|Ahead of print publication
X-linked alport syndrome presenting as bilateral lenticonus and end-stage renal disease
Mritunjay Kumar1, Shruti Kumar2, Alok Sharma3, Rashmi Kumari4
1 Department of Pediatrics, TSM Medical College and Hospital, Lucknow, Uttar Pradesh, India
2 Department of Pediatrics, SGRR Institute of Medical Sciences, Dehradun, Uttarakhand, India
3 Department of Renal Pathology, Dr Lal PathLabs Limited, New Delhi, India
4 Department of Community Medicine, RML Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Submission||25-Dec-2018|
|Date of Acceptance||07-Apr-2019|
|Date of Web Publication||28-Oct-2020|
Associate Professor, Department of Pediatrics, TSM Medical College and Hospital, Lucknow, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Alport syndrome (AS) is a type of inherited nephropathy characterized by hematuria, proteinuria, and progressive renal failure; often associated with extrarenal manifestations such as sensorineural deafness and anterior lenticonus. X-linked AS causes end-stage kidney disease in young male patients, sometimes without prominent clinical manifestation beforehand due to its heterogeneous phenotype. Here, we report a case of AS where ignorance of visual and auditory symptoms led to progression to end-stage renal disease without any renal symptom or intervention in the past.
Keywords: Alport, COL4A5, end-stage renal disease, lenticonus, sensorineural
|How to cite this URL:|
Kumar M, Kumar S, Sharma A, Kumari R. X-linked alport syndrome presenting as bilateral lenticonus and end-stage renal disease. J Integr Nephrol Androl [Epub ahead of print] [cited 2020 Dec 2]. Available from: http://www.journal-ina.com/preprintarticle.asp?id=299273
| Introduction|| |
Alport syndrome (AS) is a rare disease of ultrastructural collagen abnormality responsible for 0.2%–2.3% of all causes of end-stage renal disease (ESRD). It is associated with ultrastructural lesions of the glomerular basement membrane (GBM), sensorineural hearing loss, and/or ocular abnormalities (anterior lenticonus, macular, or peripheral flecks). The most common transmission is X-linked AS (XLAS) inheritance (80%–85%), arising from mutations in the COL4A5 gene located in Xq22.3. For autosomal recessive AS (ARAS) (15%) or autosomal dominant AS (5%), mutations of the COL4A3 and COL4A4 genes, respectively, are identified and located in 2q35-37 and both genders are equally affected. The prevalence of AS has been estimated as 1:5000-1:10,000 births for XLAS and 1:50,000 live births for ARAS. The median age of onset of ESRD in young untreated patients has been reported to be 22 years. Although anterior lenticonus is common in AS, simultaneous anterior and posterior lenticonus is a rare presentation. We present a 17-year male with AS presenting with bilateral simultaneous anterior and posterior lenticonus and ESRD.
| Case Report|| |
A 17-year-male presented with progressive hearing loss and diminution of vision over the last 3 years. He had been using hearing aid for the last 2 years. Recently, he had intermittent episodes of hematuria over the last 2 months. He was referred from an ophthalmology clinic where too frequent changes in glasses for refractory error was noticed. During his last visit to the ophthalmology clinic, his vision was found to be 6/60 in both the eyes with glasses. Pentocam scan with Scheimpflug camera revealed global corneal ectasia with normal thickness. On refraction with atropine, oil droplet reflex was seen due to the presence of both anterior and posterior lenticonus. He was referred to us for evaluation of intermittent microscopic hematuria. At the first clinical examination, his general appearance was of a healthy adolescent although higher functions could not be examined properly in view of poor hearing. Vitals were stable apart from blood pressure which was 150/90 mmHg. He was a product of the second-degree consanguineous marriage with a strong family history pertaining to his current illness. His elder sibling died at the age of 21 years from some renal disease and was hemodialysis dependent before his death. Father died at the age of 32 years and was also suffering from pulmonary tuberculosis. Mother expired about a year back, but she did not have any specific disease condition apart from severe depression. He had one elder and another younger sister and both of them were healthy without any specific concerns. He was of borderline intelligence with a poor scholastic performance possibly because of compromised hearing and vision. Rest of the general and systemic examinations were unremarkable. Complete blood count revealed hemoglobin of 10.5 g/dl, total leukocyte counts of 11,400/mm 3, and platelet count of 1.9 lakh/mm 3. General blood picture showed normocytic normochromic red blood cells (RBC's) with a normal reticulocyte index. Urinalysis revealed 3+ protein, 15–20 RBC/hpf with RBC casts, and granular casts. Kidney function test results were as follows: blood urea nitrogen 51.87 mg/dl, blood urea 111 mg/dl, serum creatinine 3.4 mg/dl, uric acid 6.4 mg/dl, albumin 3.1 g/dl, sodium 138 mEq/L, potassium 4.7 mEq/L, calcium 8.5 mg/dl, and phosphorus 4.7 mEq/L. Venous blood gas showed mild metabolic acidosis with pH of 7.27, HCO3 of 18.2, and BE of − 7.2. Ultrasonography (USG) of the kidney and urinary bladder showed a slightly smaller kidney (right kidney 9.4 cm × 4.2 cm and left kidney 10.4 cm × 4.6 cm) with increased echogenicity but maintained corticomedullary differentiation. Serum C3, C4, and Anti streptolysin O titer (ASO) titers were within normal limits. Antinuclear antibody, antineutrophil cytoplasmic antibody profile, anti-dsDNA, and viral markers (hepatitis B surface antigen, anti-hepatitis C virus, and HIV 1 and 2) were nonreactive. A probable diagnosis of AS with glomerulonephritis was made and renal biopsy was planned. He was started on oral amlodipine for hypertension and percutaneous USG-guided renal biopsy was performed. Light microscopy [Figure 1] features were of nonproliferative glomerulonephritis. There was