Ameeta Mehta

Over- and Underdosage of SOX3 Is Associated with Infundibular Hypoplasia and Hypopituitarism

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.

Expanding the Spectrum of Mutations in GH1 and GHRHR: Genetic Screening in a Large Cohort of Patients with Congenital Isolated Growth Hormone Deficiency

CONTEXT It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics. PATIENTS AND METHODS A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees). RESULTS Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR. CONCLUSIONS IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.

Mutations within the transcription factor PROP1 are rare in a cohort of patients with sporadic combined pituitary hormone deficiency (CPHD).

Objective  Mutations within the pituitary‐specific paired‐like homeobox gene PROP1 have been described in 50–100% of patients with familial combined pituitary hormone deficiency (CPHD). We screened a cohort of sporadic (n = 189) and familial (n = 44) patients with hypopituitarism (153 CPHD and 80 isolated hormone deficiencies) for mutations within the coding sequence of PROP1.

Developmental disorders of the hypothalamus and pituitary gland associated with congenital hypopituitarism

The pituitary gland is a complex organ secreting six hormones from five different cell types. It is the end product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of congenital hypopituitarism. These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, PITX1, PITX2, SOX2 and SOX3. The expression pattern of these transcription factors dictates the phenotype that results when the gene encoding the relevant transcription factor is mutated. The highly variable phenotype may consist of isolated hypopituitarism or more complex disorders such as septo-optic dysplasia and holoprosencephaly. However, the overall incidence of mutations in known transcription factors in patients with hypopituitarism is low, indicating that many genes remain to be identified; characterization of these will further elucidate the pathogenesis of this complex condition and also shed light on normal pituitary development and function.

Congenital hypopituitarism: clinical, molecular and neuroradiological correlates

Objective  Recent studies have suggested that mutations in genes encoding several hypothalamo–pituitary (H–P) transcription factors result in hypopituitarism [isolated GH deficiency (IGHD) and combined pituitary hormone deficiency (CPHD)], which may in turn be related to the neuroanatomy revealed by magnetic resonance (MR) imaging. Although studies have focused on patients with either optic nerve hypoplasia (ONH) or isolated hypopituitarism with normal optic nerves, few studies have compared the two groups. We aimed to relate the clinical phenotype of a large cohort (n = 170) of children with congenital hypopituitarism including septo‐optic dysplasia (SOD) attending a single centre to the neuroradiological and genetic findings.

The role of growth hormone in determining birth size and early postnatal growth, using congenital growth hormone deficiency (GHD) as a model

Objective  The role of GH in early human growth is unclear. Congenital GH deficiency (CGHD) provides a useful tool to explore this putative role. We have assessed the effects of CGHD on birth size and early postnatal growth, and the further impact of the presence of additional pituitary hormone deficiencies and midline brain defects on these parameters.

Molecular analysis of novel PROP1 mutations associated with combined pituitary hormone deficiency (CPHD)

Objective  Homozygous mutations in the gene encoding the pituitary transcription factor PROP1 are associated with combined pituitary hormone deficiency (CPHD) in both mice and humans with a highly variable phenotype with respect to the severity and time of initiation of pituitary hormone deficiency. We have ascertained three pedigrees with PROP1 mutations from a large cohort of patients with variable degrees of CPHD who were screened for mutations in PROP1.

An update on the biochemical diagnosis of congenital ACTH insufficiency

Objective  Congenital ACTH insufficiency due to disorders of the hypothalamo–pituitary axis is life threatening. However, the optimal method for establishing the diagnosis remains controversial. The standard Synacthen test (SST) is safe and easy to perform in infancy, but its performance has not been well evaluated in infants and children with ACTH insufficiency.

An unusual case of an atypical eating disorder masquerading as a serious multi-systemic illness

An early diagnosis and multidisciplinary team approach are mandatory in the management of eating disorders. Serious organic symptoms and nutritional effects can mimic a systemic illness, particularly in those with atypical presentations. A 15‐y‐old adolescent male presented with poor growth, low weight, abdominal pain and yellow pigmentation. Further bizarre multi‐system symptomatology resulted in a protracted admission with multiple investigations. An initial diagnosis of teratoma proved negative on abdominal laparotomy. A multidisciplinary approach followed by a feeding challenge led to the diagnosis of an eating disorder. The disorder, although more common in girls and adolescents, is increasing in incidence in both males and younger children.