Long-term effect of gonadotropin-releasing hormone agonist therapy on final and near-final height in 26 children with true precocious puberty treated at a median age of less than 5 years.

We report a long term study on the effectiveness of chronic GnRH agonist treatment on final or near-final height in 26 patients (20 females and six males) with true precocious puberty (TPP). This study differs from other treatment studies in that the median age at onset of therapy was 4.7 yr for females and 6.2 yr for males, the youngest cohort of treated patients reported to date. We compared patients treated with GnRH agonists who attained final or near-final height with a historical control group of untreated children with TPP (n = 116) matched for mean age of pubertal onset, etiology of TPP (idiopathic or neurogenic), rate of progression, and sex ratio. The current mean height of GnRH agonist-treated females who began therapy at more than 5 yr of age (157.6 +/- 6.6 cm) is already significantly greater than the mean final height of untreated females (152.7 +/- 8.6 cm). The current mean predicted height of the treated females is 164.6 +/- 9.7 cm. The current mean height of females whose treatment was started before 5 yr of age is greater (164.1 +/- 7.7 cm) than that of females whose treatment began after 5 yr of age (157.6 +/- 6.6 cm). The final height of untreated children whose age of sexual precocity was less than 5 yr at diagnosis is significantly less than that of treated patients who were less than 5 yr when they developed TPP (P = 0.0006). The current mean height of GnRH agonist-treated males is 166.3 +/- 12.2 cm, and the current mean predicted height is 170.8 +/- 11.3 cm. This is in sharp contrast to the mean final height of untreated males (155.6 +/- 7.7 cm). The current predicted height correlates negatively with the age at initiation of treatment and the initial bone age and positively with height SD for bone age in the agonist-treated children. The current mean height deviation from target height is significantly less in the 20 treated females (-1 SD) than in 93 untreated females (-2.4 SD; P = 0.006). The mean final height deviation from target height in 23 untreated males (-3.7 SD) is significantly greater than the current height deviation from target height in 6 treated males (-1.7 SD; P = 0.03). The salutary effects of long term GnRH agonist therapy on stature are more clear-cut in the younger treated children. Young untreated children may have the worst outcome with respect to final height.(ABSTRACT TRUNCATED AT 400 WORDS)

A diphasic pattern of gonadotropin secretion in patients with the syndrome of gonadal dysgenesis.

Cross sectional and longitudinal studies of plasma FSH and LH in 58 patients, age 2 days of 20 yr, with the syndrome of gonadal dysgenesis show a diphasic pattern of gonadotropin secretion. The mean basal plasma FSH level is 43 plus or minus 7 (SE) ng/ml (LER-869) in patients from 2 days to 4 yr, which is strikingly elevated. Thereafter, a decline in plasma FSH to a mean level of 4 plus or minus 0.7 (SE) ng/ml occurs between 4 and 10 yr, followed by a rise after 10 yr to 61 plus or minus 4 (SE) ng/ml. The pattern of LH (LER-960) secretion is qualitatively similar to that of FSH, although quantitatively the values for LH are 1/3 to 1/10 those for FSH. The similarity of pattern of gonadotropin secretion observed between patients with gonadal dysgenesis and normal children suggests that gonadal function does not play a decisive role in the pattern of gonadotropin secretion from infancy through adolescence, but exercises striking effects on the quantity of gonadotropin secreted.

The response of pituitary gonadotropes to synthetic LRF in children with glucocorticoid-treated congenital adrenal hyperplasia: lack of effect of intrauterine and neonatal androgen excess.

