Bernd Schweiger

A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb†

Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with unknown molecular etiology characterized by hypo‐ or aplasia of the tibiae in addition to the preaxial polydactyly (PPD) of the hands and feet and/or five‐fingered hand with absence of thumbs. We show that point mutations of a specific nucleotide within the sonic hedgehog (SHH) regulatory region (ZRS) cause WMS. In a previously unpublished WMS family, we identified the causative G>A transition at position 404 of the ZRS, and in six affected family members of a second WMS family we found a 404G>C mutation of the ZRS. The 404G>A ZRS mutation is known as the “Cuban mutation” of PPD type II (PPD2). Interestingly, the index patient of that family had tibial hypoplasia as well. These data provide the first evidence that WMS is caused by a specific ZRS mutation, which leads to strong ectopic SHH expression. In contrast, we show that complete duplications of the ZRS region lead to type Haas polysyndactyly or triphalangeal thumb‐polysyndactyly syndrome, but do not affect lower limb development. We suggest the term “ZRS‐associated syndromes” and a clinical subclassification for the continuum of limb malformations caused by different molecular alterations of the ZRS. Hum Mutat 30:1–9, 2009.

Effects of RANK-Ligand Antibody (Denosumab) Treatment on Bone Turnover Markers in a Girl With Juvenile Paget's Disease

CONTEXT Juvenile Pagets disease (JPD) is an extremely rare, yet painful and debilitating bone disease with onset occurring during early childhood. JPD can be caused by loss of function of osteoprotegerin, resulting in subsequent stimulation of osteoclasts via the receptor activator of nuclear factor-κB (RANK) pathway. Increased bone turnover and lack of bone modeling lead to severe deformities, frequent fractures, short stature, and loss of hearing. SETTING The treatment for JPD is challenging and has previously been based on administration of either calcitonin or bisphosphonates. However, with the development of denosumab, a receptor activator of nuclear factor-κB-ligand (RANKL) antibody, a treatment targeting the pathophysiology of JPD may be available. We report the effects of denosumab treatment on an 8-year-old girl with a severe form of JPD. PATIENT Before starting the denosumab treatment regimen, the patient had been treated for 3.5 years with iv pamidronate. INTERVENTION AND OUTCOME The administration of denosumab resulted in improved disease control compared with bisphosphonate, as assessed by monitoring markers of bone turnover. Alkaline phosphatase levels dropped within the normal range and remained at normal levels for 5 months after the final dose of denosumab. Additionally, bone pain was more efficiently controlled with denosumab. However, concomitant with the first injection, severe hypocalcemia developed, for which the patient was hospitalized and iv calcium supplementation was required for 13 days. CONCLUSIONS Denosumab appears to be significantly effective for osteoclast inhibition for the treatment of JPD. However, in our patient, denosumab administration was associated with severe hypocalcemia, indicating that close monitoring of calcium levels is required during treatment.

Diagnostic image quality of gadolinium-enhanced T1-weighted MRI with and without fat saturation in children with retinoblastoma

BackgroundGadolinium-enhanced T1-weighted MRI without fat saturation has been recommended for assessment of retinoblastoma.ObjectiveThe purpose of this study was to compare diagnostic image quality without and with fat saturation following gadolinium administration.Materials and methodsHigh-resolution gadolinium-enhanced T1-weighted sequences with and without fat saturation performed in children with subsequently histopathologically confirmed retinoblastoma were included. Image analysis (image quality [1 = poor, 2 = moderate, 3 = good], anatomical detail depiction, tumour extension) was performed by two neuroradiologists in consensus. Enhancement was scored and measured. Signal- and contrast-to-noise ratios were calculated. Image-assessed tumour invasiveness was compared to histopathological findings. Paired sample t-test was used for statistical analysis.ResultsThirty-six children (mean age, 19.0 ± 16.8 [SD] months) were included. Image quality and anatomical detail depiction were significantly better without fat saturation (P < 0.001). Tumour enhancement was rated higher with fat saturation (P < 0.001). Fat saturation improved detection of (post-)laminar optic nerve infiltration. Detection of choroidal invasion was improved without fat saturation. Combining both sequences was best in the assessment of tumour extension (sensitivity/specificity for (post-)laminar optic nerve infiltration, 75.0%/100.0%, and for choroidal invasion, 87.5%/85.7%).ConclusionCombined T1-weighted spin-echo imaging with and without fat saturation improved the image quality for assessment of invasiveness of retinoblastoma.

