Endocrine Disorders in Children

Endocrine Disorders in Children

Symposium on Pediatric Surgery, Part II Endocrine Disorders in Children Steven D. Chernausek, M.D.,* Nancy D. Leslie, M.D.,t Clifford A. Bloch, F .C ...

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Symposium on Pediatric Surgery, Part II

Endocrine Disorders in Children Steven D. Chernausek, M.D.,* Nancy D. Leslie, M.D.,t Clifford A. Bloch, F .C .P. (S .A .),:j: and Mark A. Sperling, M.D.§

Hormones are indispensable for normal growth and development; they direct sexual differentiation in utero, the formation of appropriate external genitalia, orderly postnatal growth, pubertal development, and the regulation of salt, water, mineral, carbohydrate, and fat metabolism. Disturbances of these processes are relatively common in children as a consequence of congenital defects in the production or action of a hormone or of an acquired disorder in a hormone-producing tissue. In this article, we provide an overview of childhood endocrine disorders in which surgical intervention may be an indispensable part of management. For each section, we only briefly review current concepts of the relevant physiology and provide appropriate references in lieu of an exhaustive (detailed) consideration, which is beyond the scope or intent of this symposium. Although we repeatedly emphasize the importance of the hypothalamic-pituitary-target gland (thyroid, adrenal, gonad) axis as a dynamic feedback system for understanding normal function and localizing the site of disturbance, we do not discuss "normal" values for circulating hormones or neurosurgical approaches to hypothalamic-pituitary lesions. Normal values of the circulating hormones depend in part on age or developmental stage and in part on normative ranges established for a given laboratory using its particular method of measurement. Accordingly, we speak of normal, increased, or decreased levels, emphasizing that these may depend on age-adjusted criteria. The role of neurosurgery is mentioned only in relation to the management of Cushing's disease. We also attempt a balanced presentation of conflicting opinion regarding surgical or medical management of a problem for which there may not yet be a consensus; this applies particularly to disorders of the thyroid and parathyroid glands. Finally, the type of surgical procedure to choose is From the Division of Pediatric Endocrinology, Children's Hospital Medical Center, Cincinnati, Ohio *Assistant Professor of Pediatrics tFellow, Pediatric Endocrinology :j:Fellow, Pediatric Endocrinology §Professor of Pediatrics

Surgical Clinics of North America-Yo!. 65, No. 6, December 1985

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discussed in the subsequent companion article, "Pediatric Endocrine Surgery." The complementary nature of these articles underscores the importance of close collaboration between pediatric surgeons and endocrinologists for optimum management of these disorders in children. THE THYROID Several technologic advances have facilitated the management of disorders of the thyroid. Application of radioimmunoassay has clarified normal thyroid physiology and permits delineation of hyperfunction and hypofunction; ultrasound permits documentation of solid from cystic nodules within the thyroid; radionuclide scans can differentiate between functioning "hot" and nonfunctioning "cold" nodules. These diagnostic tools, in conjunction with careful review of history and examination of the extent and texture of thyroid gland enlargement, are highly useful when surgical intervention is considered for a goiter or for thyroid nodules. Physiology The hypothalamic-pituitary-thyroid axis represents a classic feedback system in which normal thyroid hormone levels are maintained by appropriate secretion of pituitary thyrotropin (TSH), which, in tum, is regulated by hypothalamic thyrotropin-releasing hormone (TRH). Thyroxine and, to a lesser extent, T3 regulate TRH and TSH by inhibiting their secretion. Thyroid hormones circulate in plasma bound to a specific high-affinity carrier, thyroxine binding globulin (TBG), which can be measured indirectly via the T3 resin uptake test or directly by radioimmunoassay.22 Only free thyroid hormones, unbound to TBG or other carriers, are biologically active. However, routine radioimmunoassay measures total T4 or T3 • Therefore, abnormal TBG levels will result in an apparent increase or decrease of thyroid hormones in blood. This makes it essential to document the TBG profile directly or indirectly in patients with suspected hyperthyroidism or hypothyroidism with mild symptoms and only minor changes in circulating thyroid hormones (Table 1). With classic hyperthyroidism, T4 and T3 as well as the T3 resin uptake are elevated, but TSH is low. In a few patients with hyperthyroidism, T4 is normal and only T3 is elevated; this is the so-called T3 toxicosis synTable I.

Interpretation of T3 Resin Uptake

INCREASED T 3 RESIN UPTAKE

DECREASED T 3 RESIN UPTAKE

T4 Increased

T4 Decreased

T4 Increased

T4 Decreased

Hyperthyroidism

TBG deficiency Congenital Corticosteroids Androgens Growth hormone excess Nephrotic syndrome Major illness

TBG excess Congenital Pregnancy Estrogens Oral contraceptives Liver disease

Hypothyroidism

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drome. 22 In primary hypothyroidism, that is, the thyroid gland itself is malfunctioning, the most sensitive indicator of attenuated thyroid hormone production is an elevated TSH. In the evolution of primary hypothyroidism, T4 may remain within the normal range as the elevated TSH stimulates the remaining thyroid follicular cells to secrete T4 • Thus, with any goiter, an increased TSH level reflects incipient thyroid failure and is an indication for thyroid hormone replacement.l0 When both T4 and TSH are low, TBG deficiency must be excluded because it will result in a low total T4 , but normal free T4 , that normally suppresses TSH secretion. Chronically ill patients may also have lowered circulating concentrations ofT4 and TSH because of alterations in thyroid hormone metabolism (that is, the "sick-euthyroid" syndrome). Thus, in the absence of major illness or TBG deficiency, a low T4 and TSH reflect secondary (pituitary-TSH) or tertiary (hypothalamic-TRH) thyroid failure, which requires detailed endocrine evaluation for other pituitary hormone deficiencies and for possible intracranial lesions. In summary, the functioning status of the thyroid gland can be routinely assessed by measurement ofT4 , TSH, and the T3 resin uptake; measurement of T3 is indicated in clinically hyperthyroid patients who have a normal T4 •

GOITER

With Symptoms and Signs of Hyperthyroidism. When classic symptoms and signs of hyperthyroidism (for example, tachycardia, tremor, weight loss, proptosis, emotional lability, or sleep disturbance) are associated with a smooth goiter and an elevated T4 , the most likely diagnosis is Graves' disease. Increasingly, evidence suggests that the etiology of Graves' disease is an autoimmune disturbance with production of a family of antibodies, some of which stimulate thyroid hormone secretion by binding to the thyroid cell's receptors for TSH and simulating its effects. Other antibodies may stimulate thyroid cellular growth but not function, and still others may simultaneously destroy thyroid tissue. As a result, spontaneous remission, occasionally progressing to hypothyroidism, is part of the natural history of Graves' disease. For children and adolescents, it is generally accepted that the initial treatment of choice is antithyroid medication. 6 Propylthiouracil is the most commonly used drug because of its relative safety, its effect on inhibiting synthesis of thyroid hormone within the thyroid gland and the conversion of T4 to T3 in peripheral tissues, and its possible direct effects on suppressing the immune response to undefined thyroidal antigens. 6 Initial treatment is with doses of 300 to 450 mg per day in three divided doses. Propranolol, 60 to 120 mg per day in three divided doses, is useful to control the tachycardia and to inhibit the conversion of T4 to T3 in peripheral tissues. When clinical symptoms improve, usually after 2 to 4 weeks of treatment, the propranolol is gradually discontinued over 2 weeks and the propylthiouracil dose readjusted to maintain normal serum levels of T4 and TSH. After clinical and biochemical euthyroidism is attained, propylthiour-

