shallow orbits

Coloboma, Microphthalmia, Albinism, and Deafness

Clinical Characteristics
Ocular Features: 

A 5 year old male has been described with uveal colobomas in microphthalmic eyes plus small corneas with a pannus, dense cataracts, translucent irides, and hypopigmentation of the skin, hair and eyes.  A brain MRI showed hypoplasia of the optic nerves and chiasm.   

A 9 month old female from another family had severe microphthalmia and small optic nerves.  The internal ocular features were not reported.

Systemic Features: 

The complete phenotype is uncertain since it is based on only two reported and unrelated individuals.  The head circumference one one patient was consistent with macrocephaly accompanied by frontal bossing, shallow orbits, preauricular pits and posteriorly rotated ears.  A skeletal survey revealed evidence for osteopetrosis.  He had a sensorineural hearing deficit said to be congenital in onset.

The other patient, a 9 month old female, belonged to another nonconsanguineous family, and had similar skeletal and craniofacial features with the addition of micrognathia and hypotonia.  Congenital neurosensory hearing loss and general lack of pigmentation were noted.

All four parents have congenital sensorineural hearing loss, blue irides and fair skin with premature graying of hair.  Four sibs in the two families have phenotypes similar to that of the parents.  Only one child, a female, had no features of the phenotype.

Genetics

This condition, so far reported only in a male and a female in unrelated families, is the result of doubly heterozygous mutations in the MITF gene (3p13).  One mutation that causes Waardenburg syndrome 2  (WS2A) (193510) is combined with a dominant-negative allele (c.952_954delAGA [p.Arg318del]) to produce the phenotype.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Cole-Carpenter Syndrome 2

Clinical Characteristics
Ocular Features: 

Postnatally the eyes are prominent and hypertelorism has been reported.  The palpebral fissures slant downward and the root of the nose is angular. 

Systemic Features: 

This is primarily a skeletal disorder with impaired skull ossification and multiple bone fractures of prenatal origin.  It is sometimes confused with forms of osteogenesis imperfecta.  The skull is poorly ossified and frequent diaphyseal fractures of the long bones occur leading to motor delays and short stature.  Rib fractures are sometimes seen. Intelligence seems to be normal.  A receding chin has been noted and the hard palate is highly vaulted.  The midface is flat.

Genetics

This disorder results from compound heterozygous mutations in the SEC24D gene (4q26).  Only a few patients have been reported.

For a somewhat similar but autosomal dominant disorder see Cole-Carpenter Syndrome 1 (112240).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Physical activity should be restricted to noncontact sports and where the cranium has ossification defects a helmet should be worn.  Fractures should be appropriately treated.

References
Article Title: 

Mutations in SEC24D, Encoding a Component of the COPII Machinery, Cause a Syndromic Form of Osteogenesis Imperfecta

Garbes L, Kim K, Riess A, Hoyer-Kuhn H, Beleggia F, Bevot A, Kim MJ, Huh YH, Kweon HS, Savarirayan R, Amor D, Kakadia PM, Lindig T, Kagan KO, Becker J, Boyadjiev SA, Wollnik B, Semler O, Bohlander SK, Kim J, Netzer C. Mutations in SEC24D, Encoding a Component of the COPII Machinery, Cause a Syndromic Form of Osteogenesis Imperfecta. Am J Hum Genet. 2015 Mar 5;96(3):432-9.

PubMed ID: 
25683121

Cole-Carpenter Syndrome 1

Clinical Characteristics
Ocular Features: 

The bony orbits are shallow and the eyes appear prominent as part of the facial and skull bone deformities.  The proptosis may be progressive and eventually interfere with blinking and normal surface wetting of the cornea. 

Systemic Features: 

This condition may superficially resemble osteogenesis imperfecta with osseous deformities and frequent fractures.  However, the occurrence of craniosynostosis and hydrocephalus helps to distinguish it.  Cranial sutures may be slow to fuse and macrocephaly has been described.  Communicating hydrocephalus can be a feature and may require shunting.  Some patients have osteopenia of the long bones that fracture easily.

The facial features are said to be distinctive with midface hypoplasia, low-set ears, micrognathia, and, of course, prominent globes.  Growth may be subnormal and a variety of limb bone and digital anomalies have been described.  Intelligence is normal, however.

Genetics

This condition is the result of heterozygous mutations in the P4HB gene (17q25.3) (PDI family).

See Cole-Carpenter Syndrome 2 (616294) for a somewhat similar disorder that is recessively inherited.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

A frontal craniectomy may be necessary during early childhood to relieve the proptosis particularly when blinking is impaired.  Patients must be followed for the development of communicating hydrocephalus.  Long bone fractures require prompt treatment. 

