Familial Hematuria & Hereditary Nephritis

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Ali Poyan Mehr, M.D. [1]; Associate Editor(s)-in-Chief:

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 [The Lancet, Volume 159, Issue 4105, 3 May 1902, Pages 1243–1246 Originally published as Volume 1, Issue 4105 - " IDIOPATHIC," OR CONGENITAL, HEREDITARY AND FAMILY HEMATURIA.  LeonardG. Guthrie]. 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 and [Hurst A.F., Guy's Hosp Rep. 73:368-370, 1923]. 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 [DOI: 10.1056/NEJM195910082611502]. Other reports idnetified familial clustering of kidney disease in association with other abnormalities [PMID: 15416035]. 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) (OMIM # 611773)
• 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 references here, and other causes of hematuria and kidney disease observered in infants, children, and adolescents:

• [Differential dx1]
• [Differential dx2]
• [Differential dx3]

Epidemiology and Demographics

• The prevalence of [disease name] is approximately [number or range] per 100,000 individuals worldwide.

Age

• Patients of all age groups may develop [disease name].

• [Disease name] is more commonly observed among patients aged [age range] years old.
• [Disease name] is more commonly observed among [elderly patients/young patients/children].

Gender

• [Disease name] affects men and women equally.

• [Gender 1] are more commonly affected with [disease name] than [gender 2].
• The [gender 1] to [Gender 2] ratio is approximately [number > 1] to 1.

Race

• There is no racial predilection for [disease name].

• [Disease name] usually affects individuals of the [race 1] race.
• [Race 2] individuals are less likely to develop [disease name]

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 [PMID: 10752524]. 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 [PMID: 21071975]
  • In females the x-linked form of Alport syndrome presents later in life, and is less severe [PMID: 14514738]. 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 [PMID: 21071975].
• 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 [PMID: 5011389]. 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 testin.

• [criterion 1]
• [criterion 2]
• [criterion 3]
• [criterion 4]

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.
• Symptoms of [disease name] may include the following:

• [symptom 1]
• [symptom 2]
• [symptom 3]
• [symptom 4]
• [symptom 5]
• [symptom 6]

Laboratory Findings

• There are no specific laboratory findings associated with [disease name].

• A [positive/negative] [test name] is diagnostic of [disease name].
• An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name].
• Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

Imaging Findings

• There are no [imaging study] findings associated with [disease name].

• [Imaging study 1] is the imaging modality of choice for [disease name].
• On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3].
• [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

• [Disease name] may also be diagnosed using [diagnostic study name].
• Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].

Treatment

Medical Therapy

• There is no treatment for [disease name]; the mainstay of therapy is supportive care.

• The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2].
• [Medical therapy 1] acts by [mechanism of action 1].
• Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].

Surgery

• Surgery is the mainstay of therapy for [disease name].
• [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
• [Surgical procedure] can only be performed for patients with [disease stage] [disease name].

Prevention

• There are no primary preventive measures available for [disease name].

• Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

• Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].