Detection of a significant association between mutations in the ACVRL1 gene and hepatic involvement in German patients with hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is a heterogeneous multisystemic dysplasia of the vascular tissue. This autosomal dominant inherited disorder shows a wide variation in its phenotypic expression. Between 8 and 78% of the HHT patients show arteriovenous malformations of the liver. The molecular basis for hepatic manifestation is still unknown. Two genes are known to play a major role in the development of HHT: activin A receptor type II-like 1 gene (ACVRL1) and ENG. Previously, we and others showed that hepatic involvement is associated with mutations in the ACVRL1 gene, but rarely caused by ENG mutations. Here, we report about the sequencing analysis of a new cohort of 18 adult HHT patients. In these patients, we identified eight novel (four in ACVRL1 and four in ENG) and eight already known mutations. Statistical analysis of our entire data revealed significant differences in the distribution of ACVRL1 and ENG mutations among HHT patients with and without liver involvement (p = 0.0016). The positive predictive value for type 2 HHT (ACVRL1 positive) patients to develop liver disease until the age of 52 years is 68.4%. We conclude that molecular genetic testing of HHT patients is important for prognosis with respect to liver disease.

Genotype/phenotype correlation in a patient with partial monosomy 15 and partial trisomy 14.

We report on a girl with severe mental and psychomotor retardation caused by an unusual, unbalanced translocation t(14;15) of maternal origin. The unbalanced translocation in the patient resulted in trisomy 14pter-->q13 and monosomy 15pter-->q11.2. In addition to common features described in other patients with small proximal trisomies of chromosome 14, our patient presented with hypopigmented skin with light hair and eye color and severe speech impairment. Therefore the phenotype of the girl shows few similarities to that of Angelman syndrome patients, although the breakpoint in chromosome 15 in our patient was found to be proximal to the PWS/AS region.

Mapping of a further locus for X-linked craniofrontonasal syndrome.

Craniofrontonasal syndrome is a rare dysostosis syndrome with an unusual pattern of X-linked inheritance, because males are usually not or less severely affected than females. Previously, a CFNS locus has been localised in Xp22. We report on a haplotype analysis in a German CFNS family, mapping the CFNS locus to the pericentromeric region of the X chromosome. This discrepancy can be explained by locus heterogeneity. Furthermore, random X inactivation could be demonstrated in affected females. The most plausible interpretation for this unusual pattern of X-linked inheritance is metabolic interference. Consequently, we propose that the CFNS gene escapes X inactivation.

Congenital cataract, ataxia, external ophthalmoplegia and dysphagia in two siblings. A Marinesco-Sjögren-like syndrome.

Marinesco-Sjögren syndrome (MSS) is an autosomal recessive multiorgan disorder with clinical and genetic heterogeneity. The key features of MSS include cerebellar ataxia, early bilateral cataracts, delayed motor development, and to a varying degree mental retardation. The syndrome was recently mapped to chromosome 5q31, and loss-of-function mutations in the SIL1 gene have been identified as the primary pathology. Here, we describe two German siblings with clinical characteristics resembling those seen in many cases of MSS except that a marked cerebellar atrophy was not detectable in our patients. In addition, both patients presented with external ophthalmoplegia and paralytic dysphagia. Sequencing of all 10 exons of the SIL1 gene did not detect any SIL1 mutation in our patients.

Male infertility as a component of Carney complex.

Carney complex (CNC) is a multiple neoplasia syndrome characterised by endocrine tumours, spotty skin pigmentation, cardiac and other myxomas, psamommatous and pigmented schwannomas, large cell calcifying Sertoli cell tumours, and mammary ductal adenomas and other more rare lesions. CNC is inherited in an autosomal-dominant manner and has been mapped to at least two chromosomal loci. Patients who map to the CNC1 locus located on chromosome 17 carry inactivating mutations of the PRKAR1A gene that encodes the cAMP-dependent protein kinase regulatory subunit type 1-alpha (Kirschner et al., 2000). One gene responsible for type 2 (CNC2) is located on chromosome 2p16. Infertility in CNC can be caused by a number of factors; there is evidence that prkar1a deficiency in mice leads directly to infertility (Burton et al., 2006), but patients with CNC also have Sertoli cell tumours and a number of other reasons to affect fertility. We report on an infertile male with CNC and present evidence that male infertility should be considered as part of the phenotype of CNC.

Feasibility of double-balloon enteroscopy-assisted chromoendoscopy of the small bowel in patients with familial adenomatous polyposis.

BACKGROUND AND STUDY AIMS: Patients with familial adenomatous polyposis (FAP) are at increased risk of developing duodenal and jejunal adenocarcinomas. The aim of this study was to assess the usefulness of double-balloon enteroscopy- (DBE-) assisted chromoendoscopy for the detection and characterization of small-bowel polyps in patients with FAP. PATIENTS AND METHODS: We performed a prospective evaluation of patients with clinically and genetically proved FAP who were enrolled in an endoscopic surveillance program. DBE was performed using a Fujinon intestinoscope (FN 450P 5/20; Fujinon Corp., Omiya, Japan), and chromoendoscopy was performed using indigo carmine. The severity of small bowel polyposis was based on the Spigelman-Saurin classification. RESULTS: Nine patients underwent DBE-assisted chromoendoscopy. Small-bowel polyps (including papillary adenomas) were detected in seven patients (88 %). The mean depth of small-bowel insertion was 180 cm (range 120-320 cm). The mean Spigelman-Saurin score was 4.6 (range 0-8). Jejunal polyps were detected in six patients (67 %). Chromoendoscopy aided in the detection of additional polyps in two patients. In one patient the polyps were flat and only visible with chromoendoscopy (biopsy confirmed these to be adenomas). Jejunal polyps and advanced neoplasms were more frequent in patients with APC gene mutations in exon 15. The following endoscopic therapies were performed: polypectomy (n = 1), duodenal mucosectomy (n = 1), and ablation therapy with argon plasma coagulation (n = 2). CONCLUSIONS: DBE was found to be a helpful method for the evaluation of small-bowel polyps in patients with FAP. DBE-assisted chromoendoscopy was of further assistance for the detection of jejunal polyps.