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acil is maintained at doses of approximately one half of those used initially for 1 to 2 years in the expectation of spontaneous remission. Spontaneous remission is most likely in those with a small goiter and mild disease. Only some 40 per cent of pediatric patients enter spontaneous remission after 2 years of propylthiouracil therapy; a further 2-year course of treatment results in a further 40 per cent remission rate. Even if remission occurs, long-term periodic evaluation is mandatory because of potential relapse or progression to hypothyroidism. In the past, failure to achieve remission after 2 to 4 years of propylthiouracil therapy or noncompliance with medication was an accepted indication for surgery via subtotal thyroidectomy. However, some pediatric endocrinologists are increasingly recommending radioiodine as an alternative to failed medical therapy. Is. 39 The advantages of radioiodine for the patient are acceptability, ease of administration, efficacy, and safety. Disadvantages include a high prevalence of permanent hypothyroidism requiring life-long replacement of thyroxine and concern at potential hazards of radioisotopes inducing thyroid malignancy. This concern, however, is diminishing as accumulating experience indicates the safety of therapeutic doses of radioiodine in childhood Graves' disease.l 8• 39 Nevertheless, because of these concerns, some authorities still recommend surgery as a second line of treatment for Graves' disease in children and adolescents. 30 Before surgery, patients should be treated with propylthiouracil, propranolol, and iodine solution for 1 to 2 weeks in order to achieve biochemical euthyroidism, reduce thyroid gland vascularity, and reduce the risks of surgically inducing thyroid storm. In experienced hands, the risks of recurrent laryngeal nerve palsy and hypoparathyroidism are small but finite. In black patients, keloid scars may cause cosmetic concern, especially in women. Postoperatively, calcium levels should be monitored; permanent hypoparathyroidism with hypocalcemia should be treated with vitamin D ·analogues. As with medical management, life-long periodic reevaluation is essential because the long-term risk of permanent hypothyroidism is almost as high with surgery as with radioiodine and because hyperthyroidism may recur in the thyroid remnant. When signs and symptoms of hyperthyroidism are present and T4 is near normal but T3 is elevated, an autonomous, toxic adenoma of the thyroid gland should be suspected. Palpation of a thyroid nodule is further evidence, but definitive diagnosis requires a radionuclide scan. If only the nodule is functional and the rest of the gland totally suppressed, the diagnosis is confirmed. It may, however, be advantageous to document complete autonomy by repeating the scan 1 week after treatment with exogenous T3 at a dose of 50 to 75 j.tg per day. Documentation of autonomy in such a thyroid nodule is a clear indication for surgical extirpation as primary treatment. Although theoretically such nodules should represent an ideal instance for radioiodine, the nodules are resistant to radioiodine and usually require large doses. Hence, surgery is the treatment of choice for this condition. Thyroid function tests and a scan should be repeated several weeks after surgery. Without Signs and Symptoms of Hyperthyroidism. If the thyroid gland is diffusely enlarged, firm, bosselated, or nodular, the most likely

ENDOCRINE DISORDERS IN CHILDREN

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diagnosis is Hashimoto's thyroiditis. IfT4 and TSH levels are normal, treatment is not indicated; if the TSH level is elevated, replacement with levothyroxine (T4) at a dose of 100 j..Lg per m 2 per day is the treatment of choice. Cosmetic reasons are not an indication for surgery; such goiters often, but not always, regress with thyroid replacement therapy. A smooth, soft goiter in the presence of an elevated TSH level may indicate an inborn error of thyroid hormone synthesis. Medical treatment is given with T 4 replacement, and disappearance of the goiter is expected. If, however, the gland is diffusely enlarged and hard, and there is reason to suspect infiltration by lymphoma or histiocytosis X, biopsy, followed by surgical extirpation of the gland, is indicated. Multiple nodules in an enlarged thyroid gland usually signifY areas of lymphocytic infiltration or cystic degeneration in a Hashimoto's gland; medical management is used with T4 replacement. On the other hand, a solitary nodule in a thyroid gland that is otherwise normal to palpation represents a diagnostic challenge.

THE SOLITARY NODULE

Solitary thyroid nodules are rare in children. 20 A true nodule may present as a discrete, dominant area within an existing goiter or in the absence of any other thyroid swelling. One approach to a child who presents with a solitary nodule is outlined in the algorithm in Figure 1. In evaluating a child with a nodule, one must inquire about radiation exposure. Radiation, previously used to treat hyperplastic tonsils and cases of severe acne, resulted in an increased incidence of thyroid carcinoma. More relevant today is the periodic re-evaluation of children previously treated with radiation for leukemia, lymphoma, or solid tumors of the head and neck. A recent report estimated the incidence of thyroid carcinoma to be 4. 6 per cent in 174 long-term cancer survivors over an 11-year period. 40 These children also had chemotherapy, which appeared to increase the risk for the development of thyroid carcinoma. Thyroid carcinoma usually presents as a hard nodule that is fixed to the adjacent tissues. Regional lymph nodes may be enlarged. Any persistent cervical lymph node greater than 1 em in diameter, of firm consistency, should be viewed with suspicion for cancer in a patient with a hard thyroid nodule. Hoarseness suggests invasion of the recurrent laryngeal nerve. The key to successful evaluation and management of a child with a solitary nodule is periodic re-evaluation. Although it is generally true that cystic or functional solid nodules are seldom malignant, there are occasional reports of malignancy within them. On the other hand, it should be emphasized that although carcinoma is most likely to be present in a solid, "cold" nodule, not all cold nodules are malignant. In fact, approximately 75 per cent of solid, cold nodules are benign follicular adenomas, and only 25 per cent are carcinomas.2o What makes the approach toward management of cold nodules in children somewhat unique is that most thyroid carcinomas are well differentiated, grow slowly, and metastasize late. Thus, the early removal of a

.......

TSH, T 4 ..----------------------------------~~~L-----------------------------1 N TSH

'-.::1

~-

t-'

t TSH +.j.T4 Hashimoto's

NNTSH T4

Thyroiditis

Ultrasonography

I

-~

f

l

~

Treat with T4 and OBSERVE

3 12 II Scan

Sohd 123 I II Scan

I OBSERVE

~-----

~

I

Full replacement T 4 -1-

in lsize

Continue T4 and OBSERVE closely

af~~/J~~~;hs

APPROPRIATE SURGERY

Rest of gland not suipressed

I

N

t Calc"tltonin

z ~

f:

T3

Calcitonin t

or any t m s1ze or signs of cancer

~

I Rest of gland supp,essed

Fam. history or physical signs of ME A 11/llb

~ BIO]PSY

"'

1'1

Functional

I

I

History of irradiation and/ or signs of cancer

~ 0

~

ExciJ nodule

"C~ld'' No signs of cancer (see text)

tr.J

Solitary functional nodule

.

