Hearing loss and history of otolaryngological conditions in adults with microdeletion 22q11.2.

Previous studies have shown that the 22q11.2 microdeletion, associated with 22q11.2 deletion syndrome (22q11.2DS), conveys an increased risk of chronic otitis media, and hearing loss at young age. This study reports on hearing loss and history of otolaryngological conditions in adults with 22q11.2DS. We conducted a retrospective study of 60 adults with 22q11.2DS (41.7% male) at median age 25 (range 16-74) years who had visited an otolaryngologist and audiologist for routine assessment at a 22q11.2 expert center. Demographic, genetic, audiometric, and otolaryngological data were systematically extracted from the medical files. Regression analysis was used to evaluate the effect of age, sex, full-scale intelligence quotient, and history of chronic otitis media on the severity of hearing loss. Hearing loss, mostly high-frequency sensorineural, was found in 78.3% of adults. Higher age and history of chronic otitis media were associated with more severe hearing loss. Otolaryngological conditions with possible treatment implications included chronic otitis media (56.7%), globus pharyngeus (18.3%), balance problems (16.7%), and obstructive sleep apnea (8.3%). The results suggest that  in 22q11.2DS, high-frequency hearing loss appears to be common from a young adult age, and often unrecognized. Therefore, we recommend periodic audiometric screening in all adults, including high-frequency ranges.

Tetralogy of Fallot in the fetus - from diagnosis to delivery. 18-year experience of a tertiary Fetal Cardiology Center.

BACKGROUND: Tetralogy of Fallot (TOF) is a common congenital heart disease but very heterogeneous in terms of detailed cardiac anatomy, associated malformations, and genetic anomalies, especially when assessed prenatally. AIMS: We aimed to analyze the clinical spectrum of TOF in the prenatal period, including detailed cardiac morphology, coexisting anomalies, and their impact on short-term neonatal outcome. We also assessed changing trends in the prenatal diagnostic workup of TOF. METHODS: A retrospective cohort study including fetuses diagnosed with TOF between 2002 and 2019 was conducted in a tertiary Fetal Cardiology Center. Medical records and echocardiographic examinations were reviewed to collect demographic, sonographic, and genetic data. RESULTS: Among 326 TOF fetuses, 237 (73%) had pulmonary stenosis (TOF-PS), 72 (22%) pulmonary atresia (TOF-PA), and 17 (5%) absent pulmonary valve (TOF-APV). The yearly number of diagnoses increased during the study period, with decreasing fetal age at the time of diagnosis. Extracardiac malformations were found in 172 (53%) fetuses, cardiovascular malformations in 159 (49%), and genetic anomalies in 99 (39% of the tested group). Hypoplastic thymus, right aortic arch, and polyhydramnios were sonographic markers of microdeletion 22q11. Left-to-right ductal flow was predictive of postnatal ductal dependency. The perinatal outcome was dependent on the presence of associated anomalies and disease subtype, with TOF-APV having the worst prognosis. CONCLUSIONS: Extracardiac and genetic anomalies are common in fetuses with TOF, and, together with disease subtype and ductal flow assessment, they impact the perinatal management and outcomes. Genetic testing with array comparative genomic hybridization should be offered in all cases.

DiGeorge syndrome and anomalous right aortic arch with arch-on-arch and figure-of-eight configurations: Aortic sac maldevelopment and left brachiocephalic artery abnormal remodeling.

We report a 6-month-old female infant with deletion of chromosome 22q11.2 (DiGeorge/VFS TUPLE 1), normal atrial arrangement with concordant atrioventricular connection, pulmonary atresia, large subaortic ventricular septal defect, diminutive native pulmonary arteries, a characteristic weird-shape right aortic arch with arch-on-arch appearance and figure of 8 configuration. We presented the cardiac computed tomographic angiographic and cardiac angiographic features. Using Autodesk 3ds Max 2018 software, we explained and illustrated the speculative embryologic etiology of this bizarre aortic archanomaly with the extensive abnormal remodeling of the left brachiocephalic artery, based on a "five-embryonic aortic arches" concept. As to the best of the authors' knowledge, this is the first report of a genetically confirmed case of DiGeorge syndrome and an exceedingly rare type of right aortic arch anomaly with embryologic explanation according to the "five-embryonic-aortic-arches" concept. It seems that the constellation of pulmonary atresia, bizarreshaped right aortic arch due to abnormal development of the aortic sac, and abnormal remodeling of the left brachiocephalic artery may be strongly suggestive of DiGeorge syndrome.

First Trimester Screening for Common Trisomies and Microdeletion 22q11.2 Syndrome Using Cell-Free DNA: A Prospective Clinical Study.

