22q11 Microdeletion Research Articles

Diagnosis, Management and Outcome of Truncus Arteriosus Communis Diagnosed during Fetal Life-Cohort Study and Systematic Literature Review.

Background/Objectives: Truncus arteriosus communis (TAC) is a rare congenital heart defect characterized by a single arterial trunk that supplies systemic, pulmonary, and coronary circulations. This defect, constituting approximately 1-4% of congenital heart diseases, poses significant challenges in prenatal diagnosis, management, and postnatal outcomes. Methods: A retrospective analysis was conducted at the local tertiary referral center on cases of TAC diagnosed prenatally between 2019 and 2024. Additionally, a systematic literature review was performed to evaluate the accuracy of prenatal diagnostics and the presence of associated anomalies in fetuses with TAC and compare already published data with the local results. The review included studies that especially described the use of fetal echocardiography, the course and outcome of affected pregnancies, and subsequent management strategies. Results: The analysis of local prenatal diagnoses revealed 14 cases. Of the 11 neonates who survived to birth, the TAC diagnosis was confirmed in 7 instances. With all seven neonates undergoing surgery, the intention-to-treat survival rate was 86%, and the overall survival rate was 55%. By reviewing published case series, a total of 823 TAC cases were included in the analysis, of which 576 were diagnosed prenatally and 247 postnatally. The presence of associated cardiac and extracardiac manifestations as well as genetic anomalies was common, with a 22q11 microdeletion identified in 27% of tested cases. Conclusions: Advances in prenatal imaging and early diagnosis have enhanced the management of TAC, allowing for the detailed planning of delivery and immediate postnatal care in specialized centers. The frequent association with genetic syndromes underscores the importance of genetic counseling in managing TAC. An early surgical intervention remains crucial for improving long-term outcomes, although the condition is still associated with significant risks. Long-term follow-up studies are essential to monitor potential complications and guide future management strategies. Overall, a coordinated multidisciplinary approach from prenatal diagnosis to postnatal care is essential for improving outcomes for individuals with TAC.

Maternal Transmission of 17q12 Microdeletion: Intrafamilial Phenotypic Variability and Diagnostic Hurdles

The relatively rare proximal 17q12 microdeletion, including the deletion of the HNF1B gene, is associated with renal cysts and diabetes syndrome (RCAD). This genomic rearrangement results in a wide range of phenotypes, including renal cysts and diabetes, which are consistent with maturity-onset diabetes of the young type 5 (MODY5), Mullerian aplasia/dysgenesis, autism spectrum disorder and schizophrenia, speech delay, learning difficulties, transient neonatal hypercalcemia, and neonatal cholestasis. We describe a girl with a 17q12 microdeletion identified using CGH array analysis (about 1.4 Mb, including HNF1B and LHX1 genes). The same deletion was identified in her mother. The proband had shown cystic and hypodysplastic bilateral kidneys since birth and hypertension, while her mother had bilateral renal cysts and diabetes. Despite suggestive findings in the girl and in the mother, no clinical suspicion arose, and genetic testing was carried out only after referral to a pediatric nephrologist. In children, the identification of 17q12 microdeletion may have a significant impact on the diagnosis, prognosis, and management of renal disease and early-onset type II diabetes. This family with a 17q12 microdeletion confirms intrafamilial phenotypic variability and highlights the importance of including it early on in the analysis of the diagnostic workup of children with renal cystic diseases.

Prenatal diagnosis in fetal right aortic arch using chromosomal microarray analysis and whole exome sequencing: a Chinese single-center retrospective study

