cystic kidneys

Senior-Loken Syndromes

Clinical Characteristics
Ocular Features: 

The retinal disease associated with juvenile nephronophthisis has been variably diagnosed as retinitis pigmentosa, sector retinitis pigmentosa, Leber congenital amaurosis, and tapeto-retinal degeneration.  The retinal picture varies among members of the same pedigree and the various disorders.  Areas of bone-corpuscle pigment clumping may be seen sectorially in the periphery or throughout the fundus, and is associated with arteriolar narrowing.  The ERG usually suggests widespread receptor disease with decreased responses but often normal photopic and scotopic implicit times in some patients.  In other cases, blindness is evident in the first year of life and the fundus picture resembles Leber congenital amaurosis with a nonrecordable ERG and clinical nystagmus.  Retinal pigment changes in these cases may be absent or minimal although arteriolar narrowing is usually seen.  Visual fields are often severely constricted and vision can be limited to light perception.

Systemic Features: 

Renal disease may begin with symptoms of polydipsia and polyuria often in the first decade of life.  The kidneys are cystic and renal function becomes progressively impaired.  The polycystic disease is referred to as nephronophthisis for the kidneys often fail completely.  A few patients have had sensorineural deafness.  Liver dysfunction has been reported in some patients but it is uncertain if this is coincidental or a part of the SLNS disorder.

Genetics

This renal-retinal phenotype seems to have an autosomal recessive pattern of inheritance but is genetically and clinically heterogeneous.  Together these account for the majority of hereditary causes of end-stage renal disease in children and young adults.  At least 5 renal-retinal disorders have been identified with a great deal of phenotypic overlap requiring genotyping for distinction.  The common causative mechanism may be defects in the cilia of photoreceptors and renal epithelial cells.

SLNS1 (266900) is caused by mutations in the NPHP1 gene (2q12-13) encoding nephrocystin.  Some form of pigmentary retinopathy is frequently present although its age of presentation is highly variable.

(There is a NPHP2 disorder [602088] but no SLSN disease is associated with the NPHP2 gene [now called INVS] at 9q22-31 and encoding inversin).

SLSN3 (606995) has been mapped to 3q21-22, overlapping the NPHP3 locus.  This is a later onset, adolescent disease often presenting with anemia and renal failure occurring at a mean age of 19 years.  'Tapetoretinal degeneration' is part of the clinical picture.

SLSN4 (606996) is caused by mutations in the NPHP4 gene (encoding nephrocystin-3) and located at 1p36.  The onset of retinal disease may be later in onset than in other conditions.

SLSN5 (IQCB1)(606254) is caused by mutations in the NPHP5 gene (encoding nephrocystin-5) and located at 3q13.33-21.2.  Multiple mutations in this gene have been found and all patients have a pigmentary retinopathy.

SLSN6 (610189) results from mutations in the NPHP6 (CEP290) gene at 12q21.  Some patients have had a 'tapetoretinal degeneration'.

SLSN7 (613615) is caused by mutations in the SDCCAG8 gene at 1q44.  Some patients have retinal degeneration leading to blindness.

SLSN8 (616307) is caused by mutations in the WDR19 gene at 4p14.  Patients have severe reduction in vision and visual fields are severely restricted.  Bone spicule pigmentation can be seen in the periphery, the retinal vessels are attenuated, the ERG is undetectable, and there may be temporal pallor of the optic discs.

Hereditary disorders with isolated pigmentary retinopathy and cystic kidney disease also occur separately.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment beyond renal transplantation is available.  Low vison aids can be helpful in some patients.

References
Article Title: 

Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin

Otto EA, Loeys B, Khanna H, Hellemans J, Sudbrak R, Fan S, Muerb U, O'Toole JF, Helou J, Attanasio M, Utsch B, Sayer JA, Lillo C, Jimeno D, Coucke P, De Paepe A, Reinhardt R, Klages S, Tsuda M, Kawakami I, Kusakabe T, Omran H, Imm A, Tippens M, Raymond PA, Hill J, Beales P, He S, Kispert A, Margolis B, Williams DS, Swaroop A, Hildebrandt F. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet. 2005 Mar;37(3):282-8.

PubMed ID: 
15723066

Senior-Loken syndrome: revisited

Warady BA, Cibis G, Alon U, Blowey D, Hellerstein S. Senior-Loken syndrome: revisited. Pediatrics. 1994 Jul;94(1):111-2.

PubMed ID: 
8008515

Bardet-Biedl Syndromes

Clinical Characteristics
Ocular Features: 

The term Bardet-Biedl is applied to a clinically and genetically diverse group of disorders, of which at least 21 entities (BBS1-BBS21) are recognized.  This discussion is generically relevant to all of the phenotypes since the retinal dystrophy is common to all.

