DIABETES
A 10-year-old girl has 2-hour postprandial blood glucose of 300 mg/dL and a large amount of glucose and trace ketones in her urine. She has lost 1 kg of weight. Think: Type 1 diabetes, and start treatment with insulin.
Typical history: Polyuria, polydipsia, polyphagia, and weight loss over a period of time. The initial symptoms due to hyperglycemia may be nonspecific. Exogenous insulin is required to correct the metabolic derangement due to insulin deficiency. Children with type 2 diabetes mellitus are usually overweight and may show signs of insulin resistance such as acanthosis nigricans. Family history of type 2 diabetes in first- and second-degree relative may also be present.
See Table 16-1.
DEFINITION
Syndrome characterized by disturbance of metabolism of carbohydrate, protein, and fat, resulting in hyperglycemia and glucosuria from deficiency in insulin secretion or its action.
EPIDEMIOLOGY
Diabetes is one of the most common endocrine disorders of the pediatric age group.
Think of testing urine glucose with the onset of enuresis in a previously toilet-trained child.
TABLE 16-1. Diabetes
The prevalence of type 2 diabetes is increasing in children secondary to increasing prevalence of childhood obesity.
Classification:
Type 1 diabetes: Caused by absolute insulin deficiency. It has abrupt onset with classic symptoms of polyuria, polydipsia, polyphagia, and weight loss. Most children have positive urine ketones at onset. Incidence is roughly 1 in 400 children. It is prevalent in Caucasians of northern European decent and caused by autoimmune destruction of pancreatic islet cell. Over 80% of children are positive for immune marker of beta cell destruction (examples: islet cell antibodies, anti-glutamic acid decarboxylase antibodies, and insulin autoantibody).
Type 2 diabetes: A heterogeneous disorder mainly caused by insulin resistance with relative insulin deficiency. It is insidious in onset and diagnosis is usually delayed because of lack of symptoms early in the course of disease. It is prevalent in certain minorities such as Hispanic-American, Native American, and African-American. Its incidence is increasing in children with increasing obesity. Most of them have acanthosis nigricans (hyperpigmentation with thickening of skin into velvety irregular folds in flexural or opposed areas), which is a cutaneous manifestation of insulin resistance.
PATHOPHYSIOLOGY
Revolves around insulin deficiency or insulin resistance leading to:
↓ glucose utilization.
↑ hepatic glucose production.
SIGNS AND SYMPTOMS
Triad of polyuria, polydipsia, and polyphagia (more abrupt in type 1 diabetes).
Weight loss and enuresis are common symptoms in type 1 diabetes.
Vomiting, dehydration, and abdominal pain are hallmark of acute complication → diabetic ketoacidosis.
DIAGNOSIS
Fasting blood glucose ≥ 126 mg/dL (7 mmol/L).
Random blood glucose ≥ 200 mg/dL along with symptoms of diabetes.
Two-hour plasma glucose > 200 during a 75-g oral glucose tolerance test.
To diagnose type 2 diabetes early in children, the American Diabetes Association recommends testing children every 2 yr if they are over-weight and have two or more risk factors such as:
Obesity (body mass index > 85th percentile for age)
Family history of type 2 diabetes (first- and second-degree relatives).
Race (Native American, African-American, Hispanic, and Asian).
Signs and symptoms associated with insulin resistance (acanthosis nigricans, dyslipidemia, hypertension [HTN], and polycystic ovarian syndrome).
TREATMENT
Patient education and counseling.
Diet.
Exercise.
Insulin (0.5–1 U/kg).
Oral hypoglycemics in type 2 diabetes (such as metformin, sulfonylurea, thiazolidinediones).
DIABETIC KETOACIDOSIS (DKA)
A 3½-year-old boy is found unconscious. He has a flushed face, pulse of 160/min, respiratory rate of 30/min with shallow breaths, blood pressure 40/20 mmHg, and an unusual odor on his breath. He has a generalized tonic-clonic seizure. His mucous membranes are dry. His parents report a weight loss of 5 lb in the past month and noted that he was asking for juice. Think: DKA, and check serum glucose.
Polyuria, polydipsia, and weight loss are common symptoms in diabetes mellitus. Weight loss is due to hyperglycemia and glucosuria → lipolysis. Shallow breathing is a respiratory compensation for metabolic acidosis secondary to ketoacid accumulation. Severe dehydration is due to glucosuria → osmotic diuresis and volume depletion. Seizure may occur due to cerbrovascular event, which is a known complication of diabetic ketoacidosis.
DEFINITION
Hyperglycemia > 200 mg/dL.
Acidosis pH < 7.30.
Bicarbonate < 15 mmol/L.
Ketonemia > 3 mmol/L.
Insulin-dependent diabetes mellitus in children is associated with islet cell antibodies and ↑ prevalence of human leukocyte antigen (HLA)-DR3 and -DR4 or both.
ETIOLOGY/PATHOPHYSIOLOGY
Relative or absolute insulin deficiency → accelerated hepatic and renal glucose production and impaired glucose utilization, release of free fatty acids into circulation (from lipolysis) and ↑ fatty acid oxidation to ketone bodies.
Precipitating factors—stress, infection, trauma.
SIGNS AND SYMPTOMS
Polyuria, polydipsia, dehydration, fatigue, headache, nausea, vomiting, abdominal pain, tachycardia, tachypnea.
Dehydration in DKA is primarily intracellular and is often underestimated.
OTHER LABORATORY FINDINGS
↑ anion gap (>12–16 mEq).
↑ hemoglobin (Hgb) and hematocrit (Hct) (hemoconcentration).
↑ white blood cell (WBC) count.
↓ serum sodium (Na) (pseudohyponatremia from hyperglycemia and/or hypertriglyceridemia).
Normal or ↑ potassium (K) (from shift of K from intracellular to extracellular compartment due to acidosis).
Urinalysis reveals glucose and ketones (acetoacetate/acetone).
Serum Na ↓ 1.6 mEq/L for every 100 mg/dL rise in glucose.
TREATMENT
Careful fluid and electrolyte replacement to avoid cerebral edema. Rehydration fluid should not exceed 4000 mL/m2/day.
Bolus should be 10–20 cc/kg/hr normal saline. Repeat bolus if needed. Subsequent replacement fluid can be 0.45% or 0.9% saline with potassium.
Potassium should be given as half KCl and half KPO4.
Insulin regular (0.1 U/kg/hr).
Glucose (add glucose when blood glucose is < 250–300 mg/dL).
Total body potassium may be considerably depleted even when serum K+ is normal or ↑.
COMPLICATIONS
Hypoglycemia.
Hypokalemia.
Cerebral edema: Cause of death in patients with DKA (get a head CT for headache/mental status changes indicative of acute intracranial pressure elevation). Treatment includes immediate reduction in intravenous fluid rate, hyperventilation, and mannitol 0.5–2 g/kg q4–6h as needed.
HYPERINSULINISM
A 2-hour-old newborn has plasma glucose of 20 mg/dL. Physical examination shows a large plethoric newborn with macrocephaly. Birth weight is > 90th percentile. Think: Hyperinsulinism.
Hyperinsulinism is a common cause of hypoglycemia in early infancy. These infants may have macrosomia. Hypoglycemia may develop on the first day of life, and there may be rapid development after a few hours of feeding. The diagnostic criterion is the presence of signs and symptoms of hypoglycemia with low plasma glucose level and an inappropriately elevated insulin level. Macrosomia is due to hyperinsulinemia, as insulin is an important growth factor in intrauterine life. Transient hyperinsulinism may usually occur due to maternal diabetes. Persistent hyperinsulinism is due to genetic mutation (autosomal recessive) in the sulfonylurea receptor–inwardly rectifying K channel.
EPIDEMIOLOGY
Hyperinsulinemia is the most common cause of severe hypoglycemia in early infancy. Sixty percent develop hypoglycemia during the first month of life, 30% in the first year.
Transient Hyperinsulinemia
Excessive insulin secretion in infants from transient dysfunction in islet cell function.
Risk factors include:
Small-for-gestational-age (SGA) or premature infants.
Fetal hypoxia/asphyxia.
Infant of diabetic mother (born to mother with poorly controlled diabetes (type 1, type 2, or gestational).
Erythroblastosis fetalis.
Other causes include surreptitious insulin administration.
Permanent Hyperinsulinemia
Most common variety is an autosomal recessive defect caused by mutation in the genes coding component of KATP channel involved in glucose-regulated insulin release.
Autosomal-dominant forms of hyperinsulinism are usually milder and caused by activating mutation in glucokinase (GCK) gene and gluta-mate dehydrogenase gene (GLUD1).
Sporadic form of hyperinsulinism can result in either focal or diffuse hyperplasia of β-cell. Focal adenomatous hyperplasia is caused by loss of heterozygosity of 11p15 from somatic loss of maternal allele.
TREATMENT
Frequent feeding (feed q3–4h).
