Alport Syndrome Clinical Presentation

In any child or adolescent with persistent microscopic hematuria, carefully seek a family history of hematuria, early onset deafness, and kidney insufficiency (especially in male patients). ^[5]

In patients with typical clinical findings for Alport syndrome but a negative family history for the disease, suspect the autosomal recessive form. Occasionally, mild clinical manifestations are observed in carriers (heterozygotes) of autosomal recessive Alport syndrome (ARAS).

Renal manifestations

Hematuria

Gross or microscopic hematuria is the most common and earliest manifestation of Alport syndrome. Microscopic hematuria is observed in all males and in 95% of females. This condition is usually persistent in males, whereas it can be intermittent in females. Like immunoglobulin A (IgA) nephropathy, approximately 60-70% of patients experience episodes of gross hematuria, often precipitated by upper respiratory infection, during the first 2 decades of life. Hematuria is usually discovered during the first years of life in males. If a male patient does not present with hematuria during the first decade of life, he is unlikely to have Alport syndrome.

Proteinuria

Proteinuria is usually absent in childhood but eventually develops in males with X-linked Alport syndrome (XLAS) and in males and females with ARAS. Proteinuria usually progresses with age and can occur in the nephrotic range in as many as 30% of patients. Significant proteinuria is infrequent in females with XLAS, but it may occur.

Hypertension

This condition is usually present in males with XLAS and in males and females with ARAS. Incidence and severity increases with age and degree of kidney failure.

Hearing impairment

Sensorineural deafness is a characteristic feature observed frequently, but not universally, in patients with Alport syndrome. Some families with Alport syndrome have severe nephropathy but normal hearing. Hearing loss is never present at birth. Bilateral, high-frequency sensorineural hearing loss usually begins by late childhood or early adolescence, generally before the onset of kidney failure. In the early stages of the disease, hearing loss is detectable only by means of audiometry.

As hearing loss progresses, it extends to the low frequencies, including those of human conversation, and patients require hearing aids. Hearing impairment is always associated with renal involvement.

About 50% of male patients with X-linked Alport syndrome show sensorineural deafness by age 25 years, and about 90% are deaf by age 40 years.

Ocular manifestations

Anterior lenticonus

Anterior lenticonus, which occurs in approximately 25% of patients with XLAS, is the pathognomonic feature of Alport syndrome. In this condition, the lens surface protrudes conically into the anterior chamber of the eye because of a thin and fragile basement membrane of the lens capsule. The lenticonus is most marked anteriorly because the capsule is thinnest there, the stresses of accommodation are more marked, and the lens is least supported.

Anterior lenticonus is not present at birth but is manifested by a slowly progressive deterioration of vision, requiring patients to change the prescription of their glasses frequently. The condition is not accompanied by eye pain, redness, or night blindness, and no defect in color vision occurs.

Dot-and-fleck retinopathy

This is the most common ocular manifestation of patients with Alport syndrome, occurring in approximately 85% of males with XLAS. Rarely observed in childhood, it usually becomes apparent at the onset of kidney failure. Dot-and-fleck retinopathy is usually asymptomatic, with no associated visual impairment or night blindness.

Posterior polymorphous corneal dystrophy

This condition is rare in Alport syndrome. Most patients are asymptomatic, although some of them may develop slowly progressive visual impairment.

Temporal macular thinning

The L1649R mutation in the COL4A5 gene occasionally causes severe temporal macular thinning, a prominent sign associated with XLAS. ^[18]

Leiomyomatosis

Diffuse leiomyomatosis of the esophagus and tracheobronchial tree has been reported in some families with Alport syndrome. Symptoms usually appear in late childhood and include dysphagia, postprandial vomiting, substernal or epigastric pain, recurrent bronchitis, dyspnea, cough, and stridor. Leiomyomatosis is confirmed by computed tomography (CT) scanning or magnetic resonance imaging (MRI).

ARAS

ARAS is much less common than XLAS, accounting for 10-15% of all patients with Alport syndrome. ARAS is usually observed in consanguineous families. The parents are asymptomatic or mildly affected, while their children (ie, both boys and girls) are often equally and severely affected. The clinical features are usually identical to those observed in patients with XLAS. Kidney failure may have an earlier onset. Dot-and-fleck retinopathy and anterior lenticonus also occur in patients with ARAS.

ADAS

This rare form of Alport syndrome is present in successive generations, and males and females are often equally and severely affected. Renal manifestations and deafness are usually identical to those occurring in patients with XLAS, but kidney failure may occur at a later age. Clinical features confined to autosomal dominant Alport syndrome (ADAS) include the following:

• Bleeding tendency
• Macrothrombocytopenia
• Abnormalities of platelet aggregation (Epstein syndrome)
• Neutrophil inclusions that resemble Dohle bodies (ie, May-Hegglin anomaly, Fechtner syndrome) - Occur only occasionally

The findings on physical examination may initially be unremarkable, but with time, patients develop progressive kidney failure manifested by hypertension, edema, and anemia. Moreover, various extrarenal features may also be observed.

