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Expanding the genotypic and phenotypic description of an ultra-rare condition: A neonatal presentation of spondylo-ocular syndrome

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
Spondylo-ocular syndrome (SOS) is an ultra-rare linkeropathy syndrome caused by biallelic variants in XYLT2 (xylosyltransferase 2) gene resulting in disruption of glycosyaminoglycan synthesis due to impaired linkage of xylosyl to the proteogylcan core protein. It is associated with decreased bone mineral density, multiple fractures, vertebral flattening, and ophthalmologic complications including cataracts, retinal detachment and nystagmus. There are less than 30 patients with SOS in the literature and the description of this syndrome remains limited.

Case Presentation
The patient is a 20-month-old male who was born at 31-weeks-gestation. Pregnancy was complicated by maternal cardiomyopathy, maternal history of myomectomy, as well as thickened nuchal fold on perinatal ultrasound. Birth weight was 2.6 kg (100th percentile), length 45.5 cm (97th percentile), and head circumference 30.3 cm (89th percentile). He required NICU admission with respiratory distress and pulmonary hypertension, requiring intubation for 3 weeks. The newborn exam demonstrated hypotonia and bilateral corneal clouding. Ophthalmology exam revealed small left-sided cataract. He was referred on newborn hearing screen bilaterally. Metabolic newborn screening was normal. By age 2 months, the patient’s corneal clouding significantly cleared. He underwent repair of bilateral inguinal hernias. His repeat echocardiogram demonstrated hypoplastic left pulmonary artery, aortic and pulmonary insufficiency, as well as moderate dilation of ascending aorta (Z-score +2.3).

Diagnostic Workup
Genetics workup in the NICU included urine markers for lysosomal storage disorders (LSD) which showed abnormal ceramide trihexoside and sulfatide profile that was suggestive of possible I-cell disease, however he had normal oligosaccharide and glycosyaminoglycan analysis. Repeat urine LSD screen showed similar results. Alpha-iduronidase enzyme activity was normal. Hexosaminidase activity, serum amino acid, urine organic acid, plasma sterols, peroxisomal fatty acid profile analyses were non-diagnostic.

Trio whole exome sequencing was performed at age 4 months. The patient had a previously reported pathogenic maternal variant c.692dup, p.V232Gfs54* and a novel paternal variant of uncertain significance c.2535C>G, p.S845R in XYLT2 gene. Due to the uncertain significance of the novel paternal variant and limited data regarding neonatal phenotypes in SOS, results were initially considered non-diagnostic. The possible diagnosis of SOS was discussed and ongoing clinical follow-up was recommended.

Outcome and Follow-Up
By 6-month-old genetics follow-up visit, pulmonary hypertension resolved. Renal ultrasound demonstrated bilateral hydronephrosis. His corneal clouding had cleared but he developed bilateral continual nystagmus. He had persistent hypotonia with a normal brain magnetic resonance imaging. A sedated auditory brainstem response test demonstrated bilateral sensorineural hearing loss. The patient had undergone bilateral lensectomy at age 8 months, and left eye trabeculotomy at age 17 months for infantile glaucoma. Echocardiogram at age 17 months showed dilated aortic root (Z-score +2.5) and ascending aorta (Z=score +4.5), mild aortic and pulmonary insufficiency, dilated main pulmonary artery, mildly dysplastic aortic and pulmonary valves.

At 18 months of age, he had global developmental delay in all aspects. Dysmorphology exam was significant for macrocephaly (93rd percentile), pendular nystagmus with poor visual tracking, malar flattening, deep and narrow philtrum, low-set and posteriorly rotated ears, thoracolumbar kyphosis with protrusion over thoracolumbar vertebrae and axial hypotonia. Spinal radiographs showed mild thoracolumbar scoliosis and moderate compression deformities throughout the thoracic and lumbar spine. Multi-joint radiographs demonstrated mild osteopenia. The new skeletal findings led to a clinical diagnosis of SOS.

The patient was referred to the skeletal dysplasia clinic and metabolic bone disease specialist, and will start on zoledronic acid infusions. He continues to receive physical, occupational and vision therapies.

