autosomal dominant

Duane Retraction Syndrome 1

Clinical Characteristics
Ocular Features: 

Duane retraction syndrome is a clinically and genetically heterogeneous condition with a highly variable phenotype.  Most cases occur sporadically but others are familial and about 30% of affected individuals have other congenital anomalies.  It is also seen as part of other syndromes such as Goldenhar (164210), and Wildervanck (314600).  In the absence of other anomalies, it is called isolated Duane syndrome.  In addition, three types with autosomal dominant inheritance have been defined.  The clinical features are highly variable making distinction difficult.  Intrafamilial variation may be less than interfamilial differences.  Patients with type 1 discussed here are more likely to have esotropia with a head turn to the involved side in unilateral cases whereas those with type 2 are considered more likely to have an exotropia with a head turn toward the uninvolved side. 

This is a congenital and non-progressive strabismus syndrome.  Sporadic cases are mostly unilateral while familial ones are more likely to be bilateral.  The essential features are globe retraction upon adduction with narrowing of the lid fissure, and some limitation of abduction. Vertical deviation during adduction is sometimes seen.  Frank strabismus in primary position is evident in as many as 76% of individuals and a compensatory head turn is often adopted but amblyopia still occurs in at least 10% of individuals.  Females are affected more frequently than males.

At one point the syndrome was considered to be a myopathic disorder based on histologic changes in the lateral rectus but current thought based on MRI and neurohistologic studies favors a neuropathic etiology.  The abducens motor neurons and the sixth nerve may be absent or dysplastic.  Branches of the third nerve may also co-innervate the lateral and medial rectus muscles.  EMG studies have documented simultaneous activation of the two muscles which likely accounts for at least some of the globe retraction.  However, hypoplastic muscles, including the superior oblique, superior rectus, and levator, have also been visualized on MRI.

Systemic Features: 

None.

Genetics

Duane syndrome 1 described here follows an autosomal dominant pattern.  No specific mutant gene has been found but a locus has been identified at 8q13.

Individuals having Duane Retraction Syndrome 2 (DURS2) (604356) are often found in autosomal dominant pedigrees also.  Multiple mutations in CHN1 have been found among such individuals.  Pedigrees consistent with autosomal recessive inheritance have also been reported but the responsible genes are unknown.  Duane Retraction Syndrome (DURS3) (617041) patients with mutations in MAFB may have sensorineural hearing loss.

Features of Duane syndrome are also part of the Duane-Radial Ray Syndrome (607323).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Various treatments can be useful, ranging from prisms for mild cases to muscle surgery for a severe head turn or vertical deviations.  Patients should be followed carefully in the first decade of life for the onset of amblyopia and appropriate treatment instituted.  Because of the variability in signs, each patient requires individualized treatment.

References
Article Title: 

Duane Retraction Syndrome 2

Clinical Characteristics
Ocular Features: 

Duane retraction syndrome is a clinically and genetically heterogeneous condition with a highly variable phenotype.  It is a congenital and non-progressive strabismus syndrome.  Most cases occur sporadically but others are familial and about 30% of affected individuals have other congenital anomalies.  It is also seen as part of other syndromes such as Goldenhar (164210), and Wildervanck (314600).  In the absence of other anomalies, it is called isolated Duane syndrome.  Three heritable types with autosomal dominant familial patterns have also been defined.  Patients with type 2 discussed here are more likely to have an exotropia with a head turn toward the uninvolved side when only one eye is involved compared with Duane syndrome type 1 (126800) in which an esotropia with a head turn to the involved side is more common.  However, the clinical features are highly variable although intrafamilial differences may be less than those between families.

Sporadic cases are mostly unilateral while familial ones are more likely to be bilateral.  The essential features are globe retraction upon adduction with narrowing of the lid fissure and some limitation of abduction. Vertical deviation during adduction is sometimes seen.  Frank strabismus in primary position is evident in as many as 76% of individuals and a compensatory head turn is often adopted. Still, amblyopia occurs in at least 10% of individuals.  Females are affected more frequently than males.

