First Aid for the Pediatrics Clerkship, 3 Ed.

Endocrine Disease

 

DIABETES

Image

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

Image Diabetes is one of the most common endocrine disorders of the pediatric age group.


Image

Think of testing urine glucose with the onset of enuresis in a previously toilet-trained child.


TABLE 16-1. Diabetes

Image


Image

The prevalence of type 2 diabetes is increasing in children secondary to increasing prevalence of childhood obesity.


Image Classification:

Image 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).

Image 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:

Image ↓ glucose utilization.

Image ↑ hepatic glucose production.

SIGNS AND SYMPTOMS

Image Triad of polyuria, polydipsia, and polyphagia (more abrupt in type 1 diabetes).

Image Weight loss and enuresis are common symptoms in type 1 diabetes.

Image Vomiting, dehydration, and abdominal pain are hallmark of acute complication → diabetic ketoacidosis.

DIAGNOSIS

Image Fasting blood glucose ≥ 126 mg/dL (7 mmol/L).

Image Random blood glucose ≥ 200 mg/dL along with symptoms of diabetes.

Image Two-hour plasma glucose > 200 during a 75-g oral glucose tolerance test.

Image 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:

Image Obesity (body mass index > 85th percentile for age)

Image Family history of type 2 diabetes (first- and second-degree relatives).

Image Race (Native American, African-American, Hispanic, and Asian).

Image Signs and symptoms associated with insulin resistance (acanthosis nigricans, dyslipidemia, hypertension [HTN], and polycystic ovarian syndrome).

TREATMENT

Image Patient education and counseling.

Image Diet.

Image Exercise.

Image Insulin (0.5–1 U/kg).

Image Oral hypoglycemics in type 2 diabetes (such as metformin, sulfonylurea, thiazolidinediones).

DIABETIC KETOACIDOSIS (DKA)

Image

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

Image Hyperglycemia > 200 mg/dL.

Image Acidosis pH < 7.30.

Image Bicarbonate < 15 mmol/L.

Image Ketonemia > 3 mmol/L.


Image

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

Image 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.

Image Precipitating factors—stress, infection, trauma.

SIGNS AND SYMPTOMS

Polyuria, polydipsia, dehydration, fatigue, headache, nausea, vomiting, abdominal pain, tachycardia, tachypnea.


Image

Dehydration in DKA is primarily intracellular and is often underestimated.


OTHER LABORATORY FINDINGS

Image ↑ anion gap (>12–16 mEq).

Image ↑ hemoglobin (Hgb) and hematocrit (Hct) (hemoconcentration).

Image ↑ white blood cell (WBC) count.

Image ↓ serum sodium (Na) (pseudohyponatremia from hyperglycemia and/or hypertriglyceridemia).

Image Normal or ↑ potassium (K) (from shift of K from intracellular to extracellular compartment due to acidosis).

Image Urinalysis reveals glucose and ketones (acetoacetate/acetone).


Image

Serum Na ↓ 1.6 mEq/L for every 100 mg/dL rise in glucose.


TREATMENT

Image Careful fluid and electrolyte replacement to avoid cerebral edema. Rehydration fluid should not exceed 4000 mL/m2/day.

Image 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.

Image Potassium should be given as half KCl and half KPO4.

Image Insulin regular (0.1 U/kg/hr).

Image Glucose (add glucose when blood glucose is < 250–300 mg/dL).


Image

Total body potassium may be considerably depleted even when serum K+ is normal or ↑.


COMPLICATIONS

Image Hypoglycemia.

Image Hypokalemia.

Image 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

Image

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

Image Excessive insulin secretion in infants from transient dysfunction in islet cell function.

Image Risk factors include:

Image Small-for-gestational-age (SGA) or premature infants.

Image Fetal hypoxia/asphyxia.

Image Infant of diabetic mother (born to mother with poorly controlled diabetes (type 1, type 2, or gestational).

Image Erythroblastosis fetalis.

Image Other causes include surreptitious insulin administration.

Permanent Hyperinsulinemia

Image 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.

Image Autosomal-dominant forms of hyperinsulinism are usually milder and caused by activating mutation in glucokinase (GCK) gene and gluta-mate dehydrogenase gene (GLUD1).

Image 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

Image Frequent feeding (feed q3–4h).

Image IV glucose if necessary.

Image In severe, prolonged cases, diazoxide, somatostatin, and/or pancreatectomy.

HYPOGLYCEMIA

Image

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

Image Hyperinsulinism.

Image Hormone deficiencies (glucocorticoid, growth hormone).

Image Glycogen storage disease.

Image Defect in gluconeogenesis.

Image Fatty acid oxidation defects.

Image Organic acidemias.

Image Ketotic hypoglycemia.

Image Malnutrition, prematurity, SGA.

Image Liver failure.

Image Congenital heart diseases.

Image Tumors.

Image Poisons/drugs (salicylates, alcohol).

Image Systemic disease—sepsis, burns, cardiogenic shock.

TREATMENT

Image 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.

Image In patients with hyperinsulinemia, subcutaneous glucagon 0.03 mg/kg can reverse the hypoglycemia.

HEMOCHROMATOSIS

DEFINITION

Image ↑ storage of iron in the form of hemosiderin in parenchymal cells.

Image Liver, heart, gonad, skin, and joints.

ETIOLOGY

Image Hereditary

Image Neonatal

Image Transfusion induced

SIGNS AND SYMPTOMS

Image Cirrhosis

Image Bronzing of skin

Image Diabetes mellitus

LABORATORY FINDINGS

Image ↑ serum ferritin

Image ↑ transferrin saturation

TREATMENT

Chelation with desferoxamine, phlebotomy.

HYPERTHYROIDISM

DEFINITION

↑ secretion of thyroid hormone.

Juvenile Graves Disease

Image Occurs more frequently in females (male-to-female ratio 3:1–5:1).

Image Triad of:

Image Hyperthyroidism with diffuse goiter (almost always present; goiter is usually symmetrical, smooth, soft, and nontender).

Image Ophthalmopathy (present in over one-half of the patients).

Image Dermopathy: Pretibial myxedema is present in 1–2% of adults; it rarely occurs in children.


Image

Juvenile Graves disease causes 95% of thyrotoxicosis in children.


ETIOLOGY

Image Autoimmune disorder with antibodies against thyroid-stimulating hormone (TSH) receptor—thyrotropin-binding inhibitory immunoglobulin (TBII).

Image TBII can either stimulate or inhibit thyroid cell function.

Image Thyroid-stimulating immunoglobulin (TSI): Present in Graves disease.

Image TSH receptor–blocking antibodies: Cause hypothyroidism.

Image Clinical presentation is determined by the net effect of interaction between stimulating and blocking antibodies.

SIGNS AND SYMPTOMS

Image Gradual onset (6–12 months).

Image Emotional disturbance, change in academic performance.

Image Insomnia.

Image Palpitations.

Image Fatigue, muscle weakness, ↑ sweating.

Image ↑ appetite with ↓ or no weight gain.

Image Goiter.

