First two years' response to growth hormone treatment in very young preterm small for gestational age children.

BACKGROUND: Growth hormone (GH) is a therapeutic option for small for gestational age (SGA) children without spontaneous catch-up. There are few reports on preterm SGA children. Prematurity is an additional risk factor for adult short stature. AIM: To describe GH efficacy in preterm SGA patients. METHODS: Twenty-five preterm SGA patients, 2-4 years old, treated with GH 0.066 mg/kg/day, were compared with 14 age-matched preterm SGA historical controls. Height, weight, IGF-I, IGFBP-3, fasting glucose and insulin were measured every 6 months. RESULTS: At start of GH treatment, mean height and weight were -2.4 and -2.4 SDS, respectively. There was a significant increment in height SDS of 1.3 and 2.1 during the 1st and the 2nd year of GH therapy, respectively. There was no significant difference between the progression of chronological and bone ages. A significant increase in IGF-I, IGFBP-3 and molar ratio was observed during GH therapy. There was no difference in glucose, insulin or HOMA-IR index. CONCLUSION: We showed for the first time that the height increment of preterm SGA with GH treatment is similar to that described in other studies with term SGA patients. Therefore, short-term GH treatment in a subset of preterm SGA patients between 2-4 years of age was able to promote adequate growth recovery with no excessive bone age acceleration or adverse effects on carbohydrate metabolism.

Three-year follow-up of borderline congenital hypothyroidism.

The purpose of this study was to determine whether children with borderline hypothyroidism in the neonatal period had persistent hypothyroidism after 3 years of levothyroxine replacement therapy. Fourteen term infants with slightly abnormal newborn screening results (thyroxine <10th percentile, thyroid stimulating hormone ¿TSH <40 microU/mL) were identified. The subsequent serum confirmatory TSH results of 12 subjects were modestly elevated (5.3 to 18.8 microU/mL, normal 0.6 to 4.6), whereas 2 subjects who had borderline confirmatory TSH (4.6 and 4.7 microU/mL) had abnormal TSH responses to thyrotropin releasing hormone testing. After 3 years of therapy, levothyroxine was discontinued in 13 patients, and repeat thyroid function tests were obtained 1 month later. Levothyroxine was not discontinued in one patient because he had an elevated random TSH (10 microU/mL) while receiving therapy. At 3 years of age, 13 patients had persistently abnormal thyroid function tests (TSH >4.6 microU/mL or a thyroid releasing hormone test result consistent with primary hypothyroidism), and levothyroxine was reinitiated. Only one patient had normal thyroid function studies. Although prospective studies are still lacking, we recommend levothyroxine replacement in newborns with borderline hypothyroidism.

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.

Partial growth-hormone insensitivity: the role of growth-hormone receptor mutations in idiopathic short stature.

Mutations in the GHR locus may play a role in the cause of idiopathic short stature (ISS) by impairing growth-hormone (GH) receptor (GHR) function. At one extreme, mutations that nullify the function of the GH receptor are linked to complete GH insensitivity syndrome, or Laron syndrome, and we hypothesized that less-disruptive mutations could contribute to partial GH insensitivity syndrome. Low levels of GH binding protein may indicate mutations in the extracellular domain of the receptor, and by focusing on 14 children with ISS who had low GH binding protein and insulin-like growth factor I levels, we found three heterozygotes and one compound heterozygote for mutations in the extracellular domain of the receptor. We have since extended our study to a broader spectrum of patients, adding 76 patients with ISS who were treated with GH in a phase II study of the safety and efficacy of recombinant human GH in ISS and also adding 10 patients who were ascertained as having ISS by pediatric endocrinologists in private practice. The GHR gene has thus been analyzed in 100 patients with ISS, eight of whom were found to carry mutations: four in our original study and four with normal or elevated levels of GH binding protein. The latter group consists of three carriers of heterozygous extracellular domain mutations and one carrier of a heterozygous intracellular domain mutation. Family data suggest that the carriers of these mutations have a range of phenotypes, supporting our hypothesis that the expression of these heterozygous mutations as partial GH insensitivity syndrome depends on the genetic makeup of the person.

Pseudotumor cerebri in an infant after L-thyroxine therapy for transient neonatal hypothyroidism.