IV glucose if necessary.
In severe, prolonged cases, diazoxide, somatostatin, and/or pancreatectomy.
HYPOGLYCEMIA
A 14-year-old boy with an 8-year history of diabetes mellitus has had frequent admissions for DKA in the past 18 months. His school performance has been deteriorating. Recently, he has had frequent episodes of hypoglycemia. He is Tanner stage 2 in pubertal development, is growing at a normal rate, and has mild hepatomegaly. Think: Poorly controlled diabetes mellitus due to noncompliance.
Adolescence is a difficult age for management of any chronic disease such as diabetes. Not adhering to the treatment regimen is common in teenagers. Often, blood sugar levels are high because of missing the dose of insulin. In addition, inappropriate administration of insulin doses may result in secondary hypoglycemia. Recurrent hospitalization is the hallmark of noncompliance. Hepatomegaly is most likely due poorly controlled diabetes mellitus (Mauriac syndrome).
ETIOLOGY
Hyperinsulinism.
Hormone deficiencies (glucocorticoid, growth hormone).
Glycogen storage disease.
Defect in gluconeogenesis.
Fatty acid oxidation defects.
Organic acidemias.
Ketotic hypoglycemia.
Malnutrition, prematurity, SGA.
Liver failure.
Congenital heart diseases.
Tumors.
Poisons/drugs (salicylates, alcohol).
Systemic disease—sepsis, burns, cardiogenic shock.
TREATMENT
Acute symptomatic hypoglycemia: 0.3 g/kg glucose (3 mL/kg D10W) IV over 10 min to restore plasma glucose concentration to normal, followed by 10% dextrose at 6–8 mg/kg/min.
In patients with hyperinsulinemia, subcutaneous glucagon 0.03 mg/kg can reverse the hypoglycemia.
HEMOCHROMATOSIS
DEFINITION
↑ storage of iron in the form of hemosiderin in parenchymal cells.
Liver, heart, gonad, skin, and joints.
ETIOLOGY
Hereditary
Neonatal
Transfusion induced
SIGNS AND SYMPTOMS
Cirrhosis
Bronzing of skin
Diabetes mellitus
LABORATORY FINDINGS
↑ serum ferritin
↑ transferrin saturation
TREATMENT
Chelation with desferoxamine, phlebotomy.
HYPERTHYROIDISM
DEFINITION
↑ secretion of thyroid hormone.
Juvenile Graves Disease
Occurs more frequently in females (male-to-female ratio 3:1–5:1).
Triad of:
Hyperthyroidism with diffuse goiter (almost always present; goiter is usually symmetrical, smooth, soft, and nontender).
Ophthalmopathy (present in over one-half of the patients).
Dermopathy: Pretibial myxedema is present in 1–2% of adults; it rarely occurs in children.
Juvenile Graves disease causes 95% of thyrotoxicosis in children.
ETIOLOGY
Autoimmune disorder with antibodies against thyroid-stimulating hormone (TSH) receptor—thyrotropin-binding inhibitory immunoglobulin (TBII).
TBII can either stimulate or inhibit thyroid cell function.
Thyroid-stimulating immunoglobulin (TSI): Present in Graves disease.
TSH receptor–blocking antibodies: Cause hypothyroidism.
Clinical presentation is determined by the net effect of interaction between stimulating and blocking antibodies.
SIGNS AND SYMPTOMS
Gradual onset (6–12 months).
Emotional disturbance, change in academic performance.
Insomnia.
Palpitations.
Fatigue, muscle weakness, ↑ sweating.
↑ appetite with ↓ or no weight gain.
Goiter.
Heat intolerance.
Fine tremors.
Exophthalmos.
Menstrual irregularities.
Thyroid storm: Characterized by:
Fever (usually > 101.3°F [38.5°C]).
Severe tachycardia out of proportion to fever, leading to high-output cardiac failure.
Central nervous system (CNS) manifestations (confusion, obtundation, coma, and convulsions).
LABORATORY FINDINGS
Elevated total and free thyroxine (T4) and total and free triiodothyro-nine (T3) levels.
↓ TSH.
Elevated TBII (receptor assay).
Elevated TSI (bioassay).
TREATMENT OF HYPERTHYROIDISM
Pediatric endocrine consultation.
Propylthiouracil (PTU) 5–10 mg/kg/day q8h PO or methimazole 0.5–1 mg/kg/day q8h. Side effects occur in 20–30% and include agranulocytosis, hepatotoxicity, urticaria, arthralgia, and very rarely vasculitis.
Propranolol 1–2 mg/kg/day PO in divided doses q6–8h (0.01–0.15 mg/kg/dose IV).
Treatment with 131I (radioactive iodine) for juvenile Graves disease is increasing.
Surgical—thyroidectomy.
For thyroid storm, besides PTU and propranolol also give iodides (SSKI) 5 drops PO q8h and hydrocortisone. Both PTU and hydrocortisone inhibit the peripheral conversion of T4 to T3.
HYPOTHYROI DISM
DEFINITION
↓ production of thyroid hormone either from primary defect at the level of thyroid or secondary to hypothalamic pituitary disorder.
In serum, 99.8% of T4 and 99.7% of T3 are bound to thyroxine-binding protein. Only 0.02% of T4 and 0.3 % of T3 are present as free fractions, which are biologically active (see Table 16-2).
TABLE 16-2. Thyroid Functions in Different Thyroid Conditions
Classic findings of congenital hypothyroidism are rare in the early neonatal period due to placental transfer of some maternal thyroid hormone.
Congenital Hypothyroidism
Incidence is same worldwide (1 in 4000).
ETIOLOGY
Sporadic: Thyroid dysgenesis (absent thyroid, hypoplastic thyroid, ectopic thyroid).
Iodine deficiency remains a major cause worldwide.
Prenatal exposure to radioiodine or antithyroid medications.
Rarely hereditary: Thyroid dyshormonogenesis (defect in synthesis of thyroid hormone) and generalized thyroid hormone resistance.
SIGNS AND SYMPTOMS
Most cases are asymptomatic at birth.
Postmaturity, macrosomia.
Wide fontanelle.
Prolonged jaundice.
Macroglossia.
Hoarse cry.
Abdominal distention, constipation.
Umbilical hernia.
Hypotonia.
Goiter (in some dyshormonogenesis).
If left untreated:
Slowed development, late teeth, late milestones, short stature.
Eventual mental retardation.
Early diagnosis of congenital hypothyroidism is crucial to prevent or minimize cognitive impairment.
DIAGNOSIS
Newborn screening:
Primary T4–sequential TSH:
Used by most North American programs.
Initial filter paper blood spot: T4 with TSH measurement in specimens with low T4 values.
Uses a percentile as the cutoff, with 10th percentile being the usual standard.
Primary TSH–sequential T4:
Used in all European countries (except the Netherlands), Japan, Australia, and parts of North America.
Initial TSH measurement, supplemented by T4 in cases of high TSH.
Cutoff point for recall is TSH 20–50 μU/mL with low T4 (< 5 μg/dL) or TSH > 50 μIU/mL.
TREATMENT
Both early and high-dose treatment appear necessary.
L-thyroxine 10–15 μg/kg/day.
Acquired Hypothyroidism
A 10-year-old girl has a 3-year history of growth failure. A moderate-sized goiter is palpated. T4 is 3.1 μg/dL, and TSH 322 μU/mL. Think: Acquired hypothyroidism.
Congenital hypothyroidism is generally diagnosed in neonatal life because of newborn screening. Hypothyroidism that begins in childhood is usually Hashimoto disease. Initial signs and symptoms of hypothyroidism may be subtle. Growth retardation is usually not severe. However, if it remains unrecognized and untreated, linear growth is severely retarded and sexual maturation is also delayed. Goiter is the hallmark of classic Hashimoto disease. The results of the thyroid function test depend on stage of disease. TSH is elevated. Antithyroglobulin and anti–thyroid peroxidase (anti-TPO antibody) may be present. Iodine deficiency is one of the most common causes of acquired hypothyroidism worldwide.
Prevalence in children is 0.15% with a female-to-male ratio of 3:1.
Lymphocytic thyroiditis (Hashimoto) is the most common cause. It is an autoimmune disorder characterized by lymphocytic infiltration of thyroid and presence of:
Antithyroglobuin antibodies
Anti-TPO antibodies
Other causes include thyroid surgery and irradiation, medications (iodine, lithium, amiodarone, etc.), pituitary or hypothalamic dysfunction (secondary or tertiary acquired hypothyroidism).
Look for hypothyroidism in Down syndrome, Turner syndrome, and Klinefelter syndrome.
SIGNS AND SYMPTOMS
Goiter.
Growth deceleration.
Delayed skeletal maturation.
Fatigue, lethargy.
Constipation.
Cold intolerance.
Bradycardia.
Dry skin.
Weight gain.
Delayed deep tendon reflexes.
