Denise P. Cavalcanti

Universidade Estadual de Campinas (UNICAMP)

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Maria Teresa Vieira Sanseverino

Hospital de Clínicas de Porto Alegre

Têmis Maria Félix

Hospital de Clínicas de Porto Alegre

Juan Clinton Llerena

Fundação Oswaldo Cruz

Karina da Costa Silveira

University of Alberta

Erlane Marques Ribeiro

Hospital Infantil Albert Sabin

João Monteiro de Pina Neto

Universidade de São Paulo

Chong Ae Kim

AstraZeneca (United States)

Lavínia Schüler‐Faccini

Universidade Federal do Rio Grande do Sul

Carolina Moreno

Hospital Israelita Albert Einstein

Maria Juliana R. Doriqui

Universidade Federal do Maranhão

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Hospital Universitario La Paz

153

Universidad Autónoma de Madrid

150

Universidade Estadual de Campinas (UNICAMP)

Instituto de Salud Carlos III

Centre for Biomedical Network Research on Rare Diseases

Universidade de São Paulo

Centro de Investigación Biomédica en Red

National Center on Birth Defects and Developmental Disabilities

Inserm

National Institute on Population Medical Genetics

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Femoral‐facial syndrome: A review of the literature and 14 additional patients including a monozygotic discordant twin pair

American Journal of Medical Genetics Part A (2018)

Maria Dora Jazmin Lacarrubba‐Flores Daniel R. Carvalho Erlane Marques Ribeiro Carolina Moreno Ana Carolina Esposito

Femoral‐facial syndrome (FFS, OMIM 134780), also known as femoral hypoplasia‐unusual face syndrome, is a rare sporadic syndrome associated with maternal diabetes, and comprising femoral hypoplasia/agenesis and a distinct facies characterized by micrognathia, cleft palate, and other minor dysmorphisms. The evaluation of 14 unpublished Brazilian patients, prompted us to make an extensive literature review comparing both sets of data. From 120 previously reported individuals with FFS, 66 were excluded due to: not meeting the inclusion criteria ( n = 21); not providing sufficient data to ascertain the diagnosis ( n = 29); were better assigned to another diagnosis ( n = 3); and, being fetuses of the second trimester ( n = 13) due to the obvious difficult to confirm a typical facies. Clinical‐radiological and family information from 54 typical patients were collected and compared with the 14 new Brazilian patients. The comparison between the two sets of patients did not show any relevant differences. Femoral involvement was most frequently hypoplasia, observed in 91.2% of patients, and the typical facies was characterized by micrognathia (97%), cleft palate (61.8%), and minor dysmorphisms (frontal bossing 63.6%, short nose 91.7%, long philtrum 94.9%, and thin upper lip 92.3%). Clubfoot (55.9%) was commonly observed. Other observed findings may be part of FFS or may be simply concurrent anomalies since maternal diabetes is a common risk factor. While maternal diabetes was the only common feature observed during pregnancy (50.8%), no evidence for a monogenic basis was found. Moreover, a monozygotic discordant twin pair was described reinforcing the absence of a major genetic factor associated with FFS.

Frontal Bossing

Agenesis

10.1002/ajmg.a.40425

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Citations (9)

Clinical epidemiology of skeletal dysplasias in South America

American Journal of Medical Genetics Part A (2012)

Cecília O. Barbosa‐Buck Iêda M. Orioli Maria da Graça Dutra Jorge S. López‐Camelo Eduardo E. Castilla

Abstract Currently accepted birth prevalence for osteochondrodysplasias (OCD) of about 2/10,000 is based on few studies from small series of cases. We conducted a study based on more than 1.5 million births. OCD cases were detected from 1,544,496 births occurring and examined in 132 hospitals of ECLAMC (Latin American Collaborative Study of Congenital Malformations) between 2000 and 2007. Cases were detected and registered according to a pre‐established protocol, and then ranked in four diagnostic evidence levels (DEL), according to available documentation. For the analysis of risk factors, a healthy control sample born in the same period was used. OCD was diagnosed in 492 newborns, resulting in a prevalence per 10,000 of 3.2 (95% CI: 2.9–3.5). Perinatal lethality (stillbirths plus early neonatal deaths) occurred in 50% of cases. Prenatal ultrasound diagnosis was made in 73% of cases (n = 359). Among 211 cases from the best documented group (DEL‐1) and according to international classification, 33% of cases fit into the G‐25 (osteogenesis imperfecta), 29% in Group‐1 ( FGFR3 ), and 8% in Group‐18 (Bent bones). The prevalence of the main OCD types were: OI—0.74 (0.61–0.89); thanatophoric dysplasia—0.47 (0.36–0.59); and achondroplasia—0.44 (0.33–0.55). Paternal age (31.2 ± 8.5), parity (2.6), and parental consanguinity rate (5.4%) were higher in cases than in controls ( P < 0.001). In conclusion, the OCD overall prevalence of 3.2 per 10,000 found seems to be more realistic than previous estimates. This study also confirmed the high perinatal mortality, and the association with high paternal age, parity, and parental consanguinity rate. © 2012 Wiley Periodicals, Inc.

