RESUMEN
The etiologies of newborn deaths in neonatal intensive care units usually remain unknown, even after genetic testing. Whole-genome sequencing, combined with artificial intelligence-based methods for predicting the effects of non-coding variants, provide an avenue for resolving these deaths. Using one such method, SpliceAI, we identified a maternally inherited deep intronic PKHD1 splice variant (chr6:52030169T>C), in trans with a pathogenic missense variant (p.Thr36Met), in a newborn who died of autosomal recessive polycystic kidney disease at age 2 days. We validated the deep intronic variant's impact in maternal urine-derived cells expressing PKHD1. Reverse transcription polymerase chain reaction followed by Sanger sequencing showed that the variant causes inclusion of 147bp of the canonical intron between exons 29 and 30 of PKHD1 into the mRNA, including a premature stop codon. Allele-specific expression analysis at a heterozygous site in the mother showed that the mutant allele completely suppresses canonical splicing. In an unrelated healthy control, there was no evidence of transcripts including the novel splice junction. We returned a diagnostic report to the parents, who underwent in vitro embryo selection.
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Intrones , Riñón Poliquístico Autosómico Recesivo , Receptores de Superficie Celular , Humanos , Recién Nacido , Masculino , Intrones/genética , Mutación Missense , Riñón Poliquístico Autosómico Recesivo/genética , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Receptores de Superficie Celular/genéticaRESUMEN
The incidence of rare diseases is expected to be comparatively higher in the Middle East and North Africa (MENA) region than in other parts of the world, attributed to the high prevalence of consanguinity. Most MENA countries share social and economic statuses, cultural relativism, religious beliefs, and healthcare policies. Polycystic kidney diseases (PKDs) are the most common genetic causes of kidney failure, accounting for nearly 8.0% of dialysis cases. The development of PKDs is linked to variants in several genes, including PKD1, PKD2, PKHD1, DZIP1L, and CYS1. Autosomal recessive PKD (ARPKD) is the less common yet aggressive form of PKD. ARPKD has an estimated incidence between 1:10,000 and 1:40,000. Most patients with ARPKD require kidney replacement therapy earlier than patients with autosomal dominant polycystic kidney disease (ADPKD), often in their early years of life. This review gathered data from published research studies and reviews of ARPKD, highlighting the epidemiology, phenotypic presentation, investigations, genetic analysis, outcomes, and management. Although limited data are available, the published literature suggests that the incidence of ARPKD may be higher in the MENA region due to consanguineous marriages. Patients with ARPKD from the MENA region usually present at a later disease stage and have a relatively short time to progress to kidney failure. Limited data are available regarding the management practice in the region, which warrants further investigations.
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Riñón Poliquístico Autosómico Recesivo , Humanos , Riñón Poliquístico Autosómico Recesivo/genética , Riñón Poliquístico Autosómico Recesivo/epidemiología , Riñón Poliquístico Autosómico Recesivo/terapia , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Medio Oriente/epidemiología , África del Norte/epidemiología , Incidencia , Niño , Consanguinidad , PrevalenciaRESUMEN
The clinical features of cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis (COACH) characterize the rare autosomal recessive multisystem disorder called COACH syndrome. COACH syndrome belongs to the spectrum of Joubert syndrome and related disorders (JSRDs) and liver involvement distinguishes COACH syndrome from the rest of the JSRD spectrum. Developmental delay and oculomotor apraxia occur early but with time, these can improve and may not be readily apparent or no longer need active medical management. Congenital hepatic fibrosis and renal disease, on the other hand, may develop late, and the temporal incongruity in organ system involvement may delay the recognition of COACH syndrome. We present a case of a young adult presenting late to a Renal Genetics Clinic for evaluation of renal cystic disease with congenital hepatic fibrosis, clinically suspected to have autosomal recessive polycystic kidney disease. Following genetic testing, a reevaluation of his medical records from infancy, together with reverse phenotyping and genetic phasing, led to a diagnosis of COACH syndrome.
