downward slanting lid fissures

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

Craniofacial-Deafness-Hand Syndrome

Clinical Characteristics
Ocular Features: 

This rare syndrome has anomalies in periocular structures but not in the eye itself.  The lid fissures are downward slanting with telecanthus and hypertelorism.  The nasolacrimal duct was missing in several individuals.

Systemic Features: 

The midface is generally flat with underdeveloped maxillary bones and absent or small nasal bones but there may be frontal bossing.  The nose appears hypoplastic with a broad, flat root resulting in dystopia canthorum.  Micrognathia and a high arched palate are sometimes present.   The sinuses are often underdeveloped.  There may be ulnar deviation of the hands and fingers while flexion contractures and clinodactyly of the 5th finger are often present.  A sensorineural hearing loss is present in many individuals.  No poliosis has been reported.

Genetics

This is an autosomal dominant condition secondary to mutations in the PAX3 gene (22q36.1) in at least some patients.  Changes in the same gene are responsible for types 1 and 3 of the Waardenburg syndrome (193500, 148820).  In fact, the major mutation, a heterozygous C-to-G transversion, has been identified in the same codon in both CDHS and Waardenburg 3 (148820) patients.

More patients need to be genotyped to clarify the clinical features distinctive of Waardenburg types 1 and 3 (193500, 148820) and CDHS syndrome.  Should we consider these conditions allelic or simply the result of variable expressivity?  The appearance of the nasal root and associated structures is similar and both conditions are associated with sensorineural hearing loss.  Type 3 Waardenburg syndrome (148820) often has a cleft palate and musculoskeletal deformities of the upper limbs and fingers.  So far, no pigmentation changes have been reported in CDHS.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Surgical release of contractures could be considered.

References
Article Title: 

Donnai-Barrow Syndrome

Clinical Characteristics
Ocular Features: 

A number of ocular features have been described in this disorder, including telecanthus, hypertelorism, and iris hypoplasia with marked iris transillumination.  Myopia is commonly present and retinal detachments are a risk.  Several patients had iris colobomas.  Cataracts, small optic nerves, and macular hypoplasia have been reported as well.  The lid fissures usually slant downward. 

Systemic Features: 

The facial dysmorphology, in addition to the periocular malformations, includes a prominent brow or frontal bossing, posterior rotation of the ears, a flat nasal bridge and a short nose.  Sensorineural hearing loss is universal and at least some patients have complete or partial agenesis of the corpus callosum, and an enlarged anterior fontanel.  Diaphragmatic and umbilical hernias often occur together.  Low-molecular-weight proteinuria in the absence of aminoaciduria is a frequent feature.  Developmental delays are often seen but occasional patients have normal intellect.  Rare patients have seizures. 

Genetics

This is a rare autosomal recessive disorder caused by homozygous mutations in the LRP2 (low-density lipoprotein receptor-related protein 2 or megalin) gene located at 2q24-q31.  Some patients have an ocular phenotype resembling the Stickler syndrome (609508).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is focused on specific manifestations such as cataract and retinal detachment surgery. Patients need to be monitored throughout life for retinal disease.  Omphaloceles and diaphragmatic hernias need to be repaired.  Hearing aids may be beneficial. 

References
Article Title: 

Treacher Collins-Franceschetti Syndrome

Clinical Characteristics
Ocular Features: 

Lid fissures often have an antimongoloid slant.  Many patients (69%) have a coloboma of the lower eyelid (in contradistinction to Goldenhar spectrum syndrome [164210] in which the lid colobomas involve the upper eyelid) with a paucity of lashes and meibomian glands medially.  Colobomas may also involve the iris, choroid and optic nerve.  Other ocular features include blepharoptosis, hypoplasia of the supraorbital ridges, absent lacrimal puncti, underdevelopment of the orbicularis oculi muscle, absence of the tarsal plate, and abnormalities of the lateral canthal tendons.  Strabismus and amblyopia have been reported in a significant number of individuals.

Systemic Features: 

A variety of defects in facial development have been reported, most involving the ears, eyelids, lower jaw, and zygomatic arch.  The characteristic facial phenotype is usually evident at birth.  One-third of patients have a cleft palate.  Microtia or even anotia may be present and a conductive hearing loss can result, especially when the ossicles are malformed or absent.  The pinnae are often malformed, appearing 'crumpled', low-set, and rotated posteriorly.  There may be ear tags and blind fistulas anywhere between the tragus and angle of the mouth.  The mandible and its rami may be hypoplastic causing severe micrognathia that can result in feeding and speaking difficulties, especially when pharyngeal hypoplasia is also present.  The zygomatic arches are often underdeveloped (or even absent) and the midface is flattened.  Arhinia and cleft palate are sometimes seen.  A low hairline may be present.  Intelligence is usually normal.

Genetics

This is an autosomal dominant syndrome secondary to mutations in the TCOF1 gene located at 5q32-q33.1.  A parental gender influence is suggested by at least one study which found an increase in the number of affected offspring from affected mothers compared with those from affected fathers.  Many cases (60%) result from new mutations but a paternal age effect has not been established.  Inter- and intrafamilial clinical variation is wide.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Auditory testing should be done early since corrective action is important in the prevention of developmental delays.  Reconstructive facial surgery can be of great benefit to both cosmesis and function.  Lid reconstruction may be required for corneal protection.

References
Article Title: 

Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation

Teber OA, Gillessen-Kaesbach G, Fischer S, Bohringer S, Albrecht B, Albert A, Arslan-Kirchner M, Haan E, Hagedorn-Greiwe M, Hammans C, Henn W, Hinkel GK, Konig R, Kunstmann E, Kunze J, Neumann LM, Prott EC, Rauch A, Rott HD, Seidel H, Spranger S, Sprengel M, Zoll B, Lohmann DR, Wieczorek D. Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation. Eur J Hum Genet. 2004 Nov;12(11):879-90.

PubMed ID: 
15340364

Saethre-Chotzen Syndrome

Clinical Characteristics
Ocular Features: 

The lids are often ptotic and asymmetrically so in keeping with the skull asymmetry.  Strabismus is common.  Optic atrophy, downward slanting lid fissures, epicanthal folds, and dacryostenosis have also been reported.

Systemic Features: 

The skull is acrocephalic and asymmetrical.  The frontal hairline is low.  The external ear and especially the crus of the ear are malformed and the latter is sometimes considered a valuable diagnostic sign.  There is frequently mild soft tissue syndactyly of the third, fourth and fifth toes, and the distal phalanges of the hallux may be bifid.  Syndactyly of the fingers is sometimes present as well.  Clefting of the soft and hard palates is commonly present and a few patients have had joint contractures.  Hearing loss of all types has been reported.  Mental development seems to be normal.  An increased risk of breast cancer has been found among Swedish patients.

SCS is considered to be one of the more common types of syndromic craniosynostosis.

Genetics

Saethre-Chotzen syndrome is caused by mutations in the TWIST1 (10q26) and possibly FGFR2 genes suggesting genetic heterogeneity.  There is also a great deal of clinical heterogeneity.  This syndrome is sometimes confused with Gorlin-Chaudhry-Moss syndrome (233500).  Pedigrees are consistent with autosomal dominant inheritance.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no known treatment except for cranioplasty and repair of palate clefting.

References
Article Title: 
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