An adult with cystathionine beta-synthase deficiency, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, and deafness: A case report.

Massive sequencing platforms allow the identification of complex clinical phenotypes involving more than one autosomal recessive disorder. In this study, we report on an adult patient, born to a related couple (third degree cousins), referred for genetic evaluation due to ectopia lentis, deafness and previous diagnosis of juvenile idiopathic arthritis. He was biochemically diagnosed as having Classic Homocystinuria (HCU); Sanger sequencing of the CBS gene showed the genotype NM_000071.2(CBS):c.[833T>C];[833T>C], compatible with the diagnosis of pyridoxine-responsive HCU. As he also had symptoms not usually associated with HCU, exome sequencing was performed. In addition to the variants found in the Sanger sequencing, the following variants were identified: NM_001256317.1(TMPRSS3):c.[413C>A];[413C>A]; and the NM_005807.6(PRG4):c.[3756dup]:[3756dup], confirming the diagnosis of autosomal recessive nonsyndromic deafness and Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome (CACP), respectively. Genomic analysis allowed the refinement of the diagnosis of a complex case and improvement of the patient's treatment.

Genetic Testing Goes Beyond Imaging and Histological Evaluation in Pleuroparenchymal Fibroelastosis.

BACKGROUND: Lung biopsy remains the gold standard in the diagnosis of fibrotic interstitial lung disease (F-ILD), but there is a growing appreciation of the role of pathogenic gene variants in telomere and surfactant protein genes, especially in familial pulmonary fibrosis (FPF). Pleuroparenchymal fibroelastosis (PPFE) is a rare disease that can coexist with different patterns of F-ILD, including FPF. It can be progressive and often leads to respiratory failure and death. This study tested the hypothesis that genetic testing goes beyond radiological and histological findings in PPFE and other F-ILD further informing clinical decision-making for patients and affected family members by identifying pathological gene variants in telomere and surfactant protein genes. METHODS: This is a retrospective review of 70 patients with F-ILD in the setting of FPF or premature lung fibrosis. Six out of 70 patients were diagnosed with PPFE based on radiological or histological characteristics. All patients underwent telomere length evaluation in peripheral blood by Flow-FISH or genetic testing using a customized exome-based panel that included telomere and surfactant protein genes associated with lung fibrosis. RESULTS: Herein, we identified six individuals where radiographic or histopathological analyses of PPFE were linked with telomere biology disorders (TBD) or variants in surfactant protein genes. Each case involved individuals with either personal early-onset lung fibrosis or a family history of the disease. Assessments of telomere length and genetic testing offered insights beyond traditional radiological and histopathological evaluations. CONCLUSION: Detecting anomalies in TBD-related or surfactant protein genes can significantly refine the diagnosis and treatment strategies for individuals with PPFE and other F-ILD.

Variante incomum da síndrome de Herlyn- -Werner-Wunderlich: relato de caso / Unsual Herlyn-Werner-Wunderlich syndrome: case report

Malformações müllerianas correspondem a variações anatômicas do trato repro- dutor feminino. Comumente assintomáticas, o diagnóstico e a verdadeira incidên- cia são difíceis de determinar. A síndrome de Herlyn-Werner-Wunderlich, clas- sicamente descrita pela tríade útero didelfo, hemivagina cega e agenesia renal ipsilateral também pode ter variações diferentes. Em virtude da mesma origem embrionária dos tratos genital e urinário, anomalias renais devem ser investigadas nesses casos, sendo a mais comum a agenesia renal. Este artigo relata o caso de uma paciente de 18 anos, do sexo feminino, com história de piocolpo por cinco anos. Em propedêutica complementar, foi identificado útero com septação com- pleta associado a hemissepto de terço superior de vagina, formação de piocolpo e agenesia renal à direita. Apesar de não ser a definição clássica, o quadro está incluído nos casos de síndrome de Herlyn-Werner-Wunderlich.

