25 Endocrine and Metabolic Disorders
Endocrine and metabolic disorders affect a large number of children and may be rare (e.g., nephropathic cystinosis) or relatively common (e.g., type 1 and type 2 diabetes mellitus). This chapter begins with an overview of anatomy, physiology, and pathophysiology of the endocrine and metabolic systems and general issues related to assessment and management of these disorders. Following are two sections covering endocrine and metabolic disorders as they are managed by primary care providers in collaboration with specialists. Although there is a great degree of overlap in these disorders, distinctive processes occur in each, and as such, specific conditions may involve different approaches to assessment and management.
Anatomy and Physiology
The endocrine system regulates growth, pubertal development and reproduction; homeostasis of the individual; and the production, storage, and use of energy. Classically the endocrine system was understood to function via hormones produced in glands with action at a distant site. Now the understanding is that hormones may also act in a paracrine fashion affecting cells adjacent to the hormone-secreting cell or in an autocrine fashion in which the hormone affects the secreting cell by diffusion. Many endocrine glands are controlled by the hypothalamic-pituitary axis. Many of the hormones of the hypothalamic-pituitary axis (or molecules that are structurally similar to such hormones) are also made in the gut and other tissues.
Hormones are often activated by a feedback loop; for example, thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates pituitary thyrotropin (TSH) secretion, which in turn stimulates thyroid hormone production (T3 [triiodothyronine] and T4 [thyroxine]). Thyroid hormone levels provide feedback to the hypothalamus and pituitary thereby suppressing TRH and TSH secretion so that a balance is reached. In similar fashion, the adrenal glands secrete corticosteroids and the gonads produce progesterone, androgens, and estradiol, all of which influence hypothalamic and pituitary hormone production. For some systems, the set-point changes as individuals develop. Hormone secretion can be regulated by nerve cells and by factors important in the immune system (e.g., cytokines interact with hormones that influence weight homeostasis).
Metabolic function in the body involves complex biochemical processes to transform essential amino acids, carbohydrates, and lipids to substances or energy that can be used at the cellular level; to produce molecules; and to perform cell functions. These biochemical processes or metabolic pathways are driven by enzyme activity.
Pathophysiology
Endocrine abnormalities occur when an alteration in regulation of the normal feedback system results in hyposecretion or hypersecretion of one or more hormones. Multiple factors cause alterations in hormone production. These factors include tumors, trauma, infection, systemic disease, genetic disorders, congenital malformation or agenesis of an endocrine gland, idiopathic causes, and iatrogenic causes (e.g., medications). The defect or problem can originate at the pituitary-hypothalamic level, in organ abnormalities, or for unknown reasons that lead to unresponsiveness to endogenous hormone. Hypothyroidism and hyperthyroidism are examples of disease entities in which the interrelationships of the hypothalamic-pituitary-thyroid axis may be altered at any one of these sites.
Many metabolic diseases are caused by inborn errors of metabolism. An alteration in genetic constitution results in disrupted biochemical functioning. For example, in children with phenylketonuria (PKU, a deficiency of the enzyme phenylalanine hydroxylase), the essential amino acid phenylalanine accumulates, resulting in mental retardation if not treated within the first weeks of life. Type 1 diabetes mellitus is an example of an acquired immune-mediated metabolic disease. In diabetes, a reduction in insulin production or deficiency of its action results in abnormal metabolism of carbohydrate, protein, and fat.
Assessment
Endocrine and metabolic disorders disrupt organs throughout the body and can alter various body functions. Assessment requires a thorough family history, physical examination, and specific diagnostic testing for the suspected disorder.
History
• What is the child’s growth pattern since birth?
• Has there been a recent alteration in growth pattern?
• Is the child taking any medications that could affect endocrine or metabolic function?
• Have there been signs or symptoms of endocrine or metabolic dysfunction?
• Was there maternal exposure to radioiodine, goitrogens, or iodine medication during pregnancy?
• When did the child first show signs of sexual development?
• What is the child’s diet and exercise history?
• Is there a family history of endocrine, autoimmune, or metabolic disorders?
• Does the child have unusual odors, recurrent vomiting, or unexplained lethargy?
Physical Examination
A detailed examination should include the following:
• Measure stature. Supine length is preferred for children younger than 2 years old. Use a stadiometer for children older than 2 or 3 years. Plot height, weight, and head circumference on a standardized growth chart appropriate to the child’s age and gender. In addition, growth charts are available for children with certain genetic conditions, such as Down and Turner syndromes, and should be used to assess growth patterns of children with these conditions (see Appendix B). Serial measurements are critical to assess growth patterns over time.
