The childhood component of the ICP model is appropriate for growth analysis of short Israeli children.

OBJECTIVE: To determine whether the childhood component of the infancy-childhood-puberty (ICP) model is appropriate for growth analysis of short Israeli children. SUBJECTS AND METHODS: From 204 short, prepubertal children, 2-16 years of age, 1,516 height measurements were analyzed. For each child's measurements, a best-fitted line based on C equation of ICP has been drawn and the distribution of measurement points around that line was calculated. RESULTS: Ninety percent of the measurements were at a distance of no more than +/- 2 cm from the best-fitted ICP line. CONCLUSION: The C component of ICP model can be used as a growth analysis tool for shorter than average, prepubertal, Israeli children, older than 2 years of age.

Short stature in carriers of recessive mutation causing familial isolated growth hormone deficiency.

Isolated growth hormone deficiency (IGHD) IB is an autosomal recessive disorder characterized by a good response to exogenous growth hormone (GH) treatment without development of anti-GH antibodies. Patients with IGHD IB were found to be compound heterozygotes for deletion and frameshift mutations as well as homozygotes for splicing mutations in the GH-1 gene. Recently, a novel splicing mutation in the GH-1 gene was identified in an extended, consanguineous Arab-Bedouin family from Israel with IGHD IB. Prior to the identification of this mutation, a considerable number of children with short stature in this family were found normal on pharmacological stimulation for GH release. This observation prompted a genotype/phenotype correlation of potential heterozygotes in the family. Carriers of the mutant GH-1 allele were found as a group to have a significantly shorter stature than normal homozygote (mean standard deviation scores, 1.67 and -0.40, respectively, P<0.05). Moreover, 11 of 33 (33%) heterozygotes, but only 1 of 17 (5.9%) normal homozygotes, had their height at 2 or more SD below the mean. Overall, 48.5% of studied heterozygotes were found to be of appreciably short stature with height at or lower than the 5th centile (> or = -1.7 SD), whereas only 5.9% of the normal homozygotes did (P<0.004). This phenomenon of heterozygotes for a recessive mutation in the GH-1 gene manifesting short stature, might imply that some such mutations may account for non-GH deficiency reduced height in the general population.

Growth hormone deficiency type IB caused by cryptic splicing of the GH-1 gene.

We have found a novel mutation in intron 4 of the GH-1 gene in a Bedouin kindred with isolated growth hormone deficiency type IB (IGHD IB). RFLP analysis suggested linkage between the GH-1 gene and IGHD. Nested PCR amplification followed by single stranded conformation polymorphism (SSCP) analysis indicated sequence variation between introns 2 and 4. Sequencing showed a G-->C transversion at the fifth base in the splice donor region of intron 4. Affected individuals were homozygous for the mutation, which creates a new Mae III restriction site. Reverse transcription and PCR of GH-1 transcripts in EBV transformed lymphocytes indicated predominance of a species lacking 73 bp of exon 4. Amplification with a bridging primer showed that the same mRNA species is present in lymphocytes from normal individuals. The first 102 amino acids of the predicted protein are identical to wild-type GH, but the next 94 amino acids are completely divergent.

Once versus twice daily injections of growth hormone in children with idiopathic short stature.

The aim of this study was to compare the growth response of 22 short pre-pubertal children without growth hormone deficiency, treated with a single daily growth hormone injection (group A), to the growth response of 27 similar children, treated with the same daily dose divided into 2 subcutaneous injections per day (group B), for 1 y, in a randomized study. GH treatment significantly promoted growth parameters, height standard deviation score and height velocity standard deviation score in both groups. Serum insulin-like growth factor I was also increased. There were no significant differences in growth response, serum IGF-I levels, or the advance in bone age between the two study groups after 1 y of GH therapy. We conclude that twice daily s.c. growth hormone injections provide no advantages over once daily injection of the same dose in promoting the linear growth of short children without growth hormone deficiency.

Growth hormone therapy with three dosage regimens in children with idiopathic short stature. European Study Group Participating Investigators.

