Pediatrics_Nelson

Pediatrics_Nelson. The Diabetes Control and Complications Trial established that intensive insulin therapy, with the goal of maintaining blood glucose concentrations as close to normal as possible, can delay the onset and slow the progression of complications of diabetes (retinopathy, nephropathy, neuropathy). Attaining this goal using intensive insulin therapy can increase the risk of hypoglycemia. The adverse effects of hypoglycemia in young children may be significant because the immature CNS may be more susceptible to glycopenia. Although the risk for diabetic complications increases with duration of diabetes, there is controversy as to whether the increase of risk is slower in the prepubertal years than in adolescence and adulthood.


Pediatrics_Nelson

Pediatrics_Nelson. The goals of therapy differ, depending on the age of thepatient. For children younger than 5 years old, an appropriate goal is maintenance of blood glucose concentrationsbetween 80 and 180 mg/dL. For school-age children, 80 to 150 mg/dL is a reasonable target range. For adolescents, thegoal is 70 to 130 mg/dL. Goals of therapy also should takeinto account other individual characteristics, such as a pasthistory of severe hypoglycemia and the abilities of the patientand family.


Pediatrics_Nelson

Pediatrics_Nelson. Many types of insulin differ in duration of action and time to peak effect (Table 171-2). These insulins can be used in various combinations, depending on the needs and goals of the individual patient. The most commonly used regimen is that of multiple injections of fast-acting insulin given with meals in combination with long-acting basal insulin given at bedtime. This regimen provides flexibility but requires administration of many injections per day and will require assistance for young children. After the total daily dose of insulin is determined, 30% to 50% are given as long-acting insulin, and the remainder is given as fast-acting insulin, divided according to the need for corrections of high glucose levels and for meals. To correct for hyperglycemia, one can determine the insulin sensitivity using the 1800 rule; dividing 1800 by the total daily dose of insulin to determine how many milligrams per deciliter of glucose will decrease with one unit of insulin. The


Pediatrics_Nelson

Pediatrics_Nelson. the insulin sensitivity using the 1800 rule; dividing 1800 by the total daily dose of insulin to determine how many milligrams per deciliter of glucose will decrease with one unit of insulin. The insulin:carbohydrate ratio is used to calculate insulin for the carbohydrate content of food; 450 divided by the total daily dose determines the number of grams of carbohydrate that requires one unit of insulin.


Pediatrics_Nelson

Pediatrics_Nelson. Pumps that provide a continuous SC infusion of short-acting insulin also are available and are being used by children and adolescents who are highly motivated to achieve tight control. Lispro, aspart, and glulisine insulin are synthetic human insulin analogs in which amino acid alterations result in fast absorption and onset of action (see Table 171-2). Because of the short duration of action, these are used in combination with long-acting insulin. Glargine and detemir are insulin analogs with increased solubility at acidic pH and decreased solubility at physiologic pH. They have a duration of greater than 24 hours and act as a basal insulin.


Pediatrics_Nelson

Pediatrics_Nelson. Newly diagnosed patients in the honeymoon period may require 0.4 to 0.6 U/kg/24 hours. Prepubertal patients with diabetes longer than 1 to 2 years typically require 0.5 to 1 U/kg/24 hours. During middle adolescence when elevated GH concentrations produce relative insulin resistance, insulin requirements increase by 40% to 50%, and doses of 1 to 2 U/kg/24 hours are typical. Balancing the daily meal plan with the dosages of insulin is crucial for maintaining serum glucose concentrations within the target range and avoiding hypoglycemia or hyperglycemia. The content and schedule of meals vary according to the type of insulin regimen used. It is recommended that carbohydrates contribute 50% to 65% of the total calories, protein 12% to 20%, and fat <30%. Saturated fat should contribute <10% of the total caloric intake, and cholesterol intake should be less than 300 mg/24 hours. High fiber content is recommended.


Pediatrics_Nelson

Pediatrics_Nelson. Patients using multiple daily injections or the insulin pump can maintain a more flexible meal schedule with regard to the timing of meals and the carbohydrate content. These patients give an injection of insulin before or immediately after each meal with the total dose calculated according to the carbohydrate content of the meal. Further adjustments in the dose can be made based on the measured serum glucose concentration and plans for activity during the day. Children using a twice-aday combination of intermediate-acting and fast-acting insulins need to maintain a relatively consistent meal schedule so that carbohydrate absorption and insulin action peaks correspond. A typical meal schedule for a patient using this type of regimen involves three meals and three snacks daily. The total carbohydrate content of the meals and snacks should be kept constant.


Pediatrics_Nelson

Pediatrics_Nelson. Blood glucose should be routinely monitored before each meal and at bedtime. Hypoglycemia during the night or excessive variability in the morning glucose concentrations should prompt additional testing at 2 or 3 am to ensure that there is no consistent hypoglycemia or hyperglycemia. During periods of illness or when blood glucose concentrations are higher than 300 mg/dL, urine ketones also should be tested. Continuous glucose monitors, which provide minute-to-minute blood glucose concentration information, can be useful in following Table 171-2 Representative Profiles of Insulin INSULIN ONSET PEAK ACTION DURATION Very Short Acting Lispro, aspart, glulisine 5−15 minutes 30−90 minutes 3−5 hours Data from Wolfsdorf JI, editor: Intensive Diabetes Management, ed 4, Alexandria, VA, 2009, American Diabetes Associations. trends of blood glucose concentrations but should not be used in calculations of mealtime insulin doses.


Pediatrics_Nelson

Pediatrics_Nelson. trends of blood glucose concentrations but should not be used in calculations of mealtime insulin doses. Measurements of glycohemoglobin or hemoglobin A1c (HgbA1c) reflect the average blood glucose concentration over the preceding 3 months and provide a means for assessing long-term glycemic control. HgbA1c should be measured four times a year, and the results should be used for counseling of patients. The American Diabetes Association has set HgbA1c targets based on age with children less than 6 years having an HgbA1c target of 7.5% to 8.5%, ages 6 to 13 years HgbA1c target of less than 8%, and ages 13 to 18 years HgbA1c target of less than 7.5%. Measurements of HgbA1c are inaccurate in patients with hemoglobinopathies. Glycosylated albumin or fructosamine can be used in these cases.


Pediatrics_Nelson

Pediatrics_Nelson. Patients with DM1 for more than 3 to 5 years should receive an annual ophthalmologic examination for retinopathy. Urine should be collected annually for assessment of microalbuminuria, which suggests early renal dysfunction and indicates a high risk of progression to nephropathy. Treatment with angiotensin-converting enzyme inhibitors may halt the progression of microalbuminuria. In children with DM1, annual cholesterol measurements and periodic assessment of blood pressure are recommended. Early detection of hypertension and hypercholesterolemia with appropriate intervention can help limit future risk of coronary disease. Chronic autoimmune lymphocytic thyroiditis is particularly common and can result in hypothyroidism. Because symptoms can be subtle, thyroid function tests should be performed annually. Other disorders that occur with increased frequency in children with DM1 include celiac disease, IgA deficiency, Addison disease, and peptic ulcer disease.


Pediatrics_Nelson

Pediatrics_Nelson. Special Problems: Hypoglycemia Hypoglycemia occurs commonly in patients with DM1. For patients in adequate or better control, it is expected to occur on average once or twice a week. Severe episodes of hypoglycemia, resulting in seizures or coma or requiring assistance from another person, occur in 10% to 25% of these patients per year. Hypoglycemia in patients with DM1 results from a relative excess of insulin in relation to the serum glucose concentration. This excess can be caused by alterations in the dose, timing, or absorption of insulin; alterations of carbohydrate intake; or changes in insulin sensitivity resulting from activity. Defective counterregulatory responses also contribute to hypoglycemia. Abnormal glucagon responses to falling serum glucose concentrations develop within the first few years of the disease, and abnormalities in epinephrine release occur after a longer duration.


Pediatrics_Nelson

Pediatrics_Nelson. Lack of awareness of hypoglycemia occurs in approximately 25% of patients with diabetes. Recent episodes ofhypoglycemia may play a role in the pathophysiology ofhypoglycemia unawareness; after an episode of hypoglycemia, autonomic responses to subsequent episodes are reduced. Areturn of symptoms of hypoglycemia can be exhibited in thesepatients after 2 to 3 weeks of strict avoidance of hypoglycemicepisodes. Symptoms of hypoglycemia include symptoms resultingfrom neuroglycopenia (headache, visual changes, confusion, irritability, or seizures) and symptoms resulting fromthe catecholamine response (tremors, tachycardia, diaphoresis, or anxiety). Mild episodes can be treated with administration of rapidly absorbed oral glucose (glucose gel ortablets or fruit juices). More severe episodes that result in seizures or loss of consciousness at home should be treated with glucagon injections. IV glucose should be given in hospital settings.


Pediatrics_Nelson

Pediatrics_Nelson. Long-term complications of DM1 include retinopathy, nephropathy, neuropathy, and macrovascular disease. Evidence of organ damage caused by hyperglycemia is rare in patients with diabetes of less than 5 to 10 years’ duration; clinically apparent disease rarely occurs before 10 to 15 years’ duration. Diabetic retinopathy is the leading cause of blindness in the United States. Nephropathy eventually occurs in 30% to 40% and accounts for approximately 30% of all new adult cases of end-stage renal disease. Neuropathy occurs in 30% to 40% of postpubertal patients with DM1 and leads to sensory, motor, or autonomic deficits. Macrovascular disease results in an increased risk of myocardial infarction and stroke among individuals with diabetes.


Pediatrics_Nelson

Pediatrics_Nelson. Intensive control of diabetes, using frequent blood glucose testing and multiple daily injections of insulin or an insulin pump, can reduce the development or progression of diabetic complications, including a 76% reduction of risk for retinopathy, a 39% reduction in microalbuminuria, and a 60% reduction in clinical neuropathy. For pubertal and adult patients, the benefits of intensive therapy likely outweigh the increased risk for hypoglycemia. For younger patients, in whom the risks for hypoglycemia are greater and the benefits of tight glucose control may be lower, a less intensive regimen may be appropriate. DM2 can occur as the result of various pathophysiologic processes; however the most common form results from peripheral insulin resistance and compensatory hyperinsulinemia, followed by failure of the pancreas to maintain adequate insulin secretion (see Table 171-1).


Pediatrics_Nelson

Pediatrics_Nelson. The prevalence of DM2 in children is increasing in parallel with childhood obesity and is highest in children of ethnic groups with a high prevalence of DM2 in adults, including Native Americans, Hispanic Americans, and African Americans. Obesity, the metabolic syndrome, ethnicity, and a family history of DM2 are risk factors. Auto-antibodies to the pancreas are present among some clinically assumed to have DM2, compounding the difficulty in differentiating DM1 from DM2 at the time of diagnosis.


