Fenotipos inesperados en el síndrome de Alport: la necesidad del estudio genético / Unexpected phenotypes in Alport syndrome: the need for genetic testing

El diagnóstico del síndrome de Alport supone un reto en la edadpediátrica, debido a la ausencia de fenotipos clínicos esperados de la enfermedad, su clásica caracterización de entidad rara y la práctica muy restringida de biopsias renales con análisis rutinario de la muestra por microscopía electrónica durante la infancia. Se presentan las características clínicas y genéticas de 6 pacientes pediátricos (4 mujeres) diagnosticados de síndromede Alport en dos centros hospitalarios entre 2018 y 2021. Todos los pacientes presentaron un debut clínico claramente diferente y ninguno presentó complicaciones auditivas nioftalmológicas. La mitad carecía de antecedentes familiares de enfermedad renal crónica. Ninguna biopsia renal realizada confirmó el diagnóstico. Todos los pacientes fueron confirmadosgenéticamente y fueron el caso índice del estudio familiar. Esta serie ilustra la presencia de fenotipos clínicos inesperados en el síndrome de Alport y refleja la necesidad de incorporar el estudio genético para su diagnóstico.

The diagnosis of Alport syndrome is a challenge in the pediatric age, due to the absence of expected clinical phenotypes of the disease, its classic characterization of a rare disease and the very restricted practice of renal biopsies with routine analysis of the sample by electron microscopy during infancy. The clinical and genetic characteristics of 6 pediatric patients (4 women) diagnosed with Alport syndrome in two hospital centers between 2018 and 2021 are reported. All patients presented a clearly different clinical debut and none presented auditory or ophthalmological complications. Half had no family history of chronic kidney disease. No kidney biopsy performed confirmed the diagnosis. All patients were genetically confirmed and were the index case in the family study. This series illustrates the presence of unexpected clinical phenotypes in Alport syndrome and reflects the need for the incorporation of the genetic study for its diagnosis.

[Unexpected phenotypes in Alport syndrome: the need for genetic testing]. / Fenotipos inesperados en el síndrome de Alport: la necesidad del estudio genético.

The diagnosis of Alport syndrome is a challenge in the pediatric age, due to the absence of expected clinical phenotypes of the disease, its classic characterization of a rare disease and the very restricted practice of renal biopsies with routine analysis of the sample by electron microscopy during infancy. The clinical and genetic characteristics of 6 pediatric patients (4 women) diagnosed with Alport syndrome in two hospital centers between 2018 and 2021 are reported. All patients presented a clearly different clinical debut and none presented auditory or ophthalmological complications. Half had no family history of chronic kidney disease. No kidney biopsy performed confirmed the diagnosis. All patients were genetically confirmed and were the index case in the family study. This series illustrates the presence of unexpected clinical phenotypes in Alport syndrome and reflects the need for the incorporation of the genetic study for its diagnosis.

El diagnóstico del síndrome de Alport supone un reto en la edad pediátrica, debido a la ausencia de fenotipos clínicos esperados de la enfermedad, su clásica caracterización de entidad rara y la práctica muy restringida de biopsias renales con análisis rutinario de la muestra por microscopía electrónica durante la infancia. Se presentan las características clínicas y genéticas de 6 pacientes pediátricos (4 mujeres) diagnosticados de síndrome de Alport en dos centros hospitalarios entre 2018 y 2021. Todos los pacientes presentaron un debut clínico claramente diferente y ninguno presentó complicaciones auditivas ni oftalmológicas. La mitad carecía de antecedentes familiares de enfermedad renal crónica. Ninguna biopsia renal realizada confirmó el diagnóstico. Todos los pacientes fueron confirmados genéticamente y fueron el caso índice del estudio familiar. Esta serie ilustra la presencia de fenotipos clínicos inesperados en el síndrome de Alport y refleja la necesidad de incorporar el estudio genético para su diagnóstico.

