Primary cilia formation requires the Leigh syndrome-associated mitochondrial protein NDUFAF2.

Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.

CEP41, a ciliopathy-linked centrosomal protein, regulates microtubule assembly and cell proliferation.

Centrosomal proteins play pivotal roles in orchestrating microtubule dynamics, and their dysregulation leads to disorders, including cancer and ciliopathies. Understanding the multifaceted roles of centrosomal proteins is vital to comprehend their involvement in disease development. Here, we report novel cellular functions of CEP41, a centrosomal and ciliary protein implicated in Joubert syndrome. We show that CEP41 is an essential microtubule-associated protein with microtubule-stabilizing activity. Purified CEP41 binds to preformed microtubules, promotes microtubule nucleation and suppresses microtubule disassembly. When overexpressed in cultured cells, CEP41 localizes to microtubules and promotes microtubule bundling. Conversely, shRNA-mediated knockdown of CEP41 disrupts the interphase microtubule network and delays microtubule reassembly, emphasizing its role in microtubule organization. Further, we demonstrate that the association of CEP41 with microtubules relies on its conserved rhodanese homology domain (RHOD) and the N-terminal region. Interestingly, a disease-causing mutation in the RHOD domain impairs CEP41-microtubule interaction. Moreover, depletion of CEP41 inhibits cell proliferation and disrupts cell cycle progression, suggesting its potential involvement in cell cycle regulation. These insights into the cellular functions of CEP41 hold promise for unraveling the impact of its mutations in ciliopathies.

Acquired cystic disease associated renal cell carcinoma: A clinicopathologic and molecular study of 31 tumors.

Acquired cystic disease associated renal cell carcinomas (ACD-RCC) are rare and their molecular and histopathological characteristics are still being explored. We therefore investigated the clinicopathologic and molecular characteristics of 31 tumors. The patients were predominantly male (n = 30), with tumors mainly left-sided (n = 17), unifocal (n = 19), and unilateral (n = 29) and a mean tumor size of 25 mm (range, 3-65 mm). Microscopically, several histologic patterns were present, including pure classic sieve-like (n = 4), and varied proportions of mixed classic sieve-like with papillary (n = 23), tubulocystic (n = 9), compact tubular (n = 4) and solid (n = 1) patterns. Calcium-oxalate crystals were seen in all tumors. Molecular analysis of 9 tumors using next generation sequencing showed alterations in SMARCB1 in 3 tumors (1 with frameshift deletion and 2 with copy number loss in chromosome 22 involving SMARCB1 region), however, INI1 stain was retained in all. Nonrecurrent genetic alterations in SETD2, NF1, NOTCH4, BRCA2 and CANT1 genes were also seen. Additionally, MTOR p.Pro351Ser was identified in one tumor. Copy number analysis showed gains in chromosome 16 (n = 5), 17 (n = 2) and 8 (n = 2) as well as loss in chromosome 22 (n = 2). In summary, ACD-RCC is a recognized subtype of kidney tumors, with several histological architectural patterns. Our molecular data identifies genetic alterations in chromatin modifying genes (SMARCB1 and SETD2), which may suggest a role of such genes in ACD-RCC development.

Carbonic Anhydrase 2 Deletion Delays the Growth of Kidney Cysts Whereas Foxi1 Deletion Completely Abrogates Cystogenesis in TSC.

Tuberous sclerosis complex (TSC) presents with renal cysts and benign tumors, which eventually lead to kidney failure. The factors promoting kidney cyst formation in TSC are poorly understood. Inactivation of carbonic anhydrase 2 (Car2) significantly reduced, whereas, deletion of Foxi1 completely abrogated the cyst burden in Tsc1 KO mice. In these studies, we contrasted the ontogeny of cyst burden in Tsc1/Car2 dKO mice vs. Tsc1/Foxi1 dKO mice. Compared to Tsc1 KO, the Tsc1/Car2 dKO mice showed few small cysts at 47 days of age. However, by 110 days, the kidneys showed frequent and large cysts with overwhelming numbers of A-intercalated cells in their linings. The magnitude of cyst burden in Tsc1/Car2 dKO mice correlated with the expression levels of Foxi1 and was proportional to mTORC1 activation. This is in stark contrast to Tsc1/Foxi1 dKO mice, which showed a remarkable absence of kidney cysts at both 47 and 110 days of age. RNA-seq data pointed to profound upregulation of Foxi1 and kidney-collecting duct-specific H+-ATPase subunits in 110-day-old Tsc1/Car2 dKO mice. We conclude that Car2 inactivation temporarily decreases the kidney cyst burden in Tsc1 KO mice but the cysts increase with advancing age, along with enhanced Foxi1 expression.

