[Inequalities in time to diagnosis of Down Syndrome in Bolivia]. / Desigualdades en el tiempo hasta el diagnóstico del síndrome de Down en Bolivia.

Down Syndrome is the most common genetic condition and a leading cause of intellectual disability. Individuals in rural areas, particularly those with disabilities, often face disparities in healthcare access. Analyzing clinical records of patients diagnosed with Down Syndrome between 2013 and 2022 by the Institute of Genetics at the Universidad Mayor de San Andrés in La Paz, Bolivia, this study examined the time to diagnosis for 250 patients with Down Syndrome. The findings revealed that patients from rural areas with Down Syndrome take an average of five months to receive a diagnosis, compared to two months in urban areas (p<0.001). No significant differences were found in the time to diagnosis based on gender. However, a higher proportion of males from rural areas was observed (p=0.03). The results suggest that individuals in rural areas face challenges in receiving a timely diagnosis. On the other hand, women may not be brought to cities for proper diagnosis and treatment due to gender biases in certain communities. The importance of improving access to early diagnosis and treatment in rural areas is emphasized.

El síndrome de Down es la condición genética más común y una causa principal de discapacidad intelectual. Las personas en áreas rurales, especialmente aquellas con discapacidades, a menudo enfrentan desigualdades en el acceso a la salud. A partir de los registros clínicos de pacientes con diagnóstico confirmado de síndrome de Down entre 2013 y 2022, por el Instituto de Genética de la Universidad Mayor de San Andrés, La Paz, Bolivia, se analizó, analizó el tiempo hasta el diagnóstico de 250 pacientes con síndrome de Down, mostró que los pacientes procedentes de áreas rurales con síndrome de Down tardan cinco meses en promedio en recibir un diagnóstico, comparado a los dos meses en zonas urbanas (p<0,001). No se encontraron diferencias significativas en el tiempo hasta el diagnostico según el sexo. Sin embargo, se evidenció una mayor proporción de varones provenientes de áreas rurales (p=0,03). Los hallazgos sugieren que los individuos de áreas rurales enfrentan dificultades para recibir el diagnóstico. Por otro lado, las mujeres quizás no sean llevadas a ciudades para un diagnóstico y tratamiento adecuado debido a sesgos de género en ciertas comunidades. Se subraya la importancia de mejorar el acceso a diagnósticos y tratamientos tempranos en áreas rurales.

Application of Patient-Based Real-Time Quality Control Based on Artificial Intelligence Monitoring Platform in Continuously Quality Risk Monitoring of Down Syndrome Serum Screening.

BACKGROUND: Patient-based real-time quality control (PBRTQC) has gained attention because of its potential to continuously monitor the analytical quality in situations wherein internal quality control (IQC) is less effective. Therefore, we tried to investigate the application of PBRTQC method based on an artificial intelligence monitoring (AI-MA) platform in quality risk monitoring of Down syndrome (DS) serum screening. METHODS: The DS serum screening item determination data and relative IQC data from January 4 to September 7 in 2021 were collected. Then, PBRTQC exponentially weighted moving average (EWMA) and moving average (MA) procedures were built and optimized in the AI-MA platform. The efficiency of the EWMA and MA procedures with intelligent and traditional control rules were compared. Next, the optimal EWMA procedures that contributed to the quality assurance of serum screening were run and generated early warning cases were investigated. RESULTS: Optimal EWMA and MA procedures on the AI-MA platform were built. Comparison results showed the EWMA procedure with intelligent QC rules but not traditional quality rules contained the best efficiency. Based on the AI-MA platform, two early warning cases were generated by using the optimal EWMA procedure, which finally found were caused by instrument failure. Moreover, the EWMA procedure could truly reflect the detection accuracy and quality in situations wherein traditional IQC products were unstable or concentrations were inappropriate. CONCLUSIONS: The EWMA procedure built by the AI-MA platform could be a good complementary control tool for the DS serum screening by truly and timely reflecting the detection quality risks.

Chromosome balanced translocation in newborn fetus founded during prenatal diagnosis: Three cases reports.

