malformed ears

Heart and Brain Malformation Syndrome

Clinical Characteristics
Ocular Features: 

Microphthalmia is the cardinal ocular malformation.  Hypertelorism has been described.  Poor vision without further description has also been reported.   

Systemic Features: 

The ears are low-set, malformed, and posteriorly rotated.  The forehead is prominent and there is usually a wide anterior fontanel.  The nasal bridge is wide and frequently depressed while the lower lip is full and may be everted and split.  The palate is highly arched.  Physical growth is slow.  A ventricular septal defect is often present while the valves are hypoplastic and the aortic arch can be interrupted.

Microcephaly is often present and there may a profound delay in psychomotor development with truncal hypotonia and hyperreflexia in the limbs.   Brain imaging shows generalized atrophy with decreased myelination.  Cerebellar vermis hypoplasia has been reported.  Two of 5 patients were reported to have Dandy-Walker malformations, and a thin corpus callosum.  Seizures may occur.

Genetics

Homozygous mutations in the SMG9 gene (19q13.31) are responsible for this condition so far reported in 5 individuals in two unrelated consanguineous Arab families.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Mutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice

Shaheen R, Anazi S, Ben-Omran T, Seidahmed MZ, Caddle LB, Palmer K, Ali R, Alshidi T, Hagos S, Goodwin L, Hashem M, Wakil SM, Abouelhoda M, Colak D, Murray SA, Alkuraya FS. Mutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice. Am J Hum Genet. 2016 Apr 7;98(4):643-52.

PubMed ID: 
27018474

Ablepharon-Macrostomia Syndrome

Clinical Characteristics
Ocular Features: 

The clinical features of this syndrome remain to be fully delineated.  Important ocular anomalies include malformations and sometimes absence of the upper and lower eyelids.  The eyelashes and eyebrows may be sparse or even missing.  The lid fissures, if present, may be shortened.  Deformities of the eyelids can lead to corneal exposure and secondary vision loss. 

Systemic Features: 

Other facial malformations include macrostomia which may be secondary to aberrant lip fusion.  Micrognathia has been described.  The external ears are often rudimentary, sometimes described as rosebuds.  The nasal bridge is low and the nostrils anteverted.  The zygomatic arches may be absent.  The nipples are often missing as well.  Scalp hair is sparse or even absent while the skin is dry, coarse, and often has redundant folds (cutis laxa).  Mild skin syndactyly, camptodactyly, finger contractures, and shortening of metacarpals have been noted.  The genitalia are often ambiguous and some patients have had ventral hernias.  Hearing loss can be a feature.  Growth retardation has been seen but developmental delays if present are mild.  Intelligence can be normal. 

Genetics

The majority of sibships suggest autosomal recessive inheritance although autosomal dominant inheritance has been proposed for several. One male child has been reported to have a partial deletion of chromosome 18 but other complex rearrangements were also present.

An amino acid substitution (lysine) in the basic domain of the TWIST2 gene has been found in seven families in which ablepharon-macrostomia followed an autosomal dominant pattern.  Mutations in the same TWIST2 domain but leading to substitutions of glutamine or alanine amino acids is responsible for the Barber-Say phenotype (209885).

Mutations in the TWIST2 gene may also be responsible for Setleis syndrome (227260). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cosmetic surgery can correct at least some of the malformations. Vigorous effort may be required to maintain corneal surface wetting. 

References
Article Title: 

Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes

Marchegiani S, Davis T, Tessadori F, van Haaften G, Brancati F, Hoischen A, Huang H, Valkanas E, Pusey B, Schanze D, Venselaar H, Vulto-van Silfhout AT, Wolfe LA, Tifft CJ, Zerfas PM, Zambruno G, Kariminejad A, Sabbagh-Kermani F, Lee J, Tsokos MG, Lee CC, Ferraz V, da Silva EM, Stevens CA, Roche N, Bartsch O, Farndon P, Bermejo-Sanchez E, Brooks BP, Maduro V, Dallapiccola B, Ramos FJ, Chung HY, Le Caignec C, Martins F, Jacyk WK, Mazzanti L, Brunner HG, Bakkers J, Lin S, Malicdan MC, Boerkoel CF, Gahl WA, de Vries BB, van Haelst MM, Zenker M, Markello TC. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes. Am J Hum Genet. 2015 Jul 2;97(1):99-110.

PubMed ID: 
26119818
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