pigmentary retinopathy

Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome 3

Clinical Characteristics
Ocular Features: 

Patients have been described as having variable oculofacial features including epicanthal folds, hypertelorism, strabismus, and 'tapetoretinal degeneration'.    

Systemic Features: 

The full phenotype is variable and unknown based on the 5 reported patients from 4 families of whom 3 were consanguineous.  Recurrent infections (especially respiratory and otitis media) seem to be among the most consistent features.  Others include intrauterine growth retardation, developmental delay including psychomotor delays, a flat midface with various anomalies, low-set ears, renal dysgenesis, polydactyly, severe agammaglobulinemia, hypospadias, and cryptorchidism.  Normal T-cell function and normal B cells are present.  Conductive hearing loss, polydactyly, and scoliosis may be features as well.  Two of the 5 reported patients with ICF3 were reported to have mental retardation.  One patient died at the age of 26 years.

Genetics

Homozygosity of CDCA7 (2q31.1) mutations with centromeric instability and hypomethylation of selected juxtacentromeric heterochromatin regions is responsible for this (ICF3) autosomal recessive condition.  There is genetic heterogeneity in ICF (ICF1, ICF2, ICF3, and ICF4 [see 242860).   

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome

Thijssen PE, Ito Y, Grillo G, Wang J, Velasco G, Nitta H, Unoki M, Yoshihara M, Suyama M, Sun Y, Lemmers RJ, de Greef JC, Gennery A, Picco P, Kloeckener-Gruissem B, Gungor T, Reisli I, Picard C, Kebaili K, Roquelaure B, Iwai T, Kondo I, Kubota T, van Ostaijen-Ten Dam MM, van Tol MJ, Weemaes C, Francastel C, van der Maarel SM, Sasaki H. Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome. Nat Commun. 2015 Jul 28;6:7870.

PubMed ID: 
26216346

Spondylometaphyseal Dysplasia, Axial

Clinical Characteristics
Ocular Features: 

Due to the small number of individuals reported, the ocular phenotype is variable and likely incompletely described.  Optic atrophy and pigmentary retinopathy are the most consistent findings.  The most completely studied individual had evidence of slight bilateral optic nerve atrophy on cerebral MRI imaging as well.  There may be extensive RPE atrophy but the fundus pigmentation is usually described as resembling retinitis pigmentosa.  The ERG in several patients during the second decade of life already shows severe dysfunction of the photoreceptors, with cones the most severely impacted.  In spite of this Goldmann visual fields have been reported to be normal.  The macula and OCT have been reported as normal.  Telecanthus, nystagmus, hypertelorism, proptosis, and photophobia have been reported.  Early onset and progressive visual impairment are characteristic.

Systemic Features: 

Only 5 patients with this condition have been reported most of whom were short in stature.  There may be frontal bossing and the chest is narrow and flattened.  Moderate platyspondyly has been described with enlarged but shortened ribs and an irregular iliac crest.  Rhizomelic shortening of the limbs is common.  The femoral metaphyses are abnormal with their necks shortened and enlarged.  The ribs are enlarged but shortened as well and are flared at the ends.  Mental development and function are normal.

Genetics

This is an autosomal recessive condition due to homozygous or compound heterozygous mutations in C21orf2.

Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations

Wang Z, Iida A, Miyake N, Nishiguchi KM, Fujita K, Nakazawa T, Alswaid A, Albalwi MA, Kim OH, Cho TJ, Lim GY, Isidor B, David A, Rustad CF, Merckoll E, Westvik J, Stattin EL, Grigelioniene G, Kou I, Nakajima M, Ohashi H, Smithson S, Matsumoto N, Nishimura G, Ikegawa S. Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations. PLoS One. 2016 Mar 14;11(13).

PubMed ID: 
26974433

Axial spondylometaphysealdysplasia

Ehara S, Kim OH, Maisawa S, Takasago Y, Nishimura G. Axial spondylometaphysealdysplasia. Eur J Pediatr. 1997 Aug;156(8):627-30.

PubMed ID: 
9266195

Macular Dystrophy, Patterned 3

Clinical Characteristics
Ocular Features: 

This condition has been found in an extended pedigree among peoples originating in the West Indies.  Vision loss is noted after the age of 50 years but clinical evidence can be seen in the fourth or fifth decades. The findings are primarily in the retinal pigment epithelium but Bruch's membrane is also involved.  Choroidal neovascularization and macular scarring may be present. The fundus pigmentary pattern has been described as resembling "dried-out soil" or crocodile skin.  In late stages the fundus picture resembles retinitis pigmentosa with loss of the RPE and photoreceptors.  The loss of photoreceptors continues throughout life. An 85 year old woman with light perception only has been described. 