• Check for proportionate appearance. Measure sitting and standing heights for upper to lower segment ratio (see Chapter 32).
• Assess height age (the age corresponding to the child’s height when plotted at the 50th percentile on a growth chart) and growth velocity (linear growth in centimeters or inches over the past year).
• Inspect the child’s genitalia for signs of either normal or ambiguous genitalia.
• Identify the stage of sexual development using Tanner staging (see Chapter 8).
• Note facial, axillary, and pubic hair for presence, distribution, and texture.
• Examine the skin for presence of striae and acanthosis nigricans (see Color Plate) of the neck, axilla, breast, knuckles, and skinfolds.
• Palpate the neck for thyroid gland symmetry and size, noting enlargement or presence of nodules.
• Examine for presence of dysmorphic features.
• Examine the abdomen noting any organomegaly.
Acquired endocrine disorders are often due to either hyposecretion or hypersecretion of a specific hormone or combination of hormones, and the child may or may not appear ill. Signs of dehydration, exophthalmos, and tachycardia are physical findings associated with endocrine pathology. Newborns with metabolic disorders may initially appear well, but physical signs develop with metabolic activity. Characteristic physical findings associated with specific disease entities are presented later in this chapter.
Diagnostic Tests
Measurement of hormone levels is a key tool in the diagnosis of endocrine disorders. Specific blood and urine studies that identify end products of abnormal metabolism or elevated or diminished levels of various substances such as glucose, galactose, or amino acids are important in the diagnosis of metabolic disorders. Accurate interpretation of data requires strict adherence to laboratory protocol for collecting and managing specimens. Additionally, not all laboratories have the ability to conduct tests that are sensitive to the hormone or substance being measured (e.g., measurement of hormones in precocious puberty requires high sensitivity; measurement of ammonia levels requires strict procedures when obtaining the sample).
Radiographic and imaging studies (e.g., bone age, ultrasonography, computed tomography [CT], and magnetic resonance imaging [MRI]) are also important diagnostic tools in evaluating certain endocrine and metabolic disorders.
Many of these studies are expensive and can put additional emotional stress on a family that is already uncertain about their child’s condition.
Management Strategies
General Measures
Clinical consequences for the child affected by an endocrine or metabolic disorder vary from mild to severe. Undiagnosed and untreated, these disorders may lead to irreversible mental retardation, physical disability, neurologic damage, or death. Early detection, accurate diagnosis, and timely intervention are necessary to achieve favorable outcomes. Chronic disease issues and the effects of these diseases on lifestyle must also be addressed:
• Family, school, peer, and emotional adjustment
• Body image, self-esteem, and social competence
• Disease understanding, acceptance, and self-care
A successful outcome depends on the patient and family receiving support and encouragement in self-care, learning about the disease, and understanding the patient-parent role in managing a long-term illness or chronic condition.
Genetic Counseling
Genetic counseling is often necessary. Implications are significant for the family of a child with endocrine or metabolic disorders that are genetically linked (see Chapter 40).
Medications
Pharmacologic therapy, including hormone replacement, whether temporary or lifelong is often essential for management of these disorders. Medications may be administered via injection, creating distress in both the child and caregiver. Short, clear instructions about medications are important; how much to give, when and how to administer, possible side effects, and when to make adjustments in medication are key messages to convey.
Dietary Considerations
Metabolic diseases often require strict adherence to dietary plans and restrictions. Parents, patients, other caregivers, and school personnel must be aware of the dietary needs and restrictions and the effect of diet on the disease process. They must also be given support in order to adjust to the economic, social, and psychological demands created by such restrictions.
Patient and Parent Education
Close supervision and frequent follow-up are necessary for children with metabolic and endocrine disorders. These children are best evaluated initially and periodically by a multidisciplinary team with expertise in pediatric endocrinology and/or clinical genetics (metabolic diseases). Parent and patient education should include:
• Plan for long-term follow-up including the timing and process of transition to adult care services
The multidisciplinary team can provide the education and support needed. The primary care provider, as a part of this team, is in an ideal position to reinforce the plan of care. Additionally, essential primary health care needs and anticipatory guidance cannot be overlooked.
