autosomal dominant

Blatt Distichiasis

Clinical Characteristics
Ocular Features: 

Distichiasis, or two rows of eyelashes, is sometimes confused with districhiasis (three rows of lashes) or trichiasis.  True distichiasis often occurs in all four lids and is sometimes associated with other lid anomalies such as ptosis, trichiasis, corneal damage, congenital ectropion and absence of Meibomian glands.  It has occasionally been found only in the lower lids and much more rarely just in the upper lids. In distichiasis, the second row of lashes emerges from the orifices of the Meibomian glands which distinguishes it from acquired trichiasis in which the normally placed lashes are misdirected.  The abnormal lashes are usually thinner, shorter, and less pigmented than the normal lashes.  They number from 3-20 with an average of 12-15.

Systemic Features: 

No consistent systemic associations have been reported.

Genetics

Pedigrees consistent with autosomal dominant inheritance have been reported but no locus or gene has been identified. 

A Chinese family with affected father and one affected male and female offspring has been reported with distichiasis but no lymphedema.  A premature stop codon was found in the FOXC2 transcription gene (16q24.1) in these family members suggesting that they may have had the lymphedema-distichiasis syndrome (153400) instead. 

In some patients with anhidrotic ectodermal dysplasia (224900) there is also a double row of lashes but these exit anterior to the Meibomian gland orifices.

Distichiasis also occurs as part of the lymphedema-distichiasis syndrome (153400) as well as the blepharocheilodontic syndrome (119580). Aberrant rows of eyelashes have been reported in Setleis syndrome (227260).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Electrolysis of misdirected lashes may be used when individual lashes cause corneal damage.

References
Article Title: 

Distichiasis

Fox SA. Distichiasis. Am J Ophthalmol. 1962 Jan;53:14-8.

PubMed ID: 
13894397

Basal Cell Nevus Syndrome

Clinical Characteristics
Ocular Features: 

Eyelid basal-cell carcinomas are the most common ocular finding of this syndrome.  These malignancies may be multiple and may occur on the neck, chest, back, arms and elsewhere on the face.   Those on the eyelids generally have their onset in the postpubertal period, usually by age 35 years, and are often multiple.  Their indolent nature can result in considerably delay in diagnosis, however, and local recurrences are common.  Deformities of the skull often result in the appearance of hypertelorism and proptosis.  Epidermal cysts are found in one-fourth of patients, especially on the palms, but may occur in the tarsal conjunctiva as well.  Intratarsal keratinous eyelid cysts occur in 40% of patients.  Less common reported ocular findings are colobomas, glaucoma, nystagmus, strabismus, and cataracts but these may simply be associations.

Systemic Features: 

This disorder is one of a few in which a disposition to neoplasia is associated with skeletal deformities.  These include bifid ribs, scoliosis, skull deformities such as frontal bossing, increased occipitofrontal circumference, broad nasal root with hypertelorism, mandibular prognathia, and bony cysts.  Medulloblastoma is an infrequent but important sign.  Palmar and/or plantar pits are often present.  Basal cell carcinomas and jaw cysts occur in over 90% of patients by the age of 40 years.  Invasive oral tumors are found in 78% of individuals.

Genetics

This is an autosomal dominant disorder, caused by heterozygous mutations in the PTCH1 gene located on chromosome 9 (9q22.3).  Interestingly, somatic mutations in the PTCH1 gene have also been found in isolated cases with only basal cell carcinoma or medulloblastoma.  Perhaps 40% of cases arise de novo, i.e., without a family history, and older paternal age at conception increases the risk of new mutations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at the location of clinical disease with excision of basal cell carcinomas having the highest priority.  Patients must be monitored throughout life for new lesions as well as recurrence at treated sites. Radiotherapy and non-essential diagnostic X-rays should probably be avoided due to sensitivity to ionizing radiation.

