proptosis

Elsahy-Waters Syndrome

Clinical Characteristics
Ocular Features: 

Structural anomalies of periocular tissues are common.  Hypertelorism, proptosis, and telecanthus may be striking.  Colobomas or clefts of the upper lid are frequently seen.  The eyebrows are bushy and synophyrs may be present across a broad nasal bridge.  Megalocornea, downslanting lid fissures, glaucoma and cataracts have also been reported but are uncommon.

Systemic Features: 

The skull has been described as brachycephalic.  The midface is flat due to maxillary hypoplasia. The lower jaw is prominent and some patients have mandibular prognathism.  A bifid uvula or partial clefting of the palate are common.  Low-set and posteriorly rotated ears have been reported as well.

 Both pectus excavatum and pectus carinatum have been described.  The teeth have dysplastic enamel and often have obliterated pulp chambers and dental cysts.  Their roots may be shortened and deformed and they are often lost early.  Vertebrae may have fusion of the spines, particularly in the cervical area.  A mixed type of hearing loss is common and some degree of intellectual disability is often evident, especially in older individuals.  Most males have some degree of hypospadias.  Cryptorchidism has been reported in one individual.

Brain imaging in one case revealed no abnormalities.

Genetics

This disorder results from biallelic mutations in the CDH11 gene (16q21).  The parents have been consanguineous in most reports and no vertical transmission has been documented making autosomal recessive the most likely pattern of inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general disorder has been reported.  Eyelid and palatal defects may be surgically repaired and assistive hearing devices may be of benefit.  Special education is also likely to be helpful.

References
Article Title: 

Meester-Loeys Syndrome

Clinical Characteristics
Ocular Features: 

A variety of nondiagnostic facial features are present at birth including hypertelorism, downward slanting lid fissures, proptosis, frontal bossing, and midface hypoplasia.

Systemic Features: 

Aortic aneurysms with or without dissection have been diagnosed as early as 1 year of age but may not be apparent until teenage years.  Pectus deformities, joint hypermobility, and skin striae may be seen. Hypertrichosis, evidence of skeletal dysplasia such as hip dislocation, platyspondyly, phalangeal dysplasia, joint hypermobility, relative macrocephaly, dysplastic epiphyses of the long bones, and cervical spine instability are often present.

Genetics

This X-linked disorder is caused by a mutation in the BGN gene (Xp28).  No male-to-male transmission has been reported although both sexes are affected.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

Individual deformities might be surgically repaired.

References
Article Title: 

Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections

Meester JA, Vandeweyer G, Pintelon I, Lammens M, Van Hoorick L, De Belder S, Waitzman K, Young L, Markham LW, Vogt J, Richer J, Beauchesne LM, Unger S, Superti-Furga A, Prsa M, Dhillon R, Reyniers E, Dietz HC, Wuyts W, Mortier G, Verstraeten A, Van Laer L, Loeys BL. Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections. Genet Med. 2016 Sep 15. doi: 10.1038/gim.2016.126. [Epub ahead of print].

PubMed ID: 
27632686

Marfan Lipodystrophy Syndrome

Clinical Characteristics
Ocular Features: 

The eyes are large resulting in high myopia and apparent proptosis.  The palpebral fissures usually slant downwards and ectopia lentis may be present.  

Systemic Features: 

This syndrome shares many features of Marfan syndrome (154700) such as tall stature, dislocated lenses, myopia, high arched palate, aortic root and valvular anomalies, arachnodactyly, high arched palate, lax and hyperextensible joints, and pectus excavatum.  In addition, MFLS patients have retrognathia, intrauterine growth retardation, scarce or absent subcutaneous fat, a progeroid facies, and sometimes macrocephaly.  Postnatal growth and psychomotor development have been reported to be normal albeit with slow weight gain.