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Anomalías Múltiples , Encéfalo/anomalías , Vermis Cerebeloso , Cerebelo/anomalías , Colestasis , Coloboma , Enfermedades Genéticas Congénitas , Discapacidad Intelectual , Hepatopatías , Malformaciones del Sistema Nervioso , Riñón Poliquístico Autosómico Recesivo , Adulto Joven , Humanos , Coloboma/diagnóstico , Coloboma/genética , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Riñón Poliquístico Autosómico Recesivo/genética , Diagnóstico Tardío , Genotipo , Cirrosis Hepática/genética , Ataxia/diagnóstico , Ataxia/genética , Discapacidad Intelectual/genética , Discapacidades del DesarrolloRESUMEN
Autosomal recessive polycystic kidney disease (ARPKD) is the rare and usually early-onset form of polycystic kidney disease with a typical clinical presentation of enlarged cystic kidneys and liver involvement with congenital hepatic fibrosis or Caroli syndrome. ARPKD remains a clinical challenge in pediatrics, frequently requiring continuous and long-term multidisciplinary treatment. In this review, we aim to give an overview over clinical aspects of ARPKD and recent developments in our understanding of disease progression, risk patterns, and treatment of ARPKD.
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Enfermedad de Caroli , Riñón Poliquístico Autosómico Recesivo , Niño , Humanos , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Receptores de Superficie Celular , Pronóstico , Cirrosis Hepática/diagnóstico , Enfermedad de Caroli/diagnósticoRESUMEN
OBJECTIVE: Autosomal dominant polycystic kidney disease is an inherited kidney disorder with mutations in polycystin-1 or polycystin-2. Autosomal recessive polycystic kidney disease is a severe form of polycystic kidney disease that is characterized by enlarged kidneys and congenital hepatic fibrosis. Mutations at PKHD1 are responsible for all typical forms of autosomal recessive polycystic kidney disease. METHODS: We evaluated the children diagnosed with polycystic kidney disease between October 2020 and May 2022. The diagnosis was established by family history, ultrasound findings, and/or genetic analysis. The demographic, clinical, and laboratory findings were evaluated retrospectively. RESULTS: There were 28 children (male/female: 11:17) evaluated in this study. Genetic analysis was performed in all patients (polycystin-1 variants in 13, polycystin-2 variants in 7, and no variants in 8 patients). A total of 18 variants in polycystin-1 and polycystin-2 were identified and 9 (50%) of them were not reported before. A total of eight novel variants were identified as definite pathogenic or likely pathogenic mutations. There was no variant detected in the PKDH1 gene. CONCLUSION: Our results highlighted molecular features of Turkish children with polycystic kidney disease and demonstrated novel variations that can be utilized in clinical diagnosis and prognosis.
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Riñón Poliquístico Autosómico Recesivo , Humanos , Masculino , Niño , Femenino , Riñón Poliquístico Autosómico Recesivo/genética , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Riñón Poliquístico Autosómico Recesivo/patología , Canales Catiónicos TRPP/genética , Estudios Retrospectivos , Receptores de Superficie Celular/genética , Riñón/patología , MutaciónRESUMEN
Cystic kidney diseases, when broadly defined, have a wide differential diagnosis extending from recessive diseases with a prenatal or pediatric diagnosis, to the most common autosomal-dominant polycystic kidney disease primarily affecting adults, and several other genetic or acquired etiologies that can manifest with kidney cysts. The most likely diagnoses to consider when assessing a patient with cystic kidney disease differ depending on family history, age stratum, radiologic characteristics, and extrarenal features. Accurate identification of the underlying condition is crucial to estimate the prognosis and initiate the appropriate management, identification of extrarenal manifestations, and counseling on recurrence risk in future pregnancies. There are significant differences in the clinical approach to investigating and managing kidney cysts in children compared with adults. Next-generation sequencing has revolutionized the diagnosis of inherited disorders of the kidney, despite limitations in access and challenges in interpreting the data. Disease-modifying treatments are lacking in the majority of kidney cystic diseases. For adults with rapid progressive autosomal-dominant polycystic kidney disease, tolvaptan (V2-receptor antagonist) has been approved to slow the rate of decline in kidney function. In this article, we examine the differences in the differential diagnosis and clinical management of cystic kidney disease in children versus adults, and we highlight the progress in molecular diagnostics and therapeutics, as well as some of the gaps meriting further attention.
