Multisystem Abnormalities Research Articles

Association of Obstructive Sleep Apnea with co-morbidities in smokers versus non-smokers - an observational study

Obstructive Sleep Apnea (OSA) and smoking are important global health issues that are widely prevalent. Both are independently associated with cardiovascular, respiratory, metabolic, neurological, psychiatric, and endocrinological abnormalities and cancer, leading to premature death. Whether coexistent OSA and smoking worsen multisystem abnormalities is inconclusive. Therefore, this study was done to find the association between OSA and other morbidities among smokers and non-smokers. The objectives of this study were i) to evaluate the association of OSA with co-morbidities in smokers and non-smokers and ii) to compare the severity of OSA in smokers and non-smokers.

The role of multimodal ultrasound in diagnosis of fetal bowel dilatation and prediction of adverse neonatal outcomes: A study of 86 cases in a series of 43,562 births

ObjectiveTo investigate the diagnostic utility of multimodal ultrasound for fetal bowel dilatation (FBD) in different parts of the bowel and to examine its prognostic potential in FBD. MethodsThis retrospective study analyzed 86 fetuses with a dilated bowel identified via ultrasound in a 10-month postnatal follow-up. Both two- and three dimensional (2D and 3D, respectively) ultrasound volume imaging were used to characterize dilation across different bowel sections. The optimal intestinal diameter cut-off values for pathological bowel dilatation were determined and a predictive model for neonatal surgery was developed. ResultsThe 86 cases of dilatation were distributed as follows: duodenal (n = 36); jejunum/ileum (n = 35); and colonic (n = 15). Duodenal dilatations presented the earliest during pregnancy compared to the other 2 groups (24.4 versus [vs.] 29 vs. 33.7 weeks respectively; p < 0.05). Cases with small intestinal dilatation were delivered earlier than those with colonic dilatation (p < 0.05). Infants with duodenal dilatation had the lowest birth weight and the highest rate of multi-system abnormalities (30.6% vs. 5.7% vs. 20%; p < 0.001). More than one-half of the multi-system abnormalities had chromosomal abnormalities (multiple, 54% vs. single, 12.5%; p = 0.015). There were 2 stillbirths, 24 induced labors, 44 postnatal surgeries, and 18 normal cases after birth. In predicting adverse neonatal outcomes of jejunum/ileum dilatation using a cut-off value of 15.5 mm small intestine diameter, sensitivity was 81.5%, specificity was 62.5%, and the area under the receiver operating characteristic curve (AUC) was 0.762 (p < 0.05). For colonic dilatation, using a cut-off value of 21.5 mm colon diameter: sensitivity was 83.3%, specificity was 77.8%, and AUC was 0.861 (p < 0.05). In detecting jejunum/ileum and colonic obstruction, 3D ultrasound demonstrated significantly better diagnostic efficiency than 2D ultrasound (p < 0.05). Using the backward stepwise selection method, a predictive model for neonatal surgery in patients with jejunum/ileum and colonic dilatation was established: logit (P) = −1.58 + (2.32 × polyhydramnios) +(2.0 × ascites) +(1.14 × hyperechogenic bowel). The AUC for the prediction model was 0.874 (p < 0.05), with 76% sensitivity and 94.1% specificity. ConclusionsDuodenal dilatation occurred earlier, with a higher incidence of chromosomal abnormalities and multi-system abnormalities than dilatation of other parts of the bowel. 3D ultrasound played an important role in the detection of jejunum/ileum and colon obstructions. Clinical signs, including polyhydramnios, ascites, and strong echoes in the intestine, can be used to predict neonatal surgery.

