Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Medullary cystic disease complex

Medullary cystic disease complex is a group of hereditary tubulointerstitial diseases that shares cyst formation at the corticomedullary junction of the kidney and includes diseases with various clinical features, different modes of inheritance, and associations with extrarenal disorders.

Historical Aspects

In 1951, the disease was first described as a hereditary disorder progressing into renal failure before puberty. Although not mentioned, medullary cysts were present in one of the micrographs. It was not until the 90th that the group could be definitely classified based on molecular genetic data.

Clinical Findings

By the type of inheritance we distinguish the autosomal recessive nephronophthisis and autosomal dominant medullary cystic kidney disease.

Nephronophthisis may be divided clinically into juvenile (median age at onset, 13 yr), infantile (median age at onset, 1 to 3yr), and adolescent (median age at onset, 19 yr) forms. The two types of medullary cystic kidney disease also differ by median age at onset, which is in type 1 62 years and type 2 32 years.

Nephronophthisis types 1 through 6 indicate different genes involved in pathogenesis. Juvenile form is cause by type 1 and 4, infantile by type 2, and adolescent type 3.

Diagnosis

The clinical diagnosis is made by family history and renal symptoms. Sometimes extrarenal manifestations underpin the diagnosis. If available histomorphology provides further evidence. As cysts develop late in disease, typical pathomorphological findings, cysts restricted to the renal medulla or corticomedullary border, appear late in ultrasonography, CT, and MRI, too. Early signs are rather unspecific such as small kidneys and loss of corticomedullary differentiation. Molecular genetic testing, where available, provides a better early diagnosis.

Differentials

Medullary sponge kidney is an important differential. This benign disease does not show progressive renal failure.

Pathogenesis

All genes involved in pathogenesis of cystic kidney diseases affect tubular ciliary function. The exact mechanism by which ciliary dysfunction results in cyst formation remains to be elucidated.

