renal anomalies

Oculootofacial Dysplasia

Clinical Characteristics
Ocular Features: 

Many patients have lower lid colobomas, sometimes with malformations of the zygoma.  The palpebral fissures may appear narrow while some patients have a suggestion of hypertelorism.

Systemic Features: 

Neural development is normal but patients have significant facial dysmorphism. A variety of organ and bony malformations have been described.  Cardiac septal defects and sometimes renal malformations may be present.  The ears are large and are sometimes associated with preauricular tags.  Cleft lip and/or palate with bifid uvula, micrognathia, high nasal bridge, large nose, a short philtrum, choanal atresia, and mixed hearing loss are often present.  Choanal atresia is common.

Genetics

Biallelic loss-of-function mutations in the TXNL4A gene have been found in this presumed autosomal recessive condition. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Individual malformations can often be surgically corrected.

References
Article Title: 

Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome

Wieczorek D, Newman WG, Wieland T, Berulava T, Kaffe M, Falkenstein D, Beetz C, Graf E, Schwarzmayr T, Douzgou S, Clayton-Smith J, Daly SB, Williams SG, Bhaskar SS, Urquhart JE, Anderson B, O'Sullivan J, Boute O, Gundlach J, Czeschik JC, van Essen AJ, Hazan F, Park S, Hing A, Kuechler A, Lohmann DR, Ludwig KU, Mangold E, Steenpass L, Zeschnigk M, Lemke JR, Lourenco CM, Hehr U, Prott EC, Waldenberger M, Bohmer AC, Horsthemke B, O'Keefe RT, Meitinger T, Burn J, Ludecke HJ, Strom TM. Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome. Am J Hum Genet. 2014 Dec 4;95(6):698-707.

PubMed ID: 
25434003

Cataracts, Congenital, with Brain Hemorrhage and Subependymal Calcification

Clinical Characteristics
Ocular Features: 

Bilateral neonatal leukocoria secondary to dense congenital cataracts (not further characterized) is evident at birth. Microphthalmia and pale optic discs have each been reported in a single patient.

Systemic Features: 

Newborns have catastrophic intracranial hemorrhages with massive cystic destruction of white matter and basal ganglia.  Subependymal calcification can be seen on CT scans.  Most individuals do not live beyond the neonatal period or early infancy.  Hyperreflexia, seizures, and spasticity are frequent clinical features.  Some patients have hepatomegaly and mild renal anomalies in size and location.  The forehead may be prominent and sloping.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the JAM3 (junctional adhesion molecule 3) gene (11q25).  The gene product is one of a family of proteins that contributes to intercellular tight junctions between epithelial cells, among others, and is postulated to be important to vascular permeability as well as lens development.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Delineation of the Clinical, Molecular and Cellular Aspects of Novel JAM3 Mutations Underlying the Autosomal Recessive Hemorrhagic Destruction of the Brain, Subependymal Calcification and Congenital Cataracts

Akawi NA, Canpolat FE, White SM, Quilis-Esquerra J, Sanchez MM, Gamundi MJ, Mochida GH, Walsh CA, Ali BR, Al-Gazali L. Delineation of the Clinical, Molecular and Cellular Aspects of Novel JAM3 Mutations Underlying the Autosomal Recessive Hemorrhagic Destruction of the Brain, Subependymal Calcification and Congenital Cataracts. Hum Mutat. 2012 Dec 15.[Epub ahead of print]

PubMed ID: 
23255084

A homozygous mutation in the tight-junction protein JAM3 causes hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts

Mochida GH, Ganesh VS, Felie JM, Gleason D, Hill RS, Clapham KR, Rakiec D, Tan WH, Akawi N, Al-Saffar M, Partlow JN, Tinschert S, Barkovich AJ, Ali B, Al-Gazali L, Walsh CA. A homozygous mutation in the tight-junction protein JAM3 causes hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Am J Hum Genet. 2010 Dec 10;87(6):882-9.

