental immaturity of the hypothalamic–pituitary–thyroid axis and therefore should never be used as an explanation for low thyroid levels in the presence of an elevated TSH level.

2. Hypopituitarism in a neonate most often presents with hypoglycemia and may also cause hyponatremia, jaundice, micropenis, and undescended testes.

3. The most common cause of virilized external genitalia in a 46,XX infant is 21-hydroxylase deficiency.

4. The fetal hypothalamic–pituitary–thyroid axis is in place by the end of the first trimester but is not fully mature until 2 months postpartum (term).

5. Maternal T4 does cross the placenta and is essential for the normal neurologic development of the fetus.

6. TSH and T4 levels rise in both premature and term infants immediately after birth; however, the rise in premature infants is blunted.

7. Infants with neonatal thyrotoxicosis are at an increased risk for congestive heart failure and learning disorders.

Neonatal thyrotoxicosis normally is a self-limited disease that subsides by about 3 months of age when maternal TSIs are metabolized. However, tachycardia, irritability, and poor weight gain require treatment with methimazole with or without propranolol. The danger of treatment is oversuppression of the neonatal thyroid and consequent hypothyroidism.

The mature thyroid stops synthesis of T4 in the presence of excessive iodine (i.e., Wolff–Chaikoff effect) but escapes from this inhibition when intrathyroidal iodine pools are depleted. The fetal thyroid cannot escape the inhibition and develops into a goiter that can be large enough to require emergency transection at birth. In addition, the continued blockade of T4 production by iodine leads to fetal hypothyroidism.

Note: Premature infants are also unable to escape from the inhibitory effect of iodine and may become hypothyroid when subjected to multiple povidone-iodine washings or iodinated contrast agents, associated with an elevation of TSH. This is particularly important in infants who have required repeated procedures. ∗

Adrenal Disorders

53. Which disorders of adrenal steroidogenesis should be suspected as a possible cause for virilization of a 46,XX fetus?

54. Which disorders of adrenal steroidogenesis should be suspected as a possible cause for undervirilization of a 46,XY fetus?

55. In infants with congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency, which of the following is abnormal: (1) genetic sex, (2) gonadal differentiation, (3) internal genital formation and structure, or (4) external genitalia in females?

The answer is (4). In female infants with CAH, the karyotype (genetic sex) is normal (46XX). The müllerian ducts develop normally into a uterus and fallopian tubes without secretion of antimüllerian hormone. No wolffian duct derivatives are formed because no fetal testis is present. The elevated adrenal androgen levels cause virilization of the external genitalia. ∗

Exposure of male fetuses to progestin at 8 to 14 weeks of gestation may result in hypospadias. ∗

Adrenal hemorrhage occurs more frequently after breech delivery, with eventual calcification in some cases. Hypoxia, fetal distress, maternal diabetes, and congenital syphilis also have been associated with adrenal hemorrhage. Adrenal hemorrhage can present as an abdominal mass.

Even with bilateral adrenal hemorrhage, most infants are asymptomatic. On occasion, however, severe abnormalities of glucose, sodium, and potassium may be noted with signs of shock.

The evaluation should include a 60-minute adrenocorticotropic hormone stimulation test with measurement of baseline and 60-minute cortisols. The normal peak is greater than 20 μg/dL.

Congenital adrenal hypoplasia should be considered. A low maternal estriol level occurs because the fetus contributes to the precursors for placental formation of maternal estriols.

Congenital adrenal hypoplasia is an X-linked disorder affecting 1 in 12,500 live births. ∗

StAR protein is necessary for proper reduction of aldosterone, cortisone, and sex hormones. Its absence leads to feminization of males as part of congenital lipoid adrenal hyperplasia. In a subset of patients with congenital lipoid adrenal hyperplasia, mutations in StAR protein result in severe impairment of steroid biosynthesis in the adrenal glands and gonads. ∗

Collect the blood specimen at any time. Circadian rhythms do not affect the level of cortisol in very premature infants. Infants with extremely low birth weight may have quite low cortisol levels (9.2 ± 9.8 μg/dL) and lack the typical early-morning rise in cortisol. Whether such low corticosteroid levels in premature infants with very low birth weight indicate adrenal insufficiency is not fully known. ∗