In early stages the full-field ERG can be nomal but later rod and cone responses are severely reduced.  The OCT may show scalloped elevation at the borders of the scalloped patches corresponding to the irregular thickness of the RPE and Bruch membrance.

Knockout mice have both thickened and thinned areas of the Bruch membrane.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This autosomal dominant condition results from heterozygous mutations in MAPKAPK3 (3p21.3), a mitogene-activated kinase of the p38 signaling pathway.  It is highly expressed in the RPE.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

A dominant mutation in MAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium

Meunier I, Lenaers G, Bocquet B, Baudoin C, Piro-Megy C, Cubizolle A, Quiles M, Jean-Charles A, Cohen SY, Merle H, Gaudric A, Labesse G, Manes G, Pequignot M, Cazevieille C, Dhaenens CM, Fichard A, Ronkina N, Arthur SJ, Gaestel M, Hamel CP. A dominant mutation in MAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium. Hum Mol Genet. 2016 Mar 1;25(5):916-26.

PubMed ID: 
26744326

Short-Rib Thoracic Dysplasia 9

Clinical Characteristics
Ocular Features: 

A pigmentary retinopathy resembling retinitis pigmentosa is present in the majority of individuals.  Reduced acuity is likely responsible for the associated nystagmus and occasional strabismus.  Night blindness is a feature although the age of onset is unknown.  Visual acuity is decreased in the first decade but at least one patient at age 40 years still had vision of 20/40-20/50.  The ERG shows decreased scotopic and photopic responses as early as 12 years of age.  The retinopathy has been described as an atypical nonpigmented retinal degeneration in the peripheral retina. However, bone-spicule pigmentary deposits have been noted.  The retinal disease is progressive. 

Systemic Features: 

The LFT140 mutation has widespread effects, impacting the kidney, liver and skeletal systems.  The thorax is shortened, while the ribs are abnormally short and may result in respiratory difficulties, recurrent infections, and an early demise.  The middle phalanges of the hands and feet often have cone-shaped epiphyses, especially notable in childhood and leading to brachydactyly.  The long bones are often shortened as well.  The femoral neck can be short while the femoral epiphyses are often flattened.  Microcephaly has been reported in several individuals.

The liver may be enlarged and become fibrotic.  The kidneys often are cystic and histologically may have sclerosing glomerulonephropathy.  Kidney disease has an onset in the first decade and its progression often defines the survival prognosis.  Renal transplantation can be lifesaving when nephronophthisis develops.  Psychomotor delays have been reported but are uncommon. 

Genetics

Homozygous or compound heterozygous mutations in the IFT140 gene (16p13.3) have been identified.  However, there is some genetic heterogeneity since several patients having the typical phenotype have been reported with only heterozygous mutations.

This may be the same condition as Retinitis Pigmentosa 80 (617781) in which the same mutation occurs. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the general disease.  Renal and pulmonary function needs to be monitored with intervention as needed.  Some patients have benefitted from renal transplantation.

References
Article Title: 

Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease

Schmidts M, Frank V, Eisenberger T, Al Turki S, Bizet AA, Antony D, Rix S, Decker C, Bachmann N, Bald M, Vinke T, Toenshoff B, Di Donato N, Neuhann T, Hartley JL, Maher ER, Bogdanovic R, Peco-Antic A, Mache C, Hurles ME, Joksic I, Guc-Scekic M, Dobricic J, Brankovic-Magic M, Bolz HJ, Pazour GJ, Beales PL, Scambler PJ, Saunier S, Mitchison HM, Bergmann C. Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease. Hum Mutat. 2013 May;34(5):714-24.

PubMed ID: 
23418020

Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations

Perrault I, Saunier S, Hanein S, Filhol E, Bizet AA, Collins F, Salih MA, Gerber S, Delphin N, Bigot K, Orssaud C, Silva E, Baudouin V, Oud MM, Shannon N, Le Merrer M, Roche O, Pietrement C, Goumid J, Baumann C, Bole-Feysot C, Nitschke P, Zahrate M, Beales P, Arts HH, Munnich A, Kaplan J, Antignac C, Cormier-Daire V, Rozet JM. Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations. Am J Hum Genet. 2012 May 4;90(5):864-70.

PubMed ID: 
22503633

Macular Dystrophy with Central Cone Involvement

Clinical Characteristics
Ocular Features: 

This is primarily a cone dystrophy but there is evidence of some rod damage in older patients.  A mild decrease in central acuity is noted by individuals in the third to sixth decades.  Slight pigmentary changes and color vision abnormalities can be documented with the onset of these symptoms and a bull's eye maculopathy and severe atrophy of the central fovea may be present. An enlarging central scotoma with normal periphery can sometimes be identified.  Other patients have an atrophic appearance to the peripapillary area with a pale optic disc.  ERG responses to full-field testing are normal but multifocal studies reveal severely reduced central responses.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Compound heterozygosity for a missense mutation and a nonsense mutation in the MFSD8 gene (4q28.2) has been found among members of a Dutch sibship suggesting autosomal recessive inheritance.       

