A Severe Reaction After Phototherapy in a Neonate With X-Linked Protoporphyria.

Protoporphyria is a subtype of porphyria characterized primarily by painful phototoxic skin reactions after light exposure at specific wavelengths. Historically, phototherapy is not contraindicated in patients with protoporphyria since there have not been any reports of phototoxic reactions. However, patients with protoporphyria are advised to avoid direct sunlight. In this case report, we describe a neonate not known to have X-linked protoporphyria who received phototherapy for 1 to 2 hours. Within hours after initiation of phototherapy, this neonate developed a life-threatening reaction consisting of rash over the distribution of phototherapy, acute liver failure with coagulopathy, diffuse hypotonia with diaphragmatic failure, and subsequent acute respiratory failure that required mechanical ventilation. As in this case, patients with protoporphyria-related acute liver failure can have signs and symptoms similar to that of an acute hepatic porphyria attack. Neither neonatal reactions to phototherapy nor liver failure temporally associated with phototherapy have been reported in patients with X-linked protoporphyria. Early recognition of this entity is crucial in light of potential life-threatening complications. Therefore, providers must react quickly when neonates have abnormal reactions to phototherapy and consider protoporphyria in the differential diagnosis.

Iowa Newborn Screening Program Experience with Hemoglobinopathy Screening over the Last Two Decades and Its Increasing Global Relevance.

Hemoglobinopathies are the commonest monogenic disorder worldwide, with approximately seven percent of the world population being carriers of hemoglobinopathies. The healthcare utilization impact of thalassemia has resulted in global public health initiatives to screen for hemoglobinopathies, especially sickle cell disease (SCD). The Iowa Newborn Screening Program (INSP) has been in place for more than 50 years with a primary focus on detecting SCD. Recent changes in migration patterns have led to a global distribution of hemoglobinopathies in the western world, which has translated to an increase in the diagnosis of SCD and the incidental detection of non-sickling hemoglobinopathies within the INSP. This study documents the birth prevalence of hemoglobinopathies diagnosed in newborns through the INSP and highlights the need for newborn screening programs to evolve to meet the healthcare needs of underserved, minority populations.

CRISPR screen identifies CEBPB as contributor to dyskeratosis congenita fibroblast senescence via augmented inflammatory gene response.

Aging is the consequence of intra- and extracellular events that promote cellular senescence. Dyskeratosis congenita (DC) is an example of a premature aging disorder caused by underlying telomere/telomerase-related mutations. Cells from these patients offer an opportunity to study telomere-related aging and senescence. Our previous work has found that telomere shortening stimulates DNA damage responses (DDRs) and increases reactive oxygen species (ROS), thereby promoting entry into senescence. This work also found that telomere elongation via TERT expression, the catalytic component of the telomere-elongating enzyme telomerase, or p53 shRNA could decrease ROS by disrupting this telomere-DDR-ROS pathway. To further characterize this pathway, we performed a CRISPR/Cas9 knockout screen to identify genes that extend life span in DC cells. Of the cellular clones isolated due to increased life span, 34% had a guide RNA (gRNA) targeting CEBPB, while gRNAs targeting WSB1, MED28, and p73 were observed multiple times. CEBPB is a transcription factor associated with activation of proinflammatory response genes suggesting that inflammation may be present in DC cells. The inflammatory response was investigated using RNA sequencing to compare DC and control cells. Expression of inflammatory genes was found to be significantly elevated (P < 0.0001) in addition to a key subset of these inflammation-related genes [IL1B, IL6, IL8, IL12A, CXCL1 (GROa), CXCL2 (GROb), and CXCL5]. which are regulated by CEBPB. Exogenous TERT expression led to downregulation of RNA/protein CEBPB expression and the inflammatory response genes suggesting a telomere length-dependent mechanism to regulate CEBPB. Furthermore, unlike exogenous TERT and p53 shRNA, CEBPB shRNA did not significantly decrease ROS suggesting that CEBPB's contribution in DC cells' senescence is ROS independent. Our findings demonstrate a key role for CEBPB in engaging senescence by mobilizing an inflammatory response within DC cells.

TBX3 and EFNA4 Variant in a Family with Ulnar-Mammary Syndrome and Sagittal Craniosynostosis.