RATIONALE: Because of the normal phenotype, carriers of specific chromosomal translocations are often diagnosed only after their development of associated malignancies, recurrent miscarriages, and reproductive difficulties. In this paper, we report primary balanced fetal chromosomal translocations by performing the necessary invasive prenatal diagnosis in couples with previous malformations coupled with prenatal testing suggesting a high risk for trisomy 21. PATIENT CONCERNS: Case 1 and Case 2 couples had malformed children, and Case 3 couples had a high risk of trisomy 21 on noninvasive preconception serological testing. DIAGNOSIS AND INTERVENTION: A balanced chromosomal translocation diagnosis was confirmed by karyotyping of fetal cells obtained by amniocentesis. OUTCOMES: All 3 couples decided to continue their pregnancies after learning about the consequences of the chromosomal abnormalities. Approximately a year after the children were born, the staff of the Prenatal Diagnostic Center followed up with a phone call and found that the children physical development and intelligence were normal. LESSON: This case report reports healthy chromosomal balanced translocation newborns born to couples with poor maternal history and couples with abnormalities suggested by preconception testing, and followed up with the newborns to provide some experience in prenatal diagnosis and genetic counseling for chromosomal balanced translocations.

Creatinine levels in French children with Down syndrome up to ten years old.

Assess creatinine levels in French children with Down syndrome (DS) on the basis of the relationship between creatinine levels and age. The study included 279 children with DS aged 0 to 10 years who had been regularly monitored between 2004 and 2021 in a single genetics department and who had had at least one creatinine measurement. The creatinine level curves were established by estimating the median and the quantiles of order 2.5 and 97.5% according to age. A Generalized Additive Model for Location, Scale, and Shape was used. The results showed higher creatinine levels in children with DS than in children from the general population.   Conclusion: The present results allow to propose an original chart of creatinine levels according to age in French children with DS, which should help optimize their medical management and improve the early detection of renal diseases. What is Known: • Creatinine is a product of muscle breakdown and depends on muscle mass and children with Down syndrome have muscle and growth characteristics that differ from those of the general paediatric population. • Serum creatinine values in Japanese children with DS are higher than those of children from the general Japanese population. What is New: • Creatinine values in French children with DS are higher than those of children from the general French population. • The proposed original chart for creatinine values according to age, specifically designed for individuals up to 10 years old, should serve for further investigation, prevention, and follow-up of children with DS.

Usefulness of early morphological ultrasound in association with cell-free DNA testing in case of atypical serum markers in first trimester of pregnancy: A retrospective study over 5 years.

BACKGROUND: Early morphologic ultrasound, generally carried out in case of atypical first trimester serum markers (PAPP-A and/or free hCGß <0.30 MoM), has not been re-evaluated since the possibility of performing a cell-free fetal DNA analysis in this indication. Our objective was to evaluate the usefulness of early morphological ultrasound in case of atypical profile of serum markers performed in association with Non-Invasive Prenatal Testing (NIPT). METHODS: This was a single-center retrospective study in a tertiary maternity. Between January 2017 and December 2021, women with an atypical first trimester serum markers and low/intermediate risk for trisomy 21 (<1/50) were included. The clinical data, results of first trimester serum markers, NIPT, early morphological ultrasound and subsequent ultrasounds and other investigations (amniocentesis, pregnancy outcomes) were analyzed. RESULTS: After exclusion of women with high-risk of trisomy 21 and lost to follow-up, 163 women were included. In 72 % of cases (117/163), women had a low risk of trisomy 21, and 39 % (59/163) had an early morphological ultrasound. Early morphological ultrasound was useful to detect severe IUGR leading to the suspicion of triploidy (3/163, 1.8 %). In all other situations, it did not allow earlier management. After analysis of the 3 triploidy cases, a collapsed profile for both serum markers was demonstrated (<0.25 MoM). CONCLUSIONS: Systematic early morphological ultrasound in case of an atypical serum marker profile seems useless considering the performance of NIPT. An ultrasound restricted to women with both markers below 0.25 MoM would allow the early detection of triploidy.

