autosomal dominant

Dyskeratosis Congenita

Clinical Characteristics
Ocular Features: 

The conjunctiva and eyelids are prominently involved as part of the generalized mucocutaneous disease.  Keratinization of the lid margins, absent lacrimal puncta, trichiasis, cicatrizing conjunctivitis, entropion, ectropion, blepharitis, sparse eyelashes, and symblephara are important features.  The cornea is also involved with keratinization of the epithelial surface and vascularization.  The nasolacrimal duct is sometimes blocked.  At least one patient has been reported to have an exudative retinopathy. 

Systemic Features: 

Dyskeratosis congenita consists of a heterogeneous (genetic and clinical) group of inherited bone marrow failure and premature aging syndromes with the common feature of shortened telomeres.  There is considerable variability in the clinical features.  Prominent manifestations include nail dysplasia, oral leukoplakia, abnormal dentition, and reticulated skin pigmentation. Some patients have cognitive impairments.  Liver failure, testicular atrophy, pulmonary fibrosis, aplastic anemia, and osteoporosis along with features of aging such as premature grey hair and loss are typical.  There is an increased risk of malignancies, especially acute myelogenous leukemia.  Bone marrow failure is the major cause of early death.

Genetics

At least three autosomal dominant, three autosomal recessive, and one X-linked form of dyskeratosis congenita are recognized.  Mutations in at least 7 genes have been implicated.

Autosomal dominant disease can result from mutations in the TERC gene (DKCA1; 3q36.2; 127550), the TERT gene (DKCA2; 5p15.33; 613989), and the TINF2 gene (DKCA3; 14q12; 613990).  Mutations in the TINF2 gene are also responsible for Revesz syndrome (268130) with many features of DKC in addition to ocular findings of an exudative retinopathy resembling Coats disease.

Autosomal recessive disease is caused by mutations in the NOP10 (NOLA3) gene (DCKB1; 224230; 15q14-q15), the  NHP2 (NOLA2) gene (DKCB2; 5q35; 613987), and the WRAP53 gene (DKCB3; 17p13; 613988).  Mutations in the TERT gene may also cause autosomal recessive disease known as DKCB4 (613989).  

The X-linked disease (DKCX) (Zinsser-Engman-Cole syndrome) results from a mutation in the DKC1 gene (Xq28; 305000).  The same gene is mutated in Hoyeraal-Hreidarsson syndrome (300240) which some consider to be a more severe variant of dyskeratosis congenita with the added features of immunodeficiency, microcephaly, growth and mental retardation, and cerebellar hypoplasia. 

The majority of mutations occur in genes that provide instructions for making proteins involved in maintainence of telemeres located at the ends of chromosomes.  Shortened telomeres can result from maintainence deficiencies although the molecular mechanism(s) remain elusive.

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

Treatment for DKC with hematopoietic stem cell transplantation can be curative but its long-term efficacy is poor.  Some advocate androgen therapy first.  Lifelong cancer surveillance and frequent ocular and dental evaluations are important with specific treatment as indicated.

References
Article Title: 

Pigmented Paravenous Chorioretinal Atrophy

Clinical Characteristics
Ocular Features: 

This is a rare type of pigmentary retinopathy with few symptoms in many patients.  Pigment clumps in the form of bone spicules in a paravenous distribution appear as young as 1 year of age and may be present congenitally.  The pigment may begin peripherally and is often segmental but eventually progresses centrally along with chorioretinal atrophy involving the majority of the fundus.  For unknown reasons, males are more severely affected than females.  In one family the retinal changes were associated with hyperopia, esotropia and vitreous degeneration (cells and liquefaction).  There is considerable variation in expressivity among patients and the vision and fundus pigmentation can be highly asymmetrical in the two eyes.  ERG abnormalities likewise vary widely with decreased photopic responses in some individuals and complete lack of both scotopic and photopic responses in severely affected eyes.  Decreased night vision is not a symptom.

