Prenatal assessment of a suspected skeletal dysplasia using ultrasound presents great challenges, both in achieving an accurate diagnosis and then in assigning a correct prognosis. Although recognition of lethal skeletal dysplasias is fairly reliably accomplished using ultrasonography, differentiating between the different types to make a precise diagnosis remains difficult, with reported accuracy ranging from 31 to 65%1-7. Making a quick and accurate diagnosis is important for reducing parental anxiety, and is especially important in cases of genetic disorders, for which the recurrence risk can be up to 50%. Most of the benefit of making a precise diagnosis will lie in determining the likelihood of a recurrence and offering appropriate prenatal testing at an earlier stage in future pregnancies. There has been a recent explosion of knowledge concerning the biochemical and molecular defects associated with skeletal dysplasias8. However, the application of these findings in directing patient care is difficult, because a precise molecular diagnosis entails testing a large number of genes. To date, guidelines for the diagnosis of skeletal dysplasias advise using the constellation of abnormalities to determine the most likely differential diagnosis, and then proceeding sequentially9. For each patient, a succession of genes is examined, one at a time. As an alternative to the focused sequential approach of assessment on a gene-by-gene basis, a more efficient strategy is based on parallel evaluation of the genes most frequently associated with skeletal dysplasia on a customized multiplex panel10. Using a custom single nucleotide polymorphism (SNP) microarray (Arrays CGC®; CGC Genetics, Porto, Portugal), with 26 point mutations in the six genes (FGFR3, COL2A1, SLC26A2, CRTAP, LEPRE1 and SOX9) most frequently associated with achondroplasia, thanatophoric dysplasia, achondrogenesis Types IB and II, osteogenesis imperfecta (recessive type) and campomelic dysplasia, it is possible to identify the molecular basis of the most frequent and severe forms. We report two cases of thanatophoric dysplasia diagnosed prenatally using microarray technology. The first case concerned a 32-year-old woman, gravida 2 para 1, and the second a 43-year old woman, gravida 4 para 3. Paternal age was 37 and 47 years, respectively. Both patients presented for second-trimester anomaly scans at 20 weeks' gestation. In both cases the scans revealed that the thorax was narrow and all long bones were well below the 3rd centile in length, with curved femurs (Figure 1). The ultrasound appearances were thought to be consistent with a lethal skeletal dysplasia. Microarray tests for the condition were performed, using DNA already extracted by chorionic villus sampling in the first case and from amniocytes in the second case. Mutation c.1138A>G on FGFR3 was detected in the first case and in the second case mutation c.742C>T was found on the same gene (Figure 2). This led to a diagnosis of thanatophoric dysplasia Type 1 within 7 days of the second-trimester anomaly scan. The results were confirmed by sequence analysis. Compared with the traditional sequential testing using gene-by-gene genetic analysis, this new approach considerably reduces turnaround time and cost of diagnosis. This allows for more precise counseling of families regarding prognosis in current and future pregnancies. We therefore believe that SNP microarrays have huge potential for prenatal diagnosis. C. Guerra*†, P. Rendeiro‡, E. Pereira†, A. Rosmaninho†, R. Nogueira‡, S. Pereira§ and P. Tavares‡ †Department of Gynecology and Obstetrics, Centro Hospitalar do Alto Ave, Guimarães, Portugal ‡CGC Genetics, Porto, Portugal §Department of Gynecology and Obstetrics, Hospital S. Teotónio, Viseu, Portugal

Non-Hodgkin lymphoma (NHL) has been associated with immunological defects, chronic inflammatory and autoimmune conditions. Given the link between immune dysfunction and NHL, genetic variants in toll-like receptors (TLRs) have been regarded as potential predictive factors of susceptibility to NHL. Adequate anti-tumoral responses are known to depend on TLR9 function, such that the use of its synthetic ligand is being targeted as a therapeutic strategy. We investigated the association between the functional rs5743836 polymorphism in the TLR9 promoter and risk for B-cell NHL and its major subtypes in three independent case–control association studies from Portugal (1160 controls, 797 patients), Italy (468 controls, 494 patients) and the US (972 controls, 868 patients). We found that the rs5743836 polymorphism was significantly overtransmitted in both Portuguese (odds ratio (OR), 1.85; P=7.3E−9) and Italian (OR, 1.84; P=6.0E−5) and not in the US cohort of NHL patients. Moreover, the increased transcriptional activity of TLR9 in mononuclear cells from patients harboring rs5743836 further supports a functional effect of this polymorphism on NHL susceptibility in a population-dependent manner.

