Cardiovascular Phenotypic Spectrum of 1p36 Deletion Syndrome

Chromosome 1p36 deletion syndrome is a common genetic anomaly (prevalence: 1 in 5,000–1 in 10,000). Despite reports of cardiovascular involvement, the cardiovascular phenotypic spectrum of patients with 1p36 deletion syndrome is not well characterized. In this article, we reported the clinical course of a full-term African American boy with chromosome 1p36 deletion syndrome and neonatal onset of severe cardiac disease with moderate-to-severe biventricular dysfunction and severe pulmonary hypertension. Early neonatal onset presentation of 1p36 deletion syndrome is rare and might be associated with a more guarded prognosis. This case based study is supplemented by a comprehensive review of cardiovascular involvement in this relatively common genetic syndrome.

Mutation in the CREBBP Gene in the Girl with Toe Walking Syndrome: Clinical Case

Background. Pathogenic variants of the CREBBP gene have been revealed in patients with Rubinstein–Taybi and Menke–Hennekam syndromes, however, the toe walking symptom was not mentioned in these pathologies.Clinical Case Description. The pathogenic nucleotide variant c.5600G>A in heterozygous state in the CREBBP gene was revealed in our 9-year-old female patient with refractory toe walking and developmental speech delay. There were no abnormalities typical for Rubinstein–Taybi syndrome, but there were several signs of Menke–Hennekam syndrome.Conclusion. The genetic anomaly associated with toe walking is described. This observation allows us to critically relate to the hypothesis about the idiopathic genesis of this form of gait disorder at the absence of obvious neurological or orthopedic causes of its development.

Genetic and epigenetic concept of SARS-CoV-2 targets in different renal cancer subtypes

ObjectivesRecent advances in defining the genetic landscape of has shown the host cell- SARS-CoV-2 interaction via ACE2 protein and the presence of at least three additional virus invasion genes including TMPRSS2, FURIN, CD147/BSG. In current study, we investigated the mutation and m-RNA expression patterns of target genes by evaluating the associations between genetic and epigenetic mechanisms in the target genes and susceptibility of SARS-CoV-2 infection of renal cancer subtypes.MethodsWe investigated the mutation and m-RNA expression patterns of our target genes. The promoter methylation profiles of target genes were tested in the UALCAN database.ResultsThe total rate of carrying genetic anomaly in the target genes including was 1.6% and seven mutations, one of which had a pathogenic feature, were detected. The expression analysis results in renal cancer groups showed that while the KIRC and KIRP patients had a lower level of TMPRSS2 than the healthy control, their ACE2 level was high. KICH patients had a higher level of CD147/BSG expression than the healthy group. The promoter methylation levels of ACE2 in KIRC and KIRP were reduced.ConclusionsWe concluded that renal cancer patients may be more sensitive to SARS-CoV-2 infection, which may worsen the prognosis.

Abstract 15410: Post-operative Outcomes After Fontan Procedure in Patients With Heterotaxy and Other Situs Anomalies

Background: Heterotaxy is a multisystem disorder of situs often associated with cardiac, immune, and gastrointestinal abnormalities. Heterotaxy and other situs abnormalities (H/SA) may share ciliary dysfunction as an embryologic origin. Extracardiac manifestations of H/SA may contribute to increased morbidity and mortality after total cavopulmonary connection (Fontan) procedure. We hypothesized that patients with H/SA have worse postoperative outcomes after Fontan than patients without H/SA. Methods: We queried the Pediatric Health Information System (PHIS) database for hospitalizations with ICD-9/10 codes for Fontan procedure in patients aged 1 to 12 years from 2004 to 2019. Those coded for dextrocardia, situs inversus, asplenia/polysplenia, and atrial isomerism were defined as H/SA. Outcomes were in-hospital all-cause mortality or heart transplantation, post-operative ECMO, dialysis, postsurgical length of stay (LOS), and mechanical ventilation >4 days. Outcomes were compared between H/SA and non-H/SA controls with chi-squared or rank-sum test (reported as median (IQR)), and statistically adjusted for surgical center, age, sex, race, genetic anomaly, and pre-operative support with multivariate logistic regression (reported as adjusted odds-ratio (95% CI)). Results: Of 7,897 patients who underwent Fontan at 50 PHIS centers, 1,366 (17%) met criteria for H/SA. Patients with H/SA versus non-H/SA were older (3.7 (2.9-4.8) vs 3.4 (2.7-4.2) years; p<0.001), more female (44 vs 40%, p=0.005), and Asian or Hispanic (35% vs 24%, p<0.001). H/SA had higher rates of discharge death/transplantation (1.9 vs 1.1%, aOR 1.76 (1.02-3.04); p=0.042), post-operative ECMO (3.7 vs 2.3%, aOR 1.73 (1.28-2.33); p<0.001), dialysis (2.1 vs 1.2%, aOR 1.66 (1.06-2.59); p=0.026), prolonged intubation (13.2% vs 7.6%, aOR 1.86 (1.53-2.25); p<0.001), and longer LOS (11 (8-17) vs 9 (7-13) days; p<0.001). Conclusions: We observed increased mortality and postoperative complications in this largest report to date on patients with H/SA after Fontan. We postulate that ciliary dysfunction may contribute to increased lung and renal morbidity, and should be explored further. Adjustment for anatomic complexity and hemodynamics are required for further study .

