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The effectiveness and safety of the new Russian drug Rastan® (recombinant human growth hormone) were evaluated in children with growth hormone deficiency (GHD) and Turner's syndrome (TS). An open-labeled clinical study of the drug was performed in 35 children with GHD or TS. The main efficacy criteria were growth changes and yearly calculated height velocity; the secondary criteria were changes in height SDS and IGF-1 and IGFBP-3 levels. Rastan® was subcutaneously injected daily for 6 months; the dose of the drug being 0.033 mg/kg in GHD and 0.05 mg/day in TS. All enrolled 35 patients completed the study. During the study, the patients' growth significantly increased in all the patients (P < 0 0001), in those with GHD (P < 0.0001) and TS (P < 0.0001). Height SDS statistically significantly increased in all the patients (P < 0.0001) and in the GHD (P < 0.0001) and TS (P < 0.0001) groups. Over 6 months of therapy, the average estimated height velocity was 12.4±3.76 cm/year. There were 2-3-fold increases in lower baseline IGF-1 and IGFBR levels. The advene reactions were mild and required no drug discontinuation. Rastan® was effective and well tolerated in patients with GHD or TS.

Isolated Growth Hormone Deficiency (IGHD) due to GH1 gene defects has a variable inheritance pattern: autosomal recessive, autosomal dominant, and X-linked. the autosomal dominantly inherited form, IGHD II, is mainly caused by heterozygous mutations of splicing around the exon 3/IVs3 boundary region of the GH1 gene resulting in exon 3 skipping of transcripts. We have previously reported findings on GH1 gene mutations in 28 russian patients with severe congenital IGHD (-3.22+/-1.2 height sDs at the age of 1yr); five heterozygous dominant negative splice site mutations in intron 2, intron 3, and exon 4 of the GH1 gene were identified in 32.1% of the cohort. In the present report we describe a novel 456G>A heterozygous mutation of splicing of the last base of the 3'-acceptor splice site of exon 4 within the GH1 in a 4.2-year old, extremely short (-5.32 height sDs) girl with congenital IGHD. the mutation involves a highly conserved GGGgtg sequence of the exon 4/IVs4 boundary region of the GH1 gene. the predicted effect of the 456 G>A mutation is perturbed splicing with possible skipping of exon 4 of the GH1 gene. the novel heterozygous 456 G>A mutation in exon 4 expands the spectrum of dominant negative splicing defects within the GH1 gene, responsible for congenital IGHD.

The purpose of the study was to evaluate the efficacy of growth hormone (GH) drug Saizen in a new formulation (lyophilizate for the preparation of solution for injections as 8-mg vials in combination with bacteriostatic solvent in cartridges) in children with GH deficiency and to determine whether a Van.Click syringe-pen was handy for injection of Saizen in the new formulation. Thirty children (7 girb and 23 boys) were treated for 6 months. Ten patients had isolated GT deficiency; 18 patients had multiple adenohypophyseal hormonal deficiency; de Morsiau's syndrome was observed in 2 patients. The dose of the test drug was 0.033 mg/kg/day. During 6-month treatment, Slzen showed a good growth-stimulating effect: the mean growth rate was 11.15±0.71 cm/year; there was a 2-3-fold increase in the baseline low levels of insulin-like growth factor (ILGF-1) and ILGF-CB-3. Over 6 months of treatment, there was a significant decrease in the sum of 4 measured fat folds, which suggests a reduction in the body's adipose tissue. Significant changes were observed in biochemical parameters during the performed therapy: the decrease in the levels of total cholesterol and low-density lipoproteins, which suggests the antiatherogenic effect of GH therapy on lipid metabolism; a significant increase in the level of calcium and phosphorus, the activity of alkaline phosphatase, which is 3.5 times greater than the normal values, which indicate the acceleration of bone metabolic processes. According to the evaluation made, there were no unfavorable phenomena or significant deviation from the normal laboratory parameters, including glucose values. By and large, Sizen tolerance may be regarded as good and its treatment is safe. The use of the autoinjector for GH administration is handy and atraumatic to patients.

Children, residents of the Russian Federation, with congenital isolated growth hormone deficiency, were screened for mutations of GH-1 gene, the main gene of this deficiency. Twenty-eight children from 26 families with total congenital isolated growth hormone deficiency were examined. Direct sequencing of GH-1 detected five splicing mutations in intron 2, intron 3, and exon 4, two of them were never described previously. Three dominant negative mutations of GH-1 splicing, the basis for autosomal dominant isolated growth hormone deficiency (type II), are presented: IVS2 -2A>T, IVS3 +2T>C, and IVS3 +1GA mutation can be regarded as the most incident in type II isolated growth hormone deficiency in the Russian population.

