Two cases of polydactyly in wild brown howler monkeys (Alouatta guariba clamitans).

We report the first two cases of polydactyly in an atelid species: (i) a wild ca. 16-week-old infant female presenting seven digits in both feet and other bone malformations and (ii) a wild newborn male presenting six digits in both feet with the extra digit fused to the hallux.

Clinical utility of skin karyotype / Utilidade clínica do cariótipo de pele

ABSTRACTWe report the case of a patient with Patau syndrome, diagnosed by skin karyotype, emphasizing the applications and importance of this test. The pregnancy morphology ultrasound showed face defects and of central nervous system and heart chambers asymmetry. In the postnatal evaluation it was identified microcephaly, single central nostril, and other malformations. We performed skin karyotype that resulted in full trisomy 13. Our report highlights the possibility of performing karyotype examination in cases when it is no longer possible to obtain a blood sample, thus providing the correct diagnosis and genetic counseling for the family.

RESUMORelatamos o caso de uma paciente com síndrome de Patau, diagnosticada por meio do cariótipo de pele, salientando as aplicações e a importância deste exame. Na ultrassonografia morfológica da gravidez, apresentou malformações de face, sistema nervoso central e assimetria de câmaras cardíacas. No pós-natal, identificou-se microcefalia e narina única central, além de outras malformações. Realizamos cariótipo de pele que resultou em trissomia livre do cromossomo 13. Nosso relato destaca a possibilidade da realização deste exame em casos nos quais não é mais possível a obtenção de amostra de sangue, proporcionando assim o correto diagnóstico e aconselhamento genético para a família.

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 Fisher's 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.

Cytogenetic response to imatinib treatment in Southern Brazilian patients with chronic myelogenous leukemia and variant Philadelphia chromosome.

Variant Philadelphia (Ph) chromosome can be observed in 5-10 % of chronic myelogenous leukemia (CML) patients. However, there are only a few studies which have analyzed the prognostic implications of these complex translocations in CML patients after the advent of imatinib mesylate and the results found are conflicting. We investigated the clinical features and cytogenetic response of Brazilian chronic phase (CP) CML patients with variant Ph treated with imatinib mesylate. Among 93 CP CML patients, eight (8.6 %) exhibited complex translocations, involving one (n = 6), two (n = 1), or three (n = 1) additional chromosomes. At 6, 12, and 18 months, a complete cytogenetic response was observed in 100 % of variant Ph patients, respectively. No significant difference was found between variant Ph and standard translocation patients regarding the response to IM treatment at 6, 12, and 18 months. Likewise, there was no statistically significant difference between the two groups concerning the overall survival, failure-free survival, progression-free survival, and event-free survival. The results obtained in our study, despite our sample size, suggest, in agreement to other data found in the literature, that the presence of variant Philadelphia chromosome does not bestow a prognostic disadvantage when compared to the group with classic Ph. This observation does not suggest the need to adjust the treatment protocol due to the presence of variant Ph. However, further studies with larger sample sizes and evaluating both the cytogenetic and molecular response to IM treatment should be conducted to confirm our findings.

Anormalidades de membros na trissomia do cromossomo 18: evidência para o diagnóstico precoce / Limb abnormalities on trisomy 18: evidence for early diagnosis

OBJETIVO: Verificar a frequência e os tipos de anormalidades de membros observadas entre pacientes com trissomia do cromossomo 18, ou síndrome de Edwards (SE). MÉTODO: A amostra foi constituída de pacientes consecutivos avaliados por um serviço de genética clínica no período entre 1975 e 2008. O resultado da análise citogenética, bem como os dados clínicos, foram coletados a partir dos prontuários médicos, dando-se ênfase aos seus achados de membros. Todos foram submetidos ao exame de cariótipo no mesmo laboratório. RESULTADOS: No período de avaliação, foram identificados 50 pacientes, 33 deles (66%) do sexo feminino, com idade na primeira avaliação variando de 1 dia a 16 anos (mediana de 14 dias). A linhagem única com trissomia livre do cromossomo 18 foi a alteração cromossômica predominante (90%). Mosaicismo foi verificado em 10% dos casos. A anormalidade predominante de membros superiores observada na amostra (n = 50) foi o punho cerrado com sobreposição dos dedos (70%). Outras alterações frequentes incluíram a prega palmar única (42%) e a hipoplasia das unhas (36%). Anormalidades radiais foram observadas em 11 pacientes (22%). Quanto aos membros inferiores, a hipoplasia de unhas foi a alteração mais comum (58%), seguida do pé em mata-borrão com calcâneo proeminente (50%). Um dos pacientes possuía ainda ectrodactilia unilateral. CONCLUSÕES: Apesar da descrição clássica, as anormalidades de membros podem ser bastante variáveis na SE. Alguns pacientes podem ainda apresentar alterações não usuais, como defeitos radiais e ectrodactilia. Esses achados são de extrema importância para a suspeita e a identificação clínica precoce dos pacientes com a SE.

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.

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: 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.

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

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.

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.

Additional features in a new case of a girl presenting brachyphalangy, polydactyly and tibial aplasia/hypoplasia.