TREATMENT
L-thyroxine 2–4 μg/kg/day.
THYROID NEOPLASM
EPIDEMIOLOGY
Rare in children.
Most common pediatric endocrine tumor (differentiated thyroid cancer).
Family history (in medullary thyroid cancer).
Prior irradiation (in papillary thyroid cancer).
TYPES
Thyroid adenoma (approximately 1% are toxic adenoma and cause hyperthyroidism).
Thyroid carcinoma: Arise from:
Follicular epithelium:
Papillary carcinoma (most common; focal calcification [ie, psammoma in 40–50%]).
Follicular carcinoma (higher prevalence in areas with iodine deficiency).
Insular carcinoma (poorly differentiated).
C cells: Medullary carcinoma (produce calcitonin). Associated with type 2 multiple endocrine neoplasia (MEN).
Cervical lymphadenopathy: Rapid and painless enlargement of a thyroid growth may suggest neoplasia.
SIGNS AND SYMPTOMS
Solitary or multiple thyroid nodules (risk of malignancy in solitary nodules in children is 30–50%).
Incidence of malignancy of a thyroid neoplasm is higher in children than in adults.
DIAGNOSIS
Thyroid profile (thyroid functions are usually normal).
Calcitonin (for medullary cancer).
Thyroid ultrasound.
Fine-needle aspiration.
Definite diagnosis by surgical excision.
TREATMENT
Papillary and follicular cancer:
Near total or total thyroidectomy (complications include bleeding, hypoparathyroidism, damage to recurrent laryngeal nerve) with modified neck dissection, if needed.
Postoperative 131I ablation if the risk for recurrence is high.
Replacement thyroxine (higher doses in patients with ↑ risk of recurrence).
Medullary thyroid cancer:
Total thyroidectomy.
Prophylactic thyroidectomy if positive for MEN mutation, before age 5 yr in MEN 2A and before age 6 months in MEN 2B.
HYPERPARATHYROIDISM
A 10-year-old girl has severe abdominal pain and gross hematuria. She passes a calculus in her urine. She had received no medication and has no family history of renal stones. Think: Primary hyperparathyroidism.
Symptoms of primary hyperparathyroidism include painful bones, renal stones, abdominal groans, and psychic moans. It is a common cause of hypercalcemia. Hypercalcemia in the presence of elevated serum parathyroid hormone level confirm the diagnosis of primary hyperparathyroidism. Other biochemical findings include hypercalciuria and hypophosphatemia.
DEFINITION
Hypercalcemia accompanied by increased or inappropriately normal parathyroid hormone (PTH) level.
EPIDEMIOLOGY
Uncommon in children.
ETIOLOGY
Primary (defect of parathyroid gland):
Parathyroid adenoma.
Generalized hyperplasia of all glands (MEN 1 and MEN 2A).
Parathyroid carcinoma.
Secondary (response to hypocalcemia):
Chronic renal failure (CRF).
Renal tubular acidosis.
Vitamin D–deficiency rickets.
Treatment (with phosphorus) for hypophosphatemic rickets.
Liver failure.
Tertiary hypoparathyroidism: Adenomatous change in parathyroid in the setting of CRF.
SIGNS AND SYMPTOMS
Clinical manifestation of hypercalcemia.
Muscle weakness, anorexia, nausea, vomiting, constipation, polydipsia, polyuria, dehydration, failure to thrive, coma, seizures, fever, renal stones.
DIAGNOSIS
↑ serum Ca.
↓ serum phosphorus.
↑ urinary calcium.
↑ PTH.
Shortened QTc interval.
Subperiosteal absorption (with prolonged hyperparathyroidism).
99mTc-sestamibi scanning for parathyroid adenoma.
TREATMENT
Hypercalcemia:
Hydration (IV NS at 2–3 times maintenance).
Furosemide 1 mg/kg q6h (↑ Na and Ca excretion).
Prednisone (↓ intestinal absorption of Ca).
Calcitonin 4 U/kg SQ q12h.
Pamidronate 0.5 mg/kg infusion.
Calcimimetics suppress PTH secretion in affected gland.
Primary hyperparathyroidism:
Resection of isolated adenoma.
For generalized hyperplasia resection of 3½ glands.
Vitamin D and calcium for postop hypocalcemia, which can be severe and prolonged due to hungry bone syndrome in cases of severe hyperparathyroidism.
Secondary hyperparathyroidism: Treatment of the underlying cause.
Patients with hyperparathyroidism can develop nephrocalcinosis.
HYPOPARATHYROIDISM
DEFINITION
Decreased PTH.
ETIOLOGY
Autoimmune.
Familial: Autosomal dominant, autosomal recessive, and X-linked recessive.
DiGeorge/velocardiofacial syndrome (deletion of chromosome 22q.11.2).
Acute illness (PTH secretion is impaired in critical illness).
Severe hypomagnesemia (usually < 1 mg/dL).
Hypoparathyroidism can be seen with polyglandular autoimmune endocrinopathy: Thyroiditis, diabetes, adrenal insufficiency, mucocutaneous candidiasis.
SIGNS AND SYMPTOMS
Most common presentation is numbness, tingling, paresthesia, muscle cramps.
In severe cases, seizure, tetany, and mental status changes.
In older asymptomatic patients, hypereflexia, Chvostek’s (facial twitching), and Trousseau’s (carpopedal spasm) signs can be elicited.
DIAGNOSIS
↓ serum total Ca and ionized Ca.
↑ serum P.
Markedly ↓ PTH.
Prolonged QTc interval.
Total Ca ↓ by 0.8 mg/dL for each 1 g/dL ↓ in albumin below 4 g/dL.
↑ or ↓ in pH by 0.1 units ↓ and ↑ ionized Ca by 0.03 mmol/L, respectively.
Pay attention to heart rate with treatment for hypoparathyroidism: Bradycardia is an indication to stop calcium infusion.
DIFFERENTIAL DIAGNOSIS
Pseudohypoparathyroidism (PTH unresponsiveness). Markedly ↓ PTH.
TREATMENT
Correct hypocalcemia:
Intravenous (IV) 10% calcium gluconate 2 cc/kg gradually over 10 min for acute symptomatic hypocalcemia.
To maintain normocalcemia: Continuous IV infusion (20–80 mg Ca/kg/24 hr).
Transition to PO calcium as soon as possible (25–100 mg Ca/kg/day).
Correct hypomagnesemia.
Vitamin D (calcitriol).
CONGENITAL ADRE NAL HYPERPLASIA (CAH)
DEFINITION
Genetic defect of adrenal corticosteroid and/or mineralocorticoid synthesis.
↓ in cortisol secretion results in a ↓ in negative feedback at the level of hypothalamus and pituitary gland.
↑ ACTH secretion results in markedly elevated production of the precursors before the block.
A newborn with ambiguous genitalia is a medical and social emergency.
EPIDEMIOLOGY
Most common cause of ambiguous genitalia.
Incidence of classical 21-hydroxylase CAH is 1 in 15,000 live births.
ETIOLOGY
21-hydroxylase deficiency (90% of all CAH):
Three-quarters of cases are salt wasters.
Ambiguous genitalia in the females; normal genitalia in males.
Milder form (nonclassical variant) has normal genitalia in females and presents late with premature pubarche.
11β-hydroxylase deficiency: HTN with low K frequently present because of excessive deoxycorticosterone (DOC).
3β-hydroxysteroid dehydrogenase:
Ambiguous genitalia in both sexes.
Salt wasting is present.
17-hydroxylase/17,20-lyase deficiency:
Normal genitalia in females; undervirilized genitalia in males.
HTN with low K frequently present.
Congenital lipoid adrenal hyperplasia:
Normal genitalia in females; undervirilized genitalia in males.
Salt wasting is present.
All adrenal hormones and their precursors are low.
SIGNS AND SYMPTOMS
Clinical features result from both the hormonal deficiencies (cortisol and aldosterone) and excessive production of precursors (17-hydroxyprogesterone, androstenedione, DOC).
Female pseudohermaphroditsm: Ambiguous genitalia in female with normal 46,XX chromosome (21-hydroxylase, 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase deficiency).
Male pseudohermaphroditism: Ambiguous genitalia in male with 46,XY chromosome (3β-hydroxysteroid dehydrogenase, 17-hydroxylase/17,20-lyase deficiency, and congenital lipoid adrenal hyperplasia).
Hypoglycemia (from cortisol deficiency).
Salt wasting (21-hydroxylase, 3β-hydroxysteroid dehydrogenase, and congenital lipoid adrenal hyperplasia).
HTN with hypokalemia (11β-hydroxylase and 17 hydroxylase/17,20-lyase deficiency).
Vomiting, dehydration, and shock at 2–4 weeks of age.
Combination of hyperkalemia and hyponatremia clue to diagnosis of classical CAH of salt-wasting variety.
DIAGNOSIS
Newborn screening (elevated 17-hydroxyprogesterone level for 21-hydroxylase).