The study was undertaken to investigate the effectiveness and safety of 12-week use of the recombinant growth hormone (rGH) Nor-dithropin-Simplex (NovoNordisk, Denmark) in children with retarded intrauterine development (RIUD) and significant postnatal shortness. A group of examinees comprised 15 prepubescent children with RIUD without hormone growth hormone deficiency. The evaluation criteria were growth (absolute and SDS), the rate of growth (absolute and SDS), and the time course of changes in bone maturation, hormonal and biochemical parameters. Treatment included subcutaneous daily injections of Nordithropin-Simplex, 0.067 mg/kg, at night. Control examinations were made every 3 months. Intragroup birth height SDS averaged 3.61±1.15; body mass SDS was 3.65±0.71. Before treatment, the mean chronological age was 5.46+1.65years; the bone age averaged 1.42±0.70years less than the chronological one; growth SDS was 3.24+0.81; and growth rate SDS was -1.24±1.10. After 12-month rGH treatment, growth rate SDS increased up to 4.98±2.65 (p <0.0005), growth ∆ SDS for chronological age averaged 1.02±0.39 with variations from -3.24±0.81 to -2.22+0.78 (p < 0.0005). During 12-month therapy, bone age increase by, on the average, 0.91±0.42years. Two-fold dose rGH therapy, as compared with replacement therapy, was well tolerated and produced no serious side effects. It is concluded that 12-month therapy with Nordithropin-Simplex in a dose of 0.067 mg/kg/day in children with RIUD and significant postnatal growth retardation can induce acceleration of growth rates without causing a significant adverse reactions. Long-term multicenter centers are required to analyze the impact of rGH therapy on final growth, metabolic effects and to evaluate the safety of its long-term use.

Isolated GH deficiency (IGHD) is characterized by genetic heterogeneity, both in familial and sporadic cases. To determine if this statement can be applied to the Russian population, we performed screening for mutations in the GH-1 gene in children living in Russia with IGHD. Twenty-eight children from 26 families with total IGHD were studied. DNA fragments, covering each of four (2-5) exons of GH-1 were amplified using PCR. Single-strand conformation polymorphism analysis followed by direct DNA sequencing identified five heterozygous mutations of splicing in intron 2, intron 3, and exon 4 of GH-1; three of them were not previously reported. We concentrated here on dominant-negative mutations causing IGHD type II, which were as follows: 1) A>T transversion of the second base of the 3'-acceptor splice site of intron 2 (IVS2 -2A>T); 2) T>C transition of the second base of the 5'-donor splice site of intron 3 (IVS3 +2T>C); 3) G>A transition of the first base of the 5'-donor splice site of intron 3 (IVS3 +1G>A). Our data indicate allelic heterogeneity of IGHD type II (IGHD II). However, all mutations in Russian IGHD II patients affect splicing, a striking difference from the mutation spectrum of other IGHD forms. The IVS2 -2A>T mutation is the first identified mutation in intron 2 of GH-1. The 5'-donor splice site of intron 3 of GH-1 is a mutational hot spot, and the IVS3 +1G>A mutation can be considered to be a common molecular defect in IGHD II in Russian patients.

The prophet of Pit-1 gene (PROP1), a novel pituitary-specific homeodomain factor, has been proved to be one of the causative genes for combined pituitary hormone deficiency (CPHD). Recently, PROP1 mutations have been identified in CPHD families, including our Russian cohort. The 2-bp deletion, 296delGA (A301G302del), is the most common mutational hot spot. Furthermore, in our cohort, PROP1 mutations are more common in comparison with human POU1F1 gene mutations. Here we review the gene analysis of PROP1 in patients with CPHD.

To carry out the genetic screening for the common mutation in the first tyrosine kinase domain (TK1) of the fibroblast growth factor receptor 3 gene (FGFR3) in a Russian population, a cohort of 16 patients with hypochondroplasia diagnosed previously were studied, among them twelve familial cases and four sporadic cases. The heterozygous N540K FGFR3 mutation was detected in 9 cases (56.3%) due to that C1659A substitution in 6 patients and C1659G substitution in 3 patients, respectively. The ratios of familial and sporadic cases among patients which carried FGFR3 mutation were similar. Seven (43.7%) patients, negative cases of N540K mutation, were all familial cases. Our results support evidence of similar frequency of common type N540K mutation of FGFR3 in Russian hypochondroplasia and of the genetic heterogeneity of hypochondroplasia, suggesting the need for further search for responsible molecular abnormalities for phenotypically similar hypochondroplasia patients negative for TK1 domain mutation in FGFR3, reported in hypochondroplasia.