This is generally considered to be a stationary condition but long term follow up reveals progression of pigmentary changes, chorioretinal atrophy and increasing constriction of the peripheral visual field.  Symptoms of decreased vision may be noted as early as 3 months of age.  Some patients retain vision of 20/20 or 20/30 into midlife whereas others in the first decade already have count fingers vision.  Likewise the size of the visual field varies widely and is not correlated with age.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an autosomal dominant disorder caused by heterozygous mutations in the crumbs homolog 1 (CRB1) gene (1q31.3).

CRB1 mutations have been identified in other retinal disorders including nanophthalmos with retinitis pigmentosa, pigmented paravenous chorioretinal atrophy (172870), retinitis pigmentosa-12 (600105), and Leber congenital amaurosis 8 (613835).  No consistent retinal phenotype has been found, however.  There is often marked asymmetry between the two eyes and the rate of visual loss varies widely.  Most individuals have some patchy areas of hypoautofluorescence in the posterior pole with variable amounts of pigmentary anomalies from mild speckling to frank bone spicule formation.

   

 

   

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is available although low vision aids are likely to be helpful in selected patients.

References
Article Title: 

Macular Edema, Autosomal Dominant Cystoid

Clinical Characteristics
Ocular Features: 

Only a few families have been reported.  The macular edema can be traced to retinal capillary leakage throughout the posterior pole as revealed by fluorescein angiography.  Scattered exudates and nerve fiber layer hemorrhages are sometimes seen.  Hyperopia and strabismus are often present as well.  Veils, strands, and white punctate deposits in the vitreous have been described.  Wrinkling of the internal limiting membrane may be present.  The ERG is normal except for elevated rod dark adaptation thresholds.  Light/dark ratios are abnormal on EOG testing and mild dyschromatopsia can be demonstrated.  Patients usually notice problems with their visual acuity in the second decade of life and it can drop to 20/200 at this time with progression to 2/120 - 2/200 in older individuals.  In later stages of the disease a central zone of beaten bronze macular atrophy can be seen.  Surrounding this central atrophy is often an area with pigmentary changes resembling retinitis pigmentosa which can extend into the periphery.

This would seem to be a unique disorder in spite of some similarities to retinitis pigmentosa in which macular cysts are often seen.  The clinical course is distinctly different and the presence of vitreous deposits and hyperopia also can be used as arguments for its separateness.  Molecular DNA evidence showing lack of allelism (Vida infra) is, of course the strongest evidence.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This autosomal dominant form of progressive macular dystrophy is linked to a locus at 7p21-p15.  The mutation is close to the RP9 locus causing one type of retinitis pigmentosa but linkage analysis shows the two disorders to be non-allelic.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No specific treatment is available for the macular disease but low vision aids are likely useful, at least early in the disease.

References
Article Title: 

Familial Internal Retinal Membrane Dystrophy

Clinical Characteristics
Ocular Features: 

Folds in the internal limiting membrane are commonly seen, especially in the macula.  Intraretinal edema is seen throughout but may be most evident in the macula which often appears cystic.  Superficial microcystic changes in the retina are concentrated in the posterior pole.  The internal limiting membrane often appears thickened and filamentous material may be present in areas where it is separated from the retina.  The inner retina may have schisis cavities.  Visual acuity remains good until midlife.

This disorder is considered by some to result from a primary defect in Muller cells resulting in permeability defects on the retinal surface.  Evidence for this hypothesis comes from ERG studies in which light adapted responses showed a delayed and reduced b-wave, with broad and delayed ON and OFF responses and a missing flicker response.  However, responses may be inconsistent between the two eyes and more studies are needed.

Histologic studies show endothelial cell swelling, pericyte degeneration, and basement membrane thickening in retinal capillaries.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Several families with transmission patterns characteristic of autosomal dominant inheritance have been reported.  However, no locus or mutation has been reported.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is available.