Pediatrics_Nelson

Pediatrics_Nelson. Fasting and postprandial glucose levels for diagnosis of DM2 are the same as those for DM1. The diagnosis of DM2 may be suspected on the basis of polyuria and polydipsia in a background of the metabolic syndrome. Differentiating DM2 from DM1 in children on only clinical grounds can be challenging. The possibility of DM2 should be considered in patients who are obese, have a strong family history of DM2, have other characteristics of the metabolic syndrome, or have absence of antibodies to beta cell antigens at the time of diagnosis of diabetes. Acanthosis nigricans, a dermatologic manifestation of hyperinsulinism and insulin resistance, presents as hyperkeratotic pigmentation in the nape of the neck and in flexural areas and is noted as a sign in the metabolic syndrome. Although ketoacidosis occurs far more commonly in DM1, it also can occur in patients with DM2 under conditions of physiologic stress and cannot be used as an absolute differentiating factor. DM2 can be confirmed by the


Pediatrics_Nelson

Pediatrics_Nelson. occurs far more commonly in DM1, it also can occur in patients with DM2 under conditions of physiologic stress and cannot be used as an absolute differentiating factor. DM2 can be confirmed by the evaluation of insulin orC-peptide responses to stimulation with oral carbohydrateand in the absence of islet cell autoreactivity.


Pediatrics_Nelson

Pediatrics_Nelson. DM2 is the result of a combination of insulin resistance, relative insulin deficiency, and a secretory beta cell defect. Asymptomatic patients with mildly elevated glucose values (slightly >126 mg/dL for fasting or slightly >200 mg/dL for random glucose) may be managed initially with lifestyle modifications, including nutrition therapy (dietary adjustments) and increased exercise. Exercise has been shown to decrease insulin resistance. In most children with new-onset, uncomplicated DM2, oral agents are usually the first line of therapy. Only metformin, an insulin secretagogue, is approved by the


Pediatrics_Nelson

Pediatrics_Nelson. U.S. Food and Drug Administration for use in children. A rare side effect of metformin is lactic acidosis, occurring mainly in patients with compromised renal function. The most common side effect is gastrointestinal upset. If ketonuria or ketoacidosis occurs, insulin treatment is necessary to first achieve adequate glycemic control but may be discontinued within weeks with continuation of oral medications. Insulin therapy may be required if adequate glycemic control is not achieved with lifestyle modifications and metformin.


Pediatrics_Nelson

Pediatrics_Nelson. Because DM2 may have a long preclinical course, early diagnosis is possible in subjects at risk who have the metabolic syndrome. Significant lifestyle modifications, such as improved eating habits and increased exercise, have a role in preventing or decreasing the morbidity of DM2. Finally it is critical to monitor and manage the other components of metabolic syndrome, such as advanced pubertal development, hypertension, hyperlipidemia, and polycystic ovary syndrome in females. MODY comprises a group of dominantly inherited forms of relatively mild diabetes. Insulin resistance does not occur in these patients; instead the primary abnormality is an insufficient insulin secretory response to glycemic stimulation. Treatment depends on the type and can include the use of sulfonylureas.


Pediatrics_Nelson

Pediatrics_Nelson. Hypoglycemia in infancy and childhood can result from a largevariety of hormonal and metabolic defects (Table 172-1). Hypoglycemia occurs most frequently in the early neonatal period,often as a result of transient neonatal hyperinsulinemia ininfants of diabetic mothers or as a result of inadequate energy stores to meet the disproportionately large metabolic needs of premature or small for gestational age newborns. Hypoglycemiaduring the first few days of life in an otherwise normal newbornis less frequent and warrants concern (see Chapter 6). After theinitial 2 to 3 days of life, hypoglycemia is far less common and ismore frequently the result of endocrine or metabolic disorders(although sepsis must always be ruled out). The diagnosis of hypoglycemia should be made on the basis of a low serum glucose concentration, symptoms compatible with hypoglycemia, and resolution of the symptoms after administration of glucose.


Pediatrics_Nelson

Pediatrics_Nelson. The diagnosis of hypoglycemia should be made on the basis of a low serum glucose concentration, symptoms compatible with hypoglycemia, and resolution of the symptoms after administration of glucose. Serum glucose concentrations less than 45 mg/dL are considered to be abnormal and necessitate treatment. Serum glucose concentrations greater than 55 mg/dL occasionally can occur in normal individuals, especially with prolonged fasting, but should be considered suspect, particularly if there are concurrent symptoms of hypoglycemia (Table 172-2). Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Available @ StudentConsult.com The symptoms and signs of hypoglycemia result from direct depression of the central nervous system owing to lack of energy substrate and the counterregulatory adrenergic response to low glucose via catecholamine secretion designed to correct hypoglycemia (see Table 172-2). Compared with older children, infants do not usually show adrenergic symptoms. The signs and symptoms of hypoglycemia in infants are relatively nonspecific and include jitteriness, feeding difficulties, pallor, hypotonia, hypothermia, episodes of apnea and bradycardia, depressed levels of consciousness, and seizures. In older children, signs and symptoms include confusion, irritability, headaches, visual changes, tremors, pallor, sweating, tachycardia, weakness, seizures, and coma.


Pediatrics_Nelson

Pediatrics_Nelson. Failure to recognize and treat severe, prolonged hypoglycemia can result in serious long-term morbidity, including mental retardation and nonhypoglycemic seizures. Younger infants and patients with more severe or prolonged hypoglycemia are at greatest risk for adverse outcomes.


Pediatrics_Nelson

Pediatrics_Nelson. Normal regulation of serum glucose concentrations requires appropriate interaction of a number of hormonal signals and metabolic pathways (Figure 172-1). In a normal individual, a decrease in serum glucose concentrations leads to a suppression of insulin secretion and increased secretion of the counterregulatory hormones (growth hormone [GH], cortisol, glucagon, and epinephrine) (see Fig. 172-1). This hormonal signal promotes the release of amino acids (particularly alanine) from muscle to fuel gluconeogenesis and the release of triglyceride from adipose tissue stores to provide free fatty acids (FFAs) for hepatic ketogenesis. FFAs and ketones serve as alternate fuels for muscle. This hormonal signal also stimulates the breakdown of hepatic glycogen and promotes gluconeogenesis. Failure of any of the components of this hormonal signal can lead to hypoglycemia. Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Available @ StudentConsult.com A lack of suppression of insulin secretion in response to low serum glucose concentrations can occur in infants but is uncommon beyond the neonatal period. This situation arises most frequently in infants of diabetic mothers who were exposed to high concentrations of maternally derived glucose in utero, resulting in fetal islet cell hyperplasia. The hyperinsulinemic state is transient, usually lasting hours to days. Hyperinsulinism that persists beyond a few days of agecan result from distinct genetic disorders affecting glucose-regulated insulin release. These were previously referred to Infant of a diabetic mother Infant with erythroblastosis fetalis Persistent hyperinsulinemic hypoglycemia Glucose-6-phosphatase deficiency Amylo-1,6-glucosidase deficiency Liver phosphorylase deficiency Glycogen synthase deficiency Fructose-1,6-diphosphatase deficiency Pyruvate carboxylase deficiency Phosphoenolpyruvate carboxykinase deficiency


Pediatrics_Nelson

Pediatrics_Nelson. Fructose-1,6-diphosphatase deficiency Pyruvate carboxylase deficiency Phosphoenolpyruvate carboxykinase deficiency Long-, medium-, or short-chain fatty acid acyl-CoA dehydrogenase deficiency Carnitine deficiency (primary or secondary) Carnitine palmitoyltransferase deficiency Global hepatic dysfunction Reye syndrome Hepatitis Heart failure Sepsis, shock ACTH, Adrenocorticotropic hormone; acyl-CoA, acyl coenzyme A; IGF-2, insulin-like growth factor-2.


Pediatrics_Nelson

Pediatrics_Nelson. Global hepatic dysfunction Reye syndrome Hepatitis Heart failure Sepsis, shock ACTH, Adrenocorticotropic hormone; acyl-CoA, acyl coenzyme A; IGF-2, insulin-like growth factor-2. as nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of the newborn. In these infants, hyperplasia ofthe pancreatic islet cells develops in the absence of excessstimulation by maternal diabetes. Some of these patients havegenetic abnormalities of the islet cell sulfonylurea receptoror other genetic defects that alter the function of the adenosine triphosphate−sensitive potassium channel that regulatesinsulin secretion. Hyperinsulinism also can occur in Beckwith-Wiedemann syndrome, a condition characterized by neonatal somatic gigantism: macrosomia, macroglossia,omphalocele, visceromegaly, and earlobe creases.


Pediatrics_Nelson

Pediatrics_Nelson. Regardless of the cause, neonates with hyperinsulinism arecharacteristically large for gestational age (see Chapter 60). Hypoglycemia is severe and frequently occurs within 1 to 3 hours of a feeding. Glucose requirements are increased, oftentwo to three times the normal basal glucose requirement of 6to 8 mg/kg/min. The diagnosis of hyperinsulinism is confirmedby the detection of serum insulin concentrations greater than Headache Palpitation (tachycardia) Mental confusion Pallor Somnolence Paresthesia Dysarthria Trembling Personality changes Anxiety Inability to concentrate Weakness Staring Nausea Hunger Vomiting Convulsions *These features and perceptions of the features may be blunted if the patient is receiving β-blocking agents. 5 μU/mL during an episode of hypoglycemia. The absence ofserum and urine ketones at the time of hypoglycemia is animportant diagnostic feature, distinguishing hyperinsulinismfrom defects in counterregulatory hormone secretion.


Pediatrics_Nelson

Pediatrics_Nelson. Treatment initially involves the infusion of intravenous (IV) glucose at high rates and of diazoxide to suppress insulin secretion. If diazoxide therapy is unsuccessful, long-acting somatostatin analogs can be tried. Often medical therapy for persistent hyperinsulinemic hypoglycemia of the newborn is unsuccessful, and subtotal (90%) pancreatectomy is required to prevent long-term neurologic sequelae of hypoglycemia. In children hyperinsulinemia is a rare condition characterized by a voracious appetite, obesity, and accelerated linear growth and usually results from an islet cell adenoma. Computed tomography, magnetic resonance imaging, or radioisotope imaging of the pancreas should be attempted, but visualization of an adenoma is usually difficult. Surgical removal of the adenoma is curative.


Pediatrics_Nelson

Pediatrics_Nelson. In rare cases insulin or a hypoglycemic medication is administered by a parent or caregiver to a child as a form of child abuse, which is a condition referred to as Munchausen syndrome by proxy. This diagnosis should be suspected if extremely high insulin concentrations are detected (>100 μU/mL). C-peptide concentrations are low or undetectable, which confirms that the insulin is from an exogenous source.


Pediatrics_Nelson

Pediatrics_Nelson. Abnormalities in the secretion of counterregulatory hormonesthat produce hypoglycemia usually involve GH, cortisol, orboth. Deficiencies in glucagon and epinephrine secretion arerare. GH and cortisol deficiency occur as a result of hypopituitarism. Hypopituitarism results from congenital hypoplasiaor aplasia of the pituitary or, more commonly, from deficiencyof hypothalamic releasing factors (see Chapter 173). Clues tothis diagnosis in infants include the presence of hypoglycemia in association with midline facial or neurologic defects(e.g., cleft lip and palate or absence of the corpus callosum), pendular (roving) nystagmus (indicating visual impairment frompossible abnormalities in the development of the optic nerves, Heart, kidney, muscle, brain Brain, blood cells Figure 172-1 Regulation of serum glucose. represents inhibitions. EPI, Epinephrine; FFA, free fatty acid; GH, growth hormone; TG, triglyceride.