Whole-Exome Sequencing (WES) results of 50 patients with chronic kidney diseases: a perspective of Alport syndrome

SUMMARY OBJECTIVE: Chronic kidney disease (CKD) remains one of the major common health problems, and the number of people affected by the disease is progressively increasing in Turkey and worldwide. This study aimed to investigate molecular defects in Alport syndrome (AS) and other genes in patients with clinically suspected CKD using whole-exome sequencing (WES). METHODS: Patients with clinical suspicion of CKD were included in the study. Molecular genetic analyses were performed on genomic DNA by using WES. RESULTS: A total of 15 with 5 different pathogenic or likely pathogenic variants were identified in CKD patients, with a diagnostic rate of 30%. Eight variants of uncertain significance were also detected. In this study, 10 variants were described for the first time. As a result, we detected variants associated with CKD in our study population and found AS as the most common CKD after other related kidney diseases. CONCLUSIONS: Our results suggest that in heterogeneous diseases such as CKD, WES analysis enables accurate identification of underlying molecular defects promptly. Although CKD accounts for 10-14% of all renal dysfunction, molecular genetic diagnosis is necessary for optimal long-term treatment, prognosis, and effective genetic counseling.

Síndrome de Alport: Rol de la semiología y la genética

El síndrome de Alport es una enfermedad renal progresiva por alteración de la membrana basal glomerular secundaria a mutación en los genes COL4A4, COL4A5 y COL4A6 del colágeno tipo IV, con 3 patrones hereditarios: ligado al cromosoma X, autosómico dominante y autosómico recesivo. No existe tratamiento específico para el síndrome de Alport, el objetivo del tratamiento es evitar la progresión rápida a enfermedad renal crónica y mejorar la calidad de vida del paciente. Se reporta el caso de una femenina de 5 años que acudió al cuarto de urgencias con historia de dolor abdominal y edema en miembros inferiores con hematuria microscópica, resto de exámenes de laboratorio y gabinete con hallazgos sugestivos de apendicitis aguda. Se realizó diagnóstico de apendicitis aguda y síndrome nefrítico, sin embargo, debido a la persistencia de hematuria con proteinuria e historia familiar de hematuria, se sospecha de síndrome de Alport.  Inició tratamiento con inhibidores de la enzima convertidora de angiotensina y se realizó biopsia renal reportada sin alteraciones a la microscopía de luz sin reporte de microscopía electrónica. Cursó con proteinuria en rango nefrótico, inicia tratamiento con corticoides e inhibidores de calcineurina sin respuesta. Se obtiene reporte de panel genético confirmatorio de Alport y se suspende inmunosupresión. (provisto por Infomedic International)

Alport syndrome is a progressive kidney disease, due to alterations of the glomerular basement membrane secondary to mutations in the COL4A4, COL4A5 and COL 4A6 genes of type IV collagen with three hereditary patterns: X-linked, autosomal dominant and autosomal recessive. There is no specific treatment for Alport Syndrome. The main goal of the therapeutic options is to prevent rapid progression to chronic kidney disease and improve the patient's quality of life. The report of a 5-year-old female, who attended the emergency room with abdominal pain, edema in the lower limbs and microscopic hematuria, the rest of the laboratory and clinical studies with findings suggestive of acute appendicitis. A diagnosis of acute appendicitis and nephritic syndrome was made, however, due to the persistence of hematuria and family history, Alport syndrome was suspected. Treatment with angiotensin-converting enzyme inhibitors was started and renal biopsy was performed, reported minimal change and without electron microscopy report. The patient quickly progressed to nephrotic range proteinuria and started corticosteroids and calcineurin inhibitors without response.  A confirmatory genetic panel was performed, Alport syndrome was diagnosed, and immunosuppression was suspended. (provided by Infomedic International)