Cystic

~

I

t T4 (or tT3l

1

Excise Total t yroidectomy and nodule screen patient & family for MEA 11/llb &: OBSERVE t T3 ortm nodule or signs of cancer Extse nodule

Full replacement T 4 I t in 1size Suppr. of nodule of nodule &gland

N

I

I

OBSERVE for t in size &

BIOPSY

~

t T3

I

Con~nue

T4 and OBSERVE

"'t"' _;; 0

?t::l:l

t"'

§ ~

t:l I

No tT3 APPROortin PruAn size SURGERY

~ OBS RYE

:::::

?tr.J

t:ll

~

C"l

ENDOCRINE DISORDERS IN CHILDREN

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carcinoma in situ or a well-differentiated follicular carcinoma does not seem to improve the excellent prognosis. 41 Less differentiated carcinomas tend to grow rapidly and invade and metastasize early, allowing easier clinical detection. Therefore, provided there are no history of irradiation, no family history of medullary carcinoma of the thyroid in association with the syndrome of multiple endocrine adenomatosis type IIA or B, no rapid increase in size, no fixation to adjacent tissues, no invasion of surrounding structures, no regional lymph node enlargement or distant spread, and no suggestive hardness of the gland, some authorities recommend a trial of T4 in full replacement dosage for 3 to 6 months. 9 Others, however, recommend that, in an otherwise normal thyroid, a solitary nodule that is solid on ultrasound and cold on scan should be biopsied from the outset. 2° Furthermore, for patients on T4 replacement, any increase in size of the thyroid nodule, development of the aforementioned signs of cancer, or failure to decrease the nodule to half size by 6 to 12 months warrants biopsy and surgery. A subtotal thyroidectomy may constitute adequate treatment for papillary and well-differentiated follicular carcinomas, although some physicians advocate total thyroidectomy for all thyroidal malignancies. Total excision of the gland is warranted for medullary carcinoma of the thyroid, which is often multifocal and has a high risk of recurrence. Following surgery, all patients should be treated with thyroxine at full replacement doses in order to suppress TSH levels. Fine needle aspiration of the thyroid, though highly useful in adults, is not yet an established procedure in children. Histopathologic differentiation of benign tumors from malignant tumors requires provision of representative cellular tissue and a pathologist experienced in interpreting thyroid aspirates. If these requirements are met, however, needle biopsy is a valuable adjunct. Rapid enlargement of a cystic nodule in a thyroid gland usually represents hemorrhage into a follicular cyst and may require aspiration to relieve pain from tension. In summary, for patients with hyperthyroidism resulting from Graves' disease, surgical intervention is indicated only when medical management has failed to achieve remission; in toxic solitary adenoma, surgical excision of the functioning nodule is the appropriate primary treatment. A diffusely enlarged gland with biochemical evidence of hypothyroidism should be managed medically by exogenous T4 replacement unless there are grounds to suspect diffuse infiltration by a malignant process or there is bleeding into multiple follicular cysts. The isolated nodule, in an otherwise normal gland, requires systematic evaluation as outlined in the algorithm: cystic or solid, hot or cold, with or without features suggestive of medullary carcinoma of the thyroid, including basal and stimulated calcitonin levels, use of fine needle aspiration, and re-evaluation for change over 3 to 6 months while on full thyroid replacement therapy. THE PARATHYROID GLANDS

Parathyroid hormone plays an essential role in the fine tuning of calcium and phosphorus metabolism. Normally, parathyroid hormone levels in serum are elevated in hypocalcemia and suppressed with hypercal-

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SPERLING

cemia. 37 Hypoparathyroidism due to congenital absence or autoimmune destruction is much more common in childhood than is hyperparathyroidism. A diagnosis of hyperparathyroidism is established on the basis of an inappropriately elevated parathyroid hormone level in serum, coexistent with hypercalcemia, which is usually discovered as an incidental laboratory finding but occasionally during the evaluation of nephrolithiasis. It cannot be overemphasized that the diagnosis of hyperparathyroidism depends on the demonstration of a serum parathyroid hormone level inappropriate for the level of hypercalcemia; that is, the parathyroid hormone level may be within the normal range but inappropriate for the level of serum calcium. 37 Current technology does not permit the accurate localization of a parathyroid adenoma, but distinction from hyperplasia can sometimes be documented by preoperative sampling of the venous drainage of the parathyroid glands, with measurement of parathyroid hormone. Even so, careful surgical exploration is essential; a discrete adenoma should be removed. In its absence, three of the four parathyroid glands should be removed. Postoperative evaluation is imperative to document resolution of hyperparathyroidism. As indicated, hyperparathyroidism is an exceedingly rare cause of hypercalcemia in childhood; only one case has been identified in our large endocrine referral clinic over the past 7 years. A more detailed discussion of hyperparathyroidism and its surgical treatment in infants and children can be found in the article "Pediatric Endocrine Surgery."

FUNCTIONAL TUMORS OF THE ADRENAL CORTEX Functional tumors of the adrenal cortex may produce signs and symptoms related to overproduction of any of the three steroid hormones normally produced by the adrenal gland, that is, glucocorticoids, mineralocorticoids, and androgens.s Rarely, adrenal tumors may produce estrogen, a steroid not normally produced by the adrenal cortex. The clinical features and biochemical markers of these tumors are described in Table 2. Although listed as distinct entities, the clinical features and hormone levels may sometimes overlap. The differential diagnosis of these conditions should be carefully considered, as functional adrenal tumors are actually quite uncommon among various developmental and pathologic states, which cause a similar clinical pattern. In each clinical situation described in Table 2, the features may be mimicked by exposure to exogenous steroids in various forms. The several types of congenital adrenal hyperplasia, with varying ages at onset, may result in a pattern characterized by excesses of some steroid hormones and deficiencies of others. In congenital adrenal hyperplasia, the drive to steroid overproduction is relative cortisol deficiency and consequent increased secretion of adrenocorticotropic hormone (ACTH); as such, the biochemical abnormalities can be corrected for diagnostic and therapeutic purposes by administration of glucocorticoids. Adrenal tumors typically result in more rapid progression of virilization or feminization than true precocious puberty. In addition, true precocious puberty is characterized by active secretion of gonadotropins, which produce testicular enlargement

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Table 2.

Features of Functional Adrenal Cortical Tumors

GLUCOCORTICOID (CUSHING's SYNDROME) CLINICAL FEATURES

BIOCHEMICAL FEATURES

MINERALOCORTICOID (CONN's SYNDROME)

I

Obesity ~ Linear growth t Blood pressure Osteoporosis Hypertrichosis

Blood pressure Serum K+ muscle weakness

f Urinary-free

f Urinary

cortisol Blunted diurnal variation of serum cortisol

aldosterone ~ Plasma renin

activity Metabolic alkalosis

ANDROGEN

ESTROGEN

f Linear growth t Linear growth Accelerated skelAccelerated skeletal eta! maturation Breast maturation Sexual hair enlargement Acne Estrogen effect on vaginal t Muscle mass Voice change mucosa and Temporal balding uterus Phallic enlargement without testicular enlargement in boys Clitoromegaly without posterior labial fusion in girls t Urinary 17t Serum ketosteroids estradiol t Serum DHEA-S May have t serum testosterone

DHEA-S =dehydroepiandrosterone-sulfate

in boys. The clinical picture and biochemical markers of functional gonadal tumors may mimic those of adrenal tumors. However, many of the former are palpable; the remainder can usually be localized by pelvic ultrasound. In Cushing's syndrome, biochemical assessment is essential to both the correct diagnosis and choice of treatment.l4 Cushing's syndrome may result from an adrenal tumor producing excess cortisol with low or undetectable ACTH levels or from bilateral adrenal hyperplasia caused by excessive pituitary ACTH secretion. Ectopic ACTH secretion is a rare cause of Cushing's syndrome in children; it is characterized by marked elevation of serum ACTH. In pituitary Cushing's (Cushing's disease), the corticotrophs retain some capability for feedback inhibition by glucocorticoids, a fact that is exploited in the dexamethasone suppression test used for determining the etiology of hypercortisolism (Table 3).35 Before undertaking formal dexamethasone suppression testing, most endocrinologists recommend screening with the overnight dexamethasone suppression test or 24-hour urinary free cortisol. In the pediatric population, Cushing's disease is seen more commonly after 6 years of age.l4 Bilateral adrenalectomy was formerly considered the treatment of choice; its advantage is immediate resolution of hypercortisolism. Its disadvantages are the need for lifelong steroid replacement and the risk for expansion of the pituitary lesion (Nelson's syndrome), which develops in up to 45 per cent of patients.26 Pituitary irradiation has not

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Table 3.