Follow-up outcome analysis of 324 cases of early-onset and late-onset mild fetal ventriculomegaly: a retrospective cohort study

BackgroundMild fetal ventriculomegaly (VM) is a nonspecific finding common to several pathologies with varying prognosis and is, therefore, a challenge in fetal consultation. We aimed to perform a constant, detailed analysis of prenatal findings and postnatal outcomes in fetuses with early-onset and late-onset mild ventriculomegaly, and provide a new evidence basis and new perspective for prenatal counseling.MethodsThis is a retrospective cohort study of women with a diagnosis of mild fetal VM between January 2018 and October 2020. The population was divided into two groups according to the gestational ages (GAs) at initial diagnosis: the early-onset group (diagnosed at/before 24+6 weeks) and the late-onset group (diagnosed after 24+6 weeks). Clinical data and pregnancy outcomes were obtained from hospital records. The children’s neurodevelopment status was assessed using the Ages and Stages Questionnaire, Third Edition (ASQ-3) and telephone interviews.ResultsOur study cohort comprised 324 fetuses, out of which 94 (29%) were classified as early-onset group and 230 (71%) late-onset group. Early-onset group was more likely to have concurrent additional abnormalities, whereas in the late-onset group, isolated enlargement was more common (P = 0.01). Unilateral enlargement was more common in the late-onset group (P = 0.05), and symmetrical enlargement in the early-onset group (P < 0.01). In addition, early-onset mild VM cases were more likely to have intrauterine progression (P = 0.03), and many had a higher proportion of complex multisystem abnormalities. Compared with the late-onset group, the early-onset group was more often associated with congenital brain structure malformations. Approximately 11% of fetuses with mild VM had postnatal neurodevelopmental delay/disorders, and the risk was higher in the early-onset group (19.4% vs. 7.4%). Regression analysis showed that the GA at first diagnosis, non-isolated, and intrauterine progression significantly correlated with neurodevelopmental abnormalities.ConclusionsEarly-onset and late-onset mild VM had significantly different ultrasound features and outcomes. Early-onset mild VM may have more complex potential abnormalities and are more likely to predict poor prognosis than the late-onset.

Ophthalmologic findings in Cornelia de Lange syndrome

Introduction : Cornelia de Lange syndrome (CdLS) is a rare disease characterized by multisystem abnormalities, including various ophthalmologic problems. The purpose is to report this kind of rare case and highlight the role of ophthalmologist in visual development optimalization.&#x0D; Case Illustration : A 2-year-old boy with CdLS showing bilateral microcornea, cataracts with “dot opacities,” and chin lifts induced by ptosis. We also examined brow hypertrichosis, synophrys, and long arcuate eyelashes. High myopia and high astigmatism was found in the patient with spherical equivalent of 9.8 D. He was born with low birth weight, microcephaly, anteverted nostrils, depressed nasal bridge, thin upper lip, micrognathia, low posterior hairline, short neck, and syndactili. He also showed psychological lag and developmental impairment. Glasses was then prescribed to prevent amblyopia.&#x0D; Discussion : Individuals with CdLS may have multiple treatable ocular conditions. We recommend that patients have an initial ophthalmic examination after diagnosis of CdLS is first made, in order to establish a baseline and to assess for the presence of abnormalities that would benefit from early intervention. Examination under anesthesia may be required in some patients to adequately assess for any abnormalities, and to obtain a good refraction as well as an inspection of the retinal periphery in children with long axial length. Early intervention may greatly improve function and prevent vision loss due to amblyopia.&#x0D; Conclusion : Initial ophthalmic examination followed by routine annual screening is warranted when a diagnosis of CdLS is made, given that ocular anomalies are present in the majority of patients and may impact vision and daily functioning.

Exploring the origins of neurodevelopmental proteasomopathies associated with cardiac malformations: are neural crest cells central to certain pathological mechanisms?

Neurodevelopmental proteasomopathies constitute a recently defined class of rare Mendelian disorders, arising from genomic alterations in proteasome-related genes. These alterations result in the dysfunction of proteasomes, which are multi-subunit protein complexes essential for maintaining cellular protein homeostasis. The clinical phenotype of these diseases manifests as a syndromic association involving impaired neural development and multisystem abnormalities, notably craniofacial anomalies and malformations of the cardiac outflow tract (OFT). These observations suggest that proteasome loss-of-function variants primarily affect specific embryonic cell types which serve as origins for both craniofacial structures and the conotruncal portion of the heart. In this hypothesis article, we propose that neural crest cells (NCCs), a highly multipotent cell population, which generates craniofacial skeleton, mesenchyme as well as the OFT of the heart, in addition to many other derivatives, would exhibit a distinctive vulnerability to protein homeostasis perturbations. Herein, we introduce the diverse cellular compensatory pathways activated in response to protein homeostasis disruption and explore their potential implications for NCC physiology. Altogether, the paper advocates for investigating proteasome biology within NCCs and their early cranial and cardiac derivatives, offering a rationale for future exploration and laying the initial groundwork for therapeutic considerations.

