Kling Chong

Great Ormond Street Hospital for Children NHS Foundation Trust, Londinium, England, United Kingdom

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Publications (17)115.63 Total impact

  • 03/2014; DOI:10.1530/endoabs.34.P398
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    ABSTRACT: Recently, we reported a previously unrecognized symptom constellation comprising epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST syndrome) associated with recessive mutations in the KCNJ10 gene. Here, we provide a detailed characterization of the clinical features of the syndrome to aid patient management with respect to diagnosis, prognostic counselling, and identification of best treatment modalities. We conducted a retrospective review of the detailed neurological and neuroradiological features of nine children (four females, five males; age range at last examination 6-20y) with genetically proven EAST syndrome. All children presented with tonic-clonic seizures in infancy. Later, non-progressive, cerebellar ataxia and hearing loss were noted. Whilst seizures mostly responded well to treatment, ataxia proved to be the most debilitating feature, with three patients non-ambulant. All available magnetic resonance imaging (MRI) revealed subtle symmetrical signal changes in the cerebellar dentate nuclei. Moreover, four patients had a small corpus callosum and brainstem hypoplasia, and three had a small spinal cord. Regional quantitative volumetric analysis of the images confirmed the corpus callosum and brainstem hypoplasia and showed further patterns of variation from the norm. The neurological features of EAST syndrome appear to be non-progressive, which is important for prognostic counselling. The spectrum of EAST syndrome includes consistent abnormalities on brain MRI, which may aid diagnosis. Further longitudinal documentation is required to determine the true natural history of the disorder.
    Developmental Medicine & Child Neurology 09/2013; 55(9):846-56. DOI:10.1111/dmcn.12171 · 3.29 Impact Factor
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    ABSTRACT: Nodding syndrome is a devastating neurological disorder of uncertain aetiology affecting children in Africa. There is no diagnostic test, and risk factors and symptoms that would allow early diagnosis are poorly documented. This study aimed to describe the clinical, electrophysiological and brain imaging (MRI) features and complications of nodding syndrome in Ugandan children. Case series. 22 children with nodding syndrome brought to Mulago National Referral Hospital for assessment. Clinical features, physical and functional disabilities, EEG and brain MRI findings and a staging system with a progressive development of symptoms and complications. The median age of symptom onset was 6 (range 4-10) years and median duration of symptoms was 8.5 (range 2-11) years. 16 of 22 families reported multiple affected children. Physical manifestations and complications included stunting, wasting, lip changes and gross physical deformities. The bone age was delayed by 2 (range 1-6) years. There was peripheral muscle wasting and progressive generalised wasting. Four children had nodding as the only seizure type; 18 in addition had myoclonic, absence and/or generalised tonic-clonic seizures developing 1-3 years after the onset of illness. Psychiatric manifestations included wandering, aggression, depression and disordered perception. Cognitive assessment in three children demonstrated profound impairment. The EEG was abnormal in all, suggesting symptomatic generalised epilepsy in the majority. There were different degrees of cortical and cerebellar atrophy on brain MRI, but no hippocampal changes. Five stages with worsening physical, EEG and brain imaging features were identified: a prodrome, the development of head nodding and cognitive decline, other seizure types, multiple complications and severe disability. Nodding syndrome is a neurological disorder that may be characterised as probably symptomatic generalised epilepsy. Clinical manifestations and complications develop in stages which might be useful in defining treatment and rehabilitation. Studies of risk factors, pathogenesis, management and outcome are urgently needed.
    BMJ Open 05/2013; 3(5). DOI:10.1136/bmjopen-2012-002540 · 2.06 Impact Factor
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    ABSTRACT: Introduction:CHARGE syndrome is a multisystem disorder that, in addition to Kallmann syndrome/isolated hypogonadotrophic hypogonadism, has been associated with anterior pituitary hypoplasia (APH). However, structural abnormalities such as an ectopic posterior pituitary (EPP) have not yet been described in such patients.Objective:The aims of the study were: 1) to describe the association between CHARGE syndrome and a structurally abnormal pituitary gland; and 2) to investigate whether CHD7 variants, which are identified in 65% of CHARGE patients, are common in septo-optic dysplasia /hypopituitarism.Methods:We describe 2 patients with features of CHARGE and EPP. CHD7 was sequenced in these and other patients with septo-optic dysplasia/hypopituitarism.Results:EPP, APH, and GH, TSH, and probable LH/FSH deficiency were present in 1 patient, and EPP and APH with GH, TSH, LH/FSH, and ACTH deficiency were present in another patient, both of whom had features of CHARGE syndrome. Both had variations in CHD7 that were novel and undetected in control cohorts or in the international database of CHARGE patients, but were also present in their unaffected mothers. No CHD7 variants were detected in the patients with septo-optic dysplasia/hypopituitarism without additional CHARGE features.Conclusion:We report a novel association between CHARGE syndrome and structural abnormalities of the pituitary gland in 2 patients with variations in CHD7 that are of unknown significance. However, CHD7 mutations are an uncommon cause of septo-optic dysplasia or hypopituitarism. Our data suggest the need for evaluation of pituitary function/anatomy in patients with CHARGE syndrome.