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Dexamethasone Suppression Test for Cushing's Syndrome*

PHASE OF TEST

Basal (days 1 & 2) Low dose dexamethasone: 1.2 mg/m2/d (2 mg max) divided q 6h, days 3 & 4 High dose dexamethasone: 4.8 mg/m 2/d (8 mg max) divided q 6h days 5 & 6

URINARY-FREE CORTISOL

SERUM CORTISOL (8 A.M. f.i.g/dl)

Normal= <100 f.i.g/m 2/dt

10 to 20

<50% basal ofo Cushing's syndrome Normal usually < 25f.i.g/d

normal=<5

:550% of basal= Cushing's disease >50% of basal= Primary adrenal Hypercortisolism or ectopic ACTH syndrome (measure ACTH concentration to differentiate)

*Most protocols for dexamethasone suppression have limitations that may lead to falsepositive or false-negative results. Data should be carefully interpreted to avoid misdiagnosis. !Normal adult value is <110 flog/d.

been highly successful as primary therapy in adults, although it may be more efficacious in children. 21 However, there may be an unacceptably long latency between treatment and resolution of hypercortisolism. In addition, long-term effects may include development of other anterior pituitary hormone deficiencies. Transsphenoidal microadenomectomy has become widely used in adults and should probably be considered the first line of treatment in centers with adequate neurosurgical expertise. 36 In patients who are still growing or who desire preservation of their fertility, the procedure should be limited to tumor resection; if a discrete lesion cannot be identified and resected, bilateral adrenalectomy should be performed. "Medical adrenalectomy" with agents such as o,p'-DDD is reserved for unresectable adrenal carcinoma. There has been little experience with their long-term use in children, but they may be useful as adjuncts to more definitive therapy. Adrenal tumors are responsible for hypercortisolism more commonly in children less than 6 years of age.s The tumor histology may be that of an adenoma or carcinoma. The treatment of choice is tumor resection with preservation of contralateral adrenal tissue if possible. Remaining adrenal tissue may be profoundly suppressed because of chronic lack of stimulation by ACTH. For this reason, patients must be carefully evaluated in order to determine when normal cortisol production has resumed. Glucocorticoid coverage for physiologic stress should be provided until adequate adrenal response has been documented. The most important part of evaluation of functional adrenal tumors is careful biochemical evaluation, including documentation of lack of dexamethasone suppressibility. Once the data indicate the likelihood of adrenal

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tumor, attempts should be made to lateralize and define the extent of the tumor before surgery. The presence of virilization or feminization, a palpable mass, or calcification on a plain abdominal film should heighten the suspicion of carcinoma. Computed tomography (CT) and ultrasound are equally sensitive in localizing most large adrenal cortical tumors. 7 In children, the lack of retroperitoneal fat may hinder adequate CT examination of the adrenal glands; this is less of a problem in patients with Cushing's syndrome. Because ultrasound does not expose the child to ionizing radiation, it should be used as the primary tool for imaging the pelvis and adrenal glands. CT may be more sensitive in imaging smaller adrenal tumors, particularly in the left adrenal gland. In uncertain cases, scanning with radiolabeled iodocholesterol or selective venous sampling may be helpful. Steroid Coverage for Surgery The daily cortisol production rate of normal adrenal glands is 12.5 to 15 mg per m2 per day and increases 3- to 5-fold during physiologic stresses such as general anesthesia and surgery. Any patient known to have subnormal cortisol secretion before surgery or patients at risk for development of inadequate cortisol secretion as a consequence of the surgical procedure should therefore be given exogenous glucocorticoids during both the procedure and the postoperative period. 8 The indications for glucocorticoid coverage and a suggested schedule are described in Table 4. Mineralocorticoids are usually not necessary if hydrocortisone is used, as there is considerable mineralocorticoid effect at the doses suggested for stress. However, many patients with adrenal disease may require mineralocorticoid replacement once they are switched to a maintenance glucocorticoid schedule (Table 4). AMBIGUOUS GENITALIA Children with ambiguous genitalia have external genitalia that either appear intermediate between the typical male or female pattern or are obviously discordant with their internal sex organs. These uncommon, but fascinating, situations can result from a variety of specific disorders. EvalTable 4.

Glucocorticoid Coverage for Surgery

INDICATION

Bilateral adrenalectomy, adrenal adenomectomy, known adrenal insufficiency, adrenal suppression from exogenous glucocorticoid therapy STRESS COVERAGE

For elective procedures 50 mg/m2 cortisone acetate intramuscularly the night before and on morning of procedure; daily thereafter until patient is afebrile and taking normal diet For emergency procedures 25 mg/m2 hydrocortisone sodium succinate intravenous bolus and 50 mg/m2 cortisone acetate before procedure; continue as above Alternate schedule 50 mg/m2/day hydrocortisone sodium succinate continuous intravenous infusion or divided q 4h intravenous bolus beginning prior to procedure MAINTENANCE

15 mg/m2/day hydrocortisone+ 0.1 mg Florinef/day

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uation of affected children should begin at birth in order to acquire sufficient data to correctly assign the sex of rearing and to identify any associated problems (for example, salt loss) that could alter the infant's health. The following discussion will not exhaustively review all diagnostic possibilities but will attempt to provide a framework for the evaluation of a child with ambiguous genitalia by reviewing the control of normal sex differentiation and describing specific conditions that illustrate how differentiation can be altered. Normal Sexual Differentiation Knowledge of the normal sequence of sex differentiation and the factors that influence the morphology of the sex organs is critical for understanding the pathophysiology of the specific disorders that cause genital ambiguity and for developing a rational plan for evaluation of affected children. Analysis of normal sex differentiation reveals three important principles. First, every developing fetus has the potential to develop into either a morphologically normal male or female infant. Second, sex organ development proceeds toward the normal female pattern in the absence of any other specific "male" influences. Third, the majority of sex differentiation is complete by the twelfth week of intrauterine life. 17, 32 The control of sex differentiation is schematically illustrated in Figure 2. The Y chromosome induces the expression of the H-Y antigen, which, in turn, results in transformation of the primitive gonad into a testis. The Sertoli cells of the fetal testis secrete miillerian inhibiting factor, which acts locally to cause regression of the miillerian ducts (anlage of the uterus, fallopian tubes, and upper third of the vagina). The Leydig cells secrete testosterone, which also acts locally to stimulate differentiation of the wolffian ducts (anlage of the vas deferens, seminal vesicles, and epididymis). Circulating testosterone, normally produced by the fetal testes, is converted in the external genital tissues to dihydrotestosterone. This potent androgen stimulates phallic growth to form the penis, causes fusion of the Y - Chromosome

1

Primitive Gonad

H- Y Antigen -------7Testis

M~ ~osterone

j

~AUllerian

Duct Regression

Ovary

No Effect on \H.Hlerian Duct

L) NORMAL FEMALE

Figure 2.

j

---""Wolffian Duct Development

X. reductase

1

Dihydrotestosterone

Androgen Receptor

!

Virilization of External Genitalia

NORMAL MALE

Hormonal control of sex differentiation. (MIF = miillerian inhibiting factor.)

