Intravenous immunoglobulin treatment in childhood encephalitis (IgNiTE): a randomised controlled trial.

OBJECTIVE: To investigate whether intravenous immunoglobulin (IVIG) improves neurological outcomes in children with encephalitis when administered early in the illness. DESIGN: Phase 3b multicentre, double-blind, randomised placebo-controlled trial. SETTING: Twenty-one hospitals in the UK. PARTICIPANTS: Children aged 6 months to 16 years with a diagnosis of acute or subacute encephalitis, with a planned sample size of 308. INTERVENTION: Two doses (1 g/kg/dose) of either IVIG or matching placebo given 24-36 hours apart, in addition to standard treatment. MAIN OUTCOME MEASURE: The primary outcome was a 'good recovery' at 12 months after randomisation, defined as a score of≤2 on the Paediatric Glasgow Outcome Score Extended. SECONDARY OUTCOME MEASURES: The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and IVIG safety data. RESULTS: 18 participants were recruited from 12 hospitals and randomised to receive either IVIG (n=10) or placebo (n=8) between 23 December 2015 and 26 September 2017. The study was terminated early following withdrawal of funding due to slower than anticipated recruitment, and therefore did not reach the predetermined sample size required to achieve the primary study objective; thus, the results are descriptive. At 12 months after randomisation, 9 of the 18 participants (IVIG n=5/10 (50%), placebo n=4/8 (50%)) made a good recovery and 5 participants (IVIG n=3/10 (30%), placebo n=2/8 (25%)) made a poor recovery. Three participants (IVIG n=1/10 (10%), placebo n=2/8 (25%)) had a new diagnosis of epilepsy during the study period. Two participants were found to have specific autoantibodies associated with autoimmune encephalitis. No serious adverse events were reported in participants receiving IVIG. CONCLUSIONS: The IgNiTE (ImmunoglobuliN in the Treatment of Encephalitis) study findings support existing evidence of poor neurological outcomes in children with encephalitis. However, the study was halted prematurely and was therefore underpowered to evaluate the effect of early IVIG treatment compared with placebo in childhood encephalitis. TRIAL REGISTRATION NUMBER: Clinical Trials.gov NCT02308982; ICRCTN registry ISRCTN15791925.

Whole-Body Hypothermia, Cerebral Magnetic Resonance Biomarkers, and Outcomes in Neonates With Moderate or Severe Hypoxic-Ischemic Encephalopathy Born at Tertiary Care Centers vs Other Facilities: A Nested Study Within a Randomized Clinical Trial.

Importance: The association between place of birth and hypothermic neuroprotection after hypoxic-ischemic encephalopathy (HIE) in low- and middle-income countries (LMICs) is unknown. Objective: To ascertain the association between place of birth and the efficacy of whole-body hypothermia for protection against brain injury measured by magnetic resonance (MR) biomarkers among neonates born at a tertiary care center (inborn) or other facilities (outborn). Design, Setting, and Participants: This nested cohort study within a randomized clinical trial involved neonates at 7 tertiary neonatal intensive care units in India, Sri Lanka, and Bangladesh between August 15, 2015, and February 15, 2019. A total of 408 neonates born at or after 36 weeks' gestation with moderate or severe HIE were randomized to receive whole-body hypothermia (reduction of rectal temperatures to between 33.0 °C and 34.0 °C; hypothermia group) for 72 hours or no whole-body hypothermia (rectal temperatures maintained between 36.0 °C and 37.0 °C; control group) within 6 hours of birth, with follow-up until September 27, 2020. Exposure: 3T MR imaging, MR spectroscopy, and diffusion tensor imaging. Main Outcomes and Measures: Thalamic N-acetyl aspartate (NAA) mmol/kg wet weight, thalamic lactate to NAA peak area ratios, brain injury scores, and white matter fractional anisotropy at 1 to 2 weeks and death or moderate or severe disability at 18 to 22 months. Results: Among 408 neonates, the mean (SD) gestational age was 38.7 (1.3) weeks; 267 (65.4%) were male. A total of 123 neonates were inborn and 285 were outborn. Inborn neonates were smaller (mean [SD], 2.8 [0.5] kg vs 2.9 [0.4] kg; P = .02), more likely to have instrumental or cesarean deliveries (43.1% vs 24.7%; P = .01), and more likely to be intubated at birth (78.9% vs 29.1%; P = .001) than outborn neonates, although the rate of severe HIE was not different (23.6% vs 17.9%; P = .22). Magnetic resonance data from 267 neonates (80 inborn and 187 outborn) were analyzed. In the hypothermia vs control groups, the mean (SD) thalamic NAA levels were 8.04 (1.98) vs 8.31 (1.13) among inborn neonates (odds ratio [OR], -0.28; 95% CI, -1.62 to 1.07; P = .68) and 8.03 (1.89) vs 7.99 (1.72) among outborn neonates (OR, 0.05; 95% CI, -0.62 to 0.71; P = .89); the median (IQR) thalamic lactate to NAA peak area ratios were 0.13 (0.10-0.20) vs 0.12 (0.09-0.18) among inborn neonates (OR, 1.02; 95% CI, 0.96-1.08; P = .59) and 0.14 (0.11-0.20) vs 0.14 (0.10-0.17) among outborn neonates (OR, 1.03; 95% CI, 0.98-1.09; P = .18). There was no difference in brain injury scores or white matter fractional anisotropy between the hypothermia and control groups among inborn or outborn neonates. Whole-body hypothermia was not associated with reductions in death or disability, either among 123 inborn neonates (hypothermia vs control group: 34 neonates [58.6%] vs 34 [56.7%]; risk ratio, 1.03; 95% CI, 0.76-1.41), or 285 outborn neonates (hypothermia vs control group: 64 neonates [46.7%] vs 60 [43.2%]; risk ratio, 1.08; 95% CI, 0.83-1.41). Conclusions and Relevance: In this nested cohort study, whole-body hypothermia was not associated with reductions in brain injury after HIE among neonates in South Asia, irrespective of place of birth. These findings do not support the use of whole-body hypothermia for HIE among neonates in LMICs. Trial Registration: ClinicalTrials.gov Identifier: NCT02387385.