OBJECTIVES: The aims of the study were to assess the false-positive and uninformative test rate with first trimester cell-free DNA (cfDNA) screening for common trisomies and microdeletion 22q11.2 (22q11.2DS) and to examine women's attitudes toward such an approach. METHODS: This is a prospective study at the Prenatal Medicine Department of the University of Tübingen, Germany, at 11-13 weeks. In all pregnancies, a detailed ultrasound examination was carried out, followed by a cfDNA analysis for common trisomies and 22q11.2DS. In cases where the cfDNA analysis indicated 22q11.2DS, invasive prenatal diagnostic testing and parental testing were performed. After delivery, a detailed neonatal clinical examination was carried out including further genetic testing. Prior to counselling about the study, we asked the pregnant women who were potentially eligible for the study to anonymously report on their knowledge about 22q11.2DS. RESULTS: A total of 1,127 pregnancies were included in the final analysis of the study. The first cfDNA test was uninformative in 15 (1.33%) pregnancies. In 10 (0.89%) cases, the test remained uninformative, even after the second blood sample. There were 3 (0.27%) cases with a positive cfDNA test for 22q11.2DS. In all, 983 women returned the anonymous questionnaire prior to study participation. Only 80 (8.1%) women responded that they felt familiar or very familiar with 22q11.2DS. CONCLUSION: The addition of 22q11.2DS in first trimester cfDNA screening for common trisomies is feasible. The uninformative test rate for common trisomies and 22q11.2DS is 0.9%, and the false-positive rate for 22q11.2DS is 0.3%. Awareness and education around 22q11.2DS should be improved.

Cataract and optic disk drusen in a patient with glycogenosis and di George syndrome: clinical and molecular report.

BACKGROUND: We report the ophthalmic findings of a patient with type Ia glycogen storage disease (GSD Ia), DiGeorge syndrome (DGS), cataract and optic nerve head drusen (ONHD). CASE PRESENTATION: A 26-year-old white woman, born at term by natural delivery presented with a post-natal diagnosis of GSD Ia. Genetic testing by array-comparative genomic hybridization (CGH) for DGS was required because of her low levels of serum calcium. The patient has been followed from birth, attending the day-hospital every six months at the San Paolo Hospital, Milan, outpatient clinic for metabolic diseases and previously at another eye center. During the last day-hospital visit, a complete eye examination showed ONHD and cataract in both eyes. Next Generation Sequencing (NGS) was subsequently done to check for any association between the eye problems and metabolic aspects. CONCLUSIONS: This is the first description of ocular changes in a patient with GSD Ia and DGS. Mutations explaining GSD Ia and DGS were found but no specific causative mutation for cataract and ONHD. The metabolic etiology of her lens changes is known, whereas the pathogenesis of ONHD is not clear. Although the presence of cataract and ONHD could be a coincidence; the case reported could suggest that hypocalcemia due to DGS could be the common biochemical pathway.

[Absent or hypoplastic thymus: A marker for 22q11.2 microdeletion syndrome in case of polyhydramnios]. / La dysgénésie thymique : marqueur de microdélétion 22q11.2 dans le bilan d'un hydramnios.

OBJECTIVES: In prenatal diagnosis of 22q11.2 microdeletion syndrome, without cardiac malformation or multiple associated congenital anomalies, we study the presence of polyhydramnios and its association with thymic dysgenesis. MATERIALS AND METHODS: This was a multicenter retrospective observational study. It was performed in two multidisciplinary centers for prenatal diagnosis in the south of France between January 1, 2010 and June 30, 2013. Inclusion criteria were prenatal diagnosis of 22q11.2 deletion syndrome. We excluded from the study any fetus with cardiac malformation or multiple associated congenital anomalies. RESULTS: During the inclusion period, eleven antenatal diagnoses of 22q11.2 microdeletion syndrome have been made. Six cases were excluded: 5 fetuses with cardiac malformation and one with multiple associated congenital anomalies. Therefore, five cases of isolated polyhydramnios were included. All 5 fetuses had a thymic dysgenesis: 3 had a thymic agenesis and 1 thymic hypoplasia diagnosed by sonography and 1 had a thymic agenesis diagnosed by retrospective reading of fetal MRI. CONCLUSION: When faced with a polyhydramnios, the presence of a thymic dysgenesis should be search for by ultrasound screening and would alert to the possibility of a 22q11.2 microdeletion syndrome. The confirmation of this is diagnosis by amniocentesis would enable improved antenatal support for parents and would enable early implementation of the multidisciplinary neonatal care that is required to avoid serious complications of this syndrome.

Análisis de microdeleciones en 22q11 en pacientes colombianos con cardiopatía congénita no sindrómica / Analysis of microdeletions in 22q11 in Colombian patients with congenital heart disease

Los defectos cardiacos conforman las malformaciones congénitas más frecuentes, con una incidencia que se ha estimado entre 4 y 12 por 1000 en recién nacidos vivos. Estos tienen una etiología multifactorial en la que convergen la predisposición genética y los factores ambientales. A partir de 1990 se ha relacionado este tipo de patologías con microdelección 22q11. Se determinó la frecuencia de la microdeleción 22q11 en pacientes con cardiopatía congénita no sindrómica. Se analizaron 61 pacientes con cardiopatía congénita, a partir de ADN de sangre periférica y posterior amplificación, mediante PCR multiplex del gen TUPLE1 y del STR D10S2198, visualización electroforesis en geles de agarosa y análisis densitométrico para determinar dosis génica. Se encontraron 3 pacientes con microdeleción 22q11, para una frecuencia de 4,9%. Esta microdeleción se asoció en dos de los casos a Tetralogía de Fallot y en el otro a Defecto Septal Atrial (DSA). En conclusión, la frecuencia de microdeleción 22q11 en la población analizada es de 4,9%. Dentro de los casos de Tetralogía de Fallot, la microdeleción estaba presente en el 7,4% y en los DSA corresponde al 11,1%.