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ENDOCRINE DISORDERS IN CHILDREN

labioscrotal folds to form the scrotum and penile urethra, and ultimately produces normally formed male external genitals. 17• 19• 32 Excessive Virilization of Female Genitalia Virilization of female genitalia is due to an excess of circulating androgens during the period of differentiation of the external genitalia. Depending on the magnitude and duration of androgen exposure, the infant's genitalia may exhibit only mild clitoromegaly and partial labial fusion or may be completely virilized with development of a penile urethra. The androgens may be derived from the mother if she has a significant virilizing disorder such as an androgen-producing tumor or if she has received medications with androgenic properties (for example, certain progestins) during the critical time period. Androgens originating from the fetus may emanate from the gonads if Y chromosome-bearing cells are present (as in XO/XY mixed gonadal dysgenesis), but more commonly they are produced by the fetal adrenal. When no testes are present to secrete miillerian inhibiting factor, the uterus and fallopian tubes are normally developed and associated with normal ovaries unless gonadal dysgenesis exists. Excessive androgen production by the fetal adrenal is nearly always due to an inborn error of steroid hormone biosynthesis that compromises cortisol production. The relative cortisol deficiency induces increased secretion of ACTH, which stimulates adrenal hyperplasia. In the case of 21-hydroxylase deficiency and 11-13-hydroxylase deficiency (which together represent 95 per cent of all congenital adrenal hyperplasia), testosterone synthesis is unimpaired (Fig. 3), resulting in excessive testosterone production by the hyperplastic adrenal gland. In 3-13-hydroxysteroid dehydrogenase (3-13-HSD) deficiency, testosterone biosynthesis is diminished, but an increase over the usual female level of androgens occasionally occurs since mild virilization has been described in some cases. Aldosterone synthesis is reduced in 21-hydroxylase deficiency and 3-13-HSD deficiency, Cholesterol

j 20,22 Des. 178-HSO

17-20 Des. Pregnenolone ------~.17-0H

Pregneln;~o~:SD

j

3 8 -HSD

17 <>-OH

Progelst:;~~:

~·~r:·::·

l:~=g~

Corticosterone

androjstero3n: -HSD 17-20 Des.

17-0H

'

3 8 -HSD

178-HSO

Prolg:;~::ne~Androstjenedione

~T.-~"

j

Dehydroepi- ----~'\ndrostenediol

··-

~estojsterone 178-HSO

. . .;.,

Cortisol

Aldosterone

Figure 3. Steroid biosynthesis. (Des. =desmolase; HSD = hydroxysteroid dehydrogenase; HSO = hydroxysteroid oxidoreductase; OH =hydroxylase; OX= oxidoreductase.)

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and therefore, salt loss frequently accompanies these conditions. Although aldosterone formation requires ll-J3-hydroxylase, deoxycorticosterone has mineralocorticoid activity. Thus, individuals deficient in this enzyme have salt retention and may be hypertensive owing to overproduction of deoxycorticosterone (see Fig. 3).17, 28 The preceding disorders are inherited as autosomal recessive traits and are diagnosed by demonstrating supranormal circulating concentrations of the specific steroid precursors. Treatment is directed toward replacement of deficient hormones (glucocorticoid and mineralocorticoid as indicated) and reconstruction of the external genitalia to a form compatible with normal female sexual function. Mixed gonadal dysgenesis typically occurs in children bearing an XO/ XY mosaic karyotype. Because gonads bearing Y cell lines may produce androgens, strikingly variable degrees of virilization can be found. Establishment of the correct diagnosis is important because of the high risk (25 per cent) of the development of gonadoblastoma. 25 Removal of these gonads prior to puberty is therefore recommended. Inadequate Virilization of Male Genitalia Incomplete sexual differentiation in a male child is due either to a deficiency of testosterone production or to an intrinsic resistance of the genital tissues to the action of testosterone. Inadequate testosterone production can be associated with histologic abnormalities of the testis such as Leydig cell hypoplasia or dysgenetic gonads or could result from an inborn error of testosterone biosynthesis. Enzyme deficiencies present in the gonad that also yield congenital adrenal hyperplasia include desmolase deficiency, 3-J3-HSD deficiency, and 17-a-hydroxylase deficiency. Salt loss accompanies the first two disorders, whereas salt retention is present when 17-a-hydroxylase is deficient. Defects that reduce testosterone synthesis only, such as deficiencies of 17,20 desmolase or 17-J3-hydroxysteroid oxidoreductase in the male child, manifest as incomplete sexual differentiation without any associated glucocorticoid or mineralocorticoid abnormalities (see Fig. 3).17 Resistance to circulating testosterone may occur because of a deficiency of 5-a-reductase or because the genital tissues themselves are resistant to the enzyme's product, dihydrotestosterone. Male infants with S-areductase deficiency typically have a small hypospadiac phallus with a bifid scrotum. Wolffian duct derivatives are normal because testosterone itself promotes their differentiation. For reasons not completely understood, further virilization and phallic growth occur at puberty. The diagnosis is established by demonstrating reduced 5-a-reductase activity in genital skin fibroblasts or by observing an increased plasma testosterone/dihydrotestosterone ratio at a time when gonadal testosterone secretion is stimulated. 15, 17 The most dramatic example of androgen resistance is the complete testicular feminization syndrome. Genetic males with this X-linked recessive disorder have normal female external genitalia with testes that may be in the labia or inguinal canals. Because affected individuals are completely resistant to androgens, no sexual hair growth appears at puberty, but

ENDOCRINE DISORDERS IN CHILDREN

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breasts develop owing to peripheral conversion of testosterone to estradiol. In this, as in the disorders of testosterone metabolism, miillerian structures are absent because the fetal testes secrete miillerian inhibiting factor normally. In some cases, the androgen resistance occurs because androgen receptors capable of binding dihydrotestosterone are not present, whereas in others, receptor binding is normal and a "postreceptor defect" is presumed. A variant form of this syndrome, in which modest virilization is present, has also been described. The diagnosis is made on clinical grounds in an XY individual who manifests the morphologic features previously noted with evidence of normal testosterone secretion. At some time, gonadectomy should be performed to remove labial/inguinal gonads and to avoid the increased risk of gonadal malignancy in later life. 15, 17 Evaluation of an Infant with Ambiguous Genitalia

The proper evaluation of a child with ambiguous genitalia requires a physician who is knowledgeable in the diagnosis and treatment of the various disorders of sex differentiation and skilled in dealing with the usually anxious parents. Although assignment of sex of rearing is the first goal, physical examination at birth does not always provide sufficient information to allow a correct decision. In this situation, sex assignment should be delayed until more data are acquired to assure the optimal sex assignment. In the intervening period, it is best that the parents delay naming the child and avoid other indicators of sex assignment (for example, blue blankets for boys). Assignment of sex is ultimately based on knowledge of the specific features of the identified disorder and feasibility of reconstruction of the external genitalia. When minimal phallic tissue is present, superior results are usually obtained by surgical construction of feminine external genitalia than by attempting to create a functional male phallus. Ideally, surgery should be performed before 2 years of age so that the external genitalia are concordant with the sex of rearing during the time when gender identity is acquired. The medical evaluation of an affected infant is schematically illustrated in Figure 4. The first step is to determine if the abnormalities resulted from virilization of a girl or incomplete virilization of a boy. This can usually be determined by physical examination, assessment of internal sex organs by ultrasonography or other means, and by karyotype analysis. Scrotal gonads that are normal to palpation are nearly always testes and indicate that the disorder is one of incomplete virilization of a boy. If no gonads are palpable and normal miillerian structures are identified, the patient is a virilized girl. The karyotype is useful to confirm the initial impression and to identify an aberrant sex chromosome constitution such as XO/XY mosaicism. Further evaluation of a virilized girl is relatively simple, for after exclusion of exogenous androgens by review of the maternal medical history, the diagnosis of congenital adrenal hyperplasia can be established by measurement of the circulating concentrations of the appropriate sex steroid precursors. Definition of the specific disorder in the underdeveloped male child can be more difficult. Testosterone production should be assessed in the basal and/or stimulated state following administration of

1542 I.

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History and Physical Examination

rK~yo
2.