Karyotype.
Hyponatremia, hyperkalemia, hypochloremia, hypoglycemia.
Markedly ↑ 17-hydroxyprogesterone for gestational age and weight (for 21-hydroxylase).
Low baseline cortisol and low cortisol 60 min after 1–24 ACTH (Cortrosyn) stimulation.
Elevated plasma renin activity (PRA).
Genetic testing (DNA analysis for genetic mutations in the affected gene).
Prenatal diagnosis (in pregnancy with ↑ risk).
Most urgent tests for congenital adrenal hyperplasia:
1. Serum glucose
2. Serum electrolytes Other tests: cortisol, testosterone, 17-OH progesterone.
TREATMENT
Fluid and electrolyte replacement.
Normal saline (NS) 20 mL/kg bolus, then maintenance plus ongoing fluid losses with D5NS.
Management of hypoglycemia.
Hydrocortisone 25 mg IV bolus, then 50–100 mg/m2/24 hr (preferably as IV infusion) for acute adrenal crisis. Once crisis is improved, switch to PO 10–15 mg/m2/24 hr).
Fludrocortisone 0.1–0.2 mg/day.
Salt replacement (8–10 mEq/kg/day in the first few months of life, as Na content of formula and breast milk is quite low).
Prenatal treatment: Treat mother with a pregnancy at risk for 21-hydroxylase deficiency, with dexamethasone.
In CAH, blood should be drawn for steroid profile before the administration of hydrocortisone.
CUSHING SYNDROME
DEFINITION
Characteristic pattern of obesity with or without HTN due to excessive glucocorticoid production/exposure.
ETIOLOGY
Iatrogenic from exogenous corticosteroid (most common cause of hypercortisolism).
Cushing disease: Bilateral adrenal hyperplasia due excessive secretion of ACTH, usually by pituitary corticotroph adenoma. It is the most common cause of endogenous hypercortisolism in children.
Cushing syndrome: Excess cortisol secretion by unilateral adrenocortical tumors (adenoma, carcinoma) or bilateral adrenal hyperplasia (primary pigmented micronodular adrenal hyperplasia).
Ectopic ACTH syndrome: Malignant nonendocrine tumor produces an excessive amount of ACTH. Extremely rare in children.
Cushing disease is a state of hypercortisolism secondary to adrenocorticotropic hormone (ACTH)-producing pituitary adenoma.
SIGNS AND SYMPTOMS
Truncal obesity, rounded moon facies, buffalo hump, purple striae, easy bruising, muscle weakness, osteopenia, statural growth retardation, acne, hirsutism, hyperpigmentation, HTN, hyperglycemia, depression, cognitive impairment.
DIAGNOSIS
Elevated 24-hour urine test for free cortisol (UFC) and 17-hydroxycorticosteroid (17-OHS).
Mean rate of UFC in normal children is < 70 mg/m2/day.
Mean rate of 17-OHS is < 7 mg/g of creatinine per day.
8:00 A.M. ACTH and cortisol: Elevated ACTH level (> 29 pg/mL with elevated UFC) suggests Cushing disease or ectopic ACTH production.
Midnight plasma cortisol and ACTH (midnight cortisol > 4.4 μg/dL is highly suggestive of Cushing but does not differentiate between Cushing syndrome vs. Cushing disease).
Low-dose dexamethasone suppression test:
Overnight dose 0.03 mg/kg (max 1 mg) at 11 P.M. X1 dose or
0.03 mg/kg/day (max 0.5 q6h) for 2 days.
Normal if suppression results in plasma cortisol of < 5 μg/dL.
Nonsuppression with elevated UFC suggests the diagnosis of Cushing but does not differentiate between Cushing syndrome vs. Cushing disease.
High-dose dexamethasone suppression test:
Overnight dose of 0.12 mg/kg/day (max 8 mg) or
0.12 mg/kg/day (max 2 mg q6h) for 2 days.
Suppression (cortisol < 5 μg/dL) suggests Cushing disease, while non-suppression suggests Cushing syndrome.
24 UFC paradoxically rises in primary pigmented nodular adrenal disease after high-dose dexamethasone suppression test.
Ovine corticotropin-releasing hormone (CRH) stimulation test/bilateral petrosal sinus sampling: ↑ in ACTH after IV CRH suggests Cushing disease.
Growth retardation may be the early manifestation of Cushing syndrome. Virilization may indicate adrenal carcinoma.
Polycythemia, lymphopenia, and eosinopenia can be associated findings.
Abdominal computed tomography (CT) (adrenal tumors).
Pituitary magnetic resonance imaging (MRI) (pituitary adenoma).
DIFFERENTIAL DIAGNOSIS
Exogenous obesity (pseudo-Cushing state).
Normal growth rate.
Cortisol level suppressed by dexamethasone.
TREATMENT
Pediatric endocrine, surgical, and neurosurgical consultation.
Adrenalectomy (unilateral or bilateral for adrenal tumors or bilateral nodular hyperplasia, respectively).
Chemotherapy with mitotane for adrenal cancer with metastasis (after surgery).
Transsphenoidal resection of pituitary adenoma.
Fractionated radiotherapy for recurrent pituitary adenoma.
ADRENAL INSUFFICIENCY
DEFINITION
Adrenal cortex fails to produce enough glucocorticoid to mount response to stress.
May be primary adrenal disorder or secondary to ACTH deficiency/resistance.
Mineralocorticoid deficiency is present in primary adrenal disorder but is not part of secondary adrenal insufficiency, as aldosterone secretion depends on renin/angiotensin system.
ETIOLOGY
Primary Adrenal Insufficiency (Low Cortisol/Elevated ACTH)
Congenital:
CAH.
Congenital adrenal hypoplasia (X-linked).
ACTH resistance.
Adrenal leukodystrophy (X-linked-recessive disorder of metabolism of very long chain fatty acids).
Acquired (Addison disease):
Autoimmune destruction (80%).
Tuberculosis (TB).
Bilateral adrenal hemorrhages (meningococcal septicemia).
AIDS (opportunistic infections).
Antiphospholipid antibody syndrome.
Secondary Adrenal Insufficiency (Low Cortisol/Low ACTH)
Congenital:
Congenital hypopituitarism
Septo-optic dysplasia
Acquired:
Iatrogenic: Adrenal insufficiency from abrupt discontinuation of glucocorticoids after prolonged use.
Pituitary or hypothalamic tumors.
Failure of a suntan to disappear may be early manifestation of adrenal insufficiency; however, absence of hyperpigmentation does not exclude the diagnosis.
SIGNS AND SYMPTOMS
Weakness, fatigue, anorexia, nausea, vomiting, weight loss.
Postural hypotension (more marked in primary adrenal insufficiency).
Hyperpigmentation of skin and mucosal surfaces (in primary adrenal insufficiency due to elevated ACTH/melanocyte-stimulating hormone [MSH]).
Salt craving (in primary adrenal insufficiency).
Adrenal crisis (fever, vomiting, dehydration, and shock precipitated by infection, trauma, or surgery in susceptible patient).
DIAGNOSIS
Hyponatremia, hyperkalemia, acidosis, hypoglycemia.
A.M. plasma cortisol and ACTH level:
A.M. plasma cortisol < 3 μg/dL is indicative of adrenal insufficiency while value > 19 μg/dL makes it unlikely.
Basal plasma ACTH level invariably exceeds 100 pg/mL in primary adrenal insufficiency, while normal ACTH level does not rule out secondary adrenal insufficiency.
Antiadrenal antibodies (in autoimmune destruction of adrenal glands).
ACTH stimulation test:
1-24 ACTH (Cortrosyn) given IV or IM and cortisol level measured at baseline and 30–60 min after the injection.
For primary and severe/prolonged adrenal insufficiency use 250 μg Cortrosyn.
For secondary adrenal insufficiency that is mild or recent onset use 1 μg.
Normal response is plasma cortisol concentration of 18–20 μg/dL at 30-60 min post Cortrosyn.
CT scan of adrenal glands (in primary adrenal insufficiency).
MRI of the pituitary gland and hypothalamus (in secondary adrenal insufficiency).
TREATMENT
Hydrocortisone (10–15 mg/m2/24 hr divided in 2–3 doses). Double or triple the oral dose of glucocorticoids for febrile illness or injury.
Fludrocortisone (0.05–0.2 mg PO daily).
In acute adrenal insufficiency (adrenal crisis):
Volume replacement.
Hydrocortisone 50–100 mg IV, then 50–100 mg/m2/24 hr or methylprednisolone 7.5 mg/m2/24 hr.
Switched to oral therapy in 2–3 days.
Tumors arising in the adrenal medulla produce both epinephrine and norepinephrine. Extra-adrenal tumors produce only norepinephrine.
PHEOCHROMOCYTOMA
DEFINITION
Catecholamine-producing tumor of chromaffin tissue of adrenal medulla and sympathetic ganglia (paraganglioma).
