colobomas

Schurrs-Hoeijmakers Syndrome

Clinical Characteristics
Ocular Features: 

Mild structural variants are common among the periocular structures.  There is marked hypertelorism in many individuals, the eyebrows are full and highly arched, the eyelashes are long, and the lid fissures slant downward.  Ptosis is often evident.  Myopia, nystagmus, and strabismus are frequently noted.  Colobomas have been reported.

Systemic Features: 

There is general psychomotor delay in development.  Intellectual disability (with IQs in the 50s) and hypotonia are common.  Speech is poor and sometimes absent.   Behavioral anomalies such as aggression and features of autism have been reported.  The anterior hairline is low, the mouth is wide with downturned corners, the nose is bulbous, the ears are large and low-set, and the teeth are often widely-spaced.  Cryptorchidism is common among males.

Renal and cardiac defects are common.  Brain MRIs often show cerebellar hypoplasia, enlarged ventricles, and nonspecific white matter changes.

Genetics

No treatment for the general disorder has been published.  Physical and speech therapy might be helpful

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment for the general disorder has been published.  Physical and speech therapy might be helpful.

References
Article Title: 

Clinical delineation of the PACS1-related syndrome--Report on 19 patients

Schuurs-Hoeijmakers JH, Landsverk ML, Foulds N, Kukolich MK, Gavrilova RH, Greville-Heygate S, Hanson-Kahn A, Bernstein JA, Glass J, Chitayat D, Burrow TA, Husami A, Collins K, Wusik K, van der Aa N, Kooy F, Brown KT, Gadzicki D, Kini U, Alvarez S, Fernandez-Jaen A, McGehee F, Selby K, Tarailo-Graovac M, Van Allen M, van Karnebeek CD, Stavropoulos DJ, Marshall CR, Merico D, Gregor A, Zweier C, Hopkin RJ, Chu YW, Chung BH, de Vries BB, Devriendt K, Hurles ME, Brunner HG; DDD study. Clinical delineation of the PACS1-related syndrome--Report on 19 patients. Am J Med Genet A. 2016 Mar;170(3):670-5.

PubMed ID: 
26842493

Microphthalmia, Syndromic 5

Clinical Characteristics
Ocular Features: 

One or both eyes may be small, sometimes resembling clinical anophthalmia. Other ocular anomalies such as coloboma, microcornea, cataracts, and hypoplasia or agenesis of the optic nerve have been reported.

A pigmentary retinopathy has been described.  The retinal vessels are often attenuated and sometimes sparse.  The optic nerves and chiasm are frequently absent or hypoplastic as seen on the MRI.  ERG and VEP responses are inconsistent but are generally abnormal indicating photoreceptor malfunction.  

Systemic Features: 

Patients have a variety of systemic abnormalities including pituitary dysfunction, joint laxity, hypotonia, agenesis of the corpus callosum, and seizures.  Hypothyroidism and deficiencies of growth hormone, gonadotropins, and cortisol are present in some patients.  Developmental delay and cognitive impairment are frequently present but mental functioning is normal in some patients.  The genitalia of males are often underdeveloped.  Patients are often short in stature.

Genetics

This is an autosomal dominant condition secondary to heterozygous mutations in the OTX2 gene (14q22.3).  A variety of point mutations as well as microdeletions involving the OTX2 gene have been reported.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the syndrome but surgical and/or endocrinological treatment may be used to correct individual features.  Special education and low vision aids may be helpful in selected patients.

References
Article Title: 

Heterozygous mutations of OTX2 cause severe ocular malformations

Ragge NK, Brown AG, Poloschek CM, Lorenz B, Henderson RA, Clarke MP, Russell-Eggitt I, Fielder A, Gerrelli D, Martinez-Barbera JP, Ruddle P, Hurst J, Collin JR, Salt A, Cooper ST, Thompson PJ, Sisodiya SM, Williamson KA, Fitzpatrick DR, van Heyningen V, Hanson IM. Heterozygous mutations of OTX2 cause severe ocular malformations. Am J Hum Genet. 2005 Jun;76(6):1008-22. Apr 21. Erratum in: Am J Hum Genet. 2005 Aug;77(2):334..

PubMed ID: 
15846561

Joubert Syndrome and Related Disorders

Clinical Characteristics
Ocular Features: 

Ocular findings like systemic features are highly variable both within and between families.  Vision can be normal but in other patients it is severely reduced to the range of 20/200.  The pupils may respond sluggishly or even paradoxically to light.  ERG recordings have been reported to be normal in some patients, but absent or reduced in others.  The fundus appearance is often normal but in other individuals the pigmentation is mottled, the retinal arterioles are attenuated, and the macula has a cellophane maculopathy.  Drusen and colobomas are sometimes seen in the optic nerve while occasional patients have typical chorioretinal colobomas.  The eyebrows are often highly arched.

The oculomotor system is frequently involved.  Apraxia to some degree is common with most patients having difficulty with smooth pursuit and saccadic movements.  Compensatory head thrusting is often observed.  A pendular nystagmus may be present while esophoria or esotropia is present in many patients.

Systemic Features: 

There is a great deal of clinical heterogeneity in this group of ciliary dyskinesias.  Developmental delays, cognitive impairment, truncal ataxia, breathing irregularities, and behavioral disorders are among the more common features.  Hyperactivity and aggressiveness combined with dependency require constant vigilance and care.  Postaxial polydactyly is a feature of some cases.  Hypotonia is evident at birth.  Liver failure and renal disease develop in many individuals.  Neuroimaging of the midbrain-hindbrain area reveals agenesis or some degree of dysgenesis of the vermis with the 'molar tooth sign' in the isthmus region considered to be a diagnostic sign.  The fourth ventricle is usually enlarged while the cerebellar hemispheres may be hypoplastic.

The facies features are said to be distinctive in older individuals.  The face appears long with frontal prominence due to bitemporal narrowing, the nasal bridge and tip are prominent, the jaw is prominent, the lower lip protrudes, and the corners of the mouth are turned down.

Genetics

This is a clinically and genetically heterogeneous group of disorders with many overlapping features.  Most disorders in this disease category, known as JSRD, are inherited in an autosomal recessive pattern.  Mutations in at least 34 genes have been identified.  One, OFD1 (300804), is located on the X chromosome (Xp22.2).

There are significant clinical similarities to Meckel syndrome (249000) and Smith-Lemli-Opitz syndrome (270400).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is mostly for specific symptoms such as respiratory distress, renal disease, speech and physical therapy, low vision, and hepatic failure.

References
Article Title: 

Joubert Syndrome: Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center

Brooks BP, Zein WM, Thompson AH, Mokhtarzadeh M, Doherty DA, Parisi M, Glass IA, Malicdan MC, Vilboux T, Vemulapalli M, Mullikin JC, Gahl WA, Gunay-Aygun M. Joubert Syndrome: Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center. Ophthalmology. 2018 Jul 25. pii: S0161-6420(18)30686-9. doi: 10.1016/j.ophtha.2018.05.026. [Epub ahead of print].

PubMed ID: 
30055837

Ophthalmological findings in Joubert syndrome

Sturm V, Leiba H, Menke MN, Valente EM, Poretti A, Landau K, Boltshauser E. Ophthalmological findings in Joubert syndrome. Eye (Lond). 2010 Feb;24(2):222-5.

PubMed ID: 
19461662

Microphthalmia, Syndromic 1

Clinical Characteristics
Ocular Features: 

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

Systemic Features: 

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

Genetics

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

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

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

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

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

References
Article Title: 

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: 
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