Evaluation of growth and hormonal status in patients referred to the International Fanconi Anemia Registry.

OBJECTIVES: 1) To determine the extent of short stature in patients with Fanconi anemia (FA); 2) to determine the extent and nature of endocrinopathy in FA; 3) to assess the impact on height of any endocrinopathies in these patients; and 4) to study the correlation, if any, between height, endocrinopathy, and FA complementation group. STUDY DESIGN: Fifty-four patients with FA, 30 males and 24 females from 47 unrelated families, were prospectively evaluated in a Pediatric Clinical Research Center. The patients ranged in age from 0.1-31.9 years, with the mean age at assessment 8.6 years. RESULTS: Endocrine abnormalities were found in 44 of the 54 FA patients tested (81%), including short stature, growth hormone (GH) insufficiency, hypothyroidism, glucose intolerance, hyperinsulinism, and/or overt diabetes mellitus. Twenty-one of 48 (44%) participants had a subnormal response to GH stimulation; 19 of 53 (36%) had overt or compensated hypothyroidism, while 8 of 40 participants had reduced thyroid-hormone binding. Two patients were diabetic at the time of study; impaired glucose tolerance was found in 8 of 40 patients (25%), but most surprisingly, hyperinsulinemia was present in 28 of 39 (72%) participants tested. Significantly, spontaneous overnight GH secretion was abnormal in all patients tested (n = 13). In addition, participants demonstrated a tendency toward primary hypothyroidism with serum tetraiodothyronine levels at the lower range of normal, while also having thyrotropin (thyroid-stimulating hormone) levels at the high end of normal. Sixteen patients were assigned to FA complementation group A, (FA-A), 12 to FA-C, and 5 to FA-G; 10 of the 12 participants in FA-C were homozygous for a mutation in the intron-4 donor splice site of the FANCC gene. Patients in groups FA-A and FA-G were relatively taller than the group as a whole (but still below the mean for the general population), whereas those in FA-C had a significantly reduced height for age. GH response to stimulation testing was most consistently normal in participants from FA-G, but this did not reach statistical significance. The tendency toward hypothyroidism was more pronounced in participants belonging to complementation groups FA-C and FA-G, whereas insulin resistance was most evident in patients in FA-G, and least evident in those in FA-C. Short stature was a very common finding among the patients with a mean height >2 standard deviations below the reference mean (standard deviation score: -2.35 +/- 0.28). Patients with subnormal GH response and those with overt or compensated hypothyroidism were shorter than the group with no endocrinopathies. The heights of those participants with glucose or insulin abnormalities were less severely affected than those of normoglycemic, normoinsulinemic participants, although all were significantly below the normal mean. The mean height standard deviation score of patients with entirely normal endocrine function was also >2 standard deviations below the normal mean, demonstrating that short stature is an inherent feature of FA. CONCLUSION: Endocrinopathies are a common feature of FA, primarily manifesting as glucose/insulin abnormalities, GH insufficiency, and hypothyroidism. Although short stature is a well-recognized feature of FA, 23 patients (43%) were within 2 standard deviations, and 5 of these (9% of the total) were actually above the mean for height for the general population. Those patients with endocrine dysfunction are more likely to have short stature. These data indicate that short stature is an integral feature of FA, but that superimposed endocrinopathies further impact on growth. The demonstration of abnormal endogenous GH secretion may demonstrate an underlying hypothalamic-pituitary dysfunction that results in poor growth.

Osteoporosis: an unusual presentation of childhood Crohn's disease.

Osteoporosis is known to be associated with Crohn's disease. We report a 12-yr-old boy without a history of steroid use, in whom severe osteoporosis and multiple collapsed vertebrae were the presenting manifestations of Crohn's disease. After treatment of the Crohn's disease, he resumed normal growth and progressed through puberty. Concomitantly, he demonstrated a substantial recovery of vertebral bone mineral density and structure. Possible pathophysiological mechanisms underlying the osteoporosis and the subsequent improvement in bone density are discussed.

Autosomal dominant growth hormone (GH) deficiency type II: the Del32-71-GH deletion mutant suppresses secretion of wild-type GH.