Pediatrics_Nelson

Pediatrics_Nelson. Heart, kidney, muscle, brain Brain, blood cells Figure 172-1 Regulation of serum glucose. represents inhibitions. EPI, Epinephrine; FFA, free fatty acid; GH, growth hormone; TG, triglyceride. which can occur in septo-optic dysplasia), and the presence ofmicrophallus and cryptorchidism in boys (indicating abnormalities in gonadotropin secretion). Jaundice and hepatomegaly alsocan occur, simulating neonatal hepatitis. Despite the presence ofGH deficiency, these infants are usually of normal size at birth. Deficient cortisol secretion also can occur in primary adrenal insufficiency, resulting from a variety of causes. In infants it often results from congenital adrenal hyperplasia, most frequently as a result of 21-hydroxylase deficiency (see Chapters 177 and 178). In older children, primary adrenal insufficiency is seen most frequently in Addison disease and other disorders (see Chapter 178).


Pediatrics_Nelson

Pediatrics_Nelson. Confirmation of GH or cortisol deficiency as the cause of hypoglycemia requires the detection of low serum GH and cortisol concentrations during an episode of hypoglycemia or after other stimulatory testing. In contrast to hyperinsulinism, serum and urine ketones are positive at the time of hypoglycemia and FFAs are elevated. Treatment involves supplementation of the deficient hormones in physiologic doses. Sufficient energy stores in the form of glycogen, adipose tissue, and muscle are necessary to respond appropriately to hypoglycemia. Deficiencies in these stores are a common cause of hypoglycemia in neonates who are small for gestational age or premature (see Chapter 60). Beyond the early neonatal period, energy stores are usually sufficient to meet the metabolic requirements except in malnourished children.


Pediatrics_Nelson

Pediatrics_Nelson. A common cause of new-onset hypoglycemia is idiopathicketotic hypoglycemia, usually seen in children between 18months and 5 years of age. Patients have symptoms of hypoglycemia after a period of prolonged fasting, often in the settingof an intercurrent illness with decreased feeding. Children withthis disorder are often thin and small and may have a history ofbeing small for gestational age. Defective mobilization of alanine from muscle to fuel gluconeogenesis is thought to be the cause, although the condition may derive mostly from havinglower fuel reserves. Because there are no specific diagnostic testsfor this disorder, ketotic hypoglycemia is a diagnosis of exclusion. Treatment involves avoidance of fasting and frequent feedings of a high-protein, high-carbohydrate diet. Patients may require hospitalization for IV glucose infusion if they cannot maintain adequate oral intake during a period of illness. The disorder usually resolves spontaneously by 7 to 8 years of age.


Pediatrics_Nelson

Pediatrics_Nelson. Maintenance of normal serum glucose concentrations in thefasting state requires glucose production via glycogenolysisand gluconeogenesis and the production of alternative energysources (FFAs and ketones) via lipolysis and fatty acid oxidation. Glycogen storage diseases occur in a variety of subtypes that differ in severity (see Chapter 52). Among the subtypes that result in hypoglycemia, the most severe form is glucose-6-phosphatase deficiency, which is characterized by severe hypoglycemia, massive hepatomegaly, growth retardation, and lactic acidosis. In contrast, deficiencies in the glycogen phosphorylase enzymes may cause isolated hepatomegaly with or without hypoglycemia.


Pediatrics_Nelson

Pediatrics_Nelson. The diagnosis of glycogen storage disease is suggested by a finding of hepatomegaly without splenomegaly. Confirmation of the diagnosis requires specific biochemical studies of leukocytes or liver biopsy specimens. Treatment involves frequent high-carbohydrate feedings during the day and continuous feedings at night via nasogastric tube. Feedings of uncooked cornstarch overnight are sufficient to maintain serum glucose concentrations in some patients. Defects in gluconeogenesis are uncommon and include fructose-1,6-diphosphatase deficiency and phosphoenolpyruvate carboxykinase deficiency. Affected patients exhibit fasting hypoglycemia, hepatomegaly, lactic acidosis, and hyperuricemia. Ketosis occurs, and FFA and alanine concentrations are high. Treatment involves frequent high-carbohydrate, low-protein feedings (see Chapter 52).


Pediatrics_Nelson

Pediatrics_Nelson. Fatty acid oxidation disorders of ketogenesis include the fatty acid acyl-coenzyme A (CoA) dehydrogenase deficiencies; long-chain, medium-chain, and short-chain acyl-CoA dehydrogenase deficiencies; and hereditary carnitine deficiency (see Chapter 55). Of these disorders, medium-chain acyl-CoA dehydrogenase deficiency is the most common; it occurs in 1 in 9000 to 15,000 live births. Patients often are well in infancy and have the first episode of hypoglycemia at 2 years of age or older. Episodes of hypoglycemia usually occur with prolonged fasting or during episodes of intercurrent illness. Mild hepatomegaly may be present along with mild hyperammonemia, hyperuricemia, and mild elevations in hepatic transaminases. Ketone concentrations are low or undetected. The diagnosis is confirmed by the finding of elevated concentrations of dicarboxylic acids in the urine. Treatment involves avoidance of fasting.


Pediatrics_Nelson

Pediatrics_Nelson. Many metabolic disorders can lead to hypoglycemia, including galactosemia, hereditary fructose intolerance, and disorders of organic acid metabolism (see Table 172-1). Hypoglycemia in these disorders is usually a reflection of global hepatic dysfunction secondary to the buildup of hepatotoxic intermediates. Many of these disorders present with low concentrations of ketone bodies because ketogenesis also is affected. The finding of non–glucose-reducing substances in the urine suggests a diagnosis of galactosemia or hereditary fructose intolerance. Occurrence of symptoms after ingestion of fructose or sucrose suggests hereditary fructose intolerance. Treatment requires dietary restriction of the specific offending substances.


Pediatrics_Nelson

Pediatrics_Nelson. Hypoglycemia can occur as an adverse effect of numerousmedications (see Table 172-1). Valproate toxicity can cause a disorder similar to that seen in the fatty acid oxidationdefects. Ethanol ingestion also can cause hypoglycemia,especially in younger children, because the metabolism ofethanol results in the depletion of cofactors necessary forgluconeogenesis.


Pediatrics_Nelson

Pediatrics_Nelson. Although the list of causes of hypoglycemia is long and complex, establishing the etiology in a particular patient is important. Frequently it is difficult to make an accurate diagnosis until one can obtain a critical sample of blood and urine at the time of the hypoglycemic episode. In a child with unexplained hypoglycemia, a serum sample should be obtained before treatment for the measurement of glucose and insulin, GH, cortisol, FFAs, and β-hydroxybutyrate and acetoacetate. Measurement of serum lactate levels also should be considered. A urine specimen should be obtained for measuring ketones and reducing substances. Hypoglycemia without ketonuria suggests hyperinsulinism or a defect in fatty acid oxidation. The results of this initial testing can establish whether endocrine causes are responsible and, if not, provide initial information regarding which types of metabolic disorders are most likely. Whenever possible, additional samples of blood and urine should be frozen for


Pediatrics_Nelson

Pediatrics_Nelson. are responsible and, if not, provide initial information regarding which types of metabolic disorders are most likely. Whenever possible, additional samples of blood and urine should be frozen for further analysis, if necessary.


Pediatrics_Nelson

Pediatrics_Nelson. Acute care of a patient with hypoglycemia consists of rapid administration of IV glucose (2 mL/kg of 10% dextrose in water). After the initial bolus, an infusion of IV glucose should provide approximately 1.5 times the normal hepatic glucose production rate (8 to 12 mg/kg/min in infants, 6 to 8 mg/kg/min in children). This infusion allows for suppression of the catabolic state and prevents further decompensation in patients with certain metabolic disorders. If adrenal insufficiency is suspected, stress doses of glucocorticoids should be administered.


Pediatrics_Nelson

Pediatrics_Nelson. Normal growth is the final common pathway of many factors,including endocrine, environmental, nutritional, and geneticinfluences (see Chapter 5). A normal linear growth patternis good evidence of overall health and can be considered abioassay for the well-being of the whole child. The effects ofcertain hormones on growth and ultimate height are listed inTable 173-1. Just as various factors influence stature, stature itself influences psychological, social, and potentially economic well-being. Parental concern about the psychosocial consequences of abnormal stature often causes a family to seek medical attention.


Pediatrics_Nelson

Pediatrics_Nelson. Growth hormone (GH) secretion is pulsatile, stimulated by hypothalamic GH-releasing factor (GRF) and inhibited by GH release inhibitory factor (somatostatin, somatotropin release-inhibiting factor [SRIF]), which interact with their individual receptors on the somatotrope in a noncompetitive manner. GH is also stimulated by ghrelin, produced in the stomach. GH circulates bound to a GH-binding protein (GHBP); GHBP abundance reflects the abundance of GH receptors. GH has direct effects on tissue and also causes production and secretion of insulin-like growth factor-1 (IGF-1) in many tissues. GH stimulates IGF-1 production in liver along with production of the acid-labile subunit and the IGF-binding protein (IGF-BP3); this forms the complex that delivers IGF-1 to tissue.


Pediatrics_Nelson

Pediatrics_Nelson. IGF-1 acts primarily as a paracrine and autocrine agent and is most closely associated with postnatal growth. When IGF-1 attaches to its membrane-bound receptor, second messengers are stimulated to change the physiology of the cell and produce growth effects. IGF-1 production is influenced by disease states such as malnutrition, chronic renal and liver disease, hypothyroidism, or obesity. IGF-BP3 is measurable in clinical assays and is less influenced by nutrition and age than is IGF-1; measuring IGF-1 and IGF-BP3 is useful in evaluating GH adequacy, particularly in infancy and early childhood. Measurement of Growth


Pediatrics_Nelson

Pediatrics_Nelson. Measurement of Growth The correct measurement of an infant’s length requires one adult to hold the infant’s head still and another adult to extend the feet with the soles perpendicular to the lower legs. A caliper-likedevice, such as an infantometer, or the movable plates on an infant scale are used so that the exact distance between the two calipers or plates can be determined. Marking the position of the head and feet of an infant lying on a sheet of paper on the examining table leads to inaccuracies and may miss true disorders of growth or create false concerns about a disorder of growth in a normal child. Accurate measurements of height (standing), or length (lying down), and weight should be plotted on the Centers for Disease Control and Prevention growth charts for the timely diagnosis of growth disorders ( http:// www.cdc.gov/growthcharts/


Pediatrics_Nelson

Pediatrics_Nelson. After 2 years of age, the height of a child should be measured in the standing position. Children measured in the standing position should be barefoot against a hard surface. A Harpenden stadiometer or equivalent device is optimal for the measurement of stature. A decrease of roughly 1.25 cm in height measurement may occur when the child is measured in the standing position rather than in the lying position, leading to the inappropriate referral of many children who appear to be not growing to a subspecialist.