The same mutant gene has been identified in some patients with late infantile or early juvenile onset lysosomal storage disease known as neuronal ceroid lipofuscinoses (610951) in which there may be optic atrophy, attenuated retinal vessels, a pigmentary retinopathy, and severe vision loss.   However, it is of note that no members of the Dutch family with the macular cone dystrophy described here had extraocular manifestations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Retinal Dystrophy, Newfoundland Type

Clinical Characteristics
Ocular Features: 

There is considerable clinical heterogeneity, mostly age-dependent.  Night blindness can occur in early childhood but usually later even though scotopic responses can be undetectable in the first decade of life while photopic responses are reduced on the ERG at all ages.  Both rod and cone responses may be extinguished in later life.  Visual acuity can be decreased beginning in early childhood and legal blindness usually occurs by the second or third decade of life.  However, the loss of vision continues to progress and severe vision loss to finger-counting may be present in older individuals.  A scallop-bordered lacunar atrophy may be seen in the midperiphery.  The macula is only mildly involved by clinical examination although central retinal thinning is seen in all cases.  Dyschromatopsia is mild early and usually becomes more severe.  The visual fields are moderately to severely constricted although in younger individuals a typical ring scotoma is present.  The peripheral retina contains ‘white dots’ and often resembles the retinal changes seen in retinitis punctate albescens.

Systemic Features: 

None reported.

Genetics

Homozygous mutations in the RLBP1 gene (15q26.1) are responsible for this disorder.  Homozygous mutations in RLBP1 have also been found among patients with fundus albipunctatus (136880), retinitis punctata albescens, and in Bothnia type retinal dystrophy (607475),

NFRCD clinically resembles Bothnia type retinal dystrophy (607475) which likewise results from mutations in the RLBP1 gene but the maculae appear normal or have only a mild ‘beaten-bronze’ atrophy.

See Flecked Retina entry for somewhat similar conditions.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Retinal Dystrophy and Obesity

Clinical Characteristics
Ocular Features: 

The age of onset of symptoms is unknown but based on the report of a single family with three affected sibs, it may occur early in the second decade. Patients may note some loss of night vision and the visual fields are restricted.  The ERG responses are consistent with a generalized rod-cone dystrophy.  Fundoscopy reveals a generalized RPE atrophy together with arteriolar attenuation, peripheral pigmentary mottling and scattered white dots.  A nonspecific dyschromatopsia can be demonstrated but the fovea is relatively normal and central acuity is remarkably good.  Little is known about disease progression but an 18 year old male reported decreasing vision since the age of 11 years.  

Systemic Features: 

Obesity and a high BMI may be present.

Genetics

Homozygous mutations in the TUB gene (11p15) segregated with this disorder in a sibship from a consanguineous family.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Macular Dystrophy, Vitelliform 4

Clinical Characteristics
Ocular Features: 

This is a late onset form of vitelliform dystrophy in which symptoms are usually noted between the ages of 20 to 45 years.  The vitelliform lesions usually occur singly and are often small.  Some individuals have small drusen-like macular lesions adjacent to the vitelliform lesions, at the periphery of the macula, or even outside the macula.  The lesions contain lipofuscin which can be seen on autofluorescence photographs.  Visual acuity can remain near normal for many years.  The EOG ratio and ERG responses are usually normal or near normal.  Choroidal neovascularization has not been described. 

Systemic Features: 

There are no systemic manifestations.

Genetics

This form of vitelliform dystrophy (VMD4) is caused by heterozygous mutations in the IMPG1 gene (6q14.1).  However, rare families have been reported in which compound heterozygous or homozygous mutations have been found.  Some of the heterozygous parents of children with two mutations were found to have minor fundus changes such as tiny extramacular vitelliform spots in spite of being asymptomatic. This suggests that the transmission pattern of fundus changes may be both autosomal recessive and autosomal dominant. 

Genotyping has identified at least 5 forms of vitelliform macular dystrophy.  In addition to the iconic Best disease (VMD2, 153700) apparently first described by Friedreich Best in 1905 and now attributed to mutations in the Best1 gene, we know of at least 4 more and specific mutations have been identified in three.  No mutation or locus has yet been identified in VMD1 (153840) but it is likely a unique condition since mutations in other genes known to cause vitelliform dystrophy have been ruled out.  Other forms are VMD3 (608161) due to mutations in the PRPH2 gene, VMD4 described here, and VMD5 (616152) caused by mutations in the IMPG2 gene.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the vitelliform disease but low vision devices can be helpful in some patients for selected tasks.