Adrenal medulla (80–85%).
Extra-adrenal (15–20%), also called paragangliomas.
Usually benign, well encapsulated (< 10% malignant).
In children: Frequently familial, bilateral, and multifocal.
Recurrent tumor may appear years after initial diagnosis.
Siblings of a patient with a pheochromocytoma should be periodically evaluated because of ↑ familial incidence.
ETIOLOGY
May occur in isolation (sporadic).
Also seen in the MEN 2 (bilateral), von Hippel–Lindau, neurofibromatosis type 1, and familial carotid body tumor syndromes.
SIGNS AND SYMPTOMS
Nonspecific symptoms.
Headache, palpitations, ↑ sweating, anxiety.
Nausea, vomiting, weight loss, tremor, fatigue, chest or abdominal pain, and flushing.
Sustained HTN (in children).
Hyperglycemia.
Epinephrine-producing tumor may present with postural hypotension.
The most useful screening test for pheochromocytoma is blood pressure. Hypertensive paroxysms are an important diagnostic clue.
DIAGNOSIS
Plasma free metanephrines (metanephrine and normetanephrine): Unequivocally elevated, 4–5 times the upper limit of the reference range.
↑ urinary catecholamines or metabolites (24-hour urinary excretion of fractionated metanephrines), vanillylmandelic acid (VMA).
Serum chromogranin A.
Abdominal ultrasound (US).
Abdominal CT and MRI.
123I MIBG (metaiodobenzylguanidine) scan.
FDG PET (Flourodeoxyglucose positron emission tomography) scan.
Octreoscan.
Increased urinary norepinephrine indicates an extra-adrenal site of a pheochromocytoma, whereas increased epinephrine indicates an adrenal lesion.
DIFFERENTIAL DIAGNOSIS
Ganglioneuroma
Neuroblastoma
Ganglioneuroblastoma
TREATMENT
Surgical excision.
Preoperative α1 and α2 adrenoreceptor blockade (phenoxybenzamine) and βx adrenoreceptor blockade (propranolol, atenolol) are required to prevent hypertensive crisis and arrhythmias, respectively.
Yearly follow-up evaluation for assessment of recurrence for at least 5 years (indefinitely in children with familial pheochromocytoma).
After successful surgery of a pheochromocytoma, catecholamine excretion returns to normal in about 1 week.
HYPERPITUITARISM
Gigantism/Acromegaly
↑ GH.
If occurs before epiphyses close, → gigantism.
If after epiphyses close, → acromegaly.
ETIOLOGY
Most commonly caused by growth hormone (GH)-secreting adenoma.
CLINICAL FEATURES
Accelerated rate of linear growth.
Coarsening of facial features and mandibular prominence.
Enlargement of hands and feet.
DIAGNOSIS
Elevated insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3).
GH may be normal or elevated. GH not suppressed by glucose.
MRI of the pituitary.
TREATMENT
Transsphenoidal resection of adenoma.
Somatostatin and dopamine agonist for incomplete resection.
PROLACTIN EXCESS
ETIOLOGY
Prolactin-secreting adenoma: Microadenoma (< 1 cm) or macroadenoma (> 1 cm).
Tumor that disrupt pituitary stalk preventing inhibitory control.
Drugs (phenothiazines, estrogen, cocaine).
Hypothyroidism.
Liver or renal failure.
Macroprolactinemia (variant molecule).
Physical stress.
CLINICAL FEATURES
Galactorrhea
Menstrual irregularities/amenorrhea
Decreased libido
DIAGNOSIS
Prolactin level (> 20 ng/mL).
MRI (hypothalamic-pituitary region).
TREATMENT
Treatment of the cause.
Dopamine agonists (bromocriptine, cabergoline) are the first line of treatment.
Transsphenoidal surgery if medical treatment is unsuccessful.
Prolactin secretion chronically inhibited by dopamine in pituitary–prolactinomas responds to dopamine agonists such as bromocriptine.
HYPOPITUITARISM
An infant has hypoglycemia and a micropenis. Think: Hypopituitarism.
Hypopituitarism—growth hormone deficiency + deficiencies of other pituitary hormones. Severe hypoglycemia may be an initial presentation. Most infants present in the first few days of life with severe hypoglycemia. In males, microphallus is important diagnostic information. It is due to LH deficiency as LH stimulates testosterone production from testes during the last trimester of pregnancy causing lengthening of penis. Prolonged jaundice may be present which is due to associated central (hypothalamic or pituitary) hypothyroidism. Children who remain unrecognized may present later with failure to thrive and poor weight gain.
DEFINITION
Deficiency of more than one pituitary hormone.
PHYSIOLOGY
ACTH → adrenal glucocorticoids.
TSH → thyroid hormone.
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) → gonadal function.
Prolactin → lactation
GH → growth.
Antidiuretic hormone (ADH) → diabetes insipidus.
ETIOLOGY
Congenital:
Inherited (mutation in the gene encoding pituitary transcription factor Pit-1).
Sporadic developmental defects: Midline anomalies (septo-optic dysplasia, cleft palate), holoprosencephaly.
Acquired:
Tumors and their treatment (craniopharyngioma).
Head trauma.
CNS irradiation.
Histiocytosis X.
Autoimmune hypophysitis.
Hemochromatosis.
Disseminated tuberculosis or sarcoidosis.
SIGNS AND SYMPTOMS
Depends on missing hormone and or etiological cause.
GH deficiency (poor linear growth, hypoglycemia).
In neonates (hypoglycemia and micropenis).
LH and FSH (pubertal delay).
ADH (polyuria, polydipsia).
Visual and neurologic complaints.
Cortisol and GH are insulin counterregulatory hormones.
TREATMENT
Replacement directed toward the hormonal deficiency.
SHORT STATURE
DEFINITION
Height below the 5th percentile for age and gender: (> 2 standard deviations below the mean).
Normal
Chronological age (CA) = Bone age (BA) = Height age (HA)
Normal growth velocity depends on age and pubertal stage:
First year: 25 cm/yr
1–2 years: 12 cm/yr
2–3 years: 10 cm/yr
3–4 years: 7 cm/yr
4–5 years: 6 cm/yr
After 5 years: 5 cm/yr
During puberty (girls Tanner II–III): 10 cm/yr
During puberty (boys Tanner IV): 12 cm/yr
Genetic Potential
For males: Add 5 inches to mother’s height and average it with father’s height.
For females: Subtract 5 inches from father’s height and average it with mother’s height.
Familial (Genetic Short Stature)
Common cause of short stature.
Growth rate ↓ between 6 and 18 months.
Height within family norm (usually at least one parent has short stature).
Normal rate of growth (follow steady channel after 2–3 yr).
Normal bone age.
Puberty at average age.
The most common causes of short stature are normal variants including familial short stature and constitutional delay.
Constitutional
Most common cause of short stature.
Normal variant of growth.
Normal at birth, then growth decelerate during first 2 yr of life.
Both length and weight gain decelerate until age 2–3 yr.
Resume growth rate by 2–3 yr paralleling a lower percentile curve.
Delayed puberty (second growth deceleration at age 12–14 yr).
Delayed bone age (bone age = height age).
Nutritional
Inflammatory bowel disease.
Celiac disease.
HIV infection.
Other conditions causing malnutrition.
Psychosocial Deprivation
Children with psychosocial deprivation clinically resemble children with GH deficiency with retardation of bone age and similar findings on GH stimulation testing; however, testing and growth revert to normal when the child is removed from the deprived environment.
Small for Gestational Age
Birth weight and length < 10th percentile for gestational age.
Intrauterine Growth Retardation
Pathologically growth restricted infants.
Children with constitutional delay are the so-called “late bloomers.”
Growth Hormone Deficiency (GHD)
Pathologic cause of short stature.
Hypoglycemia and micropenis (especially if associated with hypopituitarism).
Height below genetic potential.
↓ growth velocity (< 25th percentile for age).
Downward crossing of percentiles on growth chart after age 2–3 yr.
↓ muscle mass, ↑ fat mass.
Pubertal delay.
Causes—idiopathic, hereditary, hypothalamic/pituitary malformation, hypothalamic/pituitary tumor, head trauma, CNS surgery, CNS radiation, meningitis/encephalitis, autoimmune hypophysitis, histiocytosis X, sarcoidosis, and hemochromatosis.
DIAGNOSIS
Delayed bone age.
Low IGF-1, low IGFBP-3, inadequate response to GH stimulation.
TREATMENT
Biosynthetic human GH.
Growth Hormone Insensitivity (Laron Syndrome)
Features similar to GHD.
GH receptor defect.
Elevated GH level.
Low IGF-1, IGF-2, and IGFBP-3.
Absent or low growth hormone binding protein (GHBP).
Children with poor growth due to nutritional definiencies are generally short and have low birth weight, whereas children with endocrinologic causes for poor (linear) growth are usually disproportionately heavy.