    The Journal of Clinical Endocrinology and Metabolism 03/2013; 98(4). DOI:10.1210/jc.2012-3467 · 6.31 Impact Factor
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    ABSTRACT: The aim of this study was to determine the yield of magnetic resonance imaging (MRI) after an episode of childhood convulsive status epilepticus (CSE) and to identify the clinical predictors of an abnormal brain scan. Children were recruited following an episode of CSE from an established clinical network in north London. Eighty children (age range 1mo-16y; 39 males; 41 females) were enrolled and seen for clinical assessment and brain MRI within 13 weeks of suffering from an episode of CSE. Scans were reviewed by two neuroradiologists and classified as normal (normal/normal-variant) or abnormal (minor/major abnormality). Factors predictive of an abnormal scan were investigated using logistic regression. Eighty children were recruited at a mean of 31.8 days (5-90d) after suffering from CSE. Structural abnormalities were found in 31%. Abnormal neurological examination at assessment (odds ratio [OR] 190.46), CSE that was not a prolonged febrile seizure (OR 77.12), and a continuous rather than an intermittent seizure (OR 29.98) were all predictive of an abnormal scan. No children with previous neuroimaging had new findings that altered their clinical management. Brain MRI should be considered for all children with a history of CSE who have not previously undergone MRI, especially those with non-prolonged febrile seizure CSE, those with persisting neurological abnormalities 2 to 13 weeks after CSE, and those with continuous CSE.
    Developmental Medicine & Child Neurology 01/2012; 54(4):328-33. DOI:10.1111/j.1469-8749.2011.04215.x · 3.29 Impact Factor
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    ABSTRACT: Molybdenum cofactor deficiency predominantly affects the central nervous system. There are limited data on long-term outcome or brain magnetic resonance imaging (MRI) features. We examined the clinical, brain MRI, biochemical, genetic, and electroencephalographic features and outcome in 8 children with a diagnosis of molybdenum cofactor deficiency observed in our institution over 10 years. Two modes of presentation were identified: early (classical) onset with predominantly epileptic encephalopathy in 6 neonates, and late (atypical) with global developmental impairment in 2 children. Children in both groups had varying degrees of motor, language, and visual impairment. There were no deaths. Brain MRI demonstrated cerebral infarction in all but one child in the atypical group. Distinctive features were best observed on early brain MRI: acute symmetrical involvement of the globus pallidi and subthalamic regions coexisting with older cerebral hemisphere infarction, chronic lesions suggestive of a prenatal insult, pontocerebellar hypoplasia with retrocerebellar cyst, and presence of a distinctive band at the cortical/subcortical white matter. Sequential imaging revealed progressive pontine atrophy and enlargement of retrocerebellar cyst. The brain MRI of one child with atypical presentation (verbal dyspraxia, lens dislocation) showed symmetrical cerebellar deep nuclei signal abnormality without cerebral infarction. Imaging pattern on early brain MRI (<1 week) may prompt the diagnosis, potentially allowing early treatment and disease modifications.
    Pediatric Neurology 10/2011; 45(4):246-52. DOI:10.1016/j.pediatrneurol.2011.06.006 · 1.50 Impact Factor
  • The Lancet 07/2011; 378(9787):224. DOI:10.1016/S0140-6736(11)61065-9 · 39.21 Impact Factor
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    ABSTRACT: Dysarthria following surgical resection of childhood posterior fossa tumour (PFT) is most commonly documented in a select group of participants with mutism in the acute recovery phase, thus limiting knowledge of post-operative prognosis for this population of children as a whole. Here we report on the speech characteristics of 13 cases seen long-term after surgical treatment for childhood PFT, unselected for the presence of post-operative mutism (mean time post-surgery=6y10m, range 1;4-12;6 years, two had post-operative mutism), and examine factors affecting outcome. Twenty-six age- and sex- matched healthy controls were recruited for comparison. Participants in both groups had speech assessments using detailed perceptual and acoustic methods. Over two-thirds of the group (69%) with removal of PFT had a profile of typically mild dysarthria. Prominent speech deficits included consonant imprecision, reduced rate, monopitch and monoloudness. We conclude that speech deficits may persist even up to 10 years post-surgery in participants who have not shown mutism in the acute phase. Of cases with unilateral lesions, poorer outcomes were associated with right cerebellar tumours compared to left, consistent with the notion based on adult data that speech is controlled by reciprocal right cerebellar/left frontal interactions. These results confirm the important role of the cerebellum in the control of fine speech movements in children.
