Jonathan I.M.L. Verbeke

PPIB Mutations Cause Severe Osteogenesis Imperfecta

Deficiency of cartilage-associated protein (CRTAP) or prolyl 3-hydroxylase 1(P3H1) has been reported in autosomal-recessive lethal or severe osteogenesis imperfecta (OI). CRTAP, P3H1, and cyclophilin B (CyPB) form an intracellular collagen-modifying complex that 3-hydroxylates proline at position 986 (P986) in the alpha1 chains of collagen type I. This 3-prolyl hydroxylation is decreased in patients with CRTAP and P3H1 deficiency. It was suspected that mutations in the PPIB gene encoding CyPB would also cause OI with decreased collagen 3-prolyl hydroxylation. To our knowledge we present the first two families with recessive OI caused by PPIB gene mutations. The clinical phenotype is compatible with OI Sillence type II-B/III as seen with COL1A1/2, CRTAP, and LEPRE1 mutations. The percentage of 3-hydroxylated P986 residues in patients with PPIB mutations is decreased in comparison to normal, but it is higher than in patients with CRTAP and LEPRE1 mutations. This result and the fact that CyPB is demonstrable independent of CRTAP and P3H1, along with reported decreased 3-prolyl hydroxylation due to deficiency of CRTAP lacking the catalytic hydroxylation domain and the known function of CyPB as a cis-trans isomerase, suggest that recessive OI is caused by a dysfunctional P3H1/CRTAP/CyPB complex rather than by the lack of 3-prolyl hydroxylation of a single proline residue in the alpha1 chains of collagen type I.

Whole-body MRI reveals high incidence of osteonecrosis in children treated for Hodgkin lymphoma

Osteonecrosis is a well‐recognized complication in patients treated with corticosteroids. The incidence of osteonecrosis in children treated for Hodgkin lymphoma is unknown because prospective whole‐body magnetic resonance imaging (MRI) studies are lacking in this patient population. Paediatric patients with newly diagnosed Hodgkin lymphoma who were treated according to a uniform paediatric Hodgkin protocol were eligible for inclusion in this prospective study. Whole‐body MRI was performed in all 24 included patients (mean age 15·1 years, 12 girls) both before treatment and after 2 cycles of chemotherapy, and in 16 patients after completion of chemotherapy. Osteonecrosis was identified in 10 patients (41·7%, 95% confidence interval: 22·0–61·4%), with a total of 56 osteonecrotic sites. Osteonecrosis was detected in 8 patients after 2 cycles of OEPA (vincristine, etoposide, prednisone, doxorubicin), and in 2 additional patients after completion of chemotherapy. Epiphyseal involvement of long bones was seen in 4 of 10 children. None of the patients with osteonecrosis had any signs of bone collapse at the times of scanning. Whole‐body MRI demonstrates osteonecrosis to be a common finding occurring during therapy response assessment of paediatric Hodgkin lymphoma. Detection of early epiphyseal osteonecrosis could allow for treatment before bone collapse and joint damage may occur.

Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy

Objectives: To assess frequency of gallbladder polyposis and carcinoma in metachromatic leukodystrophy (MLD). Methods: We evaluated 34 patients with MLD (average age 16.7 years, age range 2–39 years) screened for gallbladder abnormalities by ultrasound. In the case of cholecystectomy, findings at pathology were reviewed. Results: Only 8 of 34 patients (23%) had a normal gallbladder at ultrasound. Gallbladder polyps were visible in 8 patients (23%). Cholecystectomy was performed in 11 patients (32%). In these, pathology revealed various abnormalities, including hyperplastic polyps, intestinal metaplasia, prominent Rokitansky-Aschoff sinuses, and sulfatide storage. Conclusions: Our results demonstrate that gallbladder involvement is the rule rather than the exception in MLD. The high prevalence of hyperplastic polyps, a known precancerous condition, and one death from gallbladder carcinoma at a young age suggest that MLD predisposes to neoplastic gallbladder abnormalities. As novel therapies for this patient group are emerging leading to increased life expectancy, we recommend screening for gallbladder abnormalities by ultrasound in order to prevent early death.

A novel GJC2 mutation associated with hypomyelination and Müllerian agenesis syndrome: coincidence or a new entity?

In recent years, several new white matter diseases have been identified based on magnetic resonance imaging and clinical findings. For most newly defined disorders the genetic basis has been identified. However, there is still a large group of patients without a specific diagnosis. Hypomyelinating leukodystrophies are the largest group among them. In some disorders characterized by hypomyelination only central nervous system involvement is observed, but in some disorders involvement of other organs is observed as well, such as eyes or teeth. Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating disorder of the central nervous system characterized by nystagmus, ataxia, and progressive spasticity. The disease is caused by mutations in GJC2, the gene that encodes the gap junction protein connexin 47. Here we describe hypomyelination and Müllerian agenesis syndrome in a girl who is homozygous for a novel mutation in the GJC2 gene. It is an open question whether this is an association by chance or a feature of PMLD not previously noted.