Ulnar-mammary syndrome (UMS) is a rare, autosomal dominant disorder characterized by anomalies affecting the limbs, apocrine glands, dentition, and genital development. This syndrome is caused by haploinsufficiency in the T-Box3 gene (TBX3), with considerable variability in the clinical phenotype being observed even within families. We describe a one-year-old female with unilateral, postaxial polydactyly, and bilateral fifth fingernail duplication. Next-generation sequencing revealed a novel, likely pathogenic, variant predicted to affect the canonical splice site in intron 3 of the TBX3 gene (c.804 + 1G > A, IVS3 + 1G > A). This variant was inherited from the proband's father who was also diagnosed with UMS with the additional clinical finding of congenital, sagittal craniosynostosis. Subsequent whole genome analysis in the proband's father detected a variant in the EFNA4 gene (c.178C > T, p.His60Tyr), which has only been reported to be associated with sagittal craniosynostosis in one patient prior to this report but reported in other cranial suture synostosis. The findings in this family extend the genotypic spectrum of UMS, as well as the phenotypic spectrum of EFNA4-related craniosynostosis.

Co-occurrence of VHL and SDHA Pathogenic Variants: A Case Report.

Von Hippel Lindau(VHL)syndrome presents with cerebellar and spinal hemangioblastomas, renal cell cancer, neuroendocrine pancreatic tumor, and pheochromocytoma and it is caused by germline mutations in the VHL gene. Pathogenic germline variants in the succinate dehydrogenase A (SDHA) gene are associated with paraganglioma and pheochromocytoma. Here we report co-occurrence of germline pathogenic variants in both VHL and SDHA genes in a patient who presented with pancreatic neuroendocrine tumor. As these genes converge on the pseudo-hypoxia signaling pathway, further studies are warranted to determine the significance of co-occurrence of these variants in relation to tumor penetrance, disease severity, treatment response and clinical outcomes in this selected group of patients.

Retinal ciliopathies through the lens of Bardet-Biedl Syndrome: Past, present and future.

The primary cilium is a highly specialized and evolutionary conserved organelle in eukaryotes that plays a significant role in cell signaling and trafficking. Over the past few decades tremendous progress has been made in understanding the physiology of cilia and the underlying pathomechanisms of various ciliopathies. Syndromic ciliopathies consist of a group of disorders caused by ciliary dysfunction or abnormal ciliogenesis. These disorders have multiorgan involvement in addition to retinal degeneration underscoring the ubiquitous distribution of primary cilia in different cell types. Genotype-phenotype correlation is often challenging due to the allelic heterogeneity and pleiotropy of these disorders. In this review, we discuss the clinical and genetic features of syndromic ciliopathies with a focus on Bardet-Biedl syndrome (BBS) as a representative disorder. We discuss the structure and function of primary cilia and their role in retinal photoreceptors. We describe the progress made thus far in understanding the functional and genetic characterization including expression quantitative trait locus (eQTL) analysis of BBS genes. In the future directions section, we discuss the emerging technologies, such as gene therapy, as well as anticipated challenges and their implications in therapeutic development for ciliopathies.

Low incidence of venous thrombosis but high incidence of arterial thrombotic complications among critically ill COVID-19 patients in Singapore.

BACKGROUND: Arterial and venous thrombosis are reported to be common in critically ill COVID-19 patients. METHOD AND RESULTS: This is a national multicenter retrospective observational study involving all consecutive adult COVID-19 patients who required intensive care units (ICU) admission between 23 January 2020 and 30 April 2020 in Singapore. One hundred eleven patients were included and the venous and arterial thrombotic rates in ICU were 1.8% (n = 2) and 9.9% (n = 11), respectively. Major bleeding rate was 14.8% (n = 16). CONCLUSIONS: Critically ill COVID-19 patients in Singapore have lower venous thromboembolism but higher arterial thrombosis rates and bleeding manifestations than other reported cohorts.

Anti-phospholipid syndrome and COVID-19 thrombosis: connecting the dots.

As the coronavirus disease 2019 (COVID-19) pandemic, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly worldwide, it has emerged as a leading cause of mortality, resulting in >1 million deaths over the past 10 months. The pathophysiology of COVID-19 remains unclear, posing a great challenge to the medical management of patients. Recent studies have reported an unusually high prevalence of thromboembolic events in COVID-19 patients, although the mechanism remains elusive. Several studies have reported the presence of aPLs in COVID-19 patients. We have noticed similarities between COVID-19 and APS, which is an autoimmune prothrombotic disease that is often associated with an infective aetiology. Molecular mimicry and endothelial dysfunction could plausibly explain the mechanism of thrombogenesis in acquired APS. In this review, we discuss the clinicopathological similarities between COVID-19 and APS, and the potential role of therapeutic targets based on the anti-phospholipid model for COVID-19 disease.