References
Article Title: 

Macular Dystrophy, Fenestrated Type

Clinical Characteristics
Ocular Features: 

The earliest fundus findings consisting of a yellowish refractile sheen (about 1 disc diameter in size) with red fenestrations in the central macula were found in a 4 year old.  Changes in macular pigmentation were noted at the age of 16 years.  Visual acuity remains normal.  By the third decade of life an annular zone of hypopigmentation could be seen around the sheen and this gradually enlarged.  The sheen seemed to emanate below the retinal vessels but anterior to the RPE.  At the center a ‘bull’s eye’ pattern of hyperpigmentation appeared.  By the 6th decade of life paracentral scotomas were present causing some visual disturbance.  Fluorescein angiography reveals no abnormalities in the sensory retina or retinal vasculature but an annular zone of window defects around the ‘bull’s eye’ can be seen.  The scotopic ERG can be normal while the amplitudes of the photopic ERG may show a mild reduction in amplitude and the EOG light-dark ratio can also be slightly reduced.  Mild red-green color deficits can be demonstrated.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

No locus or mutation has been identified but the transmission pattern is compatible with autosomal dominant inheritance in the two reported families.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Fundus Albipunctatus

Clinical Characteristics
Ocular Features: 

This disorder is often considered to belong to the category of retinal disease known as flecked retina syndrome.  Further, the nomenclature is not standardized and varying names have been attached to the more or less characteristic fundus picture consisting of uniformly distributed small yellow-white dots in the retina.  These tend to be concentrated in the midperiphery.  The macula usually is not involved in young people although ERG evidence suggests some worsening of cone dysfunction with age and central acuity may be decreased in midlife.  Frank macular degeneration has been seen clinically .  Delayed dark adaptation can be demonstrated with delays in recovery of rod and cone function.  Patients complain of night blindness beginning in childhood with little evidence of progression.

The disease known as retinitis punctata albescens (136880) may or may not be a unique disorder.  It is sometimes grouped with fundus albipunctatus while others consider it to be a separate entity.  Evidence for its uniqueness is based on the progressive nature of field loss and the presence of pigmentary changes and retinal vascular attenuation which are not found in fundus albipunctatus.  Further, the scotopic ERG waveforms usually do not regenerate.  More discriminating studies, especially genotyping, will likely provide additional information.  It would also be useful to have additional follow-up information on families. 

Systemic Features: 

No systemic disease is associated.

Genetics

Fundus albipunctatus is a genetically heterogeneous disorder.  Mutations in two genes, PRPH2 (6p21.1) and RDH5 (12q13.2) have been found among families.  The inheritance pattern for families with mutations in PRPH2 is consistent with autosomal dominant inheritance while mutations in RDH5 result in an autosomal recessive pattern.  Mutations in RLBP1 have also been found in some families.

Gene studies so far have not been helpful in discriminating between fundus albipunctatus and retinitis punctata albescens (136880).  For example, RLBP1 mutations have been identified among members of the same kindred having the clinical diagnosis of retinitis punctata albescens (136880) among older individuals while younger patients had features of fundus albipunctatus.  Further, the latter disorder has also been described among families with mutations in PRPH2 and RHO hinting at further genetic heterogeneity.

A similar clinical picture may be seen in Bietti crystalline corneoretinopathy (210370), Bardet-Biedl syndrome (209900), and hyperoxaluria (259900).  More information on flecked retina syndromes may be found at Flecked Retina Syndromes.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available to restore full receptor cell function.  However, high oral doses of beta-carotene may lead to an improvement in night blindness. Low vision aids could be beneficial when central acuity is damaged.

References
Article Title: 

Iridogoniodysgenesis, Type 2

Clinical Characteristics
Ocular Features: 

The iris stroma is hypoplastic resulting in a usually dark chocolate color which can suggest the diagnosis at birth.  It may, however, appear slate gray in lightly pigmented individuals.  The pupil is usually normal in morphology and location.  Glaucoma may detectable in the newborn period but it may also not be diagnosed until the 4th decade or later.  It is widely accepted that the anterior chamber angle is anomalous but the architectural and cellular details are lacking.