Mullerian malformations correspond to anatomical variations of the female repro- ductive tract. Commonly asymptomatic, the diagnosis and true incidence are difficult to determine. The Herlyn-Werner-Wunderlich syndrome, classically described by the triad: uterus didelphus, blind hemivagina and ipsilateral renal agenesis, can also have different variations. Due to the same embryonic origin of the genital and urinary tracts, renal anomalies must be investigated in these cases, the most common being renal agenesis. This article reports the case of an 18-year-old female patient with a 5-year history of pyocolpus. In complementary exams, a uterus with complete septa- tion was identified, associated with a hemiseptum in the upper third of the vagina, formation of pyocolpus and renal agenesis on the right side. Despite not being the classic definition, it is included in the cases of Herlyn-Werner-Wunderlich syndrome.

Cytokine profiling in patients with hepatic glycogen storage disease: Are there clues for unsolved aspects?

INTRODUCTION: Hepatic Glycogen Storage Diseases (GSD) are rare genetic disorders in which the gluconeogenesis pathway is impaired. Cytokines control virtually every aspect of physiology and may help to elucidate some unsolved questions about phenotypes presented by GSD patients. METHODS: This was an exploratory study in which 27 GSD patients on treatment (Ia = 16, Ib = 06, III = 02, IXα = 03) and 24 healthy age- and sex-matched subjects had plasma samples tested for a panel of 20 cytokines (G-CSF,GM-CSF, IL-1α,IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-13, IL-17A, GRO, IP-10/CXCL10, MCP-1/CCL2, MIP-1α/CCL3, MIP-1ß/CCL4, MDC/CCL22, IFN-γ, TNF-α, TNF-ß, VEGF) through a multiplex kit and analyzed in comparison to controls and among patients, regarding to clinical features as anemia, hepatic adenocarcinoma and triglyceride levels. RESULTS: Patients (GSD-Ia/III/IX) presented reduced levels of IL-4 (p = 0.040), MIP-1α/CCL3 (p = 0.003), MDC/CCL22 (p < 0.001), TNF-ß (p = 0.045) and VEGF (p = 0.043) compared to controls. When different types of GSD were compared, G-CSF was higher in GSD-Ib than -Ia (p < 0.001) and than -III/IX (p = 0.033) patients; IL-10 was higher in GSD-Ib than in GSD-Ia patients (p = 0.019); and GSD-III/IX patients had increased levels of IP-10/CXCL10 than GSD-Ib patients (p = 0.019). When GSD-I patients were gathered into the same group and compared with GSD-III/IX patients, IP10/CXCL10 and MCP-1 were higher in the latter group (p = 0.005 and p = 0.013, respectively). GSD-I patients with anemia presented higher levels of IL-4 and MIP-1α in comparison with patients who had not. Triglyceride level was correlated with neutrophil count and MDC levels on GSD-Ia patients without HCA. CONCLUSION: Altogether, altered levels of cytokines in GSD-I patients reflect an imbalance in immunoregulation process. This study also indicates that neutrophils and some cytokines are affected by triglyceride levels, and future studies on the theme should consider this variable.

Fotobiomodulação na Síndrome de Stevens-Johnson no Câncer de Mama Metastático: Relato de Caso / Photobiomodulation in Stevens-Johnson Syndrome in a Metastatic Breast Cancer: Case Report / La Fotobiomodulación en el Síndrome de Stevens-Johnson en el Cáncer de Mama Metastásico: Informe de Caso

