prominent ears

Mandibulofacial Dysostosis with Alopecia

Clinical Characteristics
Ocular Features: 

The extensive dysplasia of the facial bones involves those of the orbital rims and zygomatic arches.  The orbital rims can be malformed and there is often a broad depression at the inferolateral region of the eyes.  Hypoplasia or even aplasia of the eyelids maybe present and some individuals have colobomas of the lower eyelids.  The lacrimal punctae may be temporally displaced.  The eyebrows and eyelashes are often sparse as part of the generalized alopecia.

Systemic Features: 

This is a disorder of craniofacial development resulting in extensive malformations of facial bones and skin.  Different rates of development among these structures leads to facial asymmetry in many patients. Maxillary, zygomatic arch, and mandibular bones are dysplastic resulting in micrognathia and a flat midface.   The temporomandibular joints are absent and the external ear canals are often incompletely formed.  Conductive hearing loss is common with hypoplastic ossicular chains while the pinnae are low-set, crumpled and abnormally cupped.  There may be preauricular tags or pits present.  Tooth eruption is often delayed and there may be agenesis of many permanent teeth.  The maxillary sinuses may be absent.  Cleft palate is often present.

Genetics

Heterozygous mutations in the EDNRA gene (4q31) are responsible for this condition.  No familial cases have been reported and it can be assumed that the mutations arise de novo. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the overall condition but individual anomalies such as the colobomas, dental deformities and cleft palate may be surgically repaired.  Upper airway obstruction may require tracheostomy in infants.

References
Article Title: 

Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia

Gordon CT, Weaver KN, Zechi-Ceide RM, Madsen EC, Tavares AL, Oufadem M, Kurihara Y, Adameyko I, Picard A, Breton S, Pierrot S, Biosse-Duplan M, Voisin N, Masson C, Bole-Feysot C, Nitschke P, Delrue MA, Lacombe D, Guion-Almeida ML, Moura PP, Garib DG, Munnich A, Ernfors P, Hufnagel RB, Hopkin RJ, Kurihara H, Saal HM, Weaver DD, Katsanis N, Lyonnet S, Golzio C, Clouthier DE, Amiel J. Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia. Am J Hum Genet. 2015 Apr 2;96(4):519-31.

PubMed ID: 
25772936

Cranial Dysinnervation Disorders with Strabismus and Arthrogryposis

Clinical Characteristics
Ocular Features: 

Strabismus and/or ophthalmoplegia are important features of a group of conditions known as cranial dysinnervation disorders.  Ptosis, Duane syndrome, V pattern exotropia and various degrees of ophthalmoplegia may be seen.  There may be considerable asymmetry in the manifestations in the two eyes.  Epicanthal folds, blepharophimosis, and hypermetropia are sometimes present.  Some patients have corneal leukomas, keratoglobus, high corneal astigmatism, and dysplastic optic disks. 

A pigmentary retinopathy and folds in the macula with an abnormal ERG has been reported.  Subnormal vision has been reported in some patients.

Systemic Features: 

Patients are often short in stature with pectus excavatum, spine stiffness, highly arched palate, and club feet.  Limited forearm rotation and wrist extension may be present.  The fingers appear long and often have contractures while the palmar and phalangeal creases may be absent.  Camptodactyly and clinodactyly are common.  Deep tendon reflexes are often hyporeactive and decreased muscle mass has been noted.  The muscles seem "firm" to palpation.  Restrictive lung disease has been reported.  Hearing loss is experienced by some individuals.

Genetics

Distal arthrogryposis type 5D is caused by homozygous or compound heterozygous mutations in the ECEL1 gene located at 2q36.  However, a similar phenotype (albeit with more severe ocular manifestations) results from heterozygous mutations in PIEZO2 (18p11).  Heterozygous mutations in the PIEZO2 gene have also been reported to cause distal arthrogryposis type 3 (Gordon syndrome [114300]) and Marden-Walker syndrome (248700) and all of these may be simply phenotypical variations of the same disorder.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for this condition.  Patients with subnormal vision may benefit from low vision aids and selective surgery may be helpful in reducing the physical restrictions from physical deformities.