Previous studies have demonstrated that the secretory reserve of the pituitary gland during childhood and adolescence is characterized by an age-related increase in LH secretion and a sex dichotomy of FSH secretion evoked by LRF. To determine if prenatal and neonatal androgen excess alters hypothalamic-pituitary-gonadal function, as in the neonatally androgenized rodent, we assessed pituitary sensitivity to 100 mug synthetic LRF in 9 girls and 2 boys with glucorticoid-treated congenital virilizing adrenal hyperplasia (CAH). In the 7 prepubertal girls with CAH, plasma LH following LRF rose to 2.0 plus or minus 0.4 (SE) ng/ml (LER 960) and did not differ from normal prepubertal children (1.7 plus or minus 0.1) and was lower (P less than 0.002) than in normal pubertal children (4.9 plus or minus 0.3). The 2 pubertal girls had LH rises in the pubertal range. In the 2 boys with CAH, the one with the more advanced bone age, 11-6/12 yr, developed true precocious puberty following initiation of cortisone treatment and had a pubertal LRF-evoked LH release on 3 occasions; the more immature boy, bone age 10, had a prepubertal LH rise. In the 7 prepubertal girls with CAH, plasma FSH rose to 8.1 plus or minus 1.6 (SE) ng/ml (LER 869), which did not differ from normal prepubertal girls (5.3 plus or minus 1.9), but was significantly (P less than 0.001) greater than in normal prepubertal boys (2.9 plus or minus 0.4). In these girls with CAH, basal plasma T (27.4 plus or minus 4.0 (SE) ng/dl) and 17-OHP (2703 plus or minus 1143 (SE) ng/dl) were greater than in prepubertal children, but plasma E1 and E2 were in the normal range. The pubertal boy had plasma T, E1, and E2 levels appropriate for his degree of sexual maturation. The results suggest: (1) age-related LH secretion evoked by LRF in glucocorticoid-treated CAH is appropriate for skeletal maturation; (2) the sex dichotomy of FSH secretion following LRF is preserved in CAH despite intrauterine and variable postnatal exposure to excess androgen and continuing slightly elevated plasma T during childhood; and (3) precocious puberty may follow initiation of cortisone treatment in a child with CAH whose bone age and secretory reserve of pituitary gonadotropins are in the pubertal range.

Hormonal and metabolic abnormalities associated with central nervous system germinoma in children and adolescents and the effect of therapy: report of 10 patients.

We describe the results of clinical and endocrinological investigations performed on 10 children and adolescents (5 males and 5 females) with a primary central nervous system germinoma. Eight of 10 patients were between 10-20 yr of age at the time of initial presentation. Polyuria (7 of 10) and a decrease in or cessation of linear growth (5 of 10) were the most common presenting symptoms, while only 2 of 10 patients complained of visual problems. Two patients presented with the syndrome of polyuria, adipsia, hypernatremia, profound muscle weakness, and hyperlipidemia. Initial physical exam revealed abnormal eye findings in 60%, short stature (greater than or equal to 2.5 SD) in 50%, and abnormal pubertal development in 30% of the patients. The neoplasm was located in the suprasellar-hypothalamic region in 8, caudate nucleus in 1, and pineal region in 1. Biopsy performed in 7 patients revealed the classic two-cell germinoma in all cases. Assessment of endocrine function before radiotherapy documented pituitary deficits in all patients studied. Antidiuretic hormone was deficient in 8 of 10 patients and was associated with hypoadipsia in 4. GH was deficient in al patients tested (7 of 7). TSH (5 of 8), ACTH (3 of 7), and gonadotropin (1 of 1) deficiencies were also common before treatment. Plasma PRL concentrations were elevated in 5 of 8 patients, all with suprasellar tumors. The hCG values were elevated only in the patient with sexual precocity (1 of 10). Endocrine evaluation during the postirradiation period revealed additional instances of GH (1), ACTH (1), and gonadotropin (5) deficiencies. All 10 patients are alive without evidence of active disease 6 months to 10 yr after radiation therapy (4500-5100 R). Evidence of hypothalamic-pituitary dysfunction is an early and almost universal feature of central nervous system germ cell tumors. The importance of careful evaluation and follow-up of children with acquired anterior or combined anterior and posterior pituitary dysfunction for a suprasellar tumor is stressed.

The pubertal growth spurt in eight patients with true precocious puberty and growth hormone deficiency: evidence for a direct role of sex steroids.

