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Objective: It was to verify the association between the definition of sex of rearing and, clinical and cytogenetic features among patients with genital ambiguity referred without a sex assignment., Methods: The sample consisted of 133 patients with genital ambiguity seen at a single reference service. These patients did not have a defined social sex at the first consultation and their etiological diagnosis was obtained during follow-up., Results: A total of 133 cases were included, 74 of which were reared as males and 59 as females. No correlation was found between the year of birth and the year of the first consultation with the definition of sex of rearing. However, the definition of sex of rearing was associated with age at the first consultation, severity of genital ambiguity, presence of palpable gonad(s), presence of uterus on ultrasound, karyotype, and diagnosis. Palpable gonad(s), more virilized genitalia, absence of a uterus on ultrasound, 46, XY karyotype, or a karyotype with sex chromosome abnormalities emerged as strong predictors for defining male sex. All 77 (58 %) patients over 18 years old had a gender identity in accordance with the sex of rearing; though 9 of 77 (12 %) had homo or bisexual orientation, especially girls with Congenital Adrenal Hyperplasia., Conclusions: Clinical and cytogenetic data were strongly associated with the definition of the sex of rearing of children with genital ambiguity referred to a DSD center without sex assignment. Management in a specialized center allows the establishment of a gender identity in accordance with the sex of rearing., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2024 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Low-pass whole genome sequencing (LP-WGS) has been applied as alternative method to detect copy number variants (CNVs) in the clinical setting. Compared with chromosomal microarray analysis (CMA), the sequencing-based approach provides a similar resolution of CNV detection at a lower cost. In this study, we assessed the efficiency and reliability of LP-WGS as a more affordable alternative to CMA. A total of 1363 patients with unexplained neurodevelopmental delay/intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies were enrolled. Those patients were referred from 15 nonprofit organizations and university centers located in different states in Brazil. The analysis of LP-WGS at 1x coverage (>50kb) revealed a positive testing result in 22% of the cases (304/1363), in which 219 and 85 correspond to pathogenic/likely pathogenic (P/LP) CNVs and variants of uncertain significance (VUS), respectively. The 16% (219/1363) diagnostic yield observed in our cohort is comparable to the 15%-20% reported for CMA in the literature. The use of commercial software, as demonstrated in this study, simplifies the implementation of the test in clinical settings. Particularly for countries like Brazil, where the cost of CMA presents a substantial barrier to most of the population, LP-WGS emerges as a cost-effective alternative for investigating copy number changes in cytogenetics., (© 2024 Wiley Periodicals LLC.)

Objective: The development of specific growth charts for Turner Syndrome (TS) promotes adequate assessment of growth and weight gain, and earlier diagnosis of comorbidities, and may help to analyze the effectiveness of treatments to promote growth and puberty. The aim of this study was to construct a growth chart with the largest possible series of patients with a cytogenetic diagnosis of TS from a Brazilian reference center., Methods: This is a longitudinal study, with 259 cases of TS born between 1957 and 2014 and followed between 1975 and 2019, without the use of GH or oxandrolone. 3,160 height measurements and 2,918 wt measurements were used, with subsequent calculation of the Body Mass Index (BMI). For data analysis, the "GAMLSS" package of the "R" software was used., Results: The mean target height was 157.8 cm (standard deviation 5.2; median 160.4 cm). The mean height of patients with TS at 20 years of age was 145.6 cm (standard deviation 5.9; median 146.7 cm). Height, weight, and BMI by age graphs were developed for TS girls between 2 and 20 years., Conclusion: These growth charts may be used to monitor the growth of girls with TS and to verify the effect of adjuvant treatments on promoting growth., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2024 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

This study describes genomic findings among individuals with both orofacial clefts (OC) and microphthalmia/anophthalmia/coloboma (MAC) recorded in the Brazilian Database on Craniofacial Anomalies (BDCA). Chromosomal microarray analysis (CMA) and Whole Exome Sequencing (WES) were performed in 17 individuals with OC-MAC. Clinical interpretation of molecular findings was based on data available at the BDCA and on re-examination. No copy number variants (CNVs) classified as likely pathogenic or pathogenic were detected by CMA. WES allowed a conclusive diagnosis in six individuals (35.29%), two of them with variants in the CHD7 gene, and the others with variants in the TFAP2A, POMT1, PTPN11, and TP63 genes with the following syndromes: CHARGE, CHD7-spectrum, Branchiooculofacial, POMT1-spectrum, LEOPARD, and ADULT. Variants of uncertain significance (VUS) possibly associated to the phenotypes were found in six other individuals. Among the individuals with VUSes, three individuals presented variants in genes associated to defects of cilia structure and/or function, including DYNC2H1, KIAA0586, WDR34, INTU, RPGRIP1L, KIF7, and LMNA. These results show that WES was the most effective molecular approach for OC-MAC in this cohort. This study also reinforces the genetic heterogeneity of OC-MAC, and the importance of genes related to ciliopathies in this phenotype., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

Pathogenic SOX11 variants have been associated with intellectual developmental disorder with microcephaly, and with or without ocular malformations or hypogonadotropic hypogonadism (HH) (IDDMOH, OMIM # 615866). In this article, we report seven new patients with de novo SOX11 variants. Five of the variants are missense, one nonsense, and one whole-gene deletion, most of them are novel variants. The main clinical features included neurodevelopmental delay (7/7) and intellectual disability (5/7), autism/attention deficit hyperactivity disorder (5/7), microcephaly (4/7), short stature (4/7), hypotonia (4/7), and clinodactyly of the 5th fingers (5/7). HH was confirmed in two female patients with primary amenorrhea, nonvisualized/prepubertal size of the uterus, and nonvisualized ovaries. Two of the male patients presented with micropenis, two had cryptorchidism, and one had decreased testicular size, which are suggestive findings of HH. This article contributes to the clinical characterization of patients with SOX11 variants and supports the role of this gene in HH., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