Pragmatic competence in people with dual diagnosis: down syndrome and autism spectrum disorder.

BACKGROUND: Pragmatics is an area that can be affected in a wide variety of disorders. In this sense, Syndromic Autism is defined as a disorder in which a causal link is established between an associated syndrome and Autism Spectrum Disorder (ASD). Likewise, Down Syndrome (DS) is one of the main genetically based syndromes in which ASD is described as one of its possible manifestations. In this direction, people with DS are described as social beings whereas in ASD there seems to be a specific alteration of this domain. METHODS: In this study, pragmatic performance was analysed in a sample of 72 participants, where comparisons were made between the scores obtained by children with ASD (n = 24), with DS (n = 24) and with DS + ASD (n = 24). RESULTS: The Social Communication Questionnaire (SCQ), the Block Objective and Criterial Language Battery (BLOC-SR) and the Neuropsychology subtest (NEPSY-II) aimed at Theory of Mind (ToM) identified significant differences between the groups. However, two-to-two comparisons reported no significant differences between DS and DS + ASD. CONCLUSIONS: Although several studies report differences between the three proposed groups, our data seem to suggest that ASD symptomatology in DS is associated with Intellectual Developmental Disorder (IDD). However, the lack of solid scientific evidence regarding comorbid diagnosis makes further research along these lines indispensable. TRIAL REGISTRATION: This study was approved by the Ethics Committee for Social Research at UCLM with reference CEIS-704,511-L8M4.

Pregnant women's informational needs prior to decisions about prenatal diagnosis for chromosomal anomalies-A Q methodological study.

OBJECTIVE: To study pregnant women's subjective viewpoints on what is important when receiving information prior to decision-making regarding prenatal testing for chromosomal anomalies. METHOD: Data were collected using Q methodology. During January 2020-October 2021, 45 pregnant women in Sweden completed a 50-item Q sort. Statements regarding what is important when receiving information about prenatal screening and diagnosis were prioritized through ranking in a fixed sorting grid on an 11-point scale, from "most important" to "least important." Socio-demographics and coping styles were surveyed through questionnaires. RESULTS: Three groups represented different viewpoints on what pregnant women consider important when receiving information about prenatal screening and diagnosis. Factor 1: Stepwise information and decision-making: viewing information and decision-making as a step-by-step process. Factor 2: Decision-making as a continuous process based on couple autonomy: Striving for an informed decision as a couple about tests, test results and conditions screened. Factor 3: As much information as early as possible-the importance of personal autonomy in decision-making: Prioritizing autonomous decision-making based on non-directive information early in the pregnancy. CONCLUSION: This study highlights the complexities involved when providing information. As shown by the differing viewpoints in this study, pregnant women's informational needs differ, making individual and personalized information preferable.

[Clinical application of non-invasive prenatal testing for twin pregnancies].

OBJECTIVE: To evaluate the feasibility of non-invasive prenatal testing (NIPT) for the screening of fetal chromosome aneuploidies in twin pregnancies. METHODS: A total of 2 745 women with twin-pregnancies were subjected for NIPT screening. Chromosomal karyotyping and chromosomal microarray analysis (CMA) were carried out on amniotic fluid samples from those with a high risk for fetal chromosome aneuploidies, and the diagnosis and pregnancy outcome were followed up. The sensitivity, specificity, positive predictive value and false positive rate of the NIPT were calculated. RESULTS: Compared with other chromosomal abnormalities, NIPT had a higher efficacy for trisomy 21 and sex chromosomal aneuploidy (SCA) in twin pregnancies (with sensitivity being 100%, 100%, and specificity being 99.93%, 99.9%, respectively). It is difficult to evaluate the efficacy for trisomies 18 and 13 due to the limited data. For chromosome microdeletions and microduplications spanning 15 ~ 21 Mb, NIPT also had a certain detection rate. Compared with women with natural conception, NIPT had a higher detection rate for those with twin pregnancies by assisted reproduction (P < 0.05). CONCLUSION: It is feasible to use NIPT for the detection of chromosome aneuploidies in women with twin pregnancies.