    Brain and Language 02/2011; 117(2):69-76. DOI:10.1016/j.bandl.2011.01.002 · 3.31 Impact Factor
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    ABSTRACT: Post-mortem magnetic resonance imaging (PM MRI) of brain is increasingly used in clinical practice; understanding of normal PM contrast to noise ratio (CNR), T1 and T2 values relaxation times is important for optimisation and accurate interpretation of PM MRI. We obtained T1- and T2-weighted images at 1.5 T. In the first phase of the study, we calculated CNR in twelve brain regions in 5 newborn infants after death and compared this with CNR from 5 infants during life. In the second phase, we measured deep grey matter (GM) and white matter (WM) T1 post-mortem in 18 fetuses and T1 and T2 post-mortem 6 infants prior to autopsy. Phase I: post-mortem T1- and T2-weighted CNRs were lower in most brain regions than during life. Phase II: compared with in vivo, all post-mortem images lacked GM-WM contrast and had high T2-weighted WM signal intensity. Mean (SD) post-mortem T1 in white and deep gray matter were respectively 1898 (327)ms and 1514 (202)ms in fetuses (p>0.05) and 1234 (180)ms and 1016 (161)ms in infants and newborns (p>0.05). Mean (SD) post-mortem T2 was 283 (11)ms in WM and 182 (18)ms in deep GM in infants and newborns (p<0.001). Post-mortem T1 and T2 values are higher than those reported from live cases. The difference between T1 values in GM and WM reduce after death.
    European journal of radiology 02/2011; 81(3):e232-8. DOI:10.1016/j.ejrad.2011.01.105 · 2.16 Impact Factor
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    ABSTRACT: More than 10 years ago, conventional whole-body MRI at 1.5 Tesla (T) was proposed as a more rapid, less invasive alternative to conventional invasive perinatal autopsy. However, there is poor agreement between the perinatal autopsy findings and the postmortem MRI at 1.5 T. Studies in small animals have shown that good images of anatomy can be obtained using high-field MRI at 9.4 T and have led to the present investigation. This prospective blinded study compared the diagnostic accuracy of high-field MRI at 9.4 T and conventional MRI for postmortem examination of small human fetuses. A total of 18 fetuses of less than 22 weeks' gestation were examined using 3-dimensional T2-weighted fast-spin echo sequences for whole-body MRI with 1.5 T and 9.4 T scanners before invasive autopsy. The MRI images for each system were compared to the invasive autopsy findings by investigators who were blinded to the MRI settings. Tissue contrast in 14 different regions for MRI images at 1.5 T and 9.4 T was compared separately and in a random order. The quality of the MRI images was rated on a 4-point scale. For all organ systems, high-field MRI at 9.4 T provided superior image quality scores than conventional MRI at 1.5 T and provided greater spatial resolution, higher tissue contrast, and better diagnostic information. High-field MRI also was able to detect all the structural abnormalities in fetal organs found with invasive autopsy. In contrast, conventional MRI had no diagnostic value in 14 (78%) of the cases. These findings indicate that use of MRI at 9.4 T may be a satisfactory noninvasive alternative to conventional autopsy in both large and small human fetuses.