The relative contributions of GH, insulin-like growth factor-I (IGF-I), estradiol, and testosterone to the pubertal growth spurt are incompletely understood. We studied 8 patients (5 girls and 3 boys) with true precocious puberty and GH deficiency due to CNS lesions to assess the role of sex steroids in pubertal growth independent of an increase in circulating GH. Included is 1 patient with an unusual hypothalamic lesion due to head trauma. A control group of 17 GH-sufficient patients with true precocious puberty (13 girls and 4 boys) was matched for chronological age. The GH-deficient girls grew at a mean velocity of 9.2 cm/yr (range, 7.2-14.4), and the boy's mean height velocity was 7.9 cm/yr (6.1-9.9). Mean bone age was advanced in the GH-deficient group (girls, +2.7 SD; boys, +2.6 SD), but not as much as the GH-sufficient controls (girls, +5.4 SD; boys, +4.3 SD). The mean concentration of plasma IGF-I was lower in the GH-deficient group than in the control group, but was greater than the mean concentration in age-matched prepubertal GH-deficient patients. Four GH-deficient patients were treated with a potent agonist of LRF. This caused suppression of gonadal sex steroid concentrations and a fall in mean height velocity from 9.1 to 4.3 cm/yr after 1 yr of therapy; however, circulating GH and IGF-I values were not uniformly altered. We conclude that a substantial pubertal growth spurt can occur in patients with true precocious puberty and GH deficiency that is dependent on gonadal sex steroids yet unaccompanied by normal pubertal levels of circulating GH or IGF-I. Reversal of this growth acceleration is possible with sex steroid suppression. The results, in light of previous in vivo and in vitro studies, suggest that the normal pubertal growth spurt is mediated in part by direct effects of sex steroids at the growth plate.

The effect of long acting glucocorticoids on menstrual abnormalities in patients with virilizing congenital adrenal hyperplasia.

Amenorrhea or oligomenorrhea occurs in more than 25% of young women with virilizing congenital adrenal hyperplasia due to 21-hydroxylase deficiency who are treated with conventional glucocorticoid therapy. In four such patients, we studied the variation in plasma concentration of ACTH, 17-hydroxyprogesterone (17-OHP), estradiol (E2), estrone, testosterone (T), dehydroepiandrosterone and its sulfate, androstenedione, and progesterone before and at frequent intervals after the administration of the patients' usual dose of oral glucocorticoids. We found that plasma ACTH, 17-OHP, and T were usually increased above the normal range early in the morning before the first daily dose of medication; plasma dehydroepiandrosterone and its sulfate were decreased below the normal range for the patient's pubertal stage; and androstenedione, estrone, and E2 were within the normal range. Two of the four patients had low basal plasma LH and impaired LH response to LRF. Administration of a long acting glucocorticoid (dexamethasone) to three patients, and methylprednisolone to one, resulted in continuous suppression of T into the normal range in all patients, in spite of continued abnormally increased concentration of ACTH and 17-OHP in two patients. In three patients, E2 concentrations were increased when a long acting glucocorticoid was given. In all four patients, menses began or became more regular during treatment with the long acting glucocorticoid. We conclude that a long acting glucocorticoid is useful in the management of menstrual abnormalities in adolescent patients with congenital adrenal hyperplasia who have attained their adult height, and that monitoring the concentration of serum T in them is a valuable but not infallible procedure for assessing the effectiveness of therapy.

A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom).