Image Heat intolerance.

Image Fine tremors.

Image Exophthalmos.

Image Menstrual irregularities.

Image Thyroid storm: Characterized by:

Image Fever (usually > 101.3°F [38.5°C]).

Image Severe tachycardia out of proportion to fever, leading to high-output cardiac failure.

Image Central nervous system (CNS) manifestations (confusion, obtundation, coma, and convulsions).

LABORATORY FINDINGS

Image Elevated total and free thyroxine (T4) and total and free triiodothyro-nine (T3) levels.

Image ↓ TSH.

Image Elevated TBII (receptor assay).

Image Elevated TSI (bioassay).

TREATMENT OF HYPERTHYROIDISM

Image Pediatric endocrine consultation.

Image 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.

Image Propranolol 1–2 mg/kg/day PO in divided doses q6–8h (0.01–0.15 mg/kg/dose IV).

Image Treatment with 131I (radioactive iodine) for juvenile Graves disease is increasing.

Image Surgical—thyroidectomy.

Image 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

Image ↓ production of thyroid hormone either from primary defect at the level of thyroid or secondary to hypothalamic pituitary disorder.

Image 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

Image


Image

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

Image Sporadic: Thyroid dysgenesis (absent thyroid, hypoplastic thyroid, ectopic thyroid).

Image Iodine deficiency remains a major cause worldwide.

Image Prenatal exposure to radioiodine or antithyroid medications.

Image Rarely hereditary: Thyroid dyshormonogenesis (defect in synthesis of thyroid hormone) and generalized thyroid hormone resistance.

SIGNS AND SYMPTOMS

Image Most cases are asymptomatic at birth.

Image Postmaturity, macrosomia.

Image Wide fontanelle.

Image Prolonged jaundice.

Image Macroglossia.

Image Hoarse cry.

Image Abdominal distention, constipation.

Image Umbilical hernia.

Image Hypotonia.

Image Goiter (in some dyshormonogenesis).

Image If left untreated:

Image Slowed development, late teeth, late milestones, short stature.

Image Eventual mental retardation.


Image

Early diagnosis of congenital hypothyroidism is crucial to prevent or minimize cognitive impairment.


DIAGNOSIS

Newborn screening:

Image Primary T4–sequential TSH:

Image Used by most North American programs.

Image Initial filter paper blood spot: T4 with TSH measurement in specimens with low T4 values.

Image Uses a percentile as the cutoff, with 10th percentile being the usual standard.

Image Primary TSH–sequential T4:

Image Used in all European countries (except the Netherlands), Japan, Australia, and parts of North America.

Image Initial TSH measurement, supplemented by T4 in cases of high TSH.

Image Cutoff point for recall is TSH 20–50 μU/mL with low T4 (< 5 μg/dL) or TSH > 50 μIU/mL.

TREATMENT

Image Both early and high-dose treatment appear necessary.

Image L-thyroxine 10–15 μg/kg/day.

Acquired Hypothyroidism

Image

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.

Image Prevalence in children is 0.15% with a female-to-male ratio of 3:1.

Image Lymphocytic thyroiditis (Hashimoto) is the most common cause. It is an autoimmune disorder characterized by lymphocytic infiltration of thyroid and presence of:

Image Antithyroglobuin antibodies

Image Anti-TPO antibodies

Image Other causes include thyroid surgery and irradiation, medications (iodine, lithium, amiodarone, etc.), pituitary or hypothalamic dysfunction (secondary or tertiary acquired hypothyroidism).


Image

Look for hypothyroidism in Down syndrome, Turner syndrome, and Klinefelter syndrome.


SIGNS AND SYMPTOMS

Image Goiter.

Image Growth deceleration.

Image Delayed skeletal maturation.

Image Fatigue, lethargy.

Image Constipation.

Image Cold intolerance.

Image Bradycardia.

Image Dry skin.

Image Weight gain.

Image Delayed deep tendon reflexes.

TREATMENT

L-thyroxine 2–4 μg/kg/day.

THYROID NEOPLASM

EPIDEMIOLOGY

Image Rare in children.

Image Most common pediatric endocrine tumor (differentiated thyroid cancer).

Image Family history (in medullary thyroid cancer).

Image Prior irradiation (in papillary thyroid cancer).

TYPES

Image Thyroid adenoma (approximately 1% are toxic adenoma and cause hyperthyroidism).

Image Thyroid carcinoma: Arise from:

Image Follicular epithelium:

Image Papillary carcinoma (most common; focal calcification [ie, psammoma in 40–50%]).

Image Follicular carcinoma (higher prevalence in areas with iodine deficiency).

Image Insular carcinoma (poorly differentiated).

Image C cells: Medullary carcinoma (produce calcitonin). Associated with type 2 multiple endocrine neoplasia (MEN).


Image

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%).


Image

Incidence of malignancy of a thyroid neoplasm is higher in children than in adults.


DIAGNOSIS

Image Thyroid profile (thyroid functions are usually normal).

Image Calcitonin (for medullary cancer).

Image Thyroid ultrasound.

Image Fine-needle aspiration.

Image Definite diagnosis by surgical excision.

TREATMENT

Image Papillary and follicular cancer:

Image Near total or total thyroidectomy (complications include bleeding, hypoparathyroidism, damage to recurrent laryngeal nerve) with modified neck dissection, if needed.

Image Postoperative 131I ablation if the risk for recurrence is high.

Image Replacement thyroxine (higher doses in patients with ↑ risk of recurrence).

Image Medullary thyroid cancer:

Image Total thyroidectomy.

Image Prophylactic thyroidectomy if positive for MEN mutation, before age 5 yr in MEN 2A and before age 6 months in MEN 2B.

HYPERPARATHYROIDISM

Image

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

Image Primary (defect of parathyroid gland):

Image Parathyroid adenoma.

Image Generalized hyperplasia of all glands (MEN 1 and MEN 2A).

Image Parathyroid carcinoma.

Image Secondary (response to hypocalcemia):

Image Chronic renal failure (CRF).

Image Renal tubular acidosis.

Image Vitamin D–deficiency rickets.

Image Treatment (with phosphorus) for hypophosphatemic rickets.

Image Liver failure.

Image Tertiary hypoparathyroidism: Adenomatous change in parathyroid in the setting of CRF.

SIGNS AND SYMPTOMS

Image Clinical manifestation of hypercalcemia.

Image Muscle weakness, anorexia, nausea, vomiting, constipation, polydipsia, polyuria, dehydration, failure to thrive, coma, seizures, fever, renal stones.

DIAGNOSIS

Image ↑ serum Ca.

Image ↓ serum phosphorus.

Image ↑ urinary calcium.

Image ↑ PTH.

Image Shortened QTc interval.

Image Subperiosteal absorption (with prolonged hyperparathyroidism).

Image 99mTc-sestamibi scanning for parathyroid adenoma.

TREATMENT

Image Hypercalcemia:

Image Hydration (IV NS at 2–3 times maintenance).

Image Furosemide 1 mg/kg q6h (↑ Na and Ca excretion).