Correlation between telomere shortening in maternal peripheral blood and fetal aneuploidy.

BACKGROUND: This study aimed to assess whether maternal telomere length is a more accurate predictor of trisomy 21 than maternal age while also exploring the factors influencing maternal and fetal telomere length. METHODS: Forty mothers with fetuses carrying extra maternal copies of chromosome 21 were defined as trisomy 21 cases, and 18 mothers with normal karyotype fetuses were defined as controls. Telomere lengths of maternal blood lymphocytes and amniotic fluid cells were determined using real-time polymerase chain reaction. Fetal and maternal telomere lengths were compared between the two groups. Moreover, we analyzed the factors influencing maternal and fetal telomere length in the trisomy 21 pedigree. A logistic regression model was used to analyze the correlation between maternal telomere length and trisomy 21 risk. In addition, receiver operating characteristic (ROC) curve analysis was used to determine the accuracy of using maternal telomere length as an indicator of trisomy 21 risk. RESULTS: The study revealed that both maternal and fetal telomere lengths were significantly shorter in trisomy 21 cases than in the controls. In the trisomy 21 group, the maternal age, occupation, and nationality showed no significant correlation with their telomere length; fetal telomere length exhibited a positive correlation with maternal telomere length. Furthermore, maternal telomere length shortening is associated with trisomy 21 (OR = 0.311; 95% CI, 0.109-0.885, P < 0.05). The results of ROC curve analysis indicated that a combined assessment of maternal age and maternal telomere length predicted fetal chromosome trisomy more effectively than a single assessment (area under the curve 0.808, 95% CI, 0.674-0.941, P < 0.001). CONCLUSION: Maternal age combined with maternal telomere length proved to be a superior predictor of trisomy risk. Additionally, maternal telomere length was found to influence fetal telomere length.

Kidney and urological involvement in Down syndrome: frequent, underestimated, but associated with impaired quality of life and risk of kidney failure.

Patients with Down syndrome (DS) are at risk of multiorgan dysfunction; kidney and urological impairment are common. This is due to a likely increased risk of congenital kidney and urological malformations (odds ratio of 4.5 compared to the general population in one study), more frequent associated comorbidities at risk of kidney dysfunction (such as prematurity in 9-24% of children, intrauterine growth retardation or low birth weight in 20%, and congenital heart disease in 44%), and more frequent lower urinary tract dysfunction (reported in 27-77% of children with DS). If present, malformations and comorbidities at risk of kidney dysfunction warrant regular kidney monitoring in addition to their treatment. Serum creatinine in children with DS has been shown to be higher than in the general population and asymptomatic hyperuricemia is reported in 12-33% of children or young adults with DS. Moreover cryptorchidism and testicular cancer are also more common and should be detected by clinical examination. Thus, persons with DS at risk of presenting kidney and urological impairment should be identified by prenatal ultrasonography, comorbidities at risk of kidney sequelae considered, and during regular medical follow-up, clinically examined and questioned to diagnose testicular anomalies and lower urinary tract dysfunction. This is of importance as such kidney and urological impairments are associated with impaired quality of life and mental health, and risk of kidney failure.

Keratoconus in Down syndrome: Prevalence, risk factors, severity and corneal tomographic characteristics.

