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Martinez-Frias M.L.,Institute Salud Carlos III | Martinez-Frias M.L.,CIBER ISCIII | Martinez-Frias M.L.,Complutense University of Madrid | Egues X.,Servicio de Pediatria | And 8 more authors.
American Journal of Medical Genetics, Part A | Year: 2011

Thanatophoric dysplasia (TD) is a lethal form of short-limb skeletal dysplasia that is associated with macrocephaly, and variably cloverleaf skull. Two types of TD are clinically recognized, TD1 and TD2, mainly distinguished by their radiographic characteristics. The differences between the two are principally observed in the femur, which appears curved in TD1, while it remains straight but with a proximal medial spike in TD2, and are a less severe overall affectation in TD2. Both types of TD are caused by mutations in different functional domains of the FGFR3 gene. However, whereas several mutations in the different domains of FGFR3 cause TD1, the K650E mutation involving the change of a lysine to glutamic acid ("Lys650Glu") has been found in all TD2 cases to date. Here we describe a newborn infant with TD2 associated with brain defects that have either been infrequently observed (encephalocele) or not hitherto described (holoprosencephaly). Based on recent studies, we consider encephaloceles described in TD to be pseudoencephaloceles, since they are secondary to the intracranial pressure generated by severe hydrocephaly and to severe cranial structural anomalies. Finally, to analyze the mechanisms of holoprosencephaly observed in the case described here, we include a concise review on the current understanding of how FGFs and their receptors are expressed in the rostral signaling center (particularly Fgf8). In addition, we evaluated recent observations that FGF ligands and receptors (including FGFR3) act in concert to organize the whole telencephalon activity, rather than independently patterning different areas. © 2010 Wiley-Liss, Inc.

Carrascosa-Romero M.C.,Complejo Hospitalario Universitario Of Albacete | Suela J.,NIMGenetics New Integrated Medical Genetics | Pardal-Fernandez J.M.,Complejo Hospitalario Universitario Of Albacete | Bermejo-Sanchez E.,Instituto Of Investigacion Of Enfermedades Raras Iier | And 10 more authors.
American Journal of Medical Genetics, Part A | Year: 2013

We present a girl with the characteristic clinical picture associated with Marden-Walker syndrome (MWS; OMIM 248700), including mask-like face with blepharophimosis, joint contractures, intellectual disability, a multicystic dysplastic kidney and cerebral dysgenesis. The long-term follow-up allowed us to monitor the evolution of the phenotype in this patient, and among the main findings we highlight the following: demyelination of the pyramidal tract demonstrated by transcranial magnetic stimulation and the involvement of the levator muscles of angle of mouth in fixed facial expression with relative integrity of the rest of the facial expression muscles. A 244k array comparative genomic hybridization (aCGH) was carried out and showed a de novo interstitial deletion of approximately 2.84Mb affecting only the cytoband 21q22.11 (genome coordinates chr21:31,874,016-34,711,763). We selected 10 of the most recent published cases with either total or partial deletions of cytoband 21q22.11 that provided good characterization of the genomic size or the genes in the deleted regions. We observed that in nine of the 10 cases the deleted regions included the RUNX1 gene in 21q22.12, which is not affected in the current patient's deletion or in that of Patient 3 from Roberson et al. [2011]. After a comparison of shared deleted genes between cases, and correlation of their potential phenotypes, we concluded that the pattern of defects considered for a diagnosis of MWS may represent part of the phenotypic expression of a partial or total deletion of 21q22.11. © 2013 Wiley Periodicals, Inc.

Bermejo Sanchez E.,Instituto Of Investigacion Of Enfermedades Raras Iier | Bermejo Sanchez E.,Research Center Sobre Anomalias Congenitas | Bermejo Sanchez E.,Research Center Biomedica En Red Of Enfermedades Raras Ciberer
Semergen | Year: 2010

A review is presented of the main aspects arising from the study of the frequency of congenital defects, explaining the importance and use of this knowledge, and illustrating it with different examples based on the analysis of data from the ECEMC (Estudio Colaborativo Español de Malformaciones Congénitas) (Spanish Collaborative Study of Congenital Malformations). From this analysis it was observed that the overall frequency of newborns with congenital defects in Spain has been decreasing gradually for many defects. This drop is mainly a result of voluntary termination of pregnancy (TOP) after the detection of foetal abnormalities. However, other factors, such as the improved care of pregnant women and pregnancy planning, plus the increase in the health culture of the population, could also be having some effect, although a lot less obvious than that due to TOP. This decrease in frequency has not been uniform in all the Autonomous Communities. On the other hand, there are certain defects that have shown a secular increase, arising from the improvement and general use of both prenatal and post-natal diagnostic techniques. Furthermore, it has been observed that the ethnical diversification in our country, resulting from immigration, is also having a certain impact on the frequency of newborns with congenital abnormalities in Spain. These minority population groups, in general, along with the differences in the frequency of certain recessive gene mutations, have socio-health conditions that lead to a higher risk of congenital defects. All these aspects are important and have to be taken into account when designing prevention plans for these diseases. © 2010 Elsevier España, S.L. y SEMERGEN.