Oral administration of an experimental small molecule signaling inhibitor (GDC-0449 or Vismodegib; Genetech) of the Hedgehog signaling pathway has shown promise in reduction of the number of new lesions as well as shrinkage of existing skin lesions.  BCC lesions have been successfully treated with ingenol mebutate in a single patient.

References
Article Title: 

Eyelid Cysts in Gorlin Syndrome: A Review and Reappraisal

Wolkow N, Jakobiec FA, Yoon MK. Intratarsal Keratinous Eyelid Cysts in Gorlin Syndrome: A Review and Reappraisal. Surv Ophthalmol. 2017 Dec 26. pii: S0039-6257(17)30236-9. doi: 10.1016/j.survophthal.2017.12.007.

PubMed ID: 
29287708

Basal cell nevus syndrome: a brave new world

Goldberg LH, Firoz BF, Weiss GJ, Blaydorn L, Jameson G, Von Hoff DD. Basal cell nevus syndrome: a brave new world. Arch Dermatol. 2010 Jan;146(1):17-9. PubMed PMID: 20083687.

PubMed ID: 
20083687

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. 

Meibomian gland anomalies also contribute to the corneal disease.  The glands may be decreased in number and smaller in size contributing to deficiencies of the tear film and unstable surface wetting.

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.  Surface wetting of the cornea should be periodically evaluated and appropriate topical lubrication used as needed. 

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

Sorsby Pseudoinflammatory Fundus Dystrophy

Clinical Characteristics
Ocular Features: 

Sorsby Pseudoinflammatroy Fundus Dystrophy is characterized by progressive degeneration of the central macula of the retina with edema, hemorrhages and exudates with pigment changes.  The onset is typically in the second to fourth decade with development of a disciform central macular atrophy with white and yellow spots (not drusen).  This is followed by subretinal neovascular membranes in the majority of patients.  Further degeneration occurs over years and can spread from the center to the periphery of the retina with a corresponding visual field defect.  Night blindness or difficulties adapting to changes in light intensity may be noted before the central macular degeneration occurs.  In histopathologic studies, a subretinal deposit can be observed in Bruchs membrane.

Systemic Features: 

No general systemic manifestations are associated with Sorsby Pseudoinflammatory Fundus Dystrophy.

Genetics

Sorsby Pseudoinflammatory Fundus Dystrophy is an autosomal dominant disorder, caused by mutations in the TIMP3 gene, located at 22q12.1-q13.2.  Evidence for a separate recessive form (264420) is somewhat refuted by the fact that genotyping found heterozygosity of the TIMP3 mutation in some families.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

In patients with early stages of the disease, a daily dose of 50,000 IU Vitamin A given by mouth has been shown to reverse the symptoms of night blindness.  Treatment with anti-angiogenic agents or steroids has shown improvement in visual acuity in some patients. Patients with decreased vision may find benefit with low vision aids.

References
Article Title: 

Sorsby's fundus dystrophy

Hamilton WK, Ewing CC, Ives EJ, Carruthers JD. Sorsby's fundus dystrophy. Ophthalmology 1989 Dec;96(12):1755-62.

PubMed ID: 
2695876

Sclerocornea

Clinical Characteristics
Ocular Features: 

This is a disorder of the cornea and anterior chamber that is sometimes considered to be a form of anterior segment or mesenchymal dysgenesis.  The primary feature is corneal clouding, most prominent peripherally and extending to the central cornea to a variable extent.  Vascular arcades are usually present over the area of clouding and there is no clear limbal demarcation.  Corneal fibers are often disorganized and larger than normal.  The anterior chamber may appear shallow and the iris usually has a flat appearance, often with a posterior embryotoxon.  Iris processes to the cornea and anterior synechiae are frequently present.  Some degree of microcornea has also been noted in many cases.  Rotary and horizontal nystagmus are uncommon. Sclerocornea may be a feature of cornea plana as well and the distinction between these disorders is unclear, especially in reported dominant pedigrees in which hyperopia is a feature.