Pseudohypoaldosteronism is an inherited disease (autosomal recessive or dominant pattern) characterized by renal tubular unresponsiveness to the kaliuretic and sodium and chloride reabsorptive effects of aldosterone. In contrast to CAH or adrenal insufficiency, it is accompanied by excessive levels of renin and aldosterone. Unresponsiveness to aldosterone may be generalized, in which case sodium excretion is increased in sweat, saliva, stool, and urine, or limited to the renal tubule, in which case sodium excretion is increased in urine only.

Pseuduhypoaldosteronism is treated with massive salt supplementation and potassium-lowering agents such as Kayexalate (sodium polystyrene sulfonate).

image KEY POINTS: ADRENAL DISORDERS

Pituitary Disorders

Growth hormone first appears at 10 weeks’ gestation. Levels increase in midgestation and decrease toward term.

No. Placental growth hormone is secreted only into the maternal circulation.

Gonadotropin-releasing hormone is detectable in the hypothalamus at 8 weeks’ gestation. Luteinizing hormone and follicle-stimulating hormone are present in the pituitary gland by 11 to 12 weeks’ gestation and at term are found in low levels in cord blood. The fetal testis responds to human chorionic gonadotropin (hCG), but the fetal ovary does not respond because it lacks hCG receptors.

The most common presenting symptom is hypoglycemia. Micropenis is also common in male neonates. Growth hormone deficiency may result in an exagerated jaundice (direct and indirect hyperbilirubinemia). Because growth hormone is not necessary for intrauterine linear growth, intrauterine growth restriction is not a feature of growth hormone deficiency. ∗

image KEY POINTS: PITUITARY DISORDERS

In male neonates HHG is associated with micropenis (stretched penile length <2.5 cm). Undescended testes also may be present. In female neonates there are no clinical findings of HHG.

Cleft lip and palate, optic nerve atrophy, septo-optic dysplasia, and holoprosencephaly have been noted. ∗

Disorders of Sexual Development

Sex-determining region of Y-chromosome (SRY) is thought to be the first in a cascade of transcription factors that initiate the process of testicular development. SRY is located on the short arm of the Y chromosome, and the gonad loses bipotentiality at approximately 6 to 8 weeks’ gestation. In the absence of SRY expression, the bipotential gonad will develop into an ovary.

Testosterone is produced by Leydig cells within the fetal testes by 6 weeks of gestation. In addition, the testes produce the peptide hormone, müllerian inhibitory substance (MIS), which eliminates all müllerian structures in the male. An isolated deficiency in MIS produces a normal external male phenotype, but the internal phenotype is characterized by a fallopian tube running parallel to the vas deferens.

There are a number of cases of 46,XX sex reversal in the literature. Only a minority of these cases have been shown to have been caused by translocation of SRY. At least one case of SOX9 duplication (a transcription factor downstream of SRY) has been reported. The majority of cases are unexplained at this time. ∗

The most likely diagnosis is CAH caused by steroid 21-hydroxylase deficiency because it is the most common disorder of sexual development in a newborn female and because no gonadal tissue is palpable. Other diagnoses, such as mixed gonadal dysgenesis or hermaphroditism, generally present with one palpable gonad.

Several steps leading to cortisol synthesis may be affected and produce the virilized female phenotype. The most likely missing enzyme is steroid 21-hydroxylase, and the result is a major accumulation of its immediate precursor, 17-hydroxyprogesterone. A serum radioimmunoassay for 17-hydroxyprogesterone should be diagnostic in almost all cases.

The two most likely diagnoses are mixed gonadal dysgenesis and true hermaphroditism. The combination of a descended gonad and virilization indicates the presence of some functional testicular tissue. An ovary usually does not descend into the scrotum, and an ovotestis does so only in rare cases. In mixed gonadal dysgenesis, one gonad is a streak found within the abdomen, and one testis descends into an inguinal or scrotal position. True hermaphroditism is characterized by a combination of both ovarian-follicular and testicular tissue, which may be combined within one testis (ovotestis). The rudimentary vagina and uterus reflect inadequate production of MIS despite the presence of some testicular tissue. Because the action of MIS is also paracrine, the vaginal and uterine structures are lateralized primarily to the side opposite the testis.

