Linda B. Johnston

Analysis of the intracellular signalling domain of the human growth hormone receptor in children with idiopathic short stature

OBJECTIVE To investigate the hypothesis that intracellular, dominant‐negative mutations of the growth hormone receptor (GHR) exist in children with idiopathic short stature (ISS) and partial growth hormone insensitivity (GHI).

The insulin‐like growth factor‐I (IGF‐I) gene in individuals born small for gestational age (SGA)

To investigate the association of genetic variation of the insulin‐like growth factor‐I (IGF‐I) gene with birth size small for gestational age (SGA).

The Broad Spectrum of Inherited Growth Hormone Insensitivity Syndrome

Growth hormone (GH) insensitivity syndrome (GHIS) results in severe short stature and metabolic disturbances, but when this disorder is studied in more detail it is clear that there is marked clinical and biochemical heterogeneity. Many genetic defects of the GH receptor have been reported in inherited GHIS, but it now seems likely that some cases might be the result of defects of other genes or of links in the post-receptor cascade.

Normal final height and apparent cure after pituitary irradiation for Cushing's disease in childhood: long‐term follow‐up of anterior pituitary function

Pituitary‐dependent Cushings syndrome is rare in childhood. Two patients are reported who had unsuccessful transsphenoidal microadenomectomy and therefore underwent pituitary radiotherapy. In both patients there was progressive normalization of hypothalamo–pituitary–adrenal function and at 8 and 10 years after radiotherapy their Cushings syndrome remained in remission clinically and biochemically. Most importantly, they have both achieved adult heights within their respective expected ranges with close clinical observation and replacement growth hormone therapy. Thyroid and gonadal function is normal and neither patient requires any other hormone replacement therapy. Pituitary radiotherapy is thus a safe, effective and well tolerated second‐line therapy for paediatric Cushings disease. Collaboration between the paediatric and adult departments and an experienced radiotherapist contributed to the successful outcome of these two patients.

Association Analysis of Ten Candidate Genes in a Large Multinational Cohort of Small for Gestational Age Children and Children with Idiopathic Short Stature (NESTEGG study)

Background: Fetal growth failure has been associated with an increased risk of hypertension, cardiovascular disease and diabetes in adulthood. Exploring the mechanisms underlying this association should improve our understanding of these common adult diseases. Patients and Methods: We investigated 225 SNPs in 10 genes involved in growth and glucose metabolism (GH1, GHR, IGF1, IGF1R, STAT5A, STAT5B, MAPK1, MAPK3, PPARγ and INS) in 1,437 children from the multinational NESTEGG consortium: 345 patients born small for gestational age who remained short (SGA-S), 288 who showed catch-up growth (SGA-Cu), 410 idiopathic short stature (ISS) and 394 controls. We related genotype to pre- and/or postnatal growth parameters, response to growth hormone (if applicable) and blood pressure. Results: We found several clinical associations for GH1, GHR, IGF1, IGF1R, PPARγ and MAPK1. One SNP remained significant after Bonferronis correction: IGF1R SNP rs4966035s minor allele A was significantly more prevalent among SGA and associated with smaller birth length (p = 0.000378) and birth weight (weaker association), independent of gestational age. Conclusion:IGF1R SNP rs4966035 is significantly associated with birth length, independent of gestational age. This and other associations suggest that polymorphisms in these genes might partly explain the phenotype of short children born SGA and children with ISS.

Severe hypernatraemia associated with growth hormone replacement therapy in a patient with septo-optic dysplasia

Background The anti-natriuretic properties of growth hormone (GH) are well established. Growth hormone deficiency (GHD) results in salt and water depletion and studies confirm that replacement leads to sodium and vasopressin-mediated water retention in patients with intact posterior pituitary function. Methods We report the case of a 20-year-old male patient with septo-optic dysplasia, fixed cranial diabetes insipidus (DI) and an abnormal thirst threshold. With careful parental support, his sodium levels remained stable for many years on a fixed dose of DDAVP and a supervised fluid intake of 2.5xa0l/day. Several years after the original diagnosis, he was found to be ACTH deficient and following commencement of hydrocortisone replacement therapy became hypernatraemic. A new sodium homoeostasis was established with a higher dose of DDAVP. Subsequently, he developed symptoms typical of GHD and, after biochemical confirmation, GH replacement was commenced. Results There was an immediate clinical improvement (increased alertness, improved concentration) but severe hypernatraemia developed (peak 169xa0mmol/l) necessitating revision of his desmopressin and fluid intake regimen. Conclusion Most GHD patients have intact posterior pituitary function. This case report highlights the powerful anti-natriuretic properties of GH. Endocrine physicians should be alert to this in patients with fixed DI and an abnormal thirst threshold.

Growth hormone insensitivity.

Growth hormone insensitivity (GHI) describes a group of disorders characterized by deficient biological action of GH. GH insensitivity may be of primary origin, that is, related to defects in genes coding for functional proteins essential for GH action or secondary to acquired pathology such as inflammatory or nutritional disorders. This article will describe GH insensitivity of primary origin, which in children presents as growth failure leading to adult short stature. Metabolic symptoms, such as hypoglycaemia, may also occur. Cardinal biochemical features are normal or elevated GH secretion and IGF-1 deficiency. Therapy for GH insensitivity consists of recombinant human IGF-1, which can lead to height gain resulting in catch-up growth and adult height within the normal range.