At one point the syndrome was considered to be a myopathic disorder based on histologic changes in the lateral rectus but current thought based on MRI and neurohistologic studies favors a neuropathic etiology.  The abducens motor neurons and the sixth nerve may be absent or dysplastic.  Branches of the third nerve may also co-innervate the lateral and medial rectus muscles.  EMG studies have documented simultaneous activation of the two muscles which likely accounts for at least some of the globe retraction.  However, hypoplastic muscles, including the superior oblique, superior rectus, and levator, have also been visualized on MRI.

Systemic Features: 

A variety of skeletal and uroglogic anomalies have been found in association with the ocular findings of Duane syndrome but no consistent pattern has been documented.

Genetics

Familial isolated Duane syndrome 2 individuals usually appear in an autosomal dominant pattern of inheritance caused by a mutation in CHN1 (2q31-q32.1).  The protein products appear to be involved in early neurological development and are critical to the formation of the cranial nerves that innervate the extraocular muscles.

Mutations in CHN1 are usually absent in nonfamilial cases of Duane syndrome.

For other forms of autosomal dominant Duane syndrome, see Duane Retraction Syndrome 1 (126800) and Duane Retraction Syndrome 3 (617041).

Pedigrees consistent with presumed autosomal recessive inheritance have also been reported but the responsible genes are unknown.

Features of Duane syndrome are also part of the Duane-Radial Ray Syndrome (607323).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Various treatments can be useful, ranging from prisms for mild cases to muscle surgery for a severe head turn or vertical deviations.  Patients should be followed carefully in the first decade of life for the onset of amblyopia and appropriate treatment instituted.  Because of the variability in signs, each patient requires individualized treatment.

References
Article Title: 

Glaucoma, Pigment Dispersion Syndrome

Clinical Characteristics
Ocular Features: 

This is a form of open angle glaucoma with early onset (usually before the age of 40 years).  Marked pigment deposition in the trabecular meshwork, on the lens, zonules, and the corneal endothelium can often be seen prior to elevation of the intraocular pressure. It can be present asymmetrically, even unilaterally, but primarily in early stages.  The pigment source in humans seems to be the iris in which hypopigmentation leads to radial transillumination defects and mouse models corroborate this.  The iris configuration is sometimes described as flat or even concave.  The pattern of pigment deposition on the posterior surface of the cornea is known as a Krukenberg spindle and considered diagnostic.  Untreated, the characteristic optic nerve damage and visual field changes of glaucoma eventually occur.  Early-onset and rapidly progressive nuclear cataracts have been reported in some patients.

In one longitudinal study of 113 patients diagnosed with pigment dispersion and followed for 24 years, 23 had glaucoma initially and 9 more eventually required treatment for elevated pressure. The mean age at diagnosis was 42 years and myopic males were the most commonly affected.

The syndromic nature of PDS is suggested by the association of lattice degeneration, retinal tears, and detachments in a significant number of individuals.

Systemic Features: 

No systemic disease has been reported.

Genetics

This is an autosomal dominant form of glaucoma-related optic neuropathy that shares some features with open angle juvenile glaucoma (137750), such as myopia and early onset.  The pigment dispersion syndrome described here, however, maps to a different locus (7q35-q36).  Another candidate locus is located at 18q11-q21 but the causative mutations remain elusive.

A four generation family with an apparent autosomal recessive pattern has been reported.

The autosomal dominant pattern is not always apparent from history alone and examination of relatives is necessary to document the familial nature of this disease. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The usual glaucoma therapies are indicated.  Some have advised limiting vigorous impact sports to reduce the amount of pigment released.  All individuals with pigment dispersion must be followed vigilantly for development of glaucoma as the risk is high.  It has been estimated to be 10% within 5 years and 15% in 15 years, regardless of age and family history.  Further, the pigment dispersion is progressive along with the risk of elevated pressure as eventually 30 -50% of patients develop glaucoma.  However, regression of pigment deposition, decrease of iris transillumination and even stabilization of pressure has also been noted in some, mostly younger, patients.