Pediatrics_Nelson

Pediatrics_Nelson. Measurement of the arm span is essential when the diagnoses of Marfan or Klinefelter syndrome, short-limbed dwarfism, or other dysmorphic conditions are considered. Arm span is measured as the distance between the tips of the fingers when the patient holds both arms outstretched horizontally while standing against a solid surface. The upper-to-lower segment ratio is the ratio of the upper segment (determined by subtraction of the measurement from the symphysis pubis to the floor [known as the lower segment] from the total height) to the lower segment. This ratio changes with age. A normal term Adapted from Underwood LE, Van Wyk JJ: Normal and aberrant growth. In Wilson JD, Foster DW, editors: Textbook of Endocrinology, ed 8, Philadelphia, 1992, WB Saunders. *Effect in most patients with treatment.


Pediatrics_Nelson

Pediatrics_Nelson. Saunders. *Effect in most patients with treatment. infant has an upper-to-lower ratio of 1.7:1, a 1-year-old has a ratio of 1.4:1, and a 10-year-old has a ratio of 1:1. Conditions of hypogonadism, not commonly discerned or suspected until after the normal age for onset of puberty, lead to greatly decreased upper-to-lower ratio in an adult, whereas long-lasting and untreated hypothyroidism leads to a high upper-tolower ratio in the child. Endocrine Evaluation of Growth Hormone Secretion Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. GH is a 191–amino acid protein secreted by the pituitary gland under the control of GRF and SRIF (see Fig. 170-2). GH secretion is enhanced by α-adrenergic stimulation, hypoglycemia, starvation, exercise, early stages of sleep, and stress and inhibited by β-adrenergic stimulation and hyperglycemia. Because concentrations of GH are low throughout the day, except for brief secretory peaks in the middle of the night or early morning, the daytime ascertainment of GH deficiency or sufficiency on the basis of a single determination of a random GH concentration is impossible. Adequacy of GH secretion may be determined by a stimulation test to measure peak GH secretion. A normal response is a vigorous secretory peak after stimulation; the lack of such a peak is consistent with GH deficiency. However there is a high false-positive rate (on any day, about 10% or more of normal children may not reach the normal GH peak after even two stimulatory tests). Indirect measurements of GH secretion,


Pediatrics_Nelson

Pediatrics_Nelson. there is a high false-positive rate (on any day, about 10% or more of normal children may not reach the normal GH peak after even two stimulatory tests). Indirect measurements of GH secretion, such as serum concentrations of IGF-1 and IGF-BP3, are considered better screens for GH deficiency.


Pediatrics_Nelson

Pediatrics_Nelson. The factors responsible for postnatal growth are not the same as the factors that mediate fetal growth. Thyroid hormone is essential for normal postnatal growth, although a thyroid hormone–deficient fetus achieves a normal birth length; similarly a GH-deficient fetus has a normal birth length, although in IGF-1 deficiency resulting from GH resistance (Laron dwarfism), fetuses are shorter than control subjects. Adequate thyroid hormone is necessary to allow the secretion of GH. Hypothyroid patients may appear falsely to be GH deficient; with thyroid hormone repletion, GH secretion normalizes. Gonadal steroids are important in the pubertal growth spurt. The effects of other hormones on growth are noted in Table 173-1. Short Stature of Nonendocrine Causes Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Short stature is defined as subnormal height relative to otherchildren of the same gender and age, taking family heightsinto consideration. It can be caused by numerous conditions(Table 173-2). The Centers for Disease Control and Prevention growth charts use the 3rd percentile of the growth curve as the demarcation of the lower limit. Growth failure denotes a slow growth rate regardless of stature. Ultimately aslow growth rate leads to short stature, but a disease processis detected sooner if the decreased growth rate is noted beforethe stature becomes short. Plotted on a growth chart, growthfailure appears as a curve that crosses percentiles downwardand is associated with a height velocity below the 5th percentile of height velocity for age (Fig. 173-1). A corrected mid-parental, or genetic target, height helps determine whetherthe child is growing well for the family (see Chapter 6). Todetermine a range of normal height for the family under consideration, the corrected midparental


Pediatrics_Nelson

Pediatrics_Nelson. target, height helps determine whetherthe child is growing well for the family (see Chapter 6). Todetermine a range of normal height for the family under consideration, the corrected midparental height is bracketed by2 standard deviations (SDs), which, for the United States, isapproximately 10 cm (4 in.). The presence of a height 3.5 SDsbelow the mean, a height velocity below the 5th percentilefor age, or a height below the target height corrected for mid-parental height requires a diagnostic evaluation.


Pediatrics_Nelson

Pediatrics_Nelson. Nutrition is the most important factor affecting growth on a worldwide basis (see Chapter 28). Failure to thrive may develop in the infant as a result of maternal deprivation(nutritional deficiency or aberrant psychosocial interaction) or as a result of organic illness (anorexia, nutrient losses through a form of malabsorption, or hypermetabolism caused Exogenous Diabetes mellitus under poor control Diabetes insipidus (untreated) Hypophosphatemic vitamin D-resistant rickets Virilizing congenital adrenal hyperplasia (tall child, short adult) P-450c21, P-450c11 deficiencies Turner syndrome (syndrome of gonadal dysgenesis) Noonan syndrome (pseudo-Turner syndrome) Autosomal trisomy 13, 18, 21 Laurence-Moon-Bardet-Biedl syndrome Prader-Willi syndrome Autosomal abnormalities Dysmorphic syndromes (e.g., Russell-Silver or Cornelia Gastrointestinal disorders Malabsorption (e.g., celiac disease) Disorders of swallowing Inflammatory bowel disease


Pediatrics_Nelson

Pediatrics_Nelson. Gastrointestinal disorders Malabsorption (e.g., celiac disease) Disorders of swallowing Inflammatory bowel disease Hereditary fructose intolerance Malnutrition Kwashiorkor, marasmus Iron deficiency Zinc deficiency Anorexia caused by chemotherapy for neoplasms Cerebral palsy Modified from Styne DM: Growth disorder. In Fitzgerald PA, editor: Handbook of Clinical Endocrinology, Norwalk, CT, 1986, Appleton & Lange. AIDS, Acquired immunodeficiency syndrome; CNS, central nervous system; GH, growth hormone; IGF, insulin-like growth factor. *Only if caloric intake is severely diminished.


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Pediatrics_Nelson. by hyperthyroidism or other causes) (see Chapter 21). Psycho-psychosocial environment, GH physiology normalizes, and logical difficulties also can affect growth, as in psychosocial growth occurs. or deprivation dwarfism, in which the child develops func-The common condition known as constitutional delay in tional temporary GH deficiency and poor growth as a result growth or puberty or both is considered a variation of normal of psychological abuse; when placed in a different, healthier growth, caused by a reduced tempo, or cadence, of physiologic


Pediatrics_Nelson

Pediatrics_Nelson. Figure 173-1 Patterns of linear growth. Normal growth percentiles (5th, 50th, and 95th) are shown along with typical growth curves for A, Constitutional delay of growth and adolescence (short stature with normal growth rate for bone age, delayed pubertal growth spurt, and eventual achievement of normal adult stature). B, Familial short stature (short stature in childhood and as an adult). C, Acquired pathologic growth failure (e.g., acquired untreated primary hypothyroidism) (see Chapter 5).


Pediatrics_Nelson

Pediatrics_Nelson. development (see Fig. 173-1). Usually a family member had delayed growth or puberty but achieved a normal final height. The bone age is delayed, but the growth rate remains mostly within the lower limits of normal. Constitutional delay usually leads to a delay in secondary sexual development. Genetic or familial short stature (Table 173-3) refers to the stature of a child of short parents, who is expected to reach a lower than average height and yet normal for these parents. If the parents were malnourished as children, grew up in a zone of war, or suffered famine, the heights of the parents are less predictive. Although there are differences in height associated with ethnicity, the most significant difference in stature between ethnic groups is the result of nutrition.


Pediatrics_Nelson

Pediatrics_Nelson. Phenotypic features suggesting an underlying chromosomaldisorder can occur in many syndromes. These syndromes can besuspected by attending to arm spans and upper-to-lower segmentratios. Genetic syndromes often combine obesity and decreasedheight, whereas otherwise normal obese children are usuallytaller than average and have advanced skeletal development andphysical maturation (see Table 173-2). The Prader-Willi syndrome includes fetal and infantile hypotonia, small hands and feet (acromicria), postnatal acquired obesity with an insatiableappetite, developmental delay, hypogonadism, almond-shapedeyes, and abnormalities of the snRNP (small nuclear ribonucleicparticle) portion of the 15th chromosome at 15q11-q13. Mostcases have deletion of the paternal sequence, but about 20% to25% have uniparental disomy, in which both chromosomes 15derive from the mother. Laurence-Moon-Bardet-Biedl syndrome is characterized by retinitis pigmentosa, hypogonadism, and developmental delay with an


Pediatrics_Nelson

Pediatrics_Nelson. uniparental disomy, in which both chromosomes 15derive from the mother. Laurence-Moon-Bardet-Biedl syndrome is characterized by retinitis pigmentosa, hypogonadism, and developmental delay with an autosomal dominant inheritance pattern. Laurence-Moon syndrome is associated with spastic paraplegia; Bardet-Biedl syndrome is associatedwith obesity and polydactyly. Pseudohypoparathyroidismleads to short stature and developmental delay with short fourthand fifth digits (Albright hereditary osteodystrophy phenotype),resistance to parathyroid hormone and resultant hypocalcemia,and elevated levels of serum phosphorus. Turner syndrome is characterized by a karyotype of 45XO or by a mosaic karyotypeand clinically presents with short stature, shield chest, wide-spaced nipples, wide-carrying angle of the upper extremities,high-arched palate, gonadal failure, kidney dysplasias with normal function, and aortic arch abnormalities. Affected girlsare often susceptible to autoimmune disorders.


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Pediatrics_Nelson. Available @ StudentConsult.com Available @ StudentConsult.com Classic congenital or idiopathic GH deficiency occurs in about 1 in 4000 to 1 in 10,000 children. Idiopathic GH deficiency, of unidentified specific etiology, is the most common cause of both congenital and acquired GH deficiency. Less often GH deficiency is caused by anatomic defects of the pituitary gland, such as pituitary aplasia or other midline defects, with variable degrees of deficiency of other pituitary functions. Hereditary forms of GH deficiency that affect pituitary differentiation are the result of heterogeneous defects of the gene for GH, GRF, or GH receptor. Classic GH deficiencyrefers to very reduced to absent secretion of GH; numerous short children may have intermediate forms of decreased GH secretion. Acquired GH deficiency causing late-onset growth failure suggests the possibility of a tumor of the hypothalamus or pituitary causing compression of the area (see Tables 173-2 and 173-3).