Introdução: A síndrome de Stevens-Johnson é uma condição rara e potencialmente fatal que requer diagnóstico precoce e tratamento adequado para garantir bom prognóstico. Em virtude da complexidade da síndrome e da falta de tratamento padrão para as feridas, o uso da fotobiomodulação tem sido discutido. Relato do caso: Mulher, 30 anos, com câncer de mama metastático, portadora das síndromes de Stevens-Johnson e de Li-Fraumeni Like, em uso da fotobiomodulação como estratégia adjuvante no tratamento da dor e das feridas na pele. As feridas cutâneas eritematosas envolveram quase toda a superfície corpórea, com lesões escamosas, crostosas e bolhosas, dolorosas, com pontos hemorrágicos em região posterior de ambos os lóbulos das orelhas e na região occipital, dificultando a acomodação da paciente em decúbito lateral e em posição semirreclinada. Foram realizadas duas aplicações da fotobiomodulação (vermelho, com comprimento de onda de 660 nm) nas regiões occipital e de orelhas, com dose de 2 Joules por ponto; e 4 Joules em região escapular para analgesia (infravermelho, com comprimento de onda de 808 nm). Ambas as aplicações foram seguidas de mobilização e liberação miofascial na região escapular. Em 48 horas, houve regressão das lesões cutâneas e melhora da dor, facilitando posicionamento adequado e indolor no leito. Após 15 sessões de fisioterapia, a paciente recebeu alta hospitalar. Conclusão: O uso da fotobiomodulação se mostrou eficaz para o tratamento complementar da fase aguda da síndrome de Stevens-Johnson no que diz respeito à regeneração tecidual e analgesia.

Introduction: Stevens-Johnson syndrome is a rare but potentially fatal condition, which requires early diagnosis and treatment to ensure good prognosis. Due to the complexity of the syndrome and the lack of a standard wound care treatment, the use of photobiomodulation has been discussed. Case report: A 30-year-old woman with metastatic breast cancer and Stevens-Johnson and Li-Fraumeni Like syndromes using photobiomodulation as an adjuvant strategy in the treatment of pain and skin wounds. The erythematous cutaneous lesions involved almost the entire body surface with painful, scaly, crusted and bullous lesions with bleeding spots in the posterior region of both ears lobes and in the occipital region which made it difficult to accommodate the patient in lateral decubitus and in semi-recumbent position. Two photobiomodulation applications (red, with a wavelength of 660 nm) were performed, where lesions in the occipital region and ears were treated with a dose of 2 Joules per point and 4 Joules in the scapular region for pain relief (infrared, with a wavelength of 808 nm), followed by mobilization and myofascial release in the scapular region. In 48 hours, the cutaneous lesions reduced, and the pain improved, which facilitated the adequate and painless positioning in bed. After 15 physiotherapy sessions, the patient was discharged. Conclusion: Photobiomodulation has been shown to be effective in the complementary treatment of the acute phase of Stevens-Johnson Syndrome regarding tissue regeneration and analgesia.

Introducción: El síndrome de Stevens-Johnson es una condición rara y potencialmente fatal que requiere diagnóstico temprano y tratamiento adecuado para asegurar un buen pronóstico. Debido a la complejidad del síndrome y la falta de un tratamiento estándar de las heridas, se ha discutido el uso de fotobiomodulación. Informe del caso: Mujer, 30 años, con cáncer de mama metastásico, portadora de los síndromes de Stevens-Johnson y Li-Fraumeni Like en uso de la fotobiomodulación como estrategia adyuvante para el tratamiento del dolor y las heridas cutáneas. Las heridas cutáneas eritematosas comprometían casi toda la superficie corporal, con lesiones dolorosas, descamativas, costrosas y ampollosas, con puntos hemorrágicos en la región posterior de ambos lóbulos de las orejas y en la región occipital, que dificultaban la acomodación del paciente en decúbito lateral y en posición cómoda semirrecostada. Se realizaron dos aplicaciones de fotobiomodulación (rojo, con longitud de onda de 660 nm) en región occipital y auricular con dosis de 2 Joules por punto; y 4 Joules en la región escapular para analgesia (infrarrojo, con longitud de onda de 808 nm). Ambas aplicaciones fueron seguidas de movilización y liberación miofascial en la región escapular. En 48 horas hubo una regresión de las lesiones cutáneas y mejoría del dolor, lo que facilitó una adecuada e indolora posición en la cama. Después de 15 sesiones de fisioterapia, la paciente fue dada de alta del hospital. Conclusión: El uso de la fotobiomodulación demostró ser efectivo para el tratamiento complementario de la fase aguda del síndrome de Stevens-Johnson en lo que respecta a la regeneración tisular y la analgesia.