Joubert syndrome-derived induced pluripotent stem cells show altered neuronal differentiation in vitro.

Joubert syndrome (JS) is a recessively inherited congenital ataxia characterized by hypotonia, psychomotor delay, abnormal ocular movements, intellectual disability, and a peculiar cerebellar and brainstem malformation, the "molar tooth sign." Over 40 causative genes have been reported, all encoding for proteins implicated in the structure or functioning of the primary cilium, a subcellular organelle widely present in embryonic and adult tissues. In this paper, we developed an in vitro neuronal differentiation model using patient-derived induced pluripotent stem cells (iPSCs), to evaluate possible neurodevelopmental defects in JS. To this end, iPSCs from four JS patients harboring mutations in distinct JS genes (AHI1, CPLANE1, TMEM67, and CC2D2A) were differentiated alongside healthy control cells to obtain mid-hindbrain precursors and cerebellar granule cells. Differentiation was monitored over 31 days through the detection of lineage-specific marker expression by qRT-PCR, immunofluorescence, and transcriptomics analysis. All JS patient-derived iPSCs, regardless of the mutant gene, showed a similar impairment to differentiate into mid-hindbrain and cerebellar granule cells when compared to healthy controls. In addition, analysis of primary cilium count and morphology showed notable ciliary defects in all differentiating JS patient-derived iPSCs compared to controls. These results confirm that patient-derived iPSCs are an accessible and relevant in vitro model to analyze cellular phenotypes connected to the presence of JS gene mutations in a neuronal context.

Association of Kidney Cysts With Progressive CKD After Radical Nephrectomy.

RATIONALE & OBJECTIVE: Simple kidney cysts, which are common and usually considered of limited clinical relevance, are associated with older age and lower glomerular filtration rate (GFR), but little has been known of their association with progressive chronic kidney disease (CKD). STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Patients with presurgical computed tomography or magnetic resonance imaging who underwent a radical nephrectomy for a tumor; we reviewed the retained kidney images to characterize parenchymal cysts at least 5mm in diameter according to size and location. EXPOSURE: Parenchymal cysts at least 5mm in diameter in the retained kidney. Cyst characteristics were correlated with microstructural findings on kidney histology. OUTCOME: Progressive CKD defined by dialysis, kidney transplantation, a sustained≥40% decline in eGFR for at least 3 months, or an eGFR<10mL/min/1.73m2 that was at least 5mL/min/1.73m2 below the postnephrectomy baseline for at least 3 months. ANALYTICAL APPROACH: Cox models assessed the risk of progressive CKD. Models adjusted for baseline age, sex, body mass index, hypertension, diabetes, eGFR, proteinuria, and tumor volume. Nonparametric Spearman's correlations were used to examine the association of the number and size of the cysts with clinical characteristics, kidney function, and kidney volumes. RESULTS: There were 1,195 patients with 50 progressive CKD events over a median 4.4 years of follow-up evaluation. On baseline imaging, 38% had at least 1 cyst, 34% had at least 1 cortical cyst, and 8.7% had at least 1 medullary cyst. A higher number of cysts was associated with progressive CKD and was modestly correlated with larger nephrons and more nephrosclerosis on kidney histology. The number of medullary cysts was more strongly associated with progressive CKD than the number of cortical cysts. LIMITATIONS: Patients who undergo a radical nephrectomy may differ from the general population. A radical nephrectomy may accelerate the risk of progressive CKD. Genetic testing was not performed. CONCLUSIONS: Cysts in the kidney, particularly the medulla, should be further examined as a potentially useful imaging biomarker of progressive CKD beyond the current clinical evaluation of kidney function and common CKD risk factors. PLAIN-LANGUAGE SUMMARY: Kidney cysts are common and often are considered of limited clinical relevance despite being associated with lower glomerular filtration rate. We studied a large cohort of patients who had a kidney removed due to a tumor to determine whether cysts in the retained kidney were associated with kidney health in the future. We found that more cysts in the kidney and, in particular, cysts in the deepest tissue of the kidney (the medulla) were associated with progressive kidney disease, including kidney failure where dialysis or a kidney transplantation is needed. Patients with cysts in the kidney medulla may benefit from closer monitoring.

The Predictive Power of Bosniak 3 and 4 Cystic Renal Lesion Categorization Using Contrast-Enhanced Ultrasound.