Pseudohypoparathyroidisnn Ia (PHP-Ia) results from a specific deficiency of the alpha subunit of stimulatory G protein, manifested by resistance to parathormone and a characteristic phenotype, referred to as Albright hereditary osteodystrophy (AHO). Several mutations were identified in the GNAS1 gene in individuals with PHP-Ia and pseudopseudohypoparathyroidism (PPHP). A single GNAS1 mutation may be responsible for both PHP-Ia e PPHP in the same family, when inherited from the maternal and the paternal allele, respectively. The authors present the case of a teenage boy with PHP-Ia. The study revealed the GNAS1 mutation c.899A>T (p.Lys300Ile) in exon 11. After the genetic study of his parents, we have identified the same mutation in the mother, who had only somatic alterations (AHO), not associated with hormone resistance (PPHP). This is an original mutation, not yet described in the literature. (C) 2009 Asociacion Espanola de Pediatria. Published by Elsevier Espana, S.L. All rights reserved.

The authors report a new mutation in the COL1A1 gene associated with a lethal form of osteogenesis imperfecta (OI). Mutation analysis of COL1A1 gene showed an heterozygotic mutation not yet reported in the literature - c.1894G > A (p.Gly632Ser) on exon 28.

Prenatal DiagnosisVolume 18, Issue 1 p. 87-87 Correspondence Comparison between CVS and early amniocentesis P. Tavares, P. Tavares Prenatal Diagnosis Unit, Centro de Genética Clinica, R. Sa Bandeira 746, 7E, 4000 Porto, PortugalSearch for more papers by this authorA. Tavares, A. Tavares Prenatal Diagnosis Unit, Centro de Genética Clinica, R. Sa Bandeira 746, 7E, 4000 Porto, PortugalSearch for more papers by this authorP. Rendeiro, P. Rendeiro Prenatal Diagnosis Unit, Centro de Genética Clinica, R. Sa Bandeira 746, 7E, 4000 Porto, PortugalSearch for more papers by this authorC. Palmares, C. Palmares Prenatal Diagnosis Unit, Centro de Genética Clinica, R. Sa Bandeira 746, 7E, 4000 Porto, PortugalSearch for more papers by this author P. Tavares, P. Tavares Prenatal Diagnosis Unit, Centro de Genética Clinica, R. Sa Bandeira 746, 7E, 4000 Porto, PortugalSearch for more papers by this authorA. Tavares, A. Tavares Prenatal Diagnosis Unit, Centro de Genética Clinica, R. Sa Bandeira 746, 7E, 4000 Porto, PortugalSearch for more papers by this authorP. Rendeiro, P. Rendeiro Prenatal Diagnosis Unit, Centro de Genética Clinica, R. Sa Bandeira 746, 7E, 4000 Porto, PortugalSearch for more papers by this authorC. Palmares, C. Palmares Prenatal Diagnosis Unit, Centro de Genética Clinica, R. Sa Bandeira 746, 7E, 4000 Porto, PortugalSearch for more papers by this author First published: 04 May 1999 https://doi.org/10.1002/(SICI)1097-0223(199801)18:1<87::AID-PD228>3.0.CO;2-SCitations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References Cederholm, M., Axelsson, O. (1997). A prospective comparative study on transabdominal chorionic villus sampling and amniocentesis performed at 10–13 weeks' gestation, Prenat. Diagn., 17, 311–317. 10.1002/(SICI)1097-0223(199704)17:4<311::AID-PD53>3.0.CO;2-I CASPubMedWeb of Science®Google Scholar Henry, G. P., Miller, W. A. (1992). Early amniocentesis, Reprod. Med., 37, 396. CASPubMedWeb of Science®Google Scholar Hansen, F. W., Tennant, F., Hune, S., Brookhyser, K. (1992). Early amniocentesis: outcome, risks and technical problems at ≤12·8 weeks, Am. J. Obstet. Gynecol., 166, 1707. 10.1016/0002-9378(92)91560-W PubMedWeb of Science®Google Scholar M. C. Working Party on the Evaluation of Chorion Villus Sampling (1991). Medical Research Council European trial of chorion villus sampling, Lancet, 337, 1491–1499. 10.1016/0140-6736(91)93193-D PubMedGoogle Scholar Citing Literature Volume18, Issue1January 1998Pages 87-87 ReferencesRelatedInformation