Phenotype-Genotype Correlation in Children with Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with an incidence of ∼1 in 4,000 live births. Neurofibromin, the gene product, is ubiquitously expressed at high levels in the nervous system and functions as a tumor suppressor. Haploinsufficiency of neurofibromin through mutation leads to an increased risk of developing benign and malignant tumors in affected individuals. Although NF1 has complete penetrance, it displays considerable inter- and intrafamilial variability in phenotypic expression which poses disease prediction and management problems. Some NF1 genotype-phenotype correlations have been described. To evaluate the genetic component of variable expressivity in NF1, we examined the phenotypic correlations between affected relatives in 52 NF1 patients from 45 families.

Building Bridges, Paediatric Palliative Care in Belgium: A secondary data analysis of annual paediatric liaison team reports from 2010 to 2014.

BACKGROUND: Although continuity of care in paediatric palliative care (PPC) is considered to be an essential element of quality of care, it's implementation is challenging. In Belgium, five paediatric liaison teams (PLTs) deliver palliative care. A Royal Decree issued in 2010 provides the legal framework that defines the PLTs' missions, as ensuring continuity of curative and palliative care between the hospital and home for children diagnosed with life-limiting conditions. This national study describes how PLTs ensure continuity of care by describing their activities and the characteristics of the children they cared for from 2010 to 2014. METHODS: Thematic analysis of open-ended questions was performed and descriptive statistics of aggregated data issued from annual reports, collected by the Belgian Ministry of Public Health through the Cancer Plan was used. A review panel of PLT members discussed the results and contributed to their interpretation. RESULTS: Between 2010 and 2014, 3607 children and young adults (0-21 years) were cared for by the 5 Belgian PLTs (mean of 721/per year). Of these children, 50% were diagnosed with an oncological disease, 27% with a neurological or metabolic disease. Four hundred and twenty eight (428) children had died. For 51% of them, death took place at home. PLT activities include coordination; communication; curative and palliative care; education; research and fundraising. Different perceptions of what constitutes a palliative stage, heterogeneity in reporting diagnosis and the current lack of specific valid indicators to report PPC activities were found. CONCLUSION: PLTs are offering highly individualised, flexible and integrated care from diagnosis to bereavement in all care settings. Improvements in data registration and implementation of outcome measures are foreseen.

Horner Syndrome in Children: A Clinical Condition with Serious Underlying Disease.

Aim Horner syndrome corresponds to the clinical triad of miosis, ptosis, and facial anhidrosis. These symptoms are related to injury of the oculosympathetic chain. In children, Horner syndrome is classified as congenital or acquired. While the diagnosis is made through clinical examination, there is some debate regarding the use of imaging modalities and the extent of anatomical coverage required. Methods Here, we describe two cases of children with acute Horner syndrome. We then review the literature about the different etiology and discuss the interest of some investigations. Results Case 1: An 8-month-old girl without personal or familial history, has presented a right acquired Horner syndrome without additional signs. Frontal chest radiography and ultrasonography of the neck and the abdomen was first achieved and returned normal. The cerebral and cervical magnetic resonance imaging (MRI) with angiographic sequences performed in a second time was also normal. Finally, an enhanced thoracic computed tomography (CT)-scan demonstrated a mass at the right pulmonary apex. Case 2: A 9-year-old boy without personal or familial history has presented an acute headache with loss of consciousness during a basketball competition. Upon waking up, the child has right hemiplegia, aphasia, and left Horner syndrome. The cerebral CT scan realized in the first line was normal. The MRI with angiographic sequences demonstrated M1 left carotid dissection with homolateral white matter infarction. Conclusion Imaging studies seem critical in delineating the nature and extent of any underlying pathology along the oculosympathetic pathway in children presenting a Horner syndrome. In these patients, a history of trauma or surgery may reduce the need for extensive systemic evaluation. Without such anamnesis, a decision to proceed with further evaluation is made with consideration of the relative incidence of tumor, especially neuroblastoma, or other treatable lesions. In this condition, MRI is the more sensitive and recommended investigation.

Evaluation of adherence to a convulsion management protocol for children in Rwanda.