OBJECTIVES: Contrast-enhanced ultrasound (CEUS) is increasingly utilized for the noninvasive assessment of renal cystic lesions, using the Bosniak grading system. Bosniak 3-4 lesions require surgical referral, which allows correlation with the histopathological outcome. METHODS: In this single-center, retrospective study we evaluated renal CEUS exams conducted with SonoVue® with a diagnosis of a Bosniak 3 or 4 lesion between 2019 and 2022. A total of 49 patients and 50 lesions met the inclusion criteria, 31 lesions had available histopathological results. Patient demographics, cyst morphology, and dominant imaging features were registered. The histopathological diagnosis was considered a reference standard. RESULTS: Positive predictive power (PPV) for neoplastic lesions was comparable in the Bosniak 3 and 4 categories (75 vs 93.3%, P = .33), while PPV for histopathologically malignant lesion was considerably higher in the latter group (25 vs 93.33%, P = .0002). None of the lesions which had vividly enhancing thin septa as their dominant CEUS feature were malignant. Oncocytoma, multilocular cystic renal neoplasm of low malignant potential, and cystic nephroma were the major benign entities among Bosniak 3 lesions. Localized cystic kidney disease and hemorrhagic cysts were found to be the primary mimickers leading to false positive imaging findings. CONCLUSIONS: CEUS has a high predictive power for malignancy in the Bosniak 4 category, which is not maintained in the Bosniak 3 group due to the large proportion of benign lesions. Adherence to rigorous rule-in criteria and active surveillance strategies need to be considered for equivocal CEUS Bosniak 3 lesions.

Novel compound heterozygous variants in ARL13B lead to Joubert syndrome.

Joubert syndrome (JBTS) is a systematic developmental disorder mainly characterized by a pathognomonic mid-hindbrain malformation. All known JBTS-associated genes encode proteins involved in the function of antenna-like cellular organelle, primary cilium, which plays essential roles in cellular signal transduction and development. Here, we identified four unreported variants in ARL13B in two patients with the classical features of JBTS. ARL13B is a member of the Ras GTPase family and functions in ciliogenesis and cilia-related signaling. The two missense variants in ARL13B harbored the substitutions of amino acids at evolutionarily conserved positions. Using model cell lines, we found that the accumulations of the missense variants in cilia were impaired and the variants showed attenuated functions in ciliogenesis or the trafficking of INPP5E. Overall, these findings expanded the ARL13B pathogenetic variant spectrum of JBTS.

Validation of the updated Bosniak classification (2019) in pathologically confirmed CT-categorised cysts.

INTRODUCTION: The updated Bosniak classification in 2019 (v2019) addresses vague imaging terms and revises the criteria with the intent to categorise a higher proportion of cysts in lower-risk groups and reduce benign cyst resections. The aim of the present study was to compare the diagnostic accuracy and inter-observer agreement rate of the original (v2005) and updated classifications (v2019). METHOD: Resected/biopsied cysts were categorised according to Bosniak classifications (v2005 and v2019) and the diagnostic accuracy was assessed with reference to histopathological analysis. The inter-observer agreement of v2005 and v2019 was determined. RESULTS: The malignancy rate of the cohort was 83.6% (51/61). Using v2019, a higher proportion of malignant cysts were categorised as Bosniak ≥ III (88.2% vs 84.3%) and a significantly higher percentage were categorised as Bosniak IV (68.9% vs 47.1%; p = 0.049) in comparison to v2005. v2019 would have resulted in less benign cyst resections (13.5% vs 15.7%). Calcified versus non-calcified cysts had lower rates of malignancy (57.1% vs 91.5%; RR,0.62; p = 0.002). The inter-observer agreement of v2005 was higher than that of v2019 (kappa, 0.70 vs kappa, 0.43). DISCUSSION: The updated classification improves the categorisation of malignant cysts and reduces benign cyst resection. The low inter-observer agreement remains a challenge to the updated classification system.

Autosomal Recessive Adolescent Syndromic Nephronophthisis Caused by a Novel Compound Heterozygous Pathogenic Variant.

