na Cardoso Manique Rosa

Clinical features and prognosis of a sample of patients with trisomy 13 (Patau syndrome) from Brazil.

Trisomy 13 or Patau syndrome (PS) is a chromosomal disorder characterized by a well known presentation of multiple congenital anomalies. Our objective was to determine the clinical features and prognosis observed in a sample of patients with PS. The series was composed of patients with diagnosis of PS consecutively evaluated by a Clinical Genetics Service from a reference hospital of southern Brazil, in the period between 1975 and 2012. Statistical analysis was performed using PEPI program (version 4.0), with two‐tailed Fishers exact test for comparison of frequencies (P < 0.05). The sample consisted of 30 patients, 60% male, median age at first evaluation of 9 days. Full trisomy of chromosome 13 was the main cytogenetic alteration (73%). The major clinical findings included: cryptorchidism (78%), abnormal auricles (77%), congenital heart defects (76%), polydactyly (63%), microphthalmia (60%) and micrognathia (50%). Four patients (13%) simultaneously had micro/anophthalmia, oral clefts and polydactyly. Some findings were only observed in our sample and included, among others, preauricular tags (10%), duplication of the hallux (3%) and spots following the lines of Blaschko (3%). Mosaicism (20% of cases) had a statistically significant association only with absence of cryptorchidism. The median of survival was 26 days. Patients with and without mosaicism had similar median of survival. Our findings, in agreement with the literature, show that the anomalies in patients with PS can be quite variable, sometimes even atypical. There is no pathognomonic finding, which may make the early identification of these patients challenging.

Trisomy 18: Experience of a reference hospital from the south of Brazil

Trisomy 18 is a chromosomal syndrome characterized by a broad clinical picture, as well as a very reserved prognosis. The aim of our study was to verify the clinical characteristics and survival of patients diagnosed in a referral hospital in southern Brazil. Our sample consisted of 31 patients, 22 were female (71%), ages ranging from 1 to 1,395 days (median 14 days). The majority had a single cell lineage with full trisomy of chromosome 18 (94%). Concerning pregnancy complications, pre‐eclampsia was the main abnormality described (17%). Fetal ultrasound was performed in 23 cases, and the most frequent abnormalities were polyhydramnios (41%) and intrauterine growth retardation (27%). There were no reports of prenatal identification of the syndrome. Most patients were born by cesarean due to pregnancy and fetal complications and about half of the cases were premature. Congenital heart defects represented the main major malformation observed (94%). Thirty patients (97%) progressed to death (survival ranged from 2 to 780 days, and 87% died within the first 6 months of life). Trisomy 18 is a serious chromosomal disorder with limited survival. Abnormalities of pregnancy appear to be frequent, which can lead to complications for both fetus and mother. The prenatal identification of these patients in our country is still inadequate, resulting in important implications for genetic counseling and management of these patients and their families. And this makes the possibility of interruption of pregnancy, regardless of ethical factors involved, an unlikely option.

Hematological abnormalities and 22q11.2 deletion syndrome

The 22q11.2 deletion syndrome (22q11DS) is a common genetic disease characterized by broad phenotypic variability. Despite the small number of studies describing hematological alterations in individuals with 22q11DS, it appears that these abnormalities are more frequent than previously imagined. Thus, the objective of our study was to report on a patient with 22q11DS presenting thrombocytopenia and large platelets and to review the literature. The patient, a 13-year-old boy, was originally evaluated due to craniofacial dysmorphia and speech delay. He also had a history of behavioral changes, neuropsychomotor delay and recurrent otitis/sinusitis. The identification of a 22q11.2 microdeletion by fluorescent in situ hybridization diagnosed the syndrome. Despite his hematological alterations, he only had a history of epistaxis and bruising of the upper and lower limbs. Assessments of the prothrombin time, thrombin time, partial thromboplastin time, bleeding time, fibrinogen levels and platelet aggregation (including the ristocetin induced platelet aggregation test) were all normal. Hematological alterations observed in 22q11DS are directly related to the genetic disorder itself (especially in respect to deletion of the GPIb gene) and secondary to some clinical findings, such as immunodeficiency. Macrothrombocytopenia is increasingly being considered a feature of the broad spectrum of 22q11DS and may potentially be a clinical marker for the syndrome.

