Tetrasomy 9p mosaicism associated with a normal phenotype in two cases.

Tetrasomy 9p is a rare chromosomal syndrome and about 30% of known cases exhibit mosaicism. Approximately 50 of the reported cases with tetrasomy 9p mosaicism show a characteristic facial appearance, growth failure, and developmental delay. However, 3 patients with mosaicism for isochromosome 9p and a normal phenotype have also been reported. We report 2 additional cases of clinically normal young females with tetrasomy 9p mosaicism, one of whom also exhibited X chromosome aneuploidy mosaicism leading to an overall of 6 different cell lines. STR analysis performed on this complex mosaic case indicated that the extra isochromosome was of maternal origin while the X chromosome aneuploidy was of paternal origin, indicating a postzygotic event.

Presumed infective meningoencephalitis complicated by bilateral optic neuritis.

PURPOSE: To report a case of presumed infective meningoencephalitis complicated by bilateral optic neuritis. METHODS: Interventional case report. RESULTS: A 7-year-old Pakistani girl presented with fever and multiple right-sided focal seizures. Despite empirical treatment with antibiotic, anti-viral and anti-tuberculous therapy for presumed infective meningoencephalitis, she further deteriorated, developing altered consciousness, hemiplegia and severe, bilateral optic neuritis. No infectious agent could be identified. Following the addition of high dose systemic corticosteroid therapy, her optic nerve function in both eyes began to recover. At 3-month follow-up, the hemiplegia had completely resolved, and visual acuity was 6/6 bilaterally with normal pupillary responses. CONCLUSIONS: This case demonstrates that meningoencephalitis of presumed infective origin may be complicated by acute, severe, bilateral optic neuritis, the latter often mediating profound visual loss. In the setting of rapidly deteriorating vision, aggressive corticosteroid treatment, with antimicrobial cover, albeit unproven, remains the mainstay of treatment.

Combination chemotherapy with low doses of weekly Carboplatin and oral Etoposide in poor risk small cell lung cancer.

Sixty patients with poor prognostic features, either with extensive disease (ED) or limited disease (LD) small cell lung cancer (SCLC), were treated on an out-patient basis with Carboplatin 80 mg/m2 weekly for 3 weeks and oral Etoposide, at a dose of 100 mg, every other day for 21 days. The treatment was repeated every 5 weeks. Responding patients with LD were also treated with thoracic irradiation and those who achieved complete response (CR) received prophylactic cranial radio-therapy. The overall response rate (RR) was 32.1% with 8.9% CR. The responses were better for LD (RR 58.3%, CR 25%, partial response, PR 33.3%), than those for ED (RR 25%, CR 4.5%, PR 20.5%). The median time to progression (TTP) was 4.8 months and the median survival 5.5 months. These poor results could be attributed to the bad performance status and the presence of visceral and brain metastases in this group of patients. The results could also be due to the lower maximum concentration (Cmax) and higher T1/2 of Etoposide, as measured in the blood and urine probably due to the modified regimen used in our study and to the organ insufficiency in this selected group of patients. Although, toxicity was generally mild and manageable, two toxic deaths occurred. In conclusion, this regimen appears to have a lower efficacy in terms of response and survival than that obtained in other studies using Cisplatin or Carboplatin plus Etoposide in a similar way. Therapy with this regimen, though less toxic, may not be a reliable alternative in elderly patients with visceral metastases and ECOG performance status > or = 2.

Delayed diagnosis of Duchenne muscular dystrophy.

A late diagnosis of Duchenne muscular dystrophy has implications for both child and family. This repeat audit has shown that the diagnosis continues to be delayed. The failure to recognize that non-motor, and specifically speech and language delay are common features of this disease may detract from the motor difficulties in affected children and contribute to the late diagnosis of this disorder. In the absence of a national newborn screening programme for Duchenne muscular dystrophy, all health care professionals should be made more aware of the condition and have a lower threshold for measuring a creatine phosphokinase level.

Primary malignant melanoma of meninges: atypical presentation of subacute meningitis.