Panorama da saúde de um grupo de servidores de uma universidade pública de São Paulo: síndrome metabólica, índices antropométricos e adequação da dieta / Health overview of a group of public university employees in São Paulo: metabolic syndrome, anthropometric indices, and dietary adequacy

A obesidade constatada como um problema de saúde pública está relacionada ao maior risco por doenças cardiovasculares, hipertensão arterial, resistência à insulina, diabetes tipo II, dislipidemia e síndrome metabólica. Aliados ao estilo de vida sedentário e a uma dieta inadequada, elevados índices de massa corporal circunferência cintura e relação cintura e estatura foram constatados. O objetivo desse trabalho foi caracterizar o quadro de Síndrome Metabólica, em adultos (mulheres 89 e 46 homens) pelos índices antropométricos, dados bioquímicos e a adequação da dieta. Trata-se de um estudo epidemiológico descritivo realizado com 135 servidores não docentes, categoria funcional básico, técnico e superior, de uma universidade pública no Estado de São Paulo. Foram coletados dados sóciodemográficos, inquérito alimentar, de peso, estatura, circunferência da cintura, medidas de pressão arterial e exames bioquímicos: glicemia, triglicérides e HDL-c (High-density lipoprotein-c). Resultados: 36 % dos participantes apresentou sobrepeso e 28% obesidade e 62,0% da amostra apresentou algum dos parâmetros bioquímicos alterados. O percentual de Síndrome Metabólica foi de 13,3% nos homens e 19,2% nas mulheres. Na relação cintura estatura, 81 % apresentaram índices no padrão de risco de doenças cardiovasculares ou metabólicas, a dieta inadequada nos três macronutrientes foi constatada nos participantes em 34,9% com Indice de massa corporal alterado e 37,0% com Circunferência da cintura alterado. Os resultados mostraram que a caracterização da síndrome metabólica com os parâmetros avaliados aliados à análise da dieta estabelece um quadro com informações que direcionam ações para programas até mesmo dentro de Instituições universitárias e ligadas a área da Saúde.

Obesity, recognized as a public health issue, is associated with an increased risk of cardiovascular diseases, high blood pressure, insulin resistance, type II diabetes, dyslipidemia, and metabolic syndrome. Coupled with a sedentary lifestyle and inadequate diet, elevated body mass index, waist circumference, and waist-to-height ratio have been observed. This study aimed to characterize the Metabolic Syndrome profile in adults (89 women and 46 men) using anthropometric indices, biochemical data, and dietary adequacy. This descriptive epidemiological study was conducted with 135 non-teaching staff members, including basic, technical, and higher categories, at a public university in Sao Paulo. Sociodemographic data, dietary surveys, weight, height, waist circumference, blood pressure measurements, and biochemical tests (glucose, triglycerides, and High-density lipoprotein-c) were collected. Results: 36% of participants were overweight, 28% were obese, with 62.0% of the sample showing altered biochemical parameters. The prevalence of Metabolic Syndrome was 13.3% in men and 19.2% in women. In the waist-to-height ratio, 81% had cardiovascular or metabolic disease risk range indices. An inadequate diet across all three macronutrients was observed in 34.9% of participants with altered body mass index and 37.0% with altered waist circumference. The results revealed that characterizing metabolic syndrome with the evaluated parameters and dietary analysis provides insights that guide actions for programs, even within university institutions and those connected to the health field.

Exome sequencing can misread high variant allele fraction of somatic variants in UBA1 as hemizygous in VEXAS syndrome: a case report.

BACKGROUND: VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome) is a recently described syndrome caused by a somatic missense variant at the methionine-41 (p.(Met41)) position in the ubiquitin-like modifier activating enzyme 1 (UBA1) in Xp11.3. Germline pathogenic variants in UBA1 are associated with a distinct phenotype: a syndrome with severe neurologic features associated with loss of anterior horn cells and infantile death denominated X-Linked Spinal Muscular Atrophy 2 (SMAX2) (OMIM 301,830). CASE PRESENTATION: We report a male individual with the phenotype of VEXAS syndrome that was initially identified through exome sequencing (ES) as having a hemizygous germline variant in UBA1 due to high variant allele frequency (VAF). Research Sanger sequencing was able to confirm the absence of the p.(Met41Val) variant in a skin biopsy and in gastric mucosa tissue sample confirming the variant happened as a postzygotic event. CONCLUSIONS: The present case exemplifies the diagnostic challenge that was imposed by the high VAF detected by ES that failed to correctly demonstrate that the variant was in a mosaic state. Sequencing of different tissues should be considered when there is conflict between the UBA1 variant status and the clinical findings.

