Download Genetics of Renal Disorders

Inherited of Renal System
Disorders
A wide variety of renal disease entities
are caused by single gene defects.
With exception of cystic kidney diseases,
and Alport syndrome, Liddle syndrome
and Gittelman syndromes, genetic
diseases with primary renal involvment
are rare.
Renal Cystic Diseases
• ARPKD (Autosomal Recessive PKD)
• ADPKD (Autosomal Dominant PKD)
• Juvenile Nephronophthisis – Medullary
CD
• Juvenile Nephronophthisis (autosomal recessive)
• Medullary Cystic Disease (autosomal dominant)
• Congenital Nephrosis (autosomal recessive)
• Familial Hypoplastic Glomerulocystic
Disease (autosomal dominant)
Autosomal Recessive Polycystic
Kidney Disease
• Appears early (antenatal diagnosis)
– Echogenic but homogenous kidneys on U/S due to
small cysts throughout parenchyma
• Most severe forms early in life, usually fatal
within months
• Less severe forms present later
– Always bilateral
– Always congenital hepatic fibrosis- biliary ectasia,
periportal fibrosis
• Mutation of PKHD1 gene on chromosome 6
• Large kidneys, sponge
Autosomal Dominant Polycystic
Kidney Disease
• Prevalence: 1:300 to 1:1000
• Common cause of ESRD (7-15%)
• May present in newborn but most common
presentation 30-50 years
• 90% of cases are inherited, 10% are sporadic
• Genetically heterogeneous (more than one gene)
• Two (?3) genes identified – PKD1, PKD2
– PKD1(Chromosome 16) – more hypertension, infections –
younger age at presentation, onset of renal failure
– PKD2 (Chromosome 4) – older at presentation
– PKD3 (not mapped)
ADPKD - Presentation
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Onset Age 30-50
Cysts are in medulla and cortex
Large polycystic kidneys
Hypertension
• Renin mediated
• Microscopic/ Gross hematuria
• Flank pain
• Stones in 20-30 %
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A disorder affecting multiple organ systems
GI symptoms
Liver cysts
Berry aneurysm (10 –40%)
Juvenile Nephronophthisis/
Medullary Cystic Disease
• Medullary cystic kidney disease and nephronophthisis
refer to 2 inherited diseases with similar renal morphology
characterized by bilateral small corticomedullary cysts in
kidneys of normal or reduced size and tubulointerstitial
sclerosis leading to end-stage renal disease (ESRD).
• Juvenile Nephronophthisis
– Usually autosomal recessive
– 3 types – juvenile (NPH1), adolescent (NPH2), infertile
(NPH3) genes
• Medullary Cystic Disease
– Usually autosomal dominant (MCKD1 , MCKD2)
– Older age at presentation (20-40)
Juvenile Nephronophthisis/
Medullary Cystic Disease
• Presentation
– Polydipsia / polyuria in more than 80% (not to the
degree of patients with DI) resistant to
vasopressin
– Polyuria due to inability to conserve sodium – so
salt restriction not indicated in these patients
– Salt losing nephropathy
– Associated with retinal disorders (retinitis
pigmentosa), skeletal abnormalities, hepatic
fibrosis (Juvenile NPH)
– Various syndromes associated with JN (BardetBeidl, Senior-Loken, Alström Syndrome)
Congenital Nephrosis
• Finnish Type
• Autosomal recessive - Chromosome 19
• Diffuse Mesangial Sclerosis – 1/3
familial
• Clinical Features
– Large placenta / large kidneys (in-utero)
– Early onset severe proteinuria leading to
edema, renal failure
– lethal
Genetic Syndromes with Renal
Cysts
• Autosomal dominant– von Hippel Lindau
– Tuberous Sclerosis
• Autosomal recessive
– Meckel - Gruber Syndrome
– Jeune’s Asphyxiating Thoracic Dystrophy
– Zellweger Synedrome ( Cerebrohepatorenal
Syndrome)
– Ivemark’s Syndrome (renal-hepatic-pancreatic
dysplasia)
Genetic Syndromes
with Renal Cysts
• X-linked Dominant
– Orofaciodigital Syndrome I
• Chromosomal Disorders
– Trisomy 13 (Patau)
– Trisomy 18 (Edward)
– Trisomy 21 (Down)
Alport Syndrome
• A hereditary disorder characterized
clinically by hematuria, progressive
renal failure, and, frequently,
neurosensory hearing loss and ocular
abnormalities.
• The incidence of AS is approximately
1 in 5000 births.
Alport Syndrome
• AS is a primary basement membrane
disorder arising from mutations in genes
encoding several members of the type
IV collagen family.