Inappropriate seizure management may result in high morbidity and mortality. We assessed the adherence of health professionals in southern Rwanda to a national protocol for pharmacological management of seizures in children. A questionnaire featuring a 5-year-old child with generalized prolonged seizures was administered. The questions focused on the choice of initial treatment and the sequence of management following failure of the initial treatment choice. Benzodiazepine was chosen as initial therapy by 93.7% of physicians and 90.9% of nurses. Only 49.2% of physicians and 41% of nurses would repeat the initial treatment in case of failure of the first dose and 47% of doctors would wait 30 min to intervene. In case of refractory status epilepticus, 34% of physicians would give three doses of benzodiazepine, whereas 19% did not know what to do. These results suggest poor adherence to national protocol.

Temple-Baraitser syndrome: a rare and possibly unrecognized condition.

Temple-Baraitser syndrome, previously described in two unrelated patients, is the association of severe mental retardation and abnormal thumbs and great toes. We report two additional unrelated patients with Temple-Baraitser syndrome, review clinical and radiological features of previously reported cases and discuss mode of inheritance. Patients share a consistent pattern of anomalies: hypo or aplasia of the thumb and great toe nails and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect. All patients were born to unrelated parents and occurred as a single occurrence in multiple sibships, suggesting sporadic inheritance from a de novo mutation mechanism. Comparative genomic hybridization in Patients 1, 2 and 3 did not reveal any copy number variations. We confirm that Temple-Baraitser syndrome represents a distinct syndrome, probably unrecognized, possibly caused by a de novo mutation in a not yet identified gene.

Management of diffuse glioma in children: a retrospective study of 27 cases and review of literature.

Gliomas are the most common CNS tumours in children and present either as circumscribed tumours or diffusely infiltrative neoplasms. Diffuse gliomas develop both in the cerebral hemispheres and the brainstem and have a poor prognosis. Guidelines for the therapy of these tumours are still debated. In this study, we reviewed the clinical features of 27 consecutive patients with diffuse gliomas admitted to the Department of Paediatrics of CHR Citadelle, University of Liège, between 1985 and 2005. We review their clinical presentation, diagnosis, treatment and outcome with reference to the published literature.

Microdeletions involving the SCN1A gene may be common in SCN1A-mutation-negative SMEI patients.

Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome is a rare epilepsy syndrome. In 30 to 70% of SMEI patients, truncating and missense mutations in the neuronal voltage-gated sodium-channel alpha-subunit gene (SCN1A) have been identified. The majority of patients have truncating mutations that are predicted to be loss-of-function alleles. Because mutation detection studies use PCR-based sequencing or conformation sensitive gel electrophoresis (CSGE), microdeletions, which are also predicted to be loss-of-function alleles, can easily escape detection. We selected 11 SMEI patients with or without additional features who had no SCN1A mutation detectable with sequencing analysis. In addition, none of the patients was heterozygous for any of the SNPs in SCN1A, indicating that they were either homozygous for all SNPs or hemizygous due to a microdeletion of the gene. We subsequently analyzed these patients for the presence of microdeletions in SCN1A using a quantitative PCR method named multiplex amplicon quantification (MAQ), and observed three patients missing one copy of the SCN1A gene. All three microdeletions were confirmed by fluorescence in situ hybridization (FISH). These findings demonstrate that a substantial percentage of SCN1A-mutation-negative SMEI patients with or without additional features carry a chromosomal microdeletion comprising the SCN1A gene and that haploinsufficiency of the SCN1A gene is a cause of SMEI.

Spontaneous arachnoid cyst rupture in a previously asymptomatic child: a case report.

UNLABELLED: Arachnoid cysts are benign congenital cavities arising in the subarachnoid space. Non-traumatic subdural effusion of cerebrospinal fluid is a rare complication requiring surgical treatment. CASE REPORT: A 15-year-old boy was admitted to the hospital because of symptoms related to acute intracranial hypertension (headache and vomiting). The cerebral CT-scan revealed a subdural hygroma adjoining a voluminous Sylvian arachnoid cyst. Two arachnoid cysts were incidentally discovered 11 years before this dramatic complication. Moreover, the patient had suffered a cerebral concussion 2 years earlier, but interestingly did not develop cystic hemorrhage or rupture, contrary to numerous cases previously described in the literature. The location of the cysts and their regular follow-up did not allow foreseeing a cystic rupture. Hygroma evacuation was first performed after which a subdural peritoneal shunting, using a programmable opening pressure valve, was implanted. Spontaneous rupture into the subdural space represents an unusual complication of arachnoid cysts. Clinical aspects, radiographic findings, pathogenesis and surgical management are described. It is important to point out that subdural hygroma or haematoma should never be excluded in the absence of trauma history, even in the case of small non-progressive cysts regularly supervised.