45,X/46,XY mosaicism: report on 14 patients from a Brazilian hospital. A retrospective study

CONTEXT AND OBJECTIVE 45,X/46,XY mosaicism, or mixed gonadal dysgenesis, is considered to be a rare disorder of sex development. The aim of our study was to investigate the clinical and cytogenetic characteristics of patients with this mosaicism. DESIGN AND SETTING A retrospective study in a referral hospital in southern Brazil. METHODS Our sample consisted of patients diagnosed at the clinical genetics service of a referral hospital in southern Brazil, from 1975 to 2012. Clinical and cytogenetic data were collected from the medical records. RESULTS Fourteen patients were included in the sample, with ages at the first evaluation ranging from 2 days to 38 years. Nine of them had female sex of rearing and five, male. Regarding the external genitalia, most were ambiguous (n = 10). One patient presented male phenotype and was treated for a history of azoospermia, while three patients presented female phenotype, of whom two had findings of Turner syndrome and one presented secondary amenorrhea alone. Some findings of Turner syndrome were observed even among patients with ambiguous genitalia. None presented gonadal malignancy. One patient underwent surgical correction for genital ambiguity and subsequent exchange of sex of rearing. Regarding cytogenetics, we did not observe any direct correlation between percentages of cell lines and phenotype. CONCLUSIONS 45,X/46,XY mosaicism can present with a wide variety of phenotypes resulting from the involvement of different aspects of the individual. All these observations have important implications for early recognition of these patients and their appropriate management.

Trisomy 18: Frequency, types, and prognosis of congenital heart defects in a Brazilian cohort†

Trisomy 18: Frequency, Types, and Prognosis of Congenital Heart Defects in a Brazilian Cohort Rafael F.M. Rosa, Rosana C.M. Rosa, Marina B. Lorenzen, Ceres A.V. de Oliveira, Carla Graziadio, Paulo R.G. Zen, and Giorgio A. Paskulin* Graduate Program in Pathology, Universidade Federal de Ciencias da Sa ude de Porto Alegre (UFCSPA), RS, Brazil Clinical Genetics, UFCSPA and Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), RS, Brazil Clinical Genetics, Hospital Materno Infantil Presidente Vargas (HMIPV), RS, Brazil Department of Clinical Medicine, UFCSPA, RS, Brazil Institute of Education and Research, Hospital Moinhos de Vento, RS, Brazil

AMENORRHEA AND X CHROMOSOME ABNORMALITIES

PURPOSE to correlate the clinical manifestations of patients with amenorrhea and X chromosome abnormalities. METHODS a retrospective analysis of the clinical and laboratorial findings of patients with amenorrhea and abnormalities of X chromosome, attended between January 1975 and November 2007 was performed. Their anthropometric measures were evaluated through standard growth tables, and, when present, minor and major anomalies were noted. The chromosomal study was performed through the GTG banded karyotype. RESULTS from the total of 141 patients with amenorrhea, 16% presented numerical and 13% structural abnormalities of X chromosome. From these patients with X chromosome abnormalities (n=41), 35 had a complete clinical description. All presented hypergonadotrophic hypogonadism. Primary amenorrhea was observed in 24 patients, 91.7% of them with a Turner syndrome phenotype. Despite a case with Xq22-q28 deletion, all patients with this phenotype presented alterations involving Xp (one case with an additional cell lineage 46,XY). The two remaining patients with only primary amenorrhea had proximal deletions of Xq. Among the 11 patients with secondary amenorrhea, 54.5% presented a Turner phenotype (all with isolated or mosaic X chromosome monosomy). Patients with phenotype of isolated ovarian failure had only Xq deletions and X trisomy. CONCLUSIONS the cytogenetic analysis must always be performed in women with ovarian failure of unknown cause, even in the absence of clinical dysmorphic features. This analysis is also extremely relevant in syndromic patients, because it can either confirm the diagnosis or identify patients in risk, like the cases involving a 46,XY lineage.