GooF

f>'ipabie? ~y~ /-----~INCOMPLETELY VIRILIZED MALE

3. Ultrlasound

~No

~

a) Inadequate

::~::::::~e production

(enzyme deficiency; dysgenetic testes)

Uterus? b) Inadequate testosterone action (testicular feminization syndrome; 5 Cl.- reductase deficiency)

l

Yes

1

VIRILIZED FEMALE

Consider: a)

Adrenal hyperplasia (Deficiencies of 21-0H, 11 B -OH, 3 B-HSD)

b)

Maternal androgen excess

c)

Presence of testicular tissue (mixed gonadal dysgenesis; true hermaphrodite)

Figure 4.

Evaluation of patient with ambiguous genitalia.

human chorionic gonadotrophin (see next section for details). If testosterone production is deficient, an inborn error of testosterone biosynthesis or dysgenetic gonads should be considered. If testosterone production is normal, either the patient is resistant to circulating tesosterone or an undefined event altered normal sex differentiation at a critical time during fetal life.

GONADAL DISORDERS The number of gonadal disorders necessitating surgical attention in childhood is limited. Because undescended testes and functioning gonadal neoplasms frequently require surgical treatment, the endocrine aspects of these will be briefly reviewed in the following section. Undescended Testes The undescended testis has failed to complete its migration to the scrotum and is usually found along the normal path of descent in either

ENDOCRINE DISORDERS IN CHILDREN

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the inguinal canal or the abdomen. Treatment is indicated at a young age to place the gonad in the relatively cooler environment of the scrotum and thereby preserve future testicular function. The rationale and results of various treatment modalities and the optimal timing of orchiopexy have been the subjects of several studies and have been extensively reviewed in a recent publication. 11 The majority of undescended testes are found in otherwise normal individuals, but occasionally cryptorchidism is associated with specific endocrine or genetic disorders. Early recognition of these disorders is important because the prognosis for future gonadal function may be altered and because additional problems requiring clinical attention may be present. Undescended testes may be associated with disorders of diminished testosterone secretion. When testicular descent has failed to occur in boys with inborn errors of testosterone biosynthesis, genital ambiguity is usually also present, and the need for further evaluation is apparent (see previous section). More commonly, cryptorchidism results from reduced secretion of follicle-stimulating hormone and luteinizing hormone. The pituitary deficiencies may be limited to the gonadotrophins as in Kallman's syndrome (hypogonadotrophic hypogonadism and anosmia) or may extend to other anterior pituitary hormones. Panhypopituitarism should always be suspected in an infant with a microphallus and undescended testes, especially if signs of other pituitary hormone deficiencies (for example, hypoglycemia due to deficiencies of growth hormone and ACTH-cortisol) are present. Ascertainment of the complete diagnosis is important, for replacement of the lacking hormones is necessary ,13 Cryptorchidism also occurs with increased frequency in many distinct genetic disorders. Klinefelter's syndrome (XXY) and Down's syndrome (trisomy 21) are examples of relatively common chromosomal aberrations in which cryptorchidism occurs. Undescended testes are also frequently observed in the Noonan, Prader-Willi, and many other relatively rare syndromes. When a patient with cryptorchidism manifests other morphologic abnormalities, further evaluation or consultation should ensue to determine if an associated disorder is present.l3 When no testes can be palpated (and after a virilizing disorder in a girl has been excluded), the presence of abdominal testes must be distinguished from the so-called vanishing testis syndrome. This condition refers to those genetic and phenotypic males in whom no testicular tissue can be found but who obviously had testes during fetal life to cause miillerian duct regression and virilization of the external genitalia. Failure to observe a rise in serum testosterone concentration following human chorionic gonadotropin (HCG) administration indicates a lack of functional testicular tissue and obviates the need to search for abdominal testes. 3 This test can be performed in many ways. A convenient protocol involves measurement of testosterone before and after the administration of 50 to 100 I. U. per kg of HCG every 4 days for a total offour doses.l2 Future testicular function depends on several factors. Patients with bilateral cryptorchidism who are otherwise normal have the best prognosis, with 80 per cent having evidence of normal fertility as adults. 16 In contrast, spermatogenesis appears to be reduced in the majority of patients

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with surgically corrected unilateral undescended testes, 23 suggesting that fertility may be permanently impaired. The prognosis for those individuals with the associated disorders detailed previously is modified. Patients with hypogonadotrophic hypogonadism require additional hormonal treatment for procreation to succeed. The likelihood of fertility in individuals with disorders such as Klinefelter's syndrome is obviously very low. Functioning Gonadal Tumors Tumors of the gonads may secrete sex steroids or peptide hormones such as HCG. The predominant clinical manifestations of the HCG-secreting choriocarcinomas and dysgerminomas are usually not overt signs of endocrine disturbances but rather relate to mass effects or local invasion of the neoplasm. Conversely, the presenting signs of those tumors secreting substantial amounts of sex steroids during childhood are the features of sexual precocity. This discussion, therefore, is confined to three sex hormone-secreting neoplasms that occur during childhood. Leydig Cell Tumor. Functioning testicular tumors are very rare in prepubertal boys, representing less than 1 per cent of all solid tumors of childhood. 29 Of these, nearly all are androgen-producing tumors of Leydig cell origin. An affected boy typically presents between the ages of 3 to 6 years with signs of virilization such as phallic enlargement, pubic hair development, and accelerated linear growth. The diagnosis is almost assured when asymmetric gonadal enlargement due to a testicular mass is detected. Prior to surgery, Leydig cell tumors must be distinguished from hyperplastic adrenocortical tissue located in the testis. Such a lesion may arise in boys with untreated virilizing congenital adrenal hyperplasia (21hydroxylase deficiency or ll-j3-hydroxylase deficiency). The ectopic adrenal tissue enlarges because of supranormal ACTH secretion (see previous section), secretes testosterone, and thereby induces other clinical features of androgen excess. Furthermore, this hyperplastic adrenal tissue cannot always be histologically distinguished from Leydig cell neoplasia. However, the presence of congenital adrenal hyperplasia can be readily revealed by demonstrating elevated circulating concentrations of the specific steroid precursors (17-hydroxyprogesterone or ll-deoxycortisol). If doubt still remains, exogenous glucocorticoids can be administered to determine if the excessive androgen production is suppressible. 4• 38 Surgical removal is the indicated treatment for Leydig cell tumors. Once the tumor is removed, circulating androgen concentrations rapidly revert to normal unless metastases are present. Malignancy of Leydig cell tumors is rare in adults and has not been observed in children. Therefore, the prognosis for surgical cure is excellent. 24 Granulosa Cell Tumor. About 5 per cent of all granulosa cell tumors present in childhood. These tumors of the ovarian stroma secrete estrogen; hence, affected girls develop precocious puberty. Pubic hair growth may accompany the estrogen-induced breast development when an androgen, such as androstenedione, also is secreted. The typical granulosa cell tumor is a large ovarian mass with both cystic and solid components. Because of their relatively large size, the vast majority of these tumors are palpable at