Laser iridotomy has been suggested as therapeutically useful in the reduction of the IOP but there is no statistical confirmation of this.

References
Article Title: 

BPES Syndrome

Clinical Characteristics
Ocular Features: 

This is primarily a dysplasia of the eyelids and adnexae.  The acronym is derived from the longer title sometimes used: blepharophimosis, ptosis, and epicanthus inversus syndrome.  The palpebral fissures are small and the curve of the epicanthal fold is mediolateral, but below the medial canthus.  The nasal bridge is flat or at least low, and the lids are ptotic.  Telecanthus may be present as well.  Refractive errors, strabismus, nystagmus, and amblyopia are often associated.  Entropion with trichiasis may require surgical attention.  Mutations in the FOX family of genes are associated with a wide variety of ocular anomalies including microcornea, trabecular dysgenesis, optic nerve hypoplasias and colobomas that are sporadically present in BPES syndrome.

Alacrima is a feature in many cases, caused by hypoplasia or aplasia of the major lacrimal gland.

Systemic Features: 

This condition is sometimes associated with ovarian failure although breast development is often normal.  The resultant infertility is an example of a sex-limited autosomal trait.  The syndrome can result from cytogenetic aberrations as well but individuals with these usually have other malformations such as contractures, mental defects, microcephaly, growth retardation, etc.

Some authors have considered individuals with the typical features of BPES who also have genitourinary malformations and cognitive deficits as examples of BPES plus syndrome.  A recent report, for example, describes two sibs, a male and a female, with some features of this syndrome plus posteriorly rotated ears, hypertelorism, telecanthus, micrognathia and severe psychomotor retardation.  The responsible mutation was not identified and its relationship to BPES remains unknown.  Another individual with typical ocular and systemic features of BPES in addition to cryptorchidism, developmental delay, and syndactyly, was found to have a mutation in the gene KAT6B in the absence of mutations in FOXL2

The phenotypic spectrum of this condition is extensive and it is likely that multiple mutations are collectively responsible for the clinical heterogeneity.

Genetics

This is an autosomal dominant condition with sex-limited characteristics in females (infertility, small uterus, atrophic ovaries).  The karyotype in females is normal.  It is one of the rare conditions with an apparent maternal age effect, at least in sporadic cases which are not uncommon. 

Mutations in the FOXL2 gene at 3q23 seem to be responsible for at least some familial cases. It codes for a gene active in the mesenchyme of the eyelids and in the ovarian follicle, at least in mice.  About 12% of patients do not have a FOXL2 mutation though. Numerous mutations have been found, some of which cause premature ovarian failure (sometimes labeled BPES type I) while others cause only lid maldevelopment (BPES type II).

A mutation in KAT6B (10q22.2) has been found in a single individual with features typical of BPES in whom no FOXL2 mutations were present.  It has been suggested that BPES patients without mutations in FOXL2 should be sequenced for mutations in KAT6B

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Lid surgery might be helpful in some patients with severe ptosis and/or trichiasis.

References
Article Title: 

Corneal Dystrophy, Stocker-Holt

Clinical Characteristics
Ocular Features: 

Stocker-Holt dystrophy is clinically somewhat similar to Meesmann corneal dystrophy but is caused by a different mutation and is therefore discussed separately here.  Stocker and Holt in 1954 described this disorder among 20 descendents from Moravia who settled in North Carolina (Meesmann and Wilke's report in 1939 was based on patients in Germany).  Fine, grayish punctate epithelial opacities were found in the epithelium anterior to Bowman's throughout the entire cornea even in patients as young as 7 months old.  These stain with fluorescein and are accompanied by fine linear opacities that appear in a whorled pattern.  Outside of light sensitivity and glare reported by some patients, few are symptomatic.  Spontaneous, recurrent epithelial erosions can occur.  Corneal sensitivity is reduced. Contact lenses are poorly tolerated.  Visual acuity is generally around 20/50 but can be significantly worse.  Few require keratoplasty.

Meesmann dystrophy (122100) is superficially similar but the opacities are more numerous in the interpalpebral area and the surrounding epithelium is generally clear.

