1. Inherited of Renal System Disorders

2. 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.

3. 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)

4. 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

5. 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 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)

6. ADPKD - Presentation Onset Age 30-50 Cysts are in medulla and cortex
Large polycystic kidneys
Hypertension
Renin mediated
Microscopic/ Gross hematuria
Flank pain
Stones in %
A disorder affecting multiple organ systems
GI symptoms
Liver cysts
Berry aneurysm (10 –40%)

7. 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)

8. 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 (Bardet-Beidl, Senior-Loken, Alström Syndrome)

9. 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

10. 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)

11. Genetic Syndromes with Renal Cysts
X-linked Dominant
Orofaciodigital Syndrome I
Chromosomal Disorders
Trisomy 13 (Patau)
Trisomy 18 (Edward)
Trisomy 21 (Down)

12. 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.

13. 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.

14. 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.

15. 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

17. 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

18. 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.

19. 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.

20. Renal Involvement in Multiple Congenital Anomaly Syndromes
Potter’s Syndrome
RCS: Renal Coloboma Syndrome
BOR: Brachio-oto-renal Syndrome
TBS: Townes-Brocks Syndrome
Nagar Syndrome
CHARGE Syndrome
VACTERL Syndrome
DiGeorge Syndrome

21. 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.

22. 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

23. Brachio-oto-renal Syndrome
Brachial cysts / fistulas 60%
Ear malformations (cup, lop, microtia) 30%
Preauricular pits %
Hearing loss %
Renal anomalies %
autosomal dominant, seen in 1/40,000 live births
EYA1 gene mutation

24. 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

25. Nager Syndrome Craniofacial anomalies (mandibular hypoplasia)
Preaxial limb defects (noradii, hypoplastic hallices)
Hearing loss
Renal anomalies
unknown mode of inheritance

26. CHARGE Syndrome Coloboma of iris / retina Heart defects
Atresia of choanae
Retarded Development
Genital hypoplasia
Ear Defects-hearing loss +
Renal abnormalities
Cleft lip / palate
Tracheo-esophageal fistula

27. VACTERL Vertebral anomalies Anal atresia Cardiac abnormalities
Tracheoesophageal fistula
Esophageal dysmotility
Renal anomalies
Limb defects

28. DiGeorge Syndrome thymic aplasia / hypoplasia and immunodeficiency
developmental delay
cleft lip / palate
colobomas
parathyroid hypoplasia
cardiac malformations
renal agenesis
Microdeletion in 22q11