BACKGROUND: This study investigated the prevalence, risk factors and severity of corneal tomographic features of keratoconus in Down syndrome (DS). Additionally, previous studies indicate anomalous corneal features in DS, without keratoconus, this study characterised corneal features in DS without keratoconus. METHODS: This prospective observational study included participants with DS ≥10 years old. Keratoconus diagnosis, risk factors and corneal tomographic characteristics were recorded. Participants underwent slit-lamp biomicroscopy, Scheimpflug corneal tomography, corneal topography and autorefraction. A diagnosis of keratoconus (DS-KC), suspect keratoconus (DS-SK) and non-keratoconus (DS-NK) was made based on expert review of scans by three fellowship trained anterior segment ophthalmologists. Corneal tomography parameters from one eye of each participant were analysed. RESULTS: Keratoconus affected 50 (26.3%) of 190 participants, diagnosed by corneal tomography, topography or slit-lamp signs. Corneal hydrops affected 14.0% of DS-KC participants. Eye rubbing was a significant risk factor for keratoconus (p = 0.036). 175 (92%) participants could undertake corneal tomography of which tomography assessment alone identified 47 (26.9%) DS-KC participants, 64 (36.6%) DS-SK participants and 64 (36.6%) DS-NK participants. Significant differences (p < 0.001) were identified when the DS-KC, DS-SK and DS-NK groups were compared in maximum keratometry and posterior elevation at the thinnest point respectively: median (interquartile range) 50.20 (10.30D), 47.60 (1.95D), 46.50 (2.40D); 24.0 (38.00 µm), 10.00 (13.75 µm), 8.00 (6.00 µm). The DS-SK and DS-NK cohorts had similar minimum pachymetry, however, had several significantly different parameters among which included greater maximum keratometry, posterior elevation at the thinnest point in the DS-SK group. CONCLUSIONS: Keratoconus is common in DS. Keratoconus screening with corneal tomography is recommended for early detection.

Maternal age and the risk of fetal aneuploidy: A nationwide cohort study of more than 500 000 singleton pregnancies in Denmark from 2008 to 2017.

INTRODUCTION: In this register-based study of pregnancies in Denmark, we assessed the associations between maternal age and the risk of fetal aneuploidies (trisomy 21, trisomy 18, trisomy 13, triploidy, monosomy X and other sex chromosome aberrations). Additionally, we aimed to disentangle the maternal age-related effect on fetal aneuploidies by cases with translocation trisomies and mosaicisms. MATERIAL AND METHODS: We followed a nationwide cohort of 542 375 singleton-pregnant women attending first trimester screening in Denmark between 2008 and 2017 until delivery, miscarriage or termination of pregnancy. We used six maternal age categories and retrieved information on genetically confirmed aneuploidies of the fetus and infant from the national cytogenetic register. RESULTS: We confirmed the known associations between advanced maternal age and higher risk of trisomy 21, 18, 13 and other sex chromosome aberrations, especially in women aged ≥35 years, whereas we found no age-related associations with triploidy or monosomy X. Cases with translocation trisomies and mosaicisms did not influence the overall reported association between maternal age and aneuploidies. CONCLUSION: This study provides insight into the accurate risk of fetal aneuploidies that pregnant women of advanced ages encounter.

Artificial intelligence for prenatal chromosome analysis.

This review article delves into the rapidly advancing domain of prenatal diagnostics, with a primary focus on the detection and management of chromosomal abnormalities such as trisomy 13 ("Patau syndrome)", "trisomy 18 (Edwards syndrome)", and "trisomy 21 (Down syndrome)". The objective of the study is to examine the utilization and effectiveness of novel computational methodologies, such as "machine learning (ML)", "deep learning (DL)", and data analysis, in enhancing the detection rates and accuracy of these prenatal conditions. The contribution of the article lies in its comprehensive examination of advancements in "Non-Invasive Prenatal Testing (NIPT)", prenatal screening, genomics, and medical imaging. It highlights the potential of these techniques for prenatal diagnosis and the contributions of ML and DL to these advancements. It highlights the application of ensemble models and transfer learning to improving model performance, especially with limited datasets. This also delves into optimal feature selection and fusion of high-dimensional features, underscoring the need for future research in these areas. The review finds that ML and DL have substantially improved the detection and management of prenatal conditions, despite limitations such as small sample sizes and issues related to model generalizability. It recognizes the promising results achieved through the use of ensemble models and transfer learning in prenatal diagnostics. The review also notes the increased importance of feature selection and high-dimensional feature fusion in the development and training of predictive models. The findings underline the crucial role of AI and machine learning techniques in early detection and improved therapeutic strategies in prenatal diagnostics, highlighting a pressing need for further research in this area.

Serum apelin-12 and obesity-related markers in Egyptian children with Down syndrome.

