W K Chong

Publications (3)16.94 Total impact

• Article: Congenital hypopituitarism: clinical, molecular and neuroradiological correlates

  Ameeta Mehta, Peter C. Hindmarsh, Hiten Mehta, James P.G. Turton, Isabelle Russell-Eggitt, David Taylor, W.K. Chong, Mehul T. Dattani
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  ABSTRACT: 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.Design  Clinical, biochemical, MR imaging and molecular data were analysed retrospectively in 170 patients with or ‘at-risk’ (with ONH) of hypopituitarism to determine predictors of hypopituitarism.Results  The presence of ONH was significantly associated with an absent septum pellucidum [odds ratio (OR) 31·5, 95% confidence intervals (CI) 7·3–136·6, P < 0·001], an abnormal corpus callosum (OR 10·5, 95% CI 3·8–28·6, P < 0·001) and stalk abnormalities (OR 2·3, 95% CI 1·2–4·2, P = 0·009). The risk of hypopituitarism was 27·2 times greater in patients with an undescended posterior pituitary (95% CI 3·6–205·1, P < 0·001). Anterior pituitary hypoplasia (OR 3·1, 95% CI 1·3–7·0, P = 0·006) and an absent pituitary stalk (P < 0·001) were also significantly associated with hypopituitarism. With respect to the type or severity of hypopituitarism, CPHD was more often associated with an abnormal corpus callosum (OR 6·1, 95% CI 1·4–27·4, P = 0·008) and stalk abnormalities (OR 2·8, 95% CI 1·3–6·1, P = 0·006). Male to female ratio was significantly greater in patients with normal optic nerves (3·3:1) as compared with those with ONH (1·2:1). The prevalence of diabetes insipidus, thyrotrophin and ACTH deficiencies was significantly greater in patients with ONH as compared with ‘idiopathic’ hypopituitarism. Mutations in pituitary transcription factors and genes regulating GH secretion were rare (5/170) in this cohort of patients with sporadic hypopituitarism.Conclusion  Our data suggest that individuals presenting with ONH are at high risk for neuroradiologic and endocrine abnormalities. The neuroradiologic features are predictive not only of the presence, but also of the type, of hypopituitarism. The association of midline abnormalities with hypopituitarism in this cohort suggests a common developmental origin for these features, the aetiology of which remains unidentified in the majority of cases.
  Clinical Endocrinology 08/2009; 71(3):376 - 382. · 3.17 Impact Factor
• Article: Congenital hypopituitarism: clinical, molecular and neuroradiological correlates.

  Ameeta Mehta, Peter C Hindmarsh, Hiten Mehta, James P G Turton, Isabelle Russell-Eggitt, David Taylor, W K Chong, Mehul T Dattani
  [show abstract] [hide abstract]
  ABSTRACT: 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. Clinical, biochemical, MR imaging and molecular data were analysed retrospectively in 170 patients with or 'at-risk' (with ONH) of hypopituitarism to determine predictors of hypopituitarism. The presence of ONH was significantly associated with an absent septum pellucidum [odds ratio (OR) 31.5, 95% confidence intervals (CI) 7.3-136.6, P < 0.001], an abnormal corpus callosum (OR 10.5, 95% CI 3.8-28.6, P < 0.001) and stalk abnormalities (OR 2.3, 95% CI 1.2-4.2, P = 0.009). The risk of hypopituitarism was 27.2 times greater in patients with an undescended posterior pituitary (95% CI 3.6-205.1, P < 0.001). Anterior pituitary hypoplasia (OR 3.1, 95% CI 1.3-7.0, P = 0.006) and an absent pituitary stalk (P < 0.001) were also significantly associated with hypopituitarism. With respect to the type or severity of hypopituitarism, CPHD was more often associated with an abnormal corpus callosum (OR 6.1, 95% CI 1.4-27.4, P = 0.008) and stalk abnormalities (OR 2.8, 95% CI 1.3-6.1, P = 0.006). Male to female ratio was significantly greater in patients with normal optic nerves (3.3:1) as compared with those with ONH (1.2:1). The prevalence of diabetes insipidus, thyrotrophin and ACTH deficiencies was significantly greater in patients with ONH as compared with 'idiopathic' hypopituitarism. Mutations in pituitary transcription factors and genes regulating GH secretion were rare (5/170) in this cohort of patients with sporadic hypopituitarism. Our data suggest that individuals presenting with ONH are at high risk for neuroradiologic and endocrine abnormalities. The neuroradiologic features are predictive not only of the presence, but also of the type, of hypopituitarism. The association of midline abnormalities with hypopituitarism in this cohort suggests a common developmental origin for these features, the aetiology of which remains unidentified in the majority of cases.
  Clinical Endocrinology 04/2009; 71(3):376-82. · 3.17 Impact Factor
• Article: Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism.

  Kathryn S Woods, Maria Cundall, James Turton, Karine Rizotti, Ameeta Mehta, Rodger Palmer, Jacqueline Wong, W K Chong, Mahmoud Al-Zyoud, Maryam El-Ali, Timo Otonkoski, Juan-Pedro Martinez-Barbera, Paul Q Thomas, Iain C Robinson, Robin Lovell-Badge, Karen J Woodward, Mehul T Dattani
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  ABSTRACT: 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.
  The American Journal of Human Genetics 06/2005; 76(5):833-49. · 10.60 Impact Factor