Pediatrics_Nelson

Pediatrics_Nelson. Infants with congenital GH deficiency achieve a normal or near-normal birth length and weight at term, but the growth rate slows after birth, most noticeably after age 2 to 3 years. These children become progressively shorter for age and tend to have an elevated weight-to-height ratio, appearing chubby and short. Careful measurements in the first year of life may suggest the diagnosis, but most patients elude diagnosis until several years of age. A patient with classic GH deficiency has the appearance of a cherub (a chubby, immature appearance), with a high-pitched voice resulting from an immature Karyotype Normal Normal Normal Normal 45,X or partial Normal Normal deletion of X chromosome or mosaic Stimulated GH Low Normal for bone age Normal Possibly low, or Usually normal Low Usually normal high if patient malnourished


Pediatrics_Nelson

Pediatrics_Nelson. Stimulated GH Low Normal for bone age Normal Possibly low, or Usually normal Low Usually normal high if patient malnourished ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; GH, growth hormone; GnRH, gonadotropin-releasing hormone; TRH, thyrotropin-releasing hormone; T4, thyroxine. *Possibly with GnRH, CRH, or TRH deficiency. CBC Anemia: nutritional, chronic disease, malignancy Leukopenia: bone marrow failure syndromes Thrombocytopenia: malignancy, infection ESR, CRP Inflammation of infection, inflammatory diseases, malignancy Metabolic panel Signs of acute or chronic hepatic, renal, (electrolytes, liver adrenal dysfunction; hydration and enzymes, BUN) acid-base status Carotene, folate, and Assess malabsorption; detect celiac prothrombin time; disease celiac antibody panel Urinalysis with pH Signs of renal dysfunction, hydration, water and salt homeostasis; renal tubular acidosis


Pediatrics_Nelson

Pediatrics_Nelson. Urinalysis with pH Signs of renal dysfunction, hydration, water and salt homeostasis; renal tubular acidosis Cranial imaging (MRI) Assesses hypothalamic-pituitary tumors (craniopharyngioma, glioma, germinoma) or congenital midline defects Bone age Compare with height age and evaluate height potential IGF-1, IGF-BP3 Reflects growth hormone status or nutrition Prolactin Elevated in hypothalamic dysfunction or destruction, suppressed in pituitary disease BUN, Blood urea nitrogen; CBC, complete blood count; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IGF-1, insulin-like growth factor-1; IGF-BP3, insulin-like growth factor-binding protein 3; MRI, magnetic resonance imaging.


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Pediatrics_Nelson. larynx. Unless severe hypoglycemia occurs or dysraphism (midline defects) of the head includes a central nervous system (CNS) defect that affects mentation, the patient has normal intellectual growth and age-appropriate speech. Male neonates with isolated GH deficiency with or without gonadotropin deficiency may have a microphallus (a stretched penile length of <2 cm [normal is 3 to 5 cm]) and fasting hypoglycemia. Patients who lack the adrenocorticotropic hormone (ACTH, stimulates cortisol) in addition to GH may have more profound hypoglycemia because cortisol also stimulates gluconeogenesis.


Pediatrics_Nelson

Pediatrics_Nelson. A very rare cause of growth failure is GH resistance or GH insensitivity, caused by abnormal number or function of GH receptors or by a postreceptor defect. Patients with the autosomal recessive Laron syndrome, involving mutations of the GH receptor, have a prominent forehead, hypoplastic nasal bridge, delayed dentition, sparse hair, blue sclerae, delayed bone maturation and osteoporosis, progressive adiposity, hypercholesterolemia, and low blood glucose. They have elevated serum GH concentrations, although serum IGF-1 and IGF-BP3 concentrations are low. Malnutrition, medications (corticosteroids), or severe liver disease may cause acquired GH resistance because serum GH is elevated and IGF-1 is decreased.


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Pediatrics_Nelson. If family or other medical history does not provide a likelydiagnosis, screening tests should include a metabolic panelto evaluate kidney and liver function, a complete bloodcount (CBC) to rule out anemia, a celiac panel to rule outceliac disease, and carotene and folate levels to reflect nutrition and rule out malabsorption. A urinalysis aids in theevaluation of renal function. Urinary pH and serum bicarbonate can assess for renal tubular acidosis. In a girl without another explanation for short stature, a karyotype mayrule out Turner syndrome. A bone age will establish skeletal maturation.


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Pediatrics_Nelson. If chronic disease or familial short stature are ruled out and routine laboratory testing is normal (Table 173-4), two GH stimulatory tests are commonly performed (see Table 170-2). GH testing should be offered to a patient who is short (<5th percentile and usually >3.5 SDs below the mean), growing poorly (<5th percentile growth rate for age), or whose height projection, based on bone age, is considerably below the target height when corrected for family height.


Pediatrics_Nelson

Pediatrics_Nelson. Classic GH-deficient patients do not show an increase in serum GH levels after stimulation. Some patients release GH in response to secretagogue testing but cannot release GH spontaneously during the day or night. Measuring serum IGF-1 and IGF-BP3 is suggested but not consistently helpful in establishing a diagnosis of GH deficiency. Tests for GH secretion are insensitive, not very specific, and fairly variable. In equivocal cases, an operational definition of GH deficiency might be that patients grow significantly faster when administered a normal dose of GH than before treatment. GH deficiency is treated with biosynthetic recombinant DNA–derived GH. Dosage is titrated to the growth rate. Treatment with GH carries the risk of an increased incidence of slipped capital femoral epiphysis, especially in rapidly growing adolescents, and of pseudotumor cerebri.


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Pediatrics_Nelson. Administration of GH to patients with normal GH responsiveness to secretagogues is controversial, but, as noted earlier, diagnostic tests are imperfect; if the patient is growing extremely slowly without alternative explanation, GH therapy is sometimes used. GH is effective in increasing the growth rate and final height in Turner syndrome and in chronic renal failure; GH also is used for treatment of short stature and muscle weakness of Prader-Willi syndrome. Other indications include children born small for gestational age who have not exhibited catch-up growth by 2 years of age and the long-term treatment of idiopathic short stature with height 2.25 SDs or less below the mean. Psychological support of children with severe short stature is important. Although there is controversy, marital status, satisfaction with life, and vocational achievement may be decreased in children of short stature who are not given supportive measures.


Pediatrics_Nelson

Pediatrics_Nelson. The staging of pubertal changes and the sequence of events are discussed in Chapter 67. The onset of puberty is marked by pubarche and gonadarche. Pubarche results from adrenal maturation or adrenarche and is marked with the appearance of pubic hair; other features include oiliness of hair and skin, acne, axillary hair, and body odor. Gonadarche is characterized by increasing secretion of gonadal sex steroids as a result of the maturation of the hypothalamic-pituitary-gonadal axis. These sex steroids differ by gender, consisting of testosterone from the testes and estradiol and progesterone from the ovaries. In males physical signs are pubic hair, axillary hair, facial hair, increased muscularity, deeper voice, increased penile size, and increased testicular volume. In females the physical signs are breast development, development of the female body habitus, increased size of the uterus, and menarche with regular menstrual cycles. The third component is the growth spurt of puberty.


Pediatrics_Nelson

Pediatrics_Nelson. Hypothalamic gonadotropin-releasing hormone (GnRH), produced by cells in the arcuate nucleus, is secreted from the median eminence of the hypothalamus into the pituitary portal system and reaches the membrane receptors on the pituitary gonadotropes to cause the production and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) into the circulation. The hypothalamic-pituitary-gonadal axis is active in the fetus and newborn but is suppressed in the childhood years until activity increases again at the onset of puberty.


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Pediatrics_Nelson. In females FSH stimulates the ovarian production of estrogen and, later in puberty, causes the formation and supportof corpus luteum. In males LH stimulates the productionof testosterone from the Leydig cells; later in puberty, FSHstimulates the development and support of the seminiferous tubules. The gonads also produce the protein inhibin.Both sex steroids and inhibin suppress the secretion of gonadotropins. The interplay of the products of the gonadsand GnRH modulates the serum concentrations of gonadotropins. GnRH is released in episodic pulses that vary duringdevelopment and during the menstrual period. These pulsesensure that gonadotropins are released in a pulsatile manner. With the onset of puberty, the amplitude of the pulses ofgonadotropins and, in turn, the sex steroids increases, firstat night and then throughout the day. Adrenarche generallyoccurs several years earlier than gonadarche and is heraldedby increasing circulating dehydroepiandrosterone (DHEA)or


Pediatrics_Nelson

Pediatrics_Nelson. increases, firstat night and then throughout the day. Adrenarche generallyoccurs several years earlier than gonadarche and is heraldedby increasing circulating dehydroepiandrosterone (DHEA)or androstenedione. Serum DHEA increases years before theappearance of its effects.


Pediatrics_Nelson

Pediatrics_Nelson. The normal developmental sequence in girls is thelarche (due to gonadarche) followed closely by pubarche (due to adrenarche) and finally menarche, 2 to 3 years later. In boys the first normal event is scrotal thinning followed by the enlargement of testes and by the appearance of pubic hair (long diameter of the testis greater than 2.5 cm, volume greater than 4 mL). Most of the enlargement of testes during puberty is the result of seminiferous tubule maturation. Available @ StudentConsult.com Puberty is delayed when there is no sign of pubertal development by age 13 years in girls and 14 years in boys living in the United States (Tables 174-1 and 174-2).


Pediatrics_Nelson

Pediatrics_Nelson. Patients with constitutional delay have delayed onset of pubertal development and significant bone age delay (2 standard deviations below the mean, which is equal to a 1.5to 2-year delay as a teenager). The height of the patient should remain close to the genetic potential, based on the parental heights, when reinterpreted for bone age (see Chapter 173). Usuallyheight gain is below, although fairly parallel to, the normal percentiles on the growth curve. The prepubertal nadir, or deceleration before their pubertal growth spurt, is prolonged or protracted. A family history of delayed puberty in a parent or sibling is reassuring. Spontaneous puberty usually begins in these patients by the time the bone age reaches 12 years in boys and 11 years in girls. Other causes of delayed puberty must be eliminated before a diagnosis of constitutional delay in puberty is made. Observation and reassurance are appropriate. Adult height normal for the genetic potential is generally attained. In some


Pediatrics_Nelson

Pediatrics_Nelson. be eliminated before a diagnosis of constitutional delay in puberty is made. Observation and reassurance are appropriate. Adult height normal for the genetic potential is generally attained. In some cases, boys may be treated with low-dose testosterone for a few months if the bone age is at least 11 to 12 years. Treatment is not required for longer than 4 to 8 months because endogenous hormone production usually ensues. Boys who do not initiate endogenous hormone production should be evaluated for other causes of hypogonadism. Estrogen treatment has been used in girls with constitutional delay, but there are no clear studies showing the added benefits. Young women with delayed puberty may need to be evaluated for primary amenorrhea.


