Final height in girls with turner syndrome after long-term growth hormone treatment in three dosages and low dose estrogens.

Although GH treatment for short stature in Turner syndrome is an accepted treatment in many countries, which GH dosage to use and which age to start puberty induction are issues of debate. This study shows final height (FH) in 60 girls with Turner syndrome treated in a randomized dose-response trial, combining GH treatment with low dose estrogens at a relatively young age. Girls were randomly assigned to group A (4 IU/m(2).d; approximately 0.045 mg/kg/d), group B (first year, 4 IU/m(2).d; thereafter 6 IU/m(2).d), or group C (first year, 4 IU/m(2).d; second year, 6 IU/m(2).d; thereafter, 8 IU/m(2).d). After a minimum of 4 yr of GH treatment, at a mean age of 12.7 +/- 0.7 yr, low dose micronized 17beta-estradiol was given orally. After a mean duration of GH treatment of 8.6 +/- 1.9 yr, FH was reached at a mean age of 15.8 +/- 0.9 yr. FH, expressed in centimeters or SD score, was 157.6 +/- 6.5 or -1.6 +/- 1.0 in group A, 162.9 +/- 6.1 or -0.7 +/- 1.0 in group B, and 163.6 +/- 6.0 or -0.6 +/- 1.0 in group C. The difference in FH in centimeters, corrected for height SD score and age at start of treatment, was significant between groups A and B [regression coefficient, 4.1; 95% confidence interval (CI), 1.4, 6.9; P < 0.01], and groups A and C (coefficient, 5.0; 95% CI, 2.3, 7.7; P < 0.001), but not between groups B and C (coefficient, 0.9; 95% CI, -1.8, 3.6). Fifty of the 60 girls (83%) had reached a normal FH (FH SD score, more than -2). After starting estrogen treatment, the decrease in height velocity (HV) changed significantly to a stable HV, without affecting bone maturation (change in bone age/change in chronological age). The following variables contributed significantly to predicting FH SD score: GH dose, height SD score (ref. normal girls), chronological age at start of treatment, and HV in the first year of GH treatment. GH treatment was well tolerated. In conclusion, GH treatment leads to a normalization of FH in most girls, even when puberty is induced at a normal pubertal age. The optimal GH dosage depends on height and age at the start of treatment and first year HV.

[Visual impairment in juvenile diabetes mellitus due to optic atrophy: Wolfram's syndrome]. / Opticusatrofie als oorzaak van visusstoornissen bij juveniele diabetes mellitus: het wolframsyndroom.

Wolfram's syndrome is a rare neurodegenerative disorder, which usually first manifests itself around the age of 6 years. The diagnosis can be made based on the characteristics incorporated in the 'DIDMOAD' acronym: diabetes insipidus, diabetes mellitus, optic atrophy and deafness. We present 2 boys, diagnosed with diabetes mellitus at the age of 5 and 4 years respectively. Both children developed optic atrophy over the years. These 2 cases illustrate that alongside diabetic retinopathy, possible syndromes, such as Wolfram's syndrome, should also be considered in children with diabetes mellitus and visual impairment.

Genome-wide SNP array analysis in patients with features of sotos syndrome.

BACKGROUND: Sotos syndrome is characterized by overgrowth, facial dysmorphism and learning impairment. Haploinsufficiency of NSD1 accounts for approximately 60-90% of the patients. Consequently, a considerable number of patients with features of Sotos syndrome remain without a molecular diagnosis. To date, target-gene approaches in these patients have not been successful. METHODS: Twenty-six Sotos syndrome-like patients were analyzed with a high-resolution whole-genome SNP array, and segregation was studied in the parents. RESULTS: Four possible pathogenic copy-number variants including deletions of 10p12.32-p12.31, 14q13.1, Xq21.1-q21.31 and a duplication of 15q11.2-q13.1 were detected. They varied in size from 155 kb to 13.36 Mb. The 10p12.32-p12.31 deletion revealed a candidate gene (PLXDC2) for overgrowth. The 14q13.1 deletion affected only the NPAS3 gene and the patient carrying this deletion displayed mental retardation as the main feature. The Xq21.1-q21.31 deletion and the 15q11.2-q13.1 duplication encompassed multiple genes of which several could be associated with phenotypic expression. CONCLUSION: The high-resolution genome-wide SNP array approach resulted in a detection rate of 15% of novel abnormalities and is therefore a powerful method to attain a molecular diagnosis in Sotos syndrome-like patients. Identified candidate genes provide directions for future screening of larger patient cohorts.