The most likely diagnosis is 5-alpha reductase deficiency, which was first characterized by its striking clinical presentation. Cases are clustered in the Dominican Republic, where the culture is extremely supportive.

Androgen insensitivity syndrome (AIS) is the most likely diagnosis. Patients with AIS have a normal XY karyotype. The testes are fully developed but never descend, and the external genitalia are those of a normal female. Serum testosterone levels are markedly elevated, but no virilization takes place. Because of a mutation in the androgen receptor, androgen has no effect on its target tissues. AIS, in effect, is end-organ failure based on molecular mutation; it is a syndrome in the sense that several point mutations have been identified.

Absence of the uterus and upper two thirds of the vagina is the most likely finding. These structures originate from the müllerian ducts, which involute in response to secretion of MIS. The testes are normal and produce normal amounts of testosterone and MIS.

The diagnosis is hernia uteri inguinalis.

image KEY POINTS: DISORDERS OF SEXUAL DEVELOPMENT

Absence of MIS, which is produced by the testis and results in involution of müllerian ducts during the course of normal male sexual differentiation, causes hernia uteri inguinalis. A normal-appearing testis that produces testosterone may lack the capacity to synthesize or secrete MIS. The result is a normal external prominent utricle. ∗

Hypoglycemia

In adults hypoglycemia is defined as a condition involving a plasma glucose level below 40 mg/dL. A plasma glucose concentration of 70 to 100 mg/dL is considered normal, and the therapeutic target range for adults with hypoglycemia is above 60 mg/dL. The definition in neonates is controversial. Some physicians accept significantly lower plasma glucose concentrations as normal for neonates. However, in the absence of scientific evidence that neonates tolerate lower concentrations than adults, many clinicians now believe that values below 50 mg/dL are abnormal. This definition is supported by Koh and colleagues, who demonstrated electrophysiologic changes in the brains of infants when glucose reaches 50 mg/dL. ∗†‡

Glucose is the primary fuel for the brain and accounts for over 90% of total body oxygen consumption early in fasting. Because of their larger brain-to-body size ratio, infants have greater glucose requirements than adults. Hepatic glucose production rates in infants are approximately 6 mg/kg/min (3 to 6 times greater than those of adults).

Hypoglycemia results from either abnormal control of fasting adaptations or failure of a particular fasting metabolic system. In the first 12 to 24 hours of life, normal newborns are at increased risk for hypoglycemia because gluconeogenesis and especially ketogenesis are incompletely developed. Hypoglycemia occurring or persisting after the first 24 hours of life is abnormal and implies failure of one of the fasting systems.

88a. Which infant catgories are at high risk for hypoglycemia?

89. What physical features suggest the cause of hypoglycemia in neonates?

90. Which hormonal abnormalities cause hypoglycemia in neonates?

91. How is hypoglycemia treated acutely?

Hypoglycemia can be treated emergently with oral or nasogastric tube feeding of dextrose or formula. If symptoms are severe, 2 mL/kg of 10% dextrose can be administered intravenously. Blood glucose should be checked within 15 minutes of intervention and subsequently monitored to ensure adequate treatment (plasma glucose above 60 mg/dL) and to prevent hypoglycemic episodes. If necessary, continuous IV dextrose is initiated (6 to 12 mg/kg/min).