TREATMENT
Biosynthetic IGF-1.
Hypothyroidism
Pathologic cause of short stature.
↓ growth velocity.
Delayed bone age.
Thyroid hormone is the most important hormone for linear growth in the first 2 years of life.
DIAGNOSIS
Elevated TSH, decreased T4.
TREATMENT
Synthroid (T4).
Cushing Syndrome
Pathologic cause of short stature.
↑ cortisol inhibits growth.
Abnormal weight gain.
Truncal obesity, rounded moon facies, buffalo hump, purple striae.
ETIOLOGY
Endogenous or exogenous steroids.
DIAGNOSIS
Elevated 24-hr urine test for free cortisol is the best screening test.
TREATMENT
Treat the cause.
Chromosomal Disorders
Turner syndrome
Down syndrome
Silver-Russell syndrome
Prader-Willi syndrome
TALL STATURE
DEFINITION
Height more than 2 standard deviations above the mean for age and gender.
Familial
Most common.
Hormonal
GH excess.
Early puberty: ↑ sex steroids (tall as child, short as adult from early epiphyseal closure).
CAH: ↑ adrenal androgens (tall as child, short as adult from early epiphyseal closure).
Hyperinsulinism/obesity.
Hypogonadotrophic hypogonadism (Kallmann syndrome).
Syndromes
Marfan syndrome.
Homocystinuria.
Klinefelter syndrome.
Sotos syndrome (not truly endocrine, associated mental retardation)—cerebral gigantism: In utero and postnatal overgrowth.
Beckwith-Wiedmann syndrome: Macrosomia with in utero and postnatal somatic overgrowth, macroglosia, hemihypertrophy and abdominal wall defect. Hypoglycemia due to hyperinsulinemia. ↑ incidence of tumors.
Beckwith-Weidemann syndrome: Large babies due to overproduction of IGF-2.
DIABETES INSIPIDUS (DI)
DEFINITION
Inability of kidneys to concentrate urine.
ETIOLOGY
Central (↓ ADH):
Congenital hypothalamic/pituitary defects (septo-optic dysplasia, holoprosencephaly).
Idiopathic, accidental or surgical trauma, infections (meningitis).
Neoplasms (suprasellar tumors).
Infiltrative and autoimmune diseases (histiocytosis X).
Drugs (ethanol, phenytoin).
Nephrogenic (renal unresponsiveness to ADH):
X-linked recessive (vasopressin type 2 receptor mutation): Males—early infancy.
Autosomal recessive (mutation in the renal water channel—aqua-porin-2).
Idiopathic.
Renal diseases.
Hypercalcemia.
Hypokalemia.
Drugs (lithium, demeclocycline).
SIGNS AND SYMPTOMS
Central:
Polyuria (> 1.5 L/m2/day).
Polydipsia (excessive thirst).
Enuresis.
Hypernatremic dehydration.
Nephrogenic:
Polyuria, failure to thrive (FTT), hyperpyrexia, vomiting.
Hypernatremic dehydration.
In diabetes insipidus, there is high urine output despite significant dehydration.
DIAGNOSIS
↑ serum osmolality (normal: < 290 mOsm/kg).
↑ serum Na (normal: < 145 mmol/L).
↓ urine osmolality.
Water deprivation test: Withhold fluids for 8–10 hr (may need to be done in hospital). Serum osmolality > 300 mOsm/kg with urine osmolality < 600 mOsm/kg establishes the diagnosis. Once diagnosis is established, give pitressin 1 U/m2 SQ.
Urine volume falls and osmolality doubles—central DI.
Less than twofold rise in urine osmolality—nephrogenic DI.
Plasma vasopressin (low in central DI and high in nephrogenic DI).
MRI: Posterior pituitary bright spot is diminished or absent in both forms of DI.
TREATMENT
Central:
Fluids (3–4 L/m2/day without vasopressin, 1 L/m2/day with vasopressin).
Vasopressin (desmopressin [DDAVP]) 0.025-0.2 mg bid orally, 2.5–30 μg intranasally divided qd-bid, or 0.08 μg/kg subcutaneously divided q 12).
Nephrogenic:
Fluids.
Thiazide diuretic (promotes Na excretion in the distal tubule and alters inner medullary osmolality → ↑ proximal tubular reabsorption of Na and ↑ free water reabsorption from the collecting duct).
Indomethacin 2 mg/kg/day further enhances proximal tubular sodium and water reabsorption.
SYNDROME OF INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE (SIADH)
DEFINITION
Hyponatremia with ↑ ADH.
ETIOLOGY
Encephalitis/meningitis.
Brain tumor.
Head trauma.
Psychiatric diseases.
Postictal period.
Positive pressure ventilation.
Rocky Mountain spotted fever.
Pneumonia.
AIDS.
Drugs (carbamazepine, chlorpropamide, vincristine, tricyclic antidepressant).
In SIADH, there is an absence of edema and dehydration.
SIGNS AND SYMPTOMS
Asymptomatic until Na < 120.
Headache, nausea, vomiting, irritability, seizure.
↓ urine output.
DIAGNOSIS
Hyponatremia (Na < 135 mmol/L).
↓ serum osmolality (< 275 mOsm/kg).
↑ urine osmolality (>100 mOsm/kg).
↑ urine Na (usually > 80 mEq/L).
Low serum uric acid level.
Normal renal, adrenal, and thyroid function.
Urine osmolality < 100 mOsm/kg excludes diagnosis of SIADH.
TREATMENT
Symptomatic with hyponatremia: Hypertonic (3%) saline 6 mL/kg bolus ↑ Na by 5 mmol/L. Repeat bolus until patient stops seizing.
Asymptomatic:
Fluid restriction (1000 mL/m2/day).
Demeclocycline if resistant (rarely used).
Selective V2 receptor antagonist (tolvaptan).
Oral urea (0.1–2.0 g/kg/day divided q6h) at low doses reduces natriuresis and at higher doses causes osmotic diuresis.
CEREBRAL SALT WASTING (CSW)
DEFINITION
Renal loss of Na during intracranial disease.
TABLE 16-3. Comparison Between SIADH and CSW
ADH, antidiuretic hormone; ANP, atrial natriuretic peptide; CSW, cerebral salt wasting; SIADH, syndrome of inappropriate secretion of antidiuretic hormone.
ETIOLOGY
High atrial natriuretic peptide (ANP) → natriuresis and diuresis.
SIGNS AND SYMPTOMS
Acute, intermittent excessive fluid and salt loss.
↑ urine output.
Onset within first week of CNS insult.
Duration variable usually lasts 2–4 weeks.
Dehydration (↓ extracellular fluid).
DIAGNOSIS
Hyponatremia (Na < 130 mmol/L).
Urine osmolality isotonic with plasma.
↑ urine Na (usually > 150 mEq/L).
See Table 16-3 for comparison between SIADH and CSW.
TREATMENT
Water and salt replacement (0.9 or 3% NS).
Urea.
SEXUAL DEVELOPMENT
Pubertal events are classified by Tanner staging. Puberty progresses usually with an average duration of 3–4 yr, spending roughly about one year in each stage.
See Table 16-4 and Figure 16-1.
Normal Female Progression
Thelarche → height growth spurt → pubic hair → menarche (12.5–13 yr). (In 20 % of girls, pubarche may precede thelarche).
The ↑ in height velocity in boys occurs at a later chronologic age than in girls (Tanner IV in boys, Tanner II–III in girls).
Normal Male Progression
Testicular enlargement → pubic hair → penile enlargement → height growth spurt (14–15 yr) → axillary hair.
Precocious Puberty
A 6½-year-old girl develops enlarged breasts. Six months later she begins to develop pubic and axillary hair. Her menses began at age 9. Think: Idiopathic precocious puberty.
Puberty in girls is now recognized to be occurring at earlier age. The exact cause of the precocious puberty in most cases remains unknown. Evaluation should include serum FSH, LH, estradiol, and bone age. Brain MRI should be obtained to rule out possible underlying intracranial cause.
TABLE 16-4. Tanner Stages
FIGURE 16-1. Tanner stages
DEFINITION
Onset of secondary sexual characteristics.
Girls (< 8 yr for white girls, < 7 for African-American and Hispanics).
Boys (< 9 yr).
Premature breast development (thelarche).
Premature pubic hair development (pubarche/adrenarche).
Most normal 11-year-old girls have pubic hair.
ETIOLOGY
Central or True Precocious Puberty
Premature activation of the hypothalamic-pituitary-gonadal axis.
Gonadotropin dependent: Pubertal (high) FSH and LH and sex steroids (testosterone or estradiol).
Usually idiopathic in girls, while secondary to organic lesion in boys.
CNS abnormalities:
Hypothalamic hamartoma.
Head injury.
Hydrocephalus.
Radiation.
Surgical trauma.
Tumors (astryocytoma, glioma, pinealoma, LH-secreting adenoma).