Genetics

This condition is transmitted as an autosomal dominant as the result of heterozygous mutations in FBN1 (15q21.1).  The same gene is mutated in 6 other conditions in this database including Marfan Syndrome (154700) with which it shares some features.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the overall condition but individual features such as ectopia lentis can be surgically corrected.  Patients with high myopia require frequent evaluation for retinal tears and detachments.  Cardiac monitoring likewise is important to monitor for aortic valve prolapse and dilation of the aortic root.

References
Article Title: 

CHOPS Syndrome

Clinical Characteristics
Ocular Features: 

There is usually some degree of proptosis and apparent hypertelorism.  The eyebrows are bushy and the eyelashes are luxurious.  One of three patients had cataracts and another had mild optic atrophy.

Systemic Features: 

The overall facial appearance may resemble Cornelia de Lange syndrome with hypertrichosis and a coarse, round facies.  Head circumference is low normal.  Septal defects and a patent ductus arteriosus are often present.  Laryngeal and tracheal malacia predispose to recurrent pulmonary infections and chronic lung disease.  Skeletal dysplasia includes brachydactyly and anomalous vertebral bodies resulting in short stature (3rd percentile).  Genitourinary abnormalities include cryptorchidism, horseshoe kidney, and vesiculoureteral reflux.  Delayed gastric emptying and reflux have been reported.

Genetics

Heterozygous mutations in the AFF4 gene (5q31.1) have been identified in 3 unrelated individuals with this condition.  No familial cases have been identified.  The gene is a core component of the super elongation complex that is critical to transcriptional elongation during embryogenesis.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the general disorder.  Tracheostomy was required in 2 of three reported patients. 

References
Article Title: 

Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin

Izumi K, Nakato R, Zhang Z, Edmondson AC, Noon S, Dulik MC, Rajagopalan R, Venditti CP, Gripp K, Samanich J, Zackai EH, Deardorff MA, Clark D, Allen JL, Dorsett D, Misulovin Z, Komata M, Bando M, Kaur M, Katou Y, Shirahige K, Krantz ID. Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nat Genet. 2015 Apr;47(4):338-44.

PubMed ID: 
25730767

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: 

Jackson-Weiss Syndrome

Clinical Characteristics
Ocular Features: 

The facial malformation such as the flattened midface with maxillary hypoplasia leads to shallow orbits with the result that the eyes appear proptotic.  Some but not all individuals have strabismus, usually exotropia.  Optic atrophy has not been reported. 

Systemic Features: 

Infants usually present at birth with skull deformities resembling some variant of acrocephalosyndactyly.  Some or all of the skull sutures may be fused.  In some individuals craniectomy is necessary while others have normal brain development.  Few patients have evidence of abnormal neurological development and psychometric testing reveals IQ's in the normal range.  The midface is flattened with sometimes severe maxillary hypoplasia.  No hand deformities are present. 

There may be cutaneous syndactyly of the second and third toes.  Variable tarsal fusion is often present. The great toe may be abnormally broad and deviated medially.  The first metatarsals and proximal phalanges of the great toes are generally broad.

The phenotype is highly variable and even among individuals in genetically more homogeneous populations such as the Old Order Amish the range of facial, skull, and digital anomalies include features found among all of the craniosynostosis syndromes except for Apert syndrome.

Genetics

Heterozygous mutations in the FGFR2 gene (10q26.13) are likely responsible for this autosomal dominant condition. 

Other forms of craniosynostosis in which mutations in FGFR2 have been found are: Beare-Stevenson Syndrome (123790), Crouzon Syndrome (123500), Pfeiffer Syndrome (101600), Apert Syndrome (101200), and Saethre-Chotzen Syndrome (101400).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment beyond surgical correction of selected malformations. The risk of exposure keratitis requires constant vigilance and appropriate corneal lubrication.

References
Article Title: 

Beare-Stevenson Syndrome

Clinical Characteristics
Ocular Features: 

The midface hypoplasia and shallow orbits result in the appearance of prominent eyes.  Ptosis and hypertelorism have been reported while the palpebral fissures are downslanting. One patient has been reported to have optic atrophy.  Another patient was described with cloudy corneas, irregular irides and nonreactive pupils.