Biallelic loss-of-function variants in CACHD1 cause a novel neurodevelopmental syndrome with facial dysmorphism and multisystem congenital abnormalities

PurposeWe established the genetic etiology of a syndromic neurodevelopmental condition characterized by variable cognitive impairment, recognizable facial dysmorphism, and a constellation of extra-neurological manifestations. MethodsWe performed phenotypic characterization of 6 participants from 4 unrelated families presenting with a neurodevelopmental syndrome and used exome sequencing to investigate the underlying genetic cause. To probe relevance to the neurodevelopmental phenotype and craniofacial dysmorphism, we established two- and three-dimensional human stem cell-derived neural models and generated a stable cachd1 zebrafish mutant on a transgenic cartilage reporter line. ResultsAffected individuals showed mild cognitive impairment, dysmorphism featuring oculo-auriculo abnormalities, and developmental defects involving genitourinary and digestive tracts. Exome sequencing revealed biallelic putative loss-of-function variants in CACHD1 segregating with disease in all pedigrees. RNA sequencing in CACHD1-depleted neural progenitors revealed abnormal expression of genes with key roles in Wnt signaling, neurodevelopment, and organ morphogenesis. CACHD1 depletion in neural progenitors resulted in reduced percentages of post-mitotic neurons and enlargement of 3D neurospheres. Homozygous cachd1 mutant larvae showed mandibular patterning defects mimicking human facial dysmorphism. ConclusionOur findings support the role of loss-of-function variants in CACHD1 as the cause of a rare neurodevelopmental syndrome with facial dysmorphism and multisystem abnormalities.

Cardio-Facio-Cutaneous Syndrome with an Unusual Presentation of Respiratory Failure Requiring Tracheostomy and Long-term Ventilation

Cardio-facio-cutaenous (CFC) syndrome is a phenotypically diverse disorder that is caused by mutations in the RAS/MEK/ERK signaling pathway, sharing many clinical similarities with Noonan and Costello syndromes. Classic findings of CFC include congenital cardiac anomalies, dysmorphic facial features, dermatological manifestations, and other multisystemic abnormalities. Laryngomalacia, generalized muscle weakness, and hypotonia have been reported phenotypical variants of the disorder. We describe a case of a male newborn with a genetic diagnosis of CFC syndrome who presented with respiratory failure requiring tracheostomy placement and chronic ventilation

Ovarian cyst torsion in Prader-Willi Syndrome

BackgroundPrader-Willi syndrome (PWS) is a genetic disorder involving multiple systems, with an incidence of about 1/10000–25000. Ovarian torsion (OT) is not commonly found in children. Ovarian cyst acts as one of the primary factors resulting in OT. While ovarian cyst torsion with Prader-Willi Syndrome has not been reported before.Case presentationA 12-years old female was admitted to Emergency Department of our hospital with the chief complaint of abdominal pain. The outcomes of physical examination revealed the height of 150 cm, weight of 103 kg, BMI of 45.77 kg/m2. The patient manifested the special facial features, an obese body, with the abdomen distended into a spherical shape. The fat accumulation in the abdomen significantly embarrassed the palpation. The abdominal CT scan indicated a huge cystic mass in the abdominal cavity, sized about 138 mm × 118 mm. According to medical history, the patient was born with low crying and hypotonia, who has developed the uncontrollable eating behavior since 3-years old. These abnormalities led to a speculation of PWS syndrome, so a genetic test was performed and finally confirmed it, concluding a torsion of ovarian cyst with PWS. With the multidisciplinary consultation, a careful treatment strategy containing the control of blood pressure and blood sugar, coenzyme Q10 was administrated to nourish the myocardium and the application of Growth Hormone was developed. All the above preoperative treatments have brought great benefits to patients. Thus promising the successful completion of operation. The postoperative follow-up till now indicated that the abdominal incision was well healed, without operative complications.ConclusionsThis may be the first case report. In the treatment of ovarian cyst torsion, PWS syndrome requires fully consideration, as the latter can lead to multisystem abnormalities, especially the relation to perioperative management, and even fatalities. Genetic testing should be conducted early when PWS was suspected, accompanied with adequate preparation for the perioperative period, the follow-ups of patients should be maintained for a long time after surgery.