Most cases are bilateral but there is often considerable asymmetry between the two eyes.  Visual acuity is dependent on the extent of corneal opacification but may be normal.  It is not a progressive disease.

Systemic Features: 

No systemic abnormalities have been reported.  However, sclerocornea can be a feature of numerous somatic and chromosomal disorders (e.g., oculocerbral syndrome with hypopigmentation (257800 ).

Genetics

No DNA mutations have as yet been found.  Most cases occur sporadically, and others are part of anterior chamber dysgenesis disorders.  However, rare autosomal dominant pedigrees have been reported in which the degree of opacification and anterior chamber anomalies are not as severe as those in which the pattern is most consistent with autosomal recessive inheritance.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Severe cases in which the central media is compromised may require corneal transplantation.  Glaucoma requires treatment as well.

References
Article Title: 

A review of anterior

Idrees F, Vaideanu D, Fraser SG, Sowden JC, Khaw PT. A review of anterior
segment dysgeneses.
Surv Ophthalmol. 2006 May-Jun;51(3):213-31. Review.

PubMed ID: 
16644364

Hereditary sclerocornea

Elliott JH, Feman SS, O'Day DM, Garber M. Hereditary sclerocornea. Arch
Ophthalmol. 1985 May;103(5):676-9.

PubMed ID: 
3994576

Axenfeld-Rieger Syndrome, Type 1

Clinical Characteristics
Ocular Features: 

Axenfeld-Rieger syndrome consists of a heterogeneous group of disorders with overlapping features.  Common to all types are the presence of ocular, dental, facial, skeletal abnormalities and autosomal dominant inheritance.  Anterior chamber dysgenesis of some form is universally present and severe glaucoma occurs in 50% of patients.  This may have its onset in childhood with typical symptoms of congenital glaucoma such as photophobia, excessive tearing and corneal clouding.  Hypoplasia of the iris is common and when progressive may result in an ectopic pupil and/or pseudopolycoria.  Iris insertion and Schwalbe's line are often anteriorly displaced with iridocorneal adhesions, a pattern that leads to the inclusion of this disorder among those with iridogoniodysgenesis or anterior chamber dysgenesis.  Pupillary ectropion of the posterior pigmented layer of the iris may be seen.

There is considerable clinical overlap among conditions with iris dysgenesis.  Some patients with typical systemic features of Axenfeld-Rieger syndrome may even have typical anterior chamber features of Axenfeld-Rieger anomaly in one eye and severe iris hypoplasia resembling aniridia in the other.

Systemic Features: 

Dental anomalies and mid-facial hypoplasia secondary to underdeveloped maxillary sinuses are among the most common systemic features in type 1.  The nasal root often appears abnormally broad and the lower lip appears to protrude. The teeth are frequently small and conical in shape with wide spaces between them (diastema).  Some teeth may be missing.  The umbilicus may fail to involute normally and retains excessive, redundant skin that sometimes leads to the erroneous diagnosis of an umbilical hernia for which unnecessary surgery may be performed.  Hypospadius is frequently present while cardiac defects, sensorineural deafness, and anal stenosis are less common.

Genetics

There is clinical and genetic heterogeneity in this syndrome and precise classification of many families remains elusive without knowing the genotype.  Mutations in at least four genes are responsible and all are are responsible for phenotypes transmitted in autosomal dominant patterns.  Type 1 discussed here is caused by a mutation in the homeobox transcription factor gene, PITX2, located at 4q25-q26.  A type of iris hypoplasia (IH)/iridogoniodysgenesis (IGDS) (IRID2; 137600) disorder has been classified separately but is caused by a mutation in PITX2 as well and many cases have the same systemic features.  Mutations in the same gene have also been found in ring dermoid of the cornea (180550) and in some cases of Peters anomaly (604229).