160 kb deletion in ISPD unmasking a recessive mutation in a patient with Walker–Warburg syndrome

Walker-Warburg syndrome (WWS) is a severe muscular dystrophy with eye and brain malformations. On a molecular level, WWS is a disorder of the O-linked glycosylation of α-dystroglycan and therefore referred to as one of the dystroglycanopathies. The disease family of muscular dystrophy-dystroglycanopathy (MDDG) contains a spectrum of severe to mild disorders, designated as MDDG type A to C. WWS, as the most severe manifestation, corresponds to MDDG type A. Defects in the genes POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE, GTDC2, G3GALNT2, GMPPB, B3GNT1, TMEM5 and COL4A1 and ISPD have been described as causal for several types of MDDG including WWS, but can only be confirmed in about 60-70% of the clinically diagnosed individuals. The proteins encoded by these genes are involved in the posttranslational modification of α-dystroglycan. Mutations in POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE, GMPPB, TMEM5 and COL4A1 and ISPD lead to a wide spectrum of phenotypes of congenital muscular dystrophies with or without eye and brain abnormalities. Patients with WWS frequently demonstrate a complete lack of psychomotor development, severe eye malformations, cobblestone lissencephaly and a hypoplastic cerebellum and brainstem, seizures, hydrocephalus and poor prognosis. Here, we present a boy with WWS who showed compound heterozygous changes in ISPD and discuss the clinical and radiological phenotype and the molecular genetic findings, including a novel pathogenic mutation in ISPD.

Magnetic resonance colonography including diffusion-weighted imaging in children and adolescents with inflammatory bowel disease: do we really need intravenous contrast?

ObjectivesMagnetic resonance colonography (MRC) is a well-accepted, noninvasive imaging modality for the depiction of inflammatory bowel disease. Diffusion-weighted imaging (DWI) is very helpful to display inflammatory lesions. The aim of this retrospective study was to assess whether intravenous contrast is needed to depict inflammatory lesions in bowel magnetic resonance imaging if DWI is available. Materials and MethodsThirty-seven patients (23 females, 14 males; mean age, 14.6 years) underwent MRC on a 1.5-T scanner (MAGNETOM Avanto; Siemens). Contrast-enhanced T1-weighted (ce-T1-w) sequences and DWI sequences in axial and coronal planes (b = 50, 500, 1000) were acquired. Two reviewers evaluated (1) DWI, (2) ce-T1-w MRC, as well as (3) DWI and ce-T1-w MRC concerning lesion conspicuity. The preferred b value was assessed. Colonoscopy was performed within 1 week, including biopsies serving as the reference standard. Sensitivities and specificities were calculated, and interobserver variability was assessed. ResultsMean sensitivity and specificity of the 2 readers for the depiction of inflammatory lesions were 78.4%/100% using ce-T1-w MRC, 95.2%/100% using DWI, and 93.5%/100% combining both imaging techniques compared with colonoscopy including results of the histopathological samples. In 6 patients, inflammatory lesions were only detected by DWI; in another 6 patients, DWI detected additional lesions. The &kgr; values for the 2 readers were excellent (k = 0.92–0.96). The preferred b value with the best detectability of the lesion was b1000 in 28 of the 30 patients (93.3%) with restricted diffusion. ConclusionsDiffusion-weighted imaging of the bowel identified inflammatory lesions with high accuracy and revealed lesions that were not detectable with ce-T1-w imaging alone. A b value of 1000 showed the best lesion detectability.

Imaging children suffering from lymphoma: an evaluation of different 18F-FDG PET/MRI protocols compared to whole-body DW-MRI

ObjectivesThe objectives of this study were to evaluate and compare the diagnostic potential of different PET/MRI reading protocols, entailing non-enhanced / contrast-enhanced and diffusion-weighted 18F–FDG PET/MR imaging and whole-body diffusion-weighted MRI for lesion detection and determination of the tumor stage in pediatric lymphoma patients.MethodsA total of 28 18F–FDG PET/MRI datasets were included for analysis of four different reading protocols: (1) PET/MRI utilizing sole unenhanced T2w and T1w imaging, (2) PET/MRI utilizing additional contrast enhanced sequences, (3) PET/MR imaging utilizing unenhanced, contrast enhanced and DW imaging or (4) WB-DW-MRI. Statistical analyses were performed on a per-patient and a per-lesion basis. Follow-up and prior examinations as well as histopathology served as reference standards.ResultsPET/MRI correctly identified all 17 examinations with active lymphoma disease, while WB-DW-MRI correctly identified 15/17 examinations. Sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy were 96%, 96.5%, 97%, 95%, and 96% for PET/MRI1; 97%, 96.5%, 97%, 96.5%, and 97% for PET/MRI2; 97%, 96.5%, 97%, 96.5%, and 97% for PET/MRI3 and 77%, 96%, 96%, 78.5% and 86% for MRI-DWI.Conclusion18F–FDG PET/MRI is superior to WB-DW-MRI in staging pediatric lymphoma patients. Neither application of contrast media nor DWI leads to a noticeable improvement of the diagnostic accuracy of PET/MRI. Thus, unenhanced PET/MRI may play a crucial role for the diagnostic work-up of pediatric lymphoma patients in the future.