We report the features of a new syndrome of aromatase deficiency due to molecular defects in the CYP19 (P450arom) gene in a 46,XX female. At birth, the patient presented with a nonadrenal form of female pseudohermaphrodism. At 17 months of age, laparotomy revealed normal female internal genital structures; the histological appearance of the ovaries was normal. FSH concentrations were markedly elevated at 9.4 ng/mL LER 869, and estrone and estradiol levels were undetectable (< 37 pmol/L). By 14 yr of age, she had failed to exhibit breast development. The clitoris had enlarged to 4 x 2 cm, and pubic hair was Tanner stage IV. The plasma concentration of testosterone was elevated at 3294 pmol/L, as was androstenedione at 9951 pmol/L. Plasma estradiol levels were below 37 pmol/L. ACTH and dexamethasone tests indicated a nonadrenal source of testosterone and androstenedione. Plasma gonadotropin levels were in the castrate range. Pelvic sonography and magnetic resonance imaging showed multiple 4- to 6-cm ovarian cysts bilaterally. Despite increased circulating androgens and clitoral growth, the bone age was 10 yr at chronologic age 14 2/12 yr. Estrogen replacement therapy resulted in a growth spurt, breast development, menarche, suppression of gonadotropin levels, and resolution of the cysts. The clinical findings suggested the diagnosis of P450arom deficiency. Analyses of genomic DNA from ovarian fibroblasts demonstrated two single base changes in the coding region of the P450arom gene, one at 1303 basepairs (C-T), R435C, and the other at 1310 basepairs (G-A), C437Y, in exon 10. The molecular genetic studies indicate that the patient is a compound heterozygote for these mutations. Expression of these mutations showed that the R435C mutation had 1.1% the activity of the wild-type P450arom enzyme, whereas the C437Y mutation demonstrated no activity. The cardinal features of this syndrome are a consequence of P450arom deficiency: 1) the fetal masculinization in this syndrome can be ascribed to defective placental conversion of C19 steroids to estrogens, leading to exposure of the female fetus to excessive amounts of testosterone; 2) the pubertal failure, mild virilization, multicystic ovaries, and hyperstimulation of the ovaries by FSH and LH are the result of the inability of the ovary to aromatize testosterone and androstenedione to estrogens; and 3) the striking delay in bone age at 14 2/12 yr supports the notion that estrogens, in contrast to androgens, are the major sex steroid driving skeletal maturation during puberty. Familial P450arom deficiency, although rare, may be more common than previously suspected.(ABSTRACT TRUNCATED AT 400 WORDS)

Somatomedin-C levels in children and adolescents with gonadal dysgenesis: differences from age-matched normal females and effect of chronic estrogen replacement therapy.

The factors responsible for the elevation of circulating somatomedin-C/insulin-like growth factor I (Sm-C) during normal pubertal development are uncertain. To assess the role of ovarian estrogen secretion during puberty, we examined the effect of estrogen deficiency due to primary hypogonadism on Sm-C levels in late childhood and early adolescence. The concentration of immunoreactive Sm-C was measured in 36 untreated patients with gonadal dysgenesis (age, 4-16 yr); results were compared with the pattern of change in Sm-C in 153 age-matched normal girls. Between ages 4-9 yr, patients with gonadal dysgenesis had Sm-C levels similar to those in the age-matched normal subjects. In contrast to the normal girls, Sm-C levels in patients with gonadal dysgenesis did not rise after 10 yr of age and were significantly lower than those in normal girls at 11-16 yr of age. The effect of low dose estrogen therapy was assessed in eight patients with Turner's syndrome. Their Sm-C levels were measured before and during 2-12 months of treatment with ethinyl estradiol (90-220 ng/kg X day). The mean Sm-C concentration rose from 0.72 +/- 0.06 U/ml (+/- SEM) before treatment to 1.17 +/- 0.17 U/ml during estrogen treatment (P less than 0.04). In three patients who had a similar increase in Sm-C during estrogen treatment, interruption of therapy was associated with a fall in Sm-C concentrations; when estrogen therapy was reinstituted in two of these patients, Sm-C levels rose again. These results suggest that increasing endogenous estrogen production is a major determinant of the rise of circulating Sm-C that occurs during pubertal development in normal girls. Chronic estrogen deficiency, as in untreated patients with gonadal dysgenesis, is associated with failure to manifest the elevation of Sm-C that occurs during normal puberty.

Endocrine, histological, and biochemical studies of adrenocorticotropin-producing islet cell carcinoma of the pancreas in childhood with characterization of proopiomelanocortin.