This study reports three patients with Cat-eye Syndrome (CES), two of which present a previous clinical diagnosis of Craniofacial microsomia (CFM). Chromosomal microarray analysis (CMA) revealed a tetrasomy of 1,7 Mb at the 22q11.2q11.21 region, which is the typical region triplicated in the CES, in all patients. The most frequent craniofacial features found in individuals with CFM and CES are preauricular tags and/or pits and mandibular hypoplasia. We reinforce that the candidate genes for CFM features, particularly ear malformation, preauricular tags/pits, and facial asymmetry, can be in the proximal region of the 22q11.2 region., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The chromosome 1p32p31 deletion syndrome is a contiguous gene disorder with a variable phenotype characterized by brain malformations with or without urinary tract defects, besides neurodevelopmental delay and dysmorphisms. An expanded phenotype was proposed based on additional findings, including one previous report of a patient presenting with moyamoya disease., Case Presentation: The authors report a patient presenting with early neurodevelopmental delay, hydrocephalus, renal malformation, and dysmorphisms. After presenting with a sudden choreic movement disorder, the neuroimaging investigation revealed an ischemic stroke, moyamoya disease, and bilateral incomplete hippocampal inversion. Chromosomal microarray analysis revealed a deletion of 13.2 Mb at 1p31.3p32.2, compatible with the contiguous gene syndrome caused by microdeletions of this region., Discussion/conclusion: This is the second report of a patient who developed Moyamoya disease and the first to describe bilateral incomplete hippocampal inversion in this microdeletion syndrome., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 S. Karger AG, Basel.)

22q11.2 deletion syndrome (22q11.2DS) shows significant clinical heterogeneity. This study aimed to explore the association between clinical heterogeneity in 22q11.2DS and the parental origin of the deletion. The parental origin of the deletion was determined for 61 individuals with 22q11.2DS by genotyping DNA microsatellite markers and single-nucleotide polymorphisms (SNPs). Among the 61 individuals, 29 (47.5%) had a maternal origin of the deletion, and 32 (52.5%) a paternal origin. Comparison of the frequency of the main clinical features between individuals with deletions of maternal or paternal origin showed no statistically significant difference. However, Truncus arteriosus , pulmonary atresia, seizures, and scoliosis were only found in patients with deletions of maternal origin. Also, a slight difference in the frequency of other clinical features between groups of maternal or paternal origin was noted, including congenital heart disease, endocrinological alterations, and genitourinary abnormalities, all of them more common in patients with deletions of maternal origin. Although parental origin of the deletion does not seem to contribute to the phenotypic variability of most clinical signs observed in 22q11.2DS, these findings suggest that patients with deletions of maternal origin could have a more severe phenotype. Further studies with larger samples focusing on these specific features could corroborate these findings.

The condition known as 22q11.2 deletion syndrome (MIM #188400) is a rare disease with a highly variable clinical presentation including more than 180 features; specific guidelines for screening individuals have been used to support clinical suspicion before confirmatory tests by Brazil's Craniofacial Project. Of the 2568 patients listed in the Brazilian Database on Craniofacial Anomalies, 43 individuals negative for the 22q11.2 deletion syndrome were further investigated through whole-exome sequencing. Three patients (6.7%) presented with heterozygous pathogenic variants in the KMT2A gene, including a novel variant (c.6158+1del) and two that had been previously reported (c.173dup and c.3241C>T); reverse phenotyping concluded that all three patients presented features of Wiedemann-Steiner syndrome, such as neurodevelopmental disorders and dysmorphic facial features ( n = 3), hyperactivity and anxiety ( n = 2), thick eyebrows and lower-limb hypertrichosis ( n = 2), congenital heart disease ( n = 1), short stature ( n = 1), and velopharyngeal insufficiency ( n = 2). Overlapping features between 22q11.2 deletion syndrome and Wiedemann-Steiner syndrome comprised neuropsychiatric disorders and dysmorphic characteristics involving the eyes and nose region; velopharyngeal insufficiency was seen in two patients and is an unreported finding in WDSTS. Therefore, we suggest that both conditions should be included in each other's differential diagnoses.

Introduction: The dual diagnosis of Down syndrome and Turner syndrome in the same patient was clinically identified in the early 1950s before the development of karyotyping techniques. After that, several authors reported anecdotal patients and/or reviewed series of Down-Turner double aneuploidies due to a regular 46,X,+21 constitution or different combinations of abnormal cell lines. In such cases, the most typical presentation encompasses the female sex, Down syndrome phenotype, and chromosomal mosaicism., Case Presentation: Here we report a female patient presenting with short stature, dysmorphic features, developmental delay, and learning disabilities, whose karyotype revealed a previously undescribed 45,X[47]/48,XXX,+21[3] constitution., Conclusion: This is the first case encompassing these three aneuploidies together and, contrary to most previous reports, exhibiting a predominantly Turner syndrome phenotype associated with developmental delay., (© 2024 S. Karger AG, Basel.)