BACKGROUND Nephronophthisis, an autosomal recessive ciliopathy involving mutations in primary cilium genes, is characterized by chronic tubulointerstitial nephritis and a defective urine concentrating capacity. It accounts for about 5% of renal failure in children and adolescents and usually progresses to end-stage renal disease before the age of 30 years. Nephronophthisis is associated with extrarenal manifestations, including retinitis pigmentosa in Senior-Loken syndrome (SLS), and liver fibrosis in 10-20% of cases. While some presenting patterns could be characteristic, patients may have atypical presentation, making diagnosis difficult. Tubulointerstitial fibrosis is the predominant feature on histology and as such, diagnosis depends mostly on genetic testing. Despite advances in renal genomics over the years with a better understanding of primary cilia and ciliary theory, about 40% of nephronophthisis cases go undiagnosed. As the underlying genetic etiologies are not fully understood, morphologic pathologic findings are non-specific, and treatment options are limited to dialysis and transplantation. CASE REPORT We describe a unique case of a patient with adolescent nephronophthisis who presented with advanced chronic kidney disease and severe pancytopenia, who progressed to end-stage renal disease at the age of 19, and was found to have syndromic nephronophthisis with compound heterozygous inheritance. CONCLUSIONS This report highlights the atypical presentation patterns that can be seen in syndromic nephronophthisis, the importance of genetic diagnosis when there is a high index of suspicion, and the need to further study genetic variants to better understand and diagnose the disease and to develop targeted therapy.

Novel mutation in RPGRIP1L gene causing Joubert syndrome: A case report.

INTRODUCTION: Joubert syndrome is a rare disease of genetic origin with autosomal recessive inheritance and extreme genetic heterogeneity with more than 40 causative genes. Joubert syndrome 7 is caused by mutations in the RPGRIP1L gene. PATIENT CONCERNS: Our report describes a pediatric patient with clinical features compatible with JS type 7 such as hypotonia, developmental delay and aplasia of the cerebellar vermis. DIAGNOSIS: The clinical features and the MRI of the head and neck which showed alterations at the level of the posterior fossa, with absence of the vermis and horizontal disposition of the cerebellar peduncles, were compatible with Joubert syndrome. Whole exome sequencing detected the variants RPGRIP1L (NM_015272.2) c.697A > T (p. Lys233Ter) and RPGRIP1L (NM_015272.2) c.3545 del (p.Pro1182LeufsTer25). INTERVENTIONS: Resection was performed to correct the polydactyly. At age 2 years umbilical hernia, adenoid surgery and ventilatory tubes surgery were performed. Renal biopsy confirmed interstitial fibrosis and focally accentuated mild tubular atrophy with focal tubular hypertrophy, compatible with the clinical suspicion of Joubert syndrome. Congenital hip dislocation surgery was performed. The patient underwent surgery for correction of concomitant divergent strabismus and continued with glasses for astigmatism and hyperopia. OUTCOMES: Sanger sequencing confirmed the patient´s results and the father was found to be a carrier of RPGRIP1L (NM_015272.2) c.697A > T (p. Lys233Ter) and the mother and maternal grandmother as carriers of RPGRIP1L (NM_015272.2) c.3545del (p.Pro1182LeufsTer25). RPGRIP1L:c.3545del novel variant is a deletion which changes the reading frame, altering the RPGR1_C terminal domain and giving rise to an incomplete protein whose functions will be altered. CONCLUSION: This is the first genetically confirmed case of JS in Colombia, the first carrier of biallelic RPGRIP1L gene mutations with hip dislocation and incomplete glottic closure and the first report of the novel c.3545del likely pathogenic variant causing JS.

A case of Joubert syndrome caused by novel compound heterozygous variants in the TMEM67 gene.

Joubert syndrome (JS) is a recessive disorder that is characterized by midbrain-hindbrain malformation and shows the "molar tooth sign" on magnetic resonance imaging. Mutations in 40 genes, including Abelson helper integration site 1 (AHI1), inositol polyphosphate-5-phosphatase (INPP5E), coiled-coil and c2 domain-containing protein 2A (CC2D2A), and ARL2-like protein 1 (ARL13B), can cause JS. Classic JS is a part of a group of diseases associated with JS, and its manifestations include various neurological signs such as skeletal abnormalities, ocular coloboma, renal disease, and hepatic fibrosis. Here, we present a proband with the molar tooth sign, ataxia, and developmental and psychomotor delays in a Dagestan family from Russia. Molecular genetic testing revealed two novel heterozygous variants, c.2924G>A (p.Arg975His) in exon 28 and c.1241C>G (p.Pro414Arg) in exon 12 of the transmembrane protein 67 (TMEM67) gene. These TMEM67 gene variants significantly affected the development of JS type 6. This case highlights the importance of whole exome sequencing for a proper clinical diagnosis of children with complex motor and psycho-language delays. This case also expands the clinical phenotype and genotype of TMEM67-associated diseases.