A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode.

The leucine-rich glioma-inactivated (LGI) family consists of four highly conserved paralogous genes, LGI1-4, that are highly expressed in mammalian central and/or peripheral nervous systems. LGI1 antibodies are detected in subjects with autoimmune limbic encephalitis and peripheral nerve hyperexcitability syndromes (PNHSs) such as Isaacs and Morvan syndromes. Pathogenic variations of LGI1 and LGI4 are associated with neurological disorders as disease traits including familial temporal lobe epilepsy and neurogenic arthrogryposis multiplex congenita 1 with myelin defects, respectively. No human disease has been reported associated with either LGI2 or LGI3. We implemented exome sequencing and family-based genomics to identify individuals with deleterious variants in LGI3 and utilized GeneMatcher to connect practitioners and researchers worldwide to investigate the clinical and electrophysiological phenotype in affected subjects. We also generated Lgi3-null mice and performed peripheral nerve dissection and immunohistochemistry to examine the juxtaparanode LGI3 microarchitecture. As a result, we identified 16 individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. Deep phenotypic characterization showed LGI3 LoF causes a potentially clinically recognizable PNHS trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons. Our data demonstrate bi-allelic LoF variants in LGI3 cause a clinically distinguishable disease trait of PNHS, most likely caused by disturbed Kv1 channel distribution in the absence of LGI3.

Risk factors and clinical outcomes of acute esophageal necrosis: retrospective case series of a rare disease with "black" prognosis.

Acute esophageal necrosis is a rare syndrome classically characterized by black distal esophagus with a complex pathophysiology that usually involves a combination of esophageal ischemia, gastroesophageal reflux and impaired mucosal reparative mechanisms. We retrospectively analyzed the main risk factors, clinical characteristics and outcome in all patients diagnosed with acute esophageal necrosis between January 2015 and December 2020 at our center. Ten patients were identified in a total of 26854 upper digestive endoscopies (0.04%). Most patients were male (8/10) and the mean age of presentation was 71.1 years. The most common presenting symptoms were melena and hematemesis and half the patients required red blood cell transfusion. The most common risk factors were hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, peripheral artery disease, coronary artery disease, cerebrovascular disease, heart failure and malignancy. Compromised hemodynamic state was the most common precipitating event in four patients. Other recognized precipitating events included surgical interventions, decompensated heart failure, gastrointestinal bleeding from gastric malignancy and methotrexate. Endoscopic findings revealed diffuse and circumferential black distal esophagus with abrupt transition at gastroesophageal junction and variable proximal extension at presentation. The 1-month mortality rate was 30%, mostly from severe underlying illness. In conclusion, acute esophageal necrosis is a rare cause of upper gastrointestinal bleeding that should be suspected in older patients with multiple comorbidities. Although associated with a high mortality rate, appropriate treatment may result in favorable outcome in most patients.

Vaginal stenosis in women with cervical or endometrial cancer after pelvic radiotherapy: a cross-sectional study of vaginal measurements, risk for sexual dysfunction and quality of life.