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Quistes , Neoplasias Renales , Riñón Poliquístico Autosómico Dominante , Riñón Poliquístico Autosómico Recesivo , Adulto , Embarazo , Femenino , Niño , Humanos , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Riñón Poliquístico Autosómico Recesivo/genética , Riñón Poliquístico Autosómico Recesivo/terapia , Riñón , Riñón Poliquístico Autosómico Dominante/complicaciones , Riñón Poliquístico Autosómico Dominante/diagnóstico , Riñón Poliquístico Autosómico Dominante/genética , Quistes/diagnóstico , Quistes/genética , Quistes/terapiaRESUMEN
Polycystic Kidney Diseases (PKDs) consist of a genetically and phenotypically heterogeneous group of inherited disorders characterized by numerous renal cysts. PKDs include autosomal dominant ADPKD, autosomal recessive ARPKD and atypical forms. Here, we analyzed 255 Italian patients using an NGS panel of 63 genes, plus Sanger sequencing of exon 1 of the PKD1 gene and MPLA (PKD1, PKD2 and PKHD1) analysis. Overall, 167 patients bore pathogenic/likely pathogenic variants in dominant genes, and 5 patients in recessive genes. Four patients were carriers of one pathogenic/likely pathogenic recessive variant. A total of 24 patients had a VUS variant in dominant genes, 8 patients in recessive genes and 15 patients were carriers of one VUS variant in recessive genes. Finally, in 32 patients we could not reveal any variant. Regarding the global diagnostic status, 69% of total patients bore pathogenic/likely pathogenic variants, 18.4% VUS variants and in 12.6% of patients we could not find any. PKD1 and PKD2 resulted to be the most mutated genes; additional genes were UMOD and GANAB. Among recessive genes, PKHD1 was the most mutated gene. An analysis of eGFR values showed that patients with truncating variants had a more severe phenotype. In conclusion, our study confirmed the high degree of genetic complexity at the basis of PKDs and highlighted the crucial role of molecular characterization in patients with suspicious clinical diagnosis. An accurate and early molecular diagnosis is essential to adopt the appropriate therapeutic protocol and represents a predictive factor for family members.
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Riñón Poliquístico Autosómico Dominante , Riñón Poliquístico Autosómico Recesivo , Humanos , Canales Catiónicos TRPP/genética , Riñón Poliquístico Autosómico Dominante/diagnóstico , Riñón Poliquístico Autosómico Dominante/genética , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Riñón Poliquístico Autosómico Recesivo/genética , Exones , Genes Reguladores , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) causes fibrocystic kidney disease, congenital hepatic fibrosis, and portal hypertension. Serum galectin-3 (Gal-3) and intestinal fatty acid binding protein (I-FABP) are potential biomarkers of kidney fibrosis and portal hypertension, respectively. We examined whether serum Gal-3 associates with kidney disease severity and serum I-FABP associates with liver disease severity in ARPKD. METHODS: Cross-sectional study of 29 participants with ARPKD (0.2-21 years old) and presence of native kidneys (Gal-3 analyses, n = 18) and/or native livers (I-FABP analyses, n = 21). Serum Gal-3 and I-FABP were analyzed using enzyme linked immunosorbent assay. Kidney disease severity variables included estimated glomerular filtration rate (eGFR) and height-adjusted total kidney volume (htTKV). Liver disease severity was characterized using ultrasound elastography to measure liver fibrosis, and spleen length and platelet count as markers of portal hypertension. Simple and multivariable linear regression examined associations between Gal-3 and kidney disease severity (adjusted for liver disease severity) and between I-FABP and liver disease severity (adjusted for eGFR). RESULTS: Serum Gal-3 was negatively associated with eGFR; 1 standard deviation (SD) lower eGFR was associated with 0.795 SD higher Gal-3 level (95% CI - 1.116, - 0.473; p < 0.001). This association remained significant when adjusted for liver disease severity. Serum Gal-3 was not associated with htTKV in adjusted analyses. Overall I-FABP levels were elevated, but there were no linear associations between I-FABP and liver disease severity in unadjusted or adjusted models. CONCLUSIONS: Serum Gal-3 is associated with eGFR in ARPKD, suggesting its value as a possible novel biomarker of kidney disease severity. We found no associations between serum I-FABP and ARPKD liver disease severity despite overall elevated I-FABP levels.