Pediatrics_Nelson

Pediatrics_Nelson. As a cause of delayed or absent puberty, hypogonadotropic hypogonadism may be difficult to distinguish from constitutional delay (see Tables 174-1 and 174-2). Hypogonadotropic hypogonadism precludes spontaneous entry into gonadarche; adrenarche usually occurs to some degree. Throughout childhood and in early puberty, patients with hypogonadotropic hypogonadism have normal proportions and growth. When these patients reach adulthood, eunuchoid proportions mayensue because their long bones grow for longer than normal, producing an upper-to-lower ratio below the lower limit of normal of 0.9 and an arm span greater than their height. If a patient has concurrent growth hormone (GH) deficiency, however, stature is exceptionally short, and the condition may have been diagnosed in infancy with a microphallus. Tumors (craniopharyngioma, germinoma, glioma, prolactinoma) Congenital malformations Radiation therapy Other causes


Pediatrics_Nelson

Pediatrics_Nelson. Idiopathic and genetic forms of multiple pituitary hormone deficiencies Miscellaneous disorders Prader-Willi syndrome Laurence-Moon-Bardet-Biedl syndrome Functional gonadotropin deficiency Chronic systemic disease and malnutrition Hypothyroidism Cushing disease Diabetes mellitus Hyperprolactinemia Anorexia nervosa Psychogenic amenorrhea Impaired puberty and delayed menarche in female athletes and ballet dancers (exercise amenorrhea) Hypergonadotropic hypogonadism Klinefelter syndrome (syndrome of seminiferous tubular dysgenesis) and its variants Other forms of primary testicular failure Anorchia and cryptorchidism Syndrome of gonadal dysgenesis and its variants (Turner syndrome) Other forms of primary ovarian failure XX and XY gonadal dysgenesis Familial and sporadic XX gonadal dysgenesis and its variants Familial and sporadic XY gonadal dysgenesis and its variants Noonan syndrome Galactosemia


Pediatrics_Nelson

Pediatrics_Nelson. Modified from Grumbach MM, Styne DM: Puberty. In Wilson JD, Foster DW, editors: Williams Textbook of Endocrinology, ed 9, Philadelphia, 1998, WB Saunders. CNS, Central nervous system. Disorders that can cause hypogonadism include congenital hypopituitarism, such as midline defects, tumors, infiltrative disease (hemochromatosis), and many syndromes, including Laurence-Moon-Bardet-Biedl, Prader-Willi, and Kallmann syndromes. If there is an inability to release gonadotropins but no other pituitary abnormality, the patient has isolated gonadotropin deficiency (almost universally a result of absent GnRH). Patients grow normally until the time of the pubertal growth spurt, when they fail to experience the accelerated growth characteristic of the normal growth spurt.


Pediatrics_Nelson

Pediatrics_Nelson. Kallmann syndrome combines isolated gonadotropin deficiency with disorders of olfaction. There is genetic heterogeneity; some patients have a decreased sense of smell, othershave abnormal reproduction, and some have both. Most casesare sporadic but a number of patients may have mutations inthe KAL1 gene at Xp 22.3 (X chromosome) or KAL2 gene. The mutation causes the GnRH neurons to remain ineffectuallylocated in the primitive nasal area, rather than migrating to thecorrect location at the medial basal hypothalamus. Olfactorybulbs and olfactory sulci are often absent on magnetic resonance imaging (MRI). Other symptoms include disorders ofthe hand, with one hand copying the movements of the otherhand, shortened fourth metacarpal bone, and an absent kidney. Abnormalities of the Central Nervous System Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Abnormalities of the Central Nervous System Available @ StudentConsult.com Central nervous system (CNS) tumors, including pituitary adenoma, glioma, prolactinoma, or craniopharyngioma, are important causes of gonadotropin deficiency. Craniopharyngiomas havea peak incidence in the teenage years and may cause any type ofanterior or posterior hormone deficiency. Craniopharyngiomasusually calcify, eroding the sella turcica when they expand. Theymay impinge on the optic chiasm, leading to bitemporal hemianopsia and optic atrophy. Other tumors that may affect pubertaldevelopment include astrocytomas and gliomas.


Pediatrics_Nelson

Pediatrics_Nelson. Idiopathic hypopituitarism is the congenital absence of various combinations of pituitary hormones. Although this disorder may occur in family constellations, in X-linked or autosomal recessive patterns, sporadic types of congenital idiopathic hypopituitarism are more common. Congenital hypopituitarism may manifest in a male with GH deficiency and associated gonadotropin deficiency with a microphallus or with hypoglycemia with seizures, especially if adrenocorticotropic hormone and GH deficiency occurs as well. Syndromes of Hypogonadotropic Hypogonadism Available @ StudentConsult.com Available @ StudentConsult.com Short for Prepubertal, later Prepubertal, Prepubertal, Low for Normal Normal delay in chronologic pubertal later pubertal later normal chronologic growth and age, usually age, adolescence appropriate for


Pediatrics_Nelson

Pediatrics_Nelson. From Grumbach MM, Styne DM: Puberty. In Wilson JD, Foster DW, editors: Williams Textbook of Endocrinology, ed 9, Philadelphia, 1997, WB Saunders. DHEAS, Dehydroepiandrosterone sulfate; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone. Decreased gonadotropin function occurs when voluntary Hypergonadotropic Hypogonadism dieting, malnutrition, or chronic disease results in weight lossto less than 80% of ideal weight. Anorexia nervosa is charac-


Pediatrics_Nelson

Pediatrics_Nelson. Available @ StudentConsult.com terized by striking weight loss and psychiatric disorders (seeChapter 70). Primary or secondary amenorrhea frequently is found in affected girls, and pubertal development is absent orminimal, depending on the level of weight loss and the age atonset. Regaining weight to the ideal level may not immediately reverse the condition. Increased physical activity, evenwithout weight loss, can lead to decreased menstrual frequency and gonadotropin deficiency in athletic amenorrhea; when physical activity is interrupted, menstrual function mayreturn. Chronic or systemic illness (e.g., cystic fibrosis, diabetes mellitus, inflammatory bowel disease, or hematologicdiseases) can lead to pubertal delay or to amenorrhea fromhypothalamic dysfunction. Hypothyroidism inhibits the onset of puberty and delays menstrual periods. Converselysevere primary hypothyroidism may lead to precociouspuberty.


Pediatrics_Nelson

Pediatrics_Nelson. Hypergonadotropic hypogonadism is characterized by elevated gonadotropins and low sex steroid levels resulting from primary gonadal failure. This permanent condition is almost always diagnosed following the lack of entry into gonadarche and is not suspected throughout childhood. Gonadotropins do not increase to greater than normal until shortly before or around the normal time of puberty.


Pediatrics_Nelson

Pediatrics_Nelson. Ovarian failure is diagnosed by elevated gonadotropins. Turner syndrome, the syndrome of gonadal dysgenesis, is a common cause of ovarian failure and short stature. The karyotype is classically 45,XO, but other abnormalities of the X chromosome or mosaicism are possible. The incidence of Turner syndrome is 1 in 2000 to 1 in 3000 births. The features of a girl with Turner syndrome need not be evident on physical examination or by history. The diagnosis must be considered in any girl who is short without a contributory history. Patients with other types of gonadal dysgenesis and galactosemia as well as patients treated undergoing radiation therapy or chemotherapy for malignancy may develop ovarian failure.


Pediatrics_Nelson

Pediatrics_Nelson. Klinefelter syndrome (seminiferous tubular dysgenesis) isthe most common cause of testicular failure. The karyotype is47,XXY, but variants with more X chromosomes are possible. Theincidence is approximately 1 in 500 to 1 in 1000 in males. Testosterone levels may be close to normal, at least until mid-puberty,because Leydig cell function may be spared; however seminiferous tubular function characteristically is lost, causing infertility.Commonly LH levels may be normal to elevated, whereas FSHlevels are usually more unequivocally elevated. The age of onsetof puberty is usually normal, but secondary sexual changes maynot progress because of inadequate Leydig cell function. Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Available @ StudentConsult.com In addition to other diagnoses mentioned, other conditionsneed to be considered when evaluating girls with lack ofmenses. The Mayer-Rokitansky-Kuster-Hauser syndrome ofcongenital absence of the uterus occurs in 1 in 4000 to 5000female births. Anatomic obstruction by imperforate hymen orvaginal septum also presents with normal secondary sexualdevelopment without menstruation. The complete syndromeof androgen insensitivity includes normal feminization, absence of pubic or axillary hair, and primary amenorrhea.In this syndrome, all müllerian structures, including ovaries, uterus, fallopian tubes, and upper third of the vagina, are lacking; the karyotype is 46,XY, and subjects have intra-abdominal testes.


Pediatrics_Nelson

Pediatrics_Nelson. When no secondary sexual development is present after the upper age limits of normal pubertal development, serum gonadotropin levels should be obtained to determine whether the patient has a hypogonadotropic or hypergonadotropic hypogonadism (see Table 174-2). Based on gonadotropin measurements only, the differentiation between constitutional delay in growth and hypogonadotropic hypogonadism is difficult; the gonadotropin levels are low in both conditions. Sometimes observation for months or years is necessary before the diagnosis is confirmed. Ultrasound of the pelvic structures in females would be helpful in the workup of delayed puberty.


Pediatrics_Nelson

Pediatrics_Nelson. If a permanent condition is apparent, replacement with sexsteroids is indicated. Females are given transdermal estradiol,low-dose ethinyl estradiol (5 to 10 μg) or conjugated estrogens (starting at 0.3 mg daily, increasing to 0.625 mg or 0.9 mg by6 to 12 months later) in low daily doses until breakthroughbleeding occurs, at which time cycling is started with a dosefor 25 days; on days 20 to 25, a progestational agent, such asmedroxyprogesterone acetate (5 mg), is added to mimic thenormal increases in gonadal hormones and to induce a normal menstrual period. Alternatively combined estrogen and progesterone agents (oral contraceptives) may be used after breakthrough bleeding occurs. In males testosterone enanthateor cypionate (50 to 100 mg monthly with a progressive increaseto 100 to 200 mg) is given intramuscularly once every 4 weeks.This starting regimen is appropriate for patients with hypogonadotropic or hypergonadotropic hypogonadism, and doses are increased gradually to adult


Pediatrics_Nelson

Pediatrics_Nelson. mg) is given intramuscularly once every 4 weeks.This starting regimen is appropriate for patients with hypogonadotropic or hypergonadotropic hypogonadism, and doses are increased gradually to adult levels. Oral agents are not usedfor fear of hepatotoxicity. Patients with apparent constitutionaldelay in puberty who have, by definition, passed the upper limits of normal onset of puberty may be given a 3to 6-monthcourse of low-dose, sex-appropriate gonadal steroids to seewhether spontaneous puberty occurs. This course of therapymight be repeated once without undue advancement of boneage. All patients with any form of delayed puberty are at risk fordecreased bone density; adequate calcium intake is essential. Patients with hypogonadotropic hypogonadism may be able toachieve fertility by the administration of gonadotropin therapyor pulsatile hypothalamic-releasing hormone therapy administered by a programmable pump on an appropriate schedule.Subjects with hypergonadotropic hypogonadism


Pediatrics_Nelson

Pediatrics_Nelson. administration of gonadotropin therapyor pulsatile hypothalamic-releasing hormone therapy administered by a programmable pump on an appropriate schedule.Subjects with hypergonadotropic hypogonadism have, by definition, a primary gonadal problem and are unlikely to achievespontaneous fertility.


Pediatrics_Nelson

Pediatrics_Nelson. In subjects with Turner syndrome, the goals of therapy include promoting growth with exogenous human GH supplementation and induction of the secondary sexual characteristics and of menses with low-dose cyclic estrogen/progesterone replacement therapy. Patients with Turner syndrome have had successful pregnancies after in vitro fertilization with a donor ovum and endocrine support. Available @ StudentConsult.com Precocious Puberty in the Male Precocious Puberty in the Female


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Pediatrics_Nelson. Available @ StudentConsult.com Precocious Puberty in the Male Precocious Puberty in the Female Sexual precocity (precocious puberty) is classically defined as secondary sexual development occurring before the age of 9 years in boys or 8 years in girls (Tables 174-3 and 174-4).During the past 15 to 20 years, studies from the United States and Europe reported earlier breast development in girls, as compared to historical data. Studies clearly suggest an earlier age at puberty onset in American girls in the 1980s to 1990s compared to the 1930s and 1940s. However age at menarche occurred at the same time or slightly earlier. Thus the time span from breast development to menarche seemed to have increased. The findings could reflect that exogenous or lifestyle factors may influence the typical sequence of pubertal events.


