Clinical and biochemical phenotype of familial anterior hypopituitarism from mutation of the PROP1 gene.

We have investigated the largest family with PROP1 deficiency reported to date. Eight patients, aged 17-40 yr, in two sibships with possibly related mothers but no parental consanguinity were 109-137 cm in height (-8.8 to [minus]5.9 SD score) and sexually immature. None had received hormonal therapy. Affected individuals had similarities to and significant differences from patients with insulin-like growth factor I (IGF-I) deficiency due to GH receptor deficiency (GHRD) and normal thyroid function and sexual maturation. The differences from patients with GHRD include normal hand and foot length in seven of eight, normal arm span with relatively long legs, and persistence of extremely low levels of IGF-I into adulthood; similarities include the degree of growth failure, frequent but not uniform increased body weight for height or body mass index, and the presence of limited elbow extensibility and blue scleras in six of eight. Three patients had markedly increased sella turcica area for height age and bone age, determined from lateral skull films. The degree of sellar enlargement is variable in these two sibships. Serum GH concentrations were 0.1 ng/mL or less after clonidine ingestion. Other results were: IGF-I, 3-11 ng/mL (normal, 114-492); IGF-II, 185-299 ng/mL (normal, 358-854); IGF-binding protein-1 (IGFBP-1), 12-200 ng/mL (normal, 13-73); IGFBP-2, 60-384 ng/mL (normal, 55-480); and IGFBP-3, 400-600 ng/mL (normal, 2000-4000). The very low IGF-I and normal IGFBP-1 and -2 levels differ from findings in adults with GHRD. The GH-binding protein concentration was 58-799 pmol/L, with two patients above the normal range of 66-306. LH and FSH levels were very low, with no sex differences between serum levels of estradiol (3-6 pg/mL) and testosterone (3-10 ng/dL). PRL levels all were below normal. Serum concentrations of cortisol were normal. Serum T4 levels were uniformly low (<0.2-0.5; normal, 0.8-2.7 ng/dL), free T3 values were less than normal in seven of eight subjects, and total T3 concentrations were below normal in five of eight, but TSH levels were normal (0.58-2.18; normal, 0.4-4.2 mU/L). DNA specimens from affected individuals in each sibship were homozygous for a 2-bp deletion in exon 2 of the PROPI (Prophet of Pit-I) gene, which causes a shift of reading frames and results in a translational stop signal at codon 109. The mutant protein, when expressed in vivo lacks DNA-binding and transcriptional activation functions. The consequences of the PROPI abnormality in this and other kindreds include gonadotropin deficiency as well as the expected deficiencies in products of Pit-I-dependent somatotrophs, lactotrophs, and thyrotrophs. The severity of the hormone deficiency phenotype is compatible with the complete loss of PROP1 activity.

Effects of low level radiation from the Chernobyl accident in a population with iodine deficiency.

UNLABELLED: To determine the effects of low dose radiation from 131I and 137Cs resulting from the Chernobyl disaster on the expression of endemic goiter in children, we studied children in regions with and without evidence of radiocontamination but comparable iodine insufficiency. We included 89 children in the study (radiocontaminated) region (SR) and 116 in the control region (CR) because they were either fetuses, infants, or pre-adolescents at the time of exposure. We evaluated thyroid dimensions by clinical examination and ultrasound; thyroid function by hormonal levels, and thyroglobulin measurement; histology of the thyroid by fine needle aspiration; and thyroid autoimmunity. SR subjects had 5 times the frequency of thyroid enlargement as those from CR, greatest in the younger patients. There were no instances of clinically apparent thyroid dysfunction. Antithyroid microsomal and antithyroglobulin antibodies were present in a markedly greater percentage of SR subjects. Fine needle biopsy demonstrated greater cellular proliferation in samples from SR. CONCLUSIONS: We have demonstrated findings of autoimmune thyroid disease at markedly increased frequency in a population of children with poor iodine nutriture who were exposed to low level radiation, compared to a more iodine deficient population not so exposed. These results suggest that low level radiation may induce thyroid gland changes in children who have inadequate iodine intake nutriture and reinforce the importance of adequate dietary iodine.