Biallelic loss-of-function variants in the TBC1D2B gene were recently reported as a cause of a neurodevelopmental disorder with seizures and gingival overgrowth. Here, we report two male siblings with the similar clinical characteristics. They started with gingival overgrowth and bilateral growth of soft tissues in the malar region at 3 years of age, which evolved with significant maxillary hypertrophy and compression of the brainstem due to fibrous dysplasia of facial bones. After disease evolution, they presented with mental deterioration, limb tremors, and gait ataxia. One of them also presented with seizures. Whole exome sequencing revealed a novel biallelic frameshift variant [c.595del; p.(Val199Trpfs*22)] in the TBC1D2B gene in both patients, which was confirmed and found in heterozygous state in each of their parents. There are strong similarities in clinical characteristics, age of onset, and evolution between the patients described here and cases reported in the literature, including cherubism-like phenotype with progressive gingival overgrowth and seizures. This is the fourth family in the world in which a biallelic loss-of-function variant in the TBC1D2B gene is associated with this phenotype. These results support that loss of TBC1D2B is the cause of this rare condition., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Knowledge of clinical and laboratory differences between chromosomal and undefined causes aids etiological research on non-obstructive azoospermia., Objective: Compare clinical and laboratory differences between men with non-obstructive azoospermia due to chromosomal anomalies versus undefined causes., Design and Setting: A cross-sectional retrospective study conducted at a public university hospital in Campinas (Brazil)., Methods: All men aged 20-40 years with non-obstructive azoospermia were included in the analysis., Results: The 107 cases included 14 with Klinefelter syndrome (KS) (13%), 1 with mosaic KS, 4 with sex development disorders (2 testicular XX, 1 NR5A1 gene mutation, and 1 mild androgen insensitivity syndrome) (4%), 9 with other non-obstructive azoospermia etiologies (8%), and 79 with undefined causes. The 22 chromosomal anomaly cases (14 KS, 1 mosaic KS, 2 testicular XX, 4 sex chromosome anomalies, and 1 autosomal anomaly) were compared with the 79 undefined cause cases. The KS group had lower average testicular volume, shorter penile length, and lower total testosterone levels but greater height, arm span, serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, and gynecomastia frequency (absent in the undefined group and affecting more than half of the KS group). Patients with testicular XX DSD had LH, FSH, and penile length data intermediate between the KS and undefined cause groups, testicular volume similar to the KS group, and other data similar to the undefined group., Conclusion: Clinical and laboratory data differentiate men with non-obstructive azoospermia and chromosomal anomalies, particularly KS and testicular XX, from those with undefined causes or other chromosomal anomalies.

Runs of homozygosity (ROH) in the human genome may be clinically relevant. The aim of this study was to report the frequency of increased ROH of the autosomal genome in individuals with neurodevelopmental delay/intellectual disability and/or multiple congenital anomalies, and to compare these data with a control group. Data consisted of calls of homozygosity from 265 patients and 289 controls. In total, 7.2% (19/265) of the patients showed multiple ROH exceeding 1% of autosomal genome, compared to 1.4% (4/289) in the control group (p=0.0006). Homozygosity ranged from 1.38% to 22.12% among patients, and from 1.53 to 2.40% in the control group. In turn, 1.9% (5/265) of patients presented ROH ≥10Mb in a single chromosome, compared to 0.3% (1/289) of individuals from the control group (p=0.0801). By excluding cases with reported consanguineous parents (15/24), the frequency of increased ROH was 3.4% (9/250) among patients and 1.7% (5/289) in the control group, considering multiple ROH exceeding 1% of the autosome genome and ROH ≥10Mb in a single chromosome together, although not statistically significant (p=0.1873). These results reinforce the importance of investigating ROH, which with complementary diagnostic tests can improve the diagnostic yield for patients with such conditions.

This study aims to discuss diagnostic criteria and severity assessment for craniofacial microsomia (CFM). A series of 61 patients with diverse CFM phenotypes had their clinical data collected by experienced dysmorphologists using a single protocol. Genetic abnormalities were searched through karyotype and chromosomal microarray analysis. Sex ratio, prenatal risk factors, and recurrence rate corroborated the literature. Despite the wide variability of clinical findings, ear disruption was universal. Eight patients were assigned as syndromic, four of whom had demonstrable genetic alterations. The majority of patients (67.2%) fulfilled four known diagnostic criteria, while 9.8% fulfilled one of them. Data strengthened disruptions of the ear and deafness as a semiotically valuable sign in CFM. Facial impairment should consider asymmetry as a mild expression of microsomia. Spinal and cardiac anomalies, microcephaly, and developmental delay were prevalent among extra craniofacial features and should be screened before planning treatment and follow up. The severity index was able to recognize the less and the most affected patients. However, it was not useful to support therapeutic decisions and prognosis in the clinical scenario due to syndromic and non-syndromic phenotypes overlapping. These issues make contemporary the debate on diagnostic methods and disease severity assessment for CFM. They also impact care and etiopathogenetic studies., (© 2021 Japanese Teratology Society.)

