Development of true precocious puberty following treatment of a Leydig cell tumor of the testis.

We report a prepubertal boy who developed true precocious puberty following unilateral orchidectomy for the treatment of a Leydig cell tumor.

Hypogonadism and CHARGE association.

The G of the CHARGE association represents genital hypoplasia, which is typically recognized only in males (micropenis/cryptorchidism). The cause of genital hypoplasia in this disorder has not been determined. We now report the cases of nine individuals with CHARGE association and hypogonadotropic hypogonadism, manifested by hypogenitalism and gonadotropins at or below minimal detectable levels at ages when these hormones should be readily measurable. We suggest that central hypogonadism is responsible not only for the genital hypoplasia in male patients but also for the lack of secondary sexual development in patients of both sexes. Since hypogonadotropic hypogonadism appears to be the usual cause of genital and pubertal abnormalities in CHARGE association, measurement of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations in infants up to 2-3 months of age who are suspected of having this disorder could help establish the diagnosis. Determination of serum LH and FSH concentrations in teenagers with CHARGE association could result in early diagnosis of hypogonadotropic hypogonadism, allowing for treatment of hormonal deficiencies and minimization of potential secondary psychosocial and medical problems.

The 3C syndrome: evolution of the phenotype and growth hormone deficiency.

The 3C syndrome (cranio-cerebello-cardiac dysplasia or the Ritscher-Schinzel syndrome) is a recently delineated condition involving abnormalities of the cranium (large head with prominent forehead), cerebellum (Dandy-Walker cyst and vermis hypoplasia), and cardiac (primarily septal) defects. At least 20 individuals with this condition have been reported in the past 11 years. We report on a girl with the 3C syndrome who at 13 years of age is the oldest patient reported to date. She has been followed since birth, allowing us to show the evolution of her phenotype over time. In addition, she has documented growth hormone deficiency. We suggest that growth hormone deficiency should be considered as a possible cause of the short stature often seen in this condition.

Captopril reduces the proteinuric effect of human growth hormone in adriamycin nephrosis.

Developing male Sprague-Dawley rats (125 g) with adriamycin (doxorubicin hydrochloride) nephrosis (AN) were treated with growth hormone (GH) which may induce hyperfiltration potentiating glomerulosclerosis. Since captopril (CAP) reduces hyperfiltration, we studied its effects in GH-treated rats with AN. After 41, 76, and 90 days of therapy, urine protein excretion was significantly (P<0.05) reduced in GH-treated AN plus CAP compared with AN rats receiving GH alone. After 90 days, urine protein, creatinine ratio was significantly (P<0.05) increased in GH-treated AN (95.2+/-13.9) compared with untreated AN (64.8+/-7.8) and GH-treated AN rats plus CAP (41.8+/-8.8). The mean serum cholesterol level was significantly (P<0.05) reduced in GH-treated AN rats receiving CAP compared with AN rats receiving GH alone and untreated AN controls. Histologically tubular dilation was significantly (P<0.05) reduced in GH-treated AN rats plus CAP compared with AN rats receiving GH alone. Tubular atrophy and scarring were significantly (P<0.05) increased in AN rats treated with GH compared with untreated AN rats, and normalized in GH-treated AN rats plus CAP. We conclude that CAP reduces the proteinuric response of GH in rats with AN and ameliorates tubular injury.

Single strand conformation polymorphism analysis of androgen receptor gene mutations in patients with androgen insensitivity syndromes: application for diagnosis, genetic counseling, and therapy.

Recent studies indicate that mutations in the androgen receptor gene are associated with androgen insensitivity syndromes, a heterogeneous group of related disorders involving defective sexual differentiation in karyotypic males. In this report, we address the possibility of rapid mutational analysis of the androgen receptor gene for initial diagnosis, genetic counseling, and molecular subclassification of affected patients and their families. DNA from peripheral blood leukocytes of six patients from five families with various degrees of androgen insensitivity was studied. Exons 2 to 8 of the androgen receptor gene were analyzed using a combination of single strand conformation polymorphism analysis and direct DNA sequencing. Female family members were also studied to identify heterozygote carriers. Point mutations in the AR gene were identified in all six patients, and all mutations caused amino acid substitutions. One patient with incomplete androgen insensitivity was a mosaic for the mutation. Four of the five mothers, as well as a young sister of one patient, were carriers of the mutation present in the affected child. Our data show that new mutations may occur in the androgen receptor gene leading to sporadic androgen insensitivity syndrome. Molecular genetic characterization of the variant allele can serve as a primary tool for diagnosis and subsequent therapy, and can provide a basis for distinguishing heterozygous carriers in familial androgen resistance. The identification of carriers is of substantial clinical importance for genetic counseling.

Use of the polymerase chain reaction mismatch technique to identify the HLA-DQw8 allele in patients with insulin-dependent diabetes mellitus.

