Mirlene C. S. P. Cernach

The phenotypic spectrum of congenital Zika syndrome

In October 2015, Zika virus (ZIKV) outbreak the Brazilian Ministry of Health (MoH). In response, the Brazilian Society of Medical Genetics established a task force (SBGM‐ZETF) to study the phenotype of infants born with microcephaly due to ZIKV congenital infection and delineate the phenotypic spectrum of this newly recognized teratogen. This study was based on the clinical evaluation and neuroimaging of 83 infants born during the period from July, 2015 to March, 2016 and registered by the SBGM‐ZETF. All 83 infants had significant findings on neuroimaging consistent with ZIKV congenital infection and 12 had confirmed ZIKV IgM in CSF. A recognizable phenotype of microcephaly, anomalies of the shape of skull and redundancy of the scalp consistent with the Fetal Brain Disruption Sequence (FBDS) was present in 70% of infants, but was most often subtle. In addition, features consistent with fetal immobility, ranging from dimples (30.1%), distal hand/finger contractures (20.5%), and feet malpositions (15.7%), to generalized arthrogryposis (9.6%), were present in these infants. Some cases had milder microcephaly or even a normal head circumference (HC), and other less distinctive findings. The detailed observation of the dysmorphic and neurologic features in these infants provides insight into the mechanisms and timings of the brain disruption and the sequence of developmental anomalies that may occur after prenatal infection by the ZIKV.

Investigating 22q11.2 Deletion and Other Chromosomal Aberrations in Fetuses With Heart Defects Detected by Prenatal Echocardiography

Congenital heart disease (CHD) is the most common birth defect and the leading cause of mortality in the first year of life. In fetuses with a heart defect, chromosomal abnormalities are very frequent. Besides aneuploidy, 22q11.2 deletion is one of the most recognizable chromosomal abnormalities causing CHD. The frequency of this abnormality varies in nonselected populations. This study aimed to investigate the incidence of the 22q11.2 deletion and other chromosomal alterations in a Brazilian sample of fetuses with structural cardiac anomalies detected by fetal echocardiography. In a prospective study, 68 fetuses with a heart defect were evaluated. Prenatal detection of cardiac abnormalities led to identification of aneuploidy or structural chromosomal anomaly in 35.3% of these cases. None of the fetuses with apparently normal karyotypes had a 22q11.2 deletion. The heart defects most frequently associated with chromosomal abnormalities were atrioventricular septal defect (AVSD), ventricular septal defect (VSD), and tetralogy of Fallot. Autosomal trisomies 18 and 21 were the most common chromosomal abnormalities. The study results support the strong association of chromosome alterations and cardiac malformation, especially in AVSD and VSD, for which a chromosome investigation is indicated. In fetuses with an isolated conotruncal cardiopathy, fluorescence in situ hybridization (FISH) to investigate a 22q11.2 deletion is not indicated.

Novel mutations in the TBX5 gene in patients with Holt-Oram Syndrome

The Holt-Oram syndrome (HOS) is an autosomal dominant condition characterized by upper limb and cardiac malformations. Mutations in the TBX5 gene cause HOS and have also been associated with isolated heart and arm defects. Interactions between the TBX5, GATA4 and NKX2.5 proteins have been reported in humans. We screened the TBX5, GATA4, and NKX2.5 genes for mutations, by direct sequencing, in 32 unrelated patients presenting classical (8) or atypical HOS (1), isolated congenital heart defects (16) or isolated upper-limb malformations (7). Pathogenic mutations in the TBX5 gene were found in four HOS patients, including two new mutations (c.374delG; c.678G > T) in typical patients, and the hotspot mutation c.835C > T in two patients, one of them with an atypical HOS phenotype involving lower-limb malformations. Two new mutations in the GATA4 gene were found in association with isolated upper-limb malformations, but their clinical significance remains to be established. A previously described possibly pathogenic mutation in the NKX2.5 gene (c.73C > 7) was detected in a patient with isolated heart malformations and also in his clinically normal father.

Atypical 22q11.2 deletion in a patient with DGS/VCFS spectrum.

Deletions in region 22q11.2 usually occur between two low copy repeat regions (LCRs), which are preferred chromosome sites for rearrangements. Most of the deletions encompass the same approximately 3 or approximately 1.5 Mb region, with breakpoints at LCR A and D or at LCR A and B, respectively. We report on a patient with clinical features of the 22q deletion syndrome who presents a novel, atypical deletion, smaller than 1.5 Mb, with distal breakpoint in LCR B and proximal breakpoint within no known LCR site.

Evaluation of a protocol for postmortem examination of stillbirths and neonatal deaths with congenital anomalies.