Objective: This article presents a clinical and cytogenomic approach that focuses on the diagnosis of syndromic oral clefts (OCs)., Methods: The inclusion criteria were individuals with OC presenting four or more minor signs and no major defects (non-syndromic oral clefts [NSOCs]) as well as individuals with OC presenting at least another major defect, regardless of the number of minor signs (syndromic oral clefts [SOCs]). The exclusion criteria included NSOC with less than four minor signs, SOC with known etiology, as well as atypical oral clefts., Results: Of 1647 individuals with OC recorded in the Brazilian Database of Craniofacial Anomalies, 100 individuals were selected for chromosome microarray analysis (CMA). Among these, 44 individuals were clinically classified as NSOC and 56 as SOC. CMA was performed for both groups, and abnormal CMA was identified in 9%, all previously classified as SCO. The clinical and CMA data analyses showed a significant predominance of abnormal CMA in individuals classified as SOC (p = 0.0044); prematurity, weight, length, and head circumference at birth were significantly lower in the group with abnormal CMA. Besides, minor signs were significantly higher in this group (p = 0.0090)., Conclusion: The rigorous selection of cases indicates that the significant variables could help in early recognition of SOC. This study reinforces the importance of applying the CMA technique to establish the diagnosis of SOC. This is an important and universal issue in clinical practice for intervention, care, and genetic counseling., (Copyright © 2020 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

The aim of this study was to perform 22q11.2 deletion screening and chromosomal microarray analysis (CMA) in individuals clinically diagnosed with craniofacial microsomia (CFM) and review previously published cases of CFM with genomic imbalances. It included 54 individuals who were evaluated by a clinical geneticist. Copy number variants (CNVs) in the 22q11.2 region were investigated by multiplex ligation-dependent probe amplification (MLPA) for all individuals. The CMA was performed only for individuals with additional major features. MLPA revealed pathogenic CNVs at the 22q11 region in 3/54 (5.6%) individuals. CMA revealed pathogenic CNVs in 4/17 (23.5%) individuals, including the three CNVs at the 22q11 region also detected by MLPA, and CNVs classified as variants of unknown significance (VOUS) in 4/17 (23.5%) individuals. Pathogenic alterations were found at the 2p12, 5p15, 13q13, and 22q11 regions. VOUS were found at 3q29, 5q22.2, 5q22.1, and 9p22 regions. All individuals with pathogenic alterations presented additional major features, including congenital heart disease (CHD). The literature review revealed pathogenic CNVs in 17/193 (8.8%) individuals and most of them also presented additional major features, such as CHD, renal anomalies, or developmental delay. In conclusion, CNVs should be investigated in patients with CFM and additional major features., (© 2020 Wiley Periodicals LLC.)

This article reports the present situation of Brazilian health care in genetics for Orofacial Cleft (OFC) and 22q11.2 Deletions Syndrome (22q11.2 DS) based on research conducted by Brazil's Craniofacial Project (BCFP). Established in 2003, BCFP is a voluntary and cooperative network aiming to investigate the health care of people with these diseases and other craniofacial anomalies. The initiatives and research results are presented in four sections: (a) a comprehensive report of the Brazilian public health system in craniofacial genetics; (b) multicentric studies developed on OFC and 22q11.2 DS; (c) education strategies focused on addressing these conditions for both population and health-care professionals; and (d) the nosology through the Brazilian Database on Craniofacial Anomalies (BDCA). Since 2006, BDCA uses a standardized method with detailed clinical data collection, which allows for conducting studies on nosology, genotype-phenotype correlations, and natural history; data can also contribute to public policies. Currently, the BDCA stores data on 1,724 individuals, including 1,351 (78.36%) who were primarily admitted due to OFC and 373 (21.63%) with clinical suspicion of 22q11.2 DS. Chromosomal abnormalities/genomic imbalances were represented by 92/213 (43.19%) individuals with syndromic OFC, including 43 with 22q11.2 DS, which indicates the need for chromosomal microarray analysis in this group. The nosologic diversity reinforces that monitoring clinical is the best strategy for etiological investigation. BCFP's methodology has introduced the possibility of increasing scientific knowledge and genetic diagnosis of OFC and 22q11.2 DS to in turn improve health care and policies for this group of diseases., (© 2020 Wiley Periodicals LLC.)

Background: The chromosomal microarray analysis (CMA) is recommended as a first-tier test for individuals with developmental delay (DD)/intellectual disability (ID) and/or multiple congenital anomalies. However, owing to high costs, this technique is not widely performed for diagnostic purposes in several countries. The aim of this study was to identify clinical features that could favour the hypothesis of genomic imbalances (GIs) in individuals with DD/ID., Methods: The sample consisted of 63 individuals, and all of them underwent a detailed evaluation by a clinical geneticist and were investigated by the CMA. They were divided into two groups. Group A composed of 20 individuals with pathogenic copy number variants (CNVs); and group B composed of 43 individuals with normal CMA results or variants of uncertain clinical significance (VUS)., Results: Pathogenic GIs were found in 20 cases (32%), including 11 individuals with an abnormal karyotype, VUS was found in five individuals (8%) and the results were normal in 38 individuals (60%). Major anomalies were found in 15/20 (75%) individuals in group A against 35/43 (81%) in group B. Dysmorphisms (≥5) were found in 17/20 (85%) in group A and 41/43 (95%) in group B. The most frequent major anomalies detected in group A were congenital heart disease, epilepsy and renal malformation; and in group B, they were malformations of central nervous system, congenital heart disease, microcephaly, epilepsy and hearing impairment. There was no significant statistical difference among the frequencies in groups A and B., Conclusions: Evidences point that every individual with DD/ID, with no specific clinical suspicion, should have screening for GIs as a first-tier test, regardless of the presence or absence of additional major anomalies or dysmorphisms. Future studies with a similar design would be helpful, especially in countries where the access to new technologies is still limited., (© 2019 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.)