Familial isolated GH deficiency type II is an autosomal dominant form of short stature, associated in some families with mutations that result in missplicing to produce del32-71-GH, a protein that cannot fold normally. The mechanism by which this mutant suppresses the secretion of wild-type GH encoded by the normal allele is not known. Coexpression of del32-71-GH with wild-type human GH in transient transfections of the neuroendocrine cell lines GH4C1 and AtT20 suppressed accumulation of wild-type GH. The suppression of wild-type GH accumulation by del32-71-GH was a posttranslational effect on wild-type GH caused by decreased stability, rather than decreased synthesis, of wild-type GH. Coexpression of del32-71-GH with human PRL did not suppress accumulation of PRL, indicating that there was not a general suppression of secretory pathway function. Accumulation of del32-71-GH protein was not necessary for the suppression of wild-type GH, because del32-71-GH did not accumulate in the neuroendocrine cell lines in which suppression of accumulation of wild-type GH was observed. Del32-71-GH did accumulate in transfected COS and CHO cells, but did not suppress the accumulation of wild-type GH in these cells. These studies suggest that del32-71-GH may cause GH deficiency in somatotropes of heterozygotes expressing both wild-type and del32-71-GH by decreasing the intracellular stability of wild-type GH.

HIV-associated immune dysfunction and delayed pubertal development in a cohort of young hemophiliacs. Hemophilia Growth and Development Study.

As part of the Hemophilia Growth and Development Study (HGDS), we investigated the relationship between HIV-associated immune dysfunction and delayed pubertal development in a cohort of 333 boys and adolescents with moderate or severe hemophilia who were between the ages of 6 and 19 years at study entry in 1989. Sixty-two percent of the cohort was infected with HIV in the late 1970s and early 1980s through exposure to contaminated clotting factor concentrates. The cohort was observed during follow-up at 6-month intervals; measurements taken at each follow-up visit included Tanner stage and CD4+ cell count. This analysis of data from the first 4 years of follow-up revealed statistically significant delays in pubertal development associated with increasing levels of immune dysfunction. Our results emphasize the importance of following pubertal development in HIV-infected adolescent boys since delays in maturation may reflect underlying disease progression.

Mutational analysis of PHEX gene in X-linked hypophosphatemia.

Hypophosphatemic rickets is commonly an X-linked dominant disorder (XLH or HYP) associated with a renal tubular defect in phosphate transport and bone deformities. The XLH gene, referred to as PHEX, or formerly as PEX (phosphate regulating gene with homologies to endopeptidases on the X-chromosome), encodes a 749-amino acid protein that putatively consists of an intracellular, transmembrane, and extracellular domain. PHEX mutations have been observed in XLH patients, and we have undertaken studies to characterize such mutations in 46 unrelated XLH kindreds and 22 unrelated patients with nonfamilial XLH by single stranded conformational polymorphism and DNA sequence analysis. We identified 31 mutations (7 nonsense, 6 deletions, 2 deletional insertions, 1 duplication, 2 insertions, 4 splice site, 8 missense, and 1 within the 5' untranslated region), of which 30 were scattered throughout the putative extracellular domain, together with 6 polymorphisms that had heterozygosity frequencies ranging from less than 1% to 43%. Single stranded conformational polymorphism was found to detect more than 60% of these mutations. Over 20% of the mutations were observed in nonfamilial XLH patients, who represented de novo occurrences of PHEX mutations. The unique point mutation (a-->g) of the 5'untranslated region together with the other mutations indicates that the dominant XLH phenotype is unlikely to be explained by haplo-insufficiency or a dominant negative effect.

Retinal changes mimicking diabetic retinopathy in two nondiabetic, growth hormone-treated patients.

A role for GH in the pathogenesis of diabetic retinopathy has long been postulated. Previous clinical studies, however, have been confounded by hyperglycemia. We have identified 2 cases of retinopathy associated with exogenous GH therapy in nondiabetic patients. Cases were identified through the MedWatch drug surveillance system of the U.S. Food and Drug Administration. Causality by concomitant medications was excluded by a search of the literature and the FDA data base. The first patient, an obese, 31-yr-old male with traumatic hypothalamic injury, presented with nonproliferative retinopathy and macular edema, resulting in decreased visual acuity (OD 20/40-1; OS count fingers), which required laser surgery. Human GH had been initiated at 0.009 mg/ kg.day, 14 months earlier, and titrated to 0.017 mg/kg.day. The second patient, a nonobese, 11-yr-old girl receiving GH for the management of short stature in Turner's Syndrome, presented with neovascularization. GH doses were 0.033 mg/kg.day for the first 17 months and 0.043 mg/ kg.day for the following 5 months. Cumulative laboratory and clinical observations suggest that GH and related peptides have a role in retinal pathology independent of the degree of glucose tolerance.