Disorders of Endocrine Function
Endocrine pathologies most commonly seen in children can be assessed by considering the following seven areas:
Growth Disorders
Children grow in a predictable way, and deviation from a normal growth pattern can be the first sign of an endocrine disorder. Every effort should be made to collect serial growth data so that a pattern of growth can be assessed and current growth velocity determined. Care must be taken to obtain accurate supine (for children under 2 or 3 years old) or standing measurements and to plot the child’s length or height on the appropriate growth chart (see Appendix B). A child’s predicted growth potential is based in large part on genetic potential and may change with altered nutritional status and illness patterns. An estimate of the expected stature (±2 standard deviations where 1 standard deviation equals 2 inches [4.5 cm]) for a particular child can be made by calculating a midparental target height:
Growth disorders may be classified as primary or secondary. Primary growth disorders include skeletal dysplasias, chromosomal abnormalities (e.g., Turner syndrome), and genetic short stature. Secondary growth disorders may result from undernutrition, chronic disease, endocrine disorder, and idiopathic (constitutional) growth delay [CGD]) (Box 25-1). The following discussion focuses on growth hormone deficiency (GHD) and CGD (Table 25-1).
BOX 25-1 Classification of Growth Retardation
IGF-1, Insulin-like growth factor 1; SHOX, short stature homeobox.
TABLE 25-1 Short Stature: Characteristics of Growth Hormone Deficiency and Constitutional Growth Delay in Children
Growth Hormone Deficiency
Description
Growth hormone (GH) is an anterior pituitary hormone released in response to sleep, exercise, and hypoglycemia. Secretion of GH occurs in a series of irregular and pulsatile bursts throughout the day and night, with most GH activity occurring during sleep. GH deficiency (GHD) may be either congenital or acquired. Individuals may also be resistant to GH, and GHD increases with age and immunodeficiency.
Epidemiology
Estimates of the incidence of idiopathic GHD vary; an epidemiologic study conducted in Denmark reported an incidence of child-onset GHD of 2.58/100,000 for boys and 1.7/100,000 for girls (Stochholm et al, 2006).
Clinical Findings
Findings that suggest a GHD include hypoglycemia, deficiencies of other pituitary hormones, presence of midline defects, history of treatment with cranial radiation, and low serum levels of insulin-like growth factor 1 (IGF-1) or insulin-like growth factor binding protein 3 (IGFBP-3).
History
A history obtained to evaluate the short or slowly growing child should include:
• Details of pregnancy, delivery, and newborn period
Neonatal course, including history of prolonged jaundice, hypoglycemia, microphallus (often diagnostic of congenital GHD)
• Parents’ and siblings’ height, weight, and growth pattern
• Age at which growth decelerates
• Symptoms of hypothyroidism or other known pituitary hormone deficiency
• Trauma or insult to the central nervous system (CNS)
Physical Examination
Physical examination of the short or slow-growing child should include:
• Identification of clinical clues to chronic illness or dysmorphic syndrome (e.g., childlike facies with large, prominent forehead)
• Evaluation of the fundi for signs of increased intracranial pressure
• Palpation of the thyroid gland for the presence of a goiter
• Evaluation of the stage of puberty
• Measurement of body proportions including arm span, height and upper-to-lower (U/L) body segment ratio to exclude a skeletal dysplasia (dwarfing condition). Interpretation of the U/L body segment ratio is dependent on the age of the child. At birth the U/L ratio is approximately 1.7:1; at 3 years of age it is approximately 1.3:1; and at 7 years and older approximately 1:1 (Keane, 2007).
Diagnostic Tests
If growth velocity is subnormal (including when prior heights are not available), initial evaluation should include:
• Complete blood count (CBC) and erythrocyte sedimentation rate (ESR)
• Screening for gastrointestinal (GI) illness when appropriate (e.g., celiac disease screening [serum immunoglobulin A (IgA) and transglutaminase], irritable bowel disease, stool for ova and parasites)
• Growth factors (IGF-1 and IGFBP-3)
• Thyroid function tests: Free T4 and TSH should be obtained to exclude both pituitary TSH deficiency and primary hypothyroidism
• Bone age x-ray of left wrist and hand
• Karyotype to rule out Turner syndrome in girls. Turner syndrome occurs in approximately 1:1500 to 1:2500 girls. Girls with Turner mosaicism may not manifest the typical clinical findings of Turner syndrome (e.g., cubitus valgus, webbing of the neck) thus highlighting the importance of karyotyping all females presenting with short stature (Loscalzo, 2008) (see Chapter 40).