no evidence of capillary wall thickening, segmental sclerosis, crescent formation, tuft necrosis, subendothelial/congophilic deposits, or intracapillary thrombosis in visualized glomeruli. There were focal tubular atrophy and interstitial fibrosis in 25% of sampled glomeruli. Direct immunofluorescence (DIF) study did not show segmental glomerular immune deposits (negative IgA/IgG/IgM/C3/C1q/kappa/lambda). There were focal chronic interstitial inflammation and moderate increase in tubulointerstitial chronicity. Ultrastructural examination/ Electron microscopy [Figure 2] revealed prominent alteration of collagen in GBM including splitting of GBM, basket weave-like appearance, and criss-cross pattern. There was focal effacement of foot process of visceral epithelial cells (about 60%), variability of GBM thickness with thick and thin areas (maximum and minimum GBM thickness being 124.6–839.8 nm). There was no evidence of glomerular/extraglomerular immune complex type electron dense deposits. Overall impression was that of hereditary nephritis/AS. AS gene panel (COL4A3, COL4A4, COL4A5, and COL4A5) using next-generation sequencing was sent, and it was found to be positive for COL4A5 mutation which confirmed our diagnosis of AS. Family was counseled regarding familial predisposition and poor long-term outcome for the disease condition. He was further counseled for renal replacement therapy and transplantation in near future. Routine screening evaluations for both the sisters were carried out and were unremarkable at that point although genetics couldn't be sent because of financial constraints. However, they were repeatedly conveyed about genetic screening as early as possible. He was discharged on oral amlodipine and other supportive chronic kidney disease management protocol with a regular follow-up plan in pediatric nephrology clinic.
|Figure 1: Light microscopy image suggesting nonproliferative glomerulonephritis|
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|Figure 2: Electron microscopy images (a-c) showing prominent alteration of collagen in glomerular basement membrane including splitting of glomerular basement membrane, basket weave-like appearance, and criss-cross pattern|
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| Discussion|| |
AS is a genetically and phenotypically heterogeneous disease. The X-linked form is most common, but autosomal recessive and autosomal dominant forms have also been described and are responsible for 15% of inheritance cases. Phenotypes exhibit a wide spectrum, from mild clinical forms with benign microscopic hematuria, to severe forms evolving to ESRD early in life. The fundamental abnormalities lie in the linear and/or the conformational structures of the subchains of collagen IV molecules (COL-IV-α3:α4:α5 or COL-IV-α5:α6:α5), caused by different individual genotypes involving a monogenic mutation in COL4A3, COL4A4, or COL4A5 genes. Eighty-five percentage of families have X-linked inheritance with mutations in COL4A5. Most of the others have autosomal recessive inheritance, with homozygous or compound heterozygous mutations in both gene copies of COL4A3 or COL4A4. Autosomal-dominant inheritance is rare and results from heterozygous COL4A3 or COL4A4 variants. The presenting renal manifestation is asymptomatic microscopic hematuria, which usually begins in childhood and is manifested by recurrent or persistent hematuria with or without proteinuria, many times precipitated by upper respiratory infections. ESRD usually presents in males in XLAS and in both sexes in ARAS in the second or third decade of life. However, ESRD may be the first presentation of AS as in our case. High-frequency sensorineural hearing loss is the most common cause of deafness in these children. It usually becomes evident by adolescence and usually slowly progressive. The patients with AS usually present with anterior lenticonus and renal disease. Cases with both anterior and posterior lenticonus are rare presentation. Furthermore, the presentation of visual symptoms before the onset of renal failure is very uncommon. Other ocular findings are corneal posterior polymorphous dystrophy, retinal flecks in the macula, and peripheral fundus. ARAS is suggested by the presence of one of the following features: (i) Severe early disease in both females and males, (ii) absence of severe signs in parents (they may be completely asymptomatic or may have isolated microscopic hematuria), and (iii) parental consanguinity. However, clinical and morphologic features are comparable to XLAS. The diagnosis of AS is usually suspected from the family and/or personal history of renal failure and deafness, as in our case, with or without findings of ocular abnormalities and can subsequently be confirmed or excluded in the majority of cases by the performance of a renal biopsy. Light microscopy is of limited utility and diagnosis is often confirmed by electron microscopy, which shows typical ultrastructural abnormalities of GBM. There is no specific treatment for AS. Angiotensin-converting enzyme inhibitors have been used to retard the progression of the disease. Another pharmacological therapy is cyclosporine, which can suppress proteinuria and stabilize renal function and histological changes. Either dialysis or transplantation can be performed in patients who develop ESRD. Patients with XLAS who undergo renal transplantation have been shown to have patient and graft survival rates similar to or better than those of patients with other renal diseases.
| Conclusion|| |
AS is a hereditary nephritis that may lead to ESRD in early adult life. Often, it is not preceded by classical renal manifestations such as microscopic hematuria and proteinuria. Therefore, other pointers of this rare condition along with targeted family history should not be taken for granted. Early recognition and timely intervention is the only way out to halt the progression to ESRD.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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