Síndrome de varicela congénita discordante en embarazo gemelar: a propósito de un caso

Varicella-zoster virus is a potentially teratogenic agent that can cross the placenta and cause the syndrome of congenital chickenpox, which is characterized by multisystem abnormalities. Fetal involvement has an incidence of less than 2%. The case of a dichorionic-diamniotic twin gestation of 7 weeks, whose mother consulted for symptomatic chickenpox is presented. Several tests were performed that confirmed the diagnosis and acyclovir was prescribed. The evolution of pregnancy was normal until the third trimester, with ultrasound that made us suspect the Varicella involvement of one of the fetuses. The pregnancy came to term and ended by caesarean section, with the affected fetus postnatally diagnosed with congenital chickenpox syndrome. There is no reported case in the current literature of discordant congenital varicella syndrome in twin pregnancy, so it seems a relevant case for study and knowledge of this pathology.

Waardenburg Syndrome Anesthetic Management: Two Cases Experiences

This article presents the anesthetic management of two cases of Waardenburg syndrome (WS) in patients undergoing cochlear implantation. Mutations in genes that control the neural crest cell migration and division during the embryonic period are the hallmark of the hereditary disorder known as WS. White forelock, bright blue eyes, heterochromia from iris coloring deficiency, unusual facial deformities, and sensorineural deafness are the key phenotypic characteristics of WS. The anesthetic management of patients with WS poses challenges due to their multisystem abnormalities.

(199) Anterolateral Thigh Flap Phalloplasty for Micropenis

Abstract Introduction Congenital micropenis is defined as a normally formed penis with a stretched penile length less than 2.5 standard deviations below the mean for that man’s age and ethnicity. Micropenis may present as an isolated condition or with other genital or multi-system abnormalities. Penile reconstruction or phalloplasty may be required where topical and systemic hormonal treatment have failed. The most common flap used for phalloplasty is the radial artery forearm free flap phalloplasty. Other alternatives include the anterolateral thigh (ALT), musculocutaneous latissimus dorsi and abdominal flaps. Objective The aim of this video is to illustrate the technique for penile reconstruction using a pedicled ALT flap without integrated urethra. Methods A 21-year-old man with micropenis and hypospadias from a disorder of sexual differentiation (46XY) presents for penile reconstruction following multiple failed attempts at hypospadias repair. He requested an ALT flap without integrated urethra because he is dependent on a long-term suprapubic catheter due to a hypocontractile bladder. Intraoperative vascular doppler identified 3 perforators from the descending branch of the lateral circumflex iliac artery of the left leg. The flap was designed centred on the perforators with dimensions of 14cm (length), 13cm (width at base) and 12cm (width at tip). The flap was raised carefully and transferred to the recipient groin. The neophallus was constructed and microsurgical anastomosis of the lateral cutaneous of the thigh to one of the dorsal penile nerves with 8/0 nylon was completed. The partially divided left vastus lateralis muscle was re-approximated and the skin edges drawn in and flattened. The left thigh was then resurfaced with a 14/1000 of an inch split-thickness skin graft from the contralateral thigh. All wounds were dressed. Results The man had an uneventful post-operative course with careful vascular monitoring, and he was discharged on day 10. He is currently awaiting glans-sculpting and will eventually proceed with insertion of an inflatable erectile device. Conclusions Penile reconstruction using an ALT flap can be offered to a well-informed and motivated man with a micropenis following appropriate assessment. As shown, the technique requires careful dissection of the perforator vessels and can usually be transferred as a pedicled flap. Pedicled flaps do not require microvascular anastomosis and therefore have a lower risk of vascular compromise. Further esthetic and functional refinements like the insertion of an erectile device are possible in later stages, if desired. Disclosure No