Congenital Neutropenia Is Also Associated with a High Cancer Risk: A Study from the French Severe Chronic Neutropenia Registry

Introduction: Congenital neutropenia (CN) is characterized by chronic neutropenia due to a constitutional genetic defect.1 To date, these diseases have not been considered to be frequently associated with malignant solid tumors, unlike the risk of secondary myelodysplastic syndrome leukemia, which is well-known in CN. Methods: The French Severe Chronic Neutropenia Registry (FSCNR) has prospectively enrolled CN patients since 1993. Solid tumors, identified during routine patient follow-up, were classified according to WHO criteria. We included localized lymphoma in the spectrum of malignant solid tumors. We calculated the incidence of malignant solid tumors in a cohort of CN patients. Results: Among 868 patients with various CN subtypes followed for a total of 16617 person-years, 24 patients who developed a malignant solid tumor were identified. Those cancers are described in Table 1, including the CN genetic anomaly. Cancers were almost always diagnosed in adulthood, with median age at diagnosis of 38.1 (range 10-72) years; only 3 cancers were diagnosed before age of 20 years. The cancer rate was 1.2% at 30 years of age, 7% at 40 years and 24% at 50 years (Fig. 1A). The risk-of-cancer percentages depended mainly on the associated genetic deficiency. Solid tumors were roughly distributed as follows: 33% among WHIM (CXCR4) patients, 5.3% among GATA2 patients, 2.7% among ELANE patients, 1.9 % among SBDS patients and 0.8% among for all other subtypes combined (Fig. 1B). Human papillomavirus (HPV) was the cause of cancer for 2/5 in WHIM patients and 2/6 in GATA2 patients. Three Lymphoma were identified, one in GATA2 patient and 2 in WHIM patients. Notably, our cohort's follow-up is skewed to the right, with less efficient monitoring of adults, with still limited long-term follow-up beyond 40 years. Therefore, we probably underestimated the solid-tumor risk in CN patients, as many patients, if alive, are no longer followed in hematology centers. Among 103 patients who underwent hematopoietic stem-cell transplantation (HSCT), 76 were long-term survivors. None of them developed solid tumors, which differs strikingly from the high malignancy risk associated with Fanconi anemia post-HSCT. Lastly, the FSCNR also includes and follows patients with idiopathic neutropenia. Among the 232 idiopathic neutropenia patients, followed for a total of 2866 person-years, no malignancy has been observed so far. Conclusion: Our data lead us to advance that CN patients should be considered at risk of developing solid cancers, especially after the age of 30 years. This risk, at first glance, depended on the CN-associated genetic anomaly, with CXCR4 mutation, GATA2, SBDS and ELANE being the most frequent. HSCT was not associated with a higher risk and may, in contrast, be protective. These findings warrant confirmation but represent a compelling reason to prolong follow-up into adulthood of CN patients diagnosed during childhood. No indication was found of a specific high solid-tumor risk associated with idiopathic neutropenia. Reference Donadieu J, Beaupain B, Fenneteau O, Bellanne-Chantelot C. Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history. Br.J.Haematol. 2017; 179(4): 557-574. Acknowledgments: The French SCN registry is supported by grants from Amgen, Chugai, Prolong Pharma, X4 Pharma, Inserm, the Association 111 les Arts, the Association RMHE, the Association Sportive de Saint Quentin Fallavier. The authors thank the association IRIS and Mrs Grosjean and Mr Gonnot(ASSQF), the association Barth France for their support. Disclosures Hermine: Roche: Consultancy; Celgene BMS: Consultancy, Research Funding; AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding; Alexion: Research Funding; Novartis: Research Funding. Blaise:Jazz Pharmaceuticals: Honoraria. Sicre de Fontbrune:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. cohen Beaussant:X4 Pharmaceuticals, Inc.: Current Employment.

Malignant hyperthermia, a rare perioperative complication: case series and literature review

ABSTRACT Malignant hyperthermia is a rare complication of general anesthesia appearing as an acute and potentially lethal hypermetabolic state in people carrying a genetic anomaly expressed in skeletal muscles. Malignant hyperthermia has been scarcely described in sub-Saharan Africa. Herein, we present three cases of malignant hyperthermia occurring in the perioperative period in Cameroon. The authors wish to draw attention to the clinical presentation of this rare but potentially lethal emergency, for timely diagnosis, management and follow-up geared at preventing perioperative mortality.

A-100 Neuropsychological Findings in a Case Involving a Rare Genetic Anomaly (de novo 6q24.2-q25.2 deletion on paternal chromosome 6) Associated with Intrauterine Growth Restriction (IUGR), Autism, OCD and Schizoaffective Disorder

Objective Individuals with deletions of the long arm of chromosome 6 have been known since 1975 with just over 100 cases reported as of 2015. Individuals with deletions involving band 6q25 have a high incidence of intrauterine growth retardation, intellectual disability, dysmorphic features, growth failure, and medical complications (Stagi et al, 2015). Findings will add to the literature base on this genetic anomaly. Methods A 21-year-old male was assessed to differentiate between obsessive vs. psychotic thinking. His history was notable for being born weighing 2300 grams at term, and having feeding, learning and social/emotional difficulties which progressed to OCD in later childhood. At age 15, he was determined to have a de novo 3.7 Mb microdeletion at 6q24.3. Results Neuropsychological assessment of attention, motor and executive functions reveal a variable profile with pockets of strengths relative to his own performance as well as significant normative impairment. Findings represented a significant decline from prior testing at age 10. His verbal memory was below average and his overall attention capacity was impaired. JT’s executive functioning, visual-motor integration, motor speed, and his verbal abstract reasoning were all below average. His non-verbal abstract reasoning and visual perception were intact. On results of objective, projective and neurocognitive testing, JT met criteria for diagnoses of Autism, Obsessive Compulsive Disorder, and Schizoaffective Disorder. Conclusions JT’s developmental history and symptom presentation are complex, revealing significant comorbidity; this case study describes the progression of JT’s difficulties over his lifespan, beginning with feeding difficulties, diagnoses of autism and OCD and progressing to a psychotic disorder.