Submicroscopic deletions in chromosome 19 have been rarely reported. We reported a male patient presenting with neurodevelopmental delay and facial dysmorphisms with a de novo 19p13.11p13.12 deletion of approximately 1.4 Mb. To date, there are seven cases with deletions overlapping the 19p13.11-p13.12 region described in the literature. A region of 800 kb for branchial arch defects in the proximal region of 19p13.12, and another minimal critical region of 305 kb for hypertrichosis, synophrys, and protruding front teeth have been proposed previously. We suggest that the shortest region of overlap could be refined to an approximately 53 kb region shared within all patients, encompassing part of BRD4 and AKAP8L genes and the AKAP8 gene. Based on the genotype-phenotype correlation of the present case and cases with overlapping deletions described in the literature, it was possible to recognize a consistent phenotype characterized by microcephaly, ear abnormalities, rounded face, synophrys, arched or upwardly angulated eyebrows, short nose, anteverted nares, prominent cheeks, teeth abnormalities, and developmental delay., (© 2018 Wiley Periodicals, Inc.)

Craniofacial Microsomia (CFM) also known as Oculo-auriculo-vertebral Spectrum (OAVS) or Goldenhar Syndrome, presents wide phenotypic and etiological heterogeneity. It affects mainly the structures originated from the first and second pharyngeal arches. In addition, other major anomalies may also be found, including congenital heart diseases. In this study, we report a patient with distal deletion in the 22q11.2 region and a phenotype which resembles CFM. The proband is a girl, who presented bilateral preauricular tags, left auditory canal stenosis, malar hypoplasia, cleft lip and palate, mild asymmetry of soft tissue in face, congenital heart disease, intestinal atresia, annular pancreas and hydronephrosis. The genomic imbalances investigation by Multiplex Ligation-dependent Probe Amplification (MLPA) and Chromosomal Microarray Analysis (CMA) revealed a distal deletion of 1,048 kb at 22q11.2 encompassing the region from Low Copy Repeats (LCRs) D to E. We did review of the literature and genotype-phenotype correlation. This is the sixth case of distal 22q11.2 deletion resembling CFM and the second encompassing the region between LCRs D to E. All cases share some phenotypic signs, such as preauricular tags, facial asymmetry, cleft lip and palate, and congenital heart diseases. Candidate genes in this region have been studied by having an important role in pharyngeal arches developmental and in congenital heart diseases, such as HIC2, YPEL1and MAPK1/ERK2. This case corroborates the phenotypic similarity between 22q11.2 distal deletion and CFM/OAVS. It also contributes to genotype-phenotype correlation and reinforces that candidate genes for CFM, in the 22q11.2 region, might be located between LCRs D and E., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

We report a boy carrying a recombinant chromosome 18, with terminal deletion of 10.8 Mb from 18p11.32 to 18p11.21 and a terminal duplication of 22.8 Mb from 18q21.31 to 18q23, resulting from a maternal pericentric inversion of the chromosome 18. He presented with poor growth, developmental delay, facial dysmorphisms, surgically repaired left cleft lip and palate, a mild form of holoprosencephaly characterized by single central incisor and agenesis of the septum pellucidum, and body asymmetry. Based on the systematic review of the literature, we discuss genotype-phenotype correlation and the risk for the recombinants of pericentric inversions of chromosome 18. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Pigmentary mosaicism of Ito (PMI) is a skin abnormality often characterized by hypopigmentation of skin, following, in most cases, the Blaschko lines, usually associated with extracutaneous abnormalities, especially abnormalities of the central nervous system (CNS). It is suggested that this pattern arises from the presence and migration of two cell lineages in the ectoderm layer during the embryonic period and embryonic cell migration, with different gene expression profiles associated with pigmentation. Several types of chromosomal aberrations, with or without mosaicism, have been associated with this disorder. This study comprised clinical description and cytogenetic analysis of a child with PMI. The G-banded karyotype analysis revealed a supernumerary marker chromosome in 76% of the analyzed metaphases from peripheral blood lymphocytes. Array genomic hybridization analysis showed a copy number gain between 3q26.32-3q29, of approximately 20.5 Mb. Karyotype was defined as 47,XX,+mar[38]/46,XX[12].arr 3q26.32-3q29(177,682,859- 198,043,720)x4 dn. Genes mapped in the overlapping region among this patient and three other cases described prior to this study were listed and their possible involvement on PMI pathogenesis is discussed.

Objectives: The aim of this study was to describe clinical features in subjects with palatal abnormalities and to assess the distribution of these features among those with and without 22q11.2 deletion., Design: Descriptive cohort., Patients: One hundred patients with palatal abnormalities and suspicion of 22q11.2 DS were included., Methods: All patients were evaluated by a clinical geneticist, who completed a standardized clinical protocol. The 22q11.2 deletion screening was performed with fluorescence in situ hybridization using the TUPLE1 probe and multiplex ligation-dependent probe amplification using the P250-A1 kit., Results: The 22q11.2 deletion was detected in 35 patients, in whom the most frequent clinical features were congenital heart disease (15/30 - 50%), developmental delay (19/35 - 54%), speech delay (20/35 - 57%), learning disabilities (27/35 - 77%), immunologic alterations (18/29 - 62%). In addition, the most common facial dysmorphisms in this group were long face (27/35 - 77%), typical nose (24/35 - 69%), and hooded eyelids (19/35 - 54%). Comparing features in patients with or without the deletion revealed significant differences (positively correlated with the deletion) for speech delay, learning disabilities, conductive hearing loss, number of dysmorphisms, long face, and hooded eyelids. Cleft lip and palate was negatively correlated with the deletion., Conclusions: The presence of speech delay, learning disabilities, conductive hearing loss, long face, and hooded eyelids should reinforce the suspicion of 22q11.2 DS in patients with palatal abnormalities and would help professionals direct clinical follow-up of these patients.