Systemic Features: 

No systemic abnormalities have been described.

Genetics

This is an autosomal dominant disorder resulting from heterozygous mutations in the PITX2 gene (4q25).

The same gene may be mutated in ring dermoid of the cornea (180550), Axenfeld-Rieger syndrome 1 (180500), Peters anomaly (604229), and in Axenfeld-Rieger anomaly plus (109120).

Type 1 iridogoniodysgenesis (IRID1) (601631) has many clinical similarities but is caused by DNA alterations in the FOXC1 gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Glaucoma is the most frequent result of the anterior chamber dysgenesis in IRID2.  It is often difficult to control.  Early detection is of the utmost importance and all members of at-risk families require lifelong surveillance.

References
Article Title: 

Iridogoniodysgenesis, Type 1

Clinical Characteristics
Ocular Features: 

Glaucoma often develops in the latter part of the first decade of life but has been diagnosed in the neonatal period.  It affects at least half of patients with IRID1.  The disorder may be suspected in at-risk families by the hypoplasia of the iris stroma resulting in a dark chocolate color with prominent vessels. The irides may also have a dark slate gray color.  Further, the anterior iris surface appears smooth without the usual crypts.  There are no defects in the pigment layer of the iris, and the sphincter is intact while the pupil is in the normal position.  In many patients the iris is inserted anteriorly with numerous iris processes spanning the angle and inserting into the Schwalbe line.  In yet other patients tissue seems to fill the angle obscuring other anatomical structures.

Systemic Features: 

Systemic signs and symptoms are usually absent although CNS imaging has revealed cerebellar vermis hypoplasia in one family.

Genetics

This type of iridogoniodysgenesis results from alterations in the forkhead transcription factor gene (FOXC1) (6p25.3).  It is inherited in an autosomal dominant pattern.  Rare individuals may have deletions in the 6p area while duplications in FOXC1 are more common than point mutations.

Mutations in the same gene may also be responsible for Axenfeld-Rieger syndrome type 3 (602482), Peters anomaly (604229), and anterior segment mesenchymal dysgenesis (107250).

Another iridogoniodysgenesis disorder (IRID2) (137600) is caused by mutations in the PITX2 gene (4q25-q26), while iridogoniodysgenesis and skeletal anomalies (609515) is an autosomal recessive disorder due to as yet unknown mutations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

All members of families in which this disorder segregates should have close surveillance for the presence of glaucoma which obviously requires treatment when present.

References
Article Title: 

Microcoria, Congenital

Clinical Characteristics
Ocular Features: 

This disorder is a type of anterior chamber dysgenesis since the pupil and iris anomalies are associated with goniodysgenesis (prominent iris processes and high iris root insertion) and glaucoma.  The dilator muscle of the iris is hypoplastic and even topical mydriatics have little impact on pupil size. The pupil has a mean diameter of 0.8 mm and only dilates to a mean size of 1.4 mm.  The iris stroma is also hypoplastic and often lacks crypts and collarettes.  Transillumination defects of the iris are consistently present.  Axial myopia is a feature in some families (83% of affected individuals have refractive errors in the range of -10D) and seems to be progressive .  Juvenile glaucoma is frequently present (at least 30% require treatment) and is usually detected in the second (20%) through fourth decades of life.  All patients with glaucoma have evidence of 'trabeculodysgenesis' but the same features may also be seen in some patients without glaucoma.  The intraocular pressure is difficult to control pharmacologically.  Visual acuity varies widely but no retinal changes have been described.

Ultrastructural studies show lack of myofilaments and desmin in the stromal cytoplasmic processes of the anterior pigmented cells of the iris suggesting failure of full development of the pupil dilator muscle cells.

Systemic Features: 

There are no systemic abnormalities in this condition.