Joubert syndrome: a case report of neonatal presentation and early diagnosis.

BACKGROUND: Joubert syndrome is a rare genetic condition with a prevalence of 1:80,000-1:100,000. In most cases, it shows an autosomal autosomal recessive hereditary pattern, although X-linked and autosomal dominant cases have been described. The distinctive characteristic of this syndrome is the malformation at cerebral and cerebellar levels, known as the "molar tooth sign," hypotonia, and delayed neurodevelopment. CASE REPORT: We describe the case of a newborn with transient tachypnea. However, during hospital stay, he showed other clinical signs not corresponding to the admission diagnosis, such as bradycardia, apneas, hypotonia, and alteration in swallowing mechanics. To rule out etiologies of central origin, we conducted a magnetic resonance of the brain and identified the "molar tooth sign," where the pathognomonic sign of Joubert syndrome. CONCLUSIONS: Rare genetic diseases may manifest as early as the neonatal period with non-specific signs. The early diagnosis of Joubert syndrome is reflected in better pediatric follow-up, which impacts its prognosis and the possibility of improving the patient's quality of life with a multidisciplinary management and genetic counseling.

INTRODUCCIÓN: El síndrome de Joubert es una rara condición genética con una prevalencia de 1:80,000 a 1:100,000. En la mayoría de los casos se presenta con un patrón de herencia autosómica recesiva, aunque se han reporatdo casos ligados al cromosoma X y autosómicos dominantes. La característica distintiva de este síndrome es la malformación a nivel cerebral y del cerebelo conocido como el "signo del molar", hipotonía y retraso en el neurodesarrollo. CASO CLÍNICO: Se describe el caso de un recién nacido con taquipnea transitoria del recién nacido; sin embargo, durante su estancia manifestó otros signos que no correspondían con el diagnóstico de ingreso, como bradicardia, apneas, hipotonía y alteración en la mecánica de la deglución. Para descartar etiologías de origen central, se realizó una resonancia magnética cerebral en la que se detectó el "signo del molar", patognomónico del síndrome de Joubert. CONCLUSIONES: Las enfermedades genéticas raras pueden manifestarse desde el periodo neonatal con signos muy inespecíficos. El diagnóstico precoz del Síndrome de Joubert permite un mejor seguimiento pediátrico que impacta en su pronóstico y en la posibilidad de mejorar la calidad de vida del paciente con un manejo multidisciplinario, así como brindar asesoramiento genético.

The genetic spectrum of congenital ocular motor apraxia type Cogan: an observational study, continued.

BACKGROUND: The term congenital ocular motor apraxia (COMA), coined by Cogan in 1952, designates the incapacity to initiate voluntary eye movements performing rapid gaze shift, so called saccades. While regarded as a nosological entity by some authors, there is growing evidence that COMA designates merely a neurological symptom with etiologic heterogeneity. In 2016, we reported an observational study in a cohort of 21 patients diagnosed as having COMA. Thorough re-evaluation of the neuroimaging features of these 21 subjects revealed a previously not recognized molar tooth sign (MTS) in 11 of them, thus leading to a diagnostic reassignment as Joubert syndrome (JBTS). Specific MRI features in two further individuals indicated a Poretti-Boltshauser syndrome (PTBHS) and a tubulinopathy. In eight patients, a more precise diagnosis was not achieved. We pursued this cohort aiming at clarification of the definite genetic basis of COMA in each patient. RESULTS: Using a candidate gene approach, molecular genetic panels or exome sequencing, we detected causative molecular genetic variants in 17 of 21 patients with COMA. In nine of those 11 subjects diagnosed with JBTS due to newly recognized MTS on neuroimaging, we found pathogenic mutations in five different genes known to be associated with JBTS, including KIAA0586, NPHP1, CC2D2A, MKS1, and TMEM67. In two individuals without MTS on MRI, pathogenic variants were detected in NPHP1 and KIAA0586, arriving at a diagnosis of JBTS type 4 and 23, respectively. Three patients carried heterozygous truncating variants in SUFU, representing the first description of a newly identified forme fruste of JBTS. The clinical diagnoses of PTBHS and tubulinopathy were confirmed by detection of causative variants in LAMA1 and TUBA1A, respectively. In one patient with normal MRI, biallelic pathogenic variants in ATM indicated variant ataxia telangiectasia. Exome sequencing failed to reveal causative genetic variants in the remaining four subjects, two of them with clear MTS on MRI. CONCLUSIONS: Our findings indicate marked etiologic heterogeneity in COMA with detection of causative mutations in 81% (17/21) in our cohort and nine different genes being affected, mostly genes associated with JBTS. We provide a diagnostic algorithm for COMA.

