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Case report of a PRDM5 linked brittle cornea syndrome type 2 in association with a novel SLC6A5 mutation

Selina, Agnes1,2; John, Deepa3; Loganathan, Lakshmi1,2; Madhuri, Vrisha1,2,

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doi: 10.4103/ijo.IJO_325_20
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Brittle cornea syndrome (BCS), a rare autosomal recessive connective tissue disorder with extreme corneal thinning (220-450 microns) and fragility.[12] Other ocular features include blue sclera, corneal astigmatism, high myopia, keratoconus, keratoglobus and retinal detachment.[3] Systemic features are hearing defects, joint hypermobility, skin hyperelasticity, kyphoscoliosis and dental abnormalities.[4] Mutation in ZNF469 (MIM: 612078) cause BCS type 1 and mutations in the PRDM5 (MIM: 614161) cause BCS type 2.[13] Mutations in PRDM5 produces abnormal fibrillar collagen affecting corneal integrity and alterations in retinal capillaries and Bruch's membrane.[5] Type 1 BCS has wrinkled skin involving palms and soles with scarring, molluscoid pseudotumors, and chestnut-coloured hair.[67] Whereas, in Type 2 the skin is soft with easy bruisabilty.[8] We found a mutation in the PRDM5 in association with SLC6A5 gene mutation while investigating a child with the bilateral blue sclera and corneal thinning. The SLC6A5 gene encodes for a presynaptic glycine transporter,[9] and is known to cause hyperekplexia type 3, a neurological syndrome presenting either early or late. PRDM5 gene mutation causing BCS has not been reported previously from India. A combination of these two recessive conditions has not been reported earlier in the world.

Case Report

We report a 3-year-old Indian girl, born to parents of second-degree consanguineous marriage. At birth, she had an Ortolani positive left hip instability and α angles on both sides were 59° which subsequently became 67° at 3 months. She also had blue sclera [Fig. 1]. Pedigree analysis showed no family history of ocular or any other genetic disorders.

Figure 1
Figure 1:
Face photograph showing blue sclera

At 3 years, due to her eye colour, she was re-examined to rule out collagen disorders. She was found to have hyperlaxity of joints showing 5/5 of Ruth Wynn Davies criteria. Her head circumference was 49 cm, height 94cm (between 50th and 75th centile), lower segment 46 cm and upper segment 48 cm; upper to lower segment ratio (US/LS) 1.04 (normal US/LS is 1.3 at 3 years of age), weight 13 kg (25th-50th centile), arm span 84 cm, and her hips were located. Her systemic and neurological examination was normal. Radiographs showed no fractures or spinal abnormality. Features of Ehler-Danlos, Osteogenesis imperfecta and Marfan syndrome were absent.

Her best corrected visual acuity (BCVA) using Kay pictures was 6/24, with -3.00 × 200 improving to 6/19 in the right eye (OD- oculus dextrus) and 6/48 with -3.00/-3.00 × 1600 improving to 6/24 in the left eye (OS-oculus sinister). Ocular examination showed bilateral diffuse bluish discolouration of sclera. Slit lamp examination showed bilateral thin cornea. Rest of the ocular examination was normal.

Anterior segment optical coherence tomography (OCT-Topcon) showed bilateral thin cornea [Fig. 2]. Central corneal thickness measured using Nidek Optical Biometer was 266 μm in OD and 310 μm in OS. Corneal tomographic modelling system (TMS-Tomey) showed features suggestive of keratoconus in both eyes [Fig. 3].

Figure 2
Figure 2:
Optical coherence tomography (OCT-Topcon) showing bilateral thin cornea. (a- left eye, b-right eye)
Figure 3
Figure 3:
Corneal tomographic modelling system (TMS- Tomey) showed a keratometry reading of SKI 51.53 @1220/SK2 47.33 with a cylinder of 4.20 in OD and SK1 [email protected]/SK2 49.57 with a cylinder of 3.71 in OS with features suggestive of keratoconus in both eyes. (a- left eye, b-right eye)

Child was diagnosed to have bilateral thin cornea and sclera, with myopic astigmatism OD and compound myopic astigmatism OS with features of keratoconus in corneal tomography. These features combined with blue sclerae, hip dysplasia, hyperlaxity and absence of fractures suggested Brittle Cornea syndrome Type 2.