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the time of the initial evaluation of precocious puberty. In doubtful cases, a pelvic ultrasound will reveal the tumor. The diagnosis of granulosa cell tumor should be considered in girls with precocious puberty accompanied by increased estrogen secretion and suppressed pituitary gonadotrophin secretion. Once identified, the tumor should be removed surgically. Recurrence of the tumor or metastatic disease is rare in children.31, 34 Gonadoblastoma. Gonadoblastomas are tumors that almost exclusively arise in dysgenetic gonads containing Y chromosome-bearing cells and typically containing both germ cell and stromal elements. The stromal elements of the tumors may secrete androgens ;md thereby cause progressive virilization. Individuals with an XO/XY mosaic chromosomal constitution are at high risk (25 per cent) for developing gonadoblastoma. 25 The XO/XY karyotype can be found in patients with ambiguous external genitalia (see previous section) or in girls with phenotypic Turner's syndrome. The incidence of gonadoblastoma rises sharply at the time of puberty in these patients, and therefore, prophylactic removal of dysgenetic gonads should be considered as the child approaches the pubertal age. The likelihood of surgical cure of gonadoblastoma is excellent. However, occasionally more malignant germ cell tumors (for example, choriocarcinoma) are found within the gonadoblastoma, making the prognosis less favorable. 31· 34

THE PANCREAS Endocrine disorders of the pancreas requiring direct surgical intervention are, for practical purposes, restricted to hyperinsulinemia, causing severe recurrent hypoglycemia. 2, s, 27, 33 The majority of children with hyperinsulinemic states present in infancy. These infants are typically macrosomic in the absence of a history or laboratory evidence of maternal diabetes during pregnancy. 2 Symptoms of hypoglycemia may be present from the initial hours of life and include jitteriness, myoclonic jerks, cyanotic episodes, apnea, and seizures. In neonates, the diagnosis can be strongly suspected from the clinical inspection and documentation of hypoglycemia, defined as a whole blood glucose less than 40 mg per dl in a term neonate or less than 30 mg per dl in a preterm infant. The critical step is demonstration of concomitant hyperinsulinemia and hypoglycemia in a serum sample. Insulin levels should be less than 10 f-LU per ml when blood glucose is less than 30 mg per dl; insulin levels of 10 to 15 f-LU per ml are highly suspect, whereas levels greater than 20 f-LU per ml with concurrent hypoglycemia are diagnostic of nesidioblastosis or islet cell adenoma. Insulin levels greater than 100 f-LU per ml are more common with islet cell adenoma. However, the precise diagnosis can only be established by histopathologic examination of removed pancreas. While awaiting the result --,f the insulin measurement, the infant should be treated with intravenous glucose at rates up to 20 mg per kg per min, preferably via a central line. If, after 24 hours of this therapy, hypoglycemia persists and hyperinsulinemia is suspected on clinical grounds,

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diazoxide, 10 to 20 mg per kg per day orally in three divided doses, should be begun and intravenous glucose continued. 2 Diazoxide may require 3 days to exert its maximal effect. If hypoglycemia remains after an adequate trial of diazoxide administration, corticosteroid therapy (hydrocortisone, 5 mg per kg per day, or prednisone, 1 to 2 mg per kg per day) should be added to the treatment regimen (Table 5). Once the diagnosis is confirmed by the insulin determination, surgery is indicated unless diazoxide alone can maintain euglycemia with oral feedings only. 27 1n general, persistence or recurrence of hypoglycemia after 5 or so days of diazoxide therapy is an indication for surgery. If a distinct adenoma is identified, it should be removed. Otherwise, near-total pancreatectomy (90 per cent) is indicated in order to avoid the long-term neurologic sequelae of recurrent, severe hypoglycemia in the neonate. 27 In general, the more resistant the hypoglycemia is to medical management and the higher the insulin level, the earlier is surgery indicated. Before surgery, an ultrasound and abdominal CT scan may identify a large adenoma; celiac angiography is not indicated because it has only limited success in infants in whom tumor nodules may be obscured by the normal rich vascularity of the pancreas. Glucose infusion should be continued during surgery and blood glucose levels monitored closely both intraoperatively and postoperatively in order to avoid rebound hyperglycemia when excessive insulin secretion is curtailed. Should hypoglycemia persist postoperatively, frequent feedings, including nasogastric feedings during the night, and diazoxide, 10 to 20 mg per kg per day orally in three divided doses, should be instituted and maintained until the infant can sustain overnight fasting without hypoglycemic symptoms. Side effects of diazoxide include hirsutism, hyperuricemia, edema, electrolyte disturbances, and hypertension; these are doserelated and resolve on discontinuation of the drug. The second common age period for presentation of hyperinsulinemia in children is 3 to 6 months, when feeding intervals are progressively lengthened, thereby unmasking the restraining influence of insulin on hepatic glucose output. Nocturnal seizures are the most common presentation. Symptoms can usually be provoked by several hours (6 to 18) of fasting. When symptoms are provoked, blood is drawn for glucose and insulin determinations and glucagon (30 f.Lg per kg intramuscularly or intravenously) is given; glucose and insulin are measured again 30 minutes later. Concomitant hyperinsulinemia and hypoglycemia in the fasting state

Table 5.

Sequential Therapeutic Strategy in Persistent Neonatal Hypoglycemia*

Day 1 Days 2 through 3 add Days 5 through 7 add

Intravenous glucose 5-20 mg/kg/min and/or frequent feedings Diazoxide 10--25 mg/kg/day by mouth in divided doses three times a day Hydrocortisone 5 mg/kg/day, or prednisone, 1-2 mg/kg/day

*If hypoglycemia persists and hyperinsulinemia has been confirmed, pancreatectomy sl.ould be undertaken.

ENDOCRINE DISORDERS IN CHILDREN

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or a rise in glucose of greater than 40 mg per dl above baseline following glucagon are diagnostic of hyperinsulinemia. 8 A therapeutic trial of diazoxide and supplemental feedings may be attempted for 2 to 4 weeks, but failure to maintain euglycemia prompts the need for surgery. Because hyperinsulinemia is generally less severe in infants initially diagnosed at more than 3 months of age, partial pancreatectomy (70 to 80 per cent) usually suffices. Despite near-total or partial pancreatectomy, malabsorption or other manifestations of exocrine pancreatic dysfunction are uncommon. Although most cases of neonatal hyperinsulinemia (nesidioblastosis or islet cell hyperplasia) are sporadic, some cases appear to be familial and inherited in an autosomal dominant mode. 33 Caution is therefore advised with respect to genetic counseling. In children between the ages of 1 and 5 years, hyperinsulinemic states are distinctly rare; although hypoglycemia occurs, its more common causes are counterregulatory hormone deficiencies (cortisol, growth hormone), ketotic hypoglycemia, drugs, and inborn errors of glycogen metabolism or gluconeogenesis. All are characterized by insulin levels less than 10 J.LU per ml at the time of hypoglycemia as well as by the presence of ketones in blood and urine. Definitive management is medical rather than surgical in nature. After children are 5 years of age, insulinoma may again be a major cause of hypoglycemia. An abdominal CT scan and celiac angiography may be helpful in localizing a tumor before surgical extirpation. A family history of islet cell, parathyroid, or pituitary tumors (multiple endocrine adenomatosis type I) may be present, but the majority of cases are sporadic.