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Pediatrics_Nelson. Central precocious puberty, resulting in gonadarche, emanates from premature activation of the hypothalamic-pituitarygonadal axis (GnRH-dependent). Peripheral precocious Other CNS disorders True precocious puberty after late treatment of congenital virilizing adrenal hyperplasia Chorionic gonadotropin-secreting tumors (hCG-dependent sexual precocity) CNS tumors (e.g., germinoma, chorioepithelioma, teratoma) Tumors in locations outside of the CNS (hepatoblastoma) LH-secreting pituitary adenoma Increased androgen secretion by adrenal or testis Congenital adrenal hyperplasia (21-hydroxylase deficiency, 11-hydroxylase deficiency) Males (feminization) Adrenal neoplasm Increased extraglandular conversion of circulating steroids to estrogen Females (virilization) (Congenital adrenal hyperplasia, P-450c21 deficiency, P-450c11 deficiency, 3β-Hydroxysteroid dehydrogenase deficiency) Virilizing adrenal neoplasms Virilizing ovarian neoplasms (e.g., arrhenoblastomas)


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Pediatrics_Nelson. From Grumbach MM, Styne DM: Puberty. In Wilson JD, Foster DW, editors: Williams Textbook of Endocrinology, ed 9, Philadelphia, 1998, WB Saunders. CNS, Central nervous system; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; LH, luteinizing hormone. puberty, gonadarche or adrenarche, does not involve the hypothalamic-pituitary-gonadal axis (GnRH-independent).


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Pediatrics_Nelson. puberty, gonadarche or adrenarche, does not involve the hypothalamic-pituitary-gonadal axis (GnRH-independent). In central precocious puberty, every endocrine and physical aspect of pubertal development is normal but too early; this includes tall stature, advanced bone age consistent with somatic age, increased sex steroid and pulsatile gonadotropin secretion, and increased response of LH to GnRH. The clinical course of central precocious puberty may wax and wane. Benign precocious puberty is the presumptive diagnosis in individuals who begin puberty early on a constitutional or familial basis. If no cause can be determined, the diagnosis is idiopathic precocious puberty, which occurs much more often in girls than in boys. Obese girls have earlier adrenarche, and sometimes menarche as well, than appropriate-weight girls. Compared with girls, boys with precocious puberty have a higher incidence of CNS disorders, such as tumors and hamartomas, precipitating the precocious puberty.


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Pediatrics_Nelson. Almost any condition that affects the CNS, including hydrocephalus, meningitis, encephalitis, suprasellar cysts, head trauma, epilepsy, mental retardation, and irradiation, can precipitate central precocious puberty and must be considered before central precocious puberty is diagnosed. Hamartomas are nonmalignant tumors of the tuber cinereum with a characteristic appearance on computed tomography (CT) or MRI; biopsy is rarely required. The mass of GnRH neurons secrete GnRH and cause precocious puberty. Although hamartomas are not true neoplasms, they may require neurosurgical attention. The resulting precocious puberty is responsive to medical therapy with GnRH agonists, and surgery is rarely indicated.


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Pediatrics_Nelson. Other masses that cause precocious puberty are not benign. Germinomas are noncalcifying hypothalamic or pineal tumors that frequently produce human chorionic gonadotropin (hCG), which may cause sexual precocity in prepubertal boys (hCG cross-reacts with the LH receptor because of the similarity of structure between LH and hCG). Optic or hypothalamic gliomas (with or without neurofibromatosis), astrocytomas, and ependymomas may cause precocious puberty by disrupting the negative restraint of the areas of the CNS that normally inhibit pubertal development throughout childhood. These tumors may require radiotherapy, which contributes to a significant risk for hypopituitarism. Available @ StudentConsult.com Precocious Puberty in the Female


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Pediatrics_Nelson. Available @ StudentConsult.com Precocious Puberty in the Female The most common cause of GnRH-independent precocious puberty, McCune-Albright syndrome, is more frequent in girls than boys and includes precocious gonadarche, a bone disorder with polyostotic fibrous dysplasia, and hyperpigmented cutaneous macules (café au lait spots). The precocious gonadarche results from ovarian hyperfunction and sometimes cyst formation, leading to episodic estrogen secretion. This disorder results from a post-conception somatic True precocious Pubertal values Pubertal Pubertal values of Normal pubertal MRI scan of brain to puberty 3 yr of age


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Pediatrics_Nelson. True precocious Pubertal values Pubertal Pubertal values of Normal pubertal MRI scan of brain to puberty 3 yr of age Modified from Grumbach MM, Styne DM: Puberty. In Wilson JD, Foster DW, editors: Williams Textbook of Endocrinology, ed 9, Philadelphia, 1997, WB Saunders. CNS, Central nervous system; CT, computed tomography; DHEAS, dehydroepiandrosterone sulfate; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; LH, luteinizing hormone; MRI, magnetic resonance imaging. *In supersensitive assays.


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Pediatrics_Nelson. mutation in the G protein intracellular signaling system (specifically Gsa, which leads to unregulated constitutive activation of adenylate cyclase, and of cAMP in the absence of trophic hormone stimulation), in the affected cells in ovary, bone, and skin; other endocrine organs may also autonomously hyper-function for the same reason. Hyperthyroidism, hyperadrenalism, or acromegaly may occur. Adrenal carcinomas usually secrete adrenal androgens, such as DHEA; adrenal adenomas may virilize a child as a result of the production of androgen or may feminize a child as a result of the production of estrogen. Boys may have precocious gonadarche on the basis of a rare entity called familial GnRH-independent sexual precocity with premature Leydig cell maturation. This condition, with germ cell maturation caused by an X-limited dominant defect, produces constitutive activation of the LH receptor that leads to continuous production and secretion of testosterone without requiring LH or hCG.


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Pediatrics_Nelson. The hCG-secreting tumors stimulate LH receptors and increase testosterone secretion. These tumors may be found in various places, including the pineal gland (dysgerminomas) or the liver (hepatoblastoma). Ovarian cysts may occur once or may be recurrent. High serum estrogen values may mimic ovarian tumors. Congenital adrenal hyperplasia (CAH) is a cause of virilization in girls (see Chapter 178). Evaluation of Sexual Precocity


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Pediatrics_Nelson. Evaluation of Sexual Precocity The first step in evaluating sexual precocity is to determinewhich characteristics of normal puberty are apparent (seeChapter 67) and whether estrogen effects, androgen effects,or both are present (see Table 174-4). In girls the estrogeneffect manifests as breast development, uterine increase,and, eventually, menarche. Both boys and girls manifest the androgen effect as adult body odor, pubic and axillary hair,and facial skin oiliness and acne. In boys it is also importantto note whether the testes are enlarged more than 2.5 cm inlength (4 mL volume), which implies gonadarche. If the testes are not enlarged but virilization is progressing, the source of the androgens may be the adrenal glands or exogenous sources.


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Pediatrics_Nelson. Laboratory evaluation includes determination of sex steroid levels (testosterone, estradiol, DHEAS [dehydroepiandrosterone sulfate], or androstenedione) and baseline gonadotropinconcentrations. The inherent nature of gonadotropin secretionis characterized by low secretory rates throughout childhoodand pulsatile secretion in adolescents and adults. If baselinegonadotropin values are elevated into the normal pubertalrange, central precocious puberty is likely. If baseline gonadotropins are low, however, no immediate conclusion may bedrawn as to GnRH-dependent versus GnRH-independentprecocious puberty. This distinction often requires the assessment of gonadotropin responsiveness to GnRH stimulation. Aprepubertal GnRH response is FSH predominant, whereas a pubertal response is more LH predominant. Thyroid hormonedetermination also is useful because severe primary hypothyroidism can cause incomplete precocious puberty. If there is a suggestion of a CNS anomaly or a tumor (CNS, hepatic,


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Pediatrics_Nelson. Thyroid hormonedetermination also is useful because severe primary hypothyroidism can cause incomplete precocious puberty. If there is a suggestion of a CNS anomaly or a tumor (CNS, hepatic, adrenal, ovarian, or testicular), MRI of the appropriate location isindicated. The diagnosis of central precocious puberty mandates that an MRI of the CNS be performed.


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Pediatrics_Nelson. Long-acting, superactive analogs of GnRH (leuprolide depot, histrelin depot) are the treatment of choice for central precocious puberty. They suppress gonadotropin secretion by downregulating GnRH receptors in the pituitary gonadotropes (Table 174-5), causing gonadal secretion to revert to the prepubertal state. Boys with GnRH-independent premature Leydig cell and germ cell maturation do not respond to GnRH analogs but require treatment with an inhibitor of testosterone synthesis (e.g., ketoconazole), an antiandrogen (e.g., spironolactone), or an aromatase inhibitor (e.g., testolactone or letrozole). Patients with precocious puberty from a hormone-secreting tumor require surgical removal, if possible. The precocious puberty of the McCune-Albright syndrome is GnRH independent and unresponsive to therapy with GnRH Autonomous ovarian cysts Medroxyprogesterone acetate Inhibition of ovarian steroidogenesis; regression of cyst (inhibition of FSH release)


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Pediatrics_Nelson. Autonomous ovarian cysts Medroxyprogesterone acetate Inhibition of ovarian steroidogenesis; regression of cyst (inhibition of FSH release) McCune-Albright syndrome Medroxyprogesterone acetate* Inhibition of ovarian steroidogenesis; regression of cyst (inhibition of FSH release) Boys Testolactone* Inhibition of P-450 aromatase; blocks estrogen synthesis Modified from Grumbach MM, Kaplan SL: Recent advances in the diagnosis and management of sexual precocity, Acta Paediatr Jpn 30(Suppl):155, 1988. FSH, Follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone. *If true precocious puberty develops, a GnRH agonist can be added. analog. Therapy is provided with testolactone and antiandrogens or antiestrogen, such as tamoxifen. Available @ StudentConsult.com Precocious Puberty in the Female