An informed consent for genetic analysis was obtained, blood samples collected from the child, brother and parents and pedigree analysis was done. Clinical exome sequencing (CES) was performed by CENTOGENE AG (Rostock, Germany) using Illumina platform. A novel combination of PRDM5 mutation with SLC6A5 mutation was found.

Validation was done by Sanger sequencing for proband, brother and parent samples in-house to find the inheritance pattern. A homozygous frameshift variant NM_018699.3: c. 713_716 del TTTG p.(Val238Alafs*35) was identified in exon 6 of PRDM5 gene resulting in premature termination codon. Parents and brother were heterozygous for the same mutation [Fig. 4]. A novel homozygous frameshift variant NM_004211.3: c.401dup p.(Ser135Glufs*53) was identified in exon 2 of SLC6A5 in the proband and the brother, both parents being heterozygous [Fig. 4].

Figure 4
Figure 4:
Proband showing homozygous c.713_716 del TTTG p. (Val238Alafs*35) mutation in exon 6 of PRDM5; Parents and brother were heterozygous. Proband and brother showing homozygous c.401dup p. (Ser135Glufs*53) in exon 2 ofSLC6A5 gene

In view of the genetic diagnosis and ophthalmologic findings, the child was prescribed spectacles for refractive error. Parents were counselled regarding the chances of ocular rupture from trivial trauma and protective glasses were given. The family was provided with an information sheet on the phenotypic effects of SLC6A5 mutation and the possibility of developing neurological symptoms in the fourth or fifth-decade requiring medication at that time.


Molecular analysis of our patient identified a known homozygous frameshift variant in the PRDM5 gene and a novel homozygous frameshift variant in SLC6A5 gene. This novel c.401 dup p.(Ser135Glufs*53) variant of SLC6A5 gene creates a shift in the reading frame starting at codon 135 and the new reading frame ends in a stop codon 52 positions downstream. These two genetic mutations cause BCS type 2 and Hyperekplexia type 3 respectively. BCS has been previously reported in families from the Middle East, China and Pakistan.[28101112] This particular PRDM5 mutation has been reported earlier.[8]

The pathological variants are responsible for extracellular matrix development, collagen deposition, and collagen fibril assembly which determines the corneal thickness and its integrity. It also affects the development of retinal microvasculature and Bruch's membrane.[5] However, these abnormal retinal microvascular changes are evident only on immunohistochemistry.[13]

Hyperekplexia type 3 has been reported in families from Canada, Australia, USA, UK and Netherlands.[914] This child presented with features of minor developmental dysplasia of the hip, hyperlaxity with blue sclera, thin cornea, myopic astigmatism and keratoconus. BCS has been reported in association with Ehler-Danlos, osteogenesis imperfecta and Marfan syndrome.[2] The SLC6A5 gene codes for an inhibitory neurotransmitter in the brain, spinal cord and retina causing minor and major forms of hyperekplexia.[15] There was no documentation of increased tone, startle reflex and neonatal apnoea in early infancy, or clumsiness and repeated falls in early childhood which are early manifestations.[14] Her sibling was homozygous for the SLC6A5 gene mutation and asymptomatic.


In conclusion, we report a Brittle Cornea syndrome due to a PRDM5 mutation unreported from India earlier. In addition, it is combined with hyperekplexia due to SLC6A5 mutation. This combination has not been reported in the world earlier.

2.1 Declaration of patient consent

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 cannot be guaranteed.

2.2 Financial support and sponsorship

This work was supported by the Department of Biotechnology, Government of India. Grant number BT/IN/SWEDEN/09/VM/2017. Indian council of Medical Research. Grant number:54/9/2015-HUM-BMS.

2.3 Conflicts of interest

There are no conflicts of interest.


We thank the patient and their families for their participation in this study.


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Blue sclera; Brittle cornea syndrome; hyperekplexia; keratoconus

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