Peripheral or Pseudo Precocious Puberty
Gonadotropin independent: Prepubertal (low) FSH and LH, pubertal (high) sex steroids.
Male:
Testotoxicosis: Familial male limited precocious puberty (bilateral testicular enlargement).
Tumors.
Testicular Leydig cell tumor (unilateral testicular enlargement).
Choriocarcinoma, dysgerminoma, hepatoblastoma (human chorionic gonadotropin [HCG] producing).
Adrenal tumors (testosterone secreting).
CAH.
McCune-Albright syndrome.
Exogenous sex steroid.
Female:
McCune-Albright syndrome: Ovarian cysts secreting estrogen.
Tumors:
Ovarian tumors (granulosa cell tumor, gonadoblastoma).
Choriocarcinoma, dysgerminoma, hepatoblastoma (HCG producing).
Adrenal tumors (estrogen secreting).
Exogenous sex steroids.
Precocious puberty in girls is usually idiopathic, while in boys it usually has an organic cause.
SIGNS AND SYMPTOMS
Growth acceleration.
Significantly advanced bone age.
Sexual development is progressive (in some children, particularly girls, such changes may be very slowly progressive—a variant of normal development).
DIAGNOSIS
FSH, LH.
Estradiol, testosterone.
Dehydroepiandrosterone sulfate (DHEAS), 17-hydroxyprogesterone, androstenedione.
α-fetoprotein (AFP), HCG.
Prepubertal levels (low) of gonadotropins and pubertal (high) level of estrogen or testosterone suggest gonadotropin-independent process.
Gonadotrpins may be pubertal or prepubertal at baseline while testosterone or estrogen is usually pubertal in gonadotrpin-dependent precocious puberty.
No ↑ in gonadotropins after gonadotropin-releasing hormone (GnRH) in gonadotrpin-independent precocious puberty.
Pubertal LH-dominant response (LH > 5 mIU/mL and LH-to-FSH ratio > 1) after GnRH in true, central, gonadotropin-dependent precocious puberty.
Pelvic ultrasound to evaluate ovarian and uterine size and rule out any pathology (ovarian cyst, tumor).
MRI of the head to rule out CNS abnormality in central precocious puberty.
CT abdomen and pelvis if tumor is the likely cause of peripheral precocious puberty.
TREATMENT
Treatment of underlying cause (in both central and peripheral puberty).
GnRH analogues (in central precocious puberty).
Androgen antagonist (flutamide) and aromatase inhibitor (blocks conversion of androgen to estrogen) in peripheral precocious puberty.
Premature Thelarche
DEFINITION
Isolated breast development.
Most commonly noted during the first 2 yr of life.
May occur after 2 yr due to temporary increase in FSH. Breast development is usually limited and often regresses.
SIGNS AND SYMPTOMS
Normal growth rate and bone age.
Prepubertal level of gonadotropins and estrogen.
TREATMENT
Nonprogressive and self-limiting.
Premature Adrenarche
DEFINITION
Early appearance of sexual hair (premature pubarche) without other signs of sexual development.
< 8 yr in girls (< 7 yr in African-American and Hispanic).
< 9 yr in boys.
Adult body odor is other associated feature.
ETIOLOGY
Early onset of increased adrenal androgen production (premature adrenarche).
In girls it is a risk factor for later development of polycystic ovarian syndrome (PCOS).
Nonclassical CAH may present similarly and can lead to early puberty.
DIAGNOSIS
Adrenal androgen (DHEAS): Normal for pubertal stage but elevated for chronologic age.
If androgens are significantly elevated, CAH and adrenal tumor need to be excluded.
TREATMENT
Self-limiting.
Delayed Puberty
DEFINITION
Absence of pubertal development by 14 yr in girls and 15 yr in boys.
EPIDEMIOLOGY
More common in boys.
ETIOLOGY
Female:
Constitutional.
Primary ovarian failure (idiopathic, autoimmune, chemotherapy, radiation, galactosemia, fragile X syndrome, mutation in gonodotropin receptor).
Turner syndrome.
Hypogonadotropic hypogonadism (Kallmann syndrome).
17-hydroxylase deficiency CAH.
Hypopituitarism (congenital or acquired).
Dysfunction of hypothalamic-pituitary-gonadal axis secondary to systemic illness, undernutrition, or strenuous physical activity.
Prader-Willi syndrome.
Male:
Constitutional.
Primary testicular failure (vanishing testis syndrome, bilateral cryptorchidism/torsion, infection, chemotherapy, radiation, surgical trauma, hemochromatosis, fragile X syndrome, mutation in gonodotropin receptor).
Klinefelter syndrome.
Hypogonadotropic hypogonadism (Kallmann syndrome).
Dysfunction of hypothalamic-pituitary-gonadal axis secondary to systemic illness or undernutrition.
Hypopituitarism (congenital or acquired).
Prader-Willi syndrome.
DIAGNOSIS
FSH, LH, estradiol, testosterone.
Elevated gonadotropin levels (FSH, LH) suggest primary gonadal failure—hypergonadotrophic hypogonadism.
Low gonadotropin levels suggest hypogonadotrophic hypogonadism or constitutional delay. No test definitely differentiates constitutional delay from gonadotropin deficiency until age is well into adolescence.
Chromosome analysis (for primary gonadal failure).
MRI of the head (in hypogonadotrophic hypogonadism or hypopituitarism).
Kallmann syndrome: Usually sporadic; 5% X-linked hypogonadotropic hypogonadism affecting males and rarely females, associated with anosmia, cleft lip/palate, and other midline defects.
TREATMENT
Treatment of the cause.
Females: Estrogen initially; later, cyclic estrogen progesterone.
Males: Testosterone.
MENSTRUATION
The mean age for menarche in American is 12.8 yr +/– 1.2 yr.
Menarche occurs about 2–3 yr after the initiation of puberty. Two-thirds of females reach menarche at Tanner stage IV puberty.
Fifty to sixty percent of cycles in the first 2 yr after menarche in most girls are anovulatory.
The length of a cycle is between 21 and 45 days (average is 28 days).
The length of flow is 2–7 days (average is 3–5 days).
Blood loss is on average 40 mL (range, 25–70 mL).
Amenorrhea
PRIMARY AMENORRHEA
Lack of spontaneous uterine bleeding regardless of secondary sexual characteristics by age 16 yr.
Turner syndrome is the most common cause of primary amenorrhea.
ETIOLOGY
Primary ovarian failure (elevated FSH and LH).
Chromosomal:
Turner syndrome.
Triple X syndrome.
Pure gonadal dysgenesis (46,XX or 46,XY).
Fragile X.
Classical galactosemia.
Autoimmune oophoritis.
Radiation.
Chemotherapy.
Gonadal trauma.
17-hydroxylase deficiency (CAH).
Congenital lipid hyperplasia.
FSH/LH receptor mutation.
Idiopathic.
Hypogonadotropic hypogonadism (low FSH and LH): Isolated or with hypopituitarism.
Prader-Willi syndrome.
Anorexia nervosa.
Strenuous exercise.
Structural anomalies:
Imperforate hymen.
Agenesis of Müllerian structure (Mayer-Rokitansky-Hauser syndrome).
Other:
Complete androgen insensitivity (testicular feminization syndrome).
True hermaphroditism.
SECONDARY AMENORRHEA
A 16-year-old female had the onset of breast development at the age of 12 years and menses at age 14. She has not had menses for 2 months. She is active in sports. Physical examination is normal. Think: Rule out pregnancy, then consider the sports contribution to her secondary amenorrhea.
Pregnancy is the most common cause of amenorrhea and should be excluded in any female patient of reproductive age. After pregnancy, thyroid disease and hyperprolactinemia should be considered as potential diagnoses. Amenorrhea can also occur due to exercise and participation in athletic activity. Female athlete triad (disordered eating, amenorrhea, and osteoporosis) is a well-recognized entity. Athletic amenorrhea is due to hypothalamic-pituitary axis suppression, but it is a diagnosis of exclusion. Other causes must be excluded, and evaluation should include pregnancy test, prolactin, FSH, LH, TSH, T4DHEAs, 17 Hydroxprogesterone and testosterone levels.
Absence of menstruation for 6 months or a length of time equal to three cycles after menstrual cycles have already been established.
The most common causes of secondary amenorrhea include pregnancy, stress, and PCOS.
ETIOLOGY
Pregnancy.
Turner syndrome (mosaicism).
Hyperandrogenic states (PCOS, CAH).
Hyperprolactinemia.
Hypothalamic amenorrhea.
Causes of primary amenorrhea.
DIFFERENTIAL DIAGNOSIS
Normal/low FSH:
Consider hypothalamic amenorrhea related to stress, weight loss, an eating disorder, competitive athletics, phenothiazine use, or substance abuse.