Combined pituitary hormone deficiency (CPHD) has an incidence of approximately 1 in 8000 births. Although the proportion of familial CPHD cases is unknown, about 10% have an affected first degree relative. We have recently reported three mutations in the PROP1 gene that cause CPHD in human subjects. We report here the frequency of one of these mutations, a 301-302delAG deletion in exon 2 of PROP1, in 10 independently ascertained CPHD kindreds and 21 sporadic cases of CPHD from 8 different countries. Our results show that 55% (11 of 20) of PROP1 alleles have the 301-302delAG deletion in familial CPHD cases. Interestingly, although only 12% (5 of 42) of the PROP1 alleles of our 21 sporadic cases were 301-302delAG, the frequency of this allele (in 20 of 21 of the sporadic subjects given TRH stimulation tests) was 50% (3 of 6) and 0% (0 of 34) in the CPHD cases with pituitary and hypothalamic defects, respectively. Using whole genome radiation hybrid analysis, we localized the PROP1 gene to the distal end of chromosome 5q and identified a tightly linked polymorphic marker, D5S408, which can be used in segregation studies. Analysis of this marker in affected subjects with the 301-302delAG deletion suggests that rather than being inherited from a common founder, the 301-302delAG may be a recurring mutation.

To ascertain the molecular background of combined pituitary hormone deficiency, screening for mutations in the pituitary-specific transcription factor (Pit-1/GHF-1) gene (PIT1) was performed on a cohort of 15 children from Russia with combined growth hormone (GH)/prolactin (Prl)/thyroid-stimulating hormone (TSH) deficiency. The group of patients, suspected of PIT1 mutations, consisted of four familial cases (seven patients) and eight sporadic cases. All had complete GH deficiency and complete or partial Prl and TSH deficiency. Direct sequencing of all six exons of PIT1 and its promoter region showed a C to T transition mutation at codon 14 of exon 1 in a 3 8/12-year-old girl. This novel PIT1 mutation results in a proline to leucine substitution (P14L). The patient was heterozygous for mutant and normal alleles. The heterozygous P14L mutation was also present in her mother as well as in her maternal aunt and grandmother, all of whom were phenotypically normal. There was no mutation in the father's DNA, suggesting the need for reevaluation of genomic imprinting. In other children of our series, no mutation in PIT1 or in its promotor region was identified. This is the first report on the analysis of PIT1 and its promoter region in Russian children with GH/Prl/TSH deficiency. However, as the involvement of PIT1 mutation is rare in Russia, the other negative cases need to be analyzed for another candidate gene responsible for combined GH/Pr/TSH deficiency.

Combined pituitary hormone deficiency (CPHD), including growth hormone (GH), prolactin (Prl) and thyroid-stimulating hormone (TSH) in children is now considered a heterogeneous syndrome. Recent findings on expression of mouse pituitary-specific homeodomain factors demonstrate dependence of adenopituitary ontogeny on interactive expression of these factors, suggesting their involvement in etiology of CPHD. Prophet of Pit-1 (Prop-1) gene, a novel pituitary-specific homeodomain factor, was analyzed in 14 Russian children with CPHD, in whom Pit-1 gene was intact. We found a mutational hot spot in three patients from two families in homeodomain part of the second exon of Prop-1 gene. The common 2-base pair deletion (GA296) in the homozygous state resulted in a Serine to Stop codon (S109X) substitution and generated a truncated Prop-1 protein. Parents were phenotypically normal and heterozygous for GA296 deletion, indicating an autosomal recessive inheritance. These results demonstrate a novel type of Prop-1 gene mutation as one of the causes of CPHD in Russian patients.

The efficacy and safety of SAISEN, a recombinant human growth hormone obtained from mammalian cells, was tested in children with hypophyseal nanism. The treatment duration was 1 year. The results indicate that SAISEN (ARES-SERONO) is a highly effective and safe preparation of growth hormone, noticeably stimulating the growth rate both in previously untreated children with somatotropic insufficiency, and in those previously treated with STH preparations. Therapy with SAISEN was not associated with any side effects, as shown by both clinical and laboratory data.

The paper treats of the data on the use of radioimmunoassays for the measurement of steroid hormone content (17-hydroxyprogesterone, testosterone) in blood serum and saliva of children with congenital adrenocortical dysfunction. It is confirmed that these hormones can be detected in saliva only with the aid of highly sensitive and highly specific RIA systems. A positive correlation has been established between hormonal levels in both biological fluids.

It has been shown that data on circadian rhythms of 17-hydroxyprogesterone and testosterone content in children with congenital dysfunction of the adrenal cortex before and during treatment can be used in the control of treatment adequacy. Regular adequate intake of prednisolone brings about a decrease in hormonal content both in the blood and the saliva. Serial collection of salivary samples from children over 3 years of age is feasible and painless as compared to venous puncture, causing no adverse response on the child's part.