Feldkamp M.L.,University of Utah | Botto L.D.,University of Utah | Amar E.,Rhone Alps Registry of Birth Defects REMERA | Bakker M.K.,University of Groningen | And 18 more authors.
American Journal of Medical Genetics, Part C: Seminars in Medical Genetics | Year: 2011

Cloacal exstrophy presents as a complex abdominal wall defect thought to result from a mesodermal abnormality. Anatomically, its main components are Omphalocele, bladder Exstrophy and Imperforate anus. Other associated malformations include renal malformations and Spine defects (OEIS complex). Historically, the prevalence ranges from 1 in 200,000 to 400,000 births, with higher rates in females. Cloacal exstrophy is likely etiologically heterogeneous as suggested by its recurrence in families and occurrence in monozygotic twins. The defect has been described in infants with limb-body wall, with trisomy 18, and in one pregnancy exposed to Dilantin and diazepam. Due to its rarity, the use of a nonspecific diagnostic code for case identification, and lack of validation of the clinical findings, cloacal exstrophy remains an epidemiologic challenge. The purpose of this study was to describe the prevalence, associated anomalies and maternal characteristics among infants born with cloacal exstrophy. We used data from the International Clearinghouse for Birth Defects Surveillance and Research submitted from 18 birth defect surveillance programs representing 24 countries. Cases were clinically evaluated locally and reviewed centrally by two authors. Cases of persistent cloaca were excluded. A total of 186 cases of cloacal exstrophy were identified. Overall prevalence was 1 in 131,579 births: ranging from 1 in 44,444 births in Wales to 1 in 269,464 births in South America. Live birth prevalence was 1 in 184,195 births. Prevalence ratios did not vary by maternal age. Forty-two (22.6%) cases met the criteria for the OEIS complex, whereas 60 (32.3%) were classified as OEI and 18 (9.7%) as EIS (one with suspected VATER (0.5%)). Other findings included two cases with trisomy 13 (one without a karyotype confirmation), one with mosaic trisomy 12 (0.5%), one with mosaic 45,X (0.5%) and one classified as having amnion band sequence (0.5%). Twenty-seven (14.5%) infants had other anomalies unrelated to cloacal exstrophy. Cloacal exstrophy is a rare anomaly with variability in prevalence by geographic location. The proportion of cases classified as OEIS complex was lower in this study than previously reported. Among all cases, 54.8% were reported to have an omphalocele. © 2011 Wiley Periodicals, Inc.

Martinez-Fernandez M.L.,CIBER ISCIII | Martinez-Fernandez M.L.,Institute Salud Carlos III | Bermejo-Sanchez E.,CIBER ISCIII | Bermejo-Sanchez E.,Institute Salud Carlos III | And 7 more authors.
American Journal of Medical Genetics, Part A | Year: 2014

In 2005, we reported on a family as having Frías syndrome (OMIM: 609640), with four affected members displaying a pattern of congenital defects nearly identical to those observed in a mother and son described by Frias [Frías et al. (1975). Birth Defects Orig Artic Ser 11:30-33]. These defects included growth deficiency, facial anomalies, and hand and foot alterations. We had the opportunity to study this family again due to the birth of another affected girl, who presented with similar facial characteristics to those of her elder half-sister and the rest of affected relatives, which consisted of mild exophthalmia, bilateral palpebral ptosis, downslanting palpebral fissures, and hypertelorism. We performed array-CGH, which identified an identical interstitial deletion of chromosome 14q22.1-q22.3 in the mother and two daughters. The deletion is 4.06Mb in length and includes the BMP4 gene, a member of the bone morphogenetic protein (BMP) family of secreted proteins. A review of the literature showed that deletions or mutations of this gene underlie congenital defects affecting brain, eye, teeth, and digit development. Although the clinical manifestations of the current family correlate with the defects observed in patients having either 14q22-q23 deletions or mutations of BMP4, they show a milder phenotype. In order to understand the clinical variability, we evaluated the already known functional characteristics of the BMP gene members. This gene family plays an important role during early embryogenesis, and the complex synergistic functions and redundancies of the BMPs led us to conclude that haploinsufficiency of BMP4 is likely to be responsible for the clinical expression of Frías syndrome. © 2013 Wiley Periodicals, Inc.

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