Also consider chronic disease, CNS tumor (ie, prolactinoma), pituitary infiltration or infarction as in postpartum hemorrhage or sickle cell disease, and Asherman syndrome (following endometrial curettage).
High FSH: Consider gonadal dysgenesis as in mosaic Turner syndrome or autoimmune oophoritis.
Dysmenorrhea
DEFINITION
Painful menstruation.
PRIMARY OR ESSENTIAL DYSMENORRHEA
Dysmenorrhea in the absence of any specific, pelvic pathologic condition. Associated with ovulatory cycles.
ETIOLOGY
Progesterone produced during ovulatory cycle ↑ the synthesis of the prostaglandins.
Excessive amounts of prostaglandins F2 and E2, which cause uterine contractions, tissue hypoxia and ischemia, and ↑ sensitization of pain receptors.
Dysmenorrhea is the most common gynecologic complaint.
TREATMENT
Recommend prostaglandin inhibitors for dysmenorrhea at the onset of flow or pain.
SECONDARY DYSMENORRHEA
ETIOLOGY
Underlying structural abnormality of the vagina, cervix, or uterus (endometrial polyps, fibroids).
Congenital anomalies.
Pelvic adhesions.
Endometriosis.
Foreign body such as an intrauterine device.
Endometritis: Infection, especially secondary to sexually transmitted diseases (STDs).
Complications of pregnancy such as ectopic pregnancy.
Mittelschmerz
Mid-menstrual cycle pain due to ovulation
Not pathologic
Treat symptomatically
TESTICULAR FEMINIZATION
DEFINITION
Androgen insensitivity syndrome (complete and partial form).
X-linked.
In complete insensitivity, XY male appears as unambiguous female with a short, blind-ending vaginal pouch and no uterus. Androgen receptor is either absent or unable to bind androgen.
In partial insensitivity, XY cases have either ambiguous or female genitalia with no uterus. Considerable virilization occurs at puberty, but gynecomastia also develops. Androgen receptor binding is low or normal.
SIGNS AND SYMPTOMS
Primary amenorrhea.
Normal breast development.
Pubic hair absent or sparse.
Presence of testes in inguinal hernia.
DIAGNOSIS
Testosterone level is elevated.
LH is normal or elevated.
Sex hormone binding globulin (SHBG) test: IM testosterone (2 mg/kg) unable to suppress SHBG to < 80% of the basal value suggests androgen insensitivity.
HCG stimulation (3000 mg/m2/day) every other day for 2 days shows normal testosterone response (double from baseline at 48 hr, then double again 2 days after the second injection) helps differentiate partial androgen sensitivity from causes of ambiguous genitalia due to testosterone synthesis defect.
Androgen receptor binding studies in cultured genital skin fibroblast.
DNA analysis for mutation in AR gene.
TRUE HERMAPHRODITISM
DEFINITION
Gonads comprised of both ovarian and testicular elements (ovotestis).
Most are 46,XX.
Can be familial.
ETIOLOGY
Abnormal gonadal differentiation.
SIGNS AND SYMPTOMS
Ambiguous genitalia—significant masculinization (raised as male).
Risk of malignant transformation of gonadal tissue is much lower (2%) than XY gonadal dysgenesis.
PSEUDOHERMAPHRODITISM
Female
DEFINITION
Normal gonads and uterus (both gonads are ovaries) with virilization of external genitalia in a patient with a 46,XX karyotype.
ETIOLOGY
CAH (21-hydroxylase deficiency, 11 β-hydroxylase deficiency, 3 β-hydroxysteroid dehydrogenase deficiency).
Placental aromatase deficiency (conversion of androgens to estrogens is blocked). Estriol level is undetectable. Maternal virilization during pregnancy.
Luteoma of pregnancy: Maternal virilization during pregnancy.
SIGNS AND SYMPTOMS
Virilization of external genitalia (clitoral hypertrophy, labioscrotal fusion).
Male
DEFINITION
Normal testes (both gonads are testes) with undervirilization or completely female appearing external genitalia in a patient with 46,XY karyotype.
ETIOLOGY
Androgen insensitivity.
CAH: 3β-hydroxysteroid dehydrogenase deficiency, 17-hydroxylase deficiency, and congenital lipoid adrenal hyperplasia.
Enzyme defects in testosterone synthesis (17-ketoreductase deficiency).
5α-reductase deficiency: Conversion of testosterone to dihydrotestosterone is blocked.
SIGNS AND SYMPTOMS
Undervirilization of external genitalia (small phallus, hypospadias, undescended testes) or completely female appearing genitalia.
METABOLIC BONE DISEASE
Osteopenia: Deficiency in bone mass relative to age, sex, and race norms.
Osteoporosis: Loss of bone mineral and matrix due to disproportionately low osteoblastic activity.
Osteomalacia: Defective mineralization in bone.
Rickets: Defective mineralization of cartilage in the growth plate.
Classification of Rickets
CALCIOPENIC
ETIOLOGY
Nutritional:
Vitamin D deficiency
Calcium deficiency
Genetic:
Vitamin D–dependent rickets type 1 (1α-hydroxylase deficiency causing defect in the conversion of 25(OH) vitamin D to 1,25(OH)2 vitamin D).
Vitamin D–dependent rickets type 2 (mutation in the gene coding the vitamin D receptor causing hereditary vitamin D resistance).
Drugs:
Corticosteroids
Anticonvulsants
Prematurity.
PHOSPHOPENIC
Genetic:
X-linked hypophostemic rickets (mutation in the PHEX gene).
Autosomal-dominant hereditary hypophosphatemic ricket (mutation in the gene for fibroblast growth factor 23).
Autosomal-recessive hereditary hyperphosphatemic rickets with hypercalciuria (mutation in the gene for renal sodium phosphate cotransporter NaP(i)-IIc).
Tumor-induced hypophostemia (tumor mostly of mesenchymal origin).
Dietary:
Intestinal malabsorption.
Breast-fed premature infants.
Fanconi syndrome (renal loss of glucose, phosphate, amino acids, and bicarbonate).
CLINICAL FEATURES
Genu varum (bow-legged deformity) during early childhood.
Genu valgum (knocked-knee deformity) in older children.
Enlargement of wrists and knees.
Rachitic rosary (bulging of costochondral junctions).
Harrison grooves (groove extending laterally from xiphoid process, corresponds to the diaphragmatic attachment).
Frontal bossing.
Craniotabes (generalized softening of calvaria).
Craniosynostosis.
Bone pain.
Proximal muscle weakness.
RADIOLOGICAL FEATURES
Widening of epiphyseal plates.
Cupping.
Deformities in shaft of long bones.
DIAGNOSIS
Serum calcium, phosphorous, alkaline phosphatase level:
Alkaline phosphatase is elevated in most cases of rickets. Elevation is marked in calcium and vitamin D deficiency and mild in hypophosphatemic rickets.
Serum calcium and phosphorus tend to be low or low normal in all form of calciopenic rickets.
Low serum phosphate with normal calcium level suggests the diagnosis of hypophosphatemic rickets.
25(OH) vitamin D and 1,25(OH)2 vitamin D level:
Low 25(OH) vitamin D is seen in all forms of vitamin D deficiency.
Normal 25(OH) vitamin D level with low 1,25(OH)2 vitamin D level point to 1α-hydroxylase deficiency.
1,25(OH)2 vitamin D level is elevated in hereditary vitamin D resistance.
1,25(OH)2 vitamin D level is inappropriately normal in the setting of hypophosphatemia in X-linked and autosomal-dominant hypophosphatemic rickets.
PTH level:
Moderate to severe hyperparathyroidism is characteristic of calciopenic rickets.
In hypophosphatemic rickets, PTH level may be normal or modestly elevated.
Tubular reabsorption of phosphorous (TRP).
[1-{(Urine P × Serum creatinine)/(Serum P × Urine creatinine)}] × 100
Normal TRP value 85–95% for children.
A nomogram is used to determine the renal tubular threshold maximum for phosphate as expressed per glomerular filtration rate (TMP/GFR).
Low TMP/GFR in the setting of low serum phosphate confirms inappropriate renal loses, characteristic of hypophosphatemic rickets.
TREATMENT
Nutritional rickets:
5000–15,000 IU of vitamin D PO for 4 weeks.
600,000 IU in a single dose PO/IM for noncompliance (stoss therapy).
Ensure adequate calcium intake (350–1500 mg elemental calcium per day for 6 months).
1α-hydroxylase deficiency rickets:
1,25(OH)2 vitamin D (calcitriol) 0.5–3 μg/day.
Adequate dietary calcium intake.
Hereditary vitamin D resistance:
High doses of 1,25(OH)2 vitamin D.
IV calcium in patients who do not respond to vitamin D.
Hypophosphatemic rickets:
Phosphate (250–1000 mg elemental phosphorus in 2–3 divided doses).
1,25(OH)2 vitamin D is important for successful outcome. It enhances Ca and P absorption and dampens phosphate stimulated PTH secretion.