Glomerulonefritis C3 en un paciente con síndrome de Alport: un caso raro

El síndrome de Alport es una entidad hereditaria que se produce principalmente por una mutación en los genes que codifican el colágeno tipo IV. Por otro lado, la glomerulonefritis C3 es una entidad rara que presenta un patrón de glomerulonefritis membranoproliferativa y su etiología se basa en un control anormal de la activación de la vía alternativa del complemento. A continuación se describe un caso de un paciente, de sexo masculino, que cursa con un síndrome nefrótico corticorresistente en el que se documenta un patrón de glomerulonefritis membranoproliferativa en la biopsia renal con depósitos de C3 en la inmunofluorescencia, asociada a una deleción heterocigota en el gen CFHR1 en el estudio genético de las proteínas reguladoras del complemento. Además, en el panel genético realizado por corticorresistencia se encuentra una variante COL4A5 asociada al síndrome de Alport ligado al X. Estas entidades pueden presentarse con un curso clínico diverso, pero al estar asociadas pueden acelerar la progresión a enfermedad renal crónica, por lo que se hace necesario hacer un seguimiento clínico más estricto.

Alport Syndrome is a hereditary entity that occurs mainly due to a mutation in the genes that encode type IV collagen. C3 glomerulonephritis is a rare entity with a pattern of membranoproliferative glomerulonephritis and its etiology is based on abnormal control of the activation of the alternative complement pathway. We describe a case of a male patient who presents with a corticosteroid nephrotic syndrome in which a pattern of membranoproliferative glomerulonephritis is documented in the renal biopsy with C3 deposits in the immunofluorescence, associated with a heterozygous deletion in the gene CFHR1 in the genetic study of complement regulatory proteins. Furthermore, a variant COL4A5 associated with X-linked Alport syndrome is found in the genetic panel for corticosteroid resistance. These entities can present with a diverse clinical course, but when associated they can accelerate progression to chronic kidney disease, which is why makes it necessary to do a more strict clinical follow-up.

Alport Syndrome: A Comprehensive Review on Genetics, Pathophysiology, Histology, Clinical and Therapeutic Perspectives.

BACKGROUND: Alport syndrome (AS) is a disease caused by mutations in COL4A3, COL4A4 or COL4A5, the genes that encode distinct chains of type IV collagen. The vast majority of cases present as an inherited disorder, although de novo mutations are present in around 10% of the cases. METHODS: This non-systematic review summarizes recent evidence on AS. We discuss the genetic and pathophysiology of AS, clinical manifestations, histopathology, diagnostic protocols, conventional treatment and prognostic markers of the disease. In addition, we summarize experimental findings with novel therapeutic perspectives for AS. RESULTS: The deficient synthesis of collagen heterotrimers throughout the organism leads to impaired basement membranes (BM) in several organs. As a result, the disease manifests in a wide range of conditions, particularly renal, ocular and auricular alterations. Moreover, leiomyomatosis and vascular abnormalities may also be present as atypical presentations. In this framework, diagnosis can be performed based on clinical evaluation, skin or renal biopsy and genetic screening, the latter being the gold standard. There are no formally approved treatments for AS, even though therapeutic options have been described to delay disease progression and increase life expectancy. Novel therapeutic targets under pre-clinical investigation included paricalcitol, sodium-glucose co-transporter- 2 inhibitors, bardoxolone methyl, anti-microRNA-21 oligonucleotides, recombinant human pentraxin-2, lysyl oxidase-like-2 blockers, hydroxypropyl-b-cyclodextrin, sodium 4-phenylbutyrate and stem cell therapy. CONCLUSION: AS is still a greatly under and misdiagnosed disorder. The pathophysiology is still not fully understood and genetics of the disease also have some gaps. Up to know, there is no specific and effective treatment for AS. Further studies are necessary to establish novel and effective therapeutic protocols.

Una nueva variante del gen COL4A4 (c.1856G> A). De un caso de glomeruloesclerosis focal y segmentaria a una familia con síndrome de Alport / A novel COL4A4 gene variant (c.1856G>A): from a focal segmental glomerulosclerosis case to a family with Alport syndrome