Genetics

This is an autosomal dominant disorder secondary to a mutation located at 13q13-q32.  The specific mutation responsible has not been identified but a large deletion at 13q32.1 in one patient has been reported. 

Congenital microcoria is also a feature of autosomal recessive Pierson syndrome (609049) caused by homozygous mutations in the LAMB2 gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Glaucoma often requires surgery for control of intraocular pressure.

References
Article Title: 

Submicroscopic deletions at 13q32.1 cause congenital microcoria

Fares-Taie L, Gerber S, Tawara A, Ramirez-Miranda A, Douet JY, Verdin H, Guilloux A, Zenteno JC, Kondo H, Moisset H, Passet B, Yamamoto K, Iwai M, Tanaka T, Nakamura Y, Kimura W, Bole-Feysot C, Vilotte M, Odent S, Vilotte JL, Munnich A, Regnier A, Chassaing N, De Baere E, Raymond-Letron I, Kaplan J, Calvas P, Roche O, Rozet JM. Submicroscopic deletions at 13q32.1 cause congenital microcoria. Am J Hum Genet. 2015 Apr 2;96(4):631-9.

PubMed ID: 
25772937

Mowat-Wilson Syndrome

Clinical Characteristics
Ocular Features: 

Most reports of Mowat-Wilson disorders provide only incomplete ocular findings and the full phenotype remains to be described.  Most of the reported findings are part of the facial phenotype, such as downward slanting palpebral fissures, and 'wedge-shaped' eyebrows with the medial portion visibly wider than the temporal region.  Hypertelorism, strabismus and telecanthus have also been noted.  However, optic nerve atrophyor aplasia, RPE atrophy, microphthalmia, ptosis, and cataracts are sometimes present while strabismus is more common.  Iris and other uveal colobomas may be present and at least one patient has been reported with retinal aplasia.  There may be considerable asymmetry in the features among the two eyes.

Systemic Features: 

This is a highly complex dysmorphic developmental disorder with unusual progression of facial features.  Birth weight and length are usually normal but later there is general somatic and mental growth delay with microcephaly (pre- and post natal), short stature, intellectual disability, and epilepsy (70%).  Hypotonia has been noted at birth.  A significant proportion (~50%) of patients have Hirschsprung disease with megacolon.  Congenital heart defects are common, many involving septal openings.  Hypospadias is often present with or without other genitourinary anomalies.  Teeth are often crowded and crooked.  The earlobes may be flattened and may have a central depression.

The facial features are present in early childhood but as they mature the upper half of the nasal profile becomes convex, while the nasal tip becomes longer and overhangs the philtrum.  The eyes appear more deeply set.  The chin lengthens and prognathism becomes apparent.  IQ levels cannot be determined but many individuals exhibit behavioral or emotional disturbances.

Genetics

Heterozygous mutations in ZEB2 (2q22.3) are responsible for most cases (81%) of this disorder.  A large number of molecular mutations, many of the nonsense type, have been reported. About 2-4% of patients have cytogenetic alterations involving the 2q22 region.

Another disorder with microcephaly, intellectual disability and Hirschsprung disease is Goldberg-Shprintzen syndrome (609460) with mutations in the KIAA1279 gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment may be directed at specific defects but there is no treatment for the general disorder. Individuals can live to adulthood. Treatment is largely symptomatic.  Physical and speech treatment can be helpful if initiated early.