DAX1 mutations map to putative structural domains in a deduced three-dimensional model.

The DAX1 protein is an orphan nuclear hormone receptor based on sequence similarity in the putative ligand-binding domain (LBD). DAX1 mutations result in X-linked adrenal hypoplasia congenita (AHC). Our objective was to identify DAX1 mutations in a series of families, to determine the types of mutations resulting in AHC and to locate single-amino-acid changes in a DAX1 structural model. The 14 new mutations identified among our 17 families with AHC brought the total number of families with AHC to 48 and the number of reported mutations to 42; 1 family showed gonadal mosaicism. These mutations included 23 frameshift, 12 nonsense, and six missense mutations and one single-codon deletion. We mapped the seven single-amino-acid changes to a homology model constructed by use of the three-dimensional crystal structures of the thyroid-hormone receptor and retinoid X receptor alpha. All single-amino-acid changes mapped to the C-terminal half of the DAX1 protein, in the conserved hydrophobic core of the putative LBD, and none affected residues expected to interact directly with a ligand. We conclude that most genetic alterations in DAX1 are frameshift or nonsense mutations and speculate that the codon deletion and missense mutations give insight into the structure and function of DAX1.

Identification of the oim mutation by dye terminator chemistry combined with automated direct DNA sequencing.

The homozygous oim/oim mouse, a model of moderate-to-severe human osteogenesis imperfecta, contains a G-nucleotide deletion in the Cola-2 gene (the murine pro alpha(I) collagen gene) that results in accumulation of alpha1(I) homotrimer collagen. Although these mice have a distinctive phenotype that includes multiple fractures and deformities, genotyping is necessary to distinguish them from their wildtype (+/+) and heterozygote (oim/+) littermates. In this study, the dye primer and dye terminator chemistry methods, in combination with automated direct DNA sequencing, were compared for accuracy and ease in genotyping. A total of 82 mice from 14 litters were bred and genotyped; this resulted in 18 +/+, 35 oim/+, and 29 oim/oim mice. The dye primer and dye terminator chemistry methods worked equally well for identification of the deletion mutation and thus the genotype of all of the mice. However, the dye terminator method was found to be superior on the basis of the reduced amount of sample handling and reduced quantity of reagent required.

Genetic defects in the control of growth hormone secretion.

Since growth hormone deficiency (GHD) causes short stature and metabolic derangements, the processes which control its release are important physiologically. These processes can be illuminated by an understanding of genetically determined GHD. In 2 Indian Moslem cousins from a consanguineous family, GHD resistant to growth hormone releasing hormone (GHRH) stimulation was found. No mutations were found in the growth hormone gene (GH1) (J. Phillips). The receptor for GHRH (GHRHR), implicated in the dwarfism of the little mouse, thus becomes a candidate gene to explain their GHD. Amplification and sequencing a region of GHRHR homologous to that mutated in the little mouse showed a mutation (265G*T) leading to a stop codon at position 72 which would completely prevent GHRHR expression. Subsequently, Maheshwari et al. found an identical mutation in a multiplex kindred from Sindh, Pakistan, about 800 km from the place of origin of our patients. GHD is more commonly caused by recessive or dominant mutations of GH1. The latter are of great interest in understanding the mechanism of GH secretion. In a large kindred with dominant GHD we found a heterozygous 666G*A mutation replacing of Arg with His at amino acid 183. We speculate that the introduced histidine interferes with interactions necessary for correct GH secretion.

Linkage studies of a Missouri kindred with autosomal dominant spondyloepimetaphyseal dysplasia (SEMD) indicate genetic heterogeneity.

