Acquired cerebellar lesions in adults and children can lead to the development of a complex behavioural pattern termed 'Cerebellar Cognitive Affective Syndrome' (Schmahmann and Sherman, Brain, 1998; 121: 561-79), which is characterized by reduced cognitive efficiency associated with specific neuropsychological deficits (executive and visuospatial disorders), expressive language disorders (mild agrammatism and anomia) and affective disorders with blunting of affect. It is not known whether a symptomatological picture such as this can also be found in congenital cerebellar malformations. We studied the behavioural developmental profile of 27 patients including children and adults with congenital malformations confined to the cerebellum, the largest studied sample to date. Extensive clinical and neuropsychological investigations highlight the presence of a wide range of disorders supporting the important role played by the cerebellum in the acquisition of higher-order cognitive and affective skills. The type and extent of cerebral reorganization processes in the presence of malformative lesions are difficult to predict and may possibly account for the variability of clinical phenotypes. It is, therefore, more difficult to identify a syndromic picture defined as exactly as is the case with acquired lesions. However, the pattern of deficits that we document is in remarkable agreement with the general profile of the Cerebellar Cognitive Affective Syndrome. Malformations affecting the cerebellar vermis induce affective and social disorders and evolve towards more unfavourable pictures often associated with an autistic symptomatology. Malformations of cerebellar hemispheres are more frequently associated with selective neuropsychological deficits involving mainly executive functions and visuospatial and linguistic abilities. Motor deficits are generally less severe, and tend to improve slowly and progressively, in some cases reaching almost complete functionality. Finally, the overall favourable evolution with an onset of skills in advanced age in a consistent subset of subjects suggests that individual follow-ups should be performed in order to monitor the quality and stability of impairments and acquired abilities over time.

The terminal 22q13.3 deletion syndrome is characterized by severe expressive-language delay, mild mental retardation, hypotonia, joint laxity, dolichocephaly, and minor facial dysmorphisms. We identified a child with all the features of 22q13.3 deletion syndrome. The patient's karyotype showed a de novo balanced translocation between chromosomes 12 and 22, with the breakpoint in the 22q13.3 critical region of the 22q distal deletion syndrome [46, XY, t(12;22)(q24.1;q13.3)]. FISH investigations revealed that the translocation was reciprocal, with the chromosome 22 breakpoint within the 22q subtelomeric cosmid 106G1220 and the chromosome 12q breakpoint near STS D12S317. Using Southern blot analysis and inverse PCR, we located the chromosome 12 breakpoint in an intron of the FLJ10659 gene and located the chromosome 22 breakpoint within exon 21 of the human homologue of the ProSAP2 gene. Short homologous sequences (5-bp, CTG[C/A]C) were found at the breakpoint on both derivative chromosomes. The translocation does not lead to the loss of any portion of DNA. Northern blot analysis of human tissues, using the rat ProSAP2 cDNA, showed that full-length transcripts were found only in the cerebral cortex and the cerebellum. The FLJ10659 gene is expressed in various tissues and does not show tissue-specific isoforms. The finding that ProSAP2 is included in the critical region of the 22q deletion syndrome and that our proband displays all signs and symptoms of the syndrome suggests that ProSAP2 haploinsufficiency is the cause of the 22q13.3 deletion syndrome. ProSAP2 is a good candidate for this syndrome, because it is preferentially expressed in the cerebral cortex and the cerebellum and encodes a scaffold protein involved in the postsynaptic density of excitatory synapses.

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Important claims have been made regarding the contrasting profiles of linguistic and cognitive performance observed in two genetically based syndromes, Williams syndrome (WS) and Down syndrome (DS). Earlier studies suggested a double dissociation, with language better preserved than nonverbal cognition in children and adults with WS, and an opposite profile in children and adults with DS. More recent studies show that this initial characterization was too simple, and that qualitatively different patterns of deficit observed within both language and visual–spatial cognition, in both groups. In the present study, large samples of children and adolescents with WS and age-matched DS are compared with typically developing (TD) controls matched to WS in mental age, on receptive and expressive lexical and grammatical abilities, semantic and phonological fluency, digit span and nonverbal visual–spatial span, and on 2 visual–spatial construction tasks. Study 1 confirmed distinct profiles of sparing and impairment for the 2 groups, within as well as between language and nonlinguistic domains, even after IQ variations were controlled. In Study 2 we compared performance of the children, adolescents and young adults with DS and WS included in the first study, divided on the basis of the chronological age of the participants (under 8 years; over 12 years). Although it is important to stress that these are cross-sectional rather than longitudinal data, the results demonstrated that the profile of younger children is different in respect to those of the older children; initial states of the system cannot be inferred by the final state. Possible neural substrates for these profiles and trajectories are discussed. (JINS, 2004, 10, 862–876.)

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C olorectal cancer (CRC) is the third most common cancer diagnosed in both men and women, and the second most common cause of cancer deaths in the United States. There were approximately 150 000 new cases resulting in 57 000 deaths in 2002.1 CRC is one of the most studied cancer types and its underlying aetiology best elucidated. Colorectal tumorigenesis involves a multistep process including genetic and epigenetic alterations of numerous CRC related genes that may act as either oncogenes or tumour suppressor genes. [2][3][4][5] The majority of sporadic CRCs are characterised by deletions of large chromosomal segments, which are thought to represent the loss of wild type tumour suppressor genes.6 7 About 15% of sporadic CRCs, on the other hand, show microsatellite instability (MSI), characterised by the insertion and/or deletion of simple repeat sequences and indicative of the involvement of defective mismatch repair. Birt-Hogg-Dubé syndrome (BHD, OMIM 135150) is an inherited autosomal dominant syndrome characterised by a triad of cutaneous lesions consisting of fibrofolliculomas, trichodiscomas, and acrochordons. 10 A wide spectrum of neoplastic and non-neoplastic features has been described in BHD patients, 11 including diverse types of kidney tumours 12-17 and spontaneous pneumothorax.12-16 18 BHD has also been reported to be associated with colonic polyposis and colorectal neoplasia, 13 19-22 although a large study of 223 patients from 33 BHD families could not establish such a relation. 23 We recently reported a high incidence of colorectal polyps and carcinomas in patients with confirmed BHD germline mutations, indicating that the BHD gene may be involved in colorectal tumorigenesis. 13 The BHD gene has been mapped to chromosome subband 17p11.2 12 14 and recently identified to encode a novel protein named follicullin. 15 Based on the presence of inactivating BHD mutations in BHD patients, and the detection of LOH in a significant proportion of BHD related tumours, the BHD gene was considered to be a tumour suppressor gene. A 44% frequency of frameshift mutations within a mononucleotide (C) 8 tract (nt 1733-1740) has been detected in BHD patients, 15 and this repeat tract represents a BHD mutational hot spot.13 15 Other studies have reported the presence of frameshift mutations within intragenic mononucleotide tracts of the TGFBR2 and BAX genes in CRC cell lines and tumours with high level MSI.24 25 The poly C tract of the BHD gene may therefore be a potential site of mutation in CRC characterised by MSI.We have evaluated the role of the BHD gene in 47 unselected colorectal tumours (10 polyps and 37 carcinomas) by screening all coding exons of the BHD gene for mutations and analysing 46 of the tumours for LOH in the chromosome region surrounding the BHD locus. Furthermore, alterations in BHD promoter methylation profiles were determined in 23 cases of matched normal/carcinoma tissues where a sufficient quantity of DNA was available. We report the detection of two novel somatic missense mutations of ...