Adult height in children with growth hormone deficiency: a randomized, controlled, growth hormone dose-response trial.

AIM: To investigate the effect of 2 growth hormone (GH) doses on adult height (AH) in GH deficiency (GHD). METHODS: A multicenter, randomized, controlled dose-response trial compared attained AH minus target height (TH) between children receiving 0.7 mg/m(2)/day biosynthetic GH (approx. 0.025 mg/kg/day) or 1.4 mg/m(2)/day (approx. 0.050 mg/kg/day). The patients enrolled in the trial were 20 'naïve' GHD children (had not received GH before) and 15 'transfer' GHD children (already on GH for at least 1 year). RESULTS: In the naïve group, the mean +/- SD AH minus TH was -5.3 +/- 6.1 and -2.2 +/- 6.9 cm in patients on 0.7 and 1.4 mg/m(2)/day, respectively (mean +/- SE difference 3.1 +/- 2.9; p = 0.3). In the transfer group, the mean +/- SD AH minus TH was -4.4 +/- 6.4 and +0.6 +/- 7.0 cm in patients on 0.7 and 1.4 mg/m(2)/day, respectively (mean +/- SE difference 5.0 +/- 3.5; p = 0.17). Spontaneous puberty started 1.1 years earlier in children on 1.4 compared to 0.7 mg/m(2)/day. Induction of puberty was more often delayed in transfer children on 0.7 than on 1.4 mg/m(2)/day. CONCLUSION: In our GHD patients, AH was 4-5 cm less than TH in patients on 0.7 mg/m(2)/day GH, while it was 0-2 cm less in patients on 1.4 mg/m(2)/day GH, but this difference did not reach statistical significance, probably due to limited numbers of patients, considerable variability in the growth response and earlier spontaneous puberty and pubertal induction in the children on 1.4 mg/m(2)/day.

Efficacy and safety of oxandrolone in growth hormone-treated girls with turner syndrome.

CONTEXT AND OBJECTIVE: GH therapy increases growth and adult height in Turner syndrome (TS). The benefit to risk ratio of adding the weak androgen oxandrolone (Ox) to GH is unclear. DESIGN AND PARTICIPANTS: A randomized, placebo-controlled, double-blind, dose-response study was performed in 10 centers in The Netherlands. One hundred thirty-three patients with TS were included in age group 1 (2-7.99 yr), 2 (8-11.99 yr), or 3 (12-15.99 yr). Patients were treated with GH (1.33 mg/m(2) . d) from baseline, combined with placebo (Pl) or Ox in low (0.03 mg/kg . d) or conventional (0.06 mg/kg . d) dose from the age of 8 yr and estrogens from the age of 12 yr. Adult height gain (adult height minus predicted adult height) and safety parameters were systematically assessed. RESULTS: Compared with GH+Pl, GH+Ox 0.03 increased adult height gain in the intention-to-treat analysis (mean +/- sd, 9.5 +/- 4.7 vs. 7.2 +/- 4.0 cm, P = 0.02) and per-protocol analysis (9.8 +/- 4.9 vs. 6.8 +/- 4.4 cm, P = 0.02). Partly due to accelerated bone maturation (P < 0.001), adult height gain on GH+Ox 0.06 was not significantly different from that on GH+Pl (8.3 +/- 4.7 vs. 7.2 +/- 4.0 cm, P = 0.3). Breast development was slower on GH+Ox (GH+Ox 0.03, P = 0.02; GH+Ox 0.06, P = 0.05), and more girls reported virilization on GH+Ox 0.06 than on GH+Pl (P < 0.001). CONCLUSIONS: In GH-treated girls with TS, we discourage the use of the conventional Ox dosage (0.06 mg/kg . d) because of its low benefit to risk ratio. The addition of Ox 0.03 mg/kg . d modestly increases adult height gain and has a fairly good safety profile, except for some deceleration of breast development.