Brachyphalangy, polydactyly and tibial aplasia/hypoplasia is a rare autosomal dominant disorder. The present report represents the ninth reported case and only the second case involving a female. She had a characteristic pattern of limb anomalies including agenesis of the tibiae and bilateral preaxial polydactyly of the feet, associated with genital hypoplasia. In addition our patient had wormian bones, a lacrimal sac fistula, an ectopic kidney and an anteriorly placed anus, which are findings not previously described in this condition.

Inv dup del(4)(:p13-->p16.3::p16.3-->qter) in a girl without typical manifestations of Wolf-Hirschhorn syndrome.

We report on a 4-year-old girl who presented with microcephaly, multiple minor anomalies of face and limbs, congenital heart defect, hypotonia, neuropsychomotor delay, deafness and seizures. A GTG-banded karyotype identified an additional fragment of unknown origin on the terminal region of 4p. Parental karyotypes were normal. FISH analysis using a whole chromosome paint probe for chromosome 4 and subtelomere probes showed a signal on the entire add (4) chromosome and loss of the 4p subtelomere region, respectively. Additional analysis using microsatellite markers for chromosome 4 and whole-genome array comparative genomic hybridization (array-CGH) identified a duplication of the region 4p13 --> 4p16.3. Her karyotype was thus interpreted as an inverted duplication with terminal deletion of 4p: 46,XX,der(4)(:p13 --> p16.3::p16.3 --> qter). The clinical features of our patient differed from those typically observed in Wolf-Hirschhorn syndrome and were more compatible with duplication 4(p14 --> p16.3), with preservation of the WHS critical region.

ETV6/RUNX1 fusion lacking prognostic effect in pediatric patients with acute lymphoblastic leukemia.

A Brazilian sample of 58 patients with acute lymphoblastic leukemia has been prospectively followed up with the objective of evaluating evolution of disease. Age ranged from 6 months to 16 years. Of the 58 patients, 11 were positive and 47 were negative for the ETV6/RUNX1 fusion (previously known as TEL/AML1). After a minimum follow-up period of 57 months, 2 of the ETV6/RUNX1(+) patients had died and 11 of the ETV6/RUNX1(-), for an overall survival of 77.6%. Among the 11 ETV6/RUNX1(+) patients (age range, 2 years to 13 years 7 months), all achieved a complete remission; the average overall survival was 64.2 months and the average event-free survival was 61.7 months. Among the 47 ETV6/RUNX1(-) patients, 4 did not have a complete remission; the average overall survival was of 60.8 months and the average event-free survival was 57.2 months. No significant difference was observed between overall survival and event-free survival, nor in any of the other data comparatively analyzed. The patients had a cure rate similar to that described in literature. In this small sample population, the presence of the ETV6/RUNX1 fusion did not identify statistical difference in prognosis.

Evolução clínica e fusão TEL/AML1 em pacientes pediátricos com síndrome de Down e leucemia linfoblástica aguda / Clinical evolution and TEL/AML1 fusion in pediatric patients with Down syndrome and acute lymphoblastic leukemia

O risco aumentado de desenvolvimento de leucemia apresentado pelos indivíduos portadores de síndrome de Down (SD) já é bem conhecido. Entretanto, a contribuição do cromossomo 21 extraconstitucional ao processo de leucemogênese, ainda não está bem estabelecida. A fusão TEL/AML1 é a anomalia estrutural mais frequentemente encontrada em leucemia linfoblástica aguda (LLA) da infância, mas a sua associação com a LLA em pacientes com SD não é bem clara. Nós investigamos uma amostra de quatro pacientes com LLA e SD (LLA-SD) quanto à sua evolução clínica e seus aspectos citogenéticos, inclusive com pesquisa da fusão TEL/AML1. A idade do diagnóstico variou de 5 anos e 7 meses a 13 anos e 7 meses, o número de leucócitos em sangue periférico de 7.200 a 208.000/mm³ e a porcentagem de blastos na medula óssea de 20 por cento a 95 por cento. Apenas um paciente foi positivo para a fusão TEL/AML1. Todos os pacientes entraram em remissão completa e nenhum apresentou comprometimento extramedular ou recidiva. O tempo de sobrevida variou de 67 a 82 meses e não ocorreu nenhum óbito. Em nossa série de crianças com LLA-SD, os aspectos citogenéticos e a boa evolução clínica observados estão de acordo com o relatado na literatura.

The increased risk of developing leukemia found in Down syndrome (DS) patients is already well-known. However, the contribution of the extra copy of chromosome 21 to this leukemogenesis is still not well established. The TEL/AML1 fusion is the most frequently found structural anomaly in acute lymphoblastic leukemia (ALL) in childhood, but its association with ALL in DS patients is not very clear. We investigated a sample of four patients with ALL and DS (ALL-DS) in terms of their clinical evolution and cytogenetic aspects, including a study of the TEL/AML1 fusion. The ages of the patients ranged from 5 years and 7 months to 13 years and 7 months, the number of leukocytes in peripheral blood was 7,200 to 208,000 x 106 and the percentage of blasts in the bone marrow was 20 to 95 percent. Only one patient tested positive for the TEL/AML1 fusion. All patients achieved complete remission and none presented extramedullary involvement or relapse. The survival period ranged from 67 to 82 months and there was no death. In our series of children with ALL-DS, the cytogenetic aspects and the good clinical evolution observed are in agreement with the literature.

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.

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.