A progressive rod-cone dystrophy is a cardinal feature of all forms of Bardet-Biedl syndrome.  However, a subset of patients have primary cone degeneration.  In at least some forms of this syndrome, the cause seems to be a defect in the cilia that impairs the intraciliary protein transport between the inner and outer segments of the photoreceptors.  Vision loss has an early onset and usually progresses rapidly with severe loss of central and peripheral vision by the second or third decade of life.  Night blindness may be evident by 7 or 8 years of age.  The ERG is not recordable even in early childhood.  Pigmentary changes in the retina are often labeled retinitis pigmentosa but they are atypical for the usual disease.  Early changes are more characteristic of atrophy with a paucity of pigment but later the bone spicule pattern of hyperpigmentation appears.  The macula can appear atrophic and sometimes has a bull's eye pattern.  Optic atrophy and retinal arteriole narrowing may be seen.  Bardet-Biedl syndrome is clinically similar to Biemond syndrome (210350) except for iris colobomas that occur in the latter disorder.

Systemic Features: 

Obesity, mental retardation, renal disease, and hepatic fibrosis with syndactyly, brachydactyly, and post-axial polydactyly are characteristic.  The degree of mental handicap varies widely.  Diabetes mellitus is present in about one-third of patients.  Structural deformities of genitalia as well as hypogonadism and menstrual irregularities often occur as in some other disorders but the association of severe vision loss and characteristic retinal changes are diagnostically helpful.  Kidney failure secondary to cystic nephronophthisis or other renal malformations is common. Hypercholesterolemia is found in many patients.  Many patients have motor difficulties, appearing clumsy and unsteady.  Emotional lability and inappropriate outbursts can be part of these syndromes as well.

Genetics

The syndromes of Bardet-Biedl are inherited in an autosomal recessive pattern.  At least 21 mutations have been identified.  Not all cases are caused by homozygosity of the same mutation since compound heterozygosity at two loci may also cause similar phenotypes.

Laurence-Moon syndrome (245800) is considered part of the Bardet-Biedl group of diseases in this database. 

Mutations in PNPLA6 have been found in some individuals with a form of Bardet-Biedl syndrome as well as in Boucher-Neuhauser Syndrome (215470) also known as Chorioretinopathy, Ataxia, Hypogonadism Syndrome, and Trichomegaly Plus Syndrome (275400), in this database.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment exists for these syndromes but organ specific therapy may be helpful.

Studies in a mice model suggest that the neural retina may at least partially recover in type 1 following subretinal injection of viral vectors containing the wild-type bbs1 gene.

 

References
Article Title: 

Bardet-Biedl Syndrome

Suspitsin EN, Imyanitov EN. Bardet-Biedl Syndrome. Mol Syndromol. 2016 May;7(2):62-71.

PubMed ID: 
27385362

Predominantly cone-system dysfunction as rare form of retinal degeneration in patients with molecularly confirmed Bardet-Biedl Syndrome

Scheidecker S, Hull S, Perdomo Y, Studer F, Pelletier V, Muller J, Stoetzel C, Schaefer E, Defoort-Dhellemmes S, Drumare I, Holder Graham E, Hamel Christian P, Webster Andrew R, Moore Anthony T, Puech B, Dollfus Helene J. Predominantly cone-system dysfunction as rare form of retinal degeneration in patients with molecularly confirmed Bardet-Biedl Syndrome. Am J Ophthalmol. 2015 May 14. [Epub ahead of print]. 

PubMed ID: 
25982971

Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes

Hufnagel RB, Arno G, Hein ND, Hersheson J, Prasad M, Anderson Y, Krueger LA, Gregory LC, Stoetzel C, Jaworek TJ, Hull S, Li A, Plagnol V, Willen CM, Morgan TM, Prows CA, Hegde RS, Riazuddin S, Grabowski GA, Richardson RJ, Dieterich K, Huang T, Revesz T, Martinez-Barbera JP, Sisk RA, Jefferies C, Houlden H, Dattani MT, Fink JK, Dollfus H, Moore AT, Ahmed ZM. Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes. J Med Genet. 2015 Feb;52(2):85-94.

PubMed ID: 
25480986

Mutations in IFT172 Cause Isolated Retinal Degeneration and Bardet-Biedl Syndrome

Bujakowska KM, Zhang Q, Siemiatkowska AM, Liu Q, Place E, Falk MJ, Consugar M, Lancelot ME, Antonio A, Lonjou C, Carpentier W, Mohand-Sayid S, den Hollander AI, Cremers FP, Leroy BP, Gai X, Sahel JA, van den Born LI, Collin RW, Zeitz C, Audo I, Pierce EA. Mutations in IFT172 Cause Isolated Retinal Degeneration and Bardet-Biedl Syndrome. Hum Mol Genet. 2014 Aug 28.  [Epub ahead of print].

PubMed ID: 
25168386
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