El síndrome de Alport (SA), también conocido como nefritis hereditaria, es una forma progresiva hereditaria de enfermedad glomerular que a menudo se asocia con pérdida auditiva neurosensorial y anomalías oculares. Es causada por mutaciones en los genes que codifican varios miembros de las proteínas de colágeno del tipo IV, que se hallan en las membranas basales principalmente. Los análisis genéticos de las familias afectadas han identificado cuatro modos diferentes de transmisión en pacientes con síndrome de Alport. La forma del síndrome ligada al X surge a partir de mutaciones de COL4A5 y COL4A6 en el cromosoma X, mientras que las formas autosómicas resutan de defectos genéticos tanto en el gen COL4A3 como en el COL4A4, en el cromosoma 2q35-37. Las formas digénicas incluyen pacientes con mutaciones coexistentes en COL4A3, COL4A4 y COL4A5. El resultado clínico a largo plazo en pacientes con SA con mutaciones heterocigotas de COL4A3/A4es generalmente impredecible. La glomeruloesclerosis focal y segmentaria suele desarrollarse en el SA clásico en etapas posteriores y se presenta predominantemente con proteinuria asociada con hematuria. En el caso índice presentado en este informe, a un hombre de 26 años se le realizó una biopsia de riñón debido a una proteinuria nefrótica y una hematuria microscópica acompañada de una función renal alterada. Se le diagnosticó glomeruloesclerosis focal y segmentaria. Debido a que tenía una pérdida auditiva progresiva desde el inicio del estudio, se le realizó un estudio genético de mutaciones en los genes COL4A3 y COL4A4. Se detectó una nueva mutación en el gen COL4A4 (c.1804-7T> C).Debido a que sus padres tenían un matrimonio consanguíneo, el resto de la familia fue sometida a estudio para la misma variante. Sus padres y su hermana fueron heterocigotos y homocigota para la misma variante, respectivamente. En este estudio, se demostró la existencia de una familia con síndrome de Alport con una nueva mutación en el gen COL4A4 (c.1856G> A) que, según sabemos, es el primer caso reportado.

Alport syndrome, also known as hereditary nephritis, is an inherited progressive form of glomerular disease that is often associated with sensorineural hearing loss and ocular abnormalities. It is caused by mutations in genes encoding several members of type IV colagen proteins primarily found in basement membranes. Genetic analyses of affected families have identified four different modes of transmission in patients with Alport syndrome. X-linked form of the syndrome arises from mutations of COL4A5 and COL4A6 on chromosome X, whereas autosomal forms result from genetic defects in either the COL4A3 or COL4A4 genes at chromosome 2q35-37. Digenic forms include patients with coexisting mutations in COL4A3, COL4A4, and COL4A5. The long-term clinical outcome in AS patients with heterozygous COL4A3/A4 mutations is generally unpredictable. Focal segmental glomerulosclerosis usually develops in classical AS at later stages and presents predominantly with proteinuria associated with hematuria. The index case presented in this report, a 26-year-old man, had kidney biopsy because of nephrotic proteinuria and microscopic hematuria accompanied by impaired renal function. He diagnosed focal segmental glomerulosclerosis. As he had progressive hearing loss since chidhood we conducted a genetic study for mutations in COL4A3 and COL4A4 genes. A novel mutation in COL4A4 gene (c.1804-7T>C) was detected. As his parents had consanguineous marriage we investigated the rest of the family for the same variant. His parents, and his sister were found to be heterozygote, and homozygote for the same variant, respectively. In this report we demonstrated an Alport syndrome family with a novel mutation in COL4A4 gene (c.1856G>A) that has been first reported to our best knowledge.

Female Patient with Alport Syndrome and Concomitant Membranous Nephropathy: Susceptibility or Association of Two Diseases?

Alport syndrome (AS) is a disorder of collagen IV, a component of glomerular basement membrane (GBM). The association of AS and immunocomplex nephropathies is uncommon. This is a case of a 37-year-old woman with family history of X-linked AS, including 4 affected sons. This patient developed full-blown nephrotic syndrome along a 3-month period, a presentation not consistent with AS progression. This scenario suggested an alternative diagnosis. A kidney biopsy was therefore performed, showing membranous nephropathy (MN) in addition to GBM structural alterations compatible with AS. Whole exome sequencing also confirmed the diagnosis of X-linked AS, revealing a heterozygous pathogenic mutation in COL4A5. While a negative serum anti-phospholipase A2 receptor did not rule out a primary form of MN, it was also uncertain whether positive serologic tests for syphilis could represent a secondary factor. It is currently unknown whether this unusual association represents AS susceptibility to immunocomplex-mediated diseases or simply an association of 2 disorders.