The nasopharyngeal airway: Estimation of the nares-to-mandible and nares-to-tragus distance in young children to assess current clinical practice.

BACKGROUND: Nasopharygeal airways are used in urgent situations to alleviate airway obstruction. Guidelines for measuring the length of the NPA differ between national and international guidelines, and the evidence base for these measurements is lacking. The purpose of this study was to measure the nares-epiglottis and nares-vocal cord distances in young children (neonates to 12 years) on 3D reconstructed Magnetic Resonance Imaging (MRI) brain volume scans, and to examine the relationship of these distances with the nares-tragus and nares-mandible distances. METHOD: One-hundred and seventy-six scans were reviewed. All patients had undergone MRI 3D brain volume imaging. The anatomical landmarks were identified and the nares-tragus, nares-mandible distances measured and compared to nares-epiglottis and nares-vocal cord distance using Osirix. RESULTS: The nares-epiglottis and nares-vocal cords distances significantly correlated (p-value <0.05). The nares-tragus distance showed strong correlation with the nares-epiglottis and nares-vocal cord distance compared to the nares-mandible distance (p-value <0.05). CONCLUSION: In conclusion, the length of a nasopharyngeal airway in children under the age of twelve years can be predicted using the nares-tragus external anatomical distance minus 10 mm.

Auditory Processing after Early Left Hemisphere Injury: A Case Report.

Few studies have addressed the long-term outcomes of early brain injury, especially after hemorrhagic stroke. This is the first study to report a case of acquired auditory processing disorder in a 10-year-old child who had a severe left hemorrhagic cerebral infarction at 13 months of age, compromising nearly all of the left temporal lobe. This case, therefore, is an excellent and rare opportunity to investigate the presence of neural plasticity of central auditory system in a developing brain followed severe brain damage. After assuring normal functioning of the peripheral auditory system, a series of behavioral auditory processing tests was applied in dichotic and monaural listening conditions and with verbal and non-verbal stimuli. For all verbal dichotic tasks (dichotic digits, competing words, and sentences tests), good performance on the left ear, especially for Dichotic digits test (100%), and zero performance on the right ear were observed. For monaural low-redundancy tests, the patient also exhibited good performance for auditory figure-ground and time-compressed sentences tests in the left ear. In the right ear, a very poor performance was observed, but slightly better than the same in Dichotic tasks. Impaired performance was also observed in the LiSN test in terms of spatial advantage and, for the Pitch Pattern Sequence test, the only non-verbal test applied, the patient had performance within the normal range in both ears. These results are interpreted taking into consideration the anatomical location of stroke lesion and also the influence of hemispheric specialization for language on auditory processing performance.

Mutations in SLC25A22: hyperprolinaemia, vacuolated fibroblasts and presentation with developmental delay.