Pseudotumor cerebri is generally a benign disorder. It has been reported to occur in hypothyroidism, particularly after the initiation of L-thyroxine replacement therapy. Previous case reports have involved children primarily in the peripubertal age range (approximately 8 to 13 years). We report here the development of pseudotumor cerebri in an infant who required treatment with L-thyroxine for transient neonatal hypothyroidism as a result of maternal thyroid-stimulating hormone receptor-blocking antibodies.

Physician and clinic charges for diagnosing growth hormone deficiency.

Physician and clinic charges for diagnosing growth hormone deficiency (GHD) in children are not generally known, whereas the charges for purchasing growth hormone (GH) are known. We recently surveyed the charges submitted to third-party payers for diagnosing GHD in five pediatric endocrine clinics throughout the United States: the Albert Einstein College of Medicine, Baylor College of Medicine, Health Science Schools of the State University of New York at Buffalo, Oregon Health Sciences University, and the University of Chicago. The financial data analyzed included charges for physician services and for GH testing. Different approaches to the medical examination of children with suspected GHD at these clinics prevented any comparison of physician or GH testing charges. However, the charges for diagnosing GHD could be determined for each pediatric endocrine clinic if the methods of examination were not considered. Contractual adjustments, net revenues, costs, and net margins were not surveyed. Subjective comments from the study sites suggest significantly reduced reimbursement amounts. We conclude that the total charges for diagnosing GHD submitted to third-party payers at these institutions averaged $1719.

Transient congenital hypoparathyroidism: resolution and recurrence in chromosome 22q11 deletion.

Transient congenital hypoparathyroidism (TCHP), with spontaneous resolution in infancy and subsequent recurrence in childhood, has not been associated with a specific cause. We report three patients with TCHP, initially with severe but transient neonatal hypocalcemia. During childhood, recurrence of hypoparathyroidism and recognition of phenotypic features suggested a diagnosis of velocardiofacial syndrome (VCFS). Features specific for the DiGeorge syndrome, with known clinical and genetic overlap with VCFS, were not present except for hypoparathyroidism. Genetic analysis confirmed chromosome 22q11 deletion in each patient. TCHP may be the earliest specific finding in 22q11 deletion/VCFS subgroup, with other diagnostic features emerging in later childhood. Infants with resolved TCHP need continued observation of parathyroid sufficiency, genetic analysis, and examination for anomalies associated with chromosome 22q11 deletion.

Bayley-Pinneau method of height prediction in girls with central precocious puberty: correlation with adult height.

One of the sequelae of idiopathic central precocious puberty (ICPP) can be short adult stature. In this retrospective study adult height was normal in 90% of girls with untreated ICPP (mean, 161.4 +/- 7.7 cm). The height prediction made at the time of initial examination and the height age correlated with adult height. Therefore the initial height prediction can be useful in identifying those girls with ICPP at risk for short stature.

Variable phenotypes in velocardiofacial syndrome with chromosomal deletion.

Velocardiofacial syndrome (VCF) has overlapping features with DiGeorge sequence; both result from a developmental field defect and probably represent contiguous gene deletion syndromes. The association of chromosome 22q11 deletion with DiGeorge sequence led us to do molecular analysis of chromosome 22 in 18 patients with VCF, who ranged in age from 6 to 42 years. All 18 patients had monosomy for the chromosome region 22q11. Retrospectively, we correlated the presence of the deletion with various clinical findings: 100% had cleft palate, 67% the facial phenotype, 83% cardiac disease, 94% learning disabilities, 70% ophthalmologic findings, 50% short stature, 22% psychiatric disorders, and 17% hypocalcemia. Both severely phenotypically affected and mildly affected patients had the deletion. These findings stress the importance of continued surveillance of all patients with VCF for the many medical problems that may not be present at initial diagnosis. We conclude that the presence of the gene deletion does not predict the phenotypic expression in VCF. Further studies to characterize the size of the gene deletion may facilitate better prediction of the phenotype.

Depressed serum somatomedin activity in beta-thalassemia.

We have found bioassayable somatomedin activity to be subnormal in 20 of 32 children and adults with beta-thalassemia. The levels were comparable to values reported in growth hormone-deficient subjects. Since patients with thalassemia are not growth hormone deficient, the data suggest the possibility of defective hepatic biosynthesis of somatomedin. Increased iron stores in these patients, who have secondary hemosiderosis of many organs, including the liver, may depress somatomedin activity. Therapy for one year with daily subcutaneous infusions of the iron-chelating agent deferoxamine had no effect on mean bioassayable serum somatomedin activity.