INTRODUCTION AND HYPOTHESIS: Radiotherapy (RT) for cervical (CC) and endometrial cancer (EC) is known to lead to vaginal stenosis (VS), but the comparison between vaginal anatomical measurements and the risk of sexual dysfunction presents a wide variety of results among the literature. Thus, we sought to assess the prevalence of VS, vaginal measurements, sexual dysfunction and QOL in women with CC and EC submitted to pelvic RT with or without previous surgery. METHODS: Cross-sectional study that included 61 women with CC and 69 with EC. VS was classified by the Common Terminology Criteria for Adverse Effects version 5.0 (CTCAE v5.0), sexual function by the validated Female Sexual Function Index (FSFI) and QOL by the validated World Health Organization questionnaire (WHOQOL-BREF). Acrylic cylinders were used for vaginal measurements. Uni-/multivariate analyses to address factors associated with VC in both groups were performed. RESULTS: The prevalence of VS was 79% and 67% within patients with CC and EC, respectively. Vagina length was decreased in both groups without statistical difference (7.2 ± 1.7 vs. 6.6 ± 1.8;p = 0.072). Vaginal diameter was significantly higher (p = 0.047) in women with EC (25.4 ± 6.3) than in those with CC (23.1 ± 5.7). Sexual dysfunction was highly prevalent for both CC and EC (88% vs. 91%; p = 0.598). There was no difference in all WHOQOL-BREF domains between women with CC and EC. CONCLUSIONS: VS is highly prevalent in CC and EC patients, with vaginal length decreased in both groups but with a higher vaginal diameter in those with EC. Nevertheless, sexual dysfunction is highly prevalent in both groups.

De novo PBX1 variant in a patient with glaucoma, kidney anomalies, and developmental delay: An expansion of the CAKUTHED phenotype.

An infant was referred for evaluation of congenital glaucoma and corneal clouding. In addition, he had a pelvic kidney, hypotonia, patent ductus arteriosus, abnormal pinnae, and developmental delay. Exome sequencing identified a previously unpublished de novo single nucleotide insertion in PBX1 c.400dupG (NM_002585.3), predicted to cause a frameshift resulting in a truncated protein with loss of function (p.Ala134Glyfs*65). Identification of this loss of function variant supports the diagnosis of congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED). Here, we propose glaucoma as an extra-renal manifestation associated with PBX1-related disease due to the relationship of PBX1 with MEIS1, MEIS2, and FOXC1 transcription factors associated with eye development.

Efficacy and Safety of Taliglucerase Alfa for the Treatment of Gaucher Disease: A 9-Year Experience

Abstract Gaucher disease (GD) is one of the most common lysosomal disorders, occurring in approximately 1 in 40,000 live births worldwide. Since 2014 enzyme replacement therapy (ERT) with taliglucerase alfa has been the treatment of choice for adult patients with GD in Brazil. The aim of this study was to evaluate the long-term efficacy and safety of taliglucerase alfa in a cohort of Brazilian patients treated at a referral center for inborn errors of metabolism. All patients who received at least one infusion of the enzyme at the study center were considered eligible to participate. Patients were followed for adverse reactions and events throughout the study period. Platelets, hemoglobin, chitotriosidase activity, bone marrow burden (BMB) score, bone mineral density, and the severity score index (SSI) were analyzed. For patients who were switched to taliglucerase alfa from imiglucerase, the same variables were compared before and after the switch. At 9-year follow-up, all parameters of interest had remained stable or improved. The overall rate of adverse events was lower than in other studies that evaluated long-term ERT with taliglucerase, and no serious adverse events were considered related to treatment. Based on our findings, ERT with taliglucerase alfa is an effective and safe approach for treatment of patients with GD.

Genomics Integration Into Nephrology Practice.