References
Article Title: 

Osteogenesis Imperfecta, Type VII

Clinical Characteristics
Ocular Features: 

Shallow orbits sometimes lead to severe and even progressive proptosis.  Bluish sclerae are sometimes present.

Systemic Features: 

Infants may be born with multiple fractures and adults are often short in stature.  Hypoplasia of the midface, frontal bossing, sutural craniosynostosis, hydrocephalus, and shallow orbits are frequently present and contribute to what is sometimes considered a distinctive facial dysmorphism.  Dentinogenesis imperfecta and hearing loss are variable features.  Neurological development is normal.

Multiple fractures occur and may result in marked long bone deformities, scoliosis, and short stature.  When the ribs are involved, respiratory insufficiency may result and can be responsible for early death.  Type VII osteogenesis imperfecta is sometimes considered a lethal form of OI. 

Genetics

Homozygous mutations in the CRTAP gene (3p22.3) are responsible for this condition.  This gene codes for a cartilage-associated protein and in mice is highly expressed in chondrocytes at growth plates and around the chondroosseous junction.  

This condition has been confused with Cole-Carpenter 1 syndrome (112240) but the latter is due to heterozygous mutations in P4HB (17q25.3) (PDI gene family).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Fractures require stabilization and hydrocephalus, if present, needs to be treated promptly.  Extreme proptosis can lead to inadequate hydration of the eye (especially the cornea) that may require lid surgery or orbital reconstruction.

References
Article Title: 

CRTAP mutation in a patient with Cole-Carpenter syndrome

Balasubramanian M, Pollitt RC, Chandler KE, Mughal MZ, Parker MJ, Dalton A, Arundel P, Offiah AC, Bishop NJ. CRTAP mutation in a patient with Cole-Carpenter syndrome. Am J Med Genet A. 2015 Jan 21. doi: 10.1002/ajmg.a.36916. [Epub ahead of print].

PubMed ID: 
25604815

New case of Cole-Carpenter syndrome

Amor DJ, Savarirayan R, Schneider AS, Bankier A. New case of Cole-Carpenter syndrome. Am J Med Genet. 2000 Jun 5;92(4):273-7. Review.

PubMed ID: 
10842295

Roberts Syndrome

Clinical Characteristics
Ocular Features: 

The eyes often appear prominent as the result of shallow orbits.  Hypertelorism and microphthalmia can be present.  The sclerae can have a bluish hue.   Cataracts and central corneal clouding plus scleralization and vascularization of the peripheral corneas are sometimes seen.  Lid colobomas and down-slanting palpebral fissures may be present.

Systemic Features: 

Failure of both membranous and long bones to grow properly lead to a variety of abnormalities such as craniosynostosis, hypomelia, syndactyly, oligodactyly, malar hypoplasia, short neck, micrognathia, and cleft lip and palate.  The long bones of the limbs may be underdeveloped or even absent.  Contractures of elbow, knee, and ankle joints are common as are digital anomalies.  Low birth weight and slow postnatal growth rates are usually result in short stature.  The hair is often sparse and light-colored. 

Mental development is impaired and some children are diagnosed to have mental retardation.  Cardiac defects are common.  Facial hemangiomas are often present as are septal defects and sometimes a patent ductus arteriosus.  External genitalia in both sexes appear enlarged.  The kidneys may be polycystic or horseshoe-shaped.

Genetics

This is an autosomal recessive condition caused by mutations in the ESCO2 gene (8p21.1).  Mutations in the same gene are also responsible for what some have called the SC phocomelia syndrome (269000) which has a similar but less severe phenotype.  Some consider the two disorders to be variants of the same condition and they are considered to be the same entity in this database.  The gene product is required for structural maintenance of centromeric cohesion during the cell cycle.  Microscopic anomalies of the centromeric region (puffing of the heterochromatic regions) are sometimes seen during cell division.

The Baller-Gerold syndrome (218600) has some phenotypic overlap with Roberts syndrome but is caused by mutations in a different gene (RECQL4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Severely affected infants may be stillborn or die in infancy.  Other individuals live to adulthood.  There is no treatment for this condition beyond specific correction of individual anomalies.

References
Article Title: 

Microphthalmia, Syndromic 4

Clinical Characteristics
Ocular Features: 

In several generations of an Irish family, 7 males with clinical anophthalmia were identified.  Ankyloblepharon was also present and X-rays of the orbits were identified.

Systemic Features: 

One patient was born with a cleft soft palate and had preauricular skin tags.  All individuals were considered to be mentally retarded with IQ's less than 50.

Genetics

MCOPS4 is an X-linked condition based on a single reported family.  The responsible mutation has not been identified but a locus (Xq27-q28) likely to contain the gene has been identified by multipoint linage analysis.

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

No treatment is known.

References
Article Title: 
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