A Novel COL4A5 Pathogenic Variant Joins the Dots in a Family with a Synchronous Diagnosis of Alport Syndrome and Polycystic Kidney Disease.

Alport Syndrome (AS) is the most common genetic glomerular disease, and it is caused by COL4A3, COL4A4, and COL4A5 pathogenic variants. The classic phenotypic spectrum associated with AS ranges from isolated hematuria to chronic kidney disease (CKD) with extrarenal abnormalities. Atypical presentation of the disorder is possible, and it can mislead the diagnosis. Polycystic kidney disease (PKD), which is most frequently associated with Autosomal Dominant PKD (ADPKD) due to PKD1 and PKD2 heterozygous variants, is emerging as a possible clinical manifestation in COL4A3-A5 patients. We describe a COL4A5 novel familial frameshift variant (NM_000495.5: c.1095dup p.(Leu366ValfsTer45)), which was associated with AS and PKD in the hemizygous proband, as well as with PKD, IgA glomerulonephritis and focal segmental glomerulosclerosis (FSGS) in the heterozygous mother. Establishing the diagnosis of AS can sometimes be difficult, especially in the context of misleading family history and atypical phenotypic features. This case study supports the emerging genotypic and phenotypic heterogeneity in COL4A3-A5-associated disorders, as well as the recently described association between PKD and collagen type IV (Col4) defects. We highlight the importance of the accurate phenotyping of all family members and the relevance of next-generation sequencing in the differential diagnosis of hereditary kidney disease.

Prenatal identification of a pathogenic maternal FGFR1 variant in two consecutive pregnancies with fetal forebrain malformations.

OBJECTIVE: Holoprosencephaly (HPE) is the most common aberration of forebrain development, and it leads to a wide spectrum of developmental and craniofacial anomalies. HPE etiology is highly heterogeneous and includes both chromosomal abnormalities and single-gene defects. METHODS: Here, we report an FGFR1 heterozygous variant detected by prenatal exome sequencing and inherited from the asymptomatic mother, in association with recurrent neurological abnormalities in the HPE spectrum in two consecutive pregnancies. RESULTS: Individuals with germline pathogenic variants in FGFR1 (MIM: 136350) show extensive phenotypic variability, which ranges from asymptomatic carriers to hypogonadotropic hypogonadism, arhinencephaly, Kallmann's syndrome with associated features such as cleft lip and palate, skeletal anomalies, isolated HPE, and Hartsfield syndrome. CONCLUSION: The presented case supports the role of exome sequencing in prenatal diagnosis when fetal midline structural anomalies are suggestive of a genetic etiology, as early as the first trimester of gestation. The profound heterogeneity of FGFR1 allelic disorders needs to be considered when planning prenatal screening even in asymptomatic carriers.

Descending necrotizing mediastinitis caused by retro-pharyngeal Eggerthia catenaformis infection.

Introduction: Eggerthia catenaformis, a non-spore-forming anaerobic Gram-positive bacillus component of the human fecal microbiota has rarely been reported in human diseases. In almost every case described in current literature to date, dental diseases (abscesses, periodontitis, or caries), are the most common source of the infection which extends to the brain, cervical spaces, pulmonary parenchyma, the pleural cavity, the abdominal wall, and the abdominal cavity. Case report: An 82-year-old male Caucasian patient was admitted to our Emergency Department (ED) with a painless, right submandibular mass, dyspnea, and inspiratory stridor. A CT scan of the head, neck, and chest with intravenous contrast material revealed a retrotonsillar fluid collection. Air bubbles and minimal fluid were present from the right sub-mandibular area to the lower mediastinum between the spine, the descending thoracic aorta, and the trachea. The patient underwent surgical treatment and a broad-spectrum antibiotic. The retropharyngeal fluid collection culture showed the presence of Eggerthia catenaformis. After a first period in the Intensive Care Unit, he was admitted to a Step-Down Unit (SDU) where he underwent respiratory weaning, motor rehabilitation, and gradual oral feeding resumption. At discharge, the patient maintained the tracheal cannula as he still had impaired swallowing of solid foods. Conclusions: Here we report the first case of descending necrotizing mediastinitis in a patient with a retropharyngeal abscess, in the absence of dental diseases.