Two 8-yr-old children, a boy and girl, are described with Cushing's syndrome secondary to ectopic ACTH-secreting pancreatic islet cell carcinomas. The girl, seen 28 yr ago, had strong presumptive evidence of ectopic ACTH production and hypercalcemia. The boy, studied recently, had strikingly elevated concentrations of plasma ACTH (1,500 pg/ml) and beta-lipotropin (beta LPH; 2,500 pg/ml) and showed no suppression of urinary 17-hydroxycorticoids or cortisol with low and high dose dexamethasone. He had increased plasma calcitonin (257 pg/ml), glucagon (442 pg/ml), lactate dehydrogenase (497 IU/liter), and alpha-fetoprotein (5,144 pg/ml). He also had hypokalemic alkalosis with elevated plasma deoxycorticosterone (70 ng/ml) and PRA (6.9 ng/ml.h) but normal plasma aldosterone (8.2 ng/dl) and 18-hydroxycorticosterone (7.6 ng/dl). Preoperative localization of the tumor was accomplished by computed tomographic scan of the abdomen with concurrent barium enema. Cell-free translation of the tumor mRNA produced authentic proopiomelanocortin of 35,000 mol wt, indicating that the ACTH and beta LPH were produced by the tumor from a common precursor. After removal of a large amount of metastatic tissue from the boy, clinical progression of the remaining tumor was monitored by measuring plasma ACTH and beta LPH. Episodic secretion of ACTH and beta LPH was demonstrated by taking frequent plasma samples while suppressing pituitary ACTH with oral dexamethasone. Chemotherapy and radiation proved ineffective in controlling the growth of his tumor.

Long-term outcome in children and adolescents after transsphenoidal surgery for Cushing's disease.

Cushing's disease refers specifically to an ACTH-producing pituitary adenoma that stimulates excess cortisol production. Transsphenoidal surgery is the treatment of choice in children and adolescents, but disparate cure rates have been reported, ranging from 50-98%. The discrepancies in cure rate are due primarily to the technical success of the surgery and the length and method of follow-up. We studied 42 consecutive children and adolescents (age, < or = 18 yr) who underwent transsphenoidal exploration for the primary treatment of Cushing's disease at University of California-San Francisco from 1974-1993. Only 7 patients had persistent disease, defined as evidence of Cushing's disease within 6 months of surgery, yielding an initial remission rate of 83%. We comprehensively evaluated 26 of the 35 patients who experienced an initial remission, including testing of the ACTH-adrenocortical axis. The mean duration of follow-up is 7.2 yr (range, 1.5-13.6 yr). Seven experienced a relapse of Cushing's disease, yielding a net remission rate of 73%. Relapses occurred an average of 4.2 yr postoperatively (range, 0.75-6.2 yr). Five patients experienced relapse within 5 yr of surgery, whereas 2 relapsed more than 5 yr postoperatively. Repeat transsphenoidal surgery was performed in 8 patients with persistent or recurrent disease, and 6 of these remain in remission. Low serum or urinary cortisol measurements within the first post-operative week predicted remission of Cushing's disease, but were not necessarily predictive of long-term cure. Hypercortisolism had significant effects on bone metabolism, as reflected by both diminished bone density in the majority of patients examined and decreased growth rate. Both parameters improved after surgical care, although they did not fully normalize. We conclude that transsphenoidal surgery is a safe and effective treatment for pediatric Cushing's disease, but long-term surveillance is necessary to detect possible recurrences.

Normal female infants born of mothers with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, especially those patients with the salt-losing form, have decreased fertility rates. Pregnancy experience in this population is limited. We report the pregnancy outcomes and serial measurements of maternal serum steroid levels in four women with classic 21-hydroxylase deficiency, three of whom were female pseudohermaphrodites with the salt-losing form. These glucocorticoid-treated women gave birth to four healthy female newborns with normal female external genitalia, none of whom were affected with 21-hydroxylase deficiency. In three women, circulating androgen levels increased during gestation, but remained within the normal range for pregnancy during glucocorticoid therapy. In the fourth patient, androgen levels were strikingly elevated during gestation despite increasing the dose of oral prednisone from 5 to 15 mg/day (two divided doses). Notwithstanding the high maternal serum concentration of androgens, however, placental aromatase activity was sufficient to prevent masculinization of the external genitalia of the female fetus and quite likely the fetal brain, consistent with the idea that placental aromatization of androgens to estrogens is the principal mechanism that protects the female fetus from the masculinizing effects of maternal hyperandrogenism. These four patients highlight key issues in the management of pregnancy in women with 21-hydroxylase deficiency, particularly the use of endocrine monitoring to assess adrenal androgen suppression in the mother, especially when the fetus is female. Recommendations for the management of pregnancy and delivery in these patients are discussed.