Velocardiofacial syndrome is one of the recognized forms of chromosome 22q11.2 deletion syndrome (22q11.2 DS) and has an incidence of 1 of 4,000 to 1 of 6,000 births. Nevertheless, the 22q11 deletion is not found in several patients with a 22q11.2 DS phenotype. In this situation, other chromosomal aberrations and/or mutations in the T-box 1 transcription factor C (TBX1) gene have been detected in some patients. A similar phenotype to that of the 22q11.2 DS has been reported in animal models with mutations in fibroblast growth factor 8 (Fgf8) gene. To date, FGF8 mutations have not been investigated in humans. We tested a strategy to perform laboratory testing to reduce costs in the investigation of patients presenting with the 22q11.2 DS phenotype. A total of 109 individuals with clinical suspicion were investigated using GTG-banding karyotype, fluorescence in situ hybridization, and/or multiplex ligation-dependent probe amplification. A conclusive diagnosis was achieved in 33 of 109 (30.2%) cases. In addition, mutations in the coding regions of TBX1 and FGF8 genes were investigated in selected cases where 22q11.2 deletion had been excluded, and no pathogenic mutations were detected in both genes. This study presents a strategy for molecular genetic characterization of patients presenting with the 22q11.2 DS using different laboratory techniques. This strategy could be useful in different countries, according to local resources. Also, to our knowledge, this is the first investigation of FGF8 gene in humans with this clinical suspicion.

Based on the importance of behavior and life satisfaction for the health of young people and the considerable regional differences that exist in mainland Portugal, an investigation was conducted. It sought to verify differences in levels of the practice of sport, tobacco and alcohol consumption and life satisfaction among students of the 3rd cycle of basic education living in different inland/coastal and rural/urban areas. The sample consisted of 5624 adolescents, aged between 12 and 17 years. The instrument used for data collection was the "Inventory of Health-Related Behavior of Adolescents" and a translated version of "The Satisfaction With Life Scale". The results revealed that there are higher levels of smoking among young people living in urban and inland areas, higher levels of alcohol consumption among young people living in rural and inland areas and higher levels of life satisfaction among adolescents living in urban and coastal areas. Levels of sport were identical in all geographical areas. It was also found that there were significant differences in all variables of the analysis.

The 22q11 chromosomal region contains low copy repeats (LCRs) sequences that mediate non-allelic homologous recombination, which predisposes to copy number variations (CNVs) at this locus. Hemizygous deletions of the proximal 22q11.2 region result in the 22q11.2 deletion syndrome (22q11.2 DS). In addition, 22q11.2 duplications involving the distal LCR22s have been reported. This article describes a patient presenting a 2.5-Mb de novo deletion at proximal 22q11.21 region (between LCRs A-D), combined with a 1.3-Mb maternally inherited duplication at distal 22q11.23 region (between LCRs F-H). The presence of concomitant chromosomal imbalances found in this patient has not been reported previously. Clinical and molecular data were compared with literature, in order to contribute to genotype-phenotype correlation. These findings exemplify the complexity and genetic heterogeneity observed in 22q11.2 deletion syndrome and highlights the difficulty to make genetic counseling and predict phenotypic consequences in these situations., (© 2014 Wiley Periodicals, Inc.)

We report here on six patients with a ring chromosome 22 and the range of cytogenetic and phenotypic features presented by them. Genomic analysis was carried out using classical and molecular cytogenetics, MLPA (Multiplex Ligation-dependent Probe Amplification) and genome-wide SNP-array analysis. The ring was found in all patients, but Patient 6 displayed constitutional mosaicism with a normal cell line. Five patients had deletions in the ring chromosome 22, and in four of them the breakpoints--unique for each patient--could be identified by genome-wide SNP-array analysis. One patient presented with a 22q11.2 deletion concomitant with the deletion caused by the ring formation. Common phenotypic features included autism, speech delay and seizures, as previously reported for individuals with r(22) and/or 22q13.3 deletions. Investigation of the genes within the deletions revealed multiple genes related to development of the central nervous system, psychomotor delay, severe language impairment, hypotonia, and autistic symptoms. There was no clear correlation between the severity of clinical features and the size of the deleted segment. This study underscores the variability in ring structure and clinical presentation of the r(22) and adds information to the limited literature on this rare disorder., (© 2014 Wiley Periodicals, Inc.)