Trisomy 13 (Patau syndrome) and congenital heart defects

Trisomy 13 (Patau Syndrome) and Congenital Heart Defects Janaina B. Polli, Daniela de P. Groff, Patrı́cia Petry, Vinı́cius F. Mattos, Rosana C. M. Rosa, Paulo R. G. Zen, Carla Graziadio, Giorgio A. Paskulin, and Rafael F. M. Rosa* Pediatrics Service, Hospital Materno Infantil Presidente Vargas (HMIPV), Porto Alegre, RS, Brazil Clinical Genetics, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) and Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), Porto Alegre, RS, Brazil Graduate Program in Pathology, UFCSPA, Porto Alegre, RS, Brazil Clinical Genetics, HMIPV, Porto Alegre, RS, Brazil

New report of two patients with mosaic trisomy 9 presenting unusual features and longer survival

CONTEXT Mosaic trisomy 9 is considered to be a rare chromosomal abnormality with limited survival. Our objective was to report on two patients with mosaic trisomy 9 presenting unusual findings and prolonged survival. CASE REPORTS The first patient was a boy aged six years and five months presenting weight of 14.5 kg (< P3), height of 112 cm (P10), head circumference of 49 cm (P2), prominent forehead, triangular and asymmetric face, thin lips, right microtia with overfolded helix, small hands, micropenis (< P10), small testes and hallux valgus. His lymphocyte karyotype was mos 47,XY,+9[4]/46,XY[50]. Additional cytogenetic assessment of the skin showed normal results. The second patient was a two-year-old girl who was initially assessed at five months of age, when she presented weight of 5.3 kg (< P3), height of 61.5 cm (P2-P10), head circumference of 40.5 cm (P25), sparse hair, micrognathia, right ear with overfolded helix and preauricular pit, triphalangeal thumbs and sacral dimple. She also had a history of congenital heart disease, hearing loss, hypotonia, delayed neuropsychomotor development and swallowing disorder. Her lymphocyte karyotype was mos 47,XX,+9[3]/46,XX[69]. Both patients had unusual clinical findings (the first, hemifacial hypoplasia associated with microtia, with a phenotype of oculo-auriculo-vertebral spectrum, and the second, triphalangeal thumbs and hearing loss) and survival greater than what is usually described in the literature (< 1 year). Further reports will be critical for delineating the clinical features and determining the evolution of patients with mosaic trisomy 9.

Limb abnormalities on trisomy 18: evidence for early diagnosis

OBJECTIVE To assess the frequency and types of limb abnormalities observed among patients with trisomy 18, or Edwards syndrome (ES). METHOD The sample consisted of consecutive patients evaluated by a clinical genetics service in the period from 1975 to 2008. The results of the cytogenetic analysis, as well as the clinical data were retrieved from the medical records, with special attention to limb abnormalities findings. All the karyotype analysis was performed at the same laboratory. RESULTS During the study period, 50 patients were identified, 33 (66%) of them females, with ages at the first evaluation ranging from 1 day to 16 years (median 14 days). The single lineage with free trisomy 18 was the most frequent chromosomal disorder (90%). Mosaicism was observed in 10% of the cases. Clenched fist with overlapping fingers was the predominant anomaly of the upper limbs (70%). Other common disorders included the single palmar crease (42%) and hypoplastic nails (36%). Radial abnormalities were found in 11 patients (22%). As for the lower limbs, hypoplastic nails were the most common abnormality (58%), followed by the rocker bottom foot with prominent calcaneus (50%). One patient had unilateral ectrodactyly as well. CONCLUSIONS Despite the classical description, limb anomalies can be much variable in ES. Some patients may show unusual abnormalities, such as radial defects and ectrodactyly. These findings are extremely important for the clinical suspicion and early identification of patients with ES.

Trisomy 18 (Edwards syndrome) and major gastrointestinal malformations.