Achondroplasia

Congenital malformations

10.1002/ajmg.a.35246

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Citations (87)

Incidence of congenital hydrocephalus and the role of the prenatal diagnosis

Jornal de Pediatria (2003)

Denise P. Cavalcanti Maria A. Salomão

10.2223/jped.965

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Skeletal dysplasias in Latin America

American Journal of Medical Genetics Part C Seminars in Medical Genetics (2020)

Denise P. Cavalcanti Virginia Fano Cecília Mellado Maria Dora Jazmin Lacarrubba‐Flores Cynthia Silveira

Abstract Skeletal dysplasias (SD) are disturbances in growth due to defects intrinsic to the bone and/or cartilage, usually affecting multiple bones and having a progressive character. In this article, we review the state of clinical and research SD resources available in Latin America, including three specific countries (Brazil, Argentina, and Chile), that have established multidisciplinary clinics for the care of these patients. From the epidemiological point of view, the SD prevalence of 3.2 per 10,000 births from nine South American countries included in the ECLAMC network represents the most accurate estimate not just in Latin America, but worldwide. In Brazil, there are currently five groups focused on SD. The data from one of these groups including the website www.ocd.med.br , created to assist in the diagnosis of SD, are highlighted showing that telemedicine for this purpose represents a good strategy for the region. The experience of more than 30 years of the SD multidisciplinary clinic in an Argentinian Hospital is presented, evidencing a solid experience mainly in the follow‐up of the most frequent SD, especially those belonging the FGFR3 group and OI. In Chile, a group with 20 years of experience presents its work with geneticists and pediatricians, focusing on diagnostic purposes and clinical management. Altogether, although SD health‐care and research activities in Latin America are in their early stages, the experience in these three countries seems promising and stimulating for the region as a whole.

10.1002/ajmg.c.31861

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CranFlow: An Application for Record‐Taking and Management Through the Brazilian Database on Craniofacial Anomalies

Birth Defects Research (2017)

Roberta Mazzariol Volpe-Aquino Isabella Lopes Monlleó Elaine Lustosa‐Mendes AMANDA FERREIRA MORA Agnes Cristina Fett‐Conte

Background The World Health Organization has recognized the relevance of databases on craniofacial anomalies since . To date, there is no universal standard instrument/database focused on risk factors, clinical and genetic data collection, and follow‐up that enables comparison between different populations and genotype–phenotype correlation. Although studies have shown that specific genes would impact outcomes, knowledge is not sufficient to subsidize cost‐effectiveness strategies for diagnosis, surgical decision, and a multi‐professional approach toward personalized medicine. Methods Based on a clinical genetic approach, a Web‐based application named CranFlow—Craniofacial Anomalies: Registration, Flow, and Management has been developed. It prospectively collects clinical and genetic information for the Brazilian Database on Craniofacial Anomalies (syndromic and nonsyndromic orofacial cleft, 22q11.2 deletion syndrome, and other craniofacial related disorders). A comprehensive list of CranFlow's features is provided. Results We present preliminary results on 1546 cases already recorded and followed, which allows recognizing 10% of diagnosis changes. Conclusion The identification of risk factors, consistent genetic approach associated with clinical data and follow‐up result in valuable information to develop and improve personalized treatment and studies on genotype–phenotype correlation. Adoption of CranFlow in different clinical services may support comparison between populations. This application has the potential to contribute to improvements in healthcare, quality of services, clinical and surgical outcomes, and the standard of living of individuals with craniofacial anomalies. Birth Defects Research 110:72–80, 2018. © 2017 Wiley Periodicals, Inc.

Craniofacial abnormality

Identification

10.1002/bdr2.1123

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Citations (15)

Interphase-FISH study in three patients with tetraploid/diploid mosaicism

Annales de Génétique (2004)

Denise P. Cavalcanti Luciene Zanchetta

Interphase

10.1016/j.anngen.2004.09.004

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P40 Description of a Brazilian case of atelosteogenesis II: from prenatal to preimplantation diagnosis

Reproductive BioMedicine Online (2012)

M.T.V. Sanseverino José Antônio de Azevedo Magalhães Lauréane Mittaz‐Crettol Ricardo Azambuja L. Okada

10.1016/s1472-6483(12)60257-0

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Visceral myopathy: Clinical and molecular survey of a cohort of seven new patients and state of the art of overlapping phenotypes

American Journal of Medical Genetics Part A (2016)

Carolina Moreno Konradin Metze Elizete Aparecida Lomazi Débora Romeo Bertola Ricardo Henrique Almeida Barbosa