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Hipertensión Portal , Riñón Poliquístico Autosómico Recesivo , Adolescente , Niño , Preescolar , Humanos , Lactante , Adulto Joven , Biomarcadores , Estudios Transversales , Proteínas de Unión a Ácidos Grasos , Galectina 3 , Riñón , Riñón Poliquístico Autosómico Recesivo/diagnósticoRESUMEN
BACKGROUND: Caroli disease (CD, OMIM #600643) is a rare autosomal recessive disorder characterized by polycystic segmental dilatation of the intrahepatic bile ducts and extreme variability in age of onset and clinical manifestations. When congenital hepatic fibrosis is associated with the polycystic dilatation of the biliary tract, the condition is referred as Caroli syndrome. The disease is thought to be caused by pathogenic variants in the PKHD1 gene (OMIM *606702). METHOD: We report the clinical, biochemical, and molecular characterization of three patients with a clinical suspicion of CS belonging to two different families. The genetic screening was performed using a target custom panel and sequencing was performed on Illumina platform. RESULTS: Genetic analysis revealed the presence of rare variants in the PKHD1 gene of the analyzed patients. In the first case, and his younger sister, two pathogenic variants (c.2702A>C and c.4870C>T) were found to be associated with a hepatic phenotype at clinical onset, followed by renal disease probably age-related; while in the second case, one pathogenic variant (c.5879C>G) and a complex allele with uncertain clinical significance [c.3407A>G; c.8345G>C; c.8606C>A] were found to be associated with a severe hepatic phenotype. CONCLUSION: The identification of the genetic causes of the disease and their relationship with the clinical phenotype could have a favorable impact on clinical management and complication prevention.
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Enfermedad de Caroli , Riñón Poliquístico Autosómico Recesivo , Enfermedad de Caroli/diagnóstico , Enfermedad de Caroli/genética , Pruebas Genéticas , Humanos , Fenotipo , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Riñón Poliquístico Autosómico Recesivo/genética , Riñón Poliquístico Autosómico Recesivo/patología , Receptores de Superficie Celular/genéticaRESUMEN
BACKGROUND: Autosomal recessive polycystic kidney disease is a cystic kidney disease with early onset and clinically characterized by enlarged echogenic kidneys, hypertension, varying degrees of kidney dysfunction, and liver fibrosis. It is most frequently caused by sequence variants in the PKHD1 gene, encoding fibrocystin. In more rare cases, sequence variants in DZIP1L are seen, encoding the basal body protein DAZ interacting protein 1-like protein (DZIP1L). So far, only four different DZIP1L variants have been reported. METHODS: Four children from three consanguineous families presenting with polycystic kidney disease were selected for targeted or untargeted exome sequencing. RESULTS: We identified two different, previously not reported homozygous DZIP1L sequence variants: c.193 T > C; p.(Cys65Arg), and c.216C > G; p.(Cys72Trp). Functional analyses of the c.216C > G; p.(Cys72Trp) variant indicated mislocalization of mutant DZIP1L. CONCLUSIONS: In line with published data, our results suggest a critical role of the N-terminal domain for proper protein function. Although patients with PKHD1-associated autosomal recessive polycystic kidney disease often have liver abnormalities, none of the present four patients showed any clinically relevant liver involvement. Our data demonstrate the power and efficiency of next-generation sequencing-based approaches. While DZIP1L-related polycystic kidney disease certainly represents a rare form of the disease, our results emphasize the importance of including DZIP1L in multigene panels and in the data analysis of whole-exome sequencing for cystic kidney diseases. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Proteínas Adaptadoras Transductoras de Señales , Riñón Poliquístico Autosómico Recesivo , Proteínas Adaptadoras Transductoras de Señales/análisis , Proteínas Adaptadoras Transductoras de Señales/genética , Niño , Consanguinidad , Pruebas Genéticas/métodos , Humanos , Mutación , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Riñón Poliquístico Autosómico Recesivo/genética , Receptores de Superficie Celular/genética , Secuenciación del ExomaRESUMEN
BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene. The clinical spectrum is often more variable than previously considered. We aimed to analyze the clinical features of genetically diagnosed ARPKD in the Japanese population. METHODS: We conducted a genetic analysis of patients with clinically diagnosed or suspected ARPKD in Japan. Moreover, we performed a minigene assay to elucidate the mechanisms that could affect phenotypes. RESULTS: PKHD1 pathogenic variants were identified in 32 patients (0-46 years). Approximately one-third of the patients showed prenatal anomalies, and five patients died within one year after birth. Other manifestations were detected as follows: chronic kidney disease stages 1-2 in 15/26 (57.7%), Caroli disease in 9/32 (28.1%), hepatic fibrosis in 7/32 (21.9%), systemic hypertension in 13/27 (48.1%), and congenital hypothyroidism in 3 patients. There have been reported that truncating mutations in both alleles led to severe phenotypes with perinatal demise. However, one patient without a missense mutation survived the neonatal period. In the minigene assay, c.2713C > T (p.Gln905Ter) and c.6808 + 1G > A expressed a transcript that skipped exon 25 (123 bp) and exon 41 (126 bp), resulting in an in-frame mutation, which might have contributed to the milder phenotype. Missense mutations in cases of neonatal demise did not show splicing abnormalities. CONCLUSION: Clinical manifestations ranged from cases of neonatal demise to those diagnosed in adulthood. The minigene assay results indicate the importance of functional analysis, and call into question the fundamental belief that at least one non-truncating mutation is necessary for perinatal survival.
