Pfeiffer syndrome

Disease Description (Causes and Symptoms)

• Cause: Primarily caused by mutations in the gene encoding type IV collagen (COL4A5 — X-linked). Rarely, it may also be caused by COL4A3/COL4A4 mutations (autosomal dominant or recessive). Abnormal collagen causes structural and functional damage to the basement membrane.
• Pathophysiology: The glomerular basement membrane (GBM) of the kidneys initially becomes thin, followed by segmental thickening and splitting (“splitting/lamellation”). Glomerular filtration gradually declines, progressing to proteinuria and worsening kidney function. Abnormalities in the basement membranes of the ear (inner ear) and eyes cause sensorineural hearing loss and abnormalities of the cornea, lens, and retina.
• Main symptoms:
  • Hematuria (often appearing from childhood; microscopic or gross)
  • Progressive proteinuria → nephrotic syndrome may develop
  • Chronic kidney failure (progressing to end-stage kidney disease in many men)
  • Sensorineural hearing loss (usually beginning in adolescence and progressing)
  • Ophthalmologic findings: anterior lenticonus, peripheral retinal abnormalities, and corneal changes (eye symptoms are less common than hearing loss)

Treatment Methods and Precautions

• There is no definitive treatment. The goals are to preserve kidney function, control proteinuria and blood pressure, and manage complications.
• Medication treatment
  • RAAS inhibition (ACE inhibitors: enalapril, etc., or ARBs): the most important treatment for reducing proteinuria and preserving kidney function. Early initiation is often recommended even at the proteinuria/microalbuminuria stage.
  • Blood pressure management: target blood pressure according to CKD guidelines (in consultation with a doctor). Diuretics or other medications may be used in combination if needed.
  • If edema or nephrotic syndrome is present, supportive treatment such as diuretics and albumin supplementation.
• Procedures and surgery
  • In end-stage kidney disease, dialysis or kidney transplantation (rarely, recurrent nephritis caused by anti-GBM antibodies may occur after transplantation).
  • If hearing loss is severe, hearing aids and, in some cases, a cochlear implant may be considered.
  • For ophthalmologic complications (e.g., anterior lenticonus), ophthalmologic treatment such as refractive correction or lens surgery.
• Lifestyle management
  • A low-sodium diet and limiting excessive protein intake (consult a nephrologist)
  • Avoid nephrotoxic medications (including some NSAIDs)
  • Regular self-monitoring of blood pressure and urine (hematuria and proteinuria)
  • Regular hearing and ophthalmologic examinations
• Precautions and risk of complications
  • As this is a familial genetic disease, family testing and genetic counseling are recommended.
  • During pregnancy, kidney function may change or worsen — collaboration between obstetrics and gynecology and nephrology is necessary.
  • Rarely, there is a risk of an immune reaction (anti-GBM) after transplantation.
  • As the disease progresses, the risks of end-stage kidney disease, hypertension, and cardiovascular disease increase.

Checklist Before an Outpatient Visit (Items to Bring and Example Questions)

• Items to bring
  • A list of all currently used medications (including prescription and OTC medications)
  • Previous test records: urinalysis (hematuria and proteinuria), blood tests (creatinine and eGFR), and blood pressure records
  • Family history information (hematuria, kidney failure, hearing loss, and whether there are genetic diseases)
  • Copies of previous kidney biopsy and genetic test results, if available
  • Copies of hearing and ophthalmologic examination results, if available
• Examples of useful questions during an outpatient visit (questions for the doctor)
  • Have there been any recent changes in hematuria or proteinuria? What additional tests are needed?
  • What is my current kidney function (eGFR)? How quickly is it progressing?
  • When should I start an ACE inhibitor? What are the expected benefits and side effects?
  • Whether genetic testing is recommended for family members (children and siblings), and when it should be performed
  • I am planning a pregnancy. Is there anything special I need to prepare?
• Symptoms to note before an outpatient visit
  • Timing and frequency of hematuria (gross or microscopic)
  • Peripheral edema, fatigue, urinary frequency, nocturia, and changes in urine volume
  • The onset and rate of progression of hearing loss
  • Any visual or visual-field abnormalities or eye pain

Examples of General Questions to Ask the Doctor

• What are the main side effects and monitoring requirements for this medication (e.g., an ACE inhibitor)?
• What is the expected course of progression (prognosis) of my kidney function?
• What should I pay particular attention to regarding lifestyle habits (diet and exercise)?
• Do you recommend genetic testing for family members (children and siblings)? What are the cost, procedures, and implications?

Examples of Disease-Specific Questions

• Regarding genetics and family planning: "If my/ my partner’s genotype is confirmed, what is the probability that our child will have the disease? Do you recommend genetic testing or counseling before pregnancy?"
• Regarding transplantation: "If I receive a kidney transplant, is there a risk of complications related to anti-GBM antibodies? What methods are available to prevent and monitor for them?"

Additional Notes

• Diagnosis is confirmed through family history, urinalysis, kidney biopsy (findings of GBM thinning and splitting on electron microscopy), or molecular genetic testing. Recently, genetic testing has played an important role in diagnosis and prognosis prediction.
• Prognosis varies according to the inheritance pattern and sex (for example, in X-linked disease, men tend to have more severe disease and progress to ESRD at an earlier age). Evidence is increasing that early treatment with ACE inhibitors can extend the period of preserved kidney function.