Image Prednisone (↓ intestinal absorption of Ca).

Image Calcitonin 4 U/kg SQ q12h.

Image Pamidronate 0.5 mg/kg infusion.

Image Calcimimetics suppress PTH secretion in affected gland.

Image Primary hyperparathyroidism:

Image Resection of isolated adenoma.

Image For generalized hyperplasia resection of 3½ glands.

Image Vitamin D and calcium for postop hypocalcemia, which can be severe and prolonged due to hungry bone syndrome in cases of severe hyperparathyroidism.

Image Secondary hyperparathyroidism: Treatment of the underlying cause.


Image

Patients with hyperparathyroidism can develop nephrocalcinosis.


HYPOPARATHYROIDISM

DEFINITION

Decreased PTH.

ETIOLOGY

Image Autoimmune.

Image Familial: Autosomal dominant, autosomal recessive, and X-linked recessive.

Image DiGeorge/velocardiofacial syndrome (deletion of chromosome 22q.11.2).

Image Acute illness (PTH secretion is impaired in critical illness).

Image Severe hypomagnesemia (usually < 1 mg/dL).


Image

Hypoparathyroidism can be seen with polyglandular autoimmune endocrinopathy: Thyroiditis, diabetes, adrenal insufficiency, mucocutaneous candidiasis.


SIGNS AND SYMPTOMS

Image Most common presentation is numbness, tingling, paresthesia, muscle cramps.

Image In severe cases, seizure, tetany, and mental status changes.

Image In older asymptomatic patients, hypereflexia, Chvostek’s (facial twitching), and Trousseau’s (carpopedal spasm) signs can be elicited.

DIAGNOSIS

Image ↓ serum total Ca and ionized Ca.

Image ↑ serum P.

Image Markedly ↓ PTH.

Image Prolonged QTc interval.

Image Total Ca ↓ by 0.8 mg/dL for each 1 g/dL ↓ in albumin below 4 g/dL.

Image ↑ or ↓ in pH by 0.1 units ↓ and ↑ ionized Ca by 0.03 mmol/L, respectively.


Image

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

Image Correct hypocalcemia:

Image Intravenous (IV) 10% calcium gluconate 2 cc/kg gradually over 10 min for acute symptomatic hypocalcemia.

Image To maintain normocalcemia: Continuous IV infusion (20–80 mg Ca/kg/24 hr).

Image Transition to PO calcium as soon as possible (25–100 mg Ca/kg/day).

Image Correct hypomagnesemia.

Image Vitamin D (calcitriol).

CONGENITAL ADRE NAL HYPERPLASIA (CAH)

DEFINITION

Image Genetic defect of adrenal corticosteroid and/or mineralocorticoid synthesis.

Image ↓ in cortisol secretion results in a ↓ in negative feedback at the level of hypothalamus and pituitary gland.

Image ↑ ACTH secretion results in markedly elevated production of the precursors before the block.


Image

A newborn with ambiguous genitalia is a medical and social emergency.


EPIDEMIOLOGY

Image Most common cause of ambiguous genitalia.

Image Incidence of classical 21-hydroxylase CAH is 1 in 15,000 live births.

ETIOLOGY

Image 21-hydroxylase deficiency (90% of all CAH):

Image Three-quarters of cases are salt wasters.

Image Ambiguous genitalia in the females; normal genitalia in males.

Image Milder form (nonclassical variant) has normal genitalia in females and presents late with premature pubarche.

Image 11β-hydroxylase deficiency: HTN with low K frequently present because of excessive deoxycorticosterone (DOC).

Image 3β-hydroxysteroid dehydrogenase:

Image Ambiguous genitalia in both sexes.

Image Salt wasting is present.

Image 17-hydroxylase/17,20-lyase deficiency:

Image Normal genitalia in females; undervirilized genitalia in males.

Image HTN with low K frequently present.

Image Congenital lipoid adrenal hyperplasia:

Image Normal genitalia in females; undervirilized genitalia in males.

Image Salt wasting is present.

Image All adrenal hormones and their precursors are low.

SIGNS AND SYMPTOMS

Image Clinical features result from both the hormonal deficiencies (cortisol and aldosterone) and excessive production of precursors (17-hydroxyprogesterone, androstenedione, DOC).

Image Female pseudohermaphroditsm: Ambiguous genitalia in female with normal 46,XX chromosome (21-hydroxylase, 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase deficiency).

Image Male pseudohermaphroditism: Ambiguous genitalia in male with 46,XY chromosome (3β-hydroxysteroid dehydrogenase, 17-hydroxylase/17,20-lyase deficiency, and congenital lipoid adrenal hyperplasia).

Image Hypoglycemia (from cortisol deficiency).

Image Salt wasting (21-hydroxylase, 3β-hydroxysteroid dehydrogenase, and congenital lipoid adrenal hyperplasia).

Image HTN with hypokalemia (11β-hydroxylase and 17 hydroxylase/17,20-lyase deficiency).

Image Vomiting, dehydration, and shock at 2–4 weeks of age.


Image

Combination of hyperkalemia and hyponatremia clue to diagnosis of classical CAH of salt-wasting variety.


DIAGNOSIS

Image Newborn screening (elevated 17-hydroxyprogesterone level for 21-hydroxylase).

Image Karyotype.

Image Hyponatremia, hyperkalemia, hypochloremia, hypoglycemia.

Image Markedly ↑ 17-hydroxyprogesterone for gestational age and weight (for 21-hydroxylase).

Image Low baseline cortisol and low cortisol 60 min after 1–24 ACTH (Cortrosyn) stimulation.

Image Elevated plasma renin activity (PRA).

Image Genetic testing (DNA analysis for genetic mutations in the affected gene).

Image Prenatal diagnosis (in pregnancy with ↑ risk).


Image

Most urgent tests for congenital adrenal hyperplasia:

1.     Serum glucose

2.     Serum electrolytes Other tests: cortisol, testosterone, 17-OH progesterone.


TREATMENT

Image Fluid and electrolyte replacement.

Image Normal saline (NS) 20 mL/kg bolus, then maintenance plus ongoing fluid losses with D5NS.

Image Management of hypoglycemia.

Image 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).

Image Fludrocortisone 0.1–0.2 mg/day.

Image 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).

Image Prenatal treatment: Treat mother with a pregnancy at risk for 21-hydroxylase deficiency, with dexamethasone.


Image

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

Image Iatrogenic from exogenous corticosteroid (most common cause of hypercortisolism).

Image 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.

Image Cushing syndrome: Excess cortisol secretion by unilateral adrenocortical tumors (adenoma, carcinoma) or bilateral adrenal hyperplasia (primary pigmented micronodular adrenal hyperplasia).

Image Ectopic ACTH syndrome: Malignant nonendocrine tumor produces an excessive amount of ACTH. Extremely rare in children.


Image

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

Image Elevated 24-hour urine test for free cortisol (UFC) and 17-hydroxycorticosteroid (17-OHS).

Image Mean rate of UFC in normal children is < 70 mg/m2/day.