References
Article Title: 

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and

Ivanovski I, Djuric O, Caraffi SG, Santodirocco D, Pollazzon M, Rosato S,
Cordelli DM, Abdalla E, Accorsi P, Adam MP, Ajmone PF, Badura-Stronka M, Baldo C,
Baldi M, Bayat A, Bigoni S, Bonvicini F, Breckpot J, Callewaert B, Cocchi G,
Cuturilo G, De Brasi D, Devriendt K, Dinulos MB, Hjortshoj TD, Epifanio R,
Faravelli F, Fiumara A, Formisano D, Giordano L, Grasso M, Gronborg S, Iodice A,
Iughetti L, Kuburovic V, Kutkowska-Kazmierczak A, Lacombe D, Lo Rizzo C, Luchetti
A, Malbora B, Mammi I, Mari F, Montorsi G, Moutton S, Moller RS, Muschke P,
Nielsen JEK, Obersztyn E, Pantaleoni C, Pellicciari A, Pisanti MA, Prpic I,
Poch-Olive ML, Raviglione F, Renieri A, Ricci E, Rivieri F, Santen GW, Savasta S,
Scarano G, Schanze I, Selicorni A, Silengo M, Smigiel R, Spaccini L, Sorge G,
Szczaluba K, Tarani L, Tone LG, Toutain A, Trimouille A, Valera ET, Vergano SS,
Zanotta N, Zenker M, Conidi A, Zollino M, Rauch A, Zweier C, Garavelli L.
Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and
recommendations for care
. Genet Med. 2018 Jan 4. doi: 10.1038/gim.2017.221. [Epub
ahead of print].

PubMed ID: 
29300384

Clinical spectrum of eye malformations in four patients with Mowat-Wilson syndrome

Bourchany A, Giurgea I, Thevenon J, Goldenberg A, Morin G, Bremond-Gignac D, Paillot C, Lafontaine PO, Thouvenin D, Massy J, Duncombe A, Thauvin-Robinet C, Masurel-Paulet A, Chehadeh SE, Huet F, Bron A, Creuzot-Garcher C, Lyonnet S, Faivre L. Clinical spectrum of eye malformations in four patients with Mowat-Wilson syndrome. Am J Med Genet A. 2015 Apr 21. [Epub ahead of print]

PubMed ID: 
25899569

The behavioral phenotype of Mowat-Wilson syndrome

Evans E, Einfeld S, Mowat D, Taffe J, Tonge B, Wilson M. The behavioral phenotype of Mowat-Wilson syndrome. Am J Med Genet A. 2012 Feb;158A(2):358-66. doi: 10.1002/ajmg.a.34405.

PubMed ID: 
22246645

Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature

Garavelli L, Zollino M, Mainardi PC, Gurrieri F, Rivieri F, Soli F, Verri R, Albertini E, Favaron E, Zignani M, Orteschi D, Bianchi P, Faravelli F, Forzano F, Seri M, Wischmeijer A, Turchetti D, Pompilii E, Gnoli M, Cocchi G, Mazzanti L, Bergamaschi R, De Brasi D, Sperandeo MP, Mari F, Uliana V, Mostardini R, Cecconi M, Grasso M, Sassi S, Sebastio G, Renieri A, Silengo M, Bernasconi S, Wakamatsu N, Neri G. Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature. Am J Med Genet A. 2009 Mar;149A(3):417-26. Review.

PubMed ID: 
19215041

Clinical and mutational spectrum of Mowat-Wilson syndrome

Zweier C, Thiel CT, Dufke A, Crow YJ, Meinecke P, Suri M, Ala-Mello S, Beemer F, Bernasconi S, Bianchi P, Bier A, Devriendt K, Dimitrov B, Firth H, Gallagher RC, Garavelli L, Gillessen-Kaesbach G, Hudgins L, K?SS?SSri?SSinen H, Karstens S, Krantz I, Mannhardt A, Medne L, M?ocke J, Kibaek M, Krogh LN, Peippo M, Rittinger O, Schulz S, Schelley SL, Temple IK, Dennis NR, Van der Knaap MS, Wheeler P, Yerushalmi B, Zenker M, Seidel H, Lachmeijer A, Prescott T, Kraus C, Lowry RB, Rauch A. Clinical and mutational spectrum of Mowat-Wilson syndrome. Eur J Med Genet. 2005 Apr-Jun;48(2):97-111

PubMed ID: 
16053902

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