- Alport Syndrome (Hereditary nephritis).

Alport Syndrome (Hereditary nephritis)

AS, or hereditary nephritis, is a genetically heterogeneous disease caused by mutations in the genes coding for type IV collagen, a major component of basement membranes which is present in kidney, ear, and ocular lens.

GENETICS

• The most common form of hereditary nephritis.
• Approximately 85% of patients have X-linked inheritance caused by a mutation in the COL4A5 gene encoding the α5 chain of type IV collagen.
• Autosomal recessive forms of AS (10%)are caused by mutations in the COL4A3 and COL4A4 genes on chromosome 2 encoding the α3 and α4 chains, respectively, of type IV collagen.
• An autosomal dominant form of AS linked to the COL4A3-COL4A4 gene locus occurs in 5% of cases.

PATHOLOGY
- Light microscopy:

• Kidney biopsy specimens during the 1st decade of life show few changes
• Later, the glomeruli may develop mesangial proliferation and capillary wall thickening, leading to progressive glomerular sclerosis. Tubular atrophy, interstitial inflammation and fibrosis, and lipid-containing tubular or interstitial cells, called foam cells, develop as the disease progresses.

- Immunopathologic studies are usually not diagnostic.
- Electron microscopy reveals diffuse thickening, thinning, splitting, and layering of the glomerular and tubular basement membranes.
Clinical presentation

• Single or recurrent gross hematuria may occur with URI (mostly in toddlers, young children), but most commonly persistent microscopic hematuria (more than 2 years’ duration)
• Progressive proteinuria is common > 1 g/24 h in the second decade of life.
• Extrarenal manifestations in X-linked recessive form
• Bilateral Sensorineural hearing loss begins with high frequency range deficit and progresses to involve hearing associated with normal speech, prompting the need for hearing aids. 

N.B: Hearing is normal at birth and during early childhood (never congenital).

• Ocular abnormalities: 30–40 % of patients,

- Anterior lenticonus (extrusion of the central portion of the lens into the anterior chamber)
- Macular flecks
- Corneal erosion

• Leiomyomatosis of the esophagus, tracheobronchial tree, and female genitals in association with platelet abnormalities has been reported, but is rare.

Diagnosis

• Careful family history
• Screening urinanalysis of first degree female relatives (carriers)
• Audiogram, ophthalmologic examination (critical)
• Absence of glomerular basement membrane staining for alpha 3 and 4 of type IV collagen in male hemizygotes
• Abnormal GBM architecture (basket weaving)
• AS is highly likely in the patient who has hematuria and at least 2 of the following characteristic clinical features:

- macular flecks, recurrent corneal erosions,
- GBM thickening and thinning,
- or sensorineural deafness

• Prenatal diagnosis is available for families with members who have X-linked AS and who carry an identified mutation.

Prognosis:
Risk of progression to ESRD is highest in males affected by X-linked mode of inheritance, and occurs in 75 % before 30 years

Treatment:

• Treatment is supportive and consists of control of proteinuria using angiotensin-converting enzyme inhibitors (and possibly angiotensin-2 receptor inhibitors) which can slow the rate of progression.
• Careful management of renal failure complications such as hypertension, anemia, and electrolyte imbalance is critical.
• Patients with ESRD are treated with dialysis and kidney transplantation.
• Patients do well after kidney transplantation, but may develop anti-GBM disease (antibodies directed against normal GBM in transplanted kidney) in ~ 15 % of cases.

References:

• Cynthia G. Pan and Ellis D. Avner , nelson textbook of pediatric 20ed ,
• Ellis d. avner,william e. harmon,patrick niaudet,norishige yoshikawa,francesco emma,stuart l. goldstein, Pediatric Nephrology, 7th ed

Ibrahim Samaha