Giorgio Adriano Paskulin

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.

22q11.2 deletion syndrome in patients admitted to a cardiac pediatric intensive care unit in Brazil

The 22q11.2 deletion syndrome (22q11DS) is one of the most recognizable causes of congenital heart defects (CHDs), but the frequency varies in non‐selected populations. The purpose of this study was to determine the incidence and clinical features of patients with CHD and 22q11DS admitted to a pediatric cardiology intensive care unit in Brazil. In a prospective study, we evaluated a consecutive series of 207 patients with a CHD following a clinical protocol and cytogenetic analysis by high resolution karyotype and fluorescent in situ hybridization (FISH). 22q11DS was identified in four patients (2%), a frequency similar to studies that evaluated subjects with major CHDs in other countries. Despite this similarity, we believe that the low rate of prenatal identification of CHDs and the limited access of these patients to appropriate diagnosis and care, which occur in our region, could have had an influence on this frequency. It is possible that 22q11DS patients with a severe CHD could have died before having a chance to access a tertiary hospital, leading to an underestimate of its frequency.

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.

Ear abnormalities in patients with oculo-auriculo-vertebral spectrum (Goldenhar syndrome)

UNLABELLED Oculo-auriculo-vertebral spectrum (OAVS) is a rare condition characterized by the involvement of the first branchial arches. PURPOSE To investigate the ear abnormalities of a sample of patients with OAVS. MATERIALS AND METHODS The sample consisted of 12 patients with OAVS seen at the Clinical Genetics Unit, UFCSPA/CHSCPA. The study included only patients who underwent mastoid computed tomography and with normal karyotype. We performed a review of its clinical features, giving emphasis to the ear findings. RESULTS Nine patients were male, the ages ranged from 1 day to 17 years. Ear abnormalities were observed in all patients and involved the external (n = 12), middle (n = 10) and inner ear (n = 3). Microtia was the most frequent finding (n = 12). The most common abnormalities of the middle ear were: opacification (n = 2), displacement (n = 2) and malformation of the ossicular chain. Agenesis of the internal auditory canal (n = 2) was the most frequent alteration of the inner ear. CONCLUSIONS Ear abnormalities are variable in patients with OAVS and often there is no correlation between findings in the external, middle and inner ear. The evaluation of these structures is important in the management of individuals with OAVS.

Molecular analysis of connexin26 asparagine14 mutations associated with syndromic skin phenotypes.

Abstract:  Mutations in connexin26, a cutaneous gap junction protein, cause a wide variety of skin disorders including keratitis‐ichthyosis‐deafness syndrome (KID). We previously delineated a phenotype distinct from KID, hypotrichosis‐deafness syndrome, caused by the mutation p.Asn14Lys in connexin26. However, a different mutation at the same location, p.Asn14Tyr, was reported to cause a disorder similar to KID. Distinct substitutions cause different conformational changes to the protein, each with unique consequences for its behaviour. This may explain the phenotypic differences. We found the previously described mutation p.Asn14Tyr in connexin26 in two patients from Brazil and Poland, and observe quite distinct phenotypes distinguishable from classical KID syndrome. We assessed functional consequences of p.Asn14Tyr and p.Asn14Lys, using fluorescently labelled proteins and parachute assay, comparing them with the classical KID mutation p.Asp50Asn. Our analyses show that p.Asn14Tyr, p.Asn14Lys and p.Asp50Asn have different consequences for protein localization and gap junction permeability. However, the differences between the phenotypes we observed cannot be readily explained from effects on protein trafficking or gap junction permeability.

Características clínicas de uma amostra de pacientes com a síndrome do olho do gato