RIEG2 (601499) is rare but a deletion of 13q14 has been reported in several cases.  Mapping in a large family with 11 affected individuals yielded a locus in the same region.  Clinical signs overlap types 1 and 3 with dental, craniofacial, and ocular features, but with hearing impairment and rare umbilical anomalies.

Mutations in the FOXC1 gene (6p25) may be responsible for RIEG3 (602482).  However, a family has been reported with a severe 'Axenfeld-Rieger phenotype' in which a digenic etiology may have been responsible: patients had mutations in both FOXC1 and PITX2

Heterozygous mutations in the PRDM5 gene (4q25-q26) have been identified in 4 members of a Pakistani family with typical features of the Axenfeld-Rieger syndrome. It is labeled type 4 Axenfeld-Rieger syndrome in this database. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The presence of glaucoma requires prompt and vigorous treatment but control is difficult with blindness too often the result.  Oral surgery may be beneficial for dental problems.  Low vision aids can be useful.

References
Article Title: 

Axenfeld-Rieger syndrome

Seifi M, Walter MA. Axenfeld-Rieger syndrome. Clin Genet. 2017 Oct 3. doi: 10.1111/cge.13148. [Epub ahead of print] Review.

PubMed ID: 
28972279

The Rieger syndrome

Jorgenson RJ, Levin LS, Cross HE, Yoder F, Kelly TE. The Rieger syndrome. Am J Med Genet. 1978;2(3):307-18.

PubMed ID: 
263445

Alport Syndrome (Collagen IV-Related Nephropathies)

Clinical Characteristics
Ocular Features: 

X-linked Alport syndrome is a basement membrane disease with important ocular manifestations.  The lens is usually normal at birth but lens opacities eventually occur in a significant number of individuals with the most characteristic type being anterior polar in location.  Involvement of the anterior lens capsule often results in bilateral anterior lenticonus (25%) and may be progressive.  It is claimed that the severity of the lenticonus is a valuable marker in judging the overall disease severity.  In early stages it may be difficult to detect but its presence is suggested by an 'oil droplet' reflex during retinoscopy or slit lamp examination.  All males with anterior lenticonus should be evaluated for Alport syndrome. 

Posterior polymorphous corneal dystrophy and posterior subcapsular opacities have also been noted.  The defect in basement membranes may lead to recurrent corneal erosions, even in children, which can be incapacitating and difficult to treat.  Involvement of Bruch's membrane has been considered the source of retinal pigment epithelial changes described as a flecked retina, or 'fundus albipunctatus', found in 85% of patients.  More recent evidence using OCT suggests that the dot-and-fleck retinopathy results primarily from abnormalities in the internal limiting membrane and the nerve fiber layer.  The yellowish and/or whitish flecks are most commonly located in the posterior pole and particularly in the macula.  There is no night blindness or visual impairment from the retinal involvement.  Fluorescein angiography shows patchy areas of hyperfluorescence.  The amount of visual impairment depends primarily on the extent of lens involvement.

Termporal macular thinning occurs to some extent in all types of Alport syndrome based on OCT findings.   In one series all patients with X-linked disease had temporal thinning suggesting that this might be a useful diagnostic sign.  However, similar thinning is also seen in Leber hereditary optic neuropathy (535000), and dominant optic atrophy (165500).

Systemic Features: 

Nephritis with hematuria secondary to basement membrane disease of the glomeruli is the most life threatening aspect of this disorder.  It occurs in both sexes but more commonly in males in which it has an earlier onset.  Progressive sensorineural hearing loss beginning with high frequencies occurs in many patients, often with subtle onset in childhood, but many adults retain some hearing capacity.  In males, the onset of hearing loss often occurs before kidney disease is evident.  Hearing loss is less frequent and less severe in females.  However, there is considerable clinical and genetic heterogeneity and not all patients have the complete syndrome of nephritis, deafness and ocular disease.  In fact, it has been suggested that Alport syndrome can be subtyped into at least six categories based on the extent of organ involvement.

