Hematuria, Benign Familial
A number sign (#) is used with this entry because some cases of benign familial hematuria (BFH) are caused by heterozygous mutation in the COL4A3 (120070) or the COL4A4 (120131) gene, both of which map to chromosome 2q36.Description
Benign familial hematuria is an autosomal dominant condition manifest as nonprogressive isolated microscopic hematuria that does not result in renal failure. It is characterized pathologically by thinning of the glomerular basement membrane (GBM), and can be considered the mildest end of the spectrum of renal diseases due to type IV collagen defects of the basement membrane. The most severe end of the spectrum is represented by Alport syndrome (301050; 203780, 104200), which results in end-stage renal failure and may be associated with hearing loss and ocular anomalies (review by Lemmink et al. (1996)).Clinical Features
McConville et al. (1966) described dominant inheritance of benign familial hematuria. A chemical test for hematuria, paper strips impregnated at one end with orthotoluidine which in the presence of hemoglobin is oxidized to yield a blue color, was used for diagnosis. Earlier reports have also referred to this condition (e.g., Livaditis and Ericsson, 1962; Ayoub and Vernier, 1965).
Lemmink et al. (1996) reported a large family with BFH spanning 3 generations. The index patient, a member of the third generation, presented with hematuria at the age of 5 years. He was found to carry a heterozygous mutation in the COL4A4 gene (120131.0003). Family history was negative for renal failure and deafness. Electron microscopy of a renal biopsy specimen from the proband showed regions with malformations of the GBM typical for Alport syndrome and regions that were thin. Microscopic hematuria was present in many relatives, including the 75-year-old paternal grandfather who had a normal serum creatinine concentration, indicating normal renal function. The family was complicated by the fact that the mother of the index case also had microscopic hematuria as did many of her relatives, although she did not have an identifiable mutation. The index patient, 16 years old at the time of the report, had developed proteinuria and may have inherited a COL4A4 gene mutation from both parents. Lemmink et al. (1996) speculated that the presence of 2 mutations might account for the severe histologic changes in the GBM in the proband.
Badenas et al. (2002) reported 6 unrelated Spanish families with autosomal dominant benign familial hematuria. All had persistent or recurrent microscopic hematuria not associated with other abnormalities such as renal failure or deafness. At least 1 member of each family had undergone a renal biopsy with ultrastructural examination showing a thin glomerular basement membrane. None developed proteinuria.Pathogenesis
Rogers et al. (1973) demonstrated a thin glomerular capillary basement membrane in affected individuals with benign familial hematuria.
Yoshikawa et al. (1982) reported the pathologic findings of 38 patients with familial hematuria, including those with Alport syndrome. The most common abnormality on electron microscopy, found in 27 of 31 biopsies, was complex replication of the lamina densa of the capillary basement membrane to form a 'basket weave' pattern. These changes could be seen in children under age 5 years. If neurosensory deafness or heavy proteinuria was present, the patient generally ran a progressive clinical course and fell within the spectrum of Alport syndrome. In contrast, patients from families without deafness, heavy proteinuria, or chronic renal failure showed a nonprogressive course consistent with benign familial hematuria. Their biopsies showed little or no glomerular changes other than attenuation of the lamina densa on electron microscopy.
Piel et al. (1982) reviewed the electron microscopic renal biopsy findings in 57 children with persistent hematuria, including 20 with familial nephritis, 20 with familial hematuria, and 17 with sporadic hematuria. All had either attenuation of the glomerular basement membrane, with or without additional lamination of the basement membrane. On follow-up, end-stage renal disease developed in 5 children, and only 2 of 28 no longer had hematuria. Piel et al. (1982) concluded that familial nephritis and familial 'benign' hematuria may be one disorder, or at least 'a spectrum of inherited abnormality or abnormalities in the formation of the glomerular capillary basement membrane,' with variable severity.
Dische et al. (1985) described 12 patients with thin-basement-membrane nephropathy, 3 of whom had progressive renal disease, with end-stage renal failure in 1. Further study of these patients would be required to determine whether the disorder was indeed benign.
Yoshikawa et al. (1988) studied 50 children with benign familial hematuria from 43 families; all had a nonprogressive course and none had deafness, heavy proteinuria, or chronic renal failure. Although benign familial hematuria is probably heterogeneous, widespread thinning of the glomerular basement membrane (GBM) was considered to be related to the hematuria. Yoshikawa et al. (1988) found widespread attenuation of the GBM in 19 patients, focal attenuation in 22, and normal GBM in 9.
Tiebosch et al. (1989), who referred to the condition as 'thin-basement-membrane nephropathy,' performed renal biopsy in 80 normotensive adults without azotemia but 26 of whom had recurrent macroscopic hematuria and 54 had persistent microscopic hematuria (n = 54). In 42 patients, renal tissue was normal when examined by light microscopy. Electron microscopy showed thin-basement-membrane nephropathy in 18; all but 1 of these 18 patients had microscopic hematuria which persisted during the follow-up for a median duration of 50 months. Thus, 17 of 54 patients with microscopic hematuria (31%) had thin-basement-membrane nephropathy. Tiebosch et al. (1989) noted that thin-basement-membrane nephropathy has about the same incidence as idiopathic IgA nephropathy (161950) among patients with persistent microscopic hematuria. Although they commented on the 'frequently familial' nature of the disorder, no family data were presented.Mapping
Lemmink et al. (1996) demonstrated linkage of BFH to the COL4A3 and COL4A4 genes at chromosome 2q35-q37.Molecular Genetics
In affected members of a large family segregating BFH, Lemmink et al. (1996) identified a heterozygous mutation in the COL4A4 gene (G897E; 120131.0003).
In affected members of 6 (60%) of 10 unrelated Spanish families with benign familial hematuria, Badenas et al. (2002) identified 2 different heterozygous mutations in the COL4A3 gene: G1015E (120070.0007) and G985V (120070.0008) and 4 different heterozygous mutations in the COL4A4 gene (see, e.g., 120131.0007 and 120131.0008).