velopharyngeal insufficiency

Sweeney-Cox Syndrome

Clinical Characteristics
Ocular Features: 

 Periorbital and facial anomalies were present in the two reported patients.  Pseudoproptosis (considered secondary to deficiency of the bony orbits) accentuated by midface hypoplasia, and upper lid colobomas have been observed.  The globes were described as "small" although there were no "concerns" regarding vision in the single male patient.  Electrodiagnostic tests were "normal."    

Systemic Features: 

Multiple anomalies and malformations were present in the two reported patients, an unrelated male and female.  Severe facial dysmorphism secondary to uneven skull bone formation and suture closures is present.  The metopic ridge is prominent, the orbital bones are deficient, the occiput is flattened, the anterior fontanel and coronal sutures are wide.  Midfacial hypoplasia is present.  The neck is broad and the shoulders are narrow.  The fingers are long and the distal phalanges may be fixed in flexion.  The ears are low-set, small, and cupped.  The palate is high and may be cleft.  Cutaneous syndactyly of the fingers has been observed.  Variable developmental delays/learning difficulties are present.

The male had an imperforate anus, undescended testes and a 60 dB hearing loss.  The female had a midline cleft palate with choanal atresia requiring a tracheostomy from birth and required fundoplication and gastrostomy for gastroesophageal reflux.

Genetics

Heterozygous missense mutations in the TWIST1 gene (7p21.1) were found in both reported individuals.  These appear to have arisen de novo.

Mutations in the same gene have also been found in the Saethre-Chotzen Syndrome (101400) in which some of the same skeletal features are found.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported for the general condition but individual malformations may require attention.  The lid colobomas were repaired in the female but corneal exposure remained and corneal scarring and phthisis developed in the right eye.  The left eye retained some vision ("able to see large objects").

References
Article Title: 

Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans

Kim S, Twigg SRF, Scanlon VA, Chandra A, Hansen TJ, Alsubait A, Fenwick AL, McGowan SJ, Lord H, Lester T, Sweeney E, Weber A, Cox H, Wilkie AOM, Golden A, Corsi AK. Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans. Hum Mol Genet. 2017 Jun 1;26(11):2118-2132.

PubMed ID: 
28369379

Diagnostic value of exome and whole genome sequencing in craniosynostosis

Miller KA, Twigg SR, McGowan SJ, Phipps JM, Fenwick AL, Johnson D, Wall SA, Noons P, Rees KE, Tidey EA, Craft J, Taylor J, Taylor JC, Goos JA, Swagemakers SM, Mathijssen IM, van der Spek PJ, Lord H, Lester T, Abid N, Cilliers D, Hurst JA, Morton JE, Sweeney E, Weber A, Wilson LC, Wilkie AO. Diagnostic value of exome and whole genome sequencing in craniosynostosis. J Med Genet. 2017 Apr;54(4):260-268.

PubMed ID: 
27884935

Sweeney-Cox Syndrome

Clinical Characteristics
Ocular Features: 

Ophthalmologic examinations have not been reported.  However, periorbital and facial anomalies were present in the two reported patients.  Pseudoproptosis (considered secondary to deficiency of the bony orbits) accentuated by midface hypoplasia, and upper lid colobomas have been observed.  The globes were described as "small" although there were no "concerns" regarding vision in the single male patient.  Electrodiagnostic tests were "normal."    

Systemic Features: 

Multiple anomalies and malformations were present in the two reported patients, an unrelated male and female.  Severe facial dysmorphism secondary to uneven skull bone formation and suture closures is present.  The metopic ridge is prominent, the orbital bones are deficient, the occiput is flattened, the anterior fontanel and coronal sutures are wide.  Midfacial hypoplasia is present.  The neck is broad and the shoulders are narrow.  The fingers are long and the distal phalanges may be fixed in flexion.  The ears are low-set, small, and cupped.  The palate is high and may be cleft.  Cutaneous syndactyly of the fingers has been observed.  Variable developmental delays/learning difficulties are present.

The male had an imperforate anus, undescended testes and a 60 dB hearing loss.  The female had a midline cleft palate with choanal atresia requiring a tracheostomy from birth and required fundoplication and gastrostomy for gastroesophageal reflux.  

Genetics

Heterozygous missense mutations in the TWIST1 gene (7p21.1) were found in both reported individuals.  These appear to have arisen de novo.

Mutations in the same gene have also been found in the Saethre-Chotzen Syndrome (101400) in which some of the same skeletal features are found.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported for the general condition but individual malformations may require attention.  The lid colobomas were repaired in the female but corneal exposure remained and corneal scarring and phthisis developed in the right eye.  The left eye retained some vision ("able to see large objects").

References
Article Title: 

Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans

Kim S, Twigg SRF, Scanlon VA, Chandra A, Hansen TJ, Alsubait A, Fenwick AL, McGowan SJ, Lord H, Lester T, Sweeney E, Weber A, Cox H, Wilkie AOM, Golden A, Corsi AK. Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans. Hum Mol Genet. 2017 Jun 1;26(11):2118-2132.

PubMed ID: 
28369379

Diagnostic value of exome and whole genome sequencing in craniosynostosis

Miller KA, Twigg SR, McGowan SJ, Phipps JM, Fenwick AL, Johnson D, Wall SA, Noons P, Rees KE, Tidey EA, Craft J, Taylor J, Taylor JC, Goos JA, Swagemakers SM, Mathijssen IM, van der Spek PJ, Lord H, Lester T, Abid N, Cilliers D, Hurst JA, Morton JE, Sweeney E, Weber A, Wilson LC, Wilkie AO. Diagnostic value of exome and whole genome sequencing in craniosynostosis. J Med Genet. 2017 Apr;54(4):260-268.

PubMed ID: 
27884935
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