Image Mean rate of 17-OHS is < 7 mg/g of creatinine per day.

Image 8:00 A.M. ACTH and cortisol: Elevated ACTH level (> 29 pg/mL with elevated UFC) suggests Cushing disease or ectopic ACTH production.

Image 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).

Image Low-dose dexamethasone suppression test:

Image Overnight dose 0.03 mg/kg (max 1 mg) at 11 P.M. X1 dose or

Image 0.03 mg/kg/day (max 0.5 q6h) for 2 days.

Image Normal if suppression results in plasma cortisol of < 5 μg/dL.

Image Nonsuppression with elevated UFC suggests the diagnosis of Cushing but does not differentiate between Cushing syndrome vs. Cushing disease.

Image High-dose dexamethasone suppression test:

Image Overnight dose of 0.12 mg/kg/day (max 8 mg) or

Image 0.12 mg/kg/day (max 2 mg q6h) for 2 days.

Image Suppression (cortisol < 5 μg/dL) suggests Cushing disease, while non-suppression suggests Cushing syndrome.

Image 24 UFC paradoxically rises in primary pigmented nodular adrenal disease after high-dose dexamethasone suppression test.

Image Ovine corticotropin-releasing hormone (CRH) stimulation test/bilateral petrosal sinus sampling: ↑ in ACTH after IV CRH suggests Cushing disease.


Image

Growth retardation may be the early manifestation of Cushing syndrome. Virilization may indicate adrenal carcinoma.


Image Polycythemia, lymphopenia, and eosinopenia can be associated findings.

Image Abdominal computed tomography (CT) (adrenal tumors).

Image Pituitary magnetic resonance imaging (MRI) (pituitary adenoma).

DIFFERENTIAL DIAGNOSIS

Image Exogenous obesity (pseudo-Cushing state).

Image Normal growth rate.

Image Cortisol level suppressed by dexamethasone.

TREATMENT

Image Pediatric endocrine, surgical, and neurosurgical consultation.

Image Adrenalectomy (unilateral or bilateral for adrenal tumors or bilateral nodular hyperplasia, respectively).

Image Chemotherapy with mitotane for adrenal cancer with metastasis (after surgery).

Image Transsphenoidal resection of pituitary adenoma.

Image Fractionated radiotherapy for recurrent pituitary adenoma.

ADRENAL INSUFFICIENCY

DEFINITION

Image Adrenal cortex fails to produce enough glucocorticoid to mount response to stress.

Image May be primary adrenal disorder or secondary to ACTH deficiency/resistance.

Image 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)

Image Congenital:

Image CAH.

Image Congenital adrenal hypoplasia (X-linked).

Image ACTH resistance.

Image Adrenal leukodystrophy (X-linked-recessive disorder of metabolism of very long chain fatty acids).

Image Acquired (Addison disease):

Image Autoimmune destruction (80%).

Image Tuberculosis (TB).

Image Bilateral adrenal hemorrhages (meningococcal septicemia).

Image AIDS (opportunistic infections).

Image Antiphospholipid antibody syndrome.

Secondary Adrenal Insufficiency (Low Cortisol/Low ACTH)

Image Congenital:

Image Congenital hypopituitarism

Image Septo-optic dysplasia

Image Acquired:

Image Iatrogenic: Adrenal insufficiency from abrupt discontinuation of glucocorticoids after prolonged use.

Image Pituitary or hypothalamic tumors.


Image

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

Image Weakness, fatigue, anorexia, nausea, vomiting, weight loss.

Image Postural hypotension (more marked in primary adrenal insufficiency).

Image Hyperpigmentation of skin and mucosal surfaces (in primary adrenal insufficiency due to elevated ACTH/melanocyte-stimulating hormone [MSH]).

Image Salt craving (in primary adrenal insufficiency).

Image Adrenal crisis (fever, vomiting, dehydration, and shock precipitated by infection, trauma, or surgery in susceptible patient).

DIAGNOSIS

Image Hyponatremia, hyperkalemia, acidosis, hypoglycemia.

Image A.M. plasma cortisol and ACTH level:

Image A.M. plasma cortisol < 3 μg/dL is indicative of adrenal insufficiency while value > 19 μg/dL makes it unlikely.

Image Basal plasma ACTH level invariably exceeds 100 pg/mL in primary adrenal insufficiency, while normal ACTH level does not rule out secondary adrenal insufficiency.

Image Antiadrenal antibodies (in autoimmune destruction of adrenal glands).

Image ACTH stimulation test:

Image 1-24 ACTH (Cortrosyn) given IV or IM and cortisol level measured at baseline and 30–60 min after the injection.

Image For primary and severe/prolonged adrenal insufficiency use 250 μg Cortrosyn.

Image For secondary adrenal insufficiency that is mild or recent onset use 1 μg.

Image Normal response is plasma cortisol concentration of 18–20 μg/dL at 30-60 min post Cortrosyn.

Image CT scan of adrenal glands (in primary adrenal insufficiency).

Image MRI of the pituitary gland and hypothalamus (in secondary adrenal insufficiency).

TREATMENT

Image 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.

Image Fludrocortisone (0.05–0.2 mg PO daily).

Image In acute adrenal insufficiency (adrenal crisis):

Image Volume replacement.

Image Hydrocortisone 50–100 mg IV, then 50–100 mg/m2/24 hr or methylprednisolone 7.5 mg/m2/24 hr.

Image Switched to oral therapy in 2–3 days.


Image

Tumors arising in the adrenal medulla produce both epinephrine and norepinephrine. Extra-adrenal tumors produce only norepinephrine.


PHEOCHROMOCYTOMA

DEFINITION

Image Catecholamine-producing tumor of chromaffin tissue of adrenal medulla and sympathetic ganglia (paraganglioma).

Image Adrenal medulla (80–85%).

Image Extra-adrenal (15–20%), also called paragangliomas.

Image Usually benign, well encapsulated (< 10% malignant).

Image In children: Frequently familial, bilateral, and multifocal.

Image Recurrent tumor may appear years after initial diagnosis.


Image

Siblings of a patient with a pheochromocytoma should be periodically evaluated because of ↑ familial incidence.


ETIOLOGY

Image May occur in isolation (sporadic).

Image Also seen in the MEN 2 (bilateral), von Hippel–Lindau, neurofibromatosis type 1, and familial carotid body tumor syndromes.

SIGNS AND SYMPTOMS

Image Nonspecific symptoms.

Image Headache, palpitations, ↑ sweating, anxiety.

Image Nausea, vomiting, weight loss, tremor, fatigue, chest or abdominal pain, and flushing.

Image Sustained HTN (in children).

Image Hyperglycemia.

Image Epinephrine-producing tumor may present with postural hypotension.


Image

The most useful screening test for pheochromocytoma is blood pressure. Hypertensive paroxysms are an important diagnostic clue.


DIAGNOSIS

Image Plasma free metanephrines (metanephrine and normetanephrine): Unequivocally elevated, 4–5 times the upper limit of the reference range.