Primary malignant melanoma of the meninges is described in a 5-year-old boy who presented with a 3-month history suggestive of subacute meningitis. Clinically the diagnosis of tuberculous meningitis was made and antituberculous treatment was begun. Despite this treatment, the patient's condition continued to deteriorate. Through cytologic examination of the cerebrospinal fluid malignant melanoma cells were identified, emphasizing the importance of this investigation in children with atypical meningitis. The diagnosis of malignant melanoma of the meninges was confirmed on brain biopsy.

An unusual syndrome with mental retardation and sparse hair.

We report a 16-year-old female patient with an undiagnosed syndrome, of mental retardation, sparse hair, a prominent lower lip, brachydactyly with cone-shaped epiphyses.

Epilepsy surgery in children under 3 years.

PURPOSE: Resective epilepsy surgery in early childhood has become an important treatment option for selected infants and children with epilepsy. We describe experience and clinical outcomes of children under 3 years undergoing epilepsy surgery at Great Ormond Street Hospital (GOSH). METHODS: All children under 36 months of age who had resective surgery for the purpose of treating epilepsy within the GOSH epilepsy surgery programme were ascertained using a departmental database. Aetiology, post-operative seizure frequency, pre and post-operative cognitive function, long-term complications and re-operation rates were analysed by retrospective examination of clinical records. RESULTS: Forty-two children were included in our cohort with a median age at surgery of 20 months (range 3-36 months). Surgical procedures comprised 25 functional hemispherectomies, two anatomical hemispherectomies, four multilobar resections, seven lobar resections and four focal resections. 7/42 (17%, 95% CI 8-31%) children underwent re-operation. 20/42 (48%, 95% CI 33-62%) children achieved seizure freedom. 18/42 (43%, 95% CI 29-58) demonstrated an improvement in seizure frequency and no children had an increase in seizure frequency. Post-operative complications included subsequent shunt procedure in 5/25 (20%, 95% CI 9-39%) children undergoing hemispherectomy. There were no mortalities. In 23 children pre- and post-operative DQ or IQ was determinable allowing longitudinal comparison. Five children had a decrease in DQ/IQ >15 and two children had an increase DQ/IQ >15. DISCUSSION: Epilepsy surgery in children under 3 years of age offers suitable candidates a good chance of significantly improved seizure outcome which compares with rates in older cohorts.

Immunoglobulin therapy in Guillain-Barré syndrome in children.

Four children with evolving Guillain-Barré syndrome were treated with a five-day course of intravenous immunoglobulin. No patient showed further progression of the condition and all made a rapid and complete recovery with no evidence of relapse over a six- to 24-month follow-up period. The early use of immunoglobulin in this disorder may prevent further progression of the disease and accelerate short-term recovery, with resulting medical, social and financial implications.

Neurological outcome of methylmalonic acidaemia.

OBJECTIVE: To assess the long term outcome of patients with methylmalonic acidaemia in a cross sectional study. PATIENTS: All 35 patients with methylmalonic acidaemia seen at Great Ormond Street Hospital for Children in London, UK between 1970 and 1996 were studied. They were divided into cobalamin responsive (n = 6) and non-responsive (n = 29), and early and late onset groups. RESULTS: There was a significant difference between cobalamin responsive and non-responsive groups in severity, survival, and incidence of neurological sequelae. Cobalamin responsive patients had mild disease, irrespective of age at presentation, their neurological complications were less severe, and they are all alive. The cobalamin non-responsive group comprised 19 early and nine late onset patients. The early onset patients had more severe disease at presentation and 14 have died; all late onset patients are alive. There was no significant difference in abnormal neurological signs, although early onset patients had a significantly reduced full scale intelligence quotient and poor cognitive outcome. In both groups, abnormal neurological signs continue to increase with age. CONCLUSIONS: Cobalamin responsive patients have a better long term outcome. The outcome in the non-responsive patients, particularly the early onset group, remains poor and alternative treatments should therefore be considered early in this group.

Effect of random airway sizes on aerosol deposition.