Calcifications in untreated Burkitt's lymphoma of the upper jaw.

Background: Dystrophic calcifications are uncommon in lymphomas. They may occur after chemotherapy or radiotherapy, whereas calcifications in untreated non-Hodgkin’s lymphomas are rarely reported in the litera-ture. Case Report: We report the case of a 9-year-old boy who developed tumefaction of the right upper jaw. CT examination revealed a neoplastic lesion in the right upper jaw sinus with destruction of the maxilla and sub-cutaneous fat infiltration. Furthermore the tumor showed accentuated central calcifications. Histological examina-tion revealed endemic type of Burkitt’s lymphoma of the paranasal sinus. Conclusion: Our experience showed that calcification can rarely occur also in untreated Burkitt’s lymphoma.

Loss of Functional Osteoprotegerin: More Than a Skeletal Problem.

Introduction Juvenile Pagets disease (JPD), an ultra-rare, debilitating bone disease due to loss of functional osteoprotegerin (OPG), is caused by recessive mutations in TNFRFSF11B. A genotype-phenotype correlation spanning from mild to very severe forms is described. Aim This study aimed to describe the complexity of the human phenotype of OPG deficiency in more detail and to investigate heterozygous mutation carriers for clinical signs of JPD. Patients We investigated 3 children with JPD from families of Turkish, German, and Pakistani descent and 19 family members (14 heterozygous). Results A new disease-causing 4 bp-duplication in exon 1 was detected in the German patient, and a microdeletion including TNFRFSF11B in the Pakistani patient. Skeletal abnormalities in all affected children included bowing deformities and fractures, contractures, short stature and skull involvement. Complex malformation of the inner ear and vestibular structures (2 patients) resulted in early deafness. Patients were found to be growth hormone deficient (2), displayed nephrocalcinosis (1), and gross motor (3) and mental (1) retardation. Heterozygous family members displayed low OPG levels (12), elevated bone turnover markers (7), and osteopenia (6). Short stature (1), visual impairment (2), and hearing impairment (1) were also present. Conclusion Diminished OPG levels cause complex changes affecting multiple organ systems, including pituitary function, in children with JPD and may cause osteopenia in heterozygous family members. Diagnostic and therapeutic measures should aim to address the complex phenotype.

Development of Port-Site Metastases Following Thoracoscopic Resection of a Neuroblastoma

We report a 26‐month‐old female who developed port‐site metastases of a neuroblastoma following minimally invasive thoracoscopic interventions. After diagnosis of an intrathoracic low‐risk neuroblastoma and 6 months of observation, she developed respiratory problems. She subsequently underwent total resection of a locally progressive tumor via thoracoscopy. Six months later, she developed local relapse and subcutaneous metastases within the thoracic wall. These port‐site metastases were most likely iatrogenic. After excision of metastases, the residual tumor responded well to salvage chemotherapy. The patient has remained in remission for over 4 years. Pediatr Blood Cancer

Cerebellar-dependent associative learning is impaired in very preterm born children and young adults

Preterm birth incorporates an increased risk for cerebellar developmental disorders likely contributing to motor and cognitive abnormalities. Experimental evidence of cerebellar dysfunction in preterm subjects, however, is sparse. In this study, classical eyeblink conditioning was used as a marker of cerebellar dysfunction. Standard delay conditioning was investigated in 20 adults and 32 preschool children born very preterm. Focal lesions were excluded based on structural magnetic resonance imaging. For comparison, an equal number of matched term born healthy peers were tested. Subgroups of children (12 preterm, 12 controls) were retested. Preterm subjects acquired significantly less conditioned responses (CR) compared to controls with slower learning rates. A likely explanation for these findings is that preterm birth impedes function of the cerebellum even in the absence of focal cerebellar lesions. The present findings are consistent with the assumption that prematurity results in long-term detrimental effects on the integrity of the cerebellum. It cannot be excluded, however, that extra-cerebellar pathology contributed to the present findings.