Impact of Variation in Practice in the Prenatal Reporting of Variants of Uncertain Significance by Commercial Laboratories: Need for Greater Adherence to Published Guidelines

ABSTRACT Ultrasound will identify fetal structural anomalies in up to 2% to 3% of pregnancies; these can vary from minor isolated defects to severe multisystem abnormalities. As genetic investigations into the causes can assist with prenatal and perinatal decision-making, various tests exist to assist in this endeavor. Rapid aneuploidy detection and chromosomal microarray analysis are both used for detecting chromosomal aneuploidy and microdeletions or duplications (termed copy number variations) for pregnancies with fetal abnormalities. Approximately 6% of fetuses with identifiable structural abnormalities have pathogenic copy number variations, and 32% have an abnormal karyotype. In the last 8 years, whole exome sequencing (WES) has been used for making a genetic diagnosis in the remaining undiagnosed pregnancies, and a recent meta-analysis determined an exome sequencing diagnostic yield of 31% following nondiagnostic chromosomal microarray analysis or karyotype. Use of exome sequencing is complicated, however, by its association with possibly detecting variants of uncertain significance (VUSs) and pathogenic/likely pathogenic (P/LP) variants in genes possibly noncausal for the prenatal phenotypes. Thus, the value of reporting VUSs is under debate, with various policies worldwide. This study's purpose was to evaluate the clinical impact of WES and targeted panel implementation at the clinical level when fetal structural anomalies suggest a single underlying gene disorder or syndrome. The study focus was the frequency of reporting VUSs, the diagnostic yield, and the contribution of reported VUSs toward a final diagnosis. This retrospective chart review at the Provincial Medical Genetics Program at BC Women's Hospital in Vancouver included patients undergoing WES between January 2016 and December 2020. Amniocentesis was used for obtaining fetal samples, except for 4 cases of sample acquisition at the time of pregnancy termination. A total of 124 patients underwent prenatal WES or panel testing at different commercial laboratories following the identification of fetal structural anomalies by ultrasound. Patients had either WES (n = 90) or panel testing (n = 31), with 3 patients undergoing both, as decided by the ordering clinical geneticist. Genetic diagnoses of variants classified by the laboratory as P or LP were obtained in 20 of 93 patients (21.5%) via prenatal WES and in 9 of 34 patients (26%) who underwent panel testing. The 2 tests' overall diagnostic yield was 23%. Of these, 20 patients (69%) were diagnosed with autosomal dominant disorders. Overall, 32% of patients with panel testing and 42% of patients who had WES had at least 1 VUS, and 23% of WES and 15% of panels reported more than 1 VUS. There was great variation in the reporting of VUSs between laboratories. The study uncovered a lack of strict adherence to guidelines for reporting of prenatal VUSs among various laboratories. One weakness (and strength) of the study is its use of multiple commercial laboratories for the WES, panel testing, and VUS reporting. Although this is beneficial to gain various perspectives (such as the lack of adherence to guidelines), it also diminishes the consistency of the results across the entire study because of varied procedures for diagnoses. In conclusion, this study reports on 124 pregnancies with fetal anomalies at a large tertiary care center experiencing the provision of prenatal WES (or targeted gene panels) with variant interpretation and sequencing outsourced to various laboratories. A result of 23% diagnostic yield for WES and panel testing occurred based on the laboratory-reported LP and P variants. The large number of VUSs reported by laboratories implies significant resource implications due to the time to review evidence and further examine or investigate the fetus and/or parent. This is essential, and the authors emphasize the complex nature of the required posttest genetic counseling. Based on these results, the authors strongly encourage strict adherence to recommendations on VUS reporting in the prenatal setting, with the importance of a multidisciplinary approach bringing laboratory and clinical expertise of prenatal genomics and genetics together.