BackgroundRight aortic arch (RAA) is a common congenital aortic arch abnormality. Fetuses with RAA frequently have good outcomes after birth. However, chromosomal abnormalities and genetic syndromes suggest poor prognosis for these patients. So far the underlying genetic etiology is still not identified in most RAA patients based on traditional genetic techniques and a problem is still debated whether fetuses with isolated RAA should be referred for CMA. Our study aims to investigate the genetic etiology of fetuses with right aortic arch (RAA) by chromosomal microarray analysis (CMA) and whole exome sequencing (WES) and evaluate the efficacy of CMA in fetal isolated RAA.ResultsAmong these 153 fetuses, 99 (64.7%) with isolated RAA and 54 (35.3%) with non-isolated RAA; 25.5% (39/153) with additional intracardiac anomalies (ICA), and 19.0% (29/153) with extracardiac anomalies (ECA). Tetralogy of Fallot (n = 10) and persistent left superior vena cava (n = 11) are the most common ICA and ECA, respectively. CMA detected 15 clinically significant copy number variations (CNVs) in 14 cases (9.2%); microdeletion of 22q11.21 was the most common pathogenic CNVs (7.8%). The chromosomal abnormalities rate was higher in non-isolated RAA and RAA with ICA groups than in isolated RAA group (16.7% vs. 5.1%; 20% vs. 5.1%, both p < 0.05). From five cases further undergoing WES, a diagnostic variant in MTOR gene (c.7255G > A, de novo) was first reported in prenatal, extending the prenatal manifestation of Smith–Kingsmore syndrome (OMIM: 616638); a clinically relevant variant c.3407A > T in STAG2 was identified, being inherited from the healthy mother. Moreover, the premature birth and termination rates were higher in non-isolated RAA group than in isolated RAA group (11.1% vs. 1.0%; 37.0% vs. 2.0%, both p < 0.01).ConclusionsWe demonstrate that CMA and WES are useful diagnostic tools for fetal RAA, particularly non-isolated RAA, and all fetuses with RAA should be referred for CMA. The data probably aids in prenatal diagnosis and prenatal counseling of fetal RAA.

Prenatal diagnosis of 17q12 copy number variants in fetuses via chromosomal microarray analysis - A retrospective cohort study and literature review

Purpose17q12 copy number variants (CNVs) have variable presentations and incomplete penetrance, challenging prenatal counseling and management. This study aims to investigate the intrauterine phenotype. MethodsWe included 48 fetuses diagnosed with 17q12 microdeletion or microduplication by chromosomal microarray analysis. ResultsFor 17q12 deletion, renal anomalies were found in 35 fetuses (35/37, 94.6 %), with hyperechogenic kidneys (HEK, 28/37, 75.7 %) and multicystic dysplastic kidneys (17/37, 45.9 %) being the most common findings. Duodenal obstruction (DO) was most frequently combined in 17q12 duplication fetuses. In addition, cardiac abnormalities were the first reported prenatal phenotype in 17q12 duplication fetuses. ConclusionOur study shows that HEK and DO are the most predominant presentations of 17q12 deletion and duplication, respectively, and cardiac structural abnormalities may be associated with the latter. Although 17q12 CNVs have incomplete penetrance and variable expressivity and may be mainly involved in neurodevelopmental disorders, their short-term prognosis appears positive.

Genetic components of microdeletion syndromes and their role in determining schizophrenia traits.

Schizophrenia is a neuropsychiatric disorder characterized by various symptoms such as hallucinations, delusions, and disordered thinking. The etiology of this disease is unknown; however, it has been linked to many microdeletion syndromes that are likely to contribute to the pathology of schizophrenia. In this review we have comprehensively analyzed the role of various microdeletion syndromes, like 3q29, 15q13.3, and 22q11.2, which are known to be involved with schizophrenia. A variety of factors lead to schizophrenia phenotypes, but copy number variants that disrupt gene regulation and impair brain function and cognition are one of the causes that have been identified. Multiple case studies have shown that loss of one or more genes in the microdeletion regions lead to brain activity defects. In this article, we present a coherent paradigm that connects copy number variations (CNVs) to numerous neurological and behavioral abnormalities associated with schizophrenia. It would be helpful in understanding the different aspects of the microdeletions and how they contribute in the pathophysiology of schizophrenia.

Concurrent of compound heterozygous variant of a novel in-frame deletion and the common hypomorphic haplotype in TBX6 and inherited 17q12 microdeletion in a fetus

