Early development of the renal lesions in infantile cystinosis.

To identify the early renal lesions in cystinosis, including whether the "swan neck" deformity of the proximal tubule is a congenital or an acquired lesion, we performed renal function tests and kidney biopsies on two cystinotic infants, on one at 5 and 14 months and on the other at 6 and 12 months of age. The "swan neck" deformity appears to be an acquired lesion for two reasons. First, the characteristic thin neck of the proximal tubule was not demonstrated by nephron microdissection or light microscopy until after 6 months of life. Second, electron microscopy revealed that prior to the development of the lesion, the tubular cells in the neck region of the proximal tubule were undergoing degenerative changes. Renal function tests indicated that the manifestations of the Fanconi syndrome correlated with the stages of development of the "swan neck" lesion. Minute crystalline spaces having some of the characteristics of lysosomal cystine crystals appeared in the early biopsies only in that portion of the proximal tubule which was undergoing atrophy to form the "swan neck" lesion observed in the later biopsies. These findings provide evidence of at least a temporal relationship between apparent cellular cystine accumulation and the development of the "swan neck" lesion and the Fanconi syndrome.

GAD65 and insulin B chain peptide (9-23) are not primary autoantigens in the type 1 diabetes syndrome of the BB rat.

To investigate whether GAD65 whole molecule, GAD65 p35 or insulin B chain peptide (amino acids 9-23) play an essential role in the pathogenesis of type 1 diabetes in the BioBreeding (BB) rat, we gave serial injections of GAD65, p35 or insulin B chain (9-23) to six groups of BB/Worcester rats. The individual antigens were administered either intrathymically on day 2 and intraperitoneally in MF 59-0 adjuvant 5 times during the first 5 weeks, or by intranasal instillation once neonatally and 5 days/week for the following 6 weeks. Control groups were injected with vehicle only. Age of onset of diabetes and degree of insulitis were not different between controls and antigen-treated rats. Rats that received GAD65 intrathymically and intraperitoneally developed high GAD65-antibody titers without altering diabetes development. In GAD65-treated animals, serum antibodies recognized epitopes at 3 sites on GAD65 in diabetic animals but only at 1 site in non-diabetic animals. GAD65-injected animals also showed a significant reduction of IFN-gamma mRNA expression in the thymus. This study provides evidence against the hypothesis that GAD65 and insulin B chain peptide (9-23) are primary diabetogenic autoantigens in BB rats because immunizations with these antigens and GAD65-induced immune deviation did not alter the development of diabetes.

Risk factors for developing brain herniation during diabetic ketoacidosis.

The charts were reviewed of children admitted in diabetic ketoacidosis (DKA) to one hospital within 12 years. The frequency of brain herniation after admission was nine of 153 children admitted for one or more episodes of DKA. The severity of acidosis and hypercapnea were the most reliable risk factors. None of the children who maintained a blood pH greater than 7.1 and a capillary blood partial pressure of carbon dioxide (PCO2) greater than 20 mm Hg manifested brain herniation. The rate of initial fluid administration in severe DKA was also a risk factor. Of 119 patients having a blood pH less than 7.1 or PCO2 less than 20 mm Hg, none of 32 receiving less than 25 mL/kg, one of 42 receiving 25-50 mL/kg, and eight of 40 receiving more than 50 mL/kg of intravenous fluid during the first (in Patient 9, the second) 4 hours of therapy sustained brain herniation. Equally dehydrated unaffected patients initially receiving 25-50 mL/kg/4 hours of intravenous fluid did not develop signs of hypovolemia or worsening DKA. In this series, hydrating at a rate greater than 50 mL/kg during the first 4 hours offered no advantage and was associated with an increased risk of brain herniation.

Human insulin B chain but not A chain decreases the rate of diabetes in BB rats.

The autoimmune response seen in insulin-dependent diabetes mellitus (IDDM) includes a humoral immune response against human insulin. Early insulin treatment has been used to prevent IDDM in the rodent models of IDDM, and a prevention trial is underway in humans. The metabolic effects of insulin may not be involved in this prevention since, in NOD mice, the use of metabolically inert human insulin B chain was effective. We wished to ascertain whether immunization of diabetes-prone BB/W rats with insulin B chain, A chain, or both could alter the incidence of diabetes. Immunizations began by 30 days of age and the rats were followed until 120 days of age. Only immunization with insulin B chain plus adjuvant was effective in reducing the rate of diabetes. All immunization frequencies were effective, but a significantly lower rate of diabetes was achieved with injections every week. All of the doses tested resulted in significantly lower rates of diabetes. These data confirm in the BB rat model that immunization with insulin B chain in the presence of adjuvant can reduce diabetes incidence. The absence of any metabolic effect of B chain and the requirement for adjuvant suggest that this effect is mediated via modulation of the autoimmune response.

Growth hormone therapy of Turner's syndrome: beneficial effect on adult height.

