Depending on the definitions used, up to 10% of all live-born neonates are small for gestational age (SGA). Although the vast majority of these children show catch-up growth by 2 yr of age, one in 10 does not. It is increasingly recognized that those who are born SGA are at risk of developing metabolic disease later in life. Reduced fetal growth has been shown to be associated with an increased risk of insulin resistance, obesity, cardiovascular disease, and type 2 diabetes mellitus. The majority of pathology is seen in adults who show spontaneous catch-up growth as children. There is evidence to suggest that some of the metabolic consequences of intrauterine growth retardation in children born SGA can be mitigated by ensuring early appropriate catch-up growth, while avoiding excessive weight gain. Implicitly, this argument questions current infant formula feeding practices. The risk is less clear for individuals who do not show catch-up growth and who are treated with GH for short stature. Recent data, however, suggest that long-term treatment with GH does not increase the risk of type 2 diabetes mellitus and the metabolic syndrome in young adults born SGA.

/pdf/small-for-gestational-age-short-stature-and-beyond-3wcvvl6q1o.pdf

Small for Gestational Age: Short Stature and Beyond

Normal hypothalamopituitary development is closely related to that of the forebrain and is dependent upon a complex genetic cascade of transcription factors and signaling molecules that may be either intrinsic or extrinsic to the developing Rathke’s pouch. These factors dictate organ commitment, cell differentiation, and cell proliferation within the anterior pituitary. Abnormalities in these processes are associated with congenital hypopituitarism, a spectrum of disorders that includes syndromic disorders such as septo-optic dysplasia, combined pituitary hormone deficiencies, and isolated hormone deficiencies, of which the commonest is GH deficiency. The highly variable clinical phenotypes can now in part be explained due to research performed over the last 20 yr, based mainly on naturally occurring and transgenic animal models. Mutations in genes encoding both signaling molecules and transcription factors have been implicated in the etiology of hypopituitarism, with or without other syndromic features, in mice and humans. To date, mutations in known genes account for a small proportion of cases of hypopituitarism in humans. However, these mutations have led to a greater understanding of the genetic interactions that lead to normal pituitary development. This review attempts to describe the complexity of pituitary development in the rodent, with particular emphasis on those factors that, when mutated, are associated with hypopituitarism in humans.

/pdf/genetic-regulation-of-pituitary-gland-development-in-human-503a3ktrve.pdf

Genetic Regulation of Pituitary Gland Development in Human and Mouse

PHACE (OMIM no. 606519) is a neurocutaneous syndrome that refers to the association of large, plaque-like, "segmental" hemangiomas of the face, with one or more of the following anomalies: posterior fossa brain malformations, arterial cerebrovascular anomalies, cardiovascular anomalies, eye anomalies, and ventral developmental defects, specifically sternal defects and/or supraumbilical raphe. The etiology and pathogenesis of PHACE is unknown, and potential risk factors for the syndrome have not been systematically studied. The purpose of this study was thus to determine (1) the incidence of PHACE and associated anomalies among a large cohort of hemangioma patients, (2) whether certain demographic, prenatal or perinatal risk factors predispose infants to this syndrome, and (3) whether the cutaneous distribution of the hemangioma can be correlated to the types of anomalies present. We undertook a prospective, cohort study of 1,096 children with hemangiomas, 25 of whom met criteria for PHACE. These 25 patients represented 20% of infants with segmental facial hemangiomas. Compared to previous reports, our PHACE patients had a higher incidence of cerebrovascular and cardiovascular anomalies. Two developed acute arterial ischemic stroke during infancy, while two with cardiovascular anomalies showed documented evidence of normalization, suggesting that both progressive and regressive vascular phenomena may occur in this syndrome. Correlation to the anatomic location of the hemangioma appears to be helpful in determining which structural abnormalities might be present. A comparison of demographic and perinatal data between our PHACE cases and the hemangioma cohort overall showed no major differences, except a trend for PHACE infants to be of slighter higher gestational age and born to slightly older mothers. Eighty-eight percent were female, a finding which has been noted in multiple other reports. Further research is needed to determine possible etiologies, optimal evaluation, and outcomes.

A prospective study of PHACE syndrome in infantile hemangiomas: demographic features, clinical findings, and complications.

Duplications of Xq26-27 have been implicated in the etiology of X-linked hypopituitarism associated with mental retardation (MR). Additionally, an expansion of a polyalanine tract (by 11 alanines) within the transcription factor SOX3 (Xq27.1) has been reported in patients with growth hormone deficiency and variable learning difficulties. We report a submicroscopic duplication of Xq27.1, the smallest reported to date (685.6 kb), in two siblings with variable hypopituitarism, callosal abnormalities, anterior pituitary hypoplasia (APH), an ectopic posterior pituitary (EPP), and an absent infundibulum. This duplication contains SOX3 and sequences corresponding to two transcripts of unknown function; only Sox3 is expressed in the infundibulum in mice. Next, we identified a novel seven-alanine expansion within a polyalanine tract in SOX3 in a family with panhypopituitarism in three male siblings with an absent infundibulum, severe APH, and EPP. This mutation led to reduced transcriptional activity, with impaired nuclear localization of the mutant protein. We also identified a novel polymorphism (A43T) in SOX3 in another child with hypopituitarism. In contrast to findings in previous studies, there was no evidence of MR or learning difficulties in our patients. We conclude that both over- and underdosage of SOX3 are associated with similar phenotypes, consisting of infundibular hypoplasia and hypopituitarism but not necessarily MR.

Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism

Update of guidelines for the use of growth hormone in children: the Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee.

We have previously shown that familial septo-optic dysplasia (SOD), a syndromic form of congenital hypopituitarism involving optic nerve hypoplasia and agenesis of midline brain structures, is associated with homozygosity for an inactivating mutation in the homeobox gene HESX1/Hesx1 in man and mouse. However, as most SOD/congenital hypopituitarism occurs sporadically, the possible contribution of HESX1 mutations to the aetiology of these cases is presently unclear. Interestingly, a small proportion of mice heterozygous for the Hesx1 null allele show a milder SOD phenocopy, implying that heterozygous mutations in human HESX1 could underlie some cases of congenital pituitary hypoplasia with or without midline defects. Accordingly, we have now scanned for HESX1 mutations in 228 patients with a broad spectrum of congenital pituitary defects, ranging in severity from isolated growth hormone deficiency to SOD with panhypopituitarism. Three different heterozygous missense mutations were detected in individuals with relatively mild pituitary hypoplasia or SOD, which display incomplete penetrance and variable phenotype amongst heterozygous family members. Gel shift analysis of the HESX1-S170L mutant protein, which is encoded by the C509T mutated allele, indicated that a significant reduction in relative DNA binding activity results from this mutation. Segregation analysis of a haplotype spanning 6.1 cM, which contains the HESX1 locus, indicated that only one HESX1 mutation was present in the families containing the C509T and A541G mutations. These results demonstrate that some sporadic cases of the more common mild forms of pituitary hypoplasia have a genetic basis, resulting from heterozygous mutation of the HESX1 gene.

Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia

GH therapy variably reduces the height deficit of short children born small for gestational age (SGA) but is associated with hyperinsulinemia. Intermittent, higher-dose GH regimens may be alternatives to continuous, lower-dose treatment. We examined whether the growth response to GH therapy is related to pre-treatment indices of endogenous somatotropic activity, and studied the reversibility of the insulin resistant state induced by GH. 13 non-GH deficient short SGA children were randomised to high-dose GH (100 mcg/kg/day) by daily sc injection (n = 9), or no GH treatment (n = 4) for 2 years (2/4 controls subsequently received GH treatment). Overnight GH profiles were performed at baseline; intravenous glucose tolerance tests were performed at baseline, yearly on GH treatment, and 3 months post-GH treatment. Fasting glucose, insulin and proinsulin levels were measured, insulin sensitivity estimated using Bergman's minimal model, and glucose tolerance calculated from rate of glucose disappearance. In all GH-treated children, gain in height SDS (mean gain yr 1 = +1.2 SDS) was inversely related to baseline peak overnight GH (r = -0.88, n = 10, p = 0.0008), IFG-I (r = -0.74, n = 11, p = 0.009), and fasting insulin levels (r = -0.71, n = 11, p = 0.014). GH treatment increased fasting glucose (means: baseline vs. yr 2: 3.7 vs. 4.4 mmol/l, p = 0.005), insulin (3.8 vs. 13.9 mU/l, p = 0.0002), and proinsulin levels (1.7 vs. 4.5 pmol/l, p = 0.004), and decreased insulin sensitivity (26.9 vs. 4.0 per min/mU/1 x 10(4), p = 0.002). Glucose tolerance initially decreased (baseline: 2.62 min(-1); yr 1: 2.18, p = 0.02; yr 2: 2.39, p = 0.12). However, by 3 months post-GH treatment significant improvements were seen in fasting insulin (post-GH: 5.2 mU/1, p = 0.0003 vs. yr 2), proinsulin (1.7 pmol/l, p = 0.002), and insulin sensitivity (17.6 per min/mU/1 x 10(4), p = 0.0001). Post-GH treatment, fasting glucose levels (4.1 mmol/l, p = 0.04) and glucose tolerance (2.49 min(-1), p = 0.4) were similar to baseline, and the slight increase in fasting insulin levels (5.2 mU/1, p = 0.04) was similar to that observed in non-GH treated children over the 2 yr study period (baseline vs. 2 years: 3.9 vs. 5.9 mU/1, n = 4). In conclusion, in this study of 13 short non-GH-deficient SGA children, high-dose GH therapy induced growth responses that were associated with reversible decreases in insulin sensitivity, and that were predicted by pretreatment markers of endogenous, but not stimulated, somatotropic activity.

High-dose growth hormone (GH) treatment in non-GH-deficient children born small for gestational age induces growth responses related to pretreatment GH secretion and associated with a reversible decrease in insulin sensitivity.

/pdf/the-gly972arg-variant-in-insulin-receptor-substrate-1-is-not-3vxh5il0jc.pdf

The Gly972Arg variant in insulin receptor substrate-1 is not associated with birth weight in contemporary English children. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood.

Katie Woods

Papers

Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia

High-dose growth hormone (GH) treatment in non-GH-deficient children born small for gestational age induces growth responses related to pretreatment GH secretion and associated with a reversible decrease in insulin sensitivity.

The Gly972Arg variant in insulin receptor substrate-1 is not associated with birth weight in contemporary English children. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood.

The Gly972Arg variant in insulin receptor substrate-1 is not associated with birthweight in contemporary English children