Translocations involving MLL gene are common among children with acute leukemias. Most importantly, the presence of a given MLL fusion partner dictates the outcome of patients. Patients with complex MLL rearrangements, e.g. three-way translocations could be related to a poor clinical outcome. For this purpose, we characterize 5 childhood patients with three-way translocations involving MLL gene. By LDI-PCR we identified 15 out of 17 fusion alleles and determined the localization of these breakpoints. In all cases at least one functional MLL fusion allele was present. In addition, patients displayed a remaining 3'-MLL allele that allow in principle the expression of the MLL* protein variant., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

The 22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion syndrome in humans, with a highly variable phenotype. This chromosomal region contains low copy repeat (LCR) sequences that mediate non-allelic homologous recombination which predispose to copy number abnormalities at this locus. This article describes three patients investigated for suspicion of 22q11.2DS presenting atypical copy number abnormalities overlapping or not with the common ∼3 Mb deletion. They were investigated by G-banding karyotype, Multiplex-ligation dependent probe amplification (MLPA) and array Genomic Hibridization (aGH). Clinical and molecular data were compared with literature, in order to contribute to genotype-phenotype correlation. Atypical chromosomal abnormalities were detected: 3.6 Mb deletion at 22q11.21-q11.23 between LCRs B-F in patient 1 and approximately 1.5 Mb deletion at 22q11.21-q11.22 between LCRs D-E in patients 2 and 3. The breakpoints detected in patient 1 have not been previously described. These findings exemplify the complexity and genetic heterogeneity observed in 22q11.2 region and corroborates the idea that genetic modifiers contribute to the phenotypic variability observed in proximal and distal 22q11.2 deletion syndromes., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

The 22q11.2 deletion is the most frequent interstitial deletion in humans and presents a wide phenotypic spectrum, with over 180 clinical manifestations described. Distinct studies have detected frequencies of the deletion ranging from 0 % to 75 %, depending on the studied population and selection criteria adopted. Due to the lack of consensus in this matter, several studies have been conducted aiming to define which patients would be eligible for screening; however, the issue is still up for debate. In order to contribute to the delineation of possible clinical and dysmorphologic guidelines to optimize decision making in the clinical setting, 194 individuals with variable features of the 22q11.2 deletion syndromes (22q11.2DS) were evaluated. Group I, clinical suspicion of 22q11.2DS with palatal anomalies; Group II, clinical suspicion without palatal anomalies; Group III, cardiac malformations associated with the 22q11.2DS; and Group IV, juvenile-onset schizophrenia. Multiplex ligation-dependent probe amplification was used for screening the 22q11.2 deletion, which was detected in 45 patients (23.2 %), distributed as such: Group I, 35/101 (34.7 %); Group II, 4/18 (22.2 %); Group III, 6/52 (11.5 %); and Group IV, 0/23 (0 %). Clinical data were analyzed by frequency distribution and statistically. Based on the present results and on the review of the literature, we propose a set of guidelines for screening patients with distinct manifestations of the 22q11.2DS in order to maximize resources. In addition, we report the dysmorphic features which we found to be statistically correlated with the presence of the 22q11.2DS.

We describe a female patient of 1 year and 5 months-old, referred for genetic evaluation due to neuropsychomotor delay, hearing impairment and dysmorphic features. The patient presents a partial chromosome 21 monosomy (q11.2→q21.3) in combination with a chromosome 3p terminal monosomy (p25.3→pter) due to an unbalanced de novo translocation. The translocation was confirmed by fluorescence in situ hybridization (FISH) and the breakpoints were mapped with high resolution array. After the combined analyses with these techniques the final karyotype was defined as 45,XX,der(3)t(3;21)(p25.3;q21.3)dn,-21.ish der(3)t(3;21)(RP11-329A2-,RP11-439F4-,RP11-95E11-,CTB-63H24+).arr 3p26.3p25.3(35,333-10,888,738))×1,21q11.2q21.3(13,354,643-27,357,765)×1. Analysis of microsatellite DNA markers pointed to a paternal origin for the chromosome rearrangement. This is the first case described with a partial proximal monosomy 21 combined with a 3p terminal monosomy due to a de novo unbalanced translocation., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Considering the prevalence of 22q11.2 deletion syndrome (22q11.2 DS) of around 1:4,000 and of palatal abnormalities in 70 % of the cases of 22q11.2 DS and taking into account the Brazilian health system and its current situation of medical genetic services, this study aims to contribute to establish strategies for genetic diagnosis. The access to genetic testing at 11 services was investigated and samples from 100 patients with palatal abnormalities and suspicion of 22q11.2 DS were sent to a reference center. Laboratorial techniques included karyotyping, fluorescence in situ hybridization (FISH), and multiplex ligation-dependent probe amplification. Costs were also calculated. Disparities among centers for genetic diagnosis were evident, with remarkable regional differences. Some of the obstacles encountered were difficulties for families to show up for medical appointments, complementary evaluations, and for the clinics to send the samples to the reference center. A conclusive diagnosis was reached for 38 % of patients. Combination of karyotyping and FISH had better laboratorial cost-effectiveness. These results might represent the reality for the investigation of other genetic conditions. Clinical and laboratorial approaches herein presented could be adapted for use under different genetic conditions in the Brazilian health system, which has relatively limited financial and human resources. Suggestions for the rational implementation of genetic testing in developing countries are presented.

We report on a boy presenting submucous cleft palate, hydronephrosis, ventriculoseptal defect, aniridia, and developmental delay. Additional material on 11p13 was cytogenetically visible and array analyses identified a duplicated segment on 15q25-26 chromosome region; further, array analyses revealed a small deletion (49 kb) at 11p13 region involving the ELP4 gene and a duplication at 8p23.1. Results were confirmed with both molecular and molecular cytogenetics techniques. Possibilities for etiological basis of clinical phenotype are discussed., (Copyright © 2012 Wiley Periodicals, Inc.)