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Riñón Poliquístico Autosómico Recesivo , Adulto , Femenino , Pruebas Genéticas/métodos , Humanos , Japón , Mutación , Fenotipo , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Riñón Poliquístico Autosómico Recesivo/genética , Embarazo , Receptores de Superficie Celular/genéticaRESUMEN
AIMS: Autosomal recessive polycystic kidney disease (ARPKD) is a rare inherited disease. We reviewed the clinical characteristics, management, and outcomes in Slovenian pediatric patients with ARPKD. MATERIALS AND METHODS: All patients with ARPKD who were treated at the Pediatric Nephrology Department of the University Children's Hospital in Ljubljana between 1980 and 2020 were included in the study. The data were assessed retrospectively by reviewing the patients' medical records and analyzed using descriptive statistics. RESULTS: We included 13 patients, 6 boys and 7 girls. A prenatal diagnosis was established in 3 (23%) patients. In 4 (31%) patients, the diagnosis was confirmed within the first few days of life, while in 6 (46%) patients the disease manifested later during childhood. Four babies (31%) needed ventilatory support after birth. Arterial hypertension developed in all patients. Liver function was affected in 12 (92%) patients and was the predominant clinical concern in 2 of them. Two (15%) patients presented with end-stage renal disease (ESRD). Portal hypertension was found in 7 (54%) patients. Initial sonography revealed enlarged kidneys in 12 (92%) patients, hyperechoic kidneys or poor cortico-medullary differentiation in 10 (77%), and liver abnormalities in 5 (38%) patients. Unilateral nephrectomy was necessary before dialysis in 1 patient. Six (46%) patients started maintenance dialysis at an average age of 15.3 years. Kidney transplantation was performed in 2 (15%) and liver transplantation in 1 (8%) patient. Two (15%) patients died because of sepsis or respiratory failure. CONCLUSION: ARPKD is a progressive disease leading to ESRD and renal replacement treatment in almost half of our patients. Our data confirm the phenotypic variability of ARPKD in Slovenian patients.
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Trasplante de Riñón , Trasplante de Hígado , Riñón Poliquístico Autosómico Recesivo , Adolescente , Niño , Femenino , Humanos , Masculino , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Riñón Poliquístico Autosómico Recesivo/epidemiología , Riñón Poliquístico Autosómico Recesivo/terapia , Embarazo , Estudios Retrospectivos , UltrasonografíaRESUMEN
BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is a rare severe hepatorenal disease. Survivors of pulmonary hypoplasia and patients with milder presentations often achieve long-term survival but frequently require kidney and/or liver transplantation. OBJECTIVE: To examine the use of clinical, surrogate and patient-centered outcomes in studies on ARPKD with special attention to core outcomes of the Standardized Outcomes in NephroloGy project for children with chronic kidney disease (SONG-Kids). DATA SOURCES AND STUDY ELIGIBILITY CRITERIA: A systematic MEDLINE literature search identified 367 ARPKD studies published since 1990; however, of these 134 were excluded because they did not report any clinical outcomes (e.g. only histopathological, genetic, protein structure or radiological markers), 19 studies because they only included prenatal patients and 138 because they were case reports with ≤ 3 patients. STUDY APPRAISAL: Seventy-six eligible studies were examined for study type, size, intervention, and reported outcomes by organ system and type, including all SONG-kids tier 1-3 outcomes. PARTICIPANTS: There were 3231 patient-reports of children and adults with ARPKD. RESULTS: The overwhelming majority of studies reported clinical and surrogate outcomes (75/76 (98%) and 73/76 (96%)), but only 11/76 (14%) examined patient-centered outcomes and only 2/76 (3%) used validated instruments to capture them. Of the SONG-Kids core outcomes, kidney function was reported almost universally (70/76 (92%), infection and survival in three quarters (57/76 (75%), 55/76 (72%)) and measures of life participation (including neurological impairment) only rarely and inconsistently (16/76 (21%)). LIMITATIONS: Thirty studies (39%) were of low quality as they were either narrative case reports (n = 14, 18%) and/or patients with ARPKD were an indistinguishable subgroup (n = 18, 24%). Only 28 trials compared interventions, but none were randomized. CONCLUSIONS AND IMPLICATIONS: Studies that reported clinical outcomes in ARPKD usually covered the core outcome domains of kidney function, infections, and survival, but measures of life participation and patient-centered outcomes are distinctly lacking and require more attention in future trials. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Evaluación de Resultado en la Atención de Salud , Riñón Poliquístico Autosómico Recesivo , Adulto , Niño , Humanos , Riñón , Atención Dirigida al Paciente , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Riñón Poliquístico Autosómico Recesivo/terapiaRESUMEN
BACKGROUND & AIMS: Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in PKHD1, encoding fibrocystin/polyductin (FPC). Severe disease occurs in perinates. Those who survive the neonatal period face a myriad of comorbidities, including systemic and portal hypertension, liver fibrosis, and hepatosplenomegaly. The goal here was to uncover therapeutic strategies for ARPKD. METHODS: We used wild-type and an FPC-mutant cholangiocyte cell line in 3-dimenional cysts and in confluent monolayers to evaluate protein expression using western blotting and protein trafficking using confocal microscopy. RESULTS: We found that the protein level of the cystic fibrosis transmembrane conductance regulator (CFTR) was downregulated. The levels of heat shock proteins (HSPs) were altered in the FPC-mutant cholangiocytes, with HSP27 being downregulated and HSP90 and HSP70 upregulated. FPC-mutant cholangiocytes formed cysts, but normal cells did not. Cyst growth could be reduced by increasing HSP27 protein levels, by HSP90 and HSP70 inhibitor treatments, by silencing HSP90 through messenger RNA inhibition, or by the novel approach of treating the cysts with the CFTR corrector VX-809. In wild-type cholangiocytes, CFTR is present in both apical and basolateral membranes. FPC malfunction resulted in altered colocalization of CFTR with both apical and basolateral membranes. Whereas, treatment with VX-809, increasing HSP27 or inhibiting HSP70 or HSP90 restored CFTR localization toward normal values. CONCLUSIONS: FPC malfunction induces the formation of cysts, which are fueled by alterations in HSPs and in CFTR protein levels and miss-localization. We suggest that CFTR correctors, already in clinical use to treat cystic fibrosis, could also be used as a treatment for ARPKD.
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Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Predisposición Genética a la Enfermedad , Riñón Poliquístico Autosómico Recesivo/genética , Riñón Poliquístico Autosómico Recesivo/metabolismo , Receptores de Superficie Celular/genética , Animales , Línea Celular , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Modelos Animales de Enfermedad , Degradación Asociada con el Retículo Endoplásmico , Regulación de la Expresión Génica , Silenciador del Gen , Terapia Genética/métodos , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Ratones , Ratones Noqueados , Mutación , Fenotipo , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Riñón Poliquístico Autosómico Recesivo/terapia , Transporte de Proteínas , Receptores de Superficie Celular/metabolismo , Eliminación de SecuenciaRESUMEN
This case report describes a premature male infant born after a pregnancy complicated by oligohydramnios of unknown aetiology but otherwise unremarkable prenatal scans. He had sudden onset of projectile emesis and severe hypertension in the third week of life, and further investigations revealed both pyloric stenosis and polycystic kidneys, at just 36 weeks' postmenstrual age (PMA). His course thereafter was complicated by severe refractory hypertension requiring multiple antihypertensive agents in order to gain control, although his renal function remained normal. Few case reports have previously described this unusual association, but none have presented with both entities at such an early PMA.