• Measurement of GH production may be necessary. Because secretion of GH is pulsatile, random serum measurement of the hormone is inadequate; stimulation testing using agents such as arginine, levodopa (L-dopa), clonidine, and/or glucagon is needed to accurately assess GH production.
Differential Diagnosis
Individual children with short stature may not fit nicely into a single category, but may have multiple factors contributing to their stature. Many chronic illnesses can slow linear growth, likely through a variety of mechanisms including malnutrition, acidosis, anorexia, and deficiencies of minerals (e.g., zinc and iron) and vitamins necessary for growth (Box 25-2). Typically children with poor growth as a result of chronic illness are underweight for height; their weight gain slows prior to growth deceleration. Thyroid hormones are essential to growth during childhood; sex steroids are important for normal growth during the pubertal growth spurt. Deficiency of these hormones is characterized by subnormal growth velocity, normal to increased weight for height, and delay in bone age.
Management
Children should be referred to a pediatric endocrinologist if hypothyroidism, low IGF-1 and IGFBP-3 or other hormone deficiency is confirmed, or for unexplained persistent slow growth without evidence of chronic illness. The U.S. Food and Drug Administration (FDA) has approved a number of indications for GH therapy (Box 25-3) (Schwenk, 2006). GH dosing is based on a child’s body weight with doses ranging from 0.15 to 0.30 mg/kg/wk. Response to GH therapy is greater for children receiving daily injections compared with those receiving three injections per week. During the first year of therapy, growth velocity may exceed normal growth rates as much as fourfold. Reported side effects of GH include glucose intolerance, pseudotumor cerebri, edema, growth of nevi, slipped capital femoral epiphyses, and scoliosis (Schwenk, 2006). The cost of GH therapy may present an economic burden to the family and referral to a social worker to assist in finding financial support may be appropriate.
Constitutional Growth Delay
Description
CGD is a common growth pattern variation and should not be considered a disease entity. When the child has no evidence of chronic illness, has a delay in bone age, and is growing at a normal rate for bone age, the likely diagnosis is CGD. These children generally reach normal adult height, although they may be slightly short compared with other family members.
Clinical Findings
History
The history may include the following:
• Normal length and weight at birth
• Slowed linear growth between 1 to 3 years of age and then normal growth velocity; normal height velocity is the most critical factor in diagnosing CGD
• Height at or slightly below the third percentile on standardized growth charts
• Delayed pubertal development
• History of similar growth patterns in other family members
Growth Excess
Some children, in contrast to those with CGD, are tall for their family as young children, enter puberty early, yet ultimately reach a height within the normal range for their family. Rarely will this accelerated growth require referral to a pediatric endocrinologist. Tall stature in comparison with parents’ height or rapid growth velocity in childhood can represent an underlying abnormality, however, including:
• Primary skeletal abnormalities such as Marfan syndrome, Klinefelter syndrome, and other overgrowth syndromes
• Overnutrition that advances the bone age and the timing of puberty. In these children, weight gain occurs first, and weight percentile is farther above the growth curve than height percentile.
• Excess adrenal androgens or gonadal steroids. These children have physical examination findings of early puberty.
Pubertal Disorders
The physical changes of puberty occur in response to production of sex steroids by the ovaries or testes (see Chapter 8). Hypothalamic gonadotropin-releasing hormone (GnRH) regulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland, which in turn stimulates gonadal hormone secretion.
By midgestation the fetal hypothalamic-pituitary-gonadal axis is intact; at term, the production of GnRH, LH, and FSH in this system is low. When placental and maternal hormones are removed at delivery, unrestrained production of these hormones occurs in the newborn, and the infant experiences a “mini puberty” between 2 weeks and 3 months of postnatal life. After infancy the hypothalamic GnRH pulse generator is more sensitive to feedback inhibition from the brain, and by 1 year of age, LH and FSH decrease to the prepubertal range, and the child enters a “latency” period that continues until puberty. Puberty occurs when the feedback inhibition is released and GnRH is again produced (Greiner and Kerrigan, 2006; Nathan and Palmert, 2005). The timing of the release correlates better with bone age than chronologic age.