References
Article Title: 

Mutations in IMPG1 cause vitelliform macular dystrophies

Manes G, Meunier I, Avila-Fernandez A, Banfi S, Le Meur G, Zanlonghi X, Corton M, Simonelli F, Brabet P, Labesse G, Audo I, Mohand-Said S, Zeitz C, Sahel JA, Weber M, Dollfus H, Dhaenens CM, Allorge D, De Baere E, Koenekoop RK, Kohl S, Cremers FP, Hollyfield JG, Senechal A, Hebrard M, Bocquet B, Ayuso Garcia C, Hamel CP. Mutations in IMPG1 cause vitelliform macular dystrophies. Am J Hum Genet. 2013 Sep 5;93(3):571-8.

PubMed ID: 
23993198

Macular Dystrophy, Vitelliform 3

Clinical Characteristics
Ocular Features: 

Patients generally become symptomatic (reduced vision and metamorphopsia) in the fourth and fifth decades.  Vision loss is mild as in vitelliform 1 disease and only slowly progressive in most patients.  One or sometimes more small, oval, and slightly elevated yellow lesions resembling an egg yolk may be seen in the fovea along with paracentral drusen and mild RPE changes.  The fundus changes can appear any time in adult life but little is known about their nature history.  The EOG light/dark ratio may be normal or slightly decreased and the ERG likewise can be normal or, in some cases, reveals rod and cone system abnormalities.  Optical coherence tomography shows yellowish deposits between the neurosensory retina and the RPE with foveal thinning.  Color vision has been described as normal. The visual field may show peripheral constriction or central scotomas.  Choroidal neovascularization occurs rarely.

Variability in the clinical features often leads to misdiagnosis in individual patients who are sometimes considered to have age-related macular degeneration, retinitis pigmentosa, fundus flavimaculatus, dominant drusen, butterfly macular dystrophy, and pattern dystrophy.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an autosomal dominant condition resulting from heterozygous mutations in the RDS (PRPH2) gene (6p21.1). 

The gene product of PRPH2 is active in the retina. It is important to the integrity and stability of the structures that contain light-sensitive pigments (e.g., photoreceptors).  More than 100 mutations have been identified. The resultant phenotype can be highly variable, even within members of the same family but most affected individuals have some degree of pigmentary retinopathy within the macula or throughout the posterior pole.  The altered gene product resulting from mutations in PRPH2 often leads to symptoms beginning in midlife as a result of the slow degeneration of photoreceptors.  This database contains at least 11 disorders in which PRPH2 mutations have been found.

Genotyping has identified at least 5 forms of vitelliform macular dystrophy.  In addition to the iconic Best disease (VMD2, 153700) apparently first described by Friedreich Best in 1905 and now attributed to mutations in the Best1 gene, we know of at least 4 more and specific mutations have been identified in three.  No mutation or locus has yet been identified in VMD1 (153840) but it is likely a unique condition since mutations in other genes known to cause vitelliform dystrophy have been ruled out.  Other forms are VMD3 described here, VMD4 (616151) resulting from mutations in the IMPG1 gene, and VMD5 (616152) caused by mutations in the IMPG2 gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known for this disorder.  Anti-VEGF and ablation therapy may be helpful in selected individuals with choroidal neovascularization.  Low vision aids may also be beneficial.

References
Article Title: 

Retinal Dystrophy, Cataracts, and Short Stature

Clinical Characteristics
Ocular Features: 

Patients develop progressive night vision problems in the first decade of life.  However, central acuity remains in the 20/20 to 20/30 range at least through the second decade.  Cataracts are noted during this time period as well.  Visual field constriction is present.

Pigmentary retinopathy is present, especially in the posterior poles.  Macular mottling is evident at an early age with attenuation and narrowing of the retinal arterioles.  The pigmentary changes are salt-and-pepper in appearance but there are also areas of RPE atrophy with relative sparing of the fovea.  Pigment clumping in the shape of bone spicules has been observed in the periphery.  Full field ERGs show generalized rod-cone dysfunction with scotopic function more affected.  OCT examination reveals a disruption of the outer retinal layers from the parafoveal region into the periphery.

Systemic Features: 

Early childhood psychomotor delays are evident in early childhood by the lack of fine motor and coordination skills along with learning difficulties.  Patients have facial dysmorphism with hypoplasia of the ala nasae, upslanting palpebral fissures, and malar hypoplasia.  The teeth are widely spaced and there is malocclusion.  Short stature is characteristic (fifth percentile).

Genetics

This disorder results from homozygosity of mutations in the RDH11 gene (14q24) encoding retinol dehydrogenase 11.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this condition but patients may benefit from correction of the malocclusion, special education classes, cataract removal, and low vision aids.  Physical therapy may also be helpful.

References
Article Title: 

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