Cardiac defects are the most frequent congenital malformations, with an incidence estimated between 4 and 12 per 1000 newborns. Their etiology is multifactorial and might be attributed to genetic predispositions and environmental factors. Since 1990 these types of pathologies have been associated with 22q11 microdeletion. In this study, the frequency of microdeletion 22q11 was determined in 61 patients with non-syndromic congenital heart disease. DNA was extracted from peripheral blood and TUPLE1 and STR D10S2198 genes were amplified by multiplex PCR and visualized in agarose gels. Gene content was quantified by densitometry. Three patients were found with microdeletion 22q11, representing a 4.9% frequency. This microdeletion was associated with two cases of Tetralogy of Fallot and a third case with atrial septal defect (ASD). In conclusion, the frequency for microdeletion 22q11 in the population analyzed was 4.9%. The cases that presented Teratology of Fallot had a frequency for this microdeletion of 7.4% and for ASD of 11.1%.

Valoración del timo fetal a través de la relación timo-tórax / Fetal thymus evaluation by thymus-torax ratio

Introduction: Recent advances in ultrasound technology have made possible an easy and accurate visualization of the fetal thymus in vast majority of cases. On ultrasound, thymus is visualized in the upper mediastinum, between sternum and great vessels. Despite several previous papers published, there is no consensus regarding a clear correlation between these measurements and thymus hypoplasia. Nowadays thymus evaluation is not mandatory in routine ultrasound examinations, however at referral centers its evaluation could help to identify patients with high risk for microdeletion 22 q11. Recently it has been proposed a new method to assess the thymus; the “thymus-torax ratio”, this has been proven to be altered in 95 percent of fetuses with congenital heart disease and microdeletion 22q11. This study describes the experience at our unit using this new tool as part of routine fetal examinations. Materials and methods: A descriptive study, 44 ultrasound examinations between 19 and 38 weeks of gestation, in which thymus-thoracic ratio was measured as part of the routine fetal examination at this perinatal referral center. Objective: Determinate the factibility of measurement of the thymus- thoracic ratio in routine fetal ultrasound examinations. Results: The thymus- thoracic ratio was measured successfully at our routine fetal ultrasound examinations, results were similar to those previously reported. The ratio was not affected by fetal or maternal pathology and gestational age. Discussion: The thymus thorax ratio appears to be constant through gestation despite of maternal and fetal pathologies; it seems to have advantages over other types of measurements described in previous publications. However, due to small number of cases we suggest a new analysis with a larger number of patients.

Avances recientes en ultrasonido han permitido una visualización fácil y certera del timo fetal en la gran mayoría de los fetos examinados. En el examen de ultrasonido, el timo se encuentra en el mediastino superior, entre el esternón y los grandes vasos. A pesar de numerosas publicaciones, actualmente no existe consenso respecto de las técnicas utilizadas para realizar estas mediciones y el diagnostico de hipoplasia de timo. La evaluación del timo fetal no forma parte del examen de ultrasonido de rutina. Sin embargo, en centros de referencia pudiera ser de utilidad para identificar los pacientes con alto riesgo de presentar microdelecion 22q11. Recientemente se ha propuesto una nueva forma de evaluar el timo a través de la relación timo- tórax, la cual ha probado estar alterada en el 95 por ciento de los fetos con cardiopatía congénita y microdelecion 22q11. Este estudio describe nuestra experiencia en la incorporación de esta nueva herramienta en el examen de rutina fetal. Materiales y métodos: Estudio descriptivo, 44 reportes de exámenes ultrasonográficos realizados entre las 19 y 38 semanas de gestación, en los cuales se realizó la medición de la relación timo- tórax como parte del examen fetal de rutina, en este centro de referencia perinatal. Objetivo: Describir la experiencia de la unidad en la medición de la relación timo- tórax en el examen ultrasonografico fetal de rutina. Resultados: La medición de la relación timo- tórax fue incorporada de manera exitosa como parte del protocolo estándar de mediciones realizado en la unidad, con resultados similares a los reportados previamente. La relación no fue afectada por patología fetal o materna ni edad gestacional. Discusión: la relación timo- tórax parece ser constante a través de la gestación a pesar de la presencia de patología materna o fetal, siendo una medida que aparentemente provee ventajas sobre las otras descritas previamente en la literatura. Sin embargo debido al tamaño de la muestra...