Systemic Features: 

No systemic problems are associated with this corneal disease.

Genetics

Stocker-Holt dystrophy is caused by mutations in KRT12 (17q12).  Like Meesmann dystrophy (122100), it follows an autosomal dominant pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is largely directed at symptoms from epithelial erosions using hypertonic solutions and sometimes epithelial debridement.  The cystic changes tend to recur following removal of the offending epithelium and even after corneal replacement.

References
Article Title: 

Glaucoma, Open Angle, Juvenile

Clinical Characteristics
Ocular Features: 

Primary open angle glaucoma is a genetically and clinically heterogeneous condition.  The type described here often has its onset in juveniles, much earlier than the usual type, and is much more rare.  Onset is often in the second or third decade with an average age of onset of 18 years.  It is rare for this form of POAG to be diagnosed after 40 years of age.  IOP is commonly as high as 50 mmHg and the pressure is difficult to control.  Glaucomatous changes in the optic nerve progress rapidly. The usual pharmacologic agents can be helpful early but surgical control is often required.  Myopia is common (87%) but no anterior chamber anomalies are present.  Juvenile POAG is more common in African Americans.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Juvenile onset open angle glaucoma, GLAC1A, is inherited in an autosomal dominant pattern with high penetrance.  It is caused by a mutation in MYOC located at 1q21-q31.  The usual adult onset glaucoma is caused by different mutations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The usual pharmacologic treatment may be effective in some, especially early, but some form of glaucoma filtration surgery is eventually required in over 80% of patients.

References
Article Title: 

Pfeiffer Syndrome

Clinical Characteristics
Ocular Features: 

Patients may have extreme proptosis (95%) secondary to shallow orbits and exposure keratitis (41%) is a risk.  Hypertelorism, strabismus, and antimongoloid lid slants are common.  More rare signs include anterior chamber anomalies and optic nerve hypoplasia.

Systemic Features: 

Pfeiffer syndrome has been divided into 3 types, of which cases with types 2 and 3 often die young.  Type 1 has the more typical features with midface hypoplasia, broad thumbs and toes, craniosynostosis, and often some degree of syndactyly.  Adult patients with type 1 may be only mildly affected with some degree of midface hypoplasia and minor broadening of the first digits.  Hearing loss secondary to bony defects is relatively common.  Cleft palate is uncommon.  Airway malformations especially in the trachea can cause respiratory problems.

Genetics

This is a genetically heterogeneous disorder resulting from mutations in at least 2 genes, FGFR1 (8p11.2-p11.1) and FGFR2 (10q26).  The less common cases with the latter mutation are allelic to Apert (101200), Crouzon (123500), and Jackson-Weiss (123150) syndromes.  Inheritance is autosomal dominant but some cases are only mildly affected.  New mutations exhibit a paternal age effect.

Other forms of craniosynostosis in which mutations in FGFR2 have been found are: Beare-Stevenson Syndrome (123790), and Saethre-Chotzen Syndrome (101400).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Exposure keratitis requires the usual treatment.  Fronto-orbital advancement surgery for the midface underdevelopment is generally helpful for the complications of proptosis.  Airway obstruction may require tracheostomy or surgical correction of the air passages.

References
Article Title: 

FGFR2 mutations in Pfeiffer syndrome

Lajeunie E, Ma HW, Bonaventure J, Munnich A, Le Merrer M, Renier D. FGFR2 mutations in Pfeiffer syndrome. Nat Genet. 1995 Feb;9(2):108.

PubMed ID: 
7719333

Spondyloepiphyseal Dysplasia Congenita

Clinical Characteristics
Ocular Features: 

Patients characteristically have vitreous abnormalities described as veils or stands.  The central vitreous may undergo liquefaction and the peripheral vitreous sometimes creates traction on the retina.  High myopia with progression is common and a significant proportion of patients suffer detachments of the retina even in the absence of myopia.  Lattice degeneration is frequently seen.  Most patients have 20/50 or better vision.