The initiation of puberty in girls is earlier now compared with past decades and varies by race and ethnicity. A large epidemiologic study using data from 1300 girls who participated in the third National Health and Nutrition Examination Survey (NHANES) demonstrated that Tanner stage 2 breast development was present in less than 5% of non-Hispanic Caucasian girls with normal body mass index (BMI) by the age of 8 years; however, thelarche (breast bud development) is a normal finding in non-Hispanic black and Mexican-American girls before 8 years of age. Although girls are starting puberty at a younger age than in past generations, the timing of menarche and reaching Tanner stage 5 have not changed dramatically (Rosenfield et al, 2009). Menarche typically occurs within 3 years from the start of breast development; 95% of girls will have signs of puberty by the age of 12 years and achieve menarche by the age of 14 years. Boys normally begin puberty from age 9 to 14 years. The first sign of puberty is increased testicular volume in 85% of boys. Clinicians should be concerned when puberty presents early or is delayed.
Early Puberty
Early puberty is divided into four categories: premature thelarche, premature adrenarche, isolated menarche, and true precocious puberty. Premature thelarche, isolated breast development without any other features of puberty, occurs in infant and toddler girls and is sometimes present at birth. This breast development, likely due to estrogens produced during the mini puberty of infancy or increased responsiveness of the breast primordia, can take months or years to resolve and rarely progresses to true precocious puberty.
Premature adrenarche is the early onset of pubic hair in either boys (prior to 10 years of age) or girls (prior to 8 years of age) not associated with other features of true puberty. Premature adrenarche may be caused by a mild form of congenital adrenal hyperplasia (CAH), exposure to topical testosterone, or rarely, adrenal tumor. Most often the condition is idiopathic. Children with idiopathic premature adrenarche are at increased risk for polycystic ovary syndrome and metabolic syndrome (Ibáñez et al, 2009).
Isolated menarche is an uncommon condition in which girls have one to a few episodes of vaginal bleeding without breast development. In this condition, sexual abuse, vaginal tumor, a functional estrogen-producing ovarian cyst, and primary hypothyroidism all need to be excluded.
Precocious Puberty
Description
True precocious puberty refers to the onset of multiple features of puberty earlier than the normal range. Features may include accelerated linear growth, breast development or penile enlargement, and pubic hair development. Depending on the duration of symptoms, the bone age may be advanced. Precocious puberty can be divided into two broad categories: central, gonadotropin dependent; or peripheral, gonadotropin independent (Box 25-4). Prolonged exposure to exogenous sex hormones (mother’s birth control pills or father’s topical testosterone) (Aksglaede et al, 2006) and exposure to chemicals that disrupt endocrine function (see Chapter 41) can cause precocious puberty (Cesario and Hughes, 2007).
Epidemiology
In the U.S. the incidence of precocious puberty is 0.01% to 0.05% per year. Precocious puberty is more common in females compared with males and in African-American children compared with Caucasian children (Muir, 2006). Any lesion that disrupts the normal connections between the brain and the hypothalamus can cause central precocious puberty. This condition is most often idiopathic in girls. Boys have a 30% incidence of CNS tumors in situations of central precocious puberty.
Clinical Findings
Children who present with features of puberty at a younger age than normal should have an evaluation as to the etiology. Children who start to develop signs of puberty at the early end of the normal range should be evaluated if they have rapid progression of pubertal signs resulting in a bone age more than 2 years ahead of chronologic age, or new CNS-related findings (e.g., headaches, seizures, focal neurologic defects) (Kaplowitz, 2009).
History
The history should include details (age of onset, progression, duration) of pubertal symptoms (breast tissue, pubic hair, phallic enlargement, acne, body odor, oily scalp), pattern of growth, any symptoms suggestive of a CNS lesion, and pattern of puberty in family members. Any exposure to topical estrogens or testosterone, oral estrogens, or environmental estrogen disruptors should be determined.
Physical Examination
Physical examination should include:
• Assessment of stature and growth velocity
• Description of the child’s Tanner stage
• Breast development should be evaluated by palpation rather than inspection to differentiate between the presence of true breast tissue versus fat deposition (Rosenfield et al, 2009)
• Pubic and axillary hair (girls)
• Penile length, testicular volume, and pubic and axillary hair (boys) (see Chapter 8)
Diagnostic Tests
• Premature thelarche: no laboratory studies are necessary in the infant or toddler girl unless she has other features of true puberty or continued increase in breast size
• Premature adrenarche: serum 17-hydroxyprogesterone (17-OHP) to exclude CAH and a 24-hour urine collection for 17-ketosteroids or imaging of the adrenal glands to exclude an adrenal tumor
• Isolated menarche: thyroid function tests to exclude primary hypothyroidism, and pelvic ultrasound to rule out the presence of an ovarian cyst or pelvic tumor
Diagnostic tests for children with true precocious puberty include:
• LH, FSH, and estradiol or testosterone (use a laboratory with a sensitive assay that will detect early pubertal values at the lower end of the range)
• If LH and FSH are high (in pubertal range: indication of central etiology), an MRI is indicated to exclude CNS tumor.