White-Sutton syndrome and congenital heart disease: case report and literature review

BackgroundWhite-Sutton syndrome is an autosomal dominant neurodevelopmental disorder caused by heterozygous mutation in POGZ (Pogo Transposable Element Derived with ZNF Domain). This syndrome is characterized by delayed psychomotor development apparent in infancy and abnormal facial features. To date, 80 cases have been reported in the literature; however, the phenotypic characterizations remain incomplete.Case presentationWe herein describe a 2-year-old girl harboring a novel frameshift de novo POGZ variant: c.2746del (p.Thr916ProfsTer12). This patient presented with multisystem abnormalities affecting the digestive tract and neurological functioning, as well as congenital heart disease, which involved an atrial septal defect (18 × 23 × 22 mm) with pulmonary arterial hypertension (42 mmHg). The relationship between congenital heart disease and White-Sutton syndrome as described in both the GeneReview and OMIM databases (#616,364) remains unclear. A review of the current literature revealed 18 cases of White-Sutton syndrome with POGZ variants and congenital heart disease, and we summarize their clinical features in this study.ConclusionsOur findings based on the present case and those in the literature indicate a relationship between POGZ mutation and congenital heart disease.

V11-03 PENILE RECONSTRUCTION FOR CONGENITAL MICROPENIS WITH THE ANTEROLATERAL THIGH PEDICLED FLAP

You have accessJournal of UrologyCME1 Apr 2023V11-03 PENILE RECONSTRUCTION FOR CONGENITAL MICROPENIS WITH THE ANTEROLATERAL THIGH PEDICLED FLAP Aurélie Schirmann, Nim Christopher, David Ralph, and Wai Gin Lee Aurélie SchirmannAurélie Schirmann More articles by this author , Nim ChristopherNim Christopher More articles by this author , David RalphDavid Ralph More articles by this author , and Wai Gin LeeWai Gin Lee More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003337.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Congenital micropenis is defined as a normally formed penis with a stretched penile length less than 2.5 standard deviations below the mean for that man’s age and ethnicity. Micropenis may present as an isolated condition or with other genital or multi-system abnormalities. Penile reconstruction or phalloplasty may be required where topical and systemic hormonal treatment have failed. The most common flap used for phalloplasty is the radial artery forearm free flap phalloplasty. Other alternatives include the anterolateral thigh (ALT), musculocutaneous latissimus dorsi and abdominal flaps.The aim of this video is to illustrate the technique for penile reconstruction using a pedicled ALT flap without integrated urethra. METHODS: A 21-year-old man with micropenis and hypospadias from a disorder of sexual differentiation (46XY) presents for penile reconstruction following multiple failed attempts at hypospadias repair. He requested an ALT flap without integrated urethra because he is dependent on a long-term suprapubic catheter due to a hypocontractile bladder.Intraoperative vascular doppler identified 3 perforators from the descending branch of the lateral circumflex iliac artery of the left leg. The flap was designed centred on the perforators with dimensions of 14cm (length), 13cm (width at base) and 12cm (width at tip). The flap was raised carefully and transferred to the recipient groin. The neophallus was constructed and microsurgical anastomosis of the lateral cutaneous of the thigh to one of the dorsal penile nerves with 8/0 nylon was completed. The partially divided left vastus lateralis muscle was re-approximated and the skin edges drawn in and flattened. The left thigh was then resurfaced with a 14/1000 of an inch split-thickness skin graft from the contralateral thigh. All wounds were dressed. RESULTS: The man had an uneventful post-operative course with careful vascular monitoring, and he was discharged on day 10. He is currently awaiting glans-sculpting and will eventually proceed with insertion of an inflatable erectile device. CONCLUSIONS: Penile reconstruction using an ALT flap can be offered to a well-informed and motivated man with a micropenis following appropriate assessment. As shown, the technique requires careful dissection of the perforator vessels and can usually be transferred as a pedicled flap. Pedicled flaps do not require microvascular anastomosis and therefore have a lower risk of vascular compromise. Further aesthetic and functional refinements like the insertion of an erectile device are possible in later stages, if desired. Source of Funding: None declared © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e999 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Aurélie Schirmann More articles by this author Nim Christopher More articles by this author David Ralph More articles by this author Wai Gin Lee More articles by this author Expand All Advertisement PDF downloadLoading ...

Coats' Disease in a Patient With Cornelia de Lange Syndrome: Management With Laser and Bevacizumab.

