X-linked Alport syndrome-diffuse leiomyomatosis (ORPHA:1018)
A rare renal disease characterized by the association of X-linked Alport syndrome (glomerular nephropathy, sensorineural deafness and ocular anomalies) and benign proliferation of visceral smooth muscle cells along the gastrointestinal, respiratory, and female genital tracts and clinically manifests with dysphagia, dyspnea, cough, stridor, postprandial vomiting, retrosternal or epigastric pain, recurrent pneumonia, and clitoral hypertrophy in females.
Epidemiology
Prevalence of X-linked Alport syndrome-diffuse leiomyomatosis (XLAS-DL) is unknown. It affects both males and females.
Clinical description
Symptoms of glomerular disease (hematuria, progressive proteinuria and renal impairment) typically appear late in childhood, and in males is more severe with faster progression. Patients also have sensorineural deafness and ocular anomalies (anterior lenticonus, congenital cataracts, corneal opacities, maculopathy, fleck retinopathy and temporal retinal thinning). Diffuse leiomyomatosis is severe in males and in females, and typically involves the esophagus, causing dysphagia, postprandial vomiting and retrosternal or epigastric pain. Tracheobronchial lesions lead to dyspnea, cough, stridor and recurrent pneumonia due to aspiration. Affected females show clitoral hypertrophy and variable involvement of labia majora and uterus. Perirectal or perineal leiomyomas are uncommon and associated with constipation.
Etiology
XLAS-DL is due to contiguous gene deletions encompassing the 5' ends of COL4A5 (Xq22.3) and COL4A6 (Xq22.3) genes, which respectively encode the alpha-5 and alpha-6 chain of type IV collagen. COL4A5 is an integral component of the type IV collagen 3,4,5 network, a key component of the glomerular basement membrane (GBM), and COL4A6 is a component of the type IV collagen 5,5,6 network present in Bowman's capsule but not in the healthy GBM.
Diagnostic methods
X-linked Alport syndrome is suspected on clinical presentation and family history of hematuria, deafness and/or renal impairment, and is confirmed by genetic analysis of COL4 genes. Histological evaluation of the kidney is valuable in case of equivocal or unavailable genetic testing. Immunohistochemical assays can also be performed on kidney and skin specimens, and electron microscopy provides ultrastructural analysis of basement membranes. An abnormal expression pattern of type IV collagen chains confirms the diagnosis; however, a normal expression does not eliminate diagnosis. The diagnosis of leiomyomatosis requires a biopsy of the affected tissue. Radiological imaging can identify lesions and the associated deformation of the affected tract.
Differential diagnosis
The differential diagnosis regarding the combination of glomerular disease with deafness includes Fechtner syndrome, MYH9-related disease, MELAS and May-Hegglin thrombocytopenia. The main differential diagnosis for glomerular hematuria is IgA nephropathy, familial benign hematuria and membranoproliferative glomerulonephritis. Leiomyomata can occur as sporadic benign smooth muscle tumors, without AS.
Antenatal diagnosis
Prenatal testing for at risk pregnancies is possible where the COL4A5-COL4A6 deletion has been previously identified in a family member, and if a molecular diagnosis of the inherited deletion can be reliably performed.
Genetic counseling
XLAS-DL is transmitted as X-linked dominant trait and, thus, heterozygous females will also express the disease. Genetic counseling for affected families is recommended.
Management and treatment
Regular monitoring of blood pressure and urinalysis are important to identify hypertension or microalbuminuria/proteinuria and treat accordingly with angiotensin converting enzyme inhibitors/angiotensin receptor blockers. This additionally permits timely clinical management of chronic kidney disease, including eventual renal replacement therapy with either preemptive transplantation or dialysis. Surgical intervention is required for symptomatic leiomyomas. Ocular manifestations rarely need intervention but an ophthalmologist is helpful for diagnosis since ocular involvement is often asymptomatic. Audiological evaluation should be performed regularly and hearing aids should be prescribed when appropriate.
Prognosis
The prognosis of AS is poor due to the progression to ESRD (often affecting young adults). Renal transplantation is successful in individuals with AS, since development of anti-glomerular basement membrane antibodies is a rare event.

                            Last update: 
                            February 2020


                            - Expert reviewer(s): 
                            Dr Laurence HEIDET | ERKNet* - Pr Rachel LENNON | ERKNet*


                                * European Reference Network