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Pediatrics_Nelson. Available @ StudentConsult.com Precocious Puberty in the Female Benign premature thelarche is the isolated appearance of unilateral or bilateral breast tissue in girls, usually at ages 6 months to 3 years. There are no other signs of puberty and no evidence of excessive estrogen effect (vaginal bleeding, thickening of the vaginal secretions, increased height velocity, or bone age acceleration). Ingestion or dermal application of estrogen-containing compounds must be excluded. Laboratory investigations are not usually necessary, but a pelvic ultrasound study rarely may be indicated to exclude ovarian disease. Girls with this condition should be re-evaluated at intervals of 6 to 12 months to ensure that apparent premature thelarche is not the beginning of progression into precocious puberty. The prognosis is excellent; if no progression occurs, no treatment other than reassurance is necessary. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com In males breast tissue is termed gynecomastia, and it may occur to some degree in 45% to 75% of normal pubertal boys (see Chapter 67). Androgens normally are converted to estrogen by aromatization; in early puberty, only modest amounts of androgens are produced, and the estrogen effect can overwhelm the androgen effects at this stage. Later in pubertal development, the androgen production is so great that there is little effect from the estrogen produced by aromatization. Gynecomastia also can suggest the possibility of Klinefelter syndrome as puberty progresses. Prepubertal gynecomastia suggests an unusual source of estrogen either from exogenous sources (oral or dermal estrogen administration is possible from contamination of food or ointments) or from endogenous sources (from abnormal function of adrenal gland or ovary or from increased peripheral aromatization). Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Amenorrhea Precocious Puberty in the Male Precocious Puberty in the Female


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Pediatrics_Nelson. The isolated appearance of pubic hair before age 6 to 7years in girls or before age 9 years in boys is termed premature pubarche, usually resulting from adrenarche. It is relatively common. If the pubic hair is associated with anyother feature of virilization (clitoral or penile enlargement oradvanced bone age) or other signs (acne, rapid growth, orvoice change), a detailed investigation for a pathologic causeof virilization is indicated. Measurements of serum testosterone, 17-hydroxyprogesterone, and DHEAS are indicated toinvestigate the possibility of CAH. Ultrasound studies mayreveal a hyperplastic adrenal gland or a virilizing adrenalor ovarian tumor. Most patients with isolated pubic hair donot have progressive virilization and simply have prematureadrenarche (pubarche) resulting from premature activationof DHEA secretion from the adrenal gland. The skeletal maturation, as assessed by bone age, may be slightly advancedand the height slightly increased, but testosterone


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Pediatrics_Nelson. from premature activationof DHEA secretion from the adrenal gland. The skeletal maturation, as assessed by bone age, may be slightly advancedand the height slightly increased, but testosterone concentrations are normal. DHEA levels usually are high for prepubertal age but are consistent with Tanner (sexuality maturityrating) stages II and III.


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Pediatrics_Nelson. Thyrotropin-releasing hormone (TRH), a tripeptide synthesized in the hypothalamus, stimulates the release of pituitarythyroid-stimulating hormone (TSH). Pituitary TSH is a glycoprotein that stimulates the synthesis and release of thyroidhormones by the thyroid gland. Thyroid function developsin three stages. At the end of the first trimester, the glanddescends from the floor of the primitive oral cavity to itsdefinitive position in the anterior lower neck. The hypothalamic-pituitary-thyroid axis becomes functional in the secondtrimester. Peripheral metabolism of thyroid hormones maturesin the third trimester.


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Pediatrics_Nelson. Thyroxine (T4), triiodothyronine (T3), and TSH do not cross the placenta in significant amounts. Concentrations in fetal serum reflect primarily fetal secretion and metabolism. Maternal thyroid antibodies, iodides (including radioactive iodides), and medications given to mothers to treat hyperthyroidism (methimazole and propylthiouracil) cross the placenta and affect fetal thyroid function. An infant born prematurely or with intrauterine growth restriction may have an interruption of the normal maturational process and appear to have hypothyroidism by standard tests.


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Pediatrics_Nelson. The thyroid gland concentrates iodine and binds it to tyrosine molecules to produce either monoiodotyrosine or diiodotyrosine, with subsequent coupling of two tyrosines, T4 or T3. The major fraction of circulating T3 (approximately two thirds) is derived from peripheral deiodination of T4 to T3, but some is produced by the thyroid gland itself. The conversion of T4 to T3 requires the removal of one iodine from the outer ring


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Pediatrics_Nelson. Figure 175-1 Interrelationships of the hypothalamic-pituitary-thyroid axis. Thyroid-stimulating hormone (TSH) from the pituitary gland stimulates the secretion of thyroxine (T4) and triiodothyronine (T3) from the thyroid gland. These act at the pituitary gland level to control secretion of TSH by a negative feedback mechanism. In addition, T4 is metabolized to the potent T3 within the pituitary gland by a deiodinase. Secretion of TSH is stimulated by thyrotropin-releasing hormone (TRH) from the hypothalamus and inhibited by somatostatin. Thyroid hormone acts at the hypothalamus to stimulate secretion of somatostatin (somatostatin acts as a negative signal to the pituitary secretion of TSH). CRH, Corticotropinreleasing hormone; OB-R, leptin receptor. (From Melmed S, Polonsky K, Kronenberg H, Larsen R, editors: Williams Textbook of Endocrinology, ed 10, Philadelphia, 2003, Saunders, p 101.) of tyrosine; removing an iodine from the inner ring results in Serum TSH increases just after


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Pediatrics_Nelson. H, Larsen R, editors: Williams Textbook of Endocrinology, ed 10, Philadelphia, 2003, Saunders, p 101.) of tyrosine; removing an iodine from the inner ring results in Serum TSH increases just after birth but soon decreases reverse T3, which has little biologic effect. Preferential conver-to lower values considered normal for later life. T4 secretion sion of T4 to reverse T3 rather than T3 occurs in utero and in increases after birth as a result of the peak in TSH and because all forms of severe illness, including respiratory distress syn-of maturation of thyroid metabolism. It is important to refer to drome, fevers, anorexia, cachexia, and starvation. Conversion age-adjusted normative data to interpret thyroid function tests from T4 to T3 increases immediately after birth and through-properly, whether relative to making diagnoses of hyperthyout life. T4 and T3 are noncovalently bound to a specific serum roidism or hypothyroidism or when adjusting therapy. Free T4 carrier protein,


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Pediatrics_Nelson. whether relative to making diagnoses of hyperthyout life. T4 and T3 are noncovalently bound to a specific serum roidism or hypothyroidism or when adjusting therapy. Free T4 carrier protein, thyroxine-binding globulin, and, to a lesser is the test of choice because it eliminates the effects of variation extent, albumin. Only small (<0.02%) fractions of T4 and T3 in protein binding, which can be substantial. are not bound; free T4 (as it is converted to free T3) and free Table 175-1 summarizes laboratory test results in various T3 are biologically active. Free T3 exerts metabolic effects and types of thyroid abnormalities. In usual circumstances, plasma negative feedback on TSH release (Fig. 175-1). concentrations of TSH above the normal range indicate ↓, decreased; ↑, increased; N, Normal; T4, thyroxine; TBG, thyroxine-binding globulin; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone. *TSH may be slightly elevated.


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Pediatrics_Nelson. primary hypothyroidism, and concentrations below the normal range most often indicate the presence of hyperthyroidism. Thyroid scans with 99m-pertechnetate or 123-I-iodine are occasionally indicated in the evaluation of pediatric thyroid disease. They can be useful in identifying thyroid agenesis or ectopic thyroid tissue. Available @ StudentConsult.com Short Stature Pubertal Delay Precocious Puberty in the Male Precocious Puberty in the Female Hypothyroidism is diagnosed by a decreased serum free T4 and may be the result of diseases of the thyroid gland (primary hypothyroidism), abnormalities of the pituitary gland (secondary), or abnormalities of the hypothalamus (tertiary). Hypothyroidism is congenital or acquired and may be associated with a goiter (Table 175-2).


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Pediatrics_Nelson. Congenital hypothyroidism occurs in approximately 1 in2000 to 4000 live births and is caused by dysgenesis (agenesis, aplasia, ectopia) or, less often, dyshormonogenesis (e.g.,enzyme defects). Thyroid tissue usually is not palpable inthese sporadic nongoitrous conditions. Dyshormonogenesis, disorders of intrathyroid metabolism, or goitrous congenital hypothyroidism occurs in about 1 in 30,000 livebirths. A goiter reflects an inborn error of metabolism inthe pathway of iodide incorporation or thyroid hormonebiosynthesis or reflects the transplacental passage of antithyroid drugs given to the mother. The free T4 concentration is low, and the TSH level is elevated. Routine neonatal screening programs to measure cord blood or, more often,heel-stick TSH values occur in every state in the UnitedStates. An immediate confirmatory serum sample shouldbe obtained from any infant having a positive result on ascreening test. A low free T4 and high TSH confirm the finding.


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Pediatrics_Nelson. Newborn No goiter Thyroid gland dysgenesis or ectopic location Exposure to iodides TSH deficiency TRH deficiency +/− Goiter Inborn defect in hormone synthesis* or effect Maternal goitrogen ingestion, including propylthiouracil, methimazole, iodides Severe iodide deficiency (endemic) Goiter Hashimoto thyroiditis: chronic lymphocytic thyroiditis Inborn defect in hormone synthesis or effect Goitrogenic drugs infiltrative (sarcoid, lymphoma) TRH, Thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone. *Impaired iodide transport, defective thyroglobulin iodination, defective iodotyrosine dehalogenase, or defective thyroglobulin or its coupling to iodotyrosine.


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Pediatrics_Nelson. *Impaired iodide transport, defective thyroglobulin iodination, defective iodotyrosine dehalogenase, or defective thyroglobulin or its coupling to iodotyrosine. Isolated secondary or tertiary hypothyroidism occurs in 1 in 100,000 live births; the free T4 is normal to low. When tertiary or secondary hypothyroidism is detected, assessment of other pituitary hormones and investigation of pituitary-hypothalamic anatomy via magnetic resonance imaging are indicated. Although not a hypothyroid condition, congenital thyroxine-binding globulin deficiency occurs in about 1 in 10,000 live births and is associated with low serum total T4 concentration, normal TSH, and normal serum free T4. This is a euthyroid condition and does not require treatment with thyroid hormone because it is merely a binding protein abnormality. It is commonly X-linked dominant.


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Pediatrics_Nelson. Clinical manifestations of congenital hypothyroidism in the immediate newborn period usually are subtle but become more evident weeks or months after birth. By then it is too late to ensure that there is not a detriment to the infant’s cognitive development. Newborn screening is crucial to make an early diagnosis and initiate thyroid replacement therapy by younger than 1 month of age. Findings at various stages after birth include hypothermia, acrocyanosis, respiratory distress, large fontanels, abdominal distention, lethargy and poor feeding, prolonged jaundice, edema, umbilical hernia, mottled skin, constipation, large tongue, dry skin, and hoarse cry. Thyroid hormones are crucial for maturation and differentiation of tissues, such as bone and brain (most thyroid-dependent brain maturation occurs 2 to 3 years after birth) (Table 175-3).


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Pediatrics_Nelson. When treatment (with levothyroxine) is initiated within 1 month or less after birth, the prognosis for normal intellectual development is excellent; screening programs usually offer therapy within 1 to 2 weeks of birth. If therapy is instituted after 6 months, when the signs of severe hypothyroidism are present, the likelihood of normal intellectual function is markedly decreased. Growth improves after thyroid replacement even in late diagnosed cases. The dose of levothyroxine changes with age; 10 to 15 μg/kg of levothyroxine is used for a newborn, but about 3 μg/kg is used later in childhood. In neonatal hypothyroidism, the goal is to bring the serum free T4 rapidly into the upper half of the range of normal. Suppression of TSH is not seen and not necessary in all cases because such suppression may lead to excessive doses of levothyroxine.