    Obstetrical and Gynecological Survey 11/2009; 64(12):787-789. DOI:10.1097/01.ogx.0000363245.24663.c5 · 2.36 Impact Factor
  • European Journal of Paediatric Neurology 09/2009; 13. DOI:10.1016/S1090-3798(09)70407-6 · 1.93 Impact Factor
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    ABSTRACT: Conventional whole-body MRI at 1.5 T does not provide adequate image quality of small fetuses, thus reducing its potential for use as an alternative to invasive autopsy. High-field whole-body MRI at 9.4 T provides good images of small animals. We therefore compared the diagnostic usefulness of high-field MRI with conventional MRI for post-mortem examination of human fetuses. We did whole-body MRI at 9.4 T and 1.5 T on 18 fetuses of less than 22 weeks' gestation, using three-dimensional T(2)-weighted fast-spin echo sequences, before doing invasive autopsy. Images obtained with MRI for each system were compared with the findings of invasive autopsy in a blinded manner. Tissue contrast of 14 different regions was compared on 1.5 T and 9.4 T images that were provided by paediatric radiologists separately and in a random order, and image quality was scored on a four-point scale. The primary endpoint was diagnostic accuracy. Spatial resolution, tissue contrast, and image quality of all organ systems were much better with high-field MRI than with conventional MRI. All structural abnormalities that were detected with invasive autopsy and internal examination of visceral organs were also detected with high-field MRI, whereas conventional MRI was not diagnostically useful in 14 (78%) cases. Whole-body high-field MRI is a feasible option for post-mortem examination of human fetuses, and can provide good tissue characterisation even in small fetuses (5 g). The use of MRI at 9.4 T might be helpful in the development of a minimally invasive perinatal autopsy system. Department of Health Policy Research Programme, British Heart Foundation, National Institute of Health Research, Higher Education Funding Council for England, Biotechnology and Biological Sciences Research Council, Engineering and Physical Sciences Research Council, Great Ormond Street Hospital, University College London (UCL) Institute of Child Health, UCL Hospital, and UCL.
    The Lancet 09/2009; 374(9688):467-75. DOI:10.1016/S0140-6736(09)60913-2 · 39.21 Impact Factor
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    ABSTRACT: (i) To compare original foetal brain ultrasound findings with a multidisciplinary expert opinion; (ii) to compare the multidisciplinary expert ultrasound opinion with foetal magnetic resonance imaging (MRI) findings and (iii) to determine in which circumstances foetal MRI gives additional information, and in how many cases management is changed by having information from MRI. Ultrasound scans of 51 consecutive foetuses where foetal brain MR had been performed were retrospectively reviewed by a panel consisting of maternal-foetal-medicine (MFM) consultants, a geneticist, neonatologists and MFM subspecialty trainees. The original ultrasound opinion was compared with the multidisciplinary opinion, which was then compared with MRI findings. In the cases where MRI gave additional information, an assessment was made as to whether this changed management. The multidisciplinary ultrasound opinion differed from the original opinion in 9 of 51 (17%) cases. In 19 patients (37%), the MRI gave additional information to the original ultrasound, in 7 (13%) cases, management, and in 7 (13%) cases, counselling was altered by additional information gained from MRI. The multidisciplinary ultrasound and MRI diagnoses were similar in 36 cases (71%). Multidisciplinary review of an apparently abnormal foetal brain ultrasound can provide additional diagnostic information. When compared with this level of ultrasound expertise, MRI gave additional information in 29% of cases, but only resulted in change in management in about 13%.
    Acta Paediatrica 05/2008; 97(4):414-9. DOI:10.1111/j.1651-2227.2008.00689.x · 1.84 Impact Factor
  • European Journal of Paediatric Neurology 09/2007; 11:104-104. DOI:10.1016/S1090-3798(08)70654-8 · 1.93 Impact Factor
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    Archives of Disease in Childhood - Fetal and Neonatal Edition 06/2006; 91(3):F202-3. DOI:10.1136/adc.2005.079343 · 3.86 Impact Factor
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    ABSTRACT: 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. Patients with congenital hypopituitarism were recruited from the London Centre for Paediatric Endocrinology as well as several national and international centres. The pituitary phenotype ranged from isolated growth hormone deficiency (IGHD) to panhypopituitarism. Clinical data, including endocrine and neuro-radiological studies were obtained from patient records, and DNA was collected and screened for mutations within PROP1 using PCR and single-stranded conformation polymorphism (SSCP) analysis. Positive results on SSCP were sequenced directly. The prevalence of PROP1 mutations in unselected sporadic cases of hypopituitarism was lower (1.1%) than in familial cases (29.5%). PROP1 mutations can be associated with a highly variable phenotype, and both pituitary hypoplasia and pituitary hyperplasia. We describe the waxing and waning of a pituitary mass over 20 months in association with a PROP1 mutation that is predicted to lead to complete loss of function. Additionally, we have identified a possible founder mutation in CPHD patients from the Indian subcontinent. PROP1 mutations are rare in sporadic cases of CPHD, although the prevalence rises if there is a positive family history or if the patients are carefully selected with respect to the endocrine and neuroradiological phenotype. There is considerable phenotypic variability in families with the same mutation, indicating the role of other genetic or environmental factors on phenotypic expression. Finally, the pituitary enlargement that is observed in patients with PROP1 mutations can wax and wane in size before eventual involution.
    Clinical Endocrinology 08/2005; 63(1):10-8. DOI:10.1111/j.1365-2265.2005.02291.x · 3.35 Impact Factor
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