A four-generation kindred (14 affected and 10 unaffected members) from Missouri, U.S.A. in which spondyloepimetaphyseal dysplasia (SEMD) had been inherited as an autosomal dominant disorder was investigated for linkage to 13 candidate loci: COL2AI, COL9AI, COL9A2, COL9A3, COL10A1, COL11A1, COL11A2, PSACH, FGFR3, decorin, CRTL1, COMP, and PTHRP. Mutations of COL2A1, COL9A2, COL10, and FGFR3 have been reported previously in the Strudwick type of SEMD, multiple epiphyseal dysplasia type 2 (EDM2), the Schmid type of metaphyseal dysplasia, and in achondroplasia, respectively, and the pseudoachondroplasia (PSACH) locus has been mapped to chromosome 19p12. In addition, mutations in COL9 and COL11A are associated with murine forms of degenerative joint disease and chondroplasia, respectively. The family proved informative for 12 of the 13 loci and was uninformative at the decorin locus. Linkage between this form of SEMD, designated the Missouri variant, SEMDMO, and the 12 informative candidate loci was excluded (LOD scores < -2.00 at theta = 0.005 to 0.15), thereby indicating further genetic heterogeneity in these inherited disorders of bone and cartilage development.

Growth hormone secretion in HIV-positive versus HIV-negative hemophilic males with abnormal growth and pubertal development. The Hemophilia Growth and Development Study.

UNLABELLED: Growth and pubertal development in hemophilic males, age 6-19 years at baseline, were evaluated over a 3.5-year period in 207 HIV-positive and 126 HIV-negative subjects as part of the Hemophilia Growth and Development Study. METHODS: Thyroid function, insulin-like growth factor I (IGF-1) levels, bone age, cranial magnetic resonance image normality, CD4+ counts, and serum testosterone levels of study participants were measured at baseline. An extensive endocrine evaluation was performed in subjects who demonstrated declines in height for age (measurement <5th percentile with two pervious heights >10th percentile), who had not achieved Tanner stage 4 level of pubertal development by age 15 years or who had abnormal growth velocity, which included assessment of peak stimulated growth hormone response after clonidine stimulation, 12-hour growth hormone profiles, and serum beta carotene levels (triggered protocol). RESULTS: For almost the entire group (-99%), thyroid function tests were normal for age. IGF-1 levels were normal for 93% of the cohort. A total of 120 subjects, 89 HIV-positive and 31 HIV-negative, had an abnormality of growth, pubertal development, or both; 34 (11.1%) HIV-positive and 4 (3.6%) HIV-negative subjects had declines in height (p = .001), 20 (23.3%) HIV-positive and 5 (15.8%) HIV-negative subjects had not achieved Tanner stage 4 by 15 years of age (p = .372) and 59 (43.4%) HIV-positive and 23 (25.6) HIV-negative subjects had abnormal growth velocity (p < 0.001). Among subjects with abnormal height or growth velocity, the HIV-positive group had significantly lower mean age-adjusted testosterone levels than did the HIV-negative group (p = .030). Within the HIV-positive group, older subjects with abnormal height or growth velocity had significantly lower mean bone age than subjects of similar age without growth abnormalities (p = .0092). Extensive testing was done in 39 patients (32 HIV-positive, 7 HIV-negative). Half of the HIV-positive subjects had mean 12-hour growth hormone levels <3 ng/ml, 47% had peak stimulated levels <10 ng/ml, 28% had peak spontaneous values <10 ng/ml, and 38% had low levels of IGF-1. In the HIV-positive cohort, there was no difference in the rate of abnormalities of growth hormone secretion between those with CD4+ counts > or = or <200 cells/mm3 and between those subjects that met the 1987 Centers for Disease Control (CDC) surveillance definition of AIDS. In the subset of HIV-positive patients with abnormal peak growth hormone levels after clonidine stimulation, growth hormone response correlated positively with CD4+ count (r = .657, p = .0056) and beta carotene concentration (R = .596, p = .0192). CONCLUSIONS: The results of this longitudinal study suggest that abnormalities of growth and pubertal development, particularly an abnormal growth velocity, are common in HIV-infected hemophilic boys and adolescents. These abnormalities might serve as indicators of the presence of HIV infection in this at-risk population. Since thyroid function tests and IGF-1 levels were normal, the etiology of growth impairment in HIV infection does not appear to be secondary to inadequate caloric intake or acquisition, or severe illness such as that caused by recurrent or persistent infection. Rather, HIV infection appears to lead to diminished growth hormone production or release and decreased androgen secretion, even before the development of AIDS and immunocompromise. These results provide a rationale for trials of treatment with growth hormone or androgens in patients with abnormalities of endocrine function.

Growth hormone treatment in children.