Cushing’s Triad in Pneumococcal Meningitis Due to Brainstem Ischemia: Early Detection by Diffusion-Weighted MRI

An infant with pneumococcal meningitis developed signs of raised intracranial pressure during the progression of the disease, including loss of consciousness, hypertension, bradycardia, and respiratory depression. However, both the emergency computed tomography scan findings and intracranial pressure measured by lumbar puncture were normal. Diffusion-weighted magnetic resonance imaging identified multiple lesions with restricted diffusion suggestive of ischemia in the brainstem, explaining the signs observed in the patient. These lesions could not be identified on T(2)-weighted images at that time.

OC21.07: *Additional value of advanced neurosonography and magnetic resonance imaging in fetuses at risk for brain damage

(>3) sonographic findings, respectively. PPV of major or multiple minor US abnormalities in case of symptomatic congenital infection were 80,0 % in fetuses or infants with congenital infection, and 61.5% when all exposed fetuses were considered, with a specificity of 95.7% and 98.1%, respectively. Conclusions: When fetal status is unknown, any US abnormality can only predict a symptomatic congenital infection in 41.3% of cases. The classification of US semiology as major and minor infectious criteria leads to increase US prediction performance of symptomatic congenital infection when major or multiple minor criteria are found.

Fetal MRI, lower acceptance by women in research vs. clinical setting

Abstract Aim: To determine acceptance of pregnant women to undergo fetal magnetic resonance imaging (MRI) examination in research and clinical setting. Methods: A prospective study included a research group [part of a study comparing brain ultrasound (US) to MRI in fetuses at risk for acquired brain damage] and a clinical group [fetuses with suspected (brain) anomalies after structural US examination] from 2011 to 2014. All women were advised to use sedatives. MRI declinations, use of sedation, MRI duration and imaging quality were compared between both groups. Results: Study participation was accepted in 57/104 (55%) research cases. Fetal MRI was performed in 34/104 (33%) research and 43/44 (98%) clinical cases. Reasons to decline study participation were MRI related in 41%, and participation was too burdensome in 46%. Acceptance was highest for indication infection and lowest in alloimmune thrombocytopenia and monochorionic twin pregnancy. Sedatives were used in 14/34 research and 43/43 clinical cases. Scan duration and quality were comparable (21 and 20 min in research and clinical cases, respectively, moderate/good quality in both groups). Conclusions: Pregnant women consider MRI more burdensome than professionals realize. Two-third of women at risk for fetal brain damage decline MRI examination. Future studies should evaluate which information about fetal MRI is supportive.

Diffusiegewogen MRI bij neonatale Bacillus cereus meningo-encefalitis

SummaryT1 and T2 weighted mr images of the brain are very suitable to demonstrate the integrity of the infants brain. Diffusion weighted mri is a new promising technique which is sensitive to conditions with restricted water diffusion, e.g. cytotoxic edema in infection and ischaemia. The value of this new mri technique will be discussed in relation to two patients with severe neurological problems.Two premature infants developed a Bacillus cereus infection of the central nervous system. T1 weighted mri showed a hyperintense signal in the entire cerebral cortex and white matter; some of these areas were hypointense on T2 weighted mri, suggestive of hemorrhage. On T2 weighted mri part of the cortex was abnormal whereas the basal nuclei appeared normal. dwi showed increased signal in basal nuclei and cortex, probably due to cytotoxic edema.Conclusion: Bacillus cereus infection of the central nervous system can lead to a severe hemorrhagic meningo-encephalitis. mri is an excellent technique to investigate the extent of lesions in the brain. Diffusion weighted mri has an additional value in detecting extra lesions most probably due to cytotoxic edema.samenvattingT1- en T2-gewogen magnetische resonantie beeldvorming (mri) van de hersenen is bij uitstek geschikt om de integriteit van de hersenen in beeld te brengen. Diffusiegewogen mri is een nieuwe, veelbelovende techniek die vooral gevoelig is voor verminderde diffusie van water zoals dat gezien wordt bij cytotoxisch oedeem, onder andere in het kader van acute ischemische veranderingen. De waarde van T1-, T2- en diffusiegewogen mri wordt besproken aan de hand van twee patiëntjes met een ernstig neurologisch ziektebeeld.Twee premature neonaten ontwikkelden een Bacillus cereus-infectie van het centraal zenuwstelsel. Op de T1-gewogen mri-beelden waren hyperintense afwijkingen zichtbaar in de gehele supratentoriële witte stof en cortex; deels waren deze afwijkingen hypo-intens op T2-gewogen beelden, passend bij bloed. Op de T2-gewogen mri-beelden was een deels afwijkende cortex zichtbaar; de basale kernen toonden relatief weinig afwijkingen. Op de diffusiegewogen mri-beelden was bij beide kinderen een verhoogd signaal zichtbaar in de basale kernen en de cortex, passend bij cytotoxisch oedeem.Conclusie: Bij een neonatale Bacillus cereus-infectie van het centraal zenuwstelsel kan een zeer ernstige hemorragische meningo-encefalitis optreden. mri is een zeer gevoelige techniek voor het vaststellen van de uitgebreidheid van de schade aan de hersenen. Hierbij heeft diffusiegewogen mri een toegevoegde waarde voor het vaststellen van extra afwijkingen, die meest waarschijnlijk berusten op cytotoxisch oedeem.