dry skin

Singleton-Merten Syndrome 2

Clinical Characteristics
Ocular Features: 

Glaucoma has been diagnosed in multiple members of 4 a generation Korean family in which various features of this disorder were found.  The glaucoma is likely congenital in origin as it has been diagnosed in patients as young as 3 years of age

Systemic Features: 

Calcification of the aorta and other large vessels may be identified in childhood.  The aortic valve and coronary arteries may become calcified in young adults as well, sometimes resulting in aortic stenosis.  Arthritis resulting from calcified tendons as well as ligaments of the interphalangeal and metacarpophalangeal joints may occur in young adults.  The skin is often scaly and dry with psoriatic lesions.  The terminal tufts of the digits have evidence of erosion.

Genetics

Heterozygous mutations in the DDX58 gene (9p21.1) have been associated with this disorder.  Some of the clinical features overlap those of Singleton-Merten Syndrome 2 (182250) but this is a unique disorder caused by a different mutation (IFIH1).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Glaucoma should be treated with pressure-lowering drugs and surgery.  It may be possible to decalcify cardiovascular structures in select patients and to perform valve replacement.

References
Article Title: 

Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome

Jang MA, Kim EK, Now H, Nguyen NT, Kim WJ, Yoo JY, Lee J, Jeong YM, Kim CH, Kim OH, Sohn S, Nam SH, Hong Y, Lee YS, Chang SA, Jang SY, Kim JW, Lee MS, Lim SY, Sung KS, Park KT, Kim BJ, Lee JH, Kim DK, Kee C, Ki CS. Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome. Am J Hum Genet. 2015 Feb 5;96(2):266-74.

PubMed ID: 
25620203

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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