• If LH and FSH are low (in prepubertal range: indication of peripheral puberty), complete a GnRH stimulation test to distinguish central from peripheral puberty.
Management
Treatment of precocious puberty should be done with the guidance of a pediatric endocrinologist. Management will depend on the underlying disorder, age of the child, degree of advancement of the bone age, and the child and family’s emotional response to the condition. Radiation, surgery, or chemotherapy is indicated in the case of CNS tumors. A long-acting GnRH agonist may be used to bring serum sex steroids to prepubertal levels. Treatment of precocious puberty is important to increase final adult height.
Delayed Puberty
Description
Puberty is considered delayed when a boy 14 years or older or a girl 13 years or older has no clinical features of puberty on physical examination.
Epidemiology
Any chronic condition that delays the bone age may cause delayed puberty because the timing of puberty correlates better with bone age than chronologic age (Box 25-5). In addition, failure of any part of the hypothalamic-pituitary-gonadal axis may also delay puberty (Box 25-6). The most common cause of delayed puberty is CGD (Louis et al, 2008).
Clinical Findings
History and Physical Examination
History and physical examination should focus on clinical clues indicating a chronic illness, symptoms or signs of hypothyroidism, prior history of CNS insult, or new CNS symptoms suggesting hypopituitarism. Review of systems should include questions about pattern of growth, especially growth velocity, sense of smell, and galactorrhea.
Diagnostic Tests
Laboratory investigation should include:
Adrenal Disorders
Anatomy and Physiology
Adrenal gland steroid production is under the control of the hypothalamic-pituitary axis. The hypothalamus secretes corticotropin-releasing hormone (CRH) in a pulsatile fashion, which stimulates production and secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland. ACTH regulates adrenal glucocorticoid (cortisol) and androgen production. Cortisol is produced in a series of enzymatic steps (Fig. 25-1) and is highest in the morning, low in the afternoon and evening, and lowest at midnight. Secreted in response to hypoglycemia, hypotension, pain, or other stressful events, cortisol has negative feedback on the synthesis and secretion of CRH, vasopressin, and ACTH.
FIG. 25-1 Adrenal steroidogenesis. After the steroidogenic acute regulatory (StAR) protein–mediated uptake of cholesterol into mitochondria within adrenocortical cells, aldosterone, cortisol, and adrenal androgens are synthesized through the coordinated action of a series of steroidogenic enzymes in a zone-specific fashion. A’dione, Androstenedione; DHEA, dehydroepiandrosterone; DOC, deoxycorticosterone.
(From Stewart PM: The adrenal cortex. In Larsen PR, Kronenberg HM, Melmed S, et al, editors: Williams textbook of endocrinology, ed 10, Philadelphia, 2003, Saunders, p 495.)
The adrenal gland also produces mineralocorticoid hormones (aldosterone), regulated by renal production of renin interacting with angiotensinogen to create angiotensin. The renin-angiotensin system is involved in regulation of salts, especially sodium; blood pressure; and renal blood flow. Aldosterone production also occurs in enzymatic steps, many of which are common to the cortisol production pathway.
Adrenal Insufficiency
Description
Adrenal insufficiency is characterized by a deficiency of hormones produced by the adrenal cortex; deficits of cortisol and aldosterone are perhaps the most important to body function. In primary adrenal insufficiency (hypofunctioning adrenal gland), glucocorticoid (cortisol) and mineralocorticoid (aldosterone) hormones are deficient, whereas in secondary adrenal insufficiency (hypothalamic or pituitary defect), only a glucocorticoid deficit is found. Thus, children with both forms of adrenal insufficiency have hypoglycemia and hypotension caused by cortisol deficiency. Only those with a primary adrenal insufficiency are at risk for salt-wasting crisis (hyponatremia, hyperkalemia, acidosis, and dehydration) caused by aldosterone deficiency.