Connective tissue and joint disease in diabetes mellitus.

Connective tissue is ubiquitous and subject to alterations that result in changes in the extracellular matrix of vessels and tissues leading to the long-term complications of diabetes. This article reviews only those abnormalities of interstitial connective tissue involving skeleton, joints, skin, and periarticular tissues. Abnormalities in the skin and periarticular tissues result in syndromes limiting joint movement, including limited joint mobility, Dupuytren disease, flexor tenosynovitis, carpal tunnel syndrome, stiff-hand syndrome, and shoulder-hand reflex dystrophy. Of these, only limited joint mobility and stiff-hand syndrome occur exclusively in patients with diabetes. In all of these conditions, advanced glycation end products are thought to form as a result of nonenzymatic reaction of glucose with proteins, causing stiffening.

Body changes in adolescent patients with growth hormone receptor deficiency receiving recombinant human insulin-like growth factor I and luteinizing hormone-releasing hormone analogue: preliminary results.

Auxological and body composition changes were studied in three adolescent patients (2 female, 1 male) with growth hormone receptor deficiency (GHRD) given insulin-like growth factor I (IGF-I), 120 micrograms/kg s.c. twice daily, plus a monthly intramuscular injection of 7.5 mg of a luteinizing hormone-releasing hormone (LHRH) analogue. Preliminary results from the first 12 months of the study show that height velocity was increased compared with the pretreatment values. This increase was probably due to the IGF-I therapy, as the LHRH analogue would have suppressed gonadotrophins and gonadal steroid production. There was a reduction in percentage body fat, and increases in lean mass and the lean:fat ratio, whole body mineral content and body calcium content, even when expressed per kg body weight. There was also a trend towards increased bone mineral density of the whole skeleton, lumbar spine and femoral structures, as well as a maturation of facial features. These preliminary results indicate that concomitant therapy with IGF-I and an LHRH analogue is safe and efficacious in inducing growth without advancing bone age in patients with GHRD.

Growth hormone by daily injection in patients previously treated for growth hormone deficiency.

When recombinant-DNA-derived methionyl growth hormone (met-GH) became available for patients resuming treatment, we were able to compare dose intervals in 47 prepubertal children with growth hormone deficiency. Patients were randomly assigned to one or three doses weekly or to daily injections for a total dosage of 0.3 mg/kg weekly. If the patient's annual growth failed to increase more than 2 cm above baseline, the dose interval was changed from weekly to three times a week or from three times a week to daily. In the second year of the study, all patients received daily injections. Despite a mean duration of previous treatment with growth hormone of more than 3 years, daily injections in 16 patients throughout the first year of the study resulted in a mean growth velocity (9.6 +/- 2.4 cm) comparable to that in newly treated patients given met-GH three times weekly in other trials. Administration by daily injection was more effective than injection three times per week (P less than .05) in 13 patients (7.9 +/- 2.1 cm) or once a week in four patients (7.7 +/- 1.2 cm). Second year growth velocities in 21 patients who had received once-a-week or three-times-a-week injections the first year of the study, increased significantly with a change to daily injection (7.7 +/- 2.2 vs 8.8 +/- 1.9 cm) (P less than .05).

Height screening in the community. The commercialization of growth. The role of the pediatrician.

The availability of unlimited but costly supplies of biosynthetic growth hormone has led to pressure for pharmacologic use (as opposed to replacement therapy in proven deficiency states). Commercial and altruistic motives have converged to promote community height screening among individuals who have been perceived by themselves or parents as short. This does not meet accepted criteria for health screening. Height screening of large populations of children yields few unrecognized medical conditions. If the goal of community screening is to identify abnormally short individuals (less than 3%) who might benefit from growth hormone treatment and if the unproven assumption is correct that stature correlates with success and happiness, then those less likely to appear for screening need to be recruited to avoid elitist domination. The annual cost of such growth promotion would be greater than $10 billion, with no evidence for substantial health benefits. Growth monitoring of all children through improved height measurement in schools and in physicians offices, as part of health supervision, is a more sound community approach than height screening.

Correlates of biopsy-studied nephropathy in young patients with insulin-dependent diabetes mellitus.

