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Rare case of Spondylo-ocular syndrome diagnosed in siblings from North India

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
Spondylo-ocular syndrome (SOS) is a rare autosomal recessive skeletal disorder, caused by pathogenic variants in XYLT2 gene. It is characterized by bony involvement (osteoporosis, fractures, spine involvement in form of spinal compression fractures and platyspondyly), eye and cardiac defects, hearing impairment and developmental delay. It is a type of GAG linkeropathy causing defect in the first step of Proteoglycan assembly. There is deficiency of xylosytransferase II enzyme responsible for addition of xylose moiety to GAG. This disorder has a wide phenotypic variability with a total of 25 individuals described till now worldwide.

 

Case Presentation
Two female siblings, aged 8yr 11m and 6yr 10m, born out of non-consanguineous marriage, referred in view of similar complaints of delayed development, multiple fractures of long bones, deformed chest and bilateral cataracts. Both had normal antenatal & birth history. On examination, the siblings had short stature (<-3SD) with facial dysmorphism in form of square shaped face, thick and arched eyebrows, low set ears and anteverted nares with pectus excavatum, kyphosis and distal joint laxity. Systemic examination was normal.

 

Diagnostic Workup
Blood investigations showed normal serum calcium, phosphate, alkaline phosphatase, low 25-hydroxyvitamin D and normal parathyroid hormone for both siblings ruling out metabolic defects. Ophthalmological examination showed bilateral subcapsular cataract in both siblings. Younger sibling had 6mm Atrial septal defect on 2D echocardiography and sensorineural hearing loss in left ear. Elder sibling had no heart lesion & hearing was normal. Radiological investigations (skeletal survey) done showed  there was generalized decreased bone density, flattened vertebra with increased intervertebral space in both siblings with additional multiple vertebral collapses present in younger sibling. 

Clinical suspicion of  ? Spondylo-ocular syndrome ? Osteogenesis imperfecta-microcephaly cataract syndrome kept. Whole exome sequencing sent for the elder sibling revealed homozygous variant of uncertain significance c.550_552del (p. Glu184del) in Exon 2 in XYLT2 gene (PM4 & PM2). The variant causes in frame deletion of 3 base pairs in Exon 2, resulting in deletion of glutamic acid at codon 184. Parental segregation and positive testing of younger sibling was established and hence by modified ACMG criteria (PM4,PM2,PP1,PP4), variant was classified as likely pathogenic.

 

 

Treatment and Management
On review of literature, Bisphosphates (pamidronate infusions) have been used for treatment by Chouery et al with variable results.12 year old child affected with the disorder received pamidronate infusions and author reports bone mineral density and fracture frequency improved without reshaping the compression fractures. Kauser et al (2019), reported three affected siblings on treatment with pamidronate infusions had reduction in fractures but new compression fractures still occurred. In our case, the siblings have been started on yearly Zoledronate infusions along with calcium supplementation. Cataract surgery has been planned for the elder sibling.

 

 

Outcome and Follow-Up
Since the start of infusions in 2023, elder sibling has had one new fracture. The younger sibling has had no new fracture. Pain and discomfort have improved in the siblings after a month of the injections.

Discussion
On comparing our siblings with the previous records of 25 patients of Spondylo-ocular syndrome, findings of short stature, multiple fractures, kyphosis, osteoporosis, cataract, neurodevelopmental delay and radiographic findings of platyspondyly & increased intervertebral disc matches. However, facial features like facial hypotonia, hypertelorism, low nasal bridge, prognathism, pes planus, broadened fingertips, retinal involvement, and aortic valvular involvement were not found in our case. Due to limited number of reported cases, it has been difficult to establish genotype-phenotype correlation. Also the variant is an in frame deletion leading to the necessity of further functional studies to validate the pathogeneticity of the variant.

Conclusion
Thus, we have described a novel in frame deletion in these two siblings as a possible molecular mechanism for causing Spondylo-ocular syndrome. These findings will help to extend the mutation spectrum and help in establishing better genotype-phenotype correlation.

 

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