Hypertrichosis, Fallot tetralogy, growth and developmental delay.

We report a female patient with a unique pattern of pre- and postnatal growth deficiency, tetralogy of Fallot, very long eyelashes (trichomegaly), progressive and generalized hypertrichosis lanuginosa, brain atrophy with epilepsy, and puffy hands and feet. This appears to be a "new" entity within the group of syndromal hypertrichoses, possibly pathogenetically related to, but clinically distinct from Ambras or Oliver-McFarlane syndromes.

Neonatal pulmonary hemosiderosis.

Idiopathic pulmonary hemosiderosis (IPH) is a rare complex entity characterized clinically by acute or recurrent episodes of hemoptysis secondary to diffuse alveolar hemorrhage. The radiographic features are variable, including diffuse alveolar-type infiltrates, and interstitial reticular and micronodular patterns. We describe a 3-week-old infant presenting with hemoptysis and moderate respiratory distress. Idiopathic pulmonary hemosiderosis was the first working diagnosis at the Emergency Department and was confirmed, 2 weeks later, by histological studies (bronchoalveolar lavage). The immunosuppressive therapy by 1 mg/kg/d prednisone was immediately started, the baby returned home on steroid therapy at a dose of 0,5 mg/kg/d. The diagnosis of idiopathic pulmonary hemosiderosis should be evocated at any age, even in the neonate, when the clinical presentation (hemoptysis and abnormal radiological chest images) is strongly suggestive.

Efficacy of sublingual lorazepam versus intrarectal diazepam for prolonged convulsions in Sub-Saharan Africa.

In Sub-Saharan Africa, intrarectal diazepam is the first-line anticonvulsant mostly used in children. We aimed to assess this standard care against sublingual lorazepam, a medication potentially as effective and safe, but easier to administer. A randomized controlled trial was conducted in the pediatric emergency departments of 9 hospitals. A total of 436 children aged 5 months to 10 years with convulsions persisting for more than 5 minutes were assigned to receive intrarectal diazepam (0.5 mg/kg, n = 202) or sublingual lorazepam (0.1 mg/kg, n = 234). Sublingual lorazepam stopped seizures within 10 minutes of administration in 56% of children compared with intrarectal diazepam in 79% (P < .001). The probability of treatment failure is higher in case of sublingual lorazepam use (OR = 2.95, 95% CI = 1.91-4.55). Sublingual lorazepam is less efficacious in stopping pediatric seizures than intrarectal diazepam, and intrarectal diazepam should thus be preferred as a first-line medication in this setting.

WDR62 is associated with the spindle pole and is mutated in human microcephaly.

Autosomal recessive primary microcephaly (MCPH) is a disorder of neurodevelopment resulting in a small brain. We identified WDR62 as the second most common cause of MCPH after finding homozygous missense and frame-shifting mutations in seven MCPH families. In human cell lines, we found that WDR62 is a spindle pole protein, as are ASPM and STIL, the MCPH7 and MCHP7 proteins. Mutant WDR62 proteins failed to localize to the mitotic spindle pole. In human and mouse embryonic brain, we found that WDR62 expression was restricted to neural precursors undergoing mitosis. These data lend support to the hypothesis that the exquisite control of the cleavage furrow orientation in mammalian neural precursor cell mitosis, controlled in great part by the centrosomes and spindle poles, is critical both in causing MCPH when perturbed and, when modulated, generating the evolutionarily enlarged human brain.

Duane anomaly, congenital myopathy and severe scoliosis in sibs: new AR syndrome?

We report on two sisters who show a similar pattern of anomalies consisting of bilateral Stilling-Türk-Duane retraction syndrome (type 3), non-progressive hypotonia with delayed motor milestones but normal intelligence, severe, early onset scoliosis, and short stature. Muscular biopsy revealed numerous regenerating fibers, but no specific abnormalities among the non-regenerating fibers. This combination of anomalies has not been previously reported, and could represent a new autosomal recessive syndrome. The only differential diagnosis is Crisfield-Dretakis-Sharpe syndrome, a combination of lateral gaze palsy, ptosis, and scoliosis without hypotonia, recessively inherited.