OBJECTIVE: In children with idiopathic short stature (ISS) we studied the growth-promoting effect at 4 years of recombinant human growth hormone (rhGH) therapy in three dose regimens and evaluated whether increasing the dosage after the first year could prevent a decline in height velocity (HV). DESIGN: Included were 223 patients who were treated with subcutaneous administrations of rhGH 6 days per week. They were randomized to three groups: 3 IU/m2 body surface/day, 4.5 IU/m2/day, and 3 IU/m2/day during the first year and 4.5 IU/m2/day thereafter, corresponding with dosages of 0.2 and 0.3 mg/kg body weight/week, respectively. Growth was compared with a standard of 229 untreated children with ISS [ISS standard]. RESULTS: During the first year of treatment HV almost doubled and was higher with 4.5 IU/m2 than with 3 IU/m2. In the second year HV no longer differed among the groups, but increasing the dosage slowed the rate of the fall of HV. During 4 years of therapy the height SD score for age increased by a mean (SD) of 2.5 (1.0) [ISS standards], or 1.2 (0.7) (British standards), bone age increased by 4.8 (1.3) years, and predicted adult height SD score increased by 1.5 (0.7). After 4 years the results of the group with 4.5 IU/m2 were slightly better than those of the other groups. When dropouts were included in the analysis (assuming a stable height SD score after discontinuation of rhGH therapy), height gain was still significant. CONCLUSIONS: During 4 years of rhGH therapy, growth and final height prognosis improved, slightly more with 4.5 IU/m2 than with 3 IU/m2 or 3 to 4.5 IU/m2. However, bone age advanced on average 4.8 years during this period; therefore, any effect on final height will probably be modest.

Increase of serum lipoprotein (a) levels during growth hormone therapy in normal short children.

UNLABELLED: We studied the effect of growth hormone (GH) therapy on serum lipoprotein levels and the atherogenic index in short children without GH deficiency. Fasting blood samples were collected from ten (eight males) normal, short, prepubertal children, aged 6-12 years, before, during a 1-year course of GH therapy (0.1 IU/Kg/day), and 3 months after the cessation of GH administration. An increase in serum lipoprotein(a) [Lp(a)] levels of (mean% +/- SEM) 43 +/- 14, 58 +/- 18, 61 +/- 17 above the baseline levels was noted at 3 months (P < 0.05), 6 months (P < 0.01), and 1-year (P < 0.01) respectively after the beginning of GH administration. (ANOVA, P < 0.01). An inverse relationship between baseline serum Lp(a) concentrations and the percentage increment in Lp(a) after 9 months of GH therapy (r = -0.65, P < 0.05) was observed. GH therapy over a period of 1 year had no effect on plasma cholesterol, triglycerides, low density lipoprotein-cholesterol (LDL-C), high density lipoprotein cholesterol [HDL-C] concentrations and the atherogenic index. Three months after the cessation of GH therapy, serum Lp(a) levels were not significantly different from the pre-treatment values. CONCLUSIONS: Serum Lp(a) concentrations remained above pretreatment values during a 1-year period of GH treatment in short children without GH deficiency and declined shortly after cessation of therapy. Since GH therapy for short children without GH deficiency usually continues for several years, we suggest that serum Lp(a) levels should be determined and followed regularly in such children under prolonged GH therapy.

A single amino acid substitution in the putative redox partner-binding site of P450c17 as cause of isolated 17,20-lyase deficiency.