92. Which defects in fasting metabolic systems cause hypoglycemia in neonates?

image Defects of glycogenolysis (i.e., GSDs) are associated with hepatomegaly. Examples include deficiencies of debranching enzyme (GSD type 3), liver phosphorylase (GSD type 6), and phosphorylase kinase (GSD type 9).

image Defects of gluconeogenesis include deficiencies of glucose-6-phosphatase (i.e., GSD type 1) and fructose-1,6-diphosphastase. Defects of gluconeogenesis and glycogenolysis rarely present in early infancy because neonates are not exposed to fasting for more than 4 hours at a time.

image Fatty acid oxidation disorders include medium-chain acyl dehydrogenase deficiency. Unless a neonate is breastfeeding poorly or experiences an illness that limits oral intake, a fatty acid oxidation disorder is unlikely to present in infancy. This disorder, however, can cause serious problems during fasting later in life and should be tested for as part of neonatal screening.

93. List and explain the hormonal controls necessary for fasting adaptation.

94. What tests should be included in the “critical sample” during a hypoglycemic episode?

Once hypoglycemia is confirmed (i.e., glucose ≤50 mg/dL), blood should be analyzed for the following:

Transient hyperinsulinism occurs in infants of diabetic mothers whose upregulated insulin secretion in response to a hyperglycemic fetal environment persists in the immediate postnatal period. In perinatally stressed neonates (e.g., infants who are small for gestational age or who have birth asphyxia or toxemia), hyperinsulinism caused by dysregulated insulin secretion may persist for up to several months after birth.

Initial management consists of IV dextrose and frequent or continuous feeds. In persistent cases diazoxide (5 to 15 mg/kg/day) may be effective in controlling insulin secretion.

Genetic defects of insulin secretion include recessive mutations of the β-cell sulfonylurea receptor/potassium channel genes and dominant gain of functional mutations of glucokinase and glutamate dehydrogenase. Dominant functional mutations are milder and usually appear later in infancy.

Congenital hyperinsulinism caused by severe sulfonylurea receptor/potassium channel mutation is often resistant to diazoxide. Octreotide (a somatostatin analog) tempers excessive insulin secretion but rarely prevents hypoglycemia completely or normalizes fasting tolerance. Continuous glucagon infusion can stabilize blood glucose until surgery is performed, but experience with long-term use is limited. If the combination of octreotide and frequent feeds fails, pancreatectomy is necessary. Surgery may be curative if a focal lesion is present and completely resected. ∗†

These defects necessitate frequent feedings.

image KEY POINTS: HYPOGLYCEMIA

1. A work-up for hypoglycemia should be considered in any newborn who is documented to have a blood sugar level persistently lower than 50 mg/dL.

2. The three common etiologies for hypoglycemia in a neonate are decreased production owing to an inborn error of metabolism, increased utilization, and altered hormonal regulation.

3. An infant with hypoglycemia should be carefully examined for hepatomegaly, macroglossia, macrosomia, and midline abnormalities (including clefting defects).

4. The etiology of hypoglycemia is most readily identified by measuring metabolites and hormones at the time of hypoglycemia and should include measures of glucose, free fatty acids, ketones, lactate, pyruvate, ammonia, insulin, cortisol, and growth hormone. Abnormalities in any of these studies may then necessitate definitive diagnostic studies.

5. Treatment of hypoglycemia depends on the etiology but may include avoidance of fasting, a diet altered to circumvent a metabolic block, insulin suppression with diazoxide or pancreatic resection, or replacement of growth hormone or cortisol deficiency.

6. Abnormalities of both the β-cell sulfonylurea receptor and the potassium channel have been documented to cause congenital hyperinsulinism.

These disorders are treated by instituting a high-carbohydrate diet (and for certain long-chain fatty acid oxidation disorders, metabolic diets high in medium-chain triglyceride) and by ensuring that fasting is limited to 12 hours. If an affected infant is feeding poorly or experiences vomiting, IV dextrose must be initiated emergently. The finding of euglycemia in the setting of a concurrent illness should not deter the clinician from initiating IV dextrose. By the time hypoglycemia is detected in fatty oxidation disorders, liver failure, cerebral edema, and cardiac toxicity are already present or developing. Intervention must be prompt; the mortality rate during the first episode is greater than 25%.

Neonatal Screening

Routine neonatal screening tests for the following:

The American College of Medical Genetics recommends that clinicians screen for 29 disorders during the neonatal period.