PubMed ID: 
21109224

Duane-Radial Ray Syndrome

Clinical Characteristics
Ocular Features: 

Most individuals have features of Duane’s anomaly, sometimes unilaterally.  Optic pallor with poor vision has been described in well-studied patients who also had thinning of the retinal nerve fiber layer.  The optic disk may appear hypoplastic.  Visual evoked potentials and pattern ERG amplitudes are decreased.

Other less common ocular features are microcornea, microphthalmia, ophthalmoplegia, hypertelorism, cataracts, epicanthal folds, colobomas, and chorioretinal scars.

Systemic Features: 

The systemic features are inconsistent (variable expressivity) with most patients having some variation of hypodactyly, polydactyly, syndactyly, and malformation of the hands.  The thumb is the most common digit involved and this is often associated with thenar hypoplasia.  Other skeletal features of the radial ray syndrome including absence of the radial and ulnar bones are variably present.  Hearing loss is described as sensorineural in etiology but malformations of the pinnae and external meatus are sometimes present.

Kidney anomalies include horseshoe malformations, abnormal rotation, ectopia, small size, vesicoureteric reflux, and pelvicalyceal dilatation.

Genetics

This is an autosomal dominant disorder due to heterozygous mutations in the SALL4 gene (20q13.2).

This syndrome is sometimes confused with the Holt-Oram syndrome but the latter is the result of mutations in a different gene and lacks ocular and renal abnormalities.  Duane syndrome 1 and 2 may also occur as isolated conditions.

The considerable clinical heterogeneity has led to alternate titles for this syndrome. For example, what is sometimes called the IVIC syndrome (147750) with similar features is also caused by mutations in this gene.  Duane-radial ray syndrome has also been called Okihiro syndrome. 

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is symptomatic in most cases although reconstructive surgery may be helpful for severe hand deformities.  Low vision aids may be beneficial.  

References
Article Title: 

Papillorenal Syndrome

Clinical Characteristics
Ocular Features: 

Optic disc dysplasia is the ocular hallmark of this disease.  The nerve head often has the appearance of the ‘morning glory’ anomaly but some authors describe this as a coloboma or an optic pit.  Iris colobomas do not occur and only two patients have been reported with retinal colobomas.  There may be severe visual impairment due to the dysplastic optic nerves, but macular and retinal malformations may also contribute.  Other patients have near normal vision. The central retinal vessels are anomalous or even absent with the multiple smaller vessels exiting from the periphery of the disc.  The retina and fovea have been described as hypoplastic and have pigmentary changes. There is often a superonasal visual field defect.  Retrobulbar optic nerve cysts, high myopia, and posterior staphylomas have been noted in a few patients.  As in most autosomal dominant disorders, there is considerable clinical variability.

Systemic Features: 

Kidney dysfunction leading to chronic renal disease is the most common systemic abnormality in this condition.  It can occur at any age.  This often but not always is the result of pyelonephritis secondary to urogenital anomalies causing vesicoureteral reflux.  Other renal disease such as cystic renal hypoplasia may be present.  Other patients have only mild kidney malfunction with proteinuria and elevated serum creatinine.  A minority of patients has a mild high frequency hearing loss and rare individuals have CNS malformations.  Joint laxity and soft skin have also been described.

Genetics

This is an autosomal dominant disorder resulting from heterozygous mutations in the PAX2 gene (10q24.31). Nearly half of reported cases are sporadic secondary to new mutations.  Yet other well-studied families do not have mutations in the PAX2 gene suggesting genetic heterogeneity.

Optic nerve colobomas (120430) may also result from mutations in PAX6.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Kidney failure may require renal transplantation.  Vesicoureteral reflex has been treated with ureteral reimplantation.  Low vision aids may be beneficial in some patients.  Renal hypertension requires treatment.

