Thrombin generation in children with sickle cell disease: relationship with age, hemolysis, transcranial Doppler velocity, and hydroxyurea treatment.

INTRODUCTION: Increased thrombin generation (TG) was described in sickle cell disease (SCD) children. The aim of this study was to characterize TG at the individual level and assess its relationship with age, hemolysis, transcranial Doppler velocity (TCD), and hydroxyurea treatment. PATIENTS AND METHODS: TG was triggered in the platelet-poor plasma using tissue factor and phospholipids with addition of thrombomodulin in 97 SCD at steady state and 80 control children. Patients and controls were aged from 2 to 20 years, and they were distributed in four categories of age: [2-5], [6-10], [11-15], and [16-20] years. For each subject, ratio of endogenous thrombin potential (rETP) and peak height (rPeak) was calculated as subject's value divided by the mean value of controls of the same age range. rETP and rPeak of patients were considered abnormal when > mean + 2SD of controls. LDH, total hemoglobin, and reticulocyte count were measured as markers of hemolysis. Data on hydroxyurea treatment and TCD were collected from medical records. RESULTS: Overall, 38.1% and 44.3% of patients showed elevated rETP and rPeak, respectively. rETP and rPeak decreased significantly with increasing age. In homozygous (SS) patients, TCD velocities and all markers of hemolysis correlated significantly with both rETp and rPeak. Negative correlations were observed between these ratios and the duration of hydroxyurea treatment. CONCLUSION: Elevated TG in SCD children is mainly related to younger age and to the intensity of hemolysis. There probably a link between TG and cerebral vasculopathy in these patients. Hydroxyurea may have a beneficial effect, which could be related to the duration of treatment.

Congenital Nasal Pyriform Aperture Stenosis in Association With Polymalformative Syndrome of the Midline.

Congenital nasal pyriform aperture stenosis (CNPAS) is a rare neonatal entity characterized by a reduction in the pyriform orifice of the nasal cavity. Because of its nonspecific clinical presentation as respiratory distress symptoms, it can mimic choanal atresia. Although isolated forms have been described, CNPAS is often associated with other congenital midline malformations. A single median incisor is usually found, with or without other cervical and maxillofacial malformations. The existence of hypothalamic-pituitary axis malformations with endocrine disorders is also possible and, in some cases, a moderate to severe intellectual deficit in association with other brain malformations. Radiological investigation is a central point in the multidisciplinary management of this type of polymalformative syndrome.

Metachromatic leukodystrophy without arylsulfatase A deficiency: a new case of saposin-B deficiency.

Metachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative lysosomal disease characterized by accumulation of sulfatides, extensive white matter damage and loss of both cognitive and motor functions. In vivo, the catabolism of sulfatide requires both the enzyme arylsulfatase A and a specific sphingolipid activator protein, saposin-B, encoded by the PSAP gene. Arylsulfatase A activity is deficient in the classical forms of MLD, but exceedingly rare cases of MLD are due to saposin-B deficiency. We report here a detailed clinical, radiological and histological description of a new case in a 2-year-old Italian girl, who presented as a late infantile case of MLD with normal arylsulfatase A activity, urinary excretion of sulfatides and mutations in the PSAP gene.

Atypical Rothmund-Thomson syndrome in a patient with compound heterozygous mutations in RECQL4 gene and phenotypic features in RECQL4 syndromes.