Systemic Features: 

Dwarfism with kyphosis and a barrel chest are characteristic.  The vertebrae are often flattened and malformed and the neck is short.  Delayed ossification in the epiphyses and the os pubis is common.  The disorder can be evident at birth but the full syndrome may not be evident until 3 or 4 years of age.  Radiologic studies are important in making the diagnosis.

Genetics

This is generally considered an autosomal dominant disorder secondary to mutations in the COL2A1 gene impacting type II collagen.  This type of collagen is found primarily in cartilage and vitreous and a number of type II collagenopathy disorders are associated with vitreoretinopathy and joint disease of which Stickler syndrome type I (609508, 108300) is the most common.  Other disorders in this database caused by mutations in COL2A1 are: Kniest dysplasia (156550), Stickler syndromes type I (609508, 108300 ) and II (604841), vitreoretinopathy with epiphyseal dysplasia (120140), and spondyloepiphyseal dysplasia congenita (183900).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cervical fusion is sometimes used when odontoid hypoplasia leads to hypermobility of the cervical vertebrae.  Retinal detachments, of course, need to be repaired.

References
Article Title: 

Retinal Detachment with Lattice Degeneration

Clinical Characteristics
Ocular Features: 

Lattice degeneration of the retina is well known to increase the risk of retinal detachment.  Lattice is found in 40% of all rhegmatogenous retinal detachments but is present in only 7-10% of eye bank eyes.  Lattice degeneration by itself can lead to retinal detachment in less than 1% of patients but the risk increases into the 50% range when myopia is also present. 

A four generation pedigree of 88 individuals has been reported in which 22% had lattice without myopia and 6% developed retinal detachments.  The atrophic changes were progressive since among those of the most recent generation, 9.5% had lattice at an average of 11 years whereas 75% in earlier generations had such changes at an average age of 56 years.

Systemic Features: 

No systemic abnormalities have been reported in this disorder.

Genetics

The reported pedigree showed a clear autosomal dominant pattern with male-to-male transmission.

Rhegmatogenous retinal detachments without lattice have also been reported in autosomal dominant patterns but at least some are due to mutations in COL2A1.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Repair of the retinal detachment is indicated. No information regarding the benefits of prophylactic treatment is available. It may be prudent to counsel patients with this mutation to avoid contact sports and blunt trauma.

References
Article Title: 

Vitreoretinopathy with Epiphyseal Dysplasia

Clinical Characteristics
Ocular Features: 

The axial length is relatively normal in this disorder.  The vitreous is described as highly disorganized but without membranes or the usual lamellar array.  Lattice degeneration may be seen in all quadrants and rhegmatogenous retinal detachments are a lifelong risk, occurring as early as the second decade of life.

Systemic Features: 

This is a unique type of type II collagenopathy with joint and vitreous disease.  Patients do not have the short stature or midface hypoplasia of Kniest dysplasia (156550) nor the optically empty vitreous of Stickler syndrome type I (609508, 108300) caused by mutations in the same gene.  The arthropathy secondary to the epiphyseal dysplasia is mainly in the fingers but some patients do have premature degenerative hip disease.  The fingers are described as ‘stubby’.

Genetics

Mutations in the COL2A1 gene, important for collagen formation, cause various autosomal dominant skeletal dysplasias and some [Stickler type I (609508, 108300) syndrome and Kniest dysplasia (156550)] including this one exhibit vitreoretinopathy.  This is an example of allelic heterogeneity in which various alleles of COL2A1 cause clinically distinguishable phenotypes of bone and ocular disease.  Collagen II is found in cartilage and vitreous perhaps accounting for the associated clinical findings.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Retinal detachments, of course, require repair.  The lifelong risk of detachments requires monitoring.

References
Article Title: 

The phenotypic spectrum of COL2A1 mutations

Nishimura G, Haga N, Kitoh H, Tanaka Y, Sonoda T, Kitamura M, Shirahama S, Itoh T, Nakashima E, Ohashi H, Ikegawa S. The phenotypic spectrum of COL2A1 mutations. Hum Mutat. 2005 Jul;26(1):36-43.

PubMed ID: 
15895462

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