in january 2015 , two sisters aged four ( sibling 1 ) and six ( sibling 2 ) with asymptomatic , consanguineous ( first cousin ) parents were referred to our ophthalmology department for evaluation of bilateral high astigmatism .
both siblings suffered since birth from poor vision in both eyes and photophobia since birth .
on ophthalmological examination , autorefractometer measurements for sibling 1 and sibling 2 were od 3.75  2  179/os 3.75 2.75  177 and od 2.25 7.75  166/os 3.75 5.75  174 , respectively .
reliable visual acuity measurements could not be obtained in sibling 1 , whereas best - corrected visual acuity for sibling 2 was 20/32 .
blue sclera and mild globular protrusion of the cornea were observed bilaterally in both siblings .
slit - lamp examination of the cases revealed that both corneas were globular in shape with peripheral corneal thinning .
corneal topography and pachymetry maps were obtained using a scheimpflug imaging ( pentacam , oculus optikgerte gmbh , wetzlar , germany ) [ fig . 1 ] .
maximal keratometry ( kmax ) indices for sibling 1 and sibling 2 were 52.9 d ( od)/53.5 d ( os ) and 54.4 d ( od)/55.4 d ( os ) , respectively .
the corneal thickness values for sibling 1 and sibling 2 were 241  ( od)/291  ( os ) and 286  ( od)/305  ( os ) , respectively .
corneal topographic images of the left eye of sibling 1 showing limbus - to - limbus corneal thinning the two siblings had in common the features of keratoglobus , blue sclera , atypical faces , hearing loss , and hypermobile joints [ fig . 2 ] .
therefore , they were referred to the genetic department for systemic evaluation . on general assessment
both siblings had flat midfaces , large eyes , frontal bossing , mild hypertelorism , calvarial thickening , and absent frontal sinuses , suggesting a diagnosis of marshall syndrome [ fig . 3 ] .
these siblings had also mandibular hypoplasia , hyperextensible joints , and metaphyseal widening of long bones , suggesting a diagnosis of stickler syndrome .
otoacoustic emission test was performed to evaluate hearing loss and was found abnormal in both siblings .
other detailed clinical characteristics of marshall syndrome , stickler syndrome , and our cases are presented in table 1 .
we tentatively diagnosed the sisters as having an overlapping marshall / stickler phenotype based on clinical and radiological findings .
frontal and profile views of sibling 1 ( top ) and 2 ( bottom ) absence of frontal sinus is seen in x - ray graphy of sibling 2 clinical features of marshall syndrome , stickler syndrome , and overlapping phenotype of our cases written informed consent was taken for photography and genetic analysis .
we could study only the exon 49 and exon 52 regions of the col11a1 gene , and the results were negative .
protective eyeglasses were prescribed for both siblings , and avoidance of contact sports was highly recommended owing to the high risk of perforation .
to our knowledge , this is the first report describing congenital keratoglobus with blue sclera in two siblings with overlapping marshall - stickler phenotype . in the past ,
it is proposed that the existing phenotypic overlap suggests that marshall and stickler syndromes are probably allelic expressions of the same locus .
although jun et al . demonstrated the expression of the col11a1 gene in human donor corneas , corneal disease associated with marshall - stickler syndrome due to col11a1 mutation has not yet been reported .
the altered collagen due to col11a1 mutation may weaken collagen fibers in the cornea , which could play a role in the development of keratoglobus in these cases .
furthermore , thinning and breakdown of the collagen is the main histological finding in cases of blue sclera . in practice , there are difficulties in obtaining whole genome analysis due to size and complexity of the col11a1 gene and also to the high cost of these investigations . only the exon 49 and exon 52 regions of the col11a1 gene were identified and found to be mutation negative .
furthermore , we could not screen the col2a1 gene in relation to some forms of stickler syndrome .
khalifa et al . pointed out that dominant and recessive mutations in the col11a1 gene cause marshall and stickler syndromes . in this report
, our cases were the offspring of unaffected consanguineous parents , suggesting autosomal recessive inheritance .
our cases also showed bilateral involvement . in the literature , keratoglobus with blue sclera was reported in association with connective tissue disorders .
these disorders are ehlers - danlos type vi , marfan syndrome , rubinstein  taybi syndrome , and osteogenesis imperfecta .
until now , keratoglobus with blue sclera has not been reported in association with marshall / stickler phenotype . as a connective tissue disorder
, marshall - stickler syndrome might be in the differential diagnosis of keratoglobus with blue sclera .
the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s )
has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal .
the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed .
the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s )
has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal .
the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed .
 we aimed to describe congenital keratoglobus with blue sclera in two siblings with overlapping marshall / stickler phenotype . 
 two sisters ( ages four and six ) with bilateral high astigmatism were evaluated by slit - lamp microscopy . corneal topography and 
 pachymetry maps were also obtained . 
 slit - lamp examination revealed that both corneas were globular in shape with peripheral corneal thinning . 
 pachymetry maps showed diffuse corneal thinning . 
 two siblings had in common the features of keratoglobus , blue sclera , atypical face , hearing loss , and hypermobile joints . 
 we tentatively diagnosed the sisters as having an overlapping marshall - stickler phenotype based on clinical and radiological findings . 
 marshall - stickler syndrome may exist in the differential diagnosis of keratoglobus with blue sclera . 
Case Report
Discussion
Declaration of patient consent
Financial support and sponsorship
Conflicts of interest