Mafalda Barbosa

Osteopathia Striata With Cranial Sclerosis Owing to WTX Gene Defect

Osteopathia striata with cranial sclerosis (OSCS) is an X‐linked dominant condition marked by linear striations mainly affecting the metaphyseal region of the long bones and pelvis in combination with cranial sclerosis. Recently, the disease‐causing gene was identified as the WTX gene (FAM123B), an inhibitor of WNT signaling. A correlation was suggested between the position of the mutation and male lethality. We performed genotype and phenotype studies using 18 patients from eight families with possible WTX gene defects and expanded the clinical spectrum of the affected females. All investigated families diagnosed with OSCS had WTX gene defects. One family had a WTX gene deletion; three of four point mutations were novel. The earlier reported WTX c.1072C>T was detected in four sporadic patients and appears to be a hotspot for mutations. Based on the nature of the mutation present in a surviving male patient, our data do not support the hypothesis raised by Jenkins et al. (2009) regarding a genotype‐phenotype correlation for male lethality. The finding of a gene involved in WNT signaling as the cause of this sclerosing bone phenotype is not unexpected, but further functional studies are needed to explain the specific features. The WTX gene is mutated in different types of cancer, and it remains to be explained why osteopathia striata patients appear not to have an increased risk of cancer. Copyright

Autosomal Dominant Spastic Paraplegias: A Review of 89 Families Resulting From a Portuguese Survey

IMPORTANCE Hereditary spastic paraplegias (HSPs) are a group of diseases caused by corticospinal tract degeneration. Mutations in 3 genes (SPG4, SPG3, and SPG31) are said to be the cause in half of the autosomal dominant HSPs (AD-HSPs). This study is a systematic review of families with HSP resulting from a population-based survey. Novel genotype-phenotype correlations were established. OBJECTIVE To describe the clinical, genetic, and epidemiological features of Portuguese AD-HSP families. DESIGN Retrospective medical record review. SETTING A population-based systematic survey of hereditary ataxias and spastic paraplegias conducted in Portugal from 1993 to 2004. PARTICIPANTS Families with AD-HSP. MAIN OUTCOME MEASURE Mutation detection in the most prevalent genes. RESULTS We identified 239 patients belonging to 89 AD-HSP families. The prevalence was 2.4 in 100 000. Thirty-one distinct mutations (26 in SPG4, 4 in SPG3, and 1 in SPG31) segregated in 41% of the families (33.7%, 6.2%, and 1.2% had SPG4, SPG3 and SPG31 mutations, respectively). Seven of the SPG4 mutations were novel, and 7% of all SPG4 mutations were deletions. When disease onset was before the first decade, 31% had SPG4 mutations and 27% had SPG3 mutations. In patients with SPG4 mutations, those with large deletions had the earliest disease onset, followed by those with missense, frameshift, nonsense, and alternative-splicing mutations. Rate of disease progression was not significantly different among patients with SPG3 and SPG4 mutations in a multivariate analysis. For patients with SPG4 mutations, disease progression was worst in patients with later-onset disease. CONCLUSIONS AND RELEVANCE The prevalence of AD-HSP and frequency of SPG3 and SPG4 mutations in the current study were similar to what has been described in other studies except that the frequency of SPG4 deletions was lower. In contrast, the frequency of SPG31 mutations in the current study was rare compared with other studies. The most interesting aspects of this study are that even in patients with early-onset disease the probability of finding a SPG4 mutation was higher than for patients with SPG3 mutations; there was no difference in disease progression with genotype but an association with the age at onset; 7 new SPG4 mutations were identified; and for the first time, to our knowledge, the nature of the SPG4 mutations was found to predict the age at onset.

Muenke syndrome with osteochondroma.