Systemic Features: 

Pregnancies may be complicated by polyhydramnios.  Infants are born with craniosynostosis with a cloverleaf pattern usually.  The skull is often shortened in the anteroposterior axis with flattening of the occipital region.  The skin is deeply furrowed with the cutis gyrata patterns most prominent in the posterior scalp but also present on the palms, soles, pinnae, and elsewhere.  Acanthosis nigricans is often present.

There is midface hypoplasia and nearly all individuals have intellectual disability.

The external ear canals can be atretic, the nares are often anteverted, and the mouth may be small.  An excess number of neonatal teeth and hypoplastic nails have been noted.  Hydrocephalus is common.  The umbilical stump is often unusually prominent.  Anogenital anomalies such as an anteriorly placed anus, cryptorchidism, and bifid scrotum may be present.  Pyloric stenosis is sometimes present.

Upper airway obstruction with respiratory distress may necessitate a tracheotomy. A cartilaginous tracheal sleeve replacing the normal C rings of cartilage has been found in several infants. These can be difficult to detect and their presence may have been responsible for breathing restrictions that has led to the demise of some children before two years of age.

Genetics

Reported cases have occurred sporadically.  Increased paternal age has been suggested as a factor in the occurrence of heterozygous mutations in the FGFR2 gene (10q26.13) which have been identified in some individuals.

Other forms of craniosynostosis in which mutations in FGFR2 have been found are: Crouzon Syndrome (123500), Pfeiffer Syndrome (101600), Apert Syndrome (101200), Jackson-Weiss Syndrome (123150), and Saethre-Chotzen Syndrome (101400).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no general treatment for this syndrome.  Several infants have had tracheotomies and CNS shunts.

References
Article Title: 

Beare-Stevenson cutis gyrata syndrome

Hall BD, Cadle RG, Golabi M, Morris CA, Cohen MM Jr. Beare-Stevenson cutis gyrata syndrome. Am J Med Genet. 1992 Sep 1;44(1):82-9. PubMed PMID: 1519658.

PubMed ID: 
1519658

Filippi Syndrome

Clinical Characteristics
Ocular Features: 

The ocular features have not been fully described.  The most consistent features are long eyelashes, thick (bushy) eyebrows, and 'visual disturbance'.  Most individuals have a facial dysmorphism which includes a broad nasal base suggestive of hypertelorism.  Optic atrophy and proptosis have been noted. 

Systemic Features: 

Intrauterine growth retardation is sometimes seen.  Microcephaly, short stature, syndactyly, intellectual disability (often labeled mental retardation), and a dysmorphic face are characteristic.  Some individuals have cryptorchidism, seizures, and ectodermal abnormalities including nail hypoplasia, hirsutism, and microdontia.  Mental and physical delays are common.  The syndactyly usually involves only soft tissue between toes 2, 3, and 4 and fingers 3 and 4 accompanied by clinodactyly of the 5th finger.  Polydactyly is sometimes present while radiologically the radial head may show evidence of hypoplasia. 

Genetics

Homozygosity or compound heterozygosity in the CKAP2L gene (2q13) segregates with this phenotype. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome

Hussain MS, Battaglia A, Szczepanski S, Kaygusuz E, Toliat MR, Sakakibara S, Altmuller J, Thiele H, Nurnberg G, Moosa S, Yigit G, Beleggia F, Tinschert S, Clayton-Smith J, Vasudevan P, Urquhart JE, Donnai D, Fryer A, Percin F, Brancati F, Dobbie A, Smigiel R, Gillessen-Kaesbach G, Wollnik B, Noegel AA, Newman WG, Nurnberg P. Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome. Am J Hum Genet. 2014 Nov 6;95(5):622-32.

PubMed ID: 
25439729

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

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