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Enfermedades del Prematuro , Oligohidramnios , Riñón Poliquístico Autosómico Recesivo , Estenosis Pilórica , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Riñón Poliquístico Autosómico Recesivo/diagnóstico por imagen , EmbarazoRESUMEN
The gene encoding hepatocyte nuclear factor 1ß (HNF1B), a transcription factor involved in the development of the kidney and other organs, is located on chromosome 17q12. Heterozygous deletions of chromosome 17q12, which involve 15 genes including HNF1B, are known as 17q12 deletion syndrome and are a common cause of congenital anomalies of the kidneys and urinary tract (CAKUT) and may also present as a multisystem disorder. Autosomal recessive polycystic kidney disease (ARPKD), on the other hand, is a severe form of polycystic kidney disease caused by mutations in PKHD1 (polycystic kidney and hepatic disease 1). It is important to differentiate between these two diseases because they differ significantly in inheritance patterns, renal prognosis, and extrarenal manifestations. Here we report a case of 17q12 deletion syndrome that clinically mimicked ARPKD in which genetic testing was essential for appropriate genetic counseling and monitoring of possible extrarenal manifestations. The patient presented antenatally with markedly enlarged kidneys and showed bilaterally hyperechoic kidneys with poor corticomedullary differentiation and multiple cysts on ultrasonography. There was no family history of renal disease. ARPKD was clinically suspected and genetic testing was performed to confirm diagnosis, resulting in an unexpected finding of 17q12 deletion including HNF1B. While some research has been done to identify patients that should be tested for HNF1B anomalies, this case illustrates the difficulty of recognizing HNF1B-related disease and the importance of genetic testing in appropriately managing CAKUT cases.
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Deleción Cromosómica , Cromosomas Humanos Par 17 , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Diagnóstico Diferencial , Femenino , Enfermedades Fetales/diagnóstico por imagen , Humanos , Recién Nacido , Imagen por Resonancia Magnética , Masculino , EmbarazoRESUMEN
Autosomal recessive polycystic kidney disease (ARPKD) is a severe disease of early childhood that is clinically characterized by fibrocystic changes of the kidneys and the liver. The main cause of ARPKD are variants in the PKHD1 gene encoding the large transmembrane protein fibrocystin. The mechanisms underlying the observed clinical heterogeneity in ARPKD remain incompletely understood, partly due to the fact that genotype-phenotype correlations have been limited to the association of biallelic null variants in PKHD1 with the most severe phenotypes. In this observational study we analyzed a deep clinical dataset of 304 patients with ARPKD from two independent cohorts and identified novel genotype-phenotype correlations during childhood and adolescence. Biallelic null variants frequently show severe courses. Additionally, our data suggest that the affected region in PKHD1 is important in determining the phenotype. Patients with two missense variants affecting amino acids 709-1837 of fibrocystin or a missense variant in this region and a null variant less frequently developed chronic kidney failure, and patients with missense variants affecting amino acids 1838-2624 showed better hepatic outcome. Variants affecting amino acids 2625-4074 of fibrocystin were associated with poorer hepatic outcome. Thus, our data expand the understanding of genotype-phenotype correlations in pediatric ARPKD patients and can lay the foundation for more precise and personalized counselling and treatment approaches.
Asunto(s)
Riñón Poliquístico Autosómico Recesivo , Niño , Preescolar , Estudios de Asociación Genética , Humanos , Riñón , Mutación , Fenotipo , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Riñón Poliquístico Autosómico Recesivo/genética , Receptores de Superficie Celular/genéticaRESUMEN
BACKGROUND: Both Caroli disease (CD) and autosomal recessive polycystic kidney disease (ARPKD) are autosomal recessive disorders, which are more commonly found in infants and children, for whom surviving to adulthood is rare. Early diagnosis and intervention can improve the survival rate to some extent. This study adopted the case of a 26-year-old pregnant woman to explore the clinical and imaging manifestations and progress of CD concomitant with ARPKD to enable a better understanding of the disease. CASE PRESENTATION: A 26-year-old pregnant woman was admitted to our hospital for more than 2 months following the discovery of pancytopenia and increased creatinine. Ultrasonography detected an enlarged left liver lobe, widened hepatic portal vein, splenomegaly, and dilated splenic vein. In addition, both kidneys were obviously enlarged and sonolucent areas of varying sizes were visible, but color Doppler flow imaging revealed no abnormal blood flow signals. The gestational age was approximately 25 weeks, which was consistent with the actual fetal age. Polyhydramnios was detected but no other abnormalities were identified. Magnetic resonance imaging revealed that the liver was plump, and polycystic liver disease was observed near the top of the diaphragm. The T1 and T2 weighted images were the low and high signals, respectively. The bile duct was slightly dilated; the portal vein was widened; and the spleen volume was enlarged. Moreover, the volume of both kidneys had increased to an abnormal shape, with multiple, long, roundish T1 and T2 abnormal signals being observed. Magnetic resonance cholangiopancreatography revealed that intrahepatic cystic lesions were connected with intrahepatic bile ducts. The patient underwent a genetic testing, the result showed she carried two heterozygous mutations in PKHD1. The patient was finally diagnosed with CD with concomitant ARPKD. The baby underwent a genetic test three months after birth, the result showed that the patient carried one heterozygous mutations in PKHD1, which indicated the baby was a PKHD1 carrier. CONCLUSIONS: This case demonstrates that imaging examinations are of great significance for the diagnosis and evaluation of CD with concomitant ARPKD.