Co-Inheritance of Pathogenic Variants in PKD1 and PKD2 Genes Determined by Parental Segregation and De Novo Origin: A Case Report.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, and it is typically caused by PKD1 and PKD2 heterozygous variants. Nonetheless, the extensive phenotypic variability observed among affected individuals, even within the same family, suggests a more complex pattern of inheritance. We describe an ADPKD family in which the proband presented with an earlier and more severe renal phenotype (clinical diagnosis at the age of 14 and end-stage renal disease aged 24), compared to the other affected family members. Next-generation sequencing (NGS)-based analysis of polycystic kidney disease (PKD)-associated genes in the proband revealed the presence of a pathogenic PKD2 variant and a likely pathogenic variant in PKD1, according to the American College of Medical Genetics and Genomics (ACMG) criteria. The PKD2 nonsense p.Arg872Ter variant was segregated from the proband's father, with a mild phenotype. A similar mild disease presentation was found in the proband's aunts and uncle (the father's siblings). The frameshift p.Asp3832ProfsTer128 novel variant within PKD1 carried by the proband in addition to the pathogenic PKD2 variant was not found in either parent. This report highlights that the co-inheritance of two or more PKD genes or alleles may explain the extensive phenotypic variability among affected family members, thus emphasizing the importance of NGS-based techniques in the definition of the prognostic course.

A likely pathogenic ACTG1 variant in a child showing partial phenotypic overlap with Baraitser-Winter syndrome.

Baraitser-Winter syndrome (BRWS) is a rare autosomal dominant disease (AD) caused by heterozygous variants in ACTB (BRWS1) or ACTG1 (BRWS2) genes. BRWS features developmental delay/intellectual disability of variable degree and craniofacial dysmorphisms. Brain abnormalities (especially pachygyria), microcephaly, epilepsy, as well as hearing impairment, cardiovascular and genitourinary abnormalities may be present. We report on a 4-year-old female, who was addressed to our institution because of psychomotor delay associated with microcephaly and dysmorphic features, short stature, mild bilateral sensorineural hearing loss, mild cardiac septal hypertrophy, and abdominal swelling. Clinical exome sequencing detected a c.617G>A p.(Arg206Gln) de novo variant in ACTG1 gene. Such variant has been previously reported in association with a form of AD nonsyndromic sensorineural progressive hearing loss and we classified it as likely pathogenic according to ACMG/AMP criteria, despite our patient's phenotype only partially overlapped BWRS2. Our finding supports the extreme variability of the ACTG1-related disorders, ranging from classical BRWS2 to nuanced clinical expressions not fitting the original description, and occasionally featuring previously undescribed clinical findings.

Case report: A new de novo 6q21q22.1 interstitial deletion case in a girl with cerebellar vermis hypoplasia and developmental delay and literature review.

Interstitial deletions involving 6q chromosomal region are rare. Less than 30 patients have been described to date, and fewer have been characterized by high-resolution techniques, such as chromosomal microarray. Deletions involving 6q21q22.1 region are associated with an extremely wide and heterogeneous clinical spectrum, thus genotype-phenotype correlation based on the size of the rearranged region and on the involved genes is complex, even among individuals with overlapping deletions. Here we describe the phenotypic and molecular characterization of a new 6q interstitial deletion in a girl with developmental delay, intellectual disability, cerebellar vermis hypoplasia, facial peculiar characteristics, ataxia and ocular abnormalities. Microarray analysis of the proposita revealed a 7.9 Mb interstitial de novo deletion at 6q21q22.1 chromosomal region, which spanned from nucleotides 108,337,770 to 116,279,453 (GRCh38/hg38). The present case, alongside with a systematic review of the literature, provides further evidence that could aid to the definition of the Smallest Region of Overlap and of the genomic traits that are associated with particular phenotypes, focusing on neurological findings and especially on cerebellar anomalies.

Identifying phenotypic expansions for congenital diaphragmatic hernia plus (CDH+) using DECIPHER data.

Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, UBA2, and USP9X. The role of these genes in diaphragm development was supported by their expression in the developing mouse diaphragm, their similarity to known CDH genes using data from a previously published and validated machine learning algorithm, and/or the presence of CDH in other individuals with their associated genetic disorders. Our results demonstrate how data from DECIPHER, and other public databases, can be used to identify new phenotypic expansions and suggest that CREBBP, SMARCA4, UBA2, and USP9X play a role in diaphragm development.