Renal manifestations

Clinical renal findings include the following:

• Hypertension is usually detectable by the second decade of life
• Edema and nephrotic syndrome are present in 30-40% of young adults with Alport syndrome; they are not common in early childhood, but their incidence progressively increases with age
• With onset of kidney insufficiency, symptoms of chronic anemia and osteodystrophy may become evident

Hearing impairment

In the early stages, hearing impairment is detectable only by audiometry, with bilateral hearing loss of high tones in frequencies ranging from 2000-8000 hertz (Hz).

In males with XLAS and in males and females with ARAS, the hearing deficit is progressive and eventually involves lower frequencies, including those of conversational speech.

In females with XLAS, hearing loss occurs less frequently and later in life than it does in males. The risk of developing hearing loss by age 40 years is approximately 90% in males and 10% in females with XLAS. Approximately 60% of patients with ARAS usually develop hearing loss when they are younger than 20 years. In patients with Alport syndrome, studies of brainstem auditory-evoked responses indicate the cochlea as the site of the lesion involved with hearing impairment.

Animal studies reveal marked thickening of the basement membranes of the strial vessels of the cochlea; however, only limited information is available regarding the inner ear histology in humans with Alport syndrome. Striking alterations of the stria vascularis of the cochlea are described.

Ocular manifestations

Anterior lenticonus

As previously mentioned, anterior lenticonus is the pathognomonic feature of patients with Alport syndrome, and its presence in any individual is highly suggestive of the disease. This ocular condition serves as a valuable marker of severity in Alport syndrome and is almost invariably accompanied by progressive kidney failure and hearing loss. (Patients with Alport syndrome and anterior lenticonus usually progress to end-stage renal disease (ESRD) and deafness before age 30 years.)

Diagnosis of anterior lenticonus is made by slit lamp examination. Minor degrees of lenticonus are difficult to detect but are suggested by distinctive oil droplet appearance on the red reflex on slit lamp examination.

The diagnosis is confirmed when the central part of the lens projects anteriorly 3-4 mm in an axial projection on biomicroscopic examination. The condition is usually bilateral, causes a slowly progressive axial myopia, and (rarely) may progress to anterior capsular cataract, for which surgical extraction is required.

Ultrastructure analysis of the anterior lens capsule by electron microscopy confirms the diagnosis of Alport syndrome. ^[19] This condition rarely progresses to spontaneous rupture of the lens capsule, and posterior lenticonus is very uncommon.

Dot-and-fleck retinopathy

This condition is the most common ocular manifestation in patients with Alport syndrome, occurring in approximately 85% of males with XLAS. Dot-and-fleck retinopathy is rarely observed in childhood, instead usually becoming apparent at the onset of kidney failure.

Numerous bilateral, white and yellow perimacular dots and flecks occur in this condition. These spare the fovea but can spread to the periphery. No associated visual impairment or night blindness occurs. Typically, dot-and-fleck retinopathy does not fluoresce with angiography.

These dots are thought to be located at the level of the retinal pigment epithelium–Bruch membrane–choriocapillaris complex. The abnormal basement membrane proteins in patients with Alport syndrome may result in enhanced permeability of the Bruch membrane and the underlying choriocapillaris, allowing accumulation of lipofuscin and other undefined substances in the retinal pigment epithelium or in the Bruch membrane.

Posterior polymorphous corneal dystrophy

A rare ocular sign of Alport syndrome, posterior polymorphous corneal dystrophy manifests as clear vesicles alone or in groups (string of pearls) on the endothelial surface of the cornea. This condition is usually bilateral but can be unilateral or asymmetrical. It is attributed to the lamellation and thickening of the outer layer of the Descemet membrane. The occurrence of posterior polymorphous corneal dystrophy in any individual is highly suggestive of Alport syndrome.

Macular holes

Giant macular holes have been associated with Alport syndrome. A case of bilateral full-thickness macular holes measuring > 1500 µm at their smallest diameters has been reported. The very large dimensions of both macular holes were indicative of a bad prognosis regarding hole closure. ^[20]

Leiomyomatosis

An association of Alport syndrome with diffuse leiomyomatosis of the esophagus and tracheobronchial tree is reported in at least 26 families. These patients have typical X-linked Alport syndrome, usually the juvenile type, with a high incidence of bilateral posterior subcapsular cataracts. Female patients have vulvar and clitoral leiomyomatosis and other findings like those of male patients. Symptoms appear in late childhood and include dysphagia, postprandial vomiting, recurrent bronchitis, dyspnea, cough, and stridor.