Epidemiology
Primary adrenal insufficiency may be due to an inability to produce cortisol secondary to an enzyme defect in the adrenal steroid pathway (CAH), hypoplasia of the adrenal gland, or an acquired defect (Box 25-7). Lesions of the hypothalamus or pituitary lead to secondary adrenal insufficiency. Suppression of the hypothalamic-pituitary-adrenal axis secondary to steroid use can also lead to adrenal insufficiency. Infants born extremely prematurely (24 to 28 weeks’ gestation) sometimes demonstrate symptoms of adrenal insufficiency because of immaturity of the hypothalamic-pituitary-adrenal axis.
BOX 25-7 Adrenal Insufficiency
Secondary adrenal insufficiency can occur as a result of ACTH deficiency, as one of multiple hypothalamic-pituitary deficiencies, or rarely as an isolated problem. Most often the infant or child has a syndrome known to be associated with hypopituitarism (for example septo-optic dysplasia), has also been discovered to have GHD, or has a destructive lesion (e.g., tumor or radiation to the brain) or prior CNS trauma.
CAH is caused by a deficiency of any of the enzymes in the cortisol pathway. In addition to interrupting normal cortisol production, the most common enzymatic abnormality, 21-hydroxylase (21-OH) deficiency, causes shunting of cortisol precursors to the androgen pathway resulting in production of elevated levels of adrenal androgens in utero. Female infants born with classic CAH typically have ambiguous genitalia (e.g., enlarged clitoris and/or posterior fusion of the labia) from this excessive androgen exposure in utero. However, male infants have no signs of CAH at birth with the exception of subtle hyperpigmentation and possible mild enlargement of the penis (Antal and Zhou, 2009). About 75% of children with CAH caused by 21-OH deficiency also have aldosterone deficiency. Newborn screening programs now routinely test for the presence of CAH caused by 21-OH deficiency to detect CAH early to avoid a potentially life-threatening salt-wasting crisis in affected infants.
Clinical Findings
History
Symptoms of cortisol deficiency include a history of:
Symptoms of aldosterone deficiency include:
Diagnostic Tests
• Serum glucose (hypoglycemia)
• Blood gases and bicarbonate (for metabolic acidosis)
• Electrolytes (low sodium, elevated potassium with aldosterone deficiency)
• Serum cortisol (a cortisol value greater than 20 mcg/dL indicates adrenal sufficiency. A value lower than that must be interpreted in the clinical context in which the sample was drawn. Often an ACTH stimulation test, performed in collaboration with a pediatric endocrinologist, is needed to conclusively diagnose both primary and secondary adrenal insufficiency).
• Serum ACTH (elevated in primary adrenal insufficiency)
• Serum 17-OHP (diagnostic in children with suspected CAH caused by 21-OH deficiency)
• Serum renin level (elevated with aldosterone deficiency)
Plasma renin and aldosterone levels are interpreted best if they are drawn when serum sodium levels are low.
Management
Treatment of adrenal insufficiency includes hormone replacement and is best managed by a pediatric endocrinologist. An adrenal crisis is a medical emergency requiring immediate and vigorous administration of intravenous dextrose, normal saline, and stress doses of hydrocortisone. Intravenous stress doses of hydrocortisone succinate vary with age: 25 mg in children younger than 3 years; 50 mg in children ages 3 to 12 years; and 100 mg in children older than age 12, administered every 6 hours. Parents should be instructed regarding the need for stress doses of hydrocortisone when their child has a febrile illness, surgery, or trauma; they should also be taught how to administer hydrocortisone via intramuscular injection in case the child is vomiting or otherwise unable to swallow or retain oral medication. This injection allows parents extended time to seek further medical advice or intervention.
Long-term therapy of CAH includes oral hydrocortisone in replacement doses of 8 to 10 mg/m2 (8 to 10 mg per square meter of body surface) in children with ACTH deficiency or primary adrenal insufficiency. Children with CAH tend to have higher hydrocortisone needs. If present, aldosterone deficiency must be treated with fludrocortisone acetate. Treatment of CAH requires a fine balancing act to replace steroids, thereby preventing androgen overproduction. Excess steroid intake can lead to delayed growth; not enough steroids contribute to rapid bone age growth and ultimate short stature. Individual treatment plans are essential to meet the specific needs of individual children. The primary care provider should be familiar with the medical endocrinology treatment plan and reinforce it at routine well- and sick-child visits.
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