Systematic

Cystic kidney disease
Alagille syndrome 2
Autosomal dominant polycystic kidney disease
Autosomal recessive polycystic kidney and hepatic disease 1
Branchiootorenal dysplasia
Glomerulocystic kidney disease with hyperuricemia and isosthenuria
Hajdu-Cheney syndrome
Medullary cystic disease complex
Ciliopathy
Acrocallosal syndrome
KIF7
COACH syndrome
CC2D2A
RPGRIP1L
TMEM67
Cranioectodermal dysplasia
Cranioectodermal dysplasia 1
IFT122
Cranioectodermal dysplasia 2
WDR35
Cranioectodermal dysplasia 3
IFT43
Cranioectodermal dysplasia 4
WDR19
Joubert syndrome
Joubert syndrome 01
INPP5E
Joubert syndrome 02
TMEM216
Joubert syndrome 03
AHI1
Joubert syndrome 04
NPHP1
Joubert syndrome 05
CEP290
Joubert syndrome 06
TMEM67
Joubert syndrome 07
RPGRIP1L
Joubert syndrome 08
ARL13B
Joubert syndrome 09
CC2D2A
Joubert syndrome 10
OFD1
Joubert syndrome 11
Joubert syndrome 12
KIF7
Joubert syndrome 13
TCTN1
Joubert syndrome 14
TMEM237
Joubert syndrome 15
CEP41
Joubert syndrome 16
TMEM138
Joubert syndrome 17
C5ORF42
Joubert syndrome 18
TCTN3
Joubert syndrome 19
ZNF423
Joubert syndrome 20
TMEM231
Joubert syndrome 21
CSPP1
Joubert syndrome 22
PDE6D
Joubert syndrome 23
KIAA0586
Joubert syndrome 24
TCTN2
Joubert syndrome 25
CEP104
Joubert syndrome 26
KIAA0556
Joubert syndrome 27
B9D1
Joubert syndrome 28
MKS1
Joubert syndrome 29
TMEM107
Joubert syndrome 30
ARMC9
Joubert syndrome 31
CEP120
Joubert syndrome 32
SUFU
Joubert syndrome 33
PIBF1
Joubert syndrome 34
B9D2
Joubert syndrome 35
ARL3
Leber congenital amaurosis
Leber congenital amaurosis 01
GUCY2D
Leber congenital amaurosis 02
RPE65
Leber congenital amaurosis 03
SPATA7
Leber congenital amaurosis 04
AIPL1
Leber congenital amaurosis 05
LCA5
Leber congenital amaurosis 06
RPGRIP1
Leber congenital amaurosis 07
CRX
Leber congenital amaurosis 08
CRB1
Leber congenital amaurosis 09
NMNAT1
Leber congenital amaurosis 10
CEP290
Leber congenital amaurosis 11
IMPDH1
Leber congenital amaurosis 12
RD3
Leber congenital amaurosis 13
RDH12
Leber congenital amaurosis 14
LRAT
Leber congenital amaurosis 15
TULP1
Leber congenital amaurosis 16
KCNJ13
Leber congenital amaurosis 17
GDF6
Leber congenital amaurosis 18
PRPH2
Left-right axis malformations
LEFTY2
Meckel syndrome
Meckel syndrome 02
TMEM216
Meckel syndrome 03
TMEM67
Meckel syndrome 05
RPGRIP1L
Meckel syndrome 06
CC2D2A
Meckel syndrome 08
TCTN2
Meckel syndrome 09
B9D1
Meckel syndrome 10
B9D2
Meckel syndrome 11
TMEM231
Meckel syndrome 13
TMEM107
Mental retardation, truncal obesity, retinal dystrophy and micropenis
INPP5E
Nephronophthisis
Nephronophthisis 1
NPHP1
Nephronophthisis 10
SDCCAG8
Nephronophthisis 11
TMEM67
Nephronophthisis 12
TTC21B
Nephronophthisis 13
WDR19
Nephronophthisis 14
ZNF423
Nephronophthisis 15
CEP164
Nephronophthisis 16
ANKS6
Nephronophthisis 17
IFT172
Nephronophthisis 18
CEP83
Nephronophthisis 19
DCDC2
Nephronophthisis 2
INVS
Nephronophthisis 3
NPHP3
Nephronophthisis 4
NPHP4
Nephronophthisis 5
IQCB1
Nephronophthisis 6
CEP290
Nephronophthisis 7
GLIS2
Nephronophthisis 8
RPGRIP1L
Nephronophthisis 9
NEK8
Nephronophthisis-like nephropathy 1
XPNPEP3
Orofaciodigital syndrome
Orofaciodigital syndrome 01
OFD1
Orofaciodigital syndrome 04
TCTN3
Orofaciodigital syndrome 06
C5ORF42
Orofaciodigital syndrome 16
TMEM107
Primary ciliary dyskinesia 3 with or without situs inversus
DNAH5
Retinitis pigmentosa
Retinitis pigmentosa 17
CA4
Retinitis pigmentosa 23
OFD1
Senior-Loken syndrome
Senior-Loken syndrome 1
NPHP1
Senior-Loken syndrome 3
NPHP3
Senior-Loken syndrome 4
NPHP4
Senior-Loken syndrome 5
IQCB1
Senior-Loken syndrome 6
CEP290
Senior-Loken syndrome 7
SDCCAG8
Senior-Loken syndrome 8
WDR19
Senior-Loken syndrome 9
TRAF3IP1
Short-rib thoracic dysplasia with or without polydactyly
Short-rib thoracic dysplasia with or without polydactyly 01
Short-rib thoracic dysplasia with or without polydactyly 02
IFT80
Short-rib thoracic dysplasia with or without polydactyly 03
DYNC2H1
Short-rib thoracic dysplasia with or without polydactyly 04
TTC21B
Short-rib thoracic dysplasia with or without polydactyly 05
WDR19
Short-rib thoracic dysplasia with or without polydactyly 06
NEK1
Short-rib thoracic dysplasia with or without polydactyly 07
WDR35
Short-rib thoracic dysplasia with or without polydactyly 08
WDR60
Short-rib thoracic dysplasia with or without polydactyly 09
IFT140
Short-rib thoracic dysplasia with or without polydactyly 10
IFT172
Short-rib thoracic dysplasia with or without polydactyly 11
WDR34
Short-rib thoracic dysplasia with or without polydactyly 12
Short-rib thoracic dysplasia with or without polydactyly 13
CEP120
Short-rib thoracic dysplasia with or without polydactyly 14
KIAA0586
Short-rib thoracic dysplasia with or without polydactyly 15
DYNC2LI1
Short-rib thoracic dysplasia with or without polydactyly 16
IFT52
Short-rib thoracic dysplasia with or without polydactyly 17
TCTEX1D2
Short-rib thoracic dysplasia with or without polydactyly 18
IFT43
Short-rib thoracic dysplasia with or without polydactyly 19
IFT81
Simpson-Golabi-Behmel syndrome
Simpson-Golabi-Behmel syndrome 1
GPC3
Simpson-Golabi-Behmel syndrome 2
OFD1
Medullary cystic kidney disease
Medullary cystic kidney disease 1
MUC1
Medullary cystic kidney disease 2
UMOD
Nephronophthisis
Nephronophthisis 1
NPHP1
Nephronophthisis 10
SDCCAG8
Nephronophthisis 11
TMEM67
Nephronophthisis 12
TTC21B
Nephronophthisis 13
WDR19
Nephronophthisis 14
ZNF423
Nephronophthisis 15
CEP164
Nephronophthisis 16
ANKS6
Nephronophthisis 17
IFT172
Nephronophthisis 18
CEP83
Nephronophthisis 19
DCDC2
Nephronophthisis 2
INVS
Nephronophthisis 3
NPHP3
Nephronophthisis 4
NPHP4
Nephronophthisis 5
IQCB1
Nephronophthisis 6
CEP290
Nephronophthisis 7
GLIS2
Nephronophthisis 8
RPGRIP1L
Nephronophthisis 9
NEK8
Nephronophthisis-like nephropathy 1
XPNPEP3
Senior-Loken syndrome
Senior-Loken syndrome 1
NPHP1
Senior-Loken syndrome 3
NPHP3
Senior-Loken syndrome 4
NPHP4
Senior-Loken syndrome 5
IQCB1
Senior-Loken syndrome 6
CEP290
Senior-Loken syndrome 7
SDCCAG8
Senior-Loken syndrome 8
WDR19
Senior-Loken syndrome 9
TRAF3IP1
Polycystic kidney disease with hyperinsulinemic hypoglycemia
Renal cysts and diabetes (RCAD)

References:

1.

Alexander F et al. (1970) Familial uremic medullary cystic disease.

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Update: Sept. 26, 2018