Genetics

Alport syndrome is a member of a group of disorders known as collagen IV-related nephropathies.  It is a genetically heterogeneous disease with 85% inherited in an X-linked pattern and most of the remainder occurring in an autosomal recessive pattern and only a few seemingly autosomal dominant.  All result from a defect in type IV collagen found in basement membranes.  About 80% of cases have a mutation in the COL4A5 gene which is located at Xq22.3.  Males seem to be more severely affected than females in the X-linked form of the disease but clearly this disorder affects both sexes reflecting the genetic heterogeneity, much of which remains to be delineated.  The autosomal disease generally results from mutations in the COL4A3 or COL4A4 genes and has been seen in both recessive and dominant patterns of transmission.

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

Renal transplantation can be lifesaving but a minority of individuals develop a specific antiglomerular basement membrane antibody (anti-GBM) that may lead to graft rejection.  Allograft survival rates are generally excellent though.  Lens extraction is beneficial where the media is compromised.

References
Article Title: 

Alport syndrome: a genetic study of 31 families

M'Rad R, Sanak M, Deschenes G, Zhou J, Bonaiti-Pellie C, Holvoet-Vermaut L,
Heuertz S, Gubler MC, Broyer M, Grunfeld JP, et al. Alport syndrome: a genetic
study of 31 families.
Hum Genet. 1992 Dec;90(4):420-6.

PubMed ID: 
1483700

Alagille Syndrome

Clinical Characteristics
Ocular Features: 

The ocular findings in Alagille syndrome are often of little functional significance but can be sufficient to suggest the diagnosis without further study of the systemic features.  Posterior embryotoxon is found in 95% of individuals while iris abnormalities such as ectopic pupils are seen in 45%, abnormal fundus pigmentation is common (hypopigmentation in 57%, diffuse pigment speckling in 33%), and optic disc anomalies have been reported in 76%.  One study found that 90% of individuals have optic disk drusen by ultrasonography.  The anterior chamber anomalies are considered by some to be characteristic of Axenfeld anomaly.  The presence of these ocular findings in children with cholestasis should suggest Alagille syndrome.  Ocular examination of the parents can also be helpful in this autosomal dominant disorder as some of the same changes are present in one parent in more than a third of cases.

Systemic Features: 

A variety of  systemic features, some of them serious malformations, occur in Alagille syndrome.  Among the most common is a partial intrahepatic biliary atresia leading to cholestasis and jaundice.  Skeletal malformations include 'butterfly' vertebrae, shortened digits, short stature, a broad forehead, and a pointed chin.  The tip of the nose may appear bulbous.  These features have suggested to some that there is a characteristic facial dysmorphology.  Vascular malformations are common including aneurysms affecting major vessels, valvular insufficiency, coarctation of the aorta, and stenosis and these are often responsible for the most serious health problems.  In fact, vascular events have been reported to be responsible for mortality in 34% of one cohort.  Chronic renal insufficiency develops in a minority of patients.  This disorder should always be considered in children with cholestasis, especially when accompanied by cystic kidney disease.  Brain MRIs may show diffuse or focal hyperintensity of white matter even in the absence of hepatic encephalopathy.

Genetics

This is an autosomal dominant condition secondary to various mutations in the JAG1 gene located on chromosome 20 (20p12).  Penetrance is nearly 100% but there is considerable variation in expression.  A far less common variant of this disorder, ALGS2 (610205), is caused by a mutation in the NOTCH2 gene (1p13-p11).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No cure is available but individual organ disease may be treatable.  The ocular abnormalities generally do not cause vision difficulties.

Reversible of white matter changes has been noted in a single child following liver transplantation.

 

References
Article Title: 

CT-defined phenotype of pulmonary artery

Rodriguez RM, Feinstein JA, Chan FP. CT-defined phenotype of pulmonary artery
stenoses in Alagille syndrome
. Pediatr Radiol. 2016 Apr 4. [Epub ahead of print].