Image ↑ urinary catecholamines or metabolites (24-hour urinary excretion of fractionated metanephrines), vanillylmandelic acid (VMA).

Image Serum chromogranin A.

Image Abdominal ultrasound (US).

Image Abdominal CT and MRI.

Image 123I MIBG (metaiodobenzylguanidine) scan.

Image FDG PET (Flourodeoxyglucose positron emission tomography) scan.

Image Octreoscan.


Image

Increased urinary norepinephrine indicates an extra-adrenal site of a pheochromocytoma, whereas increased epinephrine indicates an adrenal lesion.


DIFFERENTIAL DIAGNOSIS

Image Ganglioneuroma

Image Neuroblastoma

Image Ganglioneuroblastoma

TREATMENT

Image Surgical excision.

Image Preoperative α1 and α2 adrenoreceptor blockade (phenoxybenzamine) and βx adrenoreceptor blockade (propranolol, atenolol) are required to prevent hypertensive crisis and arrhythmias, respectively.

Image Yearly follow-up evaluation for assessment of recurrence for at least 5 years (indefinitely in children with familial pheochromocytoma).


Image

After successful surgery of a pheochromocytoma, catecholamine excretion returns to normal in about 1 week.


HYPERPITUITARISM

Gigantism/Acromegaly

Image ↑ GH.

Image If occurs before epiphyses close, → gigantism.

Image If after epiphyses close, → acromegaly.

ETIOLOGY

Most commonly caused by growth hormone (GH)-secreting adenoma.

CLINICAL FEATURES

Image Accelerated rate of linear growth.

Image Coarsening of facial features and mandibular prominence.

Image Enlargement of hands and feet.

DIAGNOSIS

Image Elevated insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3).

Image GH may be normal or elevated. GH not suppressed by glucose.

Image MRI of the pituitary.

TREATMENT

Image Transsphenoidal resection of adenoma.

Image Somatostatin and dopamine agonist for incomplete resection.

PROLACTIN EXCESS

ETIOLOGY

Image Prolactin-secreting adenoma: Microadenoma (< 1 cm) or macroadenoma (> 1 cm).

Image Tumor that disrupt pituitary stalk preventing inhibitory control.

Image Drugs (phenothiazines, estrogen, cocaine).

Image Hypothyroidism.

Image Liver or renal failure.

Image Macroprolactinemia (variant molecule).

Image Physical stress.

CLINICAL FEATURES

Image Galactorrhea

Image Menstrual irregularities/amenorrhea

Image Decreased libido

DIAGNOSIS

Image Prolactin level (> 20 ng/mL).

Image MRI (hypothalamic-pituitary region).

TREATMENT

Image Treatment of the cause.

Image Dopamine agonists (bromocriptine, cabergoline) are the first line of treatment.

Image Transsphenoidal surgery if medical treatment is unsuccessful.


Image

Prolactin secretion chronically inhibited by dopamine in pituitary–prolactinomas responds to dopamine agonists such as bromocriptine.


HYPOPITUITARISM

Image

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

Image ACTH → adrenal glucocorticoids.

Image TSH → thyroid hormone.

Image Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) → gonadal function.

Image Prolactin → lactation

Image GH → growth.

Image Antidiuretic hormone (ADH) → diabetes insipidus.

ETIOLOGY

Image Congenital:

Image Inherited (mutation in the gene encoding pituitary transcription factor Pit-1).

Image Sporadic developmental defects: Midline anomalies (septo-optic dysplasia, cleft palate), holoprosencephaly.

Image Acquired:

Image Tumors and their treatment (craniopharyngioma).

Image Head trauma.

Image CNS irradiation.

Image Histiocytosis X.

Image Autoimmune hypophysitis.

Image Hemochromatosis.

Image Disseminated tuberculosis or sarcoidosis.

SIGNS AND SYMPTOMS

Image Depends on missing hormone and or etiological cause.

Image GH deficiency (poor linear growth, hypoglycemia).

Image In neonates (hypoglycemia and micropenis).

Image LH and FSH (pubertal delay).

Image ADH (polyuria, polydipsia).

Image Visual and neurologic complaints.


Image

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

Image Chronological age (CA) = Bone age (BA) = Height age (HA)

Image Normal growth velocity depends on age and pubertal stage:

Image First year: 25 cm/yr

Image 1–2 years: 12 cm/yr

Image 2–3 years: 10 cm/yr

Image 3–4 years: 7 cm/yr

Image 4–5 years: 6 cm/yr

Image After 5 years: 5 cm/yr

Image During puberty (girls Tanner II–III): 10 cm/yr

Image During puberty (boys Tanner IV): 12 cm/yr

Genetic Potential

Image For males: Add 5 inches to mother’s height and average it with father’s height.

Image For females: Subtract 5 inches from father’s height and average it with mother’s height.

Familial (Genetic Short Stature)

Image Common cause of short stature.

Image Growth rate ↓ between 6 and 18 months.

Image Height within family norm (usually at least one parent has short stature).

Image Normal rate of growth (follow steady channel after 2–3 yr).

Image Normal bone age.

Image Puberty at average age.


Image

The most common causes of short stature are normal variants including familial short stature and constitutional delay.


Constitutional

Image Most common cause of short stature.

Image Normal variant of growth.

Image Normal at birth, then growth decelerate during first 2 yr of life.

Image Both length and weight gain decelerate until age 2–3 yr.

Image Resume growth rate by 2–3 yr paralleling a lower percentile curve.

Image Delayed puberty (second growth deceleration at age 12–14 yr).

Image Delayed bone age (bone age = height age).

Nutritional

Image Inflammatory bowel disease.

Image Celiac disease.

Image HIV infection.

Image Other conditions causing malnutrition.

Psychosocial Deprivation

Image 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

Image Birth weight and length < 10th percentile for gestational age.

Intrauterine Growth Retardation

Image Pathologically growth restricted infants.


Image

Children with constitutional delay are the so-called “late bloomers.”


Growth Hormone Deficiency (GHD)

Image Pathologic cause of short stature.

Image Hypoglycemia and micropenis (especially if associated with hypopituitarism).

Image Height below genetic potential.

Image ↓ growth velocity (< 25th percentile for age).

Image Downward crossing of percentiles on growth chart after age 2–3 yr.

Image ↓ muscle mass, ↑ fat mass.

Image Pubertal delay.

Image 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

Image Delayed bone age.

Image Low IGF-1, low IGFBP-3, inadequate response to GH stimulation.

TREATMENT

Biosynthetic human GH.

Growth Hormone Insensitivity (Laron Syndrome)

Image Features similar to GHD.

Image GH receptor defect.

Image Elevated GH level.

Image Low IGF-1, IGF-2, and IGFBP-3.

Image Absent or low growth hormone binding protein (GHBP).


Image

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

Image Pathologic cause of short stature.

Image ↓ growth velocity.

Image Delayed bone age.


Image

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

Image Pathologic cause of short stature.

Image ↑ cortisol inhibits growth.

Image Abnormal weight gain.