Multimodal assessment in polymicrobial infective endocarditis with silent spondylodiscitis and cerebral embolism / Evaluación multimodal en endocarditis infecciosa polimicrobiana con espondilodiscitis silenciosa y embolia cerebral

Abstract Infective endocarditis (IE) is a rare but severe disease, due to an infection of the endocardial surface of the heart. The annual incidence ranging from 3 to 7 per 100 000 person-years, with an overall mortality rates of 25%. Staphylococci and Streptococci accounted for approximately 80% of IE cases. Enterococci are the third leading cause accounted for approximately 5-18% of all cases and are increasingly linked to health-care contact. The increasing number of cardiovascular electronic devices, prosthetic valves implants along with frequent invasive diagnostic or therapeutic procedures performed in elderly, may also contribute to the rise of IE in this population. Blood cultures and echocardiographic findings are the cornerstone of the IE diagnosis, confirmed or rejected according to modified Duke criteria. Other imaging modalities as Cardiac Computed Tomography, Cardiac Magnetic Resonance Imaging and 18Ffluorodeoxyglucose Positron Emission Tomography - Computed Tomography (18FDG-PET/CT) can determine a more correct diagnosis and identify many of the endocarditis-related complications. Here, we describe a patient with aortic prosthetic valve and Enterococcus faecalis (EF) IE. Cerebral and spinal MRI and 18FDG-PET/CT, performed during the hospitalization, showed multi-organ silent periferic embolization. Furthermore, the cultural examination of the valvular surgical specimen revealed a methicillin-sensitive Staphylococcus aureus suggestive for polymicrobial endocarditis. Some Authors demonstrated a possible false-positive valve culture due to a postoperative contamination. Since contaminated cultures usually yield microorganisms compatible with endocarditis, such as coagulase-negative Staphylococci, viridans group Streptococcus species, may be difficult for the physician not to treat the patient. This case represents need for high level of suspicion to diagnose IE. Multimodality assessment improves the diagnosis and allows the detection of the complications. Moreover, a multidisciplinary team and specialized centers determine a better patient’s outcome.

Resumen La endocarditis infecciosa (EI) es una enfermedad poco frecuente pero severa, dada por una infección del endocardio. La incidencia anual oscila entre 3 y 7 por cada 100 000 personas-año, con una tasa de mortalidad general del 25%. Los estafilococos y los estreptococos representaron aproximadamente un 80% de los casos de EI. Los enterococos son la tercera causa, aportando aproximadamente 5% a 18% de todos los casos, y se vinculan cada vez más al contacto con la atención médica. El número creciente de dispositivos electrónicos cardiovasculares e implantes de válvulas protésicas, junto con los frecuentes procedimientos invasivos diagnósticos o terapéuticos en las personas ancianas, también podrían contribuir al incremento de EI en esta población. Los hemocultivos y los hallazgos ecocardiográficos son la piedra angular del diagnóstico de EI, confirmado o rechazado de acuerdo con los criterios modificados de Duke. Otras modalidades de imagenología tales como la Tomografía Computarizada Cardíaca (TCC), la Resonancia Magnética Cardíaca (RMC) y la Tomografía por Emisión de Positrones - Tomografía Computarizada con 18F-fluorodeoxiglucosa (18F-FDG PET/TC) pueden determinar un diagnóstico más preciso e identificar muchas de las complicaciones asociadas a la endocarditis. Aquí describimos un paciente con una válvula aórtica protésica y EI por EF. Una RM del cerebro y la columna vertebral y una 18F-FDG PET/TC practicadas durante la hospitalización evidenciaron embolia periférica multiorgánica silenciosa. Además, el examen por cultivo de la muestra quirúrgica valvular reveló Staphylococcus aureus sensible a la meticilina (SASM), sugestivo de endocarditis polimicrobiana. Algunos autores demostraron un posible falso positivo del cultivo valvular dado por contaminación postoperatoria. Ya que los cultivos contaminados generalmente producen microorganismos compatibles con la endocarditis, tales como estafilococos coagulasa negativos y estreptococos del grupo viridans, le puede resultar difícil al médico no tratar al paciente. Este caso representa la necesidad de tener un alto nivel de sospecha para diagnosticar la EI. La valoración multimodal mejora el diagnóstico y permite detectar complicaciones. Además, un equipo multidisciplinario y los centros especializados determinan un mejor desenlace para el paciente.