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The ROS proto-oncogene 1 (ROS1) gene is rearranged in various cancers. The translated fusion protein presents an attractive therapeutic target, since specific inhibitors have been approved for several tumor types. In glioma, ROS1 fusions are frequent within infantile hemispheric glioma, and single case reports on occurrences in other glioma types exist. However, a comprehensive analysis spanning the full width of glioma types and subtypes is lacking. We here assessed the spectrum and distribution of ROS1 fusions by screening >20,000 glioma cases for typical chromosomal alterations, with subsequent RNA-sequencing for confirmation of candidate cases. ROS1 fusions were identified in 16 cases, from low grade pilocytic astrocytoma WHO grade 1 to glioblastoma, IDH wildtype WHO grade 4. Thus, despite being enriched in some tumor types, ROS1 fusions are not pathognomonic for specific glioma types and may consitute a relevant target in a variety of cases.

Williams-Beuren syndrome is a contiguous gene syndrome caused by a hemizygous microdeletion of DNA in 7q11.23 and its prevalence is estimated at 1 : 7500. The symptoms are variable. In addition to the typical craniofacial dysmorphia, cardiovascular malformations, renal malformations, motor and mental retardation, a characteristic personality profile, and disorders of growth and puberty are common. In contrast, hypercalcaemia and nephrocalcinosis, though frequently reported, are rarely encountered. Healthcare guidelines including diagnostic procedures and follow-up examinations as well as treatments are presented. These guidelines are based on the scientific literature and the personal experience that members of the Scientific Advisory Board of the German Williams-Beuren Syndrome Association have recorded in more than 400 patients

We report three further patients with similar clinical signs to those described by Desbuquois et al. (Desbuquois G, Grenier B, Michel J, Rossignol C (1966): Arch Fr Pédiatr 23; 573-587) Two of the patients were born to consanguineous parents, confirming autosomal recessive inheritance of this condition. The patients presented with micromelic short stature, flat midface, irregular ossification of the vertebral bodies and an advanced bone age.

We present three patients with the Coffin-Lowry syndrome, two males aged 21 years and 14 months respectively, and an unrelated girl aged 11 years. In the male patients the features at different ages are reviewed. Besides, we describe the pertinent features of their affected female relatives. The contribution of the family history to making the diagnosis is stressed. The isolated female proband is much more severely affected than the female relatives of the male probands, demonstrating that the clinical picture in female carriers of Coffin-Lowry syndrome can vary considerably. The differential diagnosis of Coffin-Lowry syndrome will be discussed shortly.

We present three patients with the Coffin-Lowry syndrome, two males aged 21 years and 14 months respectively, and an unrelated girl aged 11 years. In the male patients the features at different ages are reviewed. Besides, we describe the pertinent features of their affected female relatives. The contribution of the family history to making the diagnosis is stressed. The isolated female proband is much more severely affected than the female relatives of the male probands, demonstrating that the clinical picture in female carriers of Coffin-Lowry syndrome can vary considerably. The differential diagnosis of Coffin-Lowry syndrome will be discussed shortly.

Another case of the Aicardi-Goutieres syndrome is presented. The female child was diagnosed at 4 months of age, when irritability, lack of fixation and dystonic movements were noted. Also, extensive intracerebral calcification was found on computed tomography. Nuclear magnetic resonance imaging confirmed extensive white matter disease. Repeated examination of the spinal fluid revealed chronic spinal fluid lymphocytosis. This condition belongs to the encephalopathies of infancy with intracranial calcification of genetic aetiology and unknown pathogenesis. Differentiation against other presumed entities in this group, as well as the wider differential diagnosis, are discussed.

We present two unrelated female patients with a complex pattern of congenital malformations including encephalocele, oesophageal atresia, abnormal lung lobation, congenital heart defects, anal anomalies, liver, spleen and radial defects. Clinical variability between the two cases can be seen as a result of variable expression. The pattern of anomalies in these two unrelated patients suggest that they may represent the same, as yet unknown, syndrome.

A contiguous gene syndrome due to deletions of the proximal short arm of chromosome 11 is described in eight patients belonging to four families. The main clinical features are multiple exostoses, enlarged parietal foramina, craniofacial dysostosis, and mental retardation. The patients have cytogenetic and/or molecular deletions of chromosome 11p11-p13. These deletions are located between the centromere and D11S914 in a region of approximately 20cM. The present study confirms the presence of a multiple exostoses gene on chromosome 11p. Furthermore, it suggests that the gene for isolated foramina parietalie permagna and genes associated with craniofacial dysostosis and mental retardation reside in the same chromosomal region.

The microphthalmia with linear skin defects syndrome (MLS, or MIDAS) is an X-linked dominant male-lethal disorder almost invariably associated with segmental monosomy of the Xp22 region. In two female patients, from two families, with MLS and a normal karyotype, we identified heterozygous de novo point mutations--a missense mutation (p.R217C) and a nonsense mutation (p.R197X)--in the HCCS gene. HCCS encodes the mitochondrial holocytochrome c-type synthase that functions as heme lyase by covalently adding the prosthetic heme group to both apocytochrome c and c(1). We investigated a third family, displaying phenotypic variability, in which the mother and two of her daughters carry an 8.6-kb submicroscopic deletion encompassing part of the HCCS gene. Functional analysis demonstrates that both mutant proteins (R217C and Delta 197-268) were unable to complement a Saccharomyces cerevisiae mutant deficient for the HCCS orthologue Cyc3p, in contrast to wild-type HCCS. Moreover, ectopically expressed HCCS wild-type and the R217C mutant protein are targeted to mitochondria in CHO-K1 cells, whereas the C-terminal-truncated Delta 197-268 mutant failed to be sorted to mitochondria. Cytochrome c, the final product of holocytochrome c-type synthase activity, is implicated in both oxidative phosphorylation (OXPHOS) and apoptosis. We hypothesize that the inability of HCCS-deficient cells to undergo cytochrome c-mediated apoptosis may push cell death toward necrosis that gives rise to severe deterioration of the affected tissues. In summary, we suggest that disturbance of both OXPHOS and the balance between apoptosis and necrosis, as well as the X-inactivation pattern, may contribute to the variable phenotype observed in patients with MLS.