NephronophthisisNephronophthisis

Group of renal cystic diseases

Genetically distinct

Clinical similarity

Pathological similarity

NephronophthisisNephronophthisisMedullaryMedullary Cystic DiseaseCystic Disease

Confused nomenclature

NephronophthisisARPediatric disease

Medullary Cystic DiseaseADAdult disease

Nephronophthisis Nephronophthisis

Shared Features

(a) Symptoms & signs

1. Polyuria2. Polydipsia3. Anaemia4. Growth retardation5. “Normal urinalysis”6. ESRF

NephronophthisisNephronophthisis

Shared Features

(b) PathologyNormal size kidneysCortico medullary cystsNo cysts in other organs

NephronophthisisNephronophthisis

Shared Features

(c) HistopathologyTubuli - BM thickening/attenuation

distal tubular atrophycysts

Interstitium - lymphocytesfibrosis

Glomeruli - periglomerular fibrosis

NephronophthisisNephronophthisisMedullaryMedullary Cystic DiseaseCystic Disease

InheritanceNPH MCKD

Autosomal Recessive Autosomal dominant

NPH1 2q 12-q13 (NPHP1) MCKD1 1q21NPH2 9q22-q31 (NPHP2) MCKD2 16p1NPH3 3q21-q22 (NPHP3)NPH4 1p36(NPHP4)

Syndromal causes

NPH NPH -- MCKDMCKD

Time course of ESRF (y)

median rangeNPH1 13 4-31NPH2 0.7 0-3NPH3 19 10-30MCKD1 62 50-70MCKD2 32 18-65

“SYNDROMAL” NPH“SYNDROMAL” NPH

1. Oculomotor apraxia type Cogan

Large deletion of NPHP1

Homozygous orHeterozygous with point mutation

“SYNDROMAL” NPH“SYNDROMAL” NPH

2. Senior Loken syndrome

Retinitis pigmentosa by 10yEarly – present by 2 with blindness/coarse nystagmus – not linked NHPH1

Late – night blindness leading to blindness in school age? - linked to NPHP1

“SYNDROMAL” NPH“SYNDROMAL” NPH

2. Senior Loken syndrome

NPH4 1p36 “nephroretinin”loss of function mutation

in families with early onsetSL syndrome

Other loki (NPHP1) linked to late onset SL

“SYNDROMAL” NPH“SYNDROMAL” NPH3. Liver fibrosis

4. Joubert’s syndrome type BNPHColobomaRetinal degenerationAplasia of cerebellar vermisPolydactallyDevelopmental delay

“SYNDROMAL” “SYNDROMAL” NPHNPH

5. Jeune’s syndromeasphyxiating thoracic dysplasia

Neonatal RDSlong narrow chestimproves with age

Limb shorteningmiddle and distal segments+/- polydactally+/- nail abnormality

Other skeletalshort broad ribsabnormal pelvisabnormal metaphyses

Liver disease

Nephronophthisis

“SYNDROMAL” “SYNDROMAL” NPHNPH

6. Ellis-van CreveldIdentical radiological findings to Jeune’s

also polydactallydifferentiated clinically by

*congenital heart disease*partial upper lip clefting

“SYNDROMAL” “SYNDROMAL” NPHNPH7. Bardet Biedl: 4 of 5:

Tapetoretinal degeneration mean = 8.5 (night)Mental retardation 62%ObesityPolydactallyHypogenitalism

Renal 26-100%ESRF (approx) 15%Genetics – 6 different gene locations

“SYNDROMAL” NPH“SYNDROMAL” NPH

1. OMA Cogan2. Senior Loken syndrome3. Joubert’s syndrome type B4. Jeune’s syndrome5. Ellis-van Creveld syndrome6. Bardet Biedl7. Sensenbrenner syn. (cranioecto, nph, elec-ret)8. RHYNS (retinitis pigmentosa, hypopituitarism,

nephronophthisis, mild skeletal dysplasia)

Juvenile Juvenile Nephronophthisis Nephronophthisis (NPH(NPH11))

80% Early onset polyuriapolydipsiadecreased urine conc.usually noted (approx 4 y)

Anaemia laterGrowth retardation laterHypertension rareDoes not recur in transplant

Juvenile Juvenile NephronophthisisNephronophthisisDiagnostic algorithm

clinical picture

renal ultrasound

presumed diagnosis

molecular genetic Renal biopsyPCR for homozygous

NPHP1 mutation.DNA from Diagnosis

parents & patient “established if compatible”

+ -Diagnosis Heterozygosity testing with polymorphic markers

FISH, Direct sequencing of NPHP1 exons

Juvenile Juvenile NephronophthisisNephronophthisisDifferential diagnosis

Characteristic presentationCompatible biopsyProof with genetic diagnosis

Assess for1. Other affected members2. Extra renal manifestations

Juvenile Juvenile NephronophthisisNephronophthisisGenetics: 2q13-q12 NPHP1

66% large deletionothers point mutation + deletionexpression in pit. gland

spinal cordthyroidmuscletrachea

Novel gene

Juvenile Juvenile NephronophthisisNephronophthisisNPH1

Protein: nephrocystin

Juvenile Juvenile NephronophthisisNephronophthisis

Infantile Infantile Nephronophthisis Nephronophthisis (NPH(NPH22))

9q22Large kidneys