Visceral motility dysfunction is a key feature of genetic disorders such as megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS, MIM moved from 249210 to 155310), chronic intestinal pseudo-obstruction (CIPO, MIM609629), and multisystemic smooth muscle dysfunction syndrome (MSMDS, MIM613834). The genetic bases of these conditions recently begun to be clarified with the identification of pathogenic variants in ACTG2, ACTA2, and MYH11 in individuals with visceral motility dysfunction. The MMIHS was associated with the heterozygous variant in ACTG2 and homozygous variant in MYH11, while the heterozygous variant in ACTA2 was observed in patients with MSMDS. In this study, we describe the clinical data as well as the molecular investigation of seven individuals with visceral myopathy phenotypes. Five patients presented with MMIHS, including two siblings from consanguineous parents, one had CIPO, and the other had MSMDS. In three individuals with MMIHS and in one with CIPO we identified heterozygous variant in ACTG2, one being a novel variant (c.584C>T-p.Thr195Ile). In the individual with MSMDS we identified a heterozygous variant in ACTA2. We performed the whole-exome sequencing in one sibling with MMIHS and her parents; however, the pathogenic variant responsible for her phenotype could not be identified. These results reinforce the clinical and genetic heterogeneity of the visceral myopathies. Although many cases of MMIHS are associated with ACTG2 variants, we suggest that other genes, besides MYH11, could cause the MMIHS with autosomal recessive pattern. © 2016 Wiley Periodicals, Inc.

Intestinal pseudo-obstruction

10.1002/ajmg.a.37857

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Citations (36)

Human Genetics (2023)

Karina da Costa Silveira Inara Chacon Fonseca Connor Oborn Parker Wengryn Saima Ghafoor

CYP26B1 metabolizes retinoic acid in the developing embryo to regulate its levels. A limited number of individuals with pathogenic variants in CYP26B1 have been documented with a varied phenotypic spectrum, spanning from a severe manifestation involving skull anomalies, craniosynostosis, encephalocele, radio-humeral fusion, oligodactyly, and a narrow thorax, to a milder presentation characterized by craniosynostosis, restricted radio-humeral joint mobility, hearing loss, and intellectual disability. Here, we report two families with CYP26B1-related phenotypes and describe the data obtained from functional studies of the variants. Exome and Sanger sequencing were used for variant identification in family 1 and family 2, respectively. Family 1 reflects a mild phenotype, which includes craniofacial dysmorphism with brachycephaly (without craniosynostosis), arachnodactyly, reduced radioulnar joint movement, conductive hearing loss, learning disability-and compound heterozygous CYP26B1 variants: (p.[(Pro118Leu)];[(Arg234Gln)]) were found. In family 2, a stillborn fetus presented a lethal phenotype with spina bifida occulta, hydrocephalus, poor skeletal mineralization, synostosis, limb defects, and a synonymous homozygous variant in CYP26B1: c.1083C > A. A minigene assay revealed that the synonymous variant created a new splice site, removing part of exon 5 (p.Val361_Asp382del). Enzymatic activity was assessed using a luciferase assay, demonstrating a notable reduction in exogenous retinoic acid metabolism for the variant p.Val361_Asp382del. (~ 3.5 × decrease compared to wild-type); comparatively, the variants p.(Pro118Leu) and p.(Arg234Gln) demonstrated a partial loss of metabolism (1.7× and 2.3× reduction, respectively). A proximity-dependent biotin identification assay reaffirmed previously reported ER-resident protein interactions. Additional work into these interactions is critical to determine if CYP26B1 is involved with other biological events on the ER. Immunofluorescence assay suggests that mutant CYP26B1 is still localized in the endoplasmic reticulum. These results indicate that novel pathogenic variants in CYP26B1 result in varying levels of enzymatic activity that impact retinoic acid metabolism and relate to the distinct phenotypes observed.

Sanger sequencing

10.1007/s00439-023-02598-2

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Mutational Screening of FGFR1, CER1, and CDON in a Large Cohort of Trigonocephalic Patients

The Cleft Palate-Craniofacial Journal (2006)

Fernanda Sarquis Jehee Luís Garcia Alonso Denise P. Cavalcanti Chong Ae Kim Steven A. Wall

Objective Screen the known craniosynostotic related gene, FGFR1 (exon 7), and two new identified potential candidates, CER1 and CDON, in patients with syndromic and nonsyndromic metopic craniosynostosis to determine if they might be causative genes. Design Using single-strand conformational polymorphisms (SSCPs), denaturing high-performance liquid chromatography, and/or direct sequencing, we analyzed a total of 81 patients for FGFR1 (exon 7), 70 for CER1, and 44 for CDON. Patients Patients were ascertained in the Centro de Estudos do Genoma Humano in São Paulo, Brazil (n = 39), the Craniofacial Unit, Oxford, U.K. (n = 23), and the Johns Hopkins University, Baltimore, Maryland (n = 31). Clinical inclusion criteria included a triangular head and/or forehead, with or without a metopic ridge, and a radiographic documentation of metopic synostosis. Both syndromic and nonsyndromic patients were studied. Results No sequence alterations were found for FGFR1 (exon 7). Different patterns of SSCP migration for CER1 compatible with the segregation of single nucleotide polymorphisms reported in the region were identified. Seventeen sequence alterations were detected in the coding region of CDON, seven of which are new, but segregation analysis in parents and homology studies did not indicate a pathological role. Conclusions: FGFR1 (exon 7), CER1, and CDON are not related to trigonocephaly in our sample and should not be considered as causative genes for metopic synostosis. Screening of FGFR1 (exon 7) for diagnostic purposes should not be performed in trigonocephalic patients.

Trigonocephaly

10.1597/04-206.1

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Citations (17)