OBJECTIVE: To carry out a multicenter, prospective, randomized trial of human growth hormone (GH), alone or in combination with oxandrolone (OX), in patients with Turner's syndrome (TS). METHODS: In an initial phase lasting 12 to 24 months, 70 girls with TS, verified by karyotype, were randomly assigned to one of four groups: (1) observation, (2) OX, (3) GH, or (4) GH plus OX. After completion of the first phase, group 3 subjects continued to receive GH only. All other subjects were treated with GH plus OX. Subjects were followed up until attainment of adult height and/or cessation of treatment. Data from this trial were compared with growth characteristics of 25 American historical subjects with TS (matched for age, height, parental target height, and karyotype) who never received either GH or androgens. RESULTS: Of the 70 subjects enrolled, 60 completed the clinical trial. The 17 subjects receiving GH alone all completed the trial and reached a height of 150.4+/-5.5 cm (mean +/- SD), 8.4+/-4.5 cm taller than their mean projected adult height at enrollment (95% confidence interval [CI]: 6.3 to 10.6 cm). The 43 subjects receiving GH plus OX attained a mean height of 152.1+/-5.9 cm, 10.3+/-4.7 cm taller than their mean projected adult height (95% CI: 8.9 to 11.7 cm). The historical control subjects had a mean adult height of 144.2+/-6.0 cm, precisely matching their original projected adult height of 144.2+/-6.1 cm. CONCLUSIONS: GH, either alone or in combination with OX, is capable of stimulating short-term growth and augmenting adult height in girls with TS. With early diagnosis and initiation of treatment, an adult height of more than 150 cm is a reasonable goal for most girls with TS.

Humoral hypercalcemia due to an occult renal adenoma.

Humoral hypercalcemia refers to the elevated blood calcium levels caused by neoplasms which release a bone resorptive substance into the circulation. Previously reported infants with malignant and benign solid tumors causing humoral hypercalcemia have presented with large abdominal masses. The case we describe, a hypercalcemic infant due to an occult parathyroid hormone-related protein-containing metanephric adenoma of the kidney, shows that radionuclide bone scanning can be a useful test to identify humoral hypercalcemia. Humoral hypercalcemia stemming from a soft tissue neoplasm should be ruled out, even in the absence of clinical signs of a tumor, if bone scans show generalized uptake in the absence of hypervitaminosis D or radiological signs of bone lesions, and serum parathyroid hormone is low.

Granular cell tumor of the thyroid gland in a girl receiving high-dose estrogen therapy.

We describe the first case of a granular cell tumor of the thyroid. The tumor appeared while a girl was receiving high-dose estrogen therapy for tall stature. The tumor, however, did not contain estrogen or progesterone receptors. Although granular cell tumors occur twice as commonly in women as in men, the results of this case study do not provide evidence that tumor growth is mediated by direct estrogen or progesterone stimulation.

Growth, thyroid function, and serum macromineral levels in magnesium-deficient chicks.

Growth and thyroid function were studied in Mg-deficient chicks. Dietary levels of 80 to 315 ppm Mg were compared with control levels of 578 to 787 ppm Mg. Signs of Mg deficiency appeared rapidly and acutely within 2 to 5 days at dietary levels of 250 to 260 ppm or lower. Growth and feed intake decreased progressively as the deficiency became more severe. Control chicks pair-fed with the deficient chicks gained significantly more weight. Serum Mg decreased at all levels of Mg below control, but at 260 and 315 ppm it returned to control values after 21 days on treatment. Serum Ca diminished only when dietary Mg was 250 ppm or less. Serum K increased in severely deficient chicks but decreased over time in milder deficiencies. Thyroid gland weights were unchanged. However, very young chicks fed a Mg-deficient diet had lower serum 3,5,3'-triiodothyronine (T3) whereas serum thyroxine (T4) was generally unaffected. Beyond 1 wk of age chicks that had prior access to a Mg-sufficient diet had low serum T4 levels whereas serum T3 was unchanged. Therefore, peripheral thyroid hormone metabolism is altered in a Mg deficiency, but this effect is dependent on the age at which the deficiency occurs.

Adolescent gynecomastia. Differential diagnosis and management.

Gynecomastia signifies a transient or permanent disturbance in steroid hormone physiology and occurs when the male breast is exposed to a decreased ratio of androgen to estrogen. This article discusses pubertal and pathologic gynecomastia, diagnostic approach, and treatment.

Evaluating the child with short stature.

Short stature is a common pediatric problem that requires us to decide whether a child's small size represents only normal variation or indicates the presence of an underlying disease. In a population of children two standard deviations (SD) below the mean for height (below the third percentile), about 20 per cent may be expected to have pathologic short stature with the remaining 80 per cent about equally divided between familial short stature and constitutional growth delay. In contrast, most children three SD below the mean for height have pathologic short stature. Set forth in this article is an orderly approach to identify normal variants of short stature and to investigate the causes of pathologic short stature.

Differential diagnosis of goiter.

Goiters can be detected in about 5 per cent of school-aged children. Goiters appearing during childhood are the result of distinct diseases and should be investigated rather than attributed to "physiologic hyperplasia." The etiology of the diffuse goiter can often be established by clinical evaluation, performing thyroid function tests, and measurement of serum thyroid antibodies. Unlike diffuse goiters, thyroid nodules frequently require tissue examination to exclude malignancy. The goal in evaluating children with nodular goiters is to be as selective as possible in submitting children to surgery without missing cases of cancer. The decision to perform an open biopsy should be based on detecting increased risk for cancer in the medical history, physical examination, or laboratory tests as outlined in Figure 1. Ultrasonography and fine-needle aspiration of nodules are two new methods that aid in the selection of patients for surgery or a trial of thyroid hormone suppression.

Chronic vitamin A intoxication in infants fed chicken liver.

Twin female infants were fed 120 gm of chicken liver homogenate daily for four months. They developed irritability, vomiting, and bulging anterior fontanelles. Computed tomograms of the brain revealed enlarged ventricles in both infants and dilated subarachnoid spaces in one. Plasma vitamin A concentrations were elevated. After all sources of vitamin A intake were stopped, the infants recovered without sequelae. The chicken liver homogenate contained 36,000 IU of vitamin A per 120 gm. Since infants often receive 4,000 units of vitamin A daily from fortified milk and vitamin supplements, they probably cannot be fed 60 gm of chicken liver safely more often than once weekly.