The molecular basis of isolated 17,20-lyase deficiency was clarified in a newborn male patient from Israel with micropenis, undescended testes, and hormonal pattern consistent with isolated 17,20-lyase deficiency. Analysis of the CYP17 gene revealed the presence of a compound heterozygosity. One allele carries a single base pair deletion (T at position 198 in exon 1) leading to a frame shift with the introduction of a premature stop codon, TGA, at residue 74 in place of Val. The other allele bears a missense mutation due to a single base change, T to G, which substitutes Phe417 with Cys. The proof of heterozygosity was possible via amplification and direct sequencing of genomic DNA fragments from the parents and the healthy brother of the index case. We could demonstrate that the mother is the carrier of the nonsense mutation and the father of the missense mutation. The brother carries two normal alleles for the CYP17 gene. The nonsense mutation gives no functional product. The missense mutation causes the synthesis of a protein that retains 17 alpha-hydroxylase activity but virtually no 17,20-lyase activity. Experiments based on the use of an electron donor independent from enzyme binding (iodosobenzene) demonstrated that the addition of electrons restores, at least in part, in vitro 17,20-lyase activity, with no significant influence on the 17 alpha-hydroxylase activity. This suggests that the electron transfer system plays a major role in the differential regulation of the two P450c17 activities. This is the first case of mutated CYP17 in which the in vitro model corresponds to the in vivo situation.

Subnormal cortisol response to adrenocorticotropin in isolated partial 17,20-lyase deficiency.

We describe three male children from a Bedouin clan, two of whom are siblings, who have various degrees of incomplete virilization due to isolated 17,20-lyase deficiency. The patients have low (basal and post ACTH or hCG stimulation) plasma testosterone and androstenedione levels. An abnormally high plasma 17-hydroxyprogesterone concentration was detected. A favorable response following local testosterone administration was seen in two patients. Surprisingly, an unexplained flat cortisol response to ACTH test was also noted. Although no biochemical model can yet adequately explain the impairment in cortisol response to ACTH in these patients, it seems prudent to take this lack of cortisol response into consideration. We therefore recommend hydrocortisone supplement during moderate to severe stress.

Spontaneous growth in idiopathic short stature. European Study Group.

Documenting the spontaneous growth pattern of children with idiopathic short stature (ISS) should be helpful in evaluating the effects of growth promoting treatments. Growth curves for children with ISS were constructed, based on 229 untreated children (145 boys and 84 girls) from nine European countries. The children were subdivided according to target range and onset of puberty, and the growth of these subgroups was evaluated from standard deviation scores (SDS). At birth, children with ISS were already shorter than normal (means; boys -0.8 SDS, girls -1.3 SDS). Height slowly decreased from -1.7 SDS at the age of 2 years to -2.7 SDS at the age of 16 years in boys and 13 years in girls. Final height was -1.5 SDS in boys and -1.6 SDS in girls (mean (SD): boys 164.8 (6.1) cm, girls 152.7 (5.3) cm)), which was 5-6 cm below their target height. The onset of puberty was delayed (boys 13.8 (1.3) years, girls 12.9 (1.1) years). Subclassification resulted in similar growth curves. These specific growth data may be more suitable for evaluating the effects of growth promoting treatments than population based references.

An early rise in urine N-telopeptide predicts the growth response of normal prepubertal short children to growth hormone therapy.

The effects of growth hormone (GH) therapy on biochemical markers of bone turnover were investigated in 11 short prepubertal children without GH deficiency by measuring serum osteocalcin, a marker for bone formation, and urinary concentrations of pyridinium cross-linked amino acids of collagen (PCL), and the peptide-bound pyridinoline residue N-telopeptide (NT), which are specific markers for bone resorption. GH treatment for three months increased bone turnover in this group of children: urinary PCL concentrations increased from 69 +/- 6.2 to 114 +/- 9.3 nmol/mmol Cr (p < 0.01), and urinary NT levels increased from 512 +/- 65 to 766 +/- 74 pmol BCE/mumol Cr (p = 0.058). Serum osteocalcin concentrations increased from 13.64 +/- 2.57 ng/ml to 26.45 +/- 1.39 ng/ml (p < 0.01). The increment in 12-hour urinary concentrations of PCL was highly correlated with the increment in 12-hour urinary NT levels (r = 0.92, p < 0.01). Stepwise multiple regression analysis revealed that the urinary concentrations of NT after 3 months of GH therapy were the best predictor of growth after 12 months of treatment (r = 0.78, F = 7.9, p = 0.037).