A previously developed deposition model is used to determine the total and regional deposition of inhaled aerosols in a population of human lungs by taking into account variability in airway dimensions. The results for particle sizes ranging from 0.1 micron to 8 micron aerodynamic diameter agree favorably with experimental data, thus suggesting that observed intersubject deposition variability is caused primarily by difference in airway dimensions.

EEG requests in paediatrics: an audit.

An audit of 165 requests for electroencephalography (EEG) was undertaken before and after the introduction of guidelines and recommendations, 12 months apart. Inadequate clinical information was provided in requests in both surveys; 40% of requests were considered to be unnecessary, and approximately 50% of clinicians felt that EEG could diagnose epilepsy.

Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS): a new syndrome.

There are a large number of well recognised syndromes comprising cerebellar ataxia in association with other neurological features. We report three family members who presented with a relapsing, early onset cerebellar ataxia, associated with progressive optic atrophy and sensorineural deafness. All three patients have areflexia (in the absence of a peripheral neuropathy), a pes cavus deformity, and show varying degrees of severity. Extensive neurological investigations have been normal, and the aetiology and pathophysiology of this disorder remain unclear. This may represent a separate syndrome of early onset cerebellar ataxia with associated features ("cerebellar ataxia plus"), which is likely to either have an autosomal dominant or maternal mitochondrial pattern of inheritance. The recognition of this association under the acronym of CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural deafness) may help in the delineation of a new syndrome.

Neurological outcome of patients with ornithine carbamoyltransferase deficiency.

BACKGROUND: Ornithine carbamoyltransferase (OCT) deficiency is the commonest of the inherited urea cycle disorders. AIMS: To determine the long term neurological and cognitive outcome of continuously treated surviving patients. METHODS: Twenty eight surviving children (five boys) with OCT deficiency who had been treated continuously with a low protein diet and alternative pathway therapy were identified. Those aged 5-16 years had a detailed neurological examination and psychometric testing. RESULTS: Four presented in the neonatal period and four were treated prospectively following antenatal diagnosis. Median (range) age at diagnosis for the later onset group was 19 (2-144) months; median time between onset of symptoms and diagnosis was 10 (2-48) months. Nine children had had less than three episodes of hyperammonaemic encephalopathy, the others more. Seven had focal abnormalities on neurological examination; 14 had global cognitive impairment; four had a normal IQ but specific learning difficulties. Sixteen underwent neuroimaging which was normal in three, showed focal abnormalities of the cerebral hemispheres in six, and global cerebral atrophy in seven. CONCLUSION: Eighteen of 28 surviving children with OCT deficiency had disabling neurological complications. Plasma ammonia at diagnosis was the only factor that predicted this outcome. While most neurological complications could be attributed to hyperammonaemic encephalopathy, other mechanisms may also contribute to the neurological abnormalities.

Pleuropulmonary blastoma in childhood. A malignant degeneration of pulmonary cysts.

Pleuropulmonary blastoma (PPB) is an extremely rare intrathoracic neoplasm of early childhood with an unfavorable outcome. In this article, two children with PPB associated with pre-existing pulmonary cysts are presented. It is emphasized that surgical excision is the treatment of choice for all pulmonary cysts.

A statistical description of the human tracheobronchial tree geometry.

Most physiological studies which made use of lung geometry have utilized average deterministic models of the tracheobronchial tree geometry, such as Weibel's Model A (1963). However, as shown by morphometric studies, it is well known that there are significant inter-subject and intra-subject variabilities in the structural components of the human lung. Hence, inherent inaccuracies exist when deterministic dimensions for lung geometry are used. In this paper, a statistical description of the lung geometry is presented. Using Weibel's Model A as the underlying average model, probability distributions for the lengths and the diameters of airways and for the number and volume of alveoli are proposed based on morphometric data. As a check for consistency, the probability distribution of the functional residual capacity is derived from those associated with airways and alveoli and it is compared with reported data. Results of this comparison are favorable, suggesting that the statistical description presented herein represents a self-consistent model for lung geometry which can be used for studies of problems related to pulmonary physiology.