Here, we report on a patient with Muenke syndrome with an osteochondroma, which to our knowledge, has not been previously recorded. The syndrome consists of coronal synostosis (unilateral or bilateral; macrocephaly in 3%; normal sutures in 11%), facial anomalies, hearing loss (sensorineural, 65%; mixed and conductive, 14%; unspecified, 21% (n1⁄4 126), developmental delay (language delay, motor delay or general delay), thimble-shaped middle phalanges, brachydactyly, and other bony abnormalities. The syndrome is caused by a specific FGFR3 mutation: 749C!G, resulting in Pro250Arg [Bellus et al., 1996; Muenke et al., 1997]. Over 300 cases have been reported [Doherty et al., 2007]. Clinical variability, incomplete penetrance in the presence of the mutation, birth prevalence, and the molecular basis of Muenke syndrome have been discussed and reviewed elsewhere [Moloney et al., 1997; Reardon et al., 1997; Wilkie, 1997; Graham et al., 1998; Gripp et al., 1998; Robin et al., 1998; Lajeunie et al., 1999; Cohen, 2004, 2006; Cohen and MacLean, 2000; Doherty et al., 2007]. Clinical report: A 13-year-old old boy was referred to our Genetics Clinic for mental retardation. His parents were normal and consanguinity was established (2nd cousins). A maternal first cousin was affected with Muenke syndrome and another first cousin had mental retardation of unknown cause. Height and weight were at the 75th centile, and OFC was between the 25th and 50th centile. Findings included facial anomalies, mild hearing deficit, and an osseous protuberance on the left leg. Radiographic assessment disclosed an osteochondroma in the proximal metaphysis of the left tibia, and fusion of the calcaneous and cuboid in both feet. Molecular analysis demonstrated FGFR3 Pro250Arg, establishing the diagnosis of Muenke syndrome. Because this is the first instance of an association of Muenke syndrome with osteochondroma, we wonder if other geneticists have also observed this association.

Prostate cancer in Cowden syndrome: somatic loss and germline mutation of the PTEN gene.

Germline mutations of PTEN, a tumor suppressor gene, cause a spectrum of autosomal-dominant hamartoma tumor syndrome overgrowth disorders, including Cowden syndrome (CS, MIM#158350) (1). Consensus diagnostic criteria for CS and guidelines for screening of cancer (breast, endometrium, thyroid, kidney, and skin) have beendevelopedby theNational Comprehensive Cancer Network (NCCN) (2). Somatic loss of PTEN has been described in sporadic counterpart tumors of CS as well as sporadic tumors not a component of CS: glioblastoma multiforme, melanoma, lung, pancreas, bladder, colon, and prostate. We report the case of a 58-year-oldmanwithCS.His family history was consistent with autosomal-dominant inheritance: his father, paternal uncle, and son were affected with CS. In addition to macrocephaly, throughout life, the patient had developed multiple tumors: kidney adenocarcinoma, nodular hyperplasia of the thyroid, lesions on the skin and mucous membranes (multiple sclerotic fibromas, papillomatous papules, angiomas), colon polyposis (tubular adenomas, hyperplastic polyps, submucous lipoma), and brain tumors (two meningiomas, multiple angiomas). At the age of 56, after detection of a total prostate-specific antigen value of 24.5 ng/mL, prostate biopsy results revealed, in 60% of the sample, a prostate adenocarcinomawith a combinedGleason score of 8 (4 + 4). High-grade prostate intraepithelial neoplasia was present in the remaining sample tissue. At the time of diagnosis, vertebral column metastasis (D3, D4, D5) was already evident. This cancer had developed rapidly and aggressively: at the age of 54, digital rectal examination showedaglobally voluminousprostate. Total prostate-specific antigen was normal (2.62 ng/mL). PTEN sequencing performed on DNA extracted from lymphocytes revealed a previously described heterozygous nonsense mutation, c.388C>T (p.Arg130X), confirming the clinical diagnosis of CS. Thismutation was also identified in the patient’s son. In DNA extracted from the paraffin-embedded prostate cancer biopsy samples, it was only possible to reliably amplify and sequence exons 1, 3, 4, and 5. This revealed loss of the wild-type allele of PTEN. Because no more neoplastic tissue was available, it was not possible to refine the molecular analysis of the PTEN gene or to analyze other genes associated with prostate cancer initiation and/or progression. PTEN mutations have been described in 30% of primary prostate tumors, suggesting a role for this gene in the initiation of prostate cancer (3). Somatic PTEN mutations are

Current Issues Regarding Prenatal Diagnosis of Inborn Errors of Cholesterol Biosynthesis

Maria Luis Cardoso1,2, Mafalda Barbosa3,4, Ana Maria Fortuna3 and Franklim Marques1,2 1Faculty of Pharmacy, University of Porto, Porto 2Institute for Molecular and Cell Biology, University of Porto, Porto 3Medical Genetics Centre Jacinto Magalhaes, National Health Institute Ricardo Jorge Porto 4Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga Portugal