group of renal cystic diseases genetically distinct ... · renal ultrasound presumed diagnosis...
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NephronophthisisNephronophthisis
Group of renal cystic diseases
Genetically distinct
Clinical similarity
Pathological similarity
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NephronophthisisNephronophthisisMedullaryMedullary Cystic DiseaseCystic Disease
Confused nomenclature
NephronophthisisARPediatric disease
Medullary Cystic DiseaseADAdult disease
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Nephronophthisis Nephronophthisis
Shared Features
(a) Symptoms & signs
1. Polyuria2. Polydipsia3. Anaemia4. Growth retardation5. “Normal urinalysis”6. ESRF
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NephronophthisisNephronophthisis
Shared Features
(b) PathologyNormal size kidneysCortico medullary cystsNo cysts in other organs
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NephronophthisisNephronophthisis
Shared Features
(c) HistopathologyTubuli - BM thickening/attenuation
distal tubular atrophycysts
Interstitium - lymphocytesfibrosis
Glomeruli - periglomerular fibrosis
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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
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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
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“SYNDROMAL” NPH“SYNDROMAL” NPH
1. Oculomotor apraxia type Cogan
Large deletion of NPHP1
Homozygous orHeterozygous with point mutation
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“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
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“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
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“SYNDROMAL” NPH“SYNDROMAL” NPH3. Liver fibrosis
4. Joubert’s syndrome type BNPHColobomaRetinal degenerationAplasia of cerebellar vermisPolydactallyDevelopmental delay
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“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
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“SYNDROMAL” “SYNDROMAL” NPHNPH
6. Ellis-van CreveldIdentical radiological findings to Jeune’s
also polydactallydifferentiated clinically by
*congenital heart disease*partial upper lip clefting
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“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
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“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)
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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
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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
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Juvenile Juvenile NephronophthisisNephronophthisisDifferential diagnosis
Characteristic presentationCompatible biopsyProof with genetic diagnosis
Assess for1. Other affected members2. Extra renal manifestations
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Juvenile Juvenile NephronophthisisNephronophthisisGenetics: 2q13-q12 NPHP1
66% large deletionothers point mutation + deletionexpression in pit. gland
spinal cordthyroidmuscletrachea
Novel gene
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Juvenile Juvenile NephronophthisisNephronophthisisNPH1
Protein: nephrocystin
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Juvenile Juvenile NephronophthisisNephronophthisis
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Infantile Infantile Nephronophthisis Nephronophthisis (NPH(NPH22))
9q22Large kidneys