Catch-up growth in autosomal dominant isolated growth hormone deficiency (IGHD type II).

OBJECTIVE: Data on the GH-induced catch-up growth of severely GH-deficient children affected by monogenetic defects are missing. PATIENTS: Catch-up growth of 21 prepubertal children (6 females, 15 males) affected with IGHD type II was analyzed in a retrospective chart review. At start of therapy, mean age was 6.2 years (range, 1.6-15.0), mean height SDS was -4.7 (-7.6 to -2.2), mean IGF-I SDS was -6.2 (-10.1 to -2.2). GH was substituted using a mean dose of 30.5microg/kg*d. RESULTS: Catch-up growth was characterized by a mean height gain of +0.92, +0.82, and +0.61 SDS after 1, 2, and 3 years of GH therapy, respectively. Mean height velocities were 10.7, 9.2 and 7.7cm/year during the first three years. Mean duration of complete catch-up growth was 6 years (3-9). Mean height SDS reached was -0.97 (-2.3 to +1.1), which was within the range of the estimated target height of -0.60 SDS (-1.20 to -0.15). The younger and shorter the children were at start of therapy the better they grew during the first year independent of the dose. Mean bone age was delayed at start by 2.1 years and progressed by 2.5 years during the first two years of therapy. Incomplete catch-up growth was caused by late initiation or irregular administration of GH in four cases. CONCLUSIONS: Our data suggest that GH-treated children with severe IGHD show a sustained catch-up growth over 6 years (mean) and reach their target height range. This response to GH is considered to be characteristic for young children with severe growth retardation due to IGHD.

Dominant transmission of prepubertal gynecomastia due to serum estrone excess: hormonal, biochemical, and genetic analysis in a large kindred.

Increased extraglandular aromatization has been reported to cause the rare entity of familial gynecomastia. Recently heterozygous inversions at the p450 aromatase gene promotor locus were detected in two different families with this syndrome. We studied a family in which seven affected males over three generations had inherited prepubertal gynecomastia in an autosomal dominant manner. The proband developed gynecomastia at 11.5 yr, entered puberty at 12.5 yr, but was incompletely virilized at 19 yr. A similar development was observed in his affected stepbrother and one first-degree cousin. All three boys had acceleration of prepubertal growth and bone age. The older two had a diminished pubertal growth spurt and precocious growth arrest, but their final heights were within the range of their target height. In addition, the maternal grandfather and three maternal uncles were affected, who all had been mastectomized. The mother of the proband had normal age at menarche and no macromastia. Estrone levels of the proband and the other affected boys were elevated, 17beta-estradiol levels were high-normal, and testosterone levels were low. Hormonal analyses of the affected adults, who had all fathered children, revealed pathologically low serum testosterone levels but normal to high-normal levels of estradiol and estrone. The mother of the proband had elevated estrone levels. Treatment of the proband was more effective with anastrozole than with testolactone and increased the initially reduced testes volume to normal size, promoted virilization, and normalized serum estrone and testosterone levels. Neither preadipocytes from breast fat tissue of the affected stepbrother nor peripheral lymphocytes of the affected boys exhibited increased aromatase activity in culture. Therefore, these cells can be excluded from being the source of estrone excess. In addition, serum of the proband and his stepbrother did not contain factors promoting aromatase activity as assayed using preadipocytes from control individuals.A repeat polymorphism of the p450 aromatase gene cosegregated with the disease phenotype in the family, making a mutation of the p450 aromatase gene likely. Single-strand conformational polymorphism analysis of the known alternative untranslated exons and all coding exons of the p450 aromatase gene did not indicate any mutation. In addition, fluorescent in situ hybridization analysis using four probes covering the promotor region did not reveal the presence of any major inversion at this locus. In conclusion, preadipocytes and blood cells were excluded as the cell source of increased aromatization. Fluorescent in situ hybridization and single-strand conformational polymorphism analyses did not reveal any mutation of the p450 aromatase gene, but an intragenic polymorphic marker cosegregated with the disease phenotype. Excess of serum estrone in the presence of normal 17beta-estradiol levels may be the only indicative serum parameter of this mild manifestation of aromatase excess syndrome, which includes prepubertal gynecomastia and moderate hypogonadism in men but not necessarily short stature. In women, this mode of aromatase excess may remain clinically inapparent.