Síndrome de Alport: reporte de caso y revisión / Alport sindrome: Case report and literature review

Se presenta el caso de una paciente de 4 años de edad, con hermano gemelo dicigoto asintomático, hija de padres no consanguíneos y sin antecedentes familiares de enfermedad renal. Inicia su cuadro clínico con edemas y proteinuria severa como manifestación de un síndrome nefrótico primario de cambios mínimos; este se diagnosticó por biopsia renal y, en un principio, se manejó con esteroides. Su evolución no fue adecuada debido a múltiples recaídas que la clasificaron como síndrome nefrótico corticorresistente. Por ello, se requirió un cambio en su tratamiento y una segunda biopsia renal, cuyo resultado histológico sorprendió al grupo médico tratante porque los cambios en la membrana basal glomerular confirmaban que se trataba de un Síndrome de Alport.

We present the case of a 4 year-old girl patient, with an asymptomatic dizygotic twin brother, child of non-consanguineous parents and with no family history of renal disease. Her clinical picture started with edema and severe proteinuria as manifestations of a minimal change nephrotic syndrome that was diagnosed by renal biopsy and initially treated with steroids. Her clinical course was complicated by multiple relapses that classified her as a patient presenting a steroid-resistant nephrotic syndrome, her treatment was changed and a second renal biopsy was needed. Histology outcome of biopsy surprised the treating medical group because changes in glomerular basal membrane revealed that it was in fact an Alport syndrome.

Alport syndrome: significance of gingival biopsy in the initial diagnosis and periodontal evaluation after renal transplantation

Alport Syndrome (AS) is an important hereditary disorder affecting the glomerular basement membrane. Diagnosis of AS is based on the presence of hematuric nephropathy, renal failure, hearing loss, ocular abnormalities and changes in the glomerular basement membrane of the lamina densa. The aims of this case report were to show the changes in the gingival tissues in a patient with AS under therapy with cyclosporin-A after renal transplantation and to discuss the possible role of type IV collagen in gingival basal lamina as an alternative approach for the diagnosis of AS. A 20-year-old male patient with AS underwent periodontal therapy including a series of gingivectomy surgeries. Gingival samples obtained during the second surgery were examined histopathologically and by transmission electron microscopy for further pathological examination. Gingivectomy procedures have been performed every 6 months over the last 4 years. The excessive and fibrous gingival enlargements resulted in migration of the anterior teeth, but no alveolar bone loss occurred. This is the first report to demonstrate the possible changes in the gingival tissues caused by AS. It is suggested that gingival biopsy can be an initial diagnostic tool instead of renal or skin biopsies. Proper dental and periodontal care and regular visits to the dentist could provide limited gingival hyperplasia to patients with AS.

Síndrome de Alport / Alport syndrome

El síndrome de Alport (SA) es una enfermedad hereditaria de las membranas basales, debida a mutaciones en la colágena tipo IV. Clínicamente se caracteriza por nefropatía hereditaria progresiva, comúnmente asociada a sordera sensorial y/o lesiones oculares y, en ocasiones, leiomiomatosis. Constituye de 1-2% de las causas de enfermedad renal terminal en Europa y aproximadamente 3% en la población pediátrica americana. Existen tres formas genéticas de SA: 1. Ligado al cromosoma X, debido a mutaciones en el gen COL4A5. Esta forma se presenta en aproximadamente 80-85% de los pacientes. 2. Autosómico recesivo, debido a mutaciones en ambos alelos (homocigotos) de los genes COL4A3 ó COL4A4, ubicado en el cromosoma 2q35-37. Se presenta aproximadamente en 15% de las familias. 3. Autosómico dominante, debido a una mutación heterocigota de los genes COL4A3 ó COL4A4. Se presenta aproximadamente en 5% de las familias. La evolución depende del género y de factores genéticos. Se expone la fisiopatología de la enfermedad desde el punto de vista genético y bioquímico, así como las manifestaciones clínicas e histopatológicas, estrategias de diagnóstico y las opciones terapéuticas.

