Familial Hematuria & Hereditary Nephritis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ali Poyan Mehr, M.D. [2]

Synonyms and keywords: Synonym 1; Synonym 2; Synonym 3

Overview

The term 'Familial Hematuria and Hereditary Nephritis' refers to a mixed group of inherited kidney disorders which often present in early childhood and adolescence in form of microscopic hematuria [link to hematuria chapter]. The prognosis and associate co-morbidities are highly variable and dependent on the underlying genetic disease. It can be benign as seen in 'Thin Basement-membrane Disease' or lead to early end stage kidney disease as seen in the X-linked form of Alport syndrome [reference].

Unfortunately the term 'Familial Hematuria and Hereditary Nephritis' has been used variably and can be confusing. While the use of 'nephritis' in the term may imply inflammation, the disorders grouped here are NOT inflammatory in nature, nor due they reflect the involvement of a common pathway, inheritance pattern, or pathophysiology.

Historical Perspective

• A familial pattern of early childhood hematuria was first reported by Leonard G. Guthrie in 1902 . In the subsequent years, reports of early childhood hematuria, kidney failure (some associated to deafness or occular abnormalities), and early death in male offsprings emerged . Initial reports of this familial pattern of hematuria, and kidney failure thought these presentations to be due to pyelonephritis. Later reports, based on kidney biopsies and autopsies, were proposing a glomerulonephritic process to be the primary cause . Other reports idnetified familial clustering of kidney disease in association with other abnormalities . The ever changing hypothesis of the underlying cause is perhaps a reflection of the various underlying disorders which were responsible in those families describe.

Classification

The following disorders are commonly grouped under the term 'Familial Hematuria and Hereditary Nephritis':

• Hereditary Disorders of Collagen Type IV:
  • Thin Basement Membrane Disease (Benign Familial Hematuria)
  • Alport Syndrome
  • Hereditary Angiopathy with Nephropathy, Aneurysms, and Muscle Cramps (HANAC)
• Hereditary Disorders of Laminin:
  • Pierson Syndrome
• Hereditary Disorder of basement membrane or cytoskletal gene regulation:
  • Nail-Patella Syndrome (also known as Onychoosteodysplasia, or Turner-Kieser syndrome, or Fong disease)
• Hereditary Disorders of cytoskeletal protein:
  • Epstein Syndrome
  • Fechtner Syndrome

It is arbitrary and due to historical reasons, why certain disease are commonly referenced in this category, while other forms of inherited kidney disorders of the glomerular filtration barrier are categorized elsewhere. At best, perhaps an early diagnosis of hematuria can be considered a common denominator, setting these disorders apart from most other forms of inherited kidney disorders.

Causes

• Alport syndrome can be due to:
  • Heterozygous mutations in the COL4A3 gene on the chromosome 2q36 (autosomal dominant) (OMIM # 120070)
  • Compund heterozygous mutations in the COL4A3 gene on the chromosome 2q36 (autosomal recessive) (OMIM # 120070)
  • Homozygous mutations in the COL4A3 gene on the chromosome 2q36 (autosomal recessive) (OMIM # 120070)
  • Heterozygous mutations in the COL4A4 gene on the chromosome 2q36 (autosomal dominant) (OMIM # 120131)
  • X-linked mutations in the COL4A5 gene on the X-chromosome (X-linked dominant) (OMIM # 301050)
• Thin Basement Membrane Disease, also known as Thin Basement Membrane Nephropathy or Bening Familial Hematuria is due to:
  • Heterozygous mutations in the COL4A3 gene on the chromosome 2q36 (autosomal dominant) (OMIM # 120070) or
  • Heterozygous mutations in the COL4A4 gene on the chromosome 2q36 (autosomal dominant) (OMIM # 120131)
• Hereditary Angiopathy with Nephropathy, Aneurysms, and Muscle Cramps (HANAC):
  • Heterozygous mutations in the COL4A1 gene on the chromosome 13q34 (autosomal dominant) (OMIM # 611773)
• Pierson Syndrome:
  • Homozygous or compound heterozygous mutation in the LAMB2 gene on chromosome 3p21 (autosomal recessive) (OMIM # 609049)
• Nail-Patella Syndrome:
  • Heterozygous mutation in the LIM-homeodomain protein LMX1B on the chromosome 9q33 (autosomal dominant) (OMIM #161200)
• Epstein Syndrome:
  • Heterozygous mutation in the MYH9 gene on chromosome 22q12 (autosomal dominant) (OMIM # 153650)
• Fechtner Syndrome:
  • Heterozygous mutation in the MYH9 gene on chromosome 22q12 (autosomal dominant) (OMIM # 153640)