RATIONALE & OBJECTIVE: The etiology of kidney disease remains unknown in many individuals with chronic kidney disease (CKD). We created the Mayo Clinic Nephrology Genomics Clinic to improve our ability to integrate genomic and clinical data to identify the etiology of unexplained CKD. STUDY DESIGN: Retrospective study. SETTING & PARTICIPANTS: An essential component of our program is the Nephrology Genomics Board which consists of nephrologists, geneticists, pathologists, translational omics scientists, and trainees who interpret the patient's clinical and genetic data. Since September 2016, the Board has reviewed 163 cases (15 cystic, 100 glomerular, 6 congenital anomalies of kidney and urinary tract (CAKUT), 20 stones, 15 tubulointerstitial, and 13 other). ANALYTICAL APPROACH: Testing was performed with targeted panels, single gene analysis, or analysis of kidney-related genes from exome sequencing. Variant classification was obtained based on the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. RESULTS: A definitive genetic diagnosis was achieved for 50 families (30.7%). The highest diagnostic yield was obtained in individuals with tubulointerstitial diseases (53.3%), followed by congenital anomalies of the kidney and urological tract (33.3%), glomerular (31%), cysts (26.7%), stones (25%), and others (15.4%). A further 20 (12.3%) patients had variants of interest, and variant segregation, and research activities (exome, genome, or transcriptome sequencing) are ongoing for 44 (40%) unresolved families. LIMITATIONS: Possible overestimation of diagnostic rate due to inclusion of individuals with variants with evidence of pathogenicity but classified as of uncertain significance by the clinical laboratory. CONCLUSIONS: Integration of genomic and research testing and multidisciplinary evaluation in a nephrology cohort with CKD of unknown etiology or suspected monogenic disease provided a diagnosis in a third of families. These diagnoses had prognostic implications, and often changes in management were implemented.

Histomorphometric analysis of liver biopsies of treated patients with Gaucher disease type 1.

Gaucher disease (GD) is an autosomal recessive lysosomal disorder caused by a disturbance in the metabolism of glucocerebroside in the macrophages. Most of its manifestations - hepatosplenomegaly, anemia, thrombocytopenia, and bone pain - are amenable to a macrophage-target therapy such as enzyme replacement. However, there is increasing evidence that abnormalities of the liver persist despite the specific GD treatment. In this work, we adapted histomorphometry techniques to the study of hepatocytes in GD using liver tissue of treated patients, developing the first morphometrical method for canalicular quantification in immunohistochemistry-stained liver biopsies, and exploring histomorphometric characteristics of GD. This is the first histomorphometric technique developed for canalicular analysis on histological liver biopsy samples.

Early role for a Na+,K+-ATPase (ATP1A3) in brain development.

Osmotic equilibrium and membrane potential in animal cells depend on concentration gradients of sodium (Na+) and potassium (K+) ions across the plasma membrane, a function catalyzed by the Na+,K+-ATPase α-subunit. Here, we describe ATP1A3 variants encoding dysfunctional α3-subunits in children affected by polymicrogyria, a developmental malformation of the cerebral cortex characterized by abnormal folding and laminar organization. To gain cell-biological insights into the spatiotemporal dynamics of prenatal ATP1A3 expression, we built an ATP1A3 transcriptional atlas of fetal cortical development using mRNA in situ hybridization and transcriptomic profiling of ∼125,000 individual cells with single-cell RNA sequencing (Drop-seq) from 11 areas of the midgestational human neocortex. We found that fetal expression of ATP1A3 is most abundant to a subset of excitatory neurons carrying transcriptional signatures of the developing subplate, yet also maintains expression in nonneuronal cell populations. Moving forward a year in human development, we profiled ∼52,000 nuclei from four areas of an infant neocortex and show that ATP1A3 expression persists throughout early postnatal development, most predominantly in inhibitory neurons, including parvalbumin interneurons in the frontal cortex. Finally, we discovered the heteromeric Na+,K+-ATPase pump complex may form nonredundant cell-type-specific α-ß isoform combinations, including α3-ß1 in excitatory neurons and α3-ß2 in inhibitory neurons. Together, the developmental malformation phenotype of affected individuals and single-cell ATP1A3 expression patterns point to a key role for α3 in human cortex development, as well as a cell-type basis for pre- and postnatal ATP1A3-associated diseases.

Identification of Genetic Causes of Focal Segmental Glomerulosclerosis Increases With Proper Patient Selection.

