Madeleine D. Harbison

Complete testicular feminization caused by an amino-terminal truncation of the androgen receptor with downstream initiation.

We have characterized the molecular defect causing androgen resistance in two 46,XY siblings with complete testicular feminization. Although binding studies in genital skin fibroblasts showed a reduced Bmax, an increased dissociation rate of ligand, and an 8S peak of dihydrotestosterone binding on sucrose density gradient centrifugation, no immunoreactive androgen receptor (AR) was detected in immunoblots using anti-NH2-terminal antibodies, suggesting an abnormal amino terminus. Sequence analysis of the AR gene revealed a point mutation CAG-->TAG (Gln-->Stop) at nucleotide 340. In vitro mutagenesis studies suggest the synthesis of the mutant AR is initiated downstream of the termination codon at reduced levels and that each molecule is functionally impaired. These results define a novel mechanism causing androgen resistance: the combination of decreased amount and functional impairment of AR caused by an abnormality within the amino terminus of the receptor. These findings suggest that domains important to the in vivo function of the receptor reside within the amino terminus and that disruption of these domains can occur with only subtle effects on receptor binding. Identification of this mutation made it possible to identify the mutant allele within the family and to ascertain antenatally that it was not present in a 46,XY fetal sibling of the proband at 9 wk gestation.

Haplotype analysis of the growth hormone releasing hormone receptor locus in three apparently unrelated kindreds from the indian subcontinent with the identical mutation in the GHRH receptor.

The growth hormone releasing hormone receptor (GHRHR) plays a critical role in growth. We identified three nominally unrelated kindreds harboring the identical mutation (E72X) in GHRHR, the gene that encodes GHRHR; all three families originated in the Indian subcontinent. Because of the relative geographic proximity of these populations, we employed haplotype analysis in the region of GHRHR to determine the likelihood that this mutation occurred in a common ancestor rather than having occurred on separate occasions in different individuals. Members of all three kindreds segregating the E72X mutation were genotyped for highly polymorphic dinucleotide repeat microsatellites in a 15.5 centimorgan (cM) region around GHRHR on chromosome 7p15. We conclude that the affected individuals share a common ancestor, and we use the association with linked markers to estimate the age of this unique mutation.

Genetic disruption of the oncogenic HMGA2 – PLAG1 – IGF2 pathway causes fetal growth restriction

PurposeFetal growth is a complex process involving maternal, placental and fetal factors. The etiology of fetal growth retardation remains unknown in many cases. The aim of this study is to identify novel human mutations and genes related to Silver–Russell syndrome (SRS), a syndromic form of fetal growth retardation, usually caused by epigenetic downregulation of the potent fetal growth factor IGF2.MethodsWhole-exome sequencing was carried out on members of an SRS familial case. The candidate gene from the familial case and two other genes were screened by targeted high-throughput sequencing in a large cohort of suspected SRS patients. Functional experiments were then used to link these genes into a regulatory pathway.ResultsWe report the first mutations of the PLAG1 gene in humans, as well as new mutations in HMGA2 and IGF2 in six sporadic and/or familial cases of SRS. We demonstrate that HMGA2 regulates IGF2 expression through PLAG1 and in a PLAG1-independent manner.ConclusionGenetic defects of the HMGA2–PLAG1–IGF2 pathway can lead to fetal and postnatal growth restriction, highlighting the role of this oncogenic pathway in the fine regulation of physiological fetal/postnatal growth. This work defines new genetic causes of SRS, important for genetic counseling.

Predictors of First-Year Growth Response to a Fixed-dose Growth Hormone Treatment in Children Born Small for Gestational Age: Results of an Open-Label, Multicenter Trial in the United States

BACKGROUND Previous studies of varied populations of non-uniformly defined children born small for gestational age (SGA) receiving different growth hormone (GH) regimens have found that GH treatment increased growth velocity and adult height and was safe. The GH dose was the major predictor of first year growth response. AIM To identify pre- and within-treatment predictors of growth in well defined children born SGA treated with a fixed dose of GH. METHODS 139 short, prepubertal children born SGA (i.e. birth weight and/or length > or =2 standard deviations below the mean) received Genotropin (rhGH) at 0.24 mg/kg/wk for 1 month then an additional 11 months at a dose of 0.48 mg/kg/wk, the FDA-approved dose of GH for children born SGA. RESULTS Height improved significantly by month 3, with progressive improvement over the entire 12 months (median height SDS change of 0.78). Pretreatment predictors of growth included baseline bone age, IGFBP-3, total cholesterol, WBC and height SDS minus mid-parental height SDS. Within-treatment predictors of the change (Delta) height SDS at month 12 were the A height SDS at months 3 and 6 and growth velocity SDS at months 3 and 6. CONCLUSION GH at 0.48 mg/kg/wk was well tolerated and improved growth in children born SGA; the Delta IGF-I was not predictive of the 12 month height SDS gain, while the Delta height SDS at 3 and 6 months were predictive. Underweight children grew as well as normal weight children, and both groups showed improved body composition following GH treatment.

Effect of Cyproheptadine on Weight and Growth Velocity in Children With Silver-russell Syndrome

Objectives: Nutritional management of children with Silver-Russell syndrome (SRS) is crucial, especially before initiating growth hormone therapy. Since cyproheptadine (CYP) has been reported to be orexigenic, we retrospectively investigated the effects of CYP on changes in weight and height in patients with SRS. Methods: Anthropometric parameters (weight [W], length or height [H], weight on expected weight for height [W/H], and body mass index) were recorded for 34 children with SRS receiving CYP. We specifically analyzed the anthropometric parameters (expressed in median) in a group of 23 patients treated with CYP at baseline (M0-CYP) and every 3 months (M3 to M12-CYP) after the initiation of CYP treatment. Results: The 23 children with SRS treated by CYP only had weight stagnation during the months preceding the start of treatment. Anthropometric parameters, especially the weight, differed significantly between M0-CYP and all other times (M3, M6, M9, M12-CYP). After 1 year of treatment, a gain in overall length/height and weight was observed (W: +1.1 standard deviations from the mean [SDS]; H: +0.5 SDS). At M3, significant improvements in W/H (74.9% vs 79.3% [P = 0.01]) and body mass index (−3.4 vs −2.4 SDS [P = 0.001]) were also observed. Twenty-one patients (91%) improved their weight by at least +0.5 SDS, and 12 (52%) by at least +1 SDS. Conclusions: Our results show that CYP can be effective in patients with SRS with significant improvements in growth velocity and nutritional status before initiation of growth hormone therapy. Further prospective studies are required to confirm these results.