Image 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

Image Turner syndrome

Image Down syndrome

Image Silver-Russell syndrome

Image Prader-Willi syndrome

TALL STATURE

DEFINITION

Height more than 2 standard deviations above the mean for age and gender.

Familial

Image Most common.

Hormonal

Image GH excess.

Image Early puberty: ↑ sex steroids (tall as child, short as adult from early epiphyseal closure).

Image CAH: ↑ adrenal androgens (tall as child, short as adult from early epiphyseal closure).

Image Hyperinsulinism/obesity.

Image Hypogonadotrophic hypogonadism (Kallmann syndrome).

Syndromes

Image Marfan syndrome.

Image Homocystinuria.

Image Klinefelter syndrome.

Image Sotos syndrome (not truly endocrine, associated mental retardation)—cerebral gigantism: In utero and postnatal overgrowth.

Image Beckwith-Wiedmann syndrome: Macrosomia with in utero and postnatal somatic overgrowth, macroglosia, hemihypertrophy and abdominal wall defect. Hypoglycemia due to hyperinsulinemia. ↑ incidence of tumors.


Image

Beckwith-Weidemann syndrome: Large babies due to overproduction of IGF-2.


DIABETES INSIPIDUS (DI)

DEFINITION

Inability of kidneys to concentrate urine.

ETIOLOGY

Image Central (↓ ADH):

Image Congenital hypothalamic/pituitary defects (septo-optic dysplasia, holoprosencephaly).

Image Idiopathic, accidental or surgical trauma, infections (meningitis).

Image Neoplasms (suprasellar tumors).

Image Infiltrative and autoimmune diseases (histiocytosis X).

Image Drugs (ethanol, phenytoin).

Image Nephrogenic (renal unresponsiveness to ADH):

Image X-linked recessive (vasopressin type 2 receptor mutation): Males—early infancy.

Image Autosomal recessive (mutation in the renal water channel—aqua-porin-2).

Image Idiopathic.

Image Renal diseases.

Image Hypercalcemia.

Image Hypokalemia.

Image Drugs (lithium, demeclocycline).

SIGNS AND SYMPTOMS

Image Central:

Image Polyuria (> 1.5 L/m2/day).

Image Polydipsia (excessive thirst).

Image Enuresis.

Image Hypernatremic dehydration.

Image Nephrogenic:

Image Polyuria, failure to thrive (FTT), hyperpyrexia, vomiting.

Image Hypernatremic dehydration.


Image

In diabetes insipidus, there is high urine output despite significant dehydration.


DIAGNOSIS

Image ↑ serum osmolality (normal: < 290 mOsm/kg).

Image ↑ serum Na (normal: < 145 mmol/L).

Image ↓ urine osmolality.

Image 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.

Image Urine volume falls and osmolality doubles—central DI.

Image Less than twofold rise in urine osmolality—nephrogenic DI.

Image Plasma vasopressin (low in central DI and high in nephrogenic DI).

Image MRI: Posterior pituitary bright spot is diminished or absent in both forms of DI.

TREATMENT

Image Central:

Image Fluids (3–4 L/m2/day without vasopressin, 1 L/m2/day with vasopressin).

Image 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).

Image Nephrogenic:

Image Fluids.

Image 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).

Image 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

Image Encephalitis/meningitis.

Image Brain tumor.

Image Head trauma.

Image Psychiatric diseases.

Image Postictal period.

Image Positive pressure ventilation.

Image Rocky Mountain spotted fever.

Image Pneumonia.

Image AIDS.

Image Drugs (carbamazepine, chlorpropamide, vincristine, tricyclic antidepressant).


Image

In SIADH, there is an absence of edema and dehydration.


SIGNS AND SYMPTOMS

Image Asymptomatic until Na < 120.

Image Headache, nausea, vomiting, irritability, seizure.

Image ↓ urine output.

DIAGNOSIS

Image Hyponatremia (Na < 135 mmol/L).

Image ↓ serum osmolality (< 275 mOsm/kg).

Image ↑ urine osmolality (>100 mOsm/kg).

Image ↑ urine Na (usually > 80 mEq/L).

Image Low serum uric acid level.

Image Normal renal, adrenal, and thyroid function.


Image

Urine osmolality < 100 mOsm/kg excludes diagnosis of SIADH.


TREATMENT

Image Symptomatic with hyponatremia: Hypertonic (3%) saline 6 mL/kg bolus ↑ Na by 5 mmol/L. Repeat bolus until patient stops seizing.

Image Asymptomatic:

Image Fluid restriction (1000 mL/m2/day).

Image Demeclocycline if resistant (rarely used).

Image Selective V2 receptor antagonist (tolvaptan).

Image 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

Image

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

Image Acute, intermittent excessive fluid and salt loss.

Image ↑ urine output.

Image Onset within first week of CNS insult.

Image Duration variable usually lasts 2–4 weeks.

Image Dehydration (↓ extracellular fluid).

DIAGNOSIS

Image Hyponatremia (Na < 130 mmol/L).

Image Urine osmolality isotonic with plasma.

Image ↑ urine Na (usually > 150 mEq/L).

Image See Table 16-3 for comparison between SIADH and CSW.

TREATMENT

Image Water and salt replacement (0.9 or 3% NS).

Image Urea.

SEXUAL DEVELOPMENT

Image 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.

Image 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).


Image

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

Image

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

Image

Image

FIGURE 16-1. Tanner stages

DEFINITION

Image Onset of secondary sexual characteristics.

Image Girls (< 8 yr for white girls, < 7 for African-American and Hispanics).

Image Boys (< 9 yr).

Image Premature breast development (thelarche).

Image Premature pubic hair development (pubarche/adrenarche).


Image

Most normal 11-year-old girls have pubic hair.


ETIOLOGY

Central or True Precocious Puberty

Image Premature activation of the hypothalamic-pituitary-gonadal axis.

Image Gonadotropin dependent: Pubertal (high) FSH and LH and sex steroids (testosterone or estradiol).

Image Usually idiopathic in girls, while secondary to organic lesion in boys.

Image CNS abnormalities:

Image Hypothalamic hamartoma.

Image Head injury.

Image Hydrocephalus.

Image Radiation.

Image Surgical trauma.

Image Tumors (astryocytoma, glioma, pinealoma, LH-secreting adenoma).

Peripheral or Pseudo Precocious Puberty

Image Gonadotropin independent: Prepubertal (low) FSH and LH, pubertal (high) sex steroids.

Image Male:

Image Testotoxicosis: Familial male limited precocious puberty (bilateral testicular enlargement).

Image Tumors.

Image Testicular Leydig cell tumor (unilateral testicular enlargement).

Image Choriocarcinoma, dysgerminoma, hepatoblastoma (human chorionic gonadotropin [HCG] producing).

Image Adrenal tumors (testosterone secreting).

Image CAH.

Image McCune-Albright syndrome.

Image Exogenous sex steroid.

Image Female:

Image McCune-Albright syndrome: Ovarian cysts secreting estrogen.

Image Tumors:

Image Ovarian tumors (granulosa cell tumor, gonadoblastoma).