The answer is (1). Galactosemia can cause acute liver failure promptly after institution of milk feedings. It also predisposes neonates to Escherichia coli septicemia. MSUD causes lethal depression of the function of the central nervous system in the neonatal period. Salt-losing CAH, caused by 21-hydroxylase deficiency, can cause addisonian crisis with hypovolemic/hyponatremic shock, hypoglycemia, and (most dangerous of all) severe hyperkalemia

Effective treatment of PKU, hypothyroidism, and MSUD must begin within the first few weeks of life to prevent significant problems in development. In infants with galactosemia, learning disabilities are quite prominent if treatment is not initiated early. Developmental disabilities are found in 50% of untreated homocystinuric patients, but the age at which treatment must begin is not known. ∗

The answer is (2). Some infants affected by galactosemia have cataracts shortly after birth. The female infant with CAH caused by 21-hydroxylase deficiency often has ambiguous genitalia (i.e., enlarged clitoris, labial fusion) at birth.

Sickle cell disease presents at various ages and in various ways, but the major threat to life for small infants is bacterial sepsis, with Streptococcus pneumoniae high on the list of causative organisms. Preclinical detection of sickle cell disease allows prophylaxis against pneumococcal infection. ∗

In breastfed infants the dietary carbohydrate is lactose, which is hydrolyzed during absorption to glucose and galactose, both reducing sugars. Therefore a non–glucose-reducing substance in the urine is almost certainly galactose, and its presence strongly suggests the diagnosis of galactosemia. Intake of lactose should be stopped immediately and not re-instituted until galactosemia has been ruled out by assay for red blood cell galactose-1-phosphate uridylyltransferase. Because galactosemia can be rapidly lethal, do not delay this decision until the result of the screening test is known.

It most states it is a two-tiered test in which immunoreactive trypsinogen is first measured. Babies with the highest immunoreactive trypsinogen levels are then genetically tested for the most common mutations in cystic fibrosis transmembrane conductance regulator, including the most common delta F508 mutation. ∗

To increase the specificity of newborn screening for diseases with a common genetic etiology, a two-tiered test is developed to screen for the disorder based on a metabolite or protein in the blood. The subset of newborns with the highest levels can then go on to genetic testing for the most common mutations to confirm the diagnosis genetically. This strategy has been commonly used for cystic fibrosis and medium-chain acyl-CoA dehydrogenase for which there are common mutations in the population.

image KEY POINTS: NEONATAL SCREENING

1. New technologic advances in tandem mass spectrometry have revolutionized newborn screening and allow for detection of dozens of inborn errors of metabolism from blood spots.

2. Specimens should be collected after 24 hours of life and, with the exception of sickle cell disease and G6PD deficiency, should not be affected by transfusions.

3. DNA diagnostic tests are also being added to newborn screening regimens to increase the specificity of testing and reduce the number of false-positive results.

4. The majority of positive results from newborn screening are false-positive results, and repeat or additional diagnostic testing is required to distinguish true positive results from false-positive results.

5. Treatment should be initiated as soon as the diagnosis is made; for some conditions, such as congenital hypothyroidism, PKU, and MSUD, permanent neurologic damage can result if treatment is delayed.

Tandem mass spectrometry (MS-MS) can be performed on dried blood spots and can measure hundreds of metabolites to facilitate screening of dozens of inborn errors of metabolism while more precisely quantitating the levels of the metabolites to improve screening sensitivity and specificity. ∗

Neonatal diagnosis before the onset of symptoms would allow for use of bone marrow transplantation as treatment at an age when it is most likely to be effective and allow for more normal brain development. Treatment initiation after the onset of symptoms often leaves children in a state of severe intellectual disability. ∗

The newborn screening test for SCID based on measurement of T-cell receptor excision circles (TRECs) by real-time qPCR using DNA extracted from newborn screening of dried blood spots. RECs are by-products generated during T-cell maturation and are consistently absent or present in low numbers in newborns with SCID. Identification of infants with SCID allows for prevention of life threatening infections and early bone marrow transplantation.