We have correlated pathologic findings in kidney biopsies from 12 adolescents with proteinuria or hypertension with severity of limited joint mobility (LJM) and retinopathy. We compared mean glucosylated hemoglobin (GHB) and clinical findings in these patients with those in patients without proteinuria or hypertension. Severity of LJM correlated with basement membrane thickening. Protein excretion correlated with degree of mesangial matrix increase and basement membrane changes. Retinal changes were related to basement membrane thickness and duplication. Despite treatment, blood pressures were significantly higher in patients with nephropathy than in the comparison group. Glycemic control status was generally poor and did not correlate with pathologic changes. The narrow spectrum of control did not permit assessment of possible effects of milder metabolic derangement. However, the similarity of GHB values in the groups with and without nephropathy implicates other factors. The group with clinical nephropathy had more LJM than did the comparison group, reaffirming LJM as a risk factor for early microvascular disease. Biopsy changes of nephropathy may begin relatively early in the course of diabetes (less than 7 years in three of our patients) and is already advanced when proteinuria appears.

Skeletal and joint manifestations of childhood diabetes.

The rheumatologic and skeletal manifestations of childhood diabetes have only recently been appreciated. This article reviews bone loss (osteopenia) in this population, and the differential diagnosis of the limited joint mobility commonly found in insulin-dependent diabetes in childhood.

Near-total pancreatectomy in persistent infantile hypoglycemia.

To prevent the devastating effects of hypoglycemia on the CNS of the infant, persistent infantile hypoglycemia should be recognized early and treated promptly. To avoid mental retardation, surgical intervention should not be considered as a last resort. When an insulinoma is identified at surgery, subtotal pancreatectomy is adequate in achieving normoglycemia. However, the most common cause of insulin excess in infancy appears to be islet cell hyperplasia or nesidioblastosis, both diffuse processes. In these patients, subtotal pancreatectomy is often ineffective in achieving normoglycemia. Near-total pancreatectomy, retaining the spleen and duodenum, is a safe procedure, well tolerated by infants and children, and should be considered early for the correction of hypoglycemia of infancy that is not readily controlled by medical intervention.

Clinical manifestations of hypothalamic tumors.

The regulatory function of the central nervous system encompasses diverse endocrine, metabolic, and behavioral processes. Many of these originate, are integrated, or are coordinated through hypothalamic pathways or nuclei. Thus, tumors affecting areas projecting to the hypothalamus, tumors of the hypothalamus, and tumors invading or compressing the hypothalamus can produce abnormalities of hypothalamic function.

Low dose single weekly injections of growth hormone: response during first year of therapy of hypopituitarism.

Initial year growth responses to single weekly injections of 2.5 units human growth hormone (hGH) in 29 patients with hypopituitarism (130 units/yr/patient) were compared to responses in a series using smaller doses in conjunction with androgen (48 to 112 units/yr); the US collaborative study experience with the standard dose (2 units 3 times/wk = 312 units/yr), and with two size-adjusted doses (0.06 units/kg 3 times/wk = 212 +/- 94 SD units/yr, 0.03 units/kg 3 times/wk = 116 +/- 33 units/yr); and to the British experience with much larger doses (1,040 units/yr). During the first year of hGH treatment our patients grew an average 13% faster than the androgen-supplemented and collaborative study-0.03 units/kg/dose groups. They had a similar pace to the collaborative study-312 units/yr and 0.06 units/kg/dose patients, but grew 15% more slowly than did the British patients. Growth response correlated positively with age and negatively with hGH dose per kilogram of body weight. Of 17 patients with isolated growth hormone deficiency ten developed hypothyroidism with hGH therapy, leading to a policy of routine adjunctive thyroxine replacement.

Normal intelligence in two children with Carpenter syndrome.

Previous reports have noted a constant association between the Carpenter syndrome (acrocephalopolysyndactyly, type II) and mental retardation. We report two patients with this condition with normal intelligence. These observations indicate that mental deficiency is not necessarily a component of the Carpenter syndrome and that early surgical correction of the craniosynostoses may improve the chances of normal mentality.