Midpregnancy plasma zinc in normal and growth retarded fetuses--a preliminary study.

OBJECTIVE: To determine plasma zinc concentrations in normally and abnormally growing fetuses. DESIGN: Prospective observational study. SETTING: Fetal Medicine Unit, Queen Charlotte's Maternity Hospital. SUBJECTS: 53 pregnant women attending for fetal blood sampling at between 18 and 40 weeks gestation. 27 fetuses were normal (central group), 11 fetuses were growth retarded and 15 were malformed. MAIN OUTCOME MEASURES: Plasma zinc concentrations in maternal and fetal blood at time of fetal blood sampling. RESULTS: In normally growing fetuses, between 18 and 40 weeks gestation, there was no fall in maternal plasma zinc concentration; the fetal level fell by 36%. In 10 fetuses with symmetrical growth retardation, plasma zinc concentration tended to be low, but was not significantly different from that in the normal control fetuses. CONCLUSION: The results suggest that (i) placental transfer of zinc is an uphill secretory process and that it is a rate-limiting step in the accumulation of zinc by the fetus and (ii) in fetuses with symmetrical intrauterine growth retardation, a low plasma zinc is probably a parallel phenomenon and not necessarily an aetiological factor.

The longer term outcome of children born to mothers with epilepsy.

OBJECTIVES: To determine the prevalence of cognitive delay and possible associated dysmorphic features in children exposed to antiepileptic drugs (AEDs) in utero. DESIGN: Retrospective study of children born to mothers with epilepsy. SETTING: Regional epilepsy clinics in Liverpool and Manchester, UK. PARTICIPANTS: Children aged between 6 months and 16 years born to mothers with epilepsy. MAIN OUTCOME MEASURES: Structured interviews, hospital records, clinical examination, and psychometric tests (Wechsler) were used to assess exposure and intelligence quotient (IQ). Blinded assessment of photographs was used to score children with characteristic dysmorphic features. RESULTS: A total of 249 children aged 6 and over were studied: 41 were exposed to sodium valproate, 52 to carbamazepine, 21 to phenytoin, 49 to polytherapy, and 80 were unexposed. Mean verbal IQ was significantly lower in the valproate group compared to unexposed and other monotherapy groups. Multiple regression analysis showed that both valproate exposure and frequent tonic-clonic seizures in pregnancy were significantly associated with a lower verbal IQ despite adjusting for other confounding factors. There was a significant negative correlation between dysmorphic features and verbal IQ in children exposed to valproate. CONCLUSIONS: This study identifies valproate as a drug carrying potential risks for developmental delay and cognitive impairment and is the first to suggest that frequent tonic-clonic seizures have a similar effect. Our results need to be interpreted with caution given their retrospective nature. Women with epilepsy need careful counselling about individual risk benefit of AED treatment before pregnancy.

Non-disjunction of chromosome 18.

A sample of 100 trisomy 18 conceptuses analysed separately and together with a published sample of 61 conceptuses confirms that an error in maternal meiosis II (MII) is the most frequent cause of non-disjunction for chromosome 18. This is unlike all other human trisomies that have been studied, which show a higher frequency in maternal meiosis I (MI). Maternal MI trisomy 18 shows a low frequency of recombination in proximal p and medial q, but not the reduction in proximal q observed in chromosome 21 MI non-disjunction. Maternal MII non-disjunction does not fit the entanglement model that predicts increased recombination, especially near the centromere. Whereas recent data on MII trisomy 21 show the predicted increase in recombination proximally, maternal MII trisomy 18 has non-significantly reduced recombination. Therefore, chromosome-specific factors must complicate the simple model of susceptible chiasma distributions interacting with age-dependent deterioration of the meiotic mechanism. For chromosome 18, 30% of tetrads are nullichiasmate in maternal MI non-disjunction, but nullichiasmates are not observed in maternal MII non-disjunction. Chiasma distributions from normal chromosome 18 meioses provide no evidence for normal disjunction from nullichiasmate tetrads. We extend this study to examine the remaining autosomes and find no evidence for normal disjunction from nullichiasmate tetrads generally.