Idiopathic hypothalamic diabetes insipidus, pituitary stalk thickening, and the occult intracranial germinoma in children and adolescents.

We report nine consecutive children and adolescents [five females and four males; aged 2 yr 8 months (m) to 18 yr 1 m] studied over the last 5 yr with idiopathic central diabetes insipidus. In addition to vasopressin deficiency, anterior pituitary hormone deficiencies were detected, either on evaluation at presentation or during follow-up studies over the following 3 yr. Four patients had an increased concentration of plasma PRL. One patient had multiple pituitary hormone deficiencies at diagnosis, and two others developed the same by 21 m of follow-up. Brain magnestic resonance imaging scans, performed at presentation, were originally interpreted as normal in four of nine patients, except for absence of the bright posterior pituitary signal; after retrospective review, two of nine were considered normal. All of the brain magnetic resonance imaging (MRI) scans showed positive findings by 14 m of follow-up. The first abnormal finding in all patients was isolated pituitary stalk thickening. Evaluation of cerebrospinal fluid (CSF) for hCG was positive in three of eight evaluated patients; the three positive CSF values were found at presentation and 3 and 9 m after presentation. All eight patients assessed were negative for CSF alpha-fetoprotein and cytology, and no patient had serum tumor markers. Transsphenoidal biopsy of the lesion in seven of nine patients showed a germinoma in six patients and inflammatory cells in one. The six patients with documented germinoma comprise 31% of the intracranial germinomas diagnosed in this age group at the University of California-San Francisco during the last 5 yr. The patient with mononuclear inflammatory cells on biopsy along with one other patient have had spontaneous resolution of their stalk thickening. So-called "idiopathic" central diabetes insipidus warrants close follow-up to determine the etiology, especially if anterior pituitary hormone deficiencies are detected. Normal brain MRI scans or scans that show isolated pituitary stalk thickening merit follow-up with serial contrast enhanced brain MRI for the early detection of an evolving occult hypothalamic-stalk lesion. CSF evaluation is recommended at presentation because elevated CSF hCG may precede MRI abnormalities.

Treatment of true precocious puberty with a potent luteinizing hormone-releasing factor agonist: effect on growth, sexual maturation, pelvic sonography, and the hypothalamic-pituitary-gonadal axis.

We used the LHRH agonist D-Trp6-Pro6-N-ethylamide LHRH (LHRH-A) to treat 19 children (12 girls and 7 boys) with true precocious puberty. Fourteen patients had idiopathic true precocious puberty, 4 had a hamartoma of the tuber cinereum, and 1 had a hypothalamic astrocytoma. Basal gonadotropin secretion and responses to native LHRH decreased within 1 week of initiation LHRH-A therapy, and sex steroid secretion decreased within 2 weeks to or within the prepubertal range. Ultrasonographic evaluation of the uterus indicated a postmenarchal size and shape in all 11 girls studied before treatment, which reverted to prepubertal size and configuration in 5 girls during LHRH-A therapy. The enlarged ovaries decreased in size and the multiple ovarian follicular cysts regressed. Sexual characteristics ceased advancing or reverted toward the prepubertal state in all patients receiving therapy for 6-36 months. All 5 girls with menarche before therapy had no further menses. Three girls had hot flashes after LHRH-A-induced reduction of the plasma estradiol concentration. Height velocity, SDs above the mean height velocity for age, and SDs above the mean height for age decreased during LHRH-A therapy; the velocity of skeletal maturation decreased after 12 months of LHRH-A therapy and was sustained during continued therapy over 18-36 months. In 4 patients, a subnormal growth rate (less than 4.5 cm/yr) occurred during LHRH-A therapy. Six patients had cutaneous reactions of LHRH-A, but no demonstrable circulating antibodies to LHRH-A. In 2 patients in whom LHRH-A therapy was discontinued because of skin reactions, precocious sexual maturation resumed at the previous rate for the ensuing 6-12 months; subsequently, they were desensitized to LHRH-A, and during a second course of therapy, their secondary sexual development and sex steroid levels again quickly decreased. LHRH-A proved an effective and safe treatment for true precocious puberty in boys as well as girls with central precocious puberty whether of the idiopathic type or secondary to a hamartoma of the tuber cinereum or a hypothalamic neoplasm.