Short-term growth hormone therapy increases serum lipoprotein (a) levels in normal short children without growth hormone deficiency.

We investigated the short-term effect of GH (0.1 IU/kg/day) on serum lipoprotein (a) [Lp(a)] in 8 normal short children aged 6-12 years. GH increased serum Lp(a) concentrations in all the children studied. An increase to 107 +/- 5, 161.6 +/- 14.7 and 152.5 +/- 18.5% (mean +/- SE) of baseline levels was observed after 2 (p = NS), 6 (p < 0.01) and 12 weeks (p < 0.05), respectively. Our results suggest that GH therapy may pose a significant influence on Lp(a) serum levels in non-GH-deficient short children.

Ethical and cross cultural questions concerning pediatric clinical trials.

During a clinical trial of recombinant growth hormone in a population of short stature but otherwise healthy children the following ethical problems were confronted: What are the prospective benefits compared with the foreseeable risks associated with this therapy? Can the doctor really inform the parent and/or the child about the outcomes of the treatment? Who must make the decision about participation in the trial? From which age can the child himself decide about continuing or dropping out? Since the treatment requires frequent check-ups for years, to what extent does the child become psychologically dependent upon the medical profession? Given this possibility, is the child really free to withdraw from the treatment? Is there a conflict between the doctor's autonomy to propose the treatment and the patient's autonomy to decide about participation? Is there a clear threshold between life-threatening problems and minor, cosmetic problems? These dilemmas are discussed in a cross-cultural context.

High prevalence of thyroxine-binding globulin deficiency among Bedouin infants in southern Israel.

A high prevalence of thyroxine-binding globulin deficiency was found among Bedouin newborns in the Negev area (southern Israel) during a study lasting 2 years. This prevalence is significantly higher than those reported in other populations. Moreover, thyroxine-binding globulin deficiency was found to be more common than congenital hypothyroidism among the Bedouin. The results of thyroxine-binding globulin analysis in four patients may suggest the coexistence of at least two different mutations among the Bedouin population.

The new syndrome of congenital hypoparathyroidism associated with dysmorphism, growth retardation, and developmental delay--a report of six patients.

We describe six children of Arab origin with a syndrome of congenital hypoparathyroidism, severe growth retardation, developmental delay, and dysmorphism. The most prominent dysmorphic features were microcephaly, facial and dental anomalies, and small hands and feet. Bone age was markedly retarded. Neither immunological nor chromosomal abnormalities were found. Insulin-like growth factor-1 serum levels, measured in two patients, were abnormally low.

Thyrotropin secreting pituitary adenoma associated with hypopituitarism and diabetes insipidus in an adolescent boy.

A 13 year-old boy was referred to our hospital because of several months of school performance deterioration, behavioral changes and secondary enuresis. Hyperthyroidism, diabetes insipidus and hypopituitarism due to thyrotropin secreting pituitary macroadenoma were found. Six weeks of therapy with octreotide failed to reduce the serum TSH levels and the tumor size. Transsphenoidal pituitary surgery had a transient effect on serum TSH levels as the patient redeveloped hyperthyroidism with elevated serum TSH levels. Several months had elapsed from the time the patient first presented with the symptoms to the time the diagnosis was made. Thyrotropin secreting pituitary adenoma is a rare cause of hyperthyroidism. Recognizing the signs of the disease might lead to early diagnosis and might improve the prognosis.

Effect of growth hormone treatment on quality of life of short-stature children.