We describe the natural history of the RTSII phenotype in a 7-year-old boy who developed intrauterine and postnatal growth retardation, failure to thrive and persisting diarrhoea. The growth hormone stimulation test identified an isolated growth hormone deficiency. Since infancy, the patient manifested skin lesions characterized by a very mild poikilodermic-like appearance on the cheeks only, widespread café-au-lait spots and the absence of eyebrows and eyelashes. There was no cataract. Orthopaedic and radiologic work-up identified the absence of thumb anomaly and radial head luxation and patellar hypoplasia. Neurologic, cognitive milestones and intelligence were normal. The cytogenetic work-up did not show any anomaly. Based on this clinical presentation, we carried out a sequencing analysis of the RECQL4 gene, which is responsible for Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes and found a splice site mutation (IVS10-1G>A) and a nucleotide substitution in exon 12 (L638P). The mother was identified as a carrier for the substitution in exon 12 and the father for the splice site mutation, respectively. An analysis of the transcripts focused on the RECQL4 helicase domain: in the proband only those generated from the maternal L638 allele were present. This case report emphasizes the clinical overlap between RAPADILINO and Rothmund-Thomson syndromes within a continuum phenotypic spectrum. The distinctive set of clinical signs displayed by the patient may be accounted for by his unique combination of two different RECQL4 mutations. The molecular findings provide information that enhances our comprehension of genotype-phenotype correlations in RECQL4 diseases, enables a more precise genetic counseling to the parents and facilitates a more appropriate long-term follow-up to the affected child.

Disseminated Oligodendroglial-like Leptomeningeal Tumor of Childhood: A Distinctive Entity Revised and Correlated with Pathology.

Disseminated oligodendroglial-like leptomeningeal tumor is a recently acknowledged entity whose radiological characteristics have rarely been discussed before. Typical of the childhood period, it should be differentiated clinically and radiographically from granulomatous or infectious conditions such as tuberculous meningitis, which is more common in this age group. The key to the diagnosis, even at an early stage, might be the presence of tiny T2 hyperintense lesions on the surface of the brain or spine. When suspected, a meningeal biopsy should be performed to confirm the diagnostic.

Congenital Hypothyroidism: Long-Term Experience with Early and High Levothyroxine Dosage.

AIM: To assess the management and outcome of the congenital hypothyroidism (CH) patients followed at our institution since the introduction of systemic neonatal screening for CH. STUDY DESIGN: The records of 139 CH patients referred to our center between 1978 and 2014 were retrospectively reviewed. Biochemical and imaging data at diagnosis, initial treatment and growth were analyzed. RESULTS: 111 patients had thyroid dysgenesis (64 ectopy, 46 athyreosis and 1 hypoplasia) and 28 patients had a gland in situ (17 dyshormonogenesis/goiter and 11 normal-sized gland). Levothyroxine treatment was initiated at a median age of 11 days with a mean dose of 11.4 µg/kg/day. Compared to those with ectopy, patients with athyreosis had higher thyroid-stimulating hormone (TSH) and lower thyroxine at diagnosis as well as more delayed bone maturation. Between 1978 and 2014, we observed earlier treatment and earlier TSH normalization. Birth auxology was slightly above the mean of the reference population. Growth at 1 and 6 years and school progression at 11 years were similar to those of the reference population. CONCLUSION: Ectopy is the commonest cause of CH. Children with CH treated early with a mean levothyroxine dose of 11.4 µg/kg/day had a median TSH of 3.07 mU/l at 1 month of age and normal growth.

Value of MR imaging of the brain in children with hypoxic coma.