Image Choriocarcinoma, dysgerminoma, hepatoblastoma (HCG producing).

Image Adrenal tumors (estrogen secreting).

Image Exogenous sex steroids.


Image

Precocious puberty in girls is usually idiopathic, while in boys it usually has an organic cause.


SIGNS AND SYMPTOMS

Image Growth acceleration.

Image Significantly advanced bone age.

Image Sexual development is progressive (in some children, particularly girls, such changes may be very slowly progressive—a variant of normal development).

DIAGNOSIS

Image FSH, LH.

Image Estradiol, testosterone.

Image Dehydroepiandrosterone sulfate (DHEAS), 17-hydroxyprogesterone, androstenedione.

Image α-fetoprotein (AFP), HCG.

Image Prepubertal levels (low) of gonadotropins and pubertal (high) level of estrogen or testosterone suggest gonadotropin-independent process.

Image Gonadotrpins may be pubertal or prepubertal at baseline while testosterone or estrogen is usually pubertal in gonadotrpin-dependent precocious puberty.

Image No ↑ in gonadotropins after gonadotropin-releasing hormone (GnRH) in gonadotrpin-independent precocious puberty.

Image Pubertal LH-dominant response (LH > 5 mIU/mL and LH-to-FSH ratio > 1) after GnRH in true, central, gonadotropin-dependent precocious puberty.

Image Pelvic ultrasound to evaluate ovarian and uterine size and rule out any pathology (ovarian cyst, tumor).

Image MRI of the head to rule out CNS abnormality in central precocious puberty.

Image CT abdomen and pelvis if tumor is the likely cause of peripheral precocious puberty.

TREATMENT

Image Treatment of underlying cause (in both central and peripheral puberty).

Image GnRH analogues (in central precocious puberty).

Image Androgen antagonist (flutamide) and aromatase inhibitor (blocks conversion of androgen to estrogen) in peripheral precocious puberty.

Premature Thelarche

DEFINITION

Image Isolated breast development.

Image Most commonly noted during the first 2 yr of life.

Image May occur after 2 yr due to temporary increase in FSH. Breast development is usually limited and often regresses.

SIGNS AND SYMPTOMS

Image Normal growth rate and bone age.

Image 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.

Image < 8 yr in girls (< 7 yr in African-American and Hispanic).

Image < 9 yr in boys.

Image Adult body odor is other associated feature.

ETIOLOGY

Image Early onset of increased adrenal androgen production (premature adrenarche).

Image In girls it is a risk factor for later development of polycystic ovarian syndrome (PCOS).

Image Nonclassical CAH may present similarly and can lead to early puberty.

DIAGNOSIS

Image Adrenal androgen (DHEAS): Normal for pubertal stage but elevated for chronologic age.

Image 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

Image Female:

Image Constitutional.

Image Primary ovarian failure (idiopathic, autoimmune, chemotherapy, radiation, galactosemia, fragile X syndrome, mutation in gonodotropin receptor).

Image Turner syndrome.

Image Hypogonadotropic hypogonadism (Kallmann syndrome).

Image 17-hydroxylase deficiency CAH.

Image Hypopituitarism (congenital or acquired).

Image Dysfunction of hypothalamic-pituitary-gonadal axis secondary to systemic illness, undernutrition, or strenuous physical activity.

Image Prader-Willi syndrome.

Image Male:

Image Constitutional.

Image Primary testicular failure (vanishing testis syndrome, bilateral cryptorchidism/torsion, infection, chemotherapy, radiation, surgical trauma, hemochromatosis, fragile X syndrome, mutation in gonodotropin receptor).

Image Klinefelter syndrome.

Image Hypogonadotropic hypogonadism (Kallmann syndrome).

Image Dysfunction of hypothalamic-pituitary-gonadal axis secondary to systemic illness or undernutrition.

Image Hypopituitarism (congenital or acquired).

Image Prader-Willi syndrome.

DIAGNOSIS

Image FSH, LH, estradiol, testosterone.

Image Elevated gonadotropin levels (FSH, LH) suggest primary gonadal failure—hypergonadotrophic hypogonadism.

Image Low gonadotropin levels suggest hypogonadotrophic hypogonadism or constitutional delay. No test definitely differentiates constitutional delay from gonadotropin deficiency until age is well into adolescence.

Image Chromosome analysis (for primary gonadal failure).

Image MRI of the head (in hypogonadotrophic hypogonadism or hypopituitarism).


Image

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

Image Treatment of the cause.

Image Females: Estrogen initially; later, cyclic estrogen progesterone.

Image Males: Testosterone.

MENSTRUATION

Image The mean age for menarche in American is 12.8 yr +/– 1.2 yr.

Image Menarche occurs about 2–3 yr after the initiation of puberty. Two-thirds of females reach menarche at Tanner stage IV puberty.

Image Fifty to sixty percent of cycles in the first 2 yr after menarche in most girls are anovulatory.

Image The length of a cycle is between 21 and 45 days (average is 28 days).

Image The length of flow is 2–7 days (average is 3–5 days).

Image 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.


Image

Turner syndrome is the most common cause of primary amenorrhea.


ETIOLOGY

Image Primary ovarian failure (elevated FSH and LH).

Image Chromosomal:

Image Turner syndrome.

Image Triple X syndrome.

Image Pure gonadal dysgenesis (46,XX or 46,XY).

Image Fragile X.

Image Classical galactosemia.

Image Autoimmune oophoritis.

Image Radiation.

Image Chemotherapy.

Image Gonadal trauma.

Image 17-hydroxylase deficiency (CAH).

Image Congenital lipid hyperplasia.

Image FSH/LH receptor mutation.

Image Idiopathic.

Image Hypogonadotropic hypogonadism (low FSH and LH): Isolated or with hypopituitarism.

Image Prader-Willi syndrome.

Image Anorexia nervosa.

Image Strenuous exercise.

Image Structural anomalies:

Image Imperforate hymen.

Image Agenesis of Müllerian structure (Mayer-Rokitansky-Hauser syndrome).

Image Other:

Image Complete androgen insensitivity (testicular feminization syndrome).

Image True hermaphroditism.

SECONDARY AMENORRHEA

Image

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.


Image

The most common causes of secondary amenorrhea include pregnancy, stress, and PCOS.


ETIOLOGY

Image Pregnancy.

Image Turner syndrome (mosaicism).

Image Hyperandrogenic states (PCOS, CAH).

Image Hyperprolactinemia.

Image Hypothalamic amenorrhea.

Image Causes of primary amenorrhea.

DIFFERENTIAL DIAGNOSIS

Image Normal/low FSH:

Image Consider hypothalamic amenorrhea related to stress, weight loss, an eating disorder, competitive athletics, phenothiazine use, or substance abuse.

Image 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).

Image 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

Image Progesterone produced during ovulatory cycle ↑ the synthesis of the prostaglandins.

Image Excessive amounts of prostaglandins F2 and E2, which cause uterine contractions, tissue hypoxia and ischemia, and ↑ sensitization of pain receptors.