IGF-I sensitivity in Silver-Russell syndrome with IGF2/H19 hypomethylation.

BACKGROUND: Silver-Russell syndrome (SRS) is characterized by intrauterine and postnatal growth retardation, typical facial appearance and body asymmetry. The mechanism of growth retardation is unclear. 50% of the patients have a paternal chromosome 11 epimutation-DNA hypomethylation of the imprinting center region 1 (ICR1) of the insulin-like growth factor 2 (IGF2)/H19 locus. SRS children who carry such an epimutation have increased levels of IGF-I and IGFBP-3 in relation to their stature and body weight, suggesting IGF-I resistance. No IGF-I receptor (IGF-1R) defect has been discovered. Therefore, another mechanism, probably an IGF-I post-receptor signaling defect, might be present. OBJECTIVE: The aim of this in-vitro study was to examine: 1) if IGF-I- and IGF-II-induced fibroblast growth is different in SRS children with IGF2/H19 hypomethylation compared to controls; and 2) whether there is IGF-I insensitivity in this subgroup of SRS children due to IGF-I post-receptor signaling defects. DESIGN: Four SRS patients (two males, two females; 9.2 to 16.6 years of age) with an IGF2/H19 hypomethylation defect and three age-matched healthy controls were included in the in-vitro study. Cultivated skin fibroblasts from the patients and the healthy controls were used for the experiments. Proliferation rates of fibroblasts were measured in the presence or absence of recombinant human IGF-I and IGF-II using the commercially available 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) test. PI3K (phosphoinositide 3-kinase) assay and NF-κB transcription factor assay were performed using ELISA in order to estimate the IGF-I-stimulated Akt phosphorylation and IκB phosphorylation, respectively. RESULTS: Fibroblasts from SRS patients and fibroblasts from control individuals showed a comparable potential to proliferate in serum-free medium when stimulated with IGFs. No significant differences were found between both groups concerning Akt phosphorylation and IκB phosphorylation rates. CONCLUSIONS: The results of the in-vitro study do not support the hypothesis that IGF-I/IGF-II resistance is a major pathogenetic mechanism responsible for the growth failure in the subgroup of SRS children with IGF2/H19 hypomethylation.

Mixed gonadal dysgenesis and precocious puberty.

A girl aged 5 years and 6 months presented with premature thelarche in our outpatient clinic. During long-term observation, we recorded growth acceleration, advanced bone age, and elevated oestradiol levels which together were taken to confirm the diagnosis of precocious puberty. The patient was successfully treated with a gonadotropin-releasing hormone agonist, but in view of the poor growth prognosis, recombinant human growth hormone was administered concurrently. At the age of 9 years and 6 months a mild clitoris enlargement and conspicuous muscle development without any further signs of virilization were noticed. Laboratory findings showed high values for testosterone and normal basal values for 17-hydroxyprogesterone and dehydroepinadrosterone sulphate. Explorative laparotomy revealed a gonadoblastoma arising from testicular structures on the left, a female streak gonad on the right side, and normal uterus and fallopian tubes. The karyotype was 46,XY/45,X. These findings confirmed the diagnosis of mixed gonadal dysgenesis with testosterone-producing gonadoblastoma.

Transient pseudohypoaldosteronism with complex malformation of internal genitalia. A case report.

At the age of 3 weeks, a girl presenting with acute dehydration was admitted to our hospital. Clinical and laboratory findings revealed malformations of the genitourinary tract, an acute urinary infection and electrolyte disturbances (severe hyponatremia at 115 mmol/l and mild hyperkalemia at 5.6 mmol/l). According to anamnestic data, the child was born to healthy, nonconsanguineous parents. Vaccum extraction was done in the 38th gestational week due to pathological cardiotocography (CTG) findings. Auxological parameters were within the normal range for gestational age. Normal values for 17-OH progesterone and ACTH ruled out congenital adrenal hyperplasia (CAH). Pathologically high aldosterone and plasma renin activity (PRA) confirmed the diagnosis of pseudohypoaldosteronism with salt-wasting crisis which proved to be transient.