Mutations in SLC25A22 are known to cause neonatal epileptic encephalopathy and migrating partial seizures in infancy. Using whole exome sequencing we identified four novel SLC25A22 mutations in six children from three families. Five patients presented clinical features similar to those in the literature including hypotonia, refractory neonatal-onset seizures and developmental delay. However, the sixth patients presented atypically with isolated developmental delay, developing late-onset (absence) seizures only at 7 years of age. Abnormal metabolite levels have not been documented in the nine patients described previously. One patient in our series was referred to the metabolic clinic because of persistent hyperprolinaemia and another three had raised plasma proline when tested. Analysis of the post-prandial plasma amino acid response in one patient showed abnormally high concentrations of several amino acids. This suggested that, in the fed state, when amino acids are the preferred fuel for the liver, trans-deamination of amino acids requires transportation of glutamate into liver mitochondria by SLC25A22 for deamination by glutamate dehydrogenase; SLC25A22 is an important mitochondrial glutamate transporter in liver as well as in brain. Electron microscopy of patient fibroblasts demonstrated widespread vacuolation containing neutral and phospho-lipids as demonstrated by Oil Red O and Sudan Black tinctorial staining; this might be explained by impaired activity of the proline/pyrroline-5-carboxylate (P5C) shuttle if SLC25A22 transports pyrroline-5-carboxylate/glutamate-γ-semialdehyde as well as glutamate.

Hippocampal damage and memory impairment in congenital cyanotic heart disease.

Neonatal hypoxia can lead to hippocampal atrophy, which can lead, in turn, to memory impairment. To test the generalizability of this causal sequence, we examined a cohort of 41 children aged 8-16, who, having received the arterial switch operation to correct for transposition of the great arteries, had sustained significant neonatal cyanosis but were otherwise neurodevelopmentally normal. As predicted, the cohort had significant bilateral reduction of hippocampal volumes relative to the volumes of 64 normal controls. They also had significant, yet selective, impairment of episodic memory as measured by standard tests of memory, despite relatively normal levels of intelligence, academic attainment, and verbal fluency. Across the cohort, degree of memory impairment was correlated with degree of hippocampal atrophy suggesting that even as early as neonatal life no other structure can fully compensate for hippocampal injury and its special role in serving episodic long term memory. © 2017 Wiley Periodicals, Inc.

Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome.

AIM: 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. METHOD: 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. RESULTS: 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. INTERPRETATION: 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.

Nodding syndrome in Ugandan children--clinical features, brain imaging and complications: a case series.

OBJECTIVES: 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. DESIGN: Case series. PARTICIPANTS: 22 children with nodding syndrome brought to Mulago National Referral Hospital for assessment. OUTCOME MEASURES: Clinical features, physical and functional disabilities, EEG and brain MRI findings and a staging system with a progressive development of symptoms and complications. RESULTS: 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. CONCLUSIONS: 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.

Structural pituitary abnormalities associated with CHARGE syndrome.

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 role of magnetic resonance imaging in the follow-up of children with convulsive status epilepticus.

AIM: 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. METHOD: 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. RESULTS: 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. INTERPRETATION: 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.

Post-mortem cerebral magnetic resonance imaging T1 and T2 in fetuses, newborns and infants.

UNLABELLED: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Clinical neuroimaging features and outcome in molybdenum cofactor deficiency.

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.

Post-mortem examination of human fetuses: a comparison of whole-body high-field MRI at 9.4 T with conventional MRI and invasive autopsy.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: 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.

Foetal brain imaging: ultrasound or MRI. A comparison between magnetic resonance imaging and a dedicated multidisciplinary neurosonographic opinion.

OBJECTIVES: (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. STUDY DESIGN: 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. RESULTS: 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%). CONCLUSION: 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%.

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. DESIGN AND PATIENTS: 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. RESULTS: 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. CONCLUSIONS: 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.

Joubert syndrome: long-term follow-up.

Twenty-nine patients (16 males, 13 females) with Joubert syndrome were identified from ophthalmology, neurology, and genetic databases covering a 15-year period at Great Ormond Street Hospital, London. Criteria for diagnosis included absent or markedly hypoplastic cerebellar vermis, abnormal eye movements, and developmental delay. Five patients had died. Scans and notes were available for 22 patients, and 18 cases were clinically reviewed. The median age was 10 years 10 months (range 3mo to 19y) and the median follow-up was 8 years 5 months (range 3mo to 19y, with one new patient seen at 3mo of age). Cerebellar vermis hypoplasia/aplasia with 'molar tooth sign' in the axial plane was present in 22 of 22 patients, coloboma in 6 of 22, and polydactyly in 6 of 22. In the 18 clinically reviewed, apnoea occurred in 13 patients. Five had renal problems with cysts and 4 of 5 had abnormal electroretinograms (ERGs). Visual electrophysiology was abnormal in 14 of 18 patients, and in 6 there was evidence of deterioration in the ERG. Blood investigations of organic acids, phytanic acid, very-long-chain fatty acid, and transferrin were normal in 12 patients tested. Developmental assessment showed that 6 of 15 patients aged more than 5 years were at mainstream school, and 12 of 18 had started walking between 22 months and 10 years. Speech difficulties and behavioural problems were prominent.