References
Article Title: 

Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus specific database

Bower M, Salomon R, Allanson J, Antignac C, Benedicenti F, Benetti E, Binenbaum G, Birk Jensen U, Cochat P, Decramer S, Dixon J, Drouin R, Falk M, Feret H, Gise R, Hunter A, Johnson K, Kumar R, Lavocat MP, Martin L, Morini?(r)re V, Mowat D, Murer L, Nguyen HT, Peretz-Amit G, Pierce E, Place E, Rodig N, Salerno A, Sastry S, Sato T, Sayer JA, Schaafsma GC, Shoemaker L, Stockton D, Tan WH, Tenconi R, Vanhille P, Vats A, Wang X, Warman B, Weleber RG, White SM, Wilson-Brackett C, Zand D, Eccles M, Schimmenti LA, Heidet L. Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus specific database. Hum Mutat. 2011 Dec 29. [Epub ahead of print]

PubMed ID: 
22213154

Microphthalmia, Syndromic 1

Clinical Characteristics
Ocular Features: 

Microphthalmia is often a part of other ocular and systemic anomalies.  The full range of essential features of Lenz microphthalmia remains unknown but is often diagnosed in males when colobomas and microcornea are associated with mental deficits together with urogenital and skeletal anomalies.  Microphthalmos may be unilateral and ocular cysts are common.  The globes may be sufficiently small that anophthalmia is sometimes diagnosed but this is a misnomer as some ocular tissue is always present.   Sixty per cent of eyes have colobomas which are often bilateral and may involve the optic disc, choroid, ciliary body, and iris.  Blindness is common.  

Systemic Features: 

A large number of associated systemic anomalies have been reported with this type of microphthalmia.  Skeletal features include microcephaly, spinal deformities, high arched palate, pectus excavatum, absent or dysplastic clavicles (accounting for the narrow or sagging shoulders), and digital anomalies including syndactyly, duplicated thumbs and clinodactyly.  Physical growth retardation is evident by shortness of stature.   Urogenital malformations are present in 77% of individuals and include hypospadius, cryptorchidism, hydroureter, and renal dysgenesis.  Dental anomalies include oligodontia and irregular lower incisors that may be widely spaced.  Some degree of intellectual disability is present in 63%.  The ears may be abnormally shaped, low-set, rotated posteriorly, and anteverted. 

Genetics

This is a rare X-linked disorder that is apparently due to an unknown mutation at Xq27-Xq28.  No male-to-male transmission has been observed but affected males rarely reproduce as a result of various urogenital anomalies.

A somewhat similar X-linked syndrome of microphthalmia, sometimes called OFCD syndrome (syndromic 2 microphthalmia; 300166) has been reported to be caused by mutations in BCOR (Xp11.4).  This MCOPS2 disorder is often considered to be X-linked dominant with lethality in males.

Another X-linked non-syndromic form of microphthalmia with colobomas has been reported (Microphthalmia with Coloboma, X-Linked; 300345).  In addition there is a similar disorder of simple Microphthalmia with Coloboma that is inherited either in an autosomal dominant or autosomal recessive pattern (605738, 610092, 611638, 613703, 251505 ).

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

There is no treatment beyond supportive care for specific health issues. 

References
Article Title: 

Aniridia 1

Clinical Characteristics
Ocular Features: 

Aniridia is the name of both a disorder and a group of disorders.  This because aniridia is both an isolated ocular disease and a feature of several malformation syndromes.  Absence of the iris was first reported in the early 19th century.  The hallmark of the disease is bilateral iris hypoplasia which may consist of minimal loss of iris tissue with simple radial clefts, colobomas, pseudopolycoria, and correctopia, to nearly complete absence.  Goniosocopy may be required to visualize tags of iris root when no iris is visible externally.  Glaucoma is frequently present (~67%) and often difficult to treat.  It is responsible for blindness in a significant number of patients.  About 15% of patients are diagnosed with glaucoma in each decade of life but this rises to 35% among individuals 40-49 years of age.  Hypoplasia and dysplasia of the fovea are likely responsible for the poor vision in many individuals.  Nystagmus is frequently present.  The ciliary body may also be hypoplastic. 

Visual acuity varies widely.  In many families it is less than 20/60 in all members and the majority have less than 20/200.  Photophobia can be incapacitating.  Posterior segment OCT changes suggest that outer retinal damage suggestive of a phototoxic retinopathy may also be a factor in the reduced acuity.  Cataracts (congenital in >75%), ectopia lentis (bilateral in >26%), optic nerve hypoplasia, variable degrees of corneal clouding with or without a vascularized pannus, and dysgenesis of the anterior chamber angle are frequently present. 