The allelic forms of the HLA-DQB gene have been recognized as susceptibility markers of type 1 diabetes mellitus. One of these alleles, the DQw3.2 (DQw8), accounts for the well-documented association of the DQw3 locus with the disease. This report describes a method using the polymerase chain reaction mismatch technique to amplify the three different DQw3 allele sequences in 26 insulin-dependent diabetic patients. Primers were designed that differed only at one base at the growing end of their sequences. Using a common oligonucleotide primer located downstream in the first domain of the DQB gene and three other primers located at the other end of the sequence being amplified, it was possible to identify and distinguish the DQw8 allele from the other two closely related alleles (DQw7, DQw9). This method, which could be useful in excluding HLA-related susceptibility to diabetes mellitus, is rapid and nonisotopic, and indeed could be adapted to investigate any DNA sequence polymorphism.

Thyroid Disorders in Adolescents and Young Adults.

Common thyroid disorders affecting adolescents and young adults are reviewed. Normal physiology of the thyroid gland and diagnostic tests are discussed and specific disorders and their treatment are described.

Gonadotropin-secreting pineal teratoma causing precocious puberty.

A case of precocious puberty in a 7-year-old boy with a tumor of the pineal region is reported. Human chorionic gonadotropin levels were elevated in the serum and cerebrospinal fluid. Endocrinological evaluation of the hypothalamic-pituitary axis demonstrated a normal prepubertal response. The tumor was resected and proved to be an immature teratoma. Human chorionic gonadotropin levels were markedly elevated in the tumor cyst fluid. Sexual precocity regressed and human chorionic gonadotropin levels in the serum and cerebrospinal fluid fell to normal after surgery, suggesting that the precocious puberty was secondary to ectopic human chorionic gonadotropin production by the pineal teratoma.

Adrenomyeloneuropathy presenting as Addison's disease in childhood.

Adrenoleukodystrophy, a sex-linked peroxisomal disorder that results in the impaired oxidation of long-chain saturated fatty acids and causes neurologic impairment, is a rare cause of Addison's disease in children. Adrenomyeloneuropathy is the name given to a biochemically identical but milder and more slowly progressive variant of adrenoleukodystrophy that affects young adults, in whom adrenal insufficiency may long precede nervous system dysfunction. The transmission of adrenomyeloneuropathy, like that of most cases of adrenoleukodystrophy, is sex-linked. Because of a preponderance of male patients among a group of patients with the onset of adrenal failure in childhood, we questioned whether this condition might be the initial manifestation of adrenomyeloneuropathy. We therefore measured the plasma concentrations of very-long-chain saturated fatty acids in eight patients with adrenal insufficiency; of these, five had elevated plasma hexacosanoic acid concentrations (range, 2.42 to 6.43 mumol per liter; mean normal level [+/- SD], 0.83 +/- 0.45), confirming the presence of adrenomyeloneuropathy. Magnetic resonance imaging showed clear evidence of brain involvement in all five patients. Reexploration of the family histories revealed additional missed cases. We conclude that the possibility of adrenomyeloneuropathy should be considered in any boy with Addison's disease.

Hypoglycemia: a pathophysiologic approach.

An exploration of the factors that sustain glucose levels in the normal fasting subject reveals that the single major component is conservation of glucose rather than gluconeogenesis. Conservation is achieved by recycling of glucose carbon as lactate, pyruvate and alanine, and a profound decrease in the oxidation of glucose by the brain brought about by the provision and use of ketones. What glucose continues to be oxidized is for the most part formed from glycerol. Gluconeogenesis from protein plays little part in the process. Fasting hypoglycemia results from disorders affecting either one of the two critical sustaining factors--the recycling process or the availability and use of ketones. Individual hypoglycemic entities are examined against this background.

Remission in children with hyperthyroidism treated with propylthiouracil. Long-term results.

We treated 69 hyperthyroid children with propylthiouracil, of whom 53 remained under surveillance. Of these children, 34 (64%) had an initial remission, but relapses were frequent (47%). At this writing, 24 patients (45%) were in remission, with a mean duration of remission of 55 months (range, ten to 132 months). We found that the triiodothyronine level took significantly longer than the thyroxine (T4) level to return to normal. Thus, based on the T4 level alone, treatment may have been stopped prematurely in some patients, causing the relapse rate to be falsely high. The response to therapy did not depend on the size of the goiter nor on the initial levels of T4 or triiodothyronine. Six patients had adverse reactions, which were serious in two patients.

Value of computed tomographic scanning in patients with growth hormone deficiency.

In 18 of a series of 23 patients with growth hormone deficiency, computed tomographic scanning demonstrated a markedly small sellar volume. In four of the remaining five patients, the sella was enlarged. The cause of the enlargement was readily identifiable. Computed tomographic scanning of the sella appears to provide valuable supportive evidence of hypopituitarism.