SIX2 gene haploinsufficiency leads to a recognizable phenotype with ptosis, frontonasal dysplasia, and conductive hearing loss

Abstract

Heterozygous microdeletions of chromosome 2p21 encompassing only the SIX2 gene have been described in two families to date. The clinical phenotype comprised autosomal-dominant inherited frontonasal dysplasia with ptosis in one family. In the second family, conductive hearing loss was the major clinical feature described; however, the affected persons also had ptosis. Here, we present a large family combining all three predescribed features of SIX2 gene deletion. The phenotype in four affected family members in three generations consisted of bilateral congenital ptosis, epicanthus inversus, frontonasal dysplasia with broad nasal bridge and hypertelorism, frontal bossing and large anterior fontanel in childhood, narrow ear canals, and mild conductive hearing loss with onset in childhood. Thus, the phenotypic spectrum of SIX2 haploinsufficiency is widened. Moreover, 2p21 microdeletions with SIX2 haploinsufficiency appear to lead to a recognizable phenotype with facial features resembling blepharophimosis-ptosis-epicanthus inversus syndrome.

Maternal SLE and brachytelephalangic chondrodysplasia punctata in a patient with unrelated de novo RAF1 and SIX2 variants

“…Guan et al (2016) reported nine individuals from a Chinese family, with a novel 60 kb deletion involving the SIX2 gene, associated with developmental abnormalities of the middle ear ossicles and upper eyelid, but no apparent skeletal or craniofacial abnormalities. More recently, Henn et al (2018) described multiple family members with similarities to the previously reported finding by Guan et al (2016) as well as features of blepharophimosis–ptosis–epicanthus inversus syndrome (MIM#110100). Our patient had hearing loss as well as blepharophimosis and ptosis, most probably caused by the likely pathogenic variant in the SIX2 gene.…”

“…The SIX2 ‐related frontonasal dysplasia is a newly recognized autosomal dominant condition associated with a spectrum of skeletal anomalies, conductive hearing loss and ptosis. SIX2 haploinsufficiency has been reported in three clinical reports with variable size of deletions (Guan et al, 2016; Henn et al, 2018; Hufnagel et al, 2016). Hufnagel et al (2016) reported a maternally inherited SIX2 deletion in a girl with craniofacial abnormalities including frontonasal dysplasia, spheno‐occipital synchondrosis, and sagittal craniosynostosis.…”

“…The SIX2-related frontonasal dysplasia is a newly recognized autosomal dominant condition associated with a spectrum of skeletal anomalies, conductive hearing loss and ptosis. SIX2 haploinsufficiency has been reported in three clinical reports with variable size of deletions (Guan et al, 2016;Henn et al, 2018;Hufnagel et al, 2016). Hufnagel et al (2016) Many genetic factors, including SIX2, are known to be associated with the formation of the forelimb buds, derived from the cells that constitute the lateral plate mesoderm (Ohto et al, 1998).…”

Crucial and Overlapping Roles of Six1 and Six2 in Craniofacial Development

“…Recently, heterozygous microdeletions of the SIX2 gene and flanking noncoding sequences have been associated with an FND syndrome in patients of 2 unrelated families, characterized by frontal bossing, a large anterior fontanelle, hypertelorism, a broad nasal bridge, and conductive hearing loss (Hufnagel et al 2016; Henn et al 2018). Although Six2 messenger RNAs (mRNAs) are highly expressed in frontonasal mesenchyme in mouse embryos, Six2 -null mice exhibit kidney dysgenesis and premature fusion of the bones in the cranial base but no obvious defects in frontonasal development (Oliver et al 1995; Self et al 2006; He et al 2010).…”

A new 1p36.13‐1p36.12 microdeletion syndrome characterized by learning disability, behavioral abnormalities, and ptosis

“…Congenital isolated ptosis most often occurs sporadically but can also be familial, and several loci and candidate genes have been suggested, including 1p32‐1p34.1, Xq24‐27.1, and the ZFH4 gene at 8q21.12 . Congenital ptosis can be part of numerous genetic syndromes, some examples are congenital fibrosis of the extraocular muscles ( KIF21A , PHOX2A , TUBB3 ), SIX2 haploinsufficiency, various types of myopathy, neurogenetic diseases, and mitochondrial diseases . The 1p36.13‐1p36.12 microdeletion syndrome presented here is a new syndrome with ptosis as a distinct feature.…”