GH therapy increases final height in GH-deficient children. Short-term growth acceleration is also seen in children with many other causes of shortness. This review covers the diagnosis of GH-deficiency (GHD) and the details of GH treatment and its long-term results in GH-deficient patients and in those with other conditions, including "idiopathic short stature" and Turner syndrome. The efficacy of GH in enhancing adult stature in children with diagnoses other than GHD and Turner syndrome has not been established, and the only other indication for which it is approved by the U.S. Food and Drug Administration is chronic renal insufficiency. Broadening of the indications for GH use in childhood can only occur if supported by the results of carefully performed clinical trials. (Trends Endocrinol Metab 1997;8:92-97). (c) 1997, Elsevier Science Inc.

Metabolic and clinical response to recombinant human insulin-like growth factor I in myotonic dystrophy--a clinical research center study.

Muscle weakness and wasting in myotonic dystrophy (MyD) are believed to be due to a decrease in muscle protein synthesis, secondary to insulin resistance. A 4-month, randomized, double blind, placebo-controlled trial was undertaken to assess whether recombinant human insulin-like growth factor I (rhIGF-I) may overcome the insulin resistance. Patients received either 5 mg rhIGF-I (n = 7) or placebo (n = 9), sc, twice daily. Glucose metabolism was assessed by stable label iv glucose tolerance test, amino acid metabolism by L-[13C] leucine turnover, body composition by dual energy x-ray absorptiometry and N excretion, and muscle response by manual muscle strength and neuromuscular function. In the treated group, the insulin sensitivity index, insulin action, and glucose disposal all increased (P < 0.05). Leucine flux and leucine incorporation into protein increased (P < 0.05), and the rate of leucine oxidation to leucine turnover decreased (P < 0.05), findings indicative of increased protein synthesis. Body weight and lean body mass increased, whereas percent body fat decreased (P < 0.05). An increase in manual muscle strength of 0.42 +/- 0.30 (P < 0.02) and in neuromuscular function of 17.5 +/- 11.7 (P < 0.02) occurred in the four patients who received a rhIGF-I dose greater than 70 micrograms/kg, whereas a more modest response occurred in the three patients who received a dose less than 70 micrograms/kg. Two patients showed dramatic improvement. Long term rhIGF-I therapy appears to cause metabolic and muscle improvement in optimally treated MyD patients.

Diminished material properties and altered bone structure in rat femora during pregnancy.

Pregnancy and lactation are known to cause structural and mechanical changes in bone, but the effects of pregnancy alone have not been evaluated thoroughly. This study used radiographic measurements, torsion testing, mineral analyses, and histological evaluation to determine whether there are changes in bone material and geometric properties during pregnancy in the growing rat, as implied by earlier biochemical and histological studies. The bones of pregnant 9 to 12-week-old rats and controls that were not pregnant and were matched by age (but not weight) were evaluated at times corresponding to 5, 10, 15, and 20 days of the 23-day gestation period to address the following questions: (a) How is the growth of whole bone affected by pregnancy in the growing rat (as determined by radiographic analyses)? (b) How are the mechanical properties (structural and material) of whole bone affected by pregnancy (as assessed by torsion testing)? (c) Are there changes in the characteristics of bone mineral during pregnancy (as determined by measurement of mineral content and x-ray diffraction analyses)? and (d) Are there detectable morphological or ultrastructural differences between the bones of pregnant and control rats (as assessed by analyses based on histology and back-scattered electron imaging)? The presence of statistically significant differences in this study was determined initially on the basis of a two-factor analysis of variance. In general, significant differences were noted only at late gestation (day 20), when the bones were longer and had a greater outer radius and cortical thickness; this indicates that more growth occurred during pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Delayed somatic growth and pubertal development in human immunodeficiency virus-infected hemophiliac boys: Hemophilia Growth and Development Study.

As part of the Hemophilia Growth and Development Study, we investigated the impact of human immunodeficiency virus (HIV) infection on statural growth, weight gain, and skeletal and sexual maturity in more than 300 boys with moderate to severe hemophilia, of whom 62% were infected with HIV. Age-adjusted height and weight were reduced in the HIV-infected subjects (p < 0.001). However, mean weight for height and triceps skin-fold thickness of the infected-boys closely resembled those of the uninfected group. In HIV-infected boys, height for age was positively related to the CD4+ lymphocyte count when the count was < 200 cells/mm3. Age-adjusted serum testosterone levels did not differ by HIV status, but in the infected participants the mean age-adjusted bone age was significantly reduced (p = 0.038) and the distribution of Tanner stages, adjusted for age, differed significantly (p = 0.003). The probability of advancing one or more Tanner stages in the first study year was significantly slowed in HIV-infected boys more than 14 years of age (p = 0.0003). We conclude that linear growth was significantly impaired in boys with hemophilia and HIV infection, but the wasting of malnutrition was not found. The delays in bone age and pubertal maturation strongly suggest that part of the growth failure seen in acquired immunodeficiency syndrome can be attributed to pubertal delay. We speculate that the lack of demonstrable difference in age-adjusted testosterone concentrations might reflect subtle differences in the pattern of secretion of testosterone or in the concentration of sex-hormone binding globulin.