OBJECTIVE: The cat eye syndrome is considered a rare chromosomal disease and a phenotypically quite variable condition. The objective of this study was to describe the clinical characteristics of a sample of patients with the syndrome evaluated in our Service. METHODS: Six patients with diagnosis of cat eye syndrome were retrospectively evaluated. All presented a karyotype with presence of an additional chromosome marker, inv dup(22)(pter->q11.2::q11.2->pter). One of them still had a mosaicism with a lineage with a normal chromosomal constitution. Clinical and evolution data were collected from their medical records. Fisher exact test (P<0.05) was used for comparison between the frequencies found in our study and literature. RESULTS: The main abnormalities found were preauricular skin tags/pits and imperforate anus (both observed in 83% of cases). Iris coloboma, an important feature of the syndrome was verified in 2 cases (33%). Congenital heart defect observed in 4 patients (67%), with the atrial septal defect (75%) as the most observed. Uncommon features included the hemifacial microsomia associated to microtia, besides biliary atresia. In relation to the evolution, only one of the patients died and this occurred secondary to quilothorax and sepsis. CONCLUSION: The phenotype observed in the cat eye syndrome is very variable and may overlap with that of oculo-auriculo-vertebral spectrum. Despite the good prognosis usually presented by the individuals, also from the neurological point of view, we believe that all patients with the syndrome should be evaluated as early as possible for presence of heart, biliary and anorectal malformations. This should avoid possible complications, including death.OBJECTIVE Cat eye syndrome is considered a rare chromosome disease with a highly variable phenotype. The objective of this paper was to describe the clinical characteristics of a sample of patients with cat eye syndrome who were seen at our service. METHODS This is a retrospective analysis of a sample of six patients with diagnoses of cat eye syndrome. All of these patients’ karyotypes exhibited the presence of an additional marker chromosome, inv dup(22)(pter->q11.2::q11.2->pter). One patient also exhibited mosaicism with a lineage that had a normal chromosomal constitution. Clinical and follow-up data were collected from the patients’ medical records. Fisher’s exact test was used to compare the frequencies observed in our study with figures given in the literature (P<0.05). RESULTS The main abnormalities observed were preauricular tags and/or pits and anal atresia (both observed in 83% of cases). Coloboma of the iris, an important finding with this syndrome, was observed in two cases (33%). Congenital heart disease was detected in four patients (67%) and the main defect found was interatrial communication (75%). Uncommon findings included hemifacial microsomia combined with unilateral microtia and biliary atresia. Just one of these patients died, from chylothorax and sepsis. CONCLUSION The phenotype observed in cat eye syndrome is highly variable and may be superimposed on the phenotype of the oculo-auriculo-vertebral spectrum. Although these patients usually have good prognosis, including from a neurological point of view, we believe that all patients with the syndrome should be assessed very early on for the presence of cardiac, biliary and anorectal malformations, which may avoid possible complications in the future, including patient deaths.

Esophageal stenosis in a child presenting a de novo 7q terminal deletion.

We report on the first case of a child with a de novo 7q terminal deletion [46,XX,del(7)(q35 → qter)] presenting esophageal stenosis. This cytogenetic abnormality was confirmed by FISH, using subtelomeric probes, and by a whole-genome array-CGH assay. The child also had phenotypic features previously described in patients with a similar deletion, as growth retardation, microcephaly, coloboma of papilla, ptosis, hearing loss, urinary tract anomalies, partial agenesis of sacrum, hypotonia and neuropsychomotor delay. The odontoid hypoplasia identified, in similarity with the esophageal stenosis, represents an uncommon finding. This report is also the first clinical description of a patient with an abnormality involving the sonic hedgehog gene and an esophageal alteration. It is discussed the possibility of a specific association between them, according to some results observed in studies with animal models.

New report of a familial case of Moebius syndrome presenting skeletal findings

New Report of a Familial Case of Moebius Syndrome Presenting Skeletal Findings Carla Graziadio, Marina B. Lorenzen, Rafael F.M. Rosa, Louise L.C. Pinto, Paulo R.G. Zen, Giovanni M. Travi, Fabiana Valiatti, and Giorgio A. Paskulin* Clinical Genetics, Universidade Federal de Ciências da Sa ude de Porto Alegre (UFCSPA), Rio Grande do Sul, Brazil Clinical Genetics, Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), Rio Grande do Sul, Brazil Department of Clinical Medicine, UFCSPA, Rio Grande do Sul, Brazil Graduate Program in Pathology, UFCSPA, Rio Grande do Sul, Brazil Department of Ophthalmology, CHSCPA, Rio Grande do Sul, Brazil

Report of a child with a complete de novo 17p duplication localized to the terminal region of the long arm of chromosome 17

We report the second case of a child with trisomy of the entire short arm of chromosome 17 secondary to a de novo duplication. Trisomy 17p in this patient resulted from a duplication, localized to the distal region of the long arm of the same chromosome, an abnormality not previously described. This cytogenetic abnormality was confirmed using whole chromosome paint, subtelomeric and Smith‐Magenis probes by fluorescence in situ hybridization (FISH) analysis. The child presented with phenotypic features previously described in trisomy 17p, including some specific facial dysmorphia, microcephaly, growth retardation, hypotonia, short webbed neck, congenital heart defect, minor abnormalities of the hands, agenesis of the corpus callosum and abnormalities of the iris. Iris alterations and defects involving the left side of heart and the aorta also may represent truly clinical hallmarks of this cytogenetic abnormality. In conclusion, this cytogenetic anomaly seems to represent a severe malformation entity with a poor prognosis and a recognizable clinical pattern that justifies the use of the term “17p trisomy syndrome” suggested previously by other authors.

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.