Pediatric Alport Syndrome Clinical Presentation

  • Author: Prasad Devarajan, MD; Chief Editor: Craig B Langman, MD   more...
 
Updated: Nov 29, 2011
 

History

  • Hematuria
    • Hematuria is the most common presenting symptom.
    • Persistent microscopic hematuria is usually present from early childhood.
    • Episodic gross hematuria, at times precipitated by upper respiratory infections, is common during the first 2 decades of life.
    • Other renal manifestations are described in Physical.
  • Hearing defect
    • Bilateral high-frequency sensorineural hearing loss usually begins by late childhood or early adolescence.
    • 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.
    • 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 defect: Various ocular defects, including anterior lenticonus, perimacular flecks, and corneal ulceration, lead to increasing myopia and visual disturbances.[8, 9]
  • Family history
    • In any child or adolescent with persistent microscopic hematuria, carefully seek a family history of hematuria, early onset deafness, and renal insufficiency (especially in male patients).
    • In patients with typical clinical findings of Alport syndrome but a negative family history for the disease, suspect the autosomal recessive form.
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Physical

  • Renal findings
    • Hypertension is usually detectable by the second decade of life.
    • Edema and the nephrotic syndrome are not common in early childhood; however, the incidence progressively increases with age and is present in 30-40% of young adults.
    • With onset of renal insufficiency, symptoms of chronic anemia and osteodystrophy may become evident.
  • Ocular findings
    • The anterior lenticonus is a regular conical protrusion of the central portion of the lens into the anterior chamber. With the exception of traumatic lenticonus, this lesion is pathognomonic for Alport syndrome. Anterior lenticonus predominantly affects males, is frequently bilateral, and develops during the second decade of life. Anterior lenticonus may appear as an oil droplet during the red reflex, but formal ophthalmologic examination is usually required for early detection. Anterior lenticonus may be complicated by progressive distortion of the lens and subcapsular cataracts from rupture of the anterior lens capsule, leading to visual impairment. Anterior lenticonus is reported in about 25% of children with Alport syndrome. Patients with Alport syndrome and this finding usually progress to end-stage renal disease (ESRD) and deafness before age 30 years.
    • The retinal changes of perimacular flecks affect 35% of individuals with Alport syndrome but are usually asymptomatic. The changes consist of a bilateral dot-and-fleck retinopathy resulting from superficial, densely packed, yellow-white granulations surrounding the foveal area. These lesions are specific for Alport syndrome.
    • Other uncommon lesions in persons with Alport syndrome include recurrent corneal ulceration and corneal endothelial vesicles.
  • Cochlear findings
    • Bilateral high-frequency sensorineural hearing loss usually occurs by late childhood or early adolescence in individuals with Alport syndrome. This hearing loss is most prevalent and progressive in male patients with the disease.
    • In its early stages, hearing loss is detectable only on audiometry and only in the high-frequency range (ie, 2000-8000 Hz). In one series, audiometry documented initial hearing loss in 85% of boys and male adolescents were younger than 15 years with Alport syndrome.
    • As hearing loss progresses, it extends to low frequencies, including those of human conversation, and its course roughly parallels the loss of renal function.
  • Variants
    • 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 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.
    • An association between hereditary nephritis, deafness, and megathrombocytopenia is reported as part of 2 distinct syndromes. Fechtner syndrome consists of nephritis, sensorineural hearing loss, cataracts, macrothrombocytopenia, and characteristic polymorphonuclear inclusion bodies. Epstein syndrome is similar to Fechtner syndrome but without neutrophilic inclusions. Transmission appears to be autosomal dominant in both syndromes. Platelet abnormalities may be asymptomatic or cause hemorrhagic complications. Patients have normal expression of type IV collagen and no mutations in COL4A5. The specific genetic defects underlying these associations are now known. Mutations affecting nonmuscle myosin heavy-chain type II-A results in MYH9-related hereditary macrothrombocytopenia syndromes, including 4 autosomal dominant platelet disorders (ie, Fechtner syndrome, Epstein syndrome, May-Hegglin syndrome, and Sebastian syndromes).
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Causes

  • Approximately 50-80% of patients with X-linked Alport syndrome have mutations in the COL4A5 gene. Several hundred mutations, including missense mutations, splice-site mutations, and small deletions account for most cases of X-linked Alport syndrome. Few mutations have been found in more than 1 family.
  • The most common mutation involves substitution for glycine in the collagenous domain of the a5(IV) chain by a bulky amino acid, resulting in protein-folding abnormalities.
  • Other common mutations lead to premature termination of protein translation and loss of the carboxy-terminal NC1 domain, resulting in defective interchain association and formation of the collagen network.
  • The X-linked Alport syndrome and the diffuse leiomyomatosis complex results from large deletion mutations in both COL4A5 and COL4A6. In contrast, patients with autosomal recessive Alport syndrome have mutations in COL4A3 and COL4A4.
  • An incidental observation is that heterozygous mutations in COL4A3 and COL4A4 account for most cases of the relatively benign thin basement membrane disease. In some cases, mutations found in families with this disease are identical to those that cause autosomal recessive Alport syndrome in the homozygous or compound heterozygous forms.
  • Patients with autosomal dominant Alport syndrome also have heterozygous mutations in the COL4A3 and COL4A4 genes
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Contributor Information and Disclosures
Author

Prasad Devarajan, MD  Louise M Williams Endowed Chair in Pediatrics, Professor of Pediatrics and Developmental Biology, Director of Nephrology and Hypertension, Director of Clinical Nephrology Laboratories, CEO of Dialysis Unit, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine

Prasad Devarajan, MD is a member of the following medical societies: American Heart Association, American Society of Nephrology, American Society of Pediatric Nephrology, National Kidney Foundation, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Uri S Alon, MD  Director of Bone and Mineral Disorders Clinic and Renal Research Laboratory, Children's Mercy Hospital of Kansas City; Professor, Department of Pediatrics, Division of Pediatric Nephrology, University of Missouri-Kansas City School of Medicine

Uri S Alon, MD is a member of the following medical societies: American Federation for Medical Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Luther Travis, MD  Professor Emeritus, Departments of Pediatrics, Nephrology and Diabetes, University of Texas Medical Branch School of Medicine

Luther Travis, MD is a member of the following medical societies: Alpha Omega Alpha, American Federation for Medical Research, International Society of Nephrology, and Texas Pediatric Society

Disclosure: Nothing to disclose.

Howard Trachtman, MD  Program Director, Pediatrics Research, Schneider Children's Hospital, Department of Pediatrics, Division of Nephrology, Professor, Albert Einstein College of Medicine

Howard Trachtman, MD is a member of the following medical societies: American Society of Hypertension, American Society of Nephrology, American Society of Pediatric Nephrology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Craig B Langman, MD  The Isaac A Abt, MD, Professor of Kidney Diseases, Northwestern University, The Feinberg School of Medicine; Division Head of Kidney Diseases, Children's Memorial Hospital

Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, and International Society of Nephrology

Disclosure: NIH Grant/research funds None; Raptor Pharmaceuticals, Inc Grant/research funds None; Alexion Pharmaceuticals, Inc. Grant/research funds None

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Electron micrograph from a patient with Alport syndrome revealing the typical splitting and splintering of the glomerular basement membrane (original magnification X3000). Courtesy of Glen S. Markowitz, MD, Department of Pathology, Columbia University College of Physicians and Surgeons, New York.
 
 
 
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