Risk of malignancy in T1-hyperintense Bosniak version 2019 class II and IIF cystic renal masses.

BACKGROUND: Bosniak classification version 2019 includes cystic masses in class II and IIF based partly on their hyperintense appearance at T1-weighted MRI. The prevalence of malignancy in non-enhancing heterogeneously T1-hyperintense masses is unknown, nor whether the pattern of T1 hyperintensity affects malignancy likelihood. PURPOSE: To determine the malignancy proportion among six patterns of T1 hyperintensity within non-enhancing cystic renal masses. METHODS: This retrospective, single-institution study included 72 Bosniak class II and IIF, non-enhancing, T1-hyperintense cystic renal masses. Diagnosis was confirmed by histopathology or by follow-up imaging demonstrating 5-year size and morphologic stability, decreased in size by ≥ 30%, resolution, or Bosniak down-classification. Six patterns of T1 hyperintensity were pre-defined: homogeneous (pattern A), fluid-fluid level (pattern B), peripherally markedly T1-hyperintense (pattern C), containing a T1-hyperintense non-enhancing nodule (pattern D), peripherally T1-hypointense (pattern E), and heterogeneously T1-hyperintense without a distinct pattern (pattern F). Three readers independently assigned each mass to a pattern. Individual and mean malignancy proportion were determined. Mann-Whitney test and Fischer's exact test compared the likelihood of malignancy between patterns. Inter-reader agreement was analyzed with Gwet's agreement coefficient (AC). RESULTS: Among 72 masses, the mean number of masses assigned was 11 (15%) to pattern A, 21 (29%) to pattern B, 6 (8%) to pattern C, 7 (10%) to pattern D, 5 (7%) to pattern E, and 22 (31%) to pattern F. Five of 72 masses (7%) were malignant; none was assigned pattern A, B, or D. Mean malignancy proportion was 5% (0/9, 1/6, and 0/4) for pattern C, 13% (0/4, 1/3, and 1/7) for pattern E, and 18% (5/20, 3/21, and 4/25) for pattern F. Malignant masses were more likely assigned to pattern E or F (p = 0.003-0.039). Inter-reader agreement was substantial (Gwet's AC: 0.68). CONCLUSION: Bosniak version 2019 class IIF masses that are non-enhancing and heterogeneously T1-hyperintense with a fluid-fluid level are likely benign. Those that are non-enhancing and heterogeneously T1-hyperintense without a distinct pattern have a malignancy proportion up to 25% (5/20).

The genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies.

Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease.

Scalp Tumor and Hydroureteronephrosis in Patients with Nephronophthisis and Homozygous NPHP1 Deletion.

Homozygous deletion of NPHP1 can lead to isolated nephronophthisis (NPHP) and syndromic disorders. However, the phenotype of scalp tumor and hydroureteronephrosis in NPHP patients with homozygous deletion of NPHP1 has not been reported. Clinical data, laboratory results, and genetic testing of 4 NPHP patients were collected. Examination of their eyes, heart, and urinary tract and of their hepatobiliary, skeletal, and central nervous systems was evaluated. Isolated NPHP was observed in 1 case, and syndromic disorders were observed in the other 3 patients. Their syndromic disorders showed NPHP combined with central nervous system defects, eye involvement, scalp tumor, arachnoid cyst, or hydroureteronephrosis. Large homozygous deletions covering the whole NPHP1 gene locus were identified in all 4 patients. We report a novel phenotype of scalp tumor and hydroureteronephrosis in NPHP patients with homozygous deletion of NPHP1, paving an avenue for further research on NPHP1-associated deformity in the skin and the urinary system.

Cystic Renal Masses: Old and New Paradigms.

Cystic renal masses describe a spectrum of lesions with benign and/or malignant features. Cystic renal masses are most often identified incidentally with the Bosniak classification system stratifying their malignant potential. Solid enhancing components most often represent clear cell renal cell carcinoma yet display an indolent natural history relative to pure solid renal masses. This has led to an increased adoption of active surveillance as a management strategy in those who are poor surgical candidates. This article provides a contemporary overview of historical and emerging clinical paradigms in the diagnosis and management of this distinct clinical entity.