OBJECTIVE: To increase the likelihood of finding a causative genetic variant in patients with a focal segmental glomerulosclerosis (FSGS) lesion, clinical and histologic characteristics were analyzed. PATIENTS AND METHODS: Individuals 18 years and older with an FSGS lesion on kidney biopsy evaluated at Mayo Clinic from November 1, 1999, through October 31, 2019, were divided into 4 groups based on clinical and histologic characteristics: primary FSGS, secondary FSGS with known cause, secondary FSGS without known cause, and undetermined FSGS. A targeted gene panel and a customized gene panel retrieved from exome sequencing were performed. RESULTS: The overall rate of detection of a monogenic cause was 42.9% (21/49). Individuals with undetermined FSGS had the highest rate of positivity (87.5%; 7/8) followed by secondary FSGS without an identifiable cause (61.5%; 8/13) and secondary FSGS with known cause (33.3%; 5/15). Four of 5 (80%) individuals in the latter group who had positive genetic testing results also had a family history of kidney disease. Univariate analysis showed that family history of kidney disease (odds ratio [OR], 13.8; 95% CI, 3.7 to 62.4; P<.001), absence of nephrotic syndrome (OR, 8.2; 95% CI, 1.9 to 58.1; P=.004), and female sex (OR, 5.1; 95% CI, 1.5 to 19.9; P=.01) were strong predictors of finding a causative genetic variant in the entire cohort. The most common variants were in the collagen genes (52.4%; 11/21), followed by the podocyte genes (38.1%; 8/21). CONCLUSION: In adults with FSGS lesions, proper selection of patients increases the rate of positive genetic testing significantly. The majority of individuals with undetermined FSGS in whom the clinical presentation and histologic parameters are discordant had a genetic diagnosis.

TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study.

Biallelic loss-of-function variants in the thrombospondin-type laminin G domain and epilepsy-associated repeats (TSPEAR) gene have recently been associated with ectodermal dysplasia and hearing loss. The first reports describing a TSPEAR disease association identified this gene is a cause of nonsyndromic hearing loss, but subsequent reports involving additional affected families have questioned this evidence and suggested a stronger association with ectodermal dysplasia. To clarify genotype-phenotype associations for TSPEAR variants, we characterized 13 individuals with biallelic TSPEAR variants. Individuals underwent either exome sequencing or panel-based genetic testing. Nearly all of these newly reported individuals (11/13) have phenotypes that include tooth agenesis or ectodermal dysplasia, while three newly reported individuals have hearing loss. Of the individuals displaying hearing loss, all have additional variants in other hearing-loss-associated genes, specifically TMPRSS3, GJB2, and GJB6, that present competing candidates for their hearing loss phenotype. When presented alongside previous reports, the overall evidence supports the association of TSPEAR variants with ectodermal dysplasia and tooth agenesis features but creates significant doubt as to whether TSPEAR variants are a monogenic cause of hearing loss. Further functional evidence is needed to evaluate this phenotypic association.

Patient-reported outcomes after oesophagectomy in the multicentre LASER study.

BACKGROUND: Data on the long-term symptom burden in patients surviving oesophageal cancer surgery are scarce. The aim of this study was to identify the most prevalent symptoms and their interactions with health-related quality of life. METHODS: This was a cross-sectional cohort study of patients who underwent oesophageal cancer surgery in 20 European centres between 2010 and 2016. Patients had to be disease-free for at least 1 year. They were asked to complete a 28-symptom questionnaire at a single time point, at least 1 year after surgery. Principal component analysis was used to assess for clustering and association of symptoms. Risk factors associated with the development of severe symptoms were identified by multivariable logistic regression models. RESULTS: Of 1081 invited patients, 876 (81.0 per cent) responded. Symptoms in the preceding 6 months associated with previous surgery were experienced by 586 patients (66.9 per cent). The most common severe symptoms included reduced energy or activity tolerance (30.7 per cent), feeling of early fullness after eating (30.0 per cent), tiredness (28.7 per cent), and heartburn/acid or bile regurgitation (19.6 per cent). Clustering analysis showed that symptoms clustered into six domains: lethargy, musculoskeletal pain, dumping, lower gastrointestinal symptoms, regurgitation/reflux, and swallowing/conduit problems; the latter two were the most closely associated. Surgical approach, neoadjuvant therapy, patient age, and sex were factors associated with severe symptoms. CONCLUSION: A long-term symptom burden is common after oesophageal cancer surgery.