Asunto(s)
Enfermedad de Caroli/diagnóstico , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Polihidramnios/diagnóstico , Complicaciones del Embarazo/diagnóstico , Adulto , Conductos Biliares Intrahepáticos/diagnóstico por imagen , Enfermedad de Caroli/complicaciones , Enfermedad de Caroli/genética , Pancreatocolangiografía por Resonancia Magnética , Análisis Mutacional de ADN , Femenino , Heterocigoto , Humanos , Riñón/diagnóstico por imagen , Hígado/diagnóstico por imagen , Pruebas Prenatales no Invasivas , Riñón Poliquístico Autosómico Recesivo/complicaciones , Riñón Poliquístico Autosómico Recesivo/genética , Polihidramnios/etiología , Embarazo , Complicaciones del Embarazo/genética , Receptores de Superficie Celular/genética , Ultrasonografía Doppler en ColorRESUMEN
BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is a rare ciliopathy characterized by congenital hepatic fibrosis and cystic kidney disease. Lack of data about long-term follow-up makes it difficult to discuss timing and type of organ transplantation. Our objectives were to evaluate long-term evolution and indications for transplantation, from birth to adulthood. METHODS: Neonatal survivors and patients diagnosed in postnatal period with ARPKD between 1985 January and 2017 December from 3 French pediatric centers were retrospectively enrolled in the study. RESULTS: Fifty patients with mean follow-up 12.5 ± 1 years were enrolled. ARPKD was diagnosed before birth in 24%, and at mean age 1.8 years in others. Thirty-three patients were < 1 year of age at first symptoms, which were mostly kidney-related. These most often presented high blood pressure during follow-up. Portal hypertension was diagnosed in 29 patients (58%), 4 of them with bleeding from esophageal varices. Eight patients presented cholangitis (> 3 episodes in three children). Liver function was normal in all patients. Nine children received a kidney transplant without liver complications. A 20-year-old patient received a combined liver-kidney transplant (CLKT) for recurrent cholangitis, and a 15-year-old boy an isolated liver transplant for uncontrollable variceal bleeding despite portosystemic shunt. CONCLUSIONS: Long-term outcome in patients with ARPKD is heterogeneous, and in this cohort did not depend on age at diagnosis except for blood pressure. Few patients required liver transplantation. Indications for liver or combined liver-kidney transplantation were limited to recurrent cholangitis or uncontrollable portal hypertension. Liver complications after kidney transplantation were not significant.
Asunto(s)
Colangitis , Várices Esofágicas y Gástricas , Hipertensión Portal , Riñón Poliquístico Autosómico Recesivo , Adolescente , Niño , Preescolar , Colangitis/etiología , Várices Esofágicas y Gástricas/etiología , Humanos , Hipertensión Portal/etiología , Lactante , Recién Nacido , Riñón/cirugía , Masculino , Riñón Poliquístico Autosómico Recesivo/complicaciones , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
Polycystic kidneys disease refers to cyst(s) formation in kidneys with severe consequences of end stage renal disease thus have higher mortality. It is a common genetic disease occurring either as autosomal dominant polycystic kidney (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD) with prevalence rates of 1/1000 and 1/40,000 respectively. Dominant forms presenting in later (>30) while recessive in earlier ages (infancy) and affecting both sexes and almost all race. The patient experiences many renal as well as extra-renal manifestations with marked hypertension and cyst formation in other organs predominantly in liver. Due to genetic basis, positive family history is considered as major risk factor. Ultrasonography remains the main stay of diagnosis along with family history, by indicating increased renal size and architectural modifications. Initially disease remains asymptomatic, later on symptomatic treatment is suggested with surgical interventions like cyst decortications or drainage. Dialysis proved to be beneficial in end stage renal disease. However renal transplantation is the treatment of choice.