A study was conducted on 75 perinatal deaths with congenital anomalies through clinical, radiographic, cytogenetic, and autopsy evaluation, and the diagnoses of 72 patients (96%) were determined. In 11 patients with chromosomal anomalies, the cytogenetic study was sufficient to determine the diagnosis and the reproductive risk. In these cases, the value of the autopsy results resided above all in the description of the clinical variability. Radiographic evaluation was the best method to establish a diagnosis of skeletal dysplasias (14.7%). Furthermore, the X-rays showed small skeletal defects which are difficult to see on dissection. The clinical genetic evaluation with a detailed description of the phenotype and anthropometric exam, performed by a clinical geneticist, and the autopsy with gross and microscopic evaluation, facilitated the diagnoses of 50 cases (66.7%). We concluded that, in perinatal death with congenital anomalies, the teamwork of clinical geneticists and fetal pathologists increases the probability of determining the etiological diagnosis. This is essential to define the parents’ reproductive risk, thus contributing to primary prevention of congenital anomalies.

Finlay–Marks (SEN) syndrome: A sporadic case and the delineation of the syndrome

The association of scalp defect, malformed ears, and absence of nipples was described in a familial case by Finlay and Marks in 1978 as an autosomal dominant trait. This association is known as scalpear-nipple syndrome (SEN, MIM 181270). There are nearly 30 cases reported in the literature, with variable phenotypes. We report here a Brazilian case of SEN that is close to the original description of Finlay and Marks [1978], but additionally shows coloboma of the iris. The propositus was born after an uncomplicated pregnancy, from healthy and nonconsanguineous parents. His birth weight was 3,280 g (50–97th centile), and his birth length was 45 cm (3rd centile). The father and mother were 40 and 28 years old, respectively. This was their second child, the first one being a healthy boy. Absence of nipples and a scalp defect were detected at birth. The defective scalp areas were raw at birth, and healed over in early childhood. At 7 years of age, the patientwas referred for genetic evaluation because of multiple congenital anomalies. The patient’s facial appearance was distinctive. The ears were prominent, hypoplastic, the pinna was almost absent, and the helix was folded over (Fig. 2). There was a large area of hairless, thin, atrophic and crumpled skin in the occipital region of the scalp (Fig. 3), and the nipples were absent (Fig. 1). Other features found includedepicanthus, antevertednares, short columella, prognathism, and widely spaced upper central incisors (Fig. 1). The extremities showed 2–3 cutaneous syndactyly of toes, distal nail dysplasia of both hands and feet. A banded blood karyotype showed normal 46,XY chromosomes; ultrasonographic examination of the kidneys and radiographsof the skullwere alsonormal. In addition, ophthalmologic examination showed bilateral coloboma of the iris, asymmetric pupils, and myopia. Intellectual development was normal. In 1978, Finlay and Marks described 10 affected members of a family over five generations, with the association of lumpy scalp, misshapen ears, and rudimentary nipples. The affected persons show raised firm nodules over the scalp in the occipital region, not covered by hair [Taniai et al., 2004]. The scalp lesions initially resemble those of congenital aplasia cutis. These areas heal over in early childhood, and the scalp is lumpy [Plessis et al., 1997]. Histological study shows lesions which are different from keloid scar tissue. They were described in the areas where congenital defects of the scalp usually occur and showed an excess of normal connective tissue and absence of a pilosebaceous apparatus [Finlay andMarks, 1978]. The skull radiographs of the patients were normal [Finlay and Marks, 1978]. The ear malformations include hypoplastic tragus, antitragus and lobule, over-folding of the superior helix, and flattening of the antihelix [Finlay and Marks, 1978; Plessis et al., 1997]. The nipples are rudimentary or absent, and in one proposita the breasts had not enlargedduringpregnancy, nor hadany lactation occurred [Finlay and Marks, 1978; Plessis et al., 1997]. Tuffli and Laxova [1983] reported a new dominant form of ectodermal dysplasia. They described a boy with tooth anomalies, convex nails, and an adrenal cyst. His mother presentedwith aplasia cutis vertices, nipple and breast hypoplasia, dystrophic nails, and hypertension. These cases were considered Finlay– Marks syndrome. A new sporadic case was reported by Aase and Wilroy [1988], however, no specific features were described.