Expression and purification of functional human 17 alpha-hydroxylase/17,20-lyase (P450c17) in Escherichia coli. Use of this system for study of a novel form of combined 17 alpha-hydroxylase/17,20-lyase deficiency.

Enzymatically active human 17 alpha-hydroxylase cytochrome P450 (P450c17) has been expressed in and purified from Escherichia coli. The cDNA containing modifications within the amino-terminal eight codons which are favorable for expression in E. coli, as well as codons for 4 histidine residues at the carboxyl terminus, was placed in the pCWori+ expression vector. The modified human P450c17 was detected spectrophotometrically (400 nmol of P450c17/liter culture) and was found to be integrated into E. coli membranes. This previously inaccessible human P450 was purified to electrophoretic homogeneity (10.7 nmol of P450/mg) from solubilized bacterial membranes using two sequential chromatographic steps, nickel nitrilotriacetate followed by hydroxylapatite. The expected enzymatic activities of human P450c17 were reconstituted by addition of purified rat liver NADPH-cytochrome P450 reductase, giving turnover numbers of 8.0 nmol/min/nmol P450 for pregnenolone, 6.5 nmol/min/nmol P450 for progesterone, 0.06 nmol/min/nmol P450 for 17 alpha-hydroxypregnenolone, and no detectable activity for 17 alpha-hydroxyprogesterone. This system was utilized to study the molecular basis of a novel form of combined 17 alpha-hydroxylase, 17,20-lyase deficiency resulting from compound heterozygous mutations, a missense point mutation Tyr64(TAT)--> Ser (TCT), and an Ile112 duplication (ATCATC). Upon expression of these mutant proteins in E. coli, the Tyr64 mutant has 15% of the wild type 17 alpha-hydroxylase activity, whereas the Ile112 duplication shows no activity, results consistent with the observed clinical phenotype.

Growth response of children with non-growth-hormone deficiency and marked short stature during three years of growth hormone therapy.

Short-term administration of human growth hormone to children with idiopathic short stature can improve mean growth rate and predicted adult height. It is yet unknown whether therapy would alter pubertal development or affect final height. Three-year treatment results in a group of children with idiopathic short stature are reported. For year 1 of the study, 121 prepubertal children were randomly selected to receive somatotropin, 0.3 mg/kg per week, administered subcutaneously three times weekly (n = 63), or to be nontreatment control subjects (n = 58). After 1 year, all subjects were again randomly selected to receive either three-times-weekly or daily dosing at the same total dose. For the 92 subjects who completed 36 months of treatment, mean growth rate increased from a mean of 4.6 cm/yr before treatment to a mean of 8.0 cm/yr in the first year of treatment. Daily dosing resulted in a significantly faster mean growth rate (9.0 cm/yr) than three-times-weekly dosing (7.8 cm/yr) (p = 0.0005). Mean growth rates were 7.6 and 7.2 cm/yr during years 2 and 3, respectively, and did not differ by dosing group. Mean standardized height for all subjects improved from -2.7 to -1.6 after 3 years. When the growth rate was standardized for bone age, however, subjects who remained prepubertal had a significantly greater gain in mean height SD score than subjects who became pubertal during that 3-year period (p < 0.02). Mean standardized Bayley-Pinneau predicted adult height SD score increased from -2.7 to -1.6 and was independent of the timing of pubertal onset, but for individuals this score was more variable. Year-1 growth response, expressed as growth rate or change in height SD score, was the best predictor of growth in subsequent years. Responses to therapy could not be reliably predicted from baseline anthropometric variables, plasma insulin-like growth factor I SD score, growth hormone levels. Final height assessment will be needed to determine the ultimate benefit of therapy.