Cornelia de Lange syndrome is a congenital disorder with multisystem abnormalities including multiple ocular findings. The authors report a case of Coats' disease in a patient with Cornelia de Lange syndrome who was successfully treated with laser and intravitreal bevacizumab. This case demonstrates the importance of fluorescein angiography in making the diagnosis and directing treatment and the efficacy of combined laser with intravitreal anti-vascular endothelial growth factor therapy for persistent vascular leakage associated with Coats' disease in Cornelia de Lange syndrome. [J Pediatr Ophthalmol Strabismus. 2023;60(4):e45-e48.].

P.07 Characterization of MRI brain abnormalities in X-linked myotubular myopathy

X linked myotubular myopathy (XLMTM) is a rare, typically severe, congenital myopathy that often results in significant weakness from birth, with a need for mechanical ventilation and wheelchair assistance. It is caused by a mutation in the myotubularin (<i>MTM1</i>) gene, whose gene product plays an important role in muscle cell differentiation. In addition to the important role of MTM1 in skeletal muscle, there is emerging evidence that patients with XLMTM can have multisystem abnormalities, including liver concerns and cognitive impairment. An organ system of particular interest for us is the Central Nervous System (CNS). Brain involvement has been described in different neuromuscular disorders, though not typically in congenital myopathies. In contrast to other congenital myopathies, there are a handful of case reports and informal observations of structural brain abnormalities in XLMTM. However, there has not yet been a comprehensive review of neuroimaging features in XLMTM. We have developed a multi-site study, aiming to retrospectively gather brain MRI and relevant clinical information for patients with XLMTM around the world. Our goals are to define the relative prevalence of CNS structural anomalies in XLMTM and to describe the common features of brain MRIs from XLMTM patients. In particular, we hope to elucidate unifying or common changes amongst many patients, and whether they correlate with birth-related injury, genotype, clinical phenotype, long-term outcome, or survival. We hypothesize that there is unrecognized brain involvement XLMTM, as will be reflected by brain MRI findings, and that these changes will correlate with both clinical outcomes and the degree of illness/adversity. In addition to study design, we will present our findings from the first cases collected for the study.

1166-P: Distinct Phenotypes of Multiorgan Abnormalities in Long COVID and Type 2 Diabetes Identified by Multiparametric Magnetic Resonance Imaging

Introduction: Both long COVID and Type 2 Diabetes (T2D) are multi-system conditions requiring multi-organ assessment to monitor organ health and detect co-morbidities earlier. Here, we defined multi-organ abnormalities in both patient groups with a rapid, non-contrast MRI scan. Methods: We recruited 135 long COVID patients (NCT04369807) and 135 T2D patients (NCT04114682) . MRI data were acquired for organ-specific measures of size, fat deposition and fibroinflammation (CoverScan®, Perspectum Ltd.) . Reference values were based on 92 controls and published literature. Results: There was a high prevalence of organ abnormality in both patient groups (Figure, left) , including increased fat deposition (steatosis) in liver, pancreas, and kidney (Figure, right) . 35% of T2D patients had clustering of abnormalities involving at least 2 organs, compared to 23% in long COVID. Abnormalities affecting the liver and renomegaly were more common in T2D than in long COVID. Considering only obese patients, liver fibroinflammation, hepatomegaly, and renomegaly remained significantly more prevalent in T2D than in long COVID. Conclusion: Multi-organ MRI assessment can enrich the current blunt assessment of multi-system abnormalities in diverse disease states to inform earlier intervention and treatments. Disclosure N.Eichert: Employee; Perspectum Ltd. G.Kemp: None. D.Cuthbertson: Other Relationship; AstraZeneca, Novo Nordisk. A.Banerjee: Research Support; AstraZeneca. A.Telford: Employee; Perspectum Ltd. A.Roca-fernandez: Employee; Perspectum Ltd. A.Hamid: None. H.B.Thomaides-brears: Employee; Perspectum Ltd, Stock/Shareholder; Perspectum Ltd. A.Dennis: Employee; Perspectum Ltd. R.Banerjee: Employee; Perspectum Ltd., Other Relationship; Perspectum Ltd., Stock/Shareholder; Perspectum Ltd. S.Ali: Other Relationship; NICE committee for diabetes. G.Thanabalasingham: Speaker's Bureau; Boehringer Ingelheim International GmbH. Funding EU RADIcAL grant, Innovate UK