References
Article Title: 

Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5

McMillin MJ, Beck AE, Chong JX, Shively KM, Buckingham KJ, Gildersleeve HI, Aracena MI, Aylsworth AS, Bitoun P, Carey JC, Clericuzio CL, Crow YJ, Curry CJ, Devriendt K, Everman DB, Fryer A, Gibson K, Giovannucci Uzielli ML, Graham JM Jr, Hall JG, Hecht JT, Heidenreich RA, Hurst JA, Irani S, Krapels IP, Leroy JG, Mowat D, Plant GT, Robertson SP, Schorry EK, Scott RH, Seaver LH, Sherr E, Splitt M, Stewart H, Stumpel C, Temel SG, Weaver DD, Whiteford M, Williams MS, Tabor HK, Smith JD, Shendure J, Nickerson DA; University of Washington Center for Mendelian Genomics, Bamshad MJ. Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. Am J Hum Genet. 2014 May 1;94(5):734-44.

PubMed ID: 
24726473

Sorsby Macular Coloboma Syndrome

Clinical Characteristics
Ocular Features: 

Macular colobomas, usually bilateral, are the major ocular feature of this oculoskeletal disorder.  These are non-progressive and are generally heavily pigmented.  Vision is, of course, severely reduced (20/200) and horizontal or pendular nystagmus is a feature in some cases.

Systemic Features: 

The systemic features are primarily skeletal.  Patients have short-limbed dwarfism and brachydactyly of the type B variety.  The thumbs and sometimes the large toes may be broad and bifid.  The distal two phalanges sometimes short, absent, or duplicated and the nails can be dysplastic or absent. Syndactyly of several digits in both hands and feet is common.  The ears are large and protuberant and some patients have deafness.  Oligodontia may be present.  Cartilage can have diastrophic changes.  Mental development is normal.

Genetics

In the few families reported, the transmission pattern is vertical suggesting autosomal dominant inheritance but no mutation or locus has been reported.  The mutation causing brachydactyly type B1 was not present in several cases.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Surgical treatment of digital anomalies can be beneficial.  Low vision aids could be helpful as well.

References
Article Title: 

Peters-Plus Syndrome

Clinical Characteristics
Ocular Features: 

Peters anomaly (306229) usually occurs as an isolated ocular malformation and is often unilateral.  However, in some patients with bilateral involvement it is part of a systemic syndrome or other congenital conditions such as chromosomal deletions and the fetal alcohol syndrome.  It is called Peters Plus syndrome in the condition described here because of the association of a specific combination of systemic features.

The ocular features are consistent with dysgenesis of the anterior chamber.  The clinical picture is highly variable but generally consists of iris adhesions to the cornea centrally (classical Peters anomaly), occasionally lenticular adhesions as well, and thinning of the central corneal stroma.  As a result, the cornea may become edematous, cataracts may develop, and glaucoma is common.

Systemic Features: 

Peters-plus syndrome consists of Peters anomaly plus various degrees of developmental delays and intellectual deficits, short digits and short stature, and cleft lip and palate.  The facies is said to be characteristic due to a prominent forehead, narrow palpebral fissures, and a cupid's bow-shaped upperlip. There may be preauricular pits present and the neck is often broad.  The ears may be prominent.  Congenital heart defects are present in a third of patients and a few have genitourinary anomalies.

Genetics

This is an autosomal recessive disorder of glycosylation caused by a mutation in the B3GALTL gene on chromosome 13 (13q12.3).  At least some patients have a splicing mutation in this gene leading to a skipping of exon 8.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is directed at sight preservation by correcting the major ocular defects such as glaucoma and iridocorneal adhesions.  Corneal transplants and cataract removal are sometimes required.  Releasing the anterior synechiae can lead to significant clearing of the corneal edema.  Growth hormone replacement therapy may be beneficial.

References
Article Title: 

The Peters' plus syndrome: a review

Maillette de Buy Wenniger-Prick LJ, Hennekam RC. The Peters' plus syndrome: a review. Ann Genet. 2002 Apr-Jun;45(2):97-103. Review.

PubMed ID: 
12119218
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