BackgroundTBX6, a member of the T-box gene family, encodes the transcription factor box 6 that is critical for somite segmentation in vertebrates. It is known that the compound heterozygosity of disruptive variants in trans with a common hypomorphic risk haplotype (T-C-A) in the TBX6 gene contribute to 10% of congenital scoliosis (CS) cases. The deletion of chromosome 17q12 is a rare cytogenetic abnormality, which often leads to renal cysts and diabetes mellitus. However, the affected individuals often exhibit clinical heterogeneity and incomplete penetrance.MethodsWe here present a Chinese fetus who was shown to have CS by ultrasound examination at 17 weeks of gestation. Trio whole-exome sequencing (WES) was performed to investigate the underlying genetic defects of the fetus. In vitro functional experiments, including western-blotting and luciferase transactivation assay, were performed to determine the pathogenicity of the novel variant of TBX6.ResultsWES revealed the fetus harbored a compound heterozygous variant of c.338_340del (p.Ile113del) and the common hypomorphic risk haplotype of the TBX6 gene. In vitro functional study showed the p.Ile113del variant had no impact on TBX6 expression, but almost led to complete loss of its transcriptional activity. In addition, we identified a 1.85 Mb deletion on 17q12 region in the fetus and the mother. Though there is currently no clinical phenotype associated with this copy number variation in the fetus, it can explain multiple renal cysts in the pregnant woman.ConclusionsThis study is the first to report a Chinese fetus with a single amino acid deletion variant and a T-C-A haplotype of TBX6. The clinical heterogeneity of 17q12 microdeletion poses significant challenges for prenatal genetic counseling. Our results once again suggest the complexity of prenatal genetic diagnosis.

Association of right aortic arch and agenesis of ductus arteriosus in prenatal tetralogy of Fallot spectrum and its clinical implications.

In our center, we observed an increased frequency of right aortic arch (RAA) with an agenesis of the ductus arteriosus (ADA) in prenatally diagnosed tetralogy of Fallot (ToF) and its variations. This study aimed to determine whether there is an association of RAA and ADA in fetuses with ToF. Distribution of genetic anomalies and impact on postnatal outcome were further evaluated. Single-center retrospective observational study including pregnancies with prenatal diagnosis of ToF from 2010 to 2023. All cases were subdivided into ToF with pulmonary stenosis (PS) and pulmonary atresia (PA). Clinical and echocardiographic databases were reviewed for pregnancy outcome, genetic anomalies, and postnatal course. The cohort included 169 cases, 124 (73.4%) with ToF/PS and 45(26.6%) with ToF/PA. Agenesis of the ductus arteriosus was significantly associated with RAA in both subtypes of ToF (p=0.001) compared to left aortic arch and found in 82.5% (33/40) versus 10.7% (9/84) of fetuses with ToF/PS and in 57.1% (8/14) versus 12.9% (4/31) of fetuses with ToF/PA. In both ToF/PS and ToF/PA, RAA/ADA versus RAA/patent DA revealed a significantly higher risk for the presence of genetic abnormalities, especially microdeletion 22q11.2, major aorto-pulmonary collateral arteries and a shorter time to complete surgical repair. We demonstrated a significantly increased frequency of RAA/ADA in patients with prenatally diagnosed ToF. Although this association revealed no significant impact on overall survival, the prenatal detection of RAA/ADA has implications for counseling, genetic evaluation and postnatal management.

#2412 Monoallelic NEK8-related polycystic kidney disease in an Irish ADPKD cohort