BACKGROUND AND PURPOSE: The contribution of MR imaging to identify hypoxic-ischemic injuries has been studied mostly in neonates or adults. The purpose of this study was to describe the MR imaging findings of toddlers and older children with hypoxic coma and to analyze the prognostic value of an MR imaging scoring system. METHODS: The conditions of 40 children with hypoxic coma (age range, 6 weeks to 18 years) were clinically graded according to the pediatric risk of mortality score, and MR imaging studies were performed. Sixty-four MR imaging studies were distributed in five categories according to their timing relative to the hypoxic event: days 1 through 3, 4-7, 8-15, 16-50, and after day 50. These were evaluated retrospectively by using an eight-point scoring system based on two lesion categories assessing watershed areas and basal ganglia involvement, including signal intensity and morphologic features with respect to maturation-related norms. Two age groups (< or =1 year and >1 year) were considered. The surviving children were grouped according to neurologic outcome. RESULTS: The occurrence of watershed areas or basal ganglia involvement was not significantly different in association with age. Sixteen children died. Twelve children had moderate to severe sequelae resulting from neurodevelopmental disabilities, and 12 had good neurologic outcomes. There was no correlation between pediatric risk of mortality score and neurologic evolution. There was a strong correlation between first MR imaging score (P <.001) and neurologic outcome. The sensitivity of the first MR imaging score was high (96%), even when obtained during the first 3 days, with a specificity of 50% and a positive predictive value of 82%. Six patients with definite abnormal MR imaging findings experienced good neurologic outcomes. CONCLUSION: The MR imaging scoring system proposed in this study can be used to establish an early prognosis in a significant proportion of children with hypoxic coma. It is helpful, even during the first 3 days after the event. However, some patients with definite abnormal MR imaging findings may experience good neurologic evolution.

Predictive value of electrophysiology in children with hypoxic coma.

Assessment of prognosis of children in hypoxic coma is difficult. The value of clinical evaluation is often limited. The usefulness of electrophysiologic tests has been documented mostly in adults and neonates and in cases of traumatic coma. We reviewed retrospectively 39 consecutive children with nontraumatic hypoxic coma to assess the prognostic value of EEG, visual, and auditory evoked potentials. Correlation between electrophysiology and neurologic outcome after mean follow-up period of 30 months was significant (r(s) = 0.6, P < 0.001). In contrast there was no correlation between Pediatric Risk of Mortality score (PRISM) and outcome (r(s) = -0.42, P = 0.8). Combining magnetic resonance imaging with electrophysiology further enhanced their prognostic value (r(s) = 0.69, P < 0.001). Neuroimaging was highly sensitive but less specific, and electrophysiologic tests were highly specific but less sensitive. We conclude that early electrophysiology can contribute to predicting outcome in pediatric hypoxic coma.

Reduction of the six-minute walk distance in children with sickle cell disease is correlated with silent infarct: results from a cross-sectional evaluation in a single center in Belgium.

BACKGROUND: The 6-minute walk test (6 MWT) is used in adults and children affected by a wide range of chronic diseases to evaluate their sub-maximal exercise capacity. It reflects the global response of various physiological systems in a situation simulating a daily life activity. METHODS: We analyzed factors affecting the 6 MWT in 46 Sickle Cell Disease children. Forty-two were treated with hydroxyurea (HU). Patients with normal test (>80% of the age-standardized predicted value) were compared to patients with abnormal test (≤ 80%). Baseline hematological values, clinical events, cerebrovascular disease, cardio-pulmonary parameters and disease-modifying treatment were compared according to the performance of the test. RESULTS: Among the 46 patients, 14 had an abnormal 6 MWT. In univariate analysis, both groups were similar for biological and clinical data. Six of the 14 patients with an abnormal 6 MWT had silent infarct (SI) compared to 6/32 with a normal test (P = 0.09). When excluding chronically transfused patients, 4 of the 11 patients with an abnormal 6 MWT had SI compared to 1/26 (P = 0.02). Baseline pulse oximetry was normal in both groups but slightly lower in patients with abnormal 6 MWT (P = 0.02). No patient presented exercise-induced desaturation. In multivariate analysis, the only factor associated with abnormal 6 MWT was the presence of SI (P = 0.045). CONCLUSIONS: In our cohort of 46 patients characterized by high exposure rate to HU and by the absence of severe cardiopulmonary disease, the sole factor independently associated with 6 MWT was the presence of SI. The lower exercise capacity of children with SI may reflect some subclinical neurological impairment as they do not differ by hemoglobin level or cardiopulmonary parameters.

Reversible acute methotrexate leukoencephalopathy: atypical brain MR imaging features.