While enhanced growth velocity is a well-established benefit following the initiation of growth hormone treatment (GHT), the potential benefit of GHT on quality of life (QOL) of short-stature children has not yet been documented. We compare QOL of two groups of short-stature children who attended the Endocrine Unit (EU) and were 2 SD or more below the average for age and gender. The first group included 96 patients of whom 65 were without any underlying disease, 15 had classical GH deficiency and 16 had Turner syndrome or renal disease. These patients were on GHT for at least 2 years. The other group included 33 patients. Owing to lack of resources to include these 33 patients in a clinical trial, they did not get GHT. They were normal variant of short stature, and their height was similar to the height of the 65 children included in the first group. QOL was assessed using self-administered questionnaires, which were filled out by the patients on their regular visit to the EU. QOL was defined in terms of school achievements, leisure activities, emotional and physical self-esteem, relationships with peers and family members. No significant differences were found between the two groups. The mean scores for the different domains of QOL ranged between 2.6 and 3.8 on a scale ranging from 1 (very pessimistic view) to 4 (very optimistic view).

Age as a determinant of the impact of growth hormone therapy on predicted adult height.

OBJECTIVE: Final adult height is determined by both childhood and pubertal growth. The later is a function of growth velocity and bone maturation, and both are regulated by growth hormone. In a study of the safety and efficacy of GH therapy, we analysed the impact of age on bone maturation and predicted adult height. PATIENTS AND METHODS: The subjects were 65 male patients with GH deficiency, as diagnosed by pharmacological or physiological tests, who participated in a multicentre trial and completed 3 years of hGH therapy. The age range at initiation of therapy was 3.1-15.7 years. Subcutaneous injections of hGH were given in a dose of 0.3 mg/kg/week, in thrice-weekly doses. Calculation of the adult height prediction was performed on annual growth parameters using the Bailey-Pinneau, TW-II and Roche methods. RESULTS: The rate of pubertal advancement correlated positively with the child's age at initiation of therapy. The bone age advanced in positive correlation with chronological age, and by the end of 3 years of hGH therapy the delta-bone age/delta-chronological age ratio increased to 1.5 for children with an age at start of therapy of 10.7 years. During the adolescent years, the predicted gained height over 3 years of therapy declined, in correlation with age, and became negative at a therapy-initiation age of 12.9 years. CONCLUSIONS: In a retrospective analysis of a group of children with heterogeneous GH secretory ability, GH induced acceleration of growth, around the age of normal puberty, advanced the age of pubertal onset and accelerated pubertal progression which, in turn, expedited bone maturation and thereby restricted predicted adult height gain from hGH therapy.

Effect of long-term growth hormone therapy on bone age and pubertal maturation in boys with and without classic growth hormone deficiency.

We evaluated the effect of growth hormone (GH) therapy on bone age, pubertal maturation and predicted adult height in two groups of boys treated for 4 years: 40 growth hormone-deficient boys who had growth hormone response to provocative stimulation < 10 micrograms/L (GHD group) and 43 boys whose stimulated growth hormone > or = 10 micrograms/L (group with neurosecretory dysfunction (NSD)). All patients had a subnormal integrated concentration of growth hormone < or = 3.2 micrograms/L, height < -2 SD, growth velocity < 4.5 cm/yr, and bone age < or = -2 SD for chronologic age. Patients were treated with recombinant growth hormone, 0.1 mg/kg per dose given three times a week. The pretreatment height SD of the GHD group (-3.6 +/- 1.0) was less than that of the NSD group (-2.7 +/- 0.7; p < 0.001). After 4 years of therapy, both groups had catch-up growth (GHD group to -2.0 +/- 1.3 height SD (n = 35), and NSD group to -1.4 +/- 0.7 height SD (n = 32)); the rate of height SD gain was better in patients with GHD (p < 0.01). The response to growth hormone was inversely related to pretreatment chronologic age (p < 0.001). The Tanner-Whitehouse II predicted adult height improved for both groups: +9.3 +/- 7.7 cm in the GHD group, giving an adult height SD of -0.9 +/- 1.0, and +5.4 +/- 5.5 cm in patients with NSD, for an adult height SD if -0.8 +/- 0.7. Testosterone levels became higher in the NSD group after 2 years and remained higher at year 4. We conclude that patients respond favorably to growth hormone therapy and in a manner similar to patients with GHD. Initiation of therapy at a younger age gives a greater improvement in gained height and predicted adult height.