REFERENCES 1. Axelrod, L.: Glucocorticoid therapy. Medicine, 55:3~5, 1976. 2. Aynsley-Green, A., Polak, J. M., Bloom, S. R., eta!.: Nesidioblastosis of the pancreas: Definition of the syndrome and the management of the severe neonatal hyperinsulinemic hypoglycemia. Arch. Dis. Child., 56:496-508, 1981. 3. Bardin, C. W., and Paulsen, C. A.: The testes. In Williams, R. H. (ed.): Textbook of Endocrinology. Philadelphia, W. B. Saunders Company, 1981, pp. 293-354. 4. Bishop, P. M. F., Van Meurs, D.P., Willcox, D. R. C., et al.: Interstitial-cell tumour of the testis in a child. Br. Med. J., pp. 23~242, 1960. 5. Bongiovanni, A. M.: Disorders of the adrenal cortex. In Kaplan, S. A. (ed.): Clinical Pediatric and Adolescent Endocrinology. Philadelphia, W. B. Saunders Company, 1982, pp. 171-186. 6. Cooper, D. S.: Antithyroid drugs. N. Engl. J. Med., 311:1353-1362, 1984. 7. Daneman, A., Chan, H. S., and Martin, J.: Adrenal carcinoma and adenoma in children: A review of 17 patients. Pediatr. Radio!., 13:11-18, 1983. 8. Finegold, D. M., Stanley, C. A., and Baker, L.: Glycemic response to glucagon during fasting hypoglycemia: An aid in the diagnosis ofhyperinsulinemia. J. Pediatr., 96:257259, 1980. 9. Fisher, D. A.: Thyroid nodules in childhood and their management. J. Pediatr., 89:866868, 1976. 10. Foley, T. P., Jr.: Acute, subacute, and chronic thyroiditis. In Kaplan, S. A. (ed.): Clinical Pediatric and Adolescent Endocrinology. Philadelphia, W. B. Saunders Company, 1982, pp. 96-109. 11. Fonkalsrud, E. W., and Mengel, W. (eds.): The Undescended Testis. Chicago, Year Book Medical Publishers, 1981.

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12. Forest, M.G., David, M., Annick, L., eta!.: Kinetics of the HCG-induced steroidogenic response of the human testis. III. Studies in children of the plasma levels of testosterone and HCG: Rationale for the testicular stimulation test. Pediatr. Res., 14:819-824, 1980. 13. Geffner, M. E., and Lippe, B. M.: Genetic and endocrine syndromes associated with cryptorchidism. In Fonkalsrud, E. W., and Mengel, W. (eds): The Undescended Testis. Chicago, Year Book Medical Publishers, 1981, pp. 135-143. 14. Gold, E. M.: The Cushing ;mdrome: Changing views of diagnosis and treatment. Ann. Intern. Med., 90:829-844, 1979. 15. Griffin, J. E., and Wilson, J. D.: The syndromes of androgen resistance. N. Engl. J. Med., 302:198-208, 1980. 16. Gross, R. E., and Jewett, T. C., Jr.: Surgical experience from 1,222 operations for undescended testis. J. A. M. A., 160:634-641, 1956. 17. Grumbach, M. M., and Conte, F. A.: Disorders of sex differentiation. In Williams, R. H. (ed.): Textbook of Endocrinology. Philadelphia, W. B. Saunders Company, 1981, pp. 423-514. 18. Hamburger, J. I.: Management of hyperthyroidism in children and adolescents. J. Clin. Endocrinol. Metab., 60:1019-1024, 1985. 19. Haseltine, F. P., and Ohno, S.: Mechanisms of gonadal differentiation. Science, 211:1272-1277, 1981. 20. Hung, W., et al.: Solitary thyroid nodules in children and adolescents. J. Pediatr. Surg., 17:225-229, 1982. 21. Jennings, A. S., Liddle, G. W., and Orth, D. N.: Results of treating childhood Cushing's disease with pituitary irradiation. N. Engl. J. Med., 297:957-962, 1977. 22. Lee, W. P.: Thyroid physiology and thyroid function tests. In Kaplan, S. A. (ed.): Clinical Pediatric and Adolescent Endocrinology. Philadelphia, W. B. Saunders Company, 1982, pp. 69-81. 23. Lipschultz, L. I., Caminos-Torres, R., Greenspan, C. S., eta!.: Testicular function after orchiopexy for unilaterally undescended testis. N. Engl. J. Med., 295:15-18, 1976. 24. Lipsett, M. B.: Functional tumors of the testis. In DeGroot, L. J., Cahill, G. F., Jr., Odell, W. D., eta!. (eds.): Endocrinology. New York, Grune and Stratton, 1979, pp. 1573-1576. 25. Manuel, M., Katayama, K. P., and Jones, H. W.: The age of occurrence of gonadal tumors in intersex patients with a Y chromosome. Am. J. Obstet. Gynecol., 124:293299, 1976. 26. McArthur, R. G., Hayles, A. B., and Salassa, R. M.: Childhood Cushing disease: Results of bilateral adrenalectomy. J. Pediatr., 95:214-219, 1979. 27. Moazam, F., Rodgers, B. M., Talbert, J. L., et al.: Near-total pancreatectomy in persistent infantile hypoglycemia. Arch. Surg., 117:1151-1154, 1982. 28. Parks, J. S.: Intersex. In Kaplan, S. A. (ed.): Clinical Pediatric and Adolescent Endocrinology. Philadelphia. W. B. Saunders Company, 1982, pp. 327-345. 29. Penny, R.: Disorders of the testes. In Kaplan, S. A. (ed.): Clinical Pediatric and Adolescent Endocrinology. Philadelphia, W. B. Saunders Company, 1982, pp. 300--326. 30. Reiter, E. 0., et a!.: Childhood thyromegaly: Recent developments. J. Pediatr., 99:507518, 1981. 31. Ross, G. T., Vande Wiele, R. L., and Frantz, A. G.: The ovaries and the breasts. In Williams, R. H. (ed.): Textbook of Endocrinology. Philadelphia, W. B. Saunders Company, 1981, pp. 355-422. 32. Saenger, P.: Abnormal sex differentiation. J. Pediatr., 104:1-17, 1984. 33. Schwartz, S. S., Rich, B. H., Lucky, A. W., et al.: Familial nesidioblastosis: Severe neonatal hypoglycemia in two families. J. Pediatr., 95:44-53, 1979. 34. Scully, R. E.: Ovarian tumors with endocrine manifestations. In DeGroot, L. J., Cahill, G. F., Jr., Odell, W. D., et al. (eds.): Endocrinology. New York, Grune and Stratton, 1979, pp. 1473-1488. 35. Streeten, D. H. P., Fass, F. H., Elders, M. T., et a!.: Hypercortisolism in childhood: Shortcomings of conventional diagnostic criteria. Pediatrics, 56:797-803, 1975. 36. Styne, D. M., Grumbach, M., Kaplan, S. L., et al.: Treatment of Cushing's disease in childhood and adolescence by transsphenoidal microadenomectomy. N. Engl. J. Med., 310:889-893, 1984.

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37. Tsang, R. C., and Venkataraman, P.: Pediatric parathyroid and vitamin D-related problems. In Kaplan, S. A. (ed): Clinical Pediatric and Adolescent Endocrinology. Philadelphia, W. B. Saunders Company, 1982, pp. 34~65. 38. Urban, M. D., Lee, P. A., and Plotnick, L. P.: The diagnosis of Leydig cell tumors in childhood. Am. J. Dis. Child., 132:494-497, 1978. 39. Utiger, R. D.: Treatment of Graves' disease. N. Engl. J. Med., 298:681-682, 1978. 40. Vane, D., King, D. R., and Boles, E. T., Jr.: Secondary thyroid neoplasms in pediatric cancer patients: Increased risk with improved survival. J. Pediatr. Surg., 19:855-859, 1984. 41. Werner, S. C.: Medical (suppressive) versus surgical therapy of the thyroid nodule. In Werner, S. C., and lngbar, S. H. (eds.): The Thyroid. New York, Harper and Row, 1978, pp. 576--.'583. Division of Pediatric Endocrinology Children's Hospital Medical Center Cincinnati, Ohio 45229