• Six genes, COL4A1, COL4A2, COL4A3,
COL4A4, COL4A5 and COL4A6 encode
the six chains of collagen IV.
Alport Syndrome
• Genetically heterogeneous (more than one gene)
• Three genetic forms of AS exist:
X-linked form (XLAS), which results from
mutations in the COL4A5 gene and accounts for
80-85% of cases.
Autosomal recessive form (ARAS), which is
caused by mutations in either the COL4A3 or the
COL4A4 gene and is responsible for
approximately 10-15% of cases.
Rarely autosomal dominant form (ADAS), which
is also caused by a mutation in either the COL4A3
or the COL4A4 gene accounts for the remainder
of cases.
Clinical Findings
• Gross or microscopic hematuria is the most common and earliest
manifestation, and it is usually persistent in males, whereas it
can be intermittent in females.
• Proteinuria is usually absent in childhood but eventually develops
in males with XLAS and in both males and females with ARAS.
• The risk of progression of renal failure is highest among males
with XLAS and in both males and females with ARAS.
• Bilateral sensorineural hearing loss is a characteristic feature
observed frequently, but not universally.
• Hearing loss is never present at birth.
• Anterior lenticonus occurs in approximately 15-20% of AS
patients. Pathognomonic feature if found.
• Not present at birth, but it develops and worsens with
increasing age leading to a slowly progressive deterioration of
vision
Liddle syndrome
• Rare autosomal dominant disorder
• Presented with:
hypertension
hypokalemia
metabolic alkalosis
• Renin and aldostrone are suppressed
• Caused by activating mutations in
amiloride-sensetive sodium channel
Bartter’s syndrome
• Bartter’s syndrome is usually diagnosed in
childhood, sometimes associated with growth,
mental retardation. typical facial appearance
with prominent forehead, triangular face,
drooping mouth, and large eyes and pinnae.
• The defect is impaired NaCl reabsorption in
the loop of Henle.
Gitelman’s syndrome
• Like Bartter’s an autosomal recessive
disorder, but not usually diagnosed
early in life.
• Patients may complain of polyuria,
cramps.
• They do not have hypercalciuria, but
typically have low serum magnesium
levels.
Renal Involvement in Multiple
Congenital Anomaly Syndromes
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Potter’s Syndrome
RCS: Renal Coloboma Syndrome
BOR: Brachio-oto-renal Syndrome
TBS: Townes-Brocks Syndrome
Nagar Syndrome
CHARGE Syndrome
VACTERL Syndrome
DiGeorge Syndrome
Potter’s Syndrome
• Bilateral renal agenesis or other kidney abnormalities, including
renal aplasia, dysplasia, hypoplasia, or multicystic disease.
• The characteristic phenotype of these infants is independent
of the origin of the renal abnormality and results from the
decreased volume of amniotic fluid and consequent restricted
fetal movement.
Renal Coloboma Syndrome
• Renal failure, coloboma, high frequency hearing loss
• Extreme variability of phenotype: VU reflux only to
oligomeganephronia (bilateral renal hypoplasia)
• Pax2 Gene Mutation on 10q22.1-q24.3
• Multiple mutations / polymorphisms identified
Brachio-oto-renal Syndrome
Brachial cysts / fistulas
Ear malformations (cup, lop, microtia)
Preauricular pits
Hearing loss
Renal anomalies
60%
30%
70%
75%
15%
• autosomal dominant, seen in 1/40,000 live births
• EYA1 gene mutation
Townes-Brocks Syndrome
• Ear defects (satyr, lop,
cup, pits, tags)
• Hearing loss
• Hand malformation
• Imperforate anus /
rectourinary fistula
• Renal anomalies
• Autosomal dominant
transcription factor
defect
• SALL1 gene mutation
Nager Syndrome
• Craniofacial anomalies
(mandibular hypoplasia)
• Preaxial limb defects
(noradii, hypoplastic
hallices)
• Hearing loss
• Renal anomalies
• unknown mode of
inheritance
CHARGE Syndrome
Coloboma of iris / retina
Heart defects
Atresia of choanae
Retarded Development
Genital hypoplasia
Ear Defects-hearing loss
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Renal abnormalities
Cleft lip / palate
Tracheo-esophageal
fistula
VACTERL
Vertebral anomalies
Anal atresia
Cardiac abnormalities
Tracheoesophageal fistula
Esophageal dysmotility
Renal anomalies
Limb defects
DiGeorge Syndrome
thymic aplasia / hypoplasia
and immunodeficiency
developmental delay
cleft lip / palate
colobomas
parathyroid hypoplasia
cardiac malformations
renal agenesis
Microdeletion in 22q11