Children with Down syndrome (DS) exhibit higher overweight/obesity rates than their typically developing peers. Apelin-12 is a bioactive adipokine that exerts vital roles in obesity-related cardiometabolic comorbidities. To date, apelin-12 has not been investigated in obese-DS. This study aimed to explore the possible association between serum apelin-12 and obesity-related markers and to evaluate the efficiency of apelin-12 in the prediction of metabolic syndrome (MetS) in obese-DS compared to BMI Z-score matched obese-control. The cross-sectional study included 150 prepubertal children classified into three groups; obese-DS (n = 50), obese-control (n = 50), and normal-weight-control (n = 50). Anthropometric parameters, body adiposity, fasting serum levels of blood glucose (FBG), insulin, lipid profile, and apelin-12 were evaluated. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from FBG and insulin. MetS was defined using Adult Treatment Panel III criteria modified for the pediatric age group. ROC curves were analyzed to evaluate the efficiency of apelin-12 in predicting MetS in obesity groups. Obese-DS exhibited higher body adiposity with marked central fat distribution, atherogenic lipid profile, and higher HOMA-IR compared to obese-control. Apelin-12 was significantly higher in obese-DS and obese-DS with MetS compared to obese-control and obese-control with MetS respectively (p < 0.001). The increase in apelin-12 with higher obesity grades was pronounced in obese-DS. Apelin-12 strongly correlated with body adiposity, several MetS risk factors, and HOMA-IR in obese-DS. Significantly higher AUC for apelin-12 in the diagnosis of MetS among obese-DS than obese-control (AUC = 0.948 vs. AUC = 0.807; p = 0.04). CONCLUSIONS:  The current study supports the crucial role of apelin-12 in obesity-related clinical and biochemical markers and in MetS in obese-DS and obese-control. Serum apelin-12 is a potential diagnostic biomarker for MetS with greater performance in obese-DS than obese-control raising its potential for clinical and therapeutic applications. WHAT IS KNOWN: • Obese-DS children displayed excess body adiposity, Pronounced central fat distribution, atherogenic lipid profile, higher HOMA-IR, and higher prevalence of MetS than obese-control. WHAT IS NEW: • Higher serum apelin-12 was observed in obese-DS and obese-DS with MetS than obese-control and obese-control with MetS respectively. The increase in apelin-12 level with increasing obesity grades was more pronounced in obese-DS. • Apelin-12 strongly correlated with obesity-related markers and MetS components in obese-DS. Apelin-12 performed better as a diagnostic biomarker for MetS in obese-DS than obese-control.

The impact of implicit and explicit bias about disabilities on parent experiences and information provided during prenatal screening and testing.

BACKGROUND: Prenatal screening technology has consistently raised concerns regarding the conversations and information provided about disabilities, particularly given that research shows trauma related to negative prenatal screening and diagnosis experiences among parents of children with Down syndrome.1 OBJECTIVE: To determine what information obstetric medical providers (OB/MFMs) are most and least likely to provide when delivering prenatal screening/testing results about Down syndrome (DS), the subsequent impact of bias on prenatal screening experiences, and how these issues can be addressed through training, resources, and professional guidelines. METHODS: Online surveys were distributed to parents of children with DS born between 2016 and 2021 via local DS organizations and the national DS Diagnosis Network (April 2020-December 2021). RESULTS: Of the 242 parents who completed the survey, a majority indicated that OB/MFMs were most likely to discuss medical issues and reproductive options while less than 40% reported that OB/MFMs discussed psychosocial outcomes, supports, and services. Respondents reported that the 61.3% of OB/MFMs who delivered the diagnosis as bad news or said "I'm sorry" were significantly less likely than their counterparts to provide information about life outcomes, supports and services, condition-specific resources, or more comprehensive prenatal care. Qualitative responses about screening/diagnosis experiences provided further context about the impact of implicit and explicit bias on the provision of accurate, up-to-date information. CONCLUSION: To meet information needs during prenatal screening, OB/MFMs need access to accurate, balanced, and up-to-date information about disabilities and more training on disability cultural competency and how to deliver prenatal screening/testing results without implicit or explicit bias.