HMGA2 Variants in Silver-Russell Syndrome: Homozygous and Heterozygous Occurrence

Context Silver-Russell syndrome (SRS) is a clinical and molecular heterogeneous disorder associated with short stature, typical facial gestalt, and body asymmetry. Though molecular causes of SRS can be identified in a significant number of patients, about one-half of patients currently remain without a molecular diagnosis. However, determination of the molecular cause is required for a targeted treatment and genetic counselling. Objective The aim of this study was to corroborate the role of HMGA2 as an SRS-causing gene and reevaluate its mode of inheritance. Design, Setting, Patients Patients were part of an ongoing study aiming on SRS-causing genes. They were classified according to the Netchine-Harbison clinical scoring system, and DNA samples were investigated by whole exome sequencing. Common molecular causes of SRS were excluded before. Results Three novel pathogenic HMGA2 variants were identified in 5 patients from 3 SRS families, and fulfilling diagnostic criteria of SRS. For the first time, homozygosity for a variant in HMGA2 could be identified in a severely affected sibpair, whereas parents carrying heterozygous variants had a mild phenotype. Treatment with recombinant growth hormone led to a catch-up growth in 1 patient, whereas all others did not receive growth hormone and stayed small. One patient developed type 2 diabetes at age 30 years. Conclusions Identification of novel pathogenic variants confirms HMGA2 as an SRS-causing gene; thus, HMGA2 testing should be implemented in molecular SRS diagnostic workup. Furthermore, inheritance of HMGA2 is variable depending on the severity of the variant and its consequence for protein function.

Results of growth hormone substitution therapy in children with brain tumours

Aim of the study. To estimate the effectiveness and safety of substitution therapy with growth hormone (GH) in children with various brain tumours. Materials and methods. The study involved 68 patients admitted to N.N. Burdenko Institute of Neurosurgery between 2001 and 2011 including 35 ones with craniopharyngioma, 18 with medulloblastoma, and 15 with germ cell tumours (GCT) in the chiasmosellar region. All patients suffered growth hormone insufficiency and received GH replacement therapy. Their antropometric characteristics (height and growth rate) and IGF-1 levels were measured before, 6 and 12 months after the onset of the treatment. The doses of GH varied from 0.03 to 0.034 mg/kg/day. Results. The substitution therapy with GH resulted in an increase of the growth rate in patients with craniopharyngioma from 2.3±1.6 to 9.4±1.9 cm/year (p<0.001), in those with GCT from 1.2±0.9 to 7.4±2.6 cm/year (p=0.01), and in patients with medulloblastoma from 2.3±1.5 to 6.2±2.6 cm/year (p<0.01). The growth rate in patients treated by spinal irradiation was lower than that in those given no such treatment (6.0±2.3 cm/year and 9.2±2.1 cm/year respectively; p<0.001). The tumour recurred in eight of 35 (23%) patients with craniopharyngioma during GH therapy. The frequency of relapses was not significantly different from that in patients who did not receive growth hormone. Patients with medulloblastoma and GCT did not develop relapses. No adverse reactions to GH therapy were documented in this study.

Short Children and Growth Hormone

In Reply.— Copeland raises some interesting questions and speculation regarding the treatment of "normal short" children with growth hormone that many, if not all, of the pediatric endocrinologists who treat short children are currently considering. Regarding the ethical question of who should or should not receive growth hormone, who should give it, who should pay for it, and what are the side effects: information is being gathered and will be forthcoming in stages. A statement prepared by the Ad Hoc Committee on Growth Hormone Usage of The Lawson Wilkins Pediatric Endocrine Society, chaired by Dr Louis E. Underwood, has recently been published.1