Trisomy 18 or Edwards syndrome is a chromosomal disease characterized by involvement of many organs and systems, and limited survival.1 The aim of our study was to determine the frequency and types of major gastrointestinal abnormalities observed among patients with Edwards syndrome. The sample consisted of patients consecutively evaluated over the period between 1975 and 2008 in a clinical genetics service at a referral hospital in southern Brazil. Clinical data and karyotype results were gathered from this hospital’s medical records. We use Fisher’s exact test (two-tailed) to compare frequencies (P values < 0.05 were considered significant). Thus, our sample was composed of 50 patients, of whom 33 (66%) were female. Their ages at the first evaluation ranged from 1 day to 16 years (median 14 days). Eight of the patients (16%) were born in that hospital. Presence of a single lineage with free trisomy of chromosome 18 was the main abnormality, observed in 90% of the cases. The remainder consisted of patients with mosaicism. Major gastrointestinal abnormalities were observed in eight patients (16%): two cases of esophageal atresia (4%), three of tracheoesophageal fistula (6%) (one associated with esophageal atresia), one of diaphragmatic hernia (2%) and three of omphalocele (6%). Among these eight patients, five (62%) were female. Their ages at the time of the initial evaluation ranged from one to 70 days (median 7.5 days). Only two patients (25%) presented a clinical suspicion of Edwards syndrome. Additional abnormalities, including minor and major anomalies, were observed in all cases. These included dysmorphic features like a clenched fist with overlapping fingers and major malformations like congenital heart defects. None had a chromosomal constitution with mosaicism. Three patients underwent surgical correction of their defects (one with esophageal atresia, one with tracheoesophageal fistula and one with omphalocele). In all cases, the diagnosis of Edwards syndrome was made only after surgery. Gastrointestinal malformations are frequent among patients with Edwards syndrome. In the literature, the frequency of esophageal atresia among these patients ranges from 16 to 18%.2-4 Despite the frequency of 4% observed in our study, no statistically significant difference was seen using Fisher’s exact test when we compared it with these studies. However, it is noteworthy that the samples in other studies (n = 24 to 39 patients) were smaller than in ours (n = 50). Patients with esophageal atresia usually present the associated finding of tracheoesophageal fistula,4,5 as observed in one of our two patients. Omphalocele has been described in less than 10% of the patients,2-5 which is compatible with the rate in our study (6%). Despite the possible association described in the literature,5 none of our patients with omphalocele presented a neural tube defect. Diaphragmatic hernia is considered to be a less common abnormality, and has been described in less than 8% of the patients.2-4 This frequency was similar to our study (2%). Thus, Edwards syndrome should always be considered among dysmorphic children presenting these major gastrointestinal malformations. Diagnosing it is important for proper management and for determining the prognosis for these patients. IPhD. Clinical Geneticist, Universidade Federal de Ciencias da Saude de Porto Alegre (UFCSPA) and Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), Porto Alegre, Rio Grande do Sul, Brazil. IIMD. Postgraduate, Postgraduate Program on Pathology, Universidade Federal de Ciencias da Saude de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil. IIIUndergraduate Medical Student, Universidade Federal de Ciencias da Saude de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil. IVPhD. Adjunct Professor of Clinical Genetics and Professor of the Postgraduate Program on Pathology, Universidade Federal de Ciencias da Saude de Porto Alegre (UFCSPA), and Clinical Geneticist, Universidade Federal de Ciencias da Saude de Porto Alegre (UFCSPA) and Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), Porto Alegre, Rio Grande do Sul, Brazil. VMD. Professor, Instituto de Educacao e Pesquisa (IEP), Hospital Moinhos de Vento (HMV), Porto Alegre, Rio Grande do Sul, Brazil. VIMD. Postgraduate Student, Postgraduate Program on Pathology, and Assistant Professor of Clinical Genetics, Universidade Federal de Ciencias da Saude de Porto Alegre (UFCSPA), and Clinical Geneticist, Universidade Federal de Ciencias da Saude de Porto Alegre (UFCSPA) and Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), Porto Alegre, Rio Grande do Sul, Brazil. VIIPhD. Associate Professor of Clinical Genetics and Coordinator of the Postgraduate Program on Pathology, Universidade Federal de Ciencias da Saude de Porto Alegre (UFCSPA), and Clinical Geneticist, Universidade Federal de Ciencias da Saude de Porto Alegre (UFCSPA) and Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), Porto Alegre, Rio Grande do Sul, Brazil.