Alport syndrome (AS) is a hereditary disease of basal membranes due to a mutation in type IV collagen. It is characterized by hereditary progressive nephropathy often associated with sensorineural hearing loss, ocular defects and less commonly leiomyomatosis. It accounts for 1-2% of end stage renal disease patients in Europe and approximately 3% of end stage renal disease children in America. There are 3 genetic forms of AS: 1. X-linked, due to mutation in COL4A5 gene, present in 80-85% of patients. 2. Autosomal recessive, due to mutations in both alleles of COL4A3 or COL4A4 located in the 2q35-37 chromosome, present in 15% of families with Alport syndrome. 3. Autosomal dominant, due to a heterozygous mutation in COL4A3 or COL4A6 genes, it is present in 5% of the patients. The disease genetics, biochemistry, clinical presentation, histopathology, diagnosis, prognosis and therapeutic options are reviewed.

Evolução da síndrome de alport em crianças brasileiras / The evolution of alport syndrome in Brazilian children

Objetivo: Apresentar a evolução de crianças com Síndrome de Alport e determinar manifestações preditivas de Insuficiência renal crônica. Material eMétodos: Revisão dos prontuários de todas as crianças com diagnóstico confirmado de S. Alport por biópsia com microscopia eletrônica. Resultados:Vinte e dois pacientes, de vinte diferentes famílias, com idade inicial de 7 ± 6.5 anos, com tempo médio de acompanhamento de 8 ± 8 anos foramestudados. A queixa mais freqüente foi de hematúria macroscópica com antecedente familiar de insuficiência renal crônica (IRC), seguida da de hematúriamicroscópica e antecedente familiar de hematúria . Dezenove casos tiveram evolução pôndero-estatural dentro do canal de crescimento. Hipertensãoarterial e anemia somente foram detectadas nos casos com evolução para IRC e após a sua instalação. Perda auditiva neuro-sensorial foi encontrada aos10 ± 4 anos em 09/22, sendo que todos evoluíram para IRC (p= 0,002). Proteinúria nefrótica surgiu entre oito e 12 anos de idade e somente nos casoscom evolução para IRC (p= 0,002). A média do clearance de creatinina nas faixas etárias de 4 a < 8; 8 a <12; 12 a <16 e nos >= 16 anos foramrespectivamente de 123,0; 107,1; 84,8 e 69,7 ml/min/1.73 m2 . Doze pacientes (seis de cada sexo) evoluíram para IRC classe IV, com idade média de15 ± 4 anos. Conclusões: A presença de hematúria macroscópica e o aparecimento de perda auditiva neuro-sensorial e proteinúria nefrótica forampreditivos de evolução para IRC terminal.

Objective: To present the clinical course of children with Alport Syndrome and determine predictive factors for end stage renal failure. Material e Methods:Revision of charts of patients with Alport Syndrome diagnosed by electronic microscopy of kidney biopsies. Results: Twenty-two patients, from twentydifferent families, mean age of 7± 6.5 years, mean follow-up of 8±8 years were studied. The most frequent finding was macroscopic hematuria inassociation with familiar history of chronic renal failure followed by microscopic hematuria in conjunction with familiar history of hematuria. Nineteen patientshad weight and stature inside growth channel. Hypertension and anemia only were detected in patients that already had chronic renal failure. Neurosensorialhearing loss appeared at the mean age of 10 ± 4 years in 9/22, and all of them developed chronic renal failure (p=0.002). Nephrotic proteinuriaappeared when children were between 8 and 12 year-old, and only in patients that developed chronic renal failure (p=0.002). The mean of creatinineclearance in ages from 4 to < 8 years, 8 to <12 years,12 to <16 years, and >= 16 yearswere respectively 123.0, 107.1, 84.8, and 69.7 ml/min/1.73 m2.Twelve patients (six of each sex) developed class IV chronic renal failure, at a mean age of 15 ± 4 years. Conclusion: Macroscopic hematuria, neurosensorialhearing loss and nephrotic proteinuria were predictable of progression to chronic renal failure in childhood.