Submicroscopic chromosomal anomalies play an important role in the etiology of craniofacial malformations, including midline facial defects with hypertelorism (MFDH). MFDH is a common feature combination in several conditions, of which Frontonasal Dysplasia is the most frequently encountered manifestation; in most cases the etiology remains unknown. We identified a parent to child transmission of a 6.2 Mb interstitial deletion of chromosome region 2q36.1q36.3 by array-CGH and confirmed by FISH and microsatellite analysis. The patient and her mother both presented an MFDH phenotype although the phenotype in the mother was much milder than her daughter. Inspection of haplotype segregation within the family of 2q36.1 region suggests that the deletion arose on a chromosome derived from the maternal grandfather. Evidences based on FISH, microsatellite and array-CGH analysis point to a high frequency mosaicism for presence of a deleted region 2q36 occurring in blood of the mother. The frequency of mosaicism in other tissues could not be determined. We here suggest that the milder phenotype observed in the proband's mother can be explained by the mosaic state of the deletion. This most likely arose by an early embryonic deletion in the maternal embryo resulting in both gonadal and somatic mosaicism of two cell lines, with and without the deleted chromosome. The occurrence of gonadal mosaicism increases the recurrence risk significantly and is often either underestimated or not even taken into account in genetic counseling where new mutation is suspected., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

We report on a 17-year-old patient with midline defects, ocular hypertelorism, neuropsychomotor development delay, neonatal macrosomy, and dental anomalies. DNA copy number investigations using a Whole Genome TilePath array consisting, of 30K BAC/PAC clones showed a 6.36 Mb deletion in the 9p24.1-p24.3 region and a 14.83 Mb duplication in the 20p12.1-p13 region, which derived from a maternal balanced t(9;20)(p24.1;p12.1) as shown by FISH studies. Monosomy 9p is a well-delineated chromosomal syndrome with characteristic clinical features, while chromosome 20p duplication is a rare genetic condition. Only a handful of cases of monosomy 9/trisomy 20 have been previously described. In this report, we compare the phenotype of our patient with those already reported in the literature, and discuss the role of DMRT, DOCK8, FOXD4, VLDLR, RSPO4, AVP, RASSF2, PROKR2, BMP2, MKKS, and JAG1, all genes mapping to the deleted and duplicated regions., (Copyright © 2011 Wiley Periodicals, Inc.)

Midline facial defects with hypertelorism (MFDH) are mainly characterized by ocular hypertelorism and bifid nose. They are often associated with structural and functional anomalies of the central nervous system similar to those found in 22q11.2 deletion syndromes. In addition, there are some isolated reports of MFDH and 22q11.2 deletion. These findings suggest that MFDH may be part of the spectrum of 22q11.2 deletion syndromes. To test this hypothesis, 10 individuals with MFDH were analyzed by fluorescent in situ hybridization (FISH), but no 22q11.2 deletion was detected. In view of this result, the TBX1 gene located within the 22q11.2 candidate region was screened. A new sequence variant (1132GA) was identified in one patient. This variant was not found in 110 control individuals genotyped. Considering the rarity of this condition and results of this study, the involvement of the 22q11.2 chromosomal region in the pathogenesis of MFDH could not be excluded.

Background: several authors have pointed to the urgent need of researches and actions involving teachers, in the school environment, that have a preventive and vocal health promotion character with the purpose of improving work conditions., Aim: to analyze the vocal complaints, laryngeal symptoms, vocal habits and vocal profile of teachers of a public school before and after their participation in voice workshops., Method: the study was divided in different steps: 1st step - closed interview, larynx and perceptive-auditory assessment in which 42 teachers were evaluated; 2nd step - voice workshops; 3rd step - perceptive-auditory reassessment in which 13 teachers were evaluated., Results: 73% of the subjects presented vocal complaints; 57.14% presented mild to moderate hoarseness, 78.57% presented breathiness and 52.38% vocal tension. Evaluation of the larynx indicated that 75.86% of the subjects presented glottal gaps and 34.48% mucous thickening. After the voice workshops a significant difference was observed in the level of vocal tension, both in the analysis of the /e/ vowel and in the analysis of Spontaneous Speech (p = 0.0277 for p > 0.05 for both). Improvement was observed in vocal care and in the understanding of intervening and determinant factors for vocal alterations, which are present in the teaching environment., Conclusion: health actions, such as voice workshops, are important to trigger changes in the work environment as well as in the health of teachers.

Following their activation, naive CD4+ T cells can differentiate into one of two effector cell subsets, Th1 and Th2. These two subsets have different cytokine secretion patterns and thus mediate separate arms of the immune response. It has been established that the fat-soluble vitamin D(3) metabolite 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and its nuclear receptor, the vitamin D receptor, play an important role in the immune system primarily through the transcriptional inhibition of cytokine genes that either are required for Th1 differentiation or are products of differentiated Th1 cells. Therefore, we wanted to test directly the ability of 1,25(OH)(2)D(3) to alter the Th differentiation process. Our results indicate that 1,25(OH)(2)D(3) inhibits not only the Th1 cytokine IFN-gamma but also the Th2 cytokine IL-4 in naive CD62 ligand+CD4+ T cells during their in vitro polarization. This effect is most dramatic when the ligand is present from the onset of the differentiation process. If the ligand is added after the polarization has ensued, the inhibition is significantly diminished. In activated (CD62 ligand-CD4+) T cells, 1,25(OH)(2)D(3) is still able to inhibit IFN-gamma but has no effect on IL-4 production. Our results also indicate that inhibition of these two cytokines in naive cells by vitamin D receptor and its ligand is neither a result of a cell cycle block nor an inhibition of Th1 or Th2 transcription factor expression but, rather, at least in the case of Th2 differentiation, an attenuation of IL-4 transcription by the receptor.