Image

Dysmenorrhea is the most common gynecologic complaint.


TREATMENT

Recommend prostaglandin inhibitors for dysmenorrhea at the onset of flow or pain.

SECONDARY DYSMENORRHEA

ETIOLOGY

Image Underlying structural abnormality of the vagina, cervix, or uterus (endometrial polyps, fibroids).

Image Congenital anomalies.

Image Pelvic adhesions.

Image Endometriosis.

Image Foreign body such as an intrauterine device.

Image Endometritis: Infection, especially secondary to sexually transmitted diseases (STDs).

Image Complications of pregnancy such as ectopic pregnancy.


Image

Mittelschmerz

Image Mid-menstrual cycle pain due to ovulation

Image Not pathologic

Image Treat symptomatically


TESTICULAR FEMINIZATION

DEFINITION

Image Androgen insensitivity syndrome (complete and partial form).

Image X-linked.

Image 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.

Image 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

Image Primary amenorrhea.

Image Normal breast development.

Image Pubic hair absent or sparse.

Image Presence of testes in inguinal hernia.

DIAGNOSIS

Image Testosterone level is elevated.

Image LH is normal or elevated.

Image Sex hormone binding globulin (SHBG) test: IM testosterone (2 mg/kg) unable to suppress SHBG to < 80% of the basal value suggests androgen insensitivity.

Image 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.

Image Androgen receptor binding studies in cultured genital skin fibroblast.

Image DNA analysis for mutation in AR gene.

TRUE HERMAPHRODITISM

DEFINITION

Image Gonads comprised of both ovarian and testicular elements (ovotestis).

Image Most are 46,XX.

Image Can be familial.

ETIOLOGY

Abnormal gonadal differentiation.

SIGNS AND SYMPTOMS

Image Ambiguous genitalia—significant masculinization (raised as male).

Image 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

Image CAH (21-hydroxylase deficiency, 11 β-hydroxylase deficiency, 3 β-hydroxysteroid dehydrogenase deficiency).

Image Placental aromatase deficiency (conversion of androgens to estrogens is blocked). Estriol level is undetectable. Maternal virilization during pregnancy.

Image 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

Image Androgen insensitivity.

Image CAH: 3β-hydroxysteroid dehydrogenase deficiency, 17-hydroxylase deficiency, and congenital lipoid adrenal hyperplasia.

Image Enzyme defects in testosterone synthesis (17-ketoreductase deficiency).

Image 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

Image Osteopenia: Deficiency in bone mass relative to age, sex, and race norms.

Image Osteoporosis: Loss of bone mineral and matrix due to disproportionately low osteoblastic activity.

Image Osteomalacia: Defective mineralization in bone.

Image Rickets: Defective mineralization of cartilage in the growth plate.

Classification of Rickets

CALCIOPENIC

ETIOLOGY

Image Nutritional:

Image Vitamin D deficiency

Image Calcium deficiency

Image Genetic:

Image 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).

Image Vitamin D–dependent rickets type 2 (mutation in the gene coding the vitamin D receptor causing hereditary vitamin D resistance).

Image Drugs:

Image Corticosteroids

Image Anticonvulsants

Image Prematurity.

PHOSPHOPENIC

Image Genetic:

Image X-linked hypophostemic rickets (mutation in the PHEX gene).

Image Autosomal-dominant hereditary hypophosphatemic ricket (mutation in the gene for fibroblast growth factor 23).

Image Autosomal-recessive hereditary hyperphosphatemic rickets with hypercalciuria (mutation in the gene for renal sodium phosphate cotransporter NaP(i)-IIc).

Image Tumor-induced hypophostemia (tumor mostly of mesenchymal origin).

Image Dietary:

Image Intestinal malabsorption.

Image Breast-fed premature infants.

Image Fanconi syndrome (renal loss of glucose, phosphate, amino acids, and bicarbonate).

CLINICAL FEATURES

Image Genu varum (bow-legged deformity) during early childhood.

Image Genu valgum (knocked-knee deformity) in older children.

Image Enlargement of wrists and knees.

Image Rachitic rosary (bulging of costochondral junctions).

Image Harrison grooves (groove extending laterally from xiphoid process, corresponds to the diaphragmatic attachment).

Image Frontal bossing.

Image Craniotabes (generalized softening of calvaria).

Image Craniosynostosis.

Image Bone pain.

Image Proximal muscle weakness.

RADIOLOGICAL FEATURES

Image Widening of epiphyseal plates.

Image Cupping.

Image Deformities in shaft of long bones.

DIAGNOSIS

Image Serum calcium, phosphorous, alkaline phosphatase level:

Image Alkaline phosphatase is elevated in most cases of rickets. Elevation is marked in calcium and vitamin D deficiency and mild in hypophosphatemic rickets.

Image Serum calcium and phosphorus tend to be low or low normal in all form of calciopenic rickets.

Image Low serum phosphate with normal calcium level suggests the diagnosis of hypophosphatemic rickets.

Image 25(OH) vitamin D and 1,25(OH)2 vitamin D level:

Image Low 25(OH) vitamin D is seen in all forms of vitamin D deficiency.

Image Normal 25(OH) vitamin D level with low 1,25(OH)2 vitamin D level point to 1α-hydroxylase deficiency.

Image 1,25(OH)2 vitamin D level is elevated in hereditary vitamin D resistance.

Image 1,25(OH)2 vitamin D level is inappropriately normal in the setting of hypophosphatemia in X-linked and autosomal-dominant hypophosphatemic rickets.

Image PTH level:

Image Moderate to severe hyperparathyroidism is characteristic of calciopenic rickets.

Image In hypophosphatemic rickets, PTH level may be normal or modestly elevated.

Image Tubular reabsorption of phosphorous (TRP).

[1-{(Urine P × Serum creatinine)/(Serum P × Urine creatinine)}] × 100

Image Normal TRP value 85–95% for children.

Image A nomogram is used to determine the renal tubular threshold maximum for phosphate as expressed per glomerular filtration rate (TMP/GFR).

Image Low TMP/GFR in the setting of low serum phosphate confirms inappropriate renal loses, characteristic of hypophosphatemic rickets.

TREATMENT

Image Nutritional rickets:

Image 5000–15,000 IU of vitamin D PO for 4 weeks.

Image 600,000 IU in a single dose PO/IM for noncompliance (stoss therapy).

Image Ensure adequate calcium intake (350–1500 mg elemental calcium per day for 6 months).

Image 1α-hydroxylase deficiency rickets:

Image 1,25(OH)2 vitamin D (calcitriol) 0.5–3 μg/day.

Image Adequate dietary calcium intake.

Image Hereditary vitamin D resistance:

Image High doses of 1,25(OH)2 vitamin D.

Image IV calcium in patients who do not respond to vitamin D.

Image Hypophosphatemic rickets:

Image Phosphate (250–1000 mg elemental phosphorus in 2–3 divided doses).

Image 1,25(OH)2 vitamin D is important for successful outcome. It enhances Ca and P absorption and dampens phosphate stimulated PTH secretion.

Image



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