Prevention of motion artifacts on dual isotope subtraction parathyroid scintigraphy.

A simple, effective technique is described to identify and eliminate motion artifacts which might potentially invalidate dual isotope subtraction parathyroid scintigraphy. Cobalt-57 markers, appropriately placed on the patient, allow detection of movement and permit realignment if movement occurs between imaging sequences. This technique should assure the accuracy of dual isotope parathyroid subtraction scintigraphy.

Sudden death in septo-optic dysplasia. Report of 5 cases.

OBJECTIVES: To report our experience with sudden death in children with septo-optic dysplasia and to identify specific risk factors and suggest preventive measures to minimize mortality. METHODS: Clinical data from 5 children with septo-optic dysplasia who died suddenly and unexpectedly were evaluated retrospectively. RESULTS: All children had corticotropin deficiency, all had thermoregulatory disturbances, and 4 children had diabetes insipidus. In at least 4 children, clinical deterioration was caused by fever and dehydration from a presumed viral illness, which appeared to precipitate adrenal crisis. CONCLUSIONS: Children with septo-optic dysplasia and hypocortisolism are at risk for sudden death during febrile illness. Thermoregulatory disturbances and dehydration from diabetes insipidus may potentiate clinical deterioration. Prevention of sudden death in septo-optic dysplasia requires early recognition and treatment of these major risk factors.

Medullary thyroid carcinoma. The need for early diagnosis and total thyroidectomy.

Forty patients with medullary thyroid carcinoma and 3 patients with C-cell hyperplasia were studied. Seventeen (40%) cases were sporadic and 26 (60%) were hereditary. Eight patients had type lla multiple endocrine neoplasia, 7 patients had type llb multiple endocrine neoplasia, and 11 patients had familial nonmultiple endocrine neoplasia medullary thyroid carcinoma. Mean follow-up was 6.3 years, with actuarial survival of 88% and 78% at 5 and 10 years (22 and 13 patients), respectively. Seven patients died 1.5 to 10 years after the initial operation; all had advanced disease at presentation (6 with distant, 1 with lymph node metastasis). No deaths occurred in patients with familial nonmultiple endocrine neoplasia medullary thyroid carcinoma, C-cell hyperplasia, or medullary thyroid carcinoma limited to the thyroid gland. Nineteen (68%) of 28 patients diagnosed without screening had regional or distant metastases, whereas only 6 (40%) of 15 patients diagnosed by screening had metastases. Twenty-six patients treated initially with total thyroidectomy and central neck clearance required an average of one reoperation, whereas those with lesser initial procedures required an average of two reoperations. We concluded that (1) familial nonmultiple endocrine neoplasia medullary thyroid carcinoma, early medullary thyroid carcinoma or C-cell hyperplasia, and asymptomatic patients have a good prognosis; (2) screening for medullary thyroid carcinoma by measuring serum calcitonin levels results in earlier diagnosis; and (3) total thyroidectomy and central neck clearance is the procedure of choice for medullary thyroid carcinoma.

Superior vena cava syndrome and bilateral subclavian vein thrombosis. CT and radionuclide venography correlation.

Radionuclide venography (RNV) and CT with contrast infusion were performed in a patient with superior vena cava (SVC) syndrome and upper extremity swelling due to SVC and bilateral subclavian vein thrombosis resulting from infection of a Le Veen peritoneovenous shunt. Although CT was suggestive of thrombosis and excluded extrinsic compression by a mass, obstruction of the SVC and deliniation of collateral venous channels were best demonstrated by RNV.