PubMed ID: 
27041277

Alagille syndrome: clinical and ocular pathognomonic features

El-Koofy NM, El-Mahdy R, Fahmy ME, El-Hennawy A, Farag MY, El-Karaksy HM. Alagille syndrome: clinical and ocular pathognomonic features. Eur J Ophthalmol. 2010 Jul 28. pii: 192165A5-8631-4C06-9C47-9AD63688B02A. [Epub ahead of print]

PubMed ID: 
20677167

Ocular abnormalities in Alagille syndrome

Hingorani M, Nischal KK, Davies A, Bentley C, Vivian A, Baker AJ, Mieli-Vergani G, Bird AC, Aclimandos WA. Ocular abnormalities in Alagille syndrome. Ophthalmology. 1999 Feb;106(2):330-7.

PubMed ID: 
9951486

Cornea Plana

Clinical Characteristics
Ocular Features: 

Enlargement of the cornea with flattening is characteristic of cornea plana although corneal diameters vary widely.  Corneal thinning may be present.  The mean corneal refraction value at the horizontal median has been measured at 37.8 D for the dominant form (CNA 1) of the disease, compared with 29.9 D for the recessive form (CNA 2) and 43.4 D for controls accounting for the hyperopia found among many patients.  The limbal margin may be widened with blurring of the corneolimbal junction.  Recessive cases can often be distinguished from the dominant ones by the presence of a central 5 mm area of thickening and clouding.  Recessively inherited cases are also more likely to have anterior synechiae and other iris anomalies.  Early onset arcus has been reported.

Vision in mild cases may be as good as 20/25 or 20/30 but considerably worse in recessive cases with central opacification.  Glaucoma may occur in older individuals.

Systemic Features: 

None reported.

Genetics

Multiple families in Finland have been reported with inheritance patterns suggesting autosomal recessive inheritance (CNA2).  The gene has been mapped to chromosome 12 (12q21) in a region containing the KERA gene.  A Cuban family with autosomal dominant cornea plana (CDA1) also yielded linkage to 12q where the recessive gene is located.  However, this locus could be excluded in two Finnish families suggesting that at least 3 autosomal mutations may be responsible.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Correction of the hyperopia may be helpful.  Patients need to be followed and treated for glaucoma if it develops.  Outcomes of penetrating keratoplasty are not available but the procedure carries increased risk since the stroma is often thinner than normal. 
 

References
Article Title: 

The genetics of cornea plana congenita

Tahvanainen, E.; Forsius, H.; Kolehmainen, J.; Damsten, M.; Fellman, J.; de la Chapelle, A. :  The genetics of cornea plana congenita. J. Med. Genet. 33: 116-119, 1996.

PubMed ID: 
8929947

Mutations in KERA, encoding keratocan, cause cornea plana

Pellegata, N. S.; Dieguez-Lucena, J. L.; Joensuu, T.; Lau, S.; Montgomery, K. T.; Krahe, R.; Kivela, T.; Kucherlapati, R.; Forsius, H.; de la Chapelle, A. :  Mutations in KERA, encoding keratocan, cause cornea plana. Nature Genet. 25: 91-95, 2000.

PubMed ID: 
10802664

Macrophthalmia, Colobomatous, with Microcornea

Clinical Characteristics
Ocular Features: 

Several families have been reported in which multiple family members had various ocular malformations including bilateral extensive colobomas from the iris to the optic nerve, increased axial length, microcornea, posterior staphylomas, and high myopia. In a three generation Turkish family with 13 affected individuals other features such as flatter than normal corneas, shallow anterior chambers and iridocorneal angle abnormalities with elevated intraocular pressures were described.  

Systemic Features: 

None have been reported.

Genetics

This is a contiguous gene deletion disorder located at 2p22.2 which involves the CRIM1 and FEZ2 genes.  Penetrance is high in this presumed autosomal dominant condition.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known.
 

References
Article Title: 

Pages

Subscribe to RSS - autosomal dominant