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• 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 %

• 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 (Bardet-Beidl, 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

• 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 60%Ear malformations (cup, lop, microtia) 30%Preauricular pits 70%Hearing loss 75%Renal anomalies 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 SyndromeColoboma of iris / retina Heart defectsAtresia of choanae

Retarded DevelopmentGenital hypoplasia

Ear Defects-hearing loss

+Renal abnormalitiesCleft lip / palate Tracheo-esophageal fistula

VACTERL

Vertebral anomaliesAnal atresiaCardiac abnormalitiesTracheoesophageal fistulaEsophageal dysmotilityRenal anomaliesLimb defects

DiGeorge Syndrome

thymic aplasia / hypoplasia and immunodeficiency

developmental delaycleft lip / palatecolobomasparathyroid hypoplasiacardiac malformationsrenal agenesis

Microdeletion in 22q11