A utilização da Internet na notificação dos defeitos congênitos na Declaração de Nascido Vivo em quatro maternidades públicas do Município de São Paulo, Brasil

The aim of this study was to improve the completion of item 34 on birth certificates at four maternity hospitals in the city of São Paulo, Brazil, in the year 2008. The database of the Municipal Health Departments Information System on Live Births was used to monitor trends in reporting birth defects. An electronic web-based medical record was used to refer indeterminate cases to a leading medical genetics referral center. The electronic medical record contained the patient history, physical examination, and photographs of the newborn. Four maternity hospitals were assessed, with a total of 10,000 births during the year. None of the four hospitals had a staff geneticist. According to the Information System on Live Births, there was an increase in the number of birth defects reported by the four maternity hospitals when compared to previous years and to records for the city of São Paulo as a whole. Based on the findings, the web-based referral and counter-referral method proved efficient.

22q11.2 deletion in patients with conotruncal heart defect and del22q syndrome phenotype

FUNDAMENTO: El sindrome de la delecion 22q11.2 es el mas frecuente sindrome de microdelecion humana. El fenotipo, altamente variable, se caracteriza por defecto cardiaco conotruncal, dismorfias faciales, insuficiencia velofaringea, dificultad de aprendizaje y retardo mental. OBJETIVO: El objetivo de este trabajo fue investigar la frecuencia tanto de la delecion 22q11.2 en una muestra brasilena de individuos portadores de cardiopatia conotrucal aislada, como del fenotipo del sindrome de la delacion 22q11.2. METODOS: Se estudiaron a 29 pacientes por medio de citogenetica clasica, por hibridacion in situ fluorescente (FISH) y tambien por tecnicas moleculares. RESULTADOS: El analisis citogenetico por medio de bandeo G revelo cariotipo normal en todos los pacientes, con excepcion de uno, que presento cariotipo 47,XX,+idic(22)(q11.2). Con la utilizacion de tecnicas moleculares, se observo la delecion en el 25% de los pacientes, todos portadores del fenotipo del sindrome de la delecion 22q11.2. En ningun de los casos, la delecion se heredo de los padres. La frecuencia de la delecion 22q11.2 en el grupo de pacientes portadores del espectro clinico de este sindrome resulto mayor que en el grupo de pacientes con cardiopatia conotruncal aislada. CONCLUSION: La investigacion de la presencia de delecion y su correlacion con los datos clinicos de los pacientes pueden auxiliar los pacientes y sus familias a tener un mejor aconsejamiento genetico, asi como un seguimiento clinico mas adecuado.

Interrupted aortic arch type B in A patient with cat eye syndrome

We report a patient with cat eye syndrome and interrupted aortic arch type B, a typical finding in the 22q11.2 deletion syndrome. Chromosomal analysis and fluorescent in situ hybridization (FISH) showed a supernumerary bisatellited isodicentric marker chromosome derived from chromosome 22. The segment from 22pter to 22q11.2 in the supernumerary chromosome found in our patient does not overlap with the region deleted in patients with the 22q11.2 deletion syndrome. However, the finding of an interrupted aortic arch type B is unusual in CES, although it is a frequent heart defect in the 22q11 deletion syndrome.Informamos un caso de paciente con Sindrome de Ojo de Gato (Cat Eye Syndrome-CES) e Interrupcion del Arco Aortico tipo B, un hallazgo tipico en el sindrome de la delecion 22q11.2. El analisis cromosomico y la tecnica de hibridacion in situ fluorescente (FISH) mostraron un cromosoma marcador isodicentrico supernumerario bisatelitado derivado del cromosoma 22. El segmento de 22pter a 22q11.2 en el cromosoma supernumerario encontrado en nuestro paciente no estaba en sobreposicion con la region deletada en pacientes con el sindrome de la delecion 22q11.2. Con todo, el hallazgo de interrupcion del arco aortico tipo B no es usual en el CES, sino que es un defecto cardiaco frecuente en el sindrome de delecion 22q11.

Wide clinical variability in cat eye syndrome patients: four non-related patients and three patients from the same family.

A small supernumerary marker chromosome (sSMC) derived from chromosome 22 is a relatively common cytogenetic finding. This sSMC typically results in tetrasomy for a chromosomal region that spans the chromosome 22p arm and the proximal 2 Mb of 22q11.21. Using classical cytogenetics, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and array techniques, 7 patients with sSMCs derived from chromosome 22 were studied: 4 non-related and 3 from the same family (mother, daughter, and son). The sSMCs in all patients were dicentric and bisatellited chromosomes with breakpoints in the chromosome 22 low-copy repeat A region, resulting in cat eye syndrome (CES) due to chromosome 22 partial tetrasomy 22pter→q11.2 including the cat eye chromosome region. Although all subjects presented the same chromosomal abnormality, they showed a wide range of phenotypic differences, even in the 3 patients from the same family. There are no previous reports of CES occurring within 3 patients in the same family. Thus, the clinical and follow-up data presented here contribute to a better delineation of the phenotypes and outcomes of CES patients and will be useful for genetic counseling.