Inborn Errors of Metabolism

The following clinical signs suggest metabolic disease:

Note: The signs of metabolic disease are nonspecific. More common diseases, such as sepsis, must be considered in the differential diagnosis.

No. Large ketones usually are not detectable in the urine of normal newborn infants with fasting, including those with fasting-induced hypoglycemia. Conversely, ketonuria often is present in neonates with defects in gluconeogenesis and amino acid or organic acid metabolism. The rate of use of ketones as a fuel is greater in infants compared with children. Experimental data suggest that some inborn errors of metabolism may be associated with a secondary defect in ketone body use. Severe acidemia also may perturb the use of ketones.

The following metabolic disorders are associated with distinctive odors:

The following metabolic disorders are associated with acidosis:

The neonatal transport team should first address the following:

The transport team may encounter the following:

Microencephaly (mental retardation) and congenital heart defects, which are thought to result from high levels of phenylalanine, are more commonly found in these infants.

The following inborn errors are common with neonatal seizures:

Treatment involves institution of a ketogenic diet, which shifts the brain’s metabolism to the utilization of ketone bodies rather than carbohydrates. ∗

The following are possible causes of Fanconi syndrome:

Diagnositic assessment should include the following:

image KEY POINTS: INBORN ERRORS OF METABOLISM

1. Common presentations for inborn errors of metabolism include lethargy and coma, dysmorphism, recurrent vomiting, ocular abnormalities, tachypnea unrelated to pulmonary disease, visceromegaly, unusual odors, marked hypotonia, skin or hair abnormalities, seizures, unstable body temperature, bleeding, and jaundice.

2. Common strategies for treating inborn errors of metabolism include avoidance of fasting; dietary manipulation to avoid substrates that cannot be metabolized; medications to clear toxic by-product; supplementation with high doses of cofactors and vitamins used by the deficient enzyme; and, when appropriate, enzyme replacement therapy or organ transplants (e.g., liver or bone marrow transplant).

3. Infants with inborn errors of metabolism may not be symptomatic until metabolically stressed by an intercurrent illness or fasting.

4. Fetal development for inborn errors of metabolism may be normal if the metabolites are able to cross the placenta and may be metabolized by the mother for the fetus.

5. Sudden infant death syndrome can be caused by inborn errors of metabolism, and a family history of a death in infancy of unknown etiology should prompt screening for inborn errors of metabolism.

Ammonia can be difficult to measure accurately because it must be run immediately by the laboratory. An ammonia level greater than 100 mmol/L is cause for concern and should be repeated. An ammonia level greater than 300 mmol/L is an emergency and may necessitate preparing for hemodialysis if it is confirmed.

Secure the airway; if necessary, intubate preemptively. Make sure that the infant receives nothing by mouth, and maintain on IV glucose only. Give IV arginine. Hemodialyze if ammonia levels are above 300 mmol/L and increasing. Administer sodium phenylbutyrate (trade name Buphenyl) and sodium benzoate as ammonia scavenger. ∗

Treatment includes a diet low in phenylalanine, methionine and tyrosine. The drug 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) has been successful in the management of tyrosinemia. NTBC works by inhibiting the proximal tyrosine metabolic pathway. Babies should be monitored for coagulopathies resulting from problems with liver synthetic function.

See Table 8-4.

TABLE 8-4

SUMMARY OF MAJOR FINDINGS IN THE FIVE MAJOR KINDS OF METABOLIC DISEASE

image

CSF, Cerebrospinal fluid.

From Spitzer A. Intensive care of the neonate. St Louis: Mosby; 2005. p 1209.

Nothing. The baby should not receive anything by mouth but should instead be given IV fluids containing only dextrose and electrolytes with enough dextrose to keep the baby anabolic.

At the time the baby is most severely clinically affected, the diagnostic yield is highest.

Standard treatment is a phenylalanine-restricted formula providing just enough phenylalanine for normal growth and development. Tetrahydrobiopterin, the cofactor for phenylalanine hydroxylase, is now also approved by the Food and Drug Administration as an adjuvant to diet modification in some patients. Not all patients respond to tetrahydrobiopterin.

The following strategies can be used:

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