A multisystem, cardio-renal investigation of post-COVID-19 illness

The pathophysiology and trajectory of post-Coronavirus Disease 2019 (COVID-19) syndrome is uncertain. To clarify multisystem involvement, we undertook a prospective cohort study including patients who had been hospitalized with COVID-19 (ClinicalTrials.gov ID NCT04403607). Serial blood biomarkers, digital electrocardiography and patient-reported outcome measures were obtained in-hospital and at 28–60 days post-discharge when multisystem imaging using chest computed tomography with pulmonary and coronary angiography and cardio-renal magnetic resonance imaging was also obtained. Longer-term clinical outcomes were assessed using electronic health records. Compared to controls (n = 29), at 28–60 days post-discharge, people with COVID-19 (n = 159; mean age, 55 years; 43% female) had persisting evidence of cardio-renal involvement and hemostasis pathway activation. The adjudicated likelihood of myocarditis was ‘very likely’ in 21 (13%) patients, ‘probable’ in 65 (41%) patients, ‘unlikely’ in 56 (35%) patients and ‘not present’ in 17 (11%) patients. At 28–60 days post-discharge, COVID-19 was associated with worse health-related quality of life (EQ-5D-5L score 0.77 (0.23) versus 0.87 (0.20)), anxiety and depression (PHQ-4 total score 3.59 (3.71) versus 1.28 (2.67)) and aerobic exercise capacity reflected by predicted maximal oxygen utilization (20.0 (7.6) versus 29.5 (8.0) ml/kg/min) (all P < 0.01). During follow-up (mean, 450 days), 24 (15%) patients and two (7%) controls died or were rehospitalized, and 108 (68%) patients and seven (26%) controls received outpatient secondary care (P = 0.017). The illness trajectory of patients after hospitalization with COVID-19 includes persisting multisystem abnormalities and health impairments that could lead to substantial demand on healthcare services in the future.

A novel DPH5-related diphthamide-deficiency syndrome causing embryonic lethality or profound neurodevelopmental disorder

Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs). Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate-ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants. DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2. We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.

Deep phenotyping and association with diagnostic yield of prenatal exome sequencing for fetal brain abnormalities

To evaluate whether deep prenatal phenotyping of fetal brain abnormalities (FBA) increases diagnostic yield of trio-exome sequencing (ES) compared to standard phenotyping. Prospective prenatal ES study recruiting from multiple sites. Participants were eligible if a fetal anomaly was diagnosed and subsequently found to have a normal microarray. Deep phenotyping was defined as phenotype based on targeted ultrasound plus pre or postnatal MRI, autopsy, and/or known phenotypes of other affected family members. Standard phenotyping was defined as phenotype based on targeted ultrasound alone. Fetal brain abnormalities were categorized by major brain findings on prenatal ultrasound, with some cases having more than one FBA finding. Cases with diagnostic ES results were compared to those with non-diagnostic results by available phenotyping as well as diagnosed FBA. Data were analyzed using t-test, chi-square, and pairwise comparisons as appropriate. A total of 153 trios were sequenced, of which 62 (41%) had an FBA diagnosed on prenatal ultrasound. Of the 62 trios with FBA, 21 (34%) cases had a diagnostic ES result and 41 (66%) had a non-diagnostic result. There was no difference in the number of cases with multisystem organ abnormalities between groups (90% vs 72%, p=0.12). Individual modalities of deep phenotyping were not associated with diagnostic ES results (Table 1). Anomalies of the posterior fossa and corpus callosum were the most common FBA identified (Table 2). Those with deep phenotyping available were not more likely to receive a diagnostic ES result (unadjusted OR 1.5, [0.5, 4.3] p=0.4). Neural tube defect was significantly associated with receipt of a non-diagnostic ES result (0% vs 17%, p=0.04). Deep phenotyping was not associated with increased diagnostic yield of ES for FBA in this small cohort. Of the FBA identified, neural tube defects were associated with non-diagnostic ES results. Further study is needed to identify specific prenatal and postnatal phenotypic variables that may increase diagnostic yield in the context of sequencing efforts.View Large Image Figure ViewerDownload Hi-res image Download (PPT)