Differentiating Familial Hematuria & Hereditary Nephritis from other Diseases

• Familial Hematuria & Hereditary Nephritis refers to a mixed group of disorders which can significantly overlap with other categories of inherited glomerular kidney disorders (e.g. genetic forms of FSGS). While this differentiation is arbitrary and due to historical reasons, a clear distinction must be made between the familial forms of hematuria referenced here, and other causes of hematuria and kidney disease observered in infants, children, and adolescents:

• Genetic forms of FSGS, e.g. autosomal recessive nephrotic syndrome of the Finnish type (NPHS1 mutation), podocin related autosomal recessive proteinuria/ESRD (NPHS2 mutation), autosomal dominant FSGS (α-actinine 4, ACTN4 mutation), and others. In genetic forms of FSGS, proteinuria is the hallmark, and hematuria mostly absent. Decline in renal function and endstage kidney disease is highly variable and based on the underlying genetic defect.
• Inflammatory glomerular disorders, e.g. lupus nephritis, infection related glomerulonephritis and others. These are often accompanied by other clinical and laboratory findings (e.g. ESR, CRP, complement levels, serologies).
• Interstitial nephritis: Drugs, infectious agents, as well as autoimmune causes of interstitial nephritis
• Pyelonephritis: Urine culture, and imaging studies to rule out structural abnormalities of the uro-genital tract which can predispose to reflux, obstruction, and recurrent infection should be performed and rules out.

Epidemiology and Demographics

• The prevalence of the individual diseases grouped together under Familial Hematuria & Hereditary Nephritis varies and is:
  • Alport Syndrome: approximately [number or range] per 100,000 individuals worldwide.
  • Thin Basement Membrane Disease: approximately [number or range] per 100,000 individuals worldwide.
  • Hereditary Angiopathy with Nephropathy, Aneurysms, and Muscle Cramps: approximately [number or range] per 100,000 individuals worldwide.
  • Pierson Syndrome: approximately [number or range] per 100,000 individuals worldwide.
  • Epstein Syndrome: approximately [number or range] per 100,000 individuals worldwide.
  • Fechtner Syndrome: approximately [number or range] per 100,000 individuals worldwide

Natural History, Complications and Prognosis

• Alport Syndrome:
  • The x-linked form of Alport Syndrome is more severe in males, leading to early end stage kidney disease between the ages 15-35 in the majority of affected individuals . By age 40 almost all male patients have developed end stage kidney disease. In contrary, only about less than one third of females will go to develop end stage kidney disease
  • In females the x-linked form of Alport syndrome presents later in life, and is less severe . Nevertheless, end stage kidney disease can reach a prevalence of to 30% in this patient population.
  • The autosomal recessive form of Alport syndrome is more severe and presents earlier in life than the autosomal dominat form
• Thin Basement Membrane Disease:
• Hereditary Angiopathy with Nephropathy, Aneurysms, and Muscle Cramps (HANAC):
• Nail-Patella Syndrome:
• Epstein Syndrome:
  • This syndrome has been describe as a familial form of nephritis, associated with macrothrombocytopenia, renal failure, and hearing loss . Presentation resembles that of Alport Syndrome, and genetic testing may be required to distinguish these two disorders.
• Fechtner Syndrome:

Diagnosis

Diagnostic Criteria

• 'Familial Hematuria' or 'Hereditary Nephritis' are clinical presentations rather than a diagnosis. A familial pattern of hematuria, proteinuria and kidney disease may raise the suspicion of a genetic disorder related to the above mentioned structural components of the glomerular filtration barrier (collagen type IV, laminin, cytoskeletal components). Characteristic findings on a kidney biopsy (e.g. thinning and irregularities of the glomerular basement membrane), with or without ocular defects and hearing impairment may further strengthen the suspicion of a genetic defect in collagen IV, laminin, or myosin heavy chain biosynthesis, or cyteskeletal regulating proteins. Kidney biopsy can strenghte the clinical suspicion, however ultimate diagnosis is made through genetic testing.

Physical Findings

• The X-linked Alport syndrome in males as well as the autosomal recessive form of Alport syndrome are associated with ocular defects (corneal and retinal defects, and anterior lenticonus), and hearing loss during childhood.