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.

Walker-Warburg syndrome (WWS) is a rare form of autosomal recessive, congenital muscular dystrophy that is associated with brain and eye anomalies. Several genes encoding proteins involved in abnormal α-dystroglycan glycosylation have been implicated in the aetiology of WWS, most recently the ISPD gene. Typical WWS brain anomalies, such as cobblestone lissencephaly, hydrocephalus and cerebellar malformations, can be prenatally detected through routine ultrasound examinations. Here, we report two karyotypically normal foetuses with multiple brain anomalies that corresponded to WWS symptoms. Using a SNP-array examination on the amniotic fluid DNA, a homozygous microdeletion was identified at 7p21.2p21.1 within the ISPD gene. Published data and our findings led us to the conclusion that a homozygous segmental intragenic deletion of the ISPD gene causes the most severe phenotype of Walker-Warburg syndrome. Our results also clearly supports the use of chromosomal microarray analysis as a first-line diagnostic test in patients with a foetus with one or more major structural abnormalities identified on ultrasonographic examination.