BACKGROUND: Unusual acute symptomatic and reversible early-delayed leukoencephalopathy has been reported to be induced by methotrexate (MTX). OBJECTIVE: We aimed to identify the occurrence of such atypical MTX neurotoxicity in children and document its MR presentation. MATERIALS AND METHODS: We retrospectively reviewed the clinical findings and brain MRI obtained in 90 children treated with MTX for acute lymphoblastic leukaemia or non-B malignant non-Hodgkin lymphoma. All 90 patients had normal brain imaging before treatment. In these patients, brain imaging was performed after treatment completion and/or relapse and/or occurrence of neurological symptoms. RESULTS: Of the 90 patients, 15 (16.7%) showed signs of MTX neurotoxicity on brain MRI, 9 (10%) were asymptomatic, and 6 (6.7%) showed signs of acute leukoencephalopathy. On the routine brain MRI performed at the end of treatment, all asymptomatic patients had classical MR findings of reversible MTX neurotoxicity, such as abnormal high-intensity areas localized in the deep periventricular white matter on T2-weighted images. In contrast, the six symptomatic patients had atypical brain MRI characterized by T2 high-intensity areas in the supratentorial cortex and subcortical white matter (n=6), cerebellar cortex and white matter (n=4), deep periventricular white matter (n=2) and thalamus (n=1). MR normalization occurred later than clinical recovery in these six patients. CONCLUSIONS: In addition to mostly asymptomatic classical MTX neurotoxicity, MTX may induce severe but reversible unusual leukoencephalopathy. It is important to recognize this clinicoradiological presentation in the differential diagnosis of acute neurological deterioration in children treated with MTX.

Sonographic imaging of the paediatric female pelvis.

Several conditions necessitate a pelvic ultrasound in their management. In this paper, we will first review the embryology of the female genital system and the normal morphology of the uterus and ovaries from birth to puberty. Thereafter, this paper aims to categorise pelvic pathologies based on their clinical presentations. We will consider successively ambiguous genitalia, precocious puberty, delayed puberty and amenorrhea, gynaecological masses and, finally, pelvic pain of gynaecological origin. Ultrasound is the key screening tool and often the only examination indicated. The appropriateness of other modalities, such as computed tomography and magnetic resonance imaging, will be discussed. The aim of this article is to help radiologists form a sensible imaging plan when presented with a diagnostic dilemma involving the pelvis in female children.

MR imaging of fetal sacrococcygeal teratoma: diagnosis and assessment.

OBJECTIVE: The purpose of this study was to evaluate the usefulness of MR imaging in the diagnosis and assessment of fetal sacrococcygeal teratoma and to determine if MR imaging provides information not seen on obstetric sonography. SUBJECTS AND METHODS: Twelve pregnant women were referred for fetal MR imaging of sacrococcygeal teratoma seen at obstetric sonography. The presence, size, content extension, and compressive effects of each mass were determined and correlated with the sonographic findings and with postnatal studies, including surgery and pathology. The extent of each sacrococcygeal teratoma was classified according to the American Association of the Pediatrics Surgery Section (types I-IV). RESULTS: There is a complete agreement of sonographic and MR imaging measurements. The sacrococcygeal teratomas appeared cystic with few septa in three fetuses, markedly septated or even microcystic in eight, and completely solid in one. The sonographic description of the content corresponded well to MR imaging findings in 10 of 12 fetuses. An agreement on the extent of each mass was observed in nine patients, whereas there is a disagreement in three, including in one fetus with an extension of the tumor within the spinal canal recognized only at MR imaging. The MR imaging findings were confirmed by postnatal studies in 10 patients. CONCLUSION: Sacrococcygeal teratomas had characteristic MR imaging appearances that allowed a complete assessment in most fetuses. Because of MR imaging, the prenatal evaluation was changed in some patients and affected counseling of the parents and treatment. MR imaging is a valuable adjunct to obstetric sonography for the prenatal evaluation of sacrococcygeal teratoma.