Increased corneal thickness (>600 microns) has been found in some series and should be considered when IOP measurements are made.  In early stages of the disease, focal opacities are present in the basal epithelium, associated with sub-basal nerves.  Dendritic cells can infiltrate the central epithelium and normal limbal palisade architecture is absent.  The tear film is often unstable.

Systemic Features: 

In addition to 'pure' aniridia in which no systemic features are found, at least six disorders have been reported in which systemic anomalies do occur.  Three of these have associated renal anomalies, including Wilms tumor with other genitourinary anomalies and mental retardation, sometimes called WAGR (194072) syndrome, another (612469) with similar features plus obesity sometime called WAGRO (612469) syndrome reported in isolated patients, and yet another with partial aniridia (206750) and unilateral renal agenesis and psychomotor retardation reported in a single family.  Aniridia with dysplastic or absent patella (106220) has been reported in a single three generation family.  Cerebellar ataxia and mental retardation with motor deficits (Gillespie syndrome; 206700) have been found in other families with anirdia.  Another 3 generation family has been reported in which aniridia, microcornea and spontaneously resorbed cataracts occured (106230).

About one-third of patients with aniridia also have Wilms tumor and many have some cognitive deficits.

Genetics

The majority of cases have a mutation in the paired box gene (PAX6) complex, or at least include this locus when chromosomal aberrations such as deletions are present in the region (11p13).  This complex (containing at least 9 genes) is multifunctional and important to the tissue regulation of numerous developmental genes.   PAX6 mutations, encoding a highly conserved transcription regulator, generally cause hypoplasia of the iris and foveal hypoplasia but are also important in CNS development.  It has been suggested that PAX6 gene dysfunction may be the only gene defect associated with aniridia.  More than 300 specific mutations, most causing premature truncation of the polypeptide, have been identified.  

AN1 results from mutations in the PAX6 gene.  Two additional forms of aniridia have been reported in which functional alterations in genes that modulate the expression of PAX6 are responsible: AN2 (617141) with mutations in ELP4 and AN3 (617142) with mutations in TRIM44.  Both ELP4 and TRIM44 are regulators of the PAX6 transcription gene.

Associated abnormalities may be due to a second mutation in the WT1 gene in WAGR (194072) syndrome, a deletion syndrome involving both WT1 and PAX6 genes at 11p13.  The WAGRO syndrome (612469) is caused by a contiguous deletion in chromosome 11 (11p12-p13) involving three genes: WT1, PAX6, and BDNF.  All types are likely inherited as autosomal dominant disorders although nearly one-third of cases occur sporadically.

Mutations in PAX6 associated with aniridia can cause other anterior chamber malformations such as Peters anomaly (604229).

Gillespie syndrome (206700 ) is an allelic disorder with neurological abnormalities including cerebellar ataxia and mental retardation.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at the associated threats to vision such as glaucoma, corneal opacities, and cataracts.  Glaucoma is the most serious threat and is the most difficult to treat. The best results have been reported with glaucoma drainage devices.  All patients should have eye examinations at appropriate intervals throughout life, focused on glaucoma screening.  It is well to keep in mind that foveal maldevelopment often precludes significant improvement in acuity and heroic measures must be carefully evaluated.  Specifically, corneal transplants and glaucoma control measures frequently fail.

Low vision aids are often helpful.  Tinted lenses can minimize photophobia.  Occupational and vocational training should be considered for older individuals.

Young children with aniridia should have periodic examinations with renal imaging as recommended by a urologist.

In mice, postnatal topical ocular application of ataluren-based eyedrop formulations can reverse malformations caused by PAX6 mutations.

References
Article Title: 

Familial aniridia with preserved

Elsas FJ, Maumenee IH, Kenyon KR, Yoder F. Familial aniridia with preserved ocular function. Am J Ophthalmol. 1977 May;83(5):718-24.

PubMed ID: 
868970
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