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD), commonly caused by pathogenic variants in PKD1 and PKD2 genes, leads to enlarged cystic kidneys and typically present in adulthood where ∼70% of affected patients progress to kidney failure by their 7th decade of life. Recently, new genes have been reported that appear to explain some of the previously unresolved ADPKD-like cases. An example is the NEK8 gene, where monoallelic variants are reported to cause early-onset ADPKD with progressive phenotype. We are reporting 4 Irish families with monoallelic NEK8 variants. Method In-depth clinical and radiological evaluations were conducted on 250 families with polycystic kidney disease referred to the Irish Kidney Gene Project. All patients underwent genomic testing using gene-panel and exome Next Generation Sequencing (NGS), while multiple ligation probe amplification analysis of PKD1 or PKD2 was utilized in genetically unresolved families. The American College of Medical Genetics and Genomics guidelines were applied to assess variant pathogenicity. Results To date, 471 individuals representing 250 distinct families (F) have been studied, including 105 (42%) families with two or more individuals (326 individuals). 55.2% have reached end-stage kidney failure, with an average age of 49.1 ± 14.3 years. We identified pathogenic / likely pathogenic variants in 76% (190/250) of families, with variants in PKD1 accounting for 76.8% (146/190) and PKD2 accounting for 15.3% (29/190) of families, respectively. In familial cases with non-PKD1/PKD2 variants, we identified pathogenic variants in a small proportion of families with ADPKD-like phenotypes: IFT140 variants (n = 4), ALG5 (n = 2), 17q12 microdeletion (n = 2) and DNAJB11, ALG8, and ALG9 variants (n = 1 each). Upon thorough review of all genetically unresolved PKD families, 4 (6.7%) families were identified with monoallelic protein-kinase domain NEK8 variants [NM_178170.3]: p.R45W (in 2 families) and two other missense variants: p.N69D and p.R140L, none of which contained a second NEK8 variant despite extensive analysis. Autosomal dominant segregation was confirmed in two parent-child pairs, whereas the remaining two index patients reported no family history of kidney disease. The median age at the initial presentation was 12 years (IQR: 2.5–27.3), with a median follow-up period of 22.5 years at the last evaluation. The phenotype of all patients was consistent with polycystic kidney disease with the absence of liver and pancreatic cysts. All patients were diagnosed with hypertension at an average age of 15.3 ± 12.2 years. Cerebral aneurysms were detected in two patients (F1: at age 61 years and F4: at age 54 years), while F3 was reported to have childhood-onset frontal bossing, prominence cerebrospinal fluid, and large arachnoid cysts. Approximately 67% [4/6] patients progressed to end-stage kidney failure by the 3rd decade of life. Compared to families with PKD1/PKD2 variants, families with NEK8 variants were characterized by earlier average age at initial presentation (14.5 versus 29.9 years; p 0.01) and progression to end-stage kidney failure (15.5 versus 49.6 years; p &amp;lt; 0.0001). Table 1 summarizes the clinical and genetic characteristics of the reported families. Conclusion We provide further evidence that monoallelic NEK8 variants cause early presentation and progressive ADPKD-like phenotype. Sequencing for monoallelic NEK8 variants in patients with childhood and early-adulthood cystic kidney disease can inform renal prognosis, treatment planning, familial screening and reproductive choices.

The first case of hyperosmolar diabetic ketoacidosis in a patient diagnosed with MODY 5 (maturity-onset diabetes of the young type 5) and 17q12 microdeletion syndrome.

The first case of hyperosmolar diabetic ketoacidosis in a patient diagnosed with MODY 5 (maturity-onset diabetes of the young type 5) and 17q12 microdeletion syndrome.

Antenatal description of large 4q13.2q21.23 deletion and outcomes.

4q21 microdeletion syndrome is an emergent non-recurrent genomic disorder characterized by facial dysmorphy, progressive growth retardation, severe intellectual deficit, and absent or severely delayed speech. Deletions occur in clusters along 4q interstitial or terminal regions. 4q chromosomal aberrations are variable in type, size, and breakpoint. Genotype-phenotype correlation is a challenging task. The recurrent antenatal feature associated a posteriori with this syndrome is intrauterine growth retardation. There are very few precise antenatal descriptions of this syndrome. We report here the first antenatal history of one of the largest deletion of this region. Our case harbored a 16.9 Mb deletion encompassing 135 protein coding genes including 20 OMIM morbid genes involved in neurological and cognitive abilities. Those breakpoints overlap two clusters of described microdeletion syndromes of cytogenetic band 4q13 and 4q21. From the end of the second trimester, set of call signs associated with this syndrome can be completed by: excess of amniotic fluid, mild growth retardation, short long bones, bony anomalies of the extremities, and bulging cheeks. So, emphasis should be placed on the examination of the extremities, and the face during the routine targeted prenatal ultrasound.

Prenatal diagnosis and family analysis of 17q12 microdeletion syndrome with fetal renal abnormalities.

To analyze the prenatal diagnosis, parental verification, and pregnancy outcomes of three fetuses with 17ql2 microdeletion syndrome. We retrospectively reviewed 46 singleton pregnancies with anomalies in the urinary system who underwent amniocentesis from Feb 2022 to October 2023 in the Prenatal Diagnosis Center of Lianyungang Maternal and Child Health Hospital. These fetuses were subjected to chromosomal microarray analysis (CMA) and/or trio whole-exome sequencing (Trio-WES). We specifically evaluated these cases' prenatal renal ultrasound findings and clinical characteristics of the affected parents. Three fetuses were diagnosed as 17q12 microdeletions, and the detection rate was 6.5% in fetuses with anomalies in the urinary system (3/46). The heterogeneous deletions range from 1.494 to 1.66Mb encompassing the complete hepatocyte nuclear factor 1 homeobox B (HNF1B) gene. Fetuses with 17q12 deletion exhibited varied renal phenotypes. Moreover, the clinical phenotypes of the affected parents differed greatly in the two cases (case 2 and case 3) in which the deletion was inherited. For case 3, the mother manifested classic symptoms of 17q12 deletion syndrome as well as unreported characteristics, such as very high myopia. Our findings demonstrate the necessity and significance of offering prenatal genetic testing when various renal anomalies are detected. In addition, our study broadens the phenotypic spectrum of 17q12 deletions. Most importantly, our findings may allow timely supportive genetic counseling and guidance for pregnancy in affected families, e.g., with the help of preimplantation genetic testing (PGT).

Prenatal Diagnosis of Ductus Arteriosus Anomalies: A Single-Center Study.

To evaluate the fetal ductus arteriosus anomalies diagnosed by fetal echocardiography. The perinatal outcomes and associated cardiac and genetic anomalies are also explored. The fetal echocardiography records of 2366 fetuses were evaluated retrospectively. Thirty-seven pregnancies prenatally diagnosed with ductus arteriosus anomalies and evaluated after delivery were enrolled in the study. Perinatal and obstetric outcomes were analyzed. The incidence of ductus arteriosus anomaly in our series was 1.5% (37/2366). The most frequent ductus arteriosus anomaly detected was right-sided ductus arteriosus followed by aneurysm, constriction and bilateral ductus arteriosus with an incidence of 51.3%, 27.1%, 18.9% and 2.7%, respectively. There were 19 fetuses with right-sided ductus arteriosus, of which 15 had tetralogy of Fallot. There were 2 chromosomal anomalies (22q11 microdeletion) in this group. Of the 7 fetuses with ductus arteriosus constriction, 3 (3/7, 42.9%) died in-utero. There were 2 (2/10, 20%) neonatal deaths due to hypoplastic left heart syndrome in the ductus arteriosus aneurysm group. Various types of ductus arteriosus anomalies can be diagnosed prenatally. Perinatal outcomes mostly dependent on the type of the ductus arteriosus anomaly and accompanying cardiac malformations.

Cases of Digeorge Syndrome

Abstract DiGeorge syndrome is a primary immunodeficiency caused by the abnormal growth of the third and fourth pharyngeal pouches throughout prenatal development. It is typified by a triad: hypocalcemia due to hypoparathyroidism, some heart defects, and thymic hypoplasia or aplasia. This syndrome is associated with a microdeletion in the chromosomal region 22q11.2. DiGeorge syndrome together with other dysfunctions like velo-cardio-facial syndrome and Takao syndrome have overlapping traits. The symptoms are hidden under the name CATCH22. It describes signs like a cardiac defect, abnormal facies, thyme hypoplasia, cleft palate, hypocalcemia, and chromosome 22q11.2 deletions. Its incidence is estimated to be approximately 1:3000 live births. The disorder is inherited in an autosomal dominant pattern or arises from de novo mutation. 22q11.2 microdeletion is associated with an increased risk of developing mental diseases, including schizophrenia. In the general population, 1-2% of people suffer from schizophrenia. In DiGeorge syndrome this ratio is much higher, around 25-30%. Nowadays, the fluorescence in situ hybridization (FISH) is a gold standard method for the diagnosis of microdeletion syndrome. Currently, there is no effective therapy to prevent the development of the disease.

Hypersensitivity to Psychotropic Medications in a Patient With 17q12 Microdeletion Syndrome: A Case Report.

Hypersensitivity to Psychotropic Medications in a Patient With 17q12 Microdeletion Syndrome: A Case Report.

Optometry in adults with microdeletion 22q11.2: The eye as a window to the brain

PurposeThe 22q11.2 deletion syndrome (22q11.2DS) has an estimated prevalence of 1:2148 live births and is associated with an increased risk of schizophrenia, cognitive decline and early-onset Parkinson’s disease. Because retinal and cerebral tissue share embryological, physiological and anatomical characteristics, retinal blood vessel morphology and retinal nerve fiber layer (RNFL) thickness have been proposed as non-invasive biomarkers for psychiatric and neurodegenerative disorders. In this exploratory study, we examined these potential biomarkers in adults with 22q11.2DS relative to controls, and in relation to age. MethodsCentral retinal artery and vein equivalent, fractal dimension, and vascular tortuosity, obtained through fundoscopy, and peripapillary RNFL and macular thickness, obtained through optical coherence tomography, were compared between adults with 22q11.2DS and sex- and age-matched controls. ResultsMean retinal vascular fractal dimension and tortuosity values were significantly higher in the group of adults with 22q11.2DS than in controls (p < 0.001; p < 0.001). RNFL was thicker in the nasal segment (p = 0.002) in 22q11.2DS, and a trend for thinner RNFL in the nasal and temporal inferior segments (p = 0.05 and p = 0.06, respectively) was found. There were significant negative correlations with age for fractal dimension (p < 0.001) and RNFL thickness in the global (p = 0.007), temporal inferior (p = 0.005) and temporal superior (p = 0.04) segments in adults with 22q11.2DS, but not in controls. ConclusionsOur results indicate higher retinal vascular fractal dimension and tortuosity, and a decrease in fractal dimension and RNFL thickness in relation to age in adults with 22q11.2DS. Our findings support future studies that focus on retinal fractal dimension and RNFL thickness as potential biomarkers for age-related manifestations in 22q11.2 including psychotic and (early) neurodegenerative disorders.

Prenatal diagnosis of polycystic renal diseases: diagnostic yield, novel disease-causing variants, and genotype–phenotype correlations

BackgroundPolycystic renal disease (PRD) is a frequent congenital anomaly of the kidneys, but research utilizing chromosomal microarray analysis (CMA) and exome sequencing (ES) in PRD fetuses remains sparse, with the majority of studies focusing on the multisystem or genitourinary system. ObjectiveThis study aims to describe the detection rate of detectable genetic causes of fetal PRD at different levels, and novel disease-causing variants and explores genotype-phenotype correlations. Study DesignThis study included 220 fetal PRD from January 2014 to June 2022. Cases were divided into three groups: isolated multicystic dysplastic kidneys (MCDK), non-isolated MCDK, and suspected polycystic kidney disease group. We reviewed data on maternal demographics, ultrasonographic results, CMA/ES results, and pregnancy outcomes. ResultsIn our cohort, CMA identified 19 (8.6%) fetuses carrying chromosomal abnormalities, and the most common CNV was 17q12 microdeletion (7/220, 3.2%). Furthermore, 94 families chose to perform trio-ES testing, and 21 fetuses (22.3%) were found to harbor P/LP variants. For PRD, there was a significant difference in the live birth rate (91/130 vs. 46/80 vs. 1/10, p < 0.001). Among 138 live birth cases, 106 (78.5%) underwent postnatal ultrasound review, of which 95 (89.6%) had a consistent prenatal-postnatal ultrasound diagnosis. ConclusionsTaken together, either for isolated or non-isolated PRD, our data show high detection efficiency for both testing tools. Novel pathogenic variants have expanded the disease spectrum of PRD-associated genes while enriching the genotype-phenotype correlation. Therefore, we consider it feasible to perform CMA + ES testing in fetal PRD. Moreover, prenatal-postnatal ultrasound concordance was greater, while the live birth rate was higher and prognosis was better when known genetic disorders were excluded, showing that genetic testing results significantly influenced pregnancy decisions.

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 thatin 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.

SAT086 Early-onset HNF1B-MODY With Persistent Insulin Requirement In A 2-year-old Female

Abstract Disclosure: F. Ighalo: None. S.R. Kelly: None. M. Tosur: None. M.E. Craven: None. Introduction: Diabetes related to HNF1B pathogenic variants or deletions (maturity-onset diabetes of the young 5 [MODY 5]) typically presents in adolescence or early adulthood, with a median age of 20 years. Bustamante et al. previously described two patients with 17q12 deletion encompassing HNF1B presenting with diabetes and pre-diabetes before the age of 3, who were managed with dietary intervention alone without insulin requirement. This case describes a 2-year-old diagnosed with HNF1B-MODY after developing hyperglycemia in the setting of an acute illness, who continued to require insulin therapy following recovery. Clinical Case: A 2-year-old female with a history of recurrent viral infections and failure to thrive was admitted to the intensive care unit in hypovolemic shock due to hemolytic uremic syndrome due to Shiga toxin. On hospital day 7, while on supraphysiologic steroid doses, she developed hyperglycemia with glucoses above 600 mg/dL. She required an insulin drip to maintain blood glucoses between 100 and 200 mg/dL. Her four-month hospital stay was complicated by cardiogenic shock requiring extracorporeal mechanical oxygenation, renal failure requiring hemodialysis, respiratory failure resulting in a tracheostomy, and dysphagia resulting in a gastrostomy tube. During this time, she continued to require insulin despite being weaned off steroids and transitioning from total parenteral nutrition to gastrostomy tube feeds. Her hemoglobin A1c one month post-diagnosis was 4.9%, and continued to rise to 6.6% and 7.6% at 3 and 4 months post-diagnosis, respectively. Testing for islet autoantibodies was negative. A chromosomal microarray analysis revealed a micro-deletion in chromosome 17q12 that included the HNF1B gene. MRI showed a near total absent pancreas, and multiple small cysts scattered throughout both kidneys. She also had fecal elastase levels in the insufficient range (135 mcg/g, normal &amp;gt;200 mcg/g). Six weeks after the start of insulin drip, she was transitioned from an insulin drip to subcutaneous insulin injections, and eventually placed on an insulin pump prior to discharge. With continued clinical improvement, her insulin doses decreased, but she was not able to come off insulin completely. She had gradual decline in her insulin requirements from 1.0 units/kg/day down to 0.1 units/kg/day at time of discharge. Her current insulin requirement at 6 months post-diagnosis is 0.2 units/kg/day. Conclusion: This case represents the rare development of diabetes before adolescence in HNF1B-MODY, and one of the most severe presentations seen in a prepubertal child requiring persistent insulin therapy at 6 months post-diagnosis. Potential contribution of complicated hospital course on persistent insulin requirement in the setting of 17q12 micro-deletion cannot be excluded. Presentation: Saturday, June 17, 2023

Genetic insights into the Tetralogy of Fallot

Tetralogy of Fallot (TOF), (OMIM #187500) one of the first known congenital heart disease (CHDs) with a rising frequency of adult patients, is a suitable paradigm for our analysis given the expanding abundance of genetic data available and these clinical consequences. Given the complexity of cardiac development, it has been associated with untreated maternal diabetes, maternal intake of retinoic acid, phenylketonuria, chromosomal anomalies (trisomies 21, 18, 13), microdeletions of chromosome 22q11.2, and it is not unexpected that a variety of transcription factors and signaling molecules involved in 9 cardiogenesis have been linked to TOF, with the literature consistently reporting the existence of new, previously unrecognized genes. The well studied genes GATA4, NKX2.5, JAG1, FOXC2, TBX5, and TBX1, which have previously been linked to TOF, are the focus of this review.

Experience in prenatal ultrasound diagnosis of fetal microtia and associated abnormalities.

Prenatal ultrasound features, associated anomalies and genetic abnormalities of microtia cases were analyzed to explore the feasibility and value of prenatal ultrasound for the diagnosis of microtia. The ultrasonographic features, associated anomalies, chromosome examination results and follow-up results of 81 fetuses with congenital microtia were analyzed retrospectively. Among the 81 fetuses with microtia diagnosed after birth, 2 cases were missed diagnosis on prenatal ultrasound, and 1 case was diagnosed as unilateral microtia by prenatal ultrasound but was found to be bilateral microtia after birth. Microtia was accompanied by an accessory auricle in 4 cases (4.94%) and low-set ears in 7 cases (8.64%). 22 cases (27.16%) were complicated with other structural anomalies, including 11 cases (13.58%) of cardiac anomalies, 7 cases (8.64%) of ultrasonographic soft marker anomalies, 6 cases (7.41%) of facial anomalies, 6 cases (7.41%) of nervous system anomalies, 3 cases (3.70%) of urogenital system anomalies, 3 cases (3.70%) of digestive tract anomalies and 2 cases (2.47%) of limb anomalies. Chromosome karyotype analysis and gene detection were performed in 44 cases. Trisomy 18, trisomy 13, trisomy 21, pericentric inversion of chromosome 9, partial loss of heterozygosity on chromosome 14, 22q11 microdeletion and a normal karyotype were found in 2 cases, 2 cases, 3 cases, 1 case, 1 case, 1 case, and 34 cases, respectively. In summary, microtia is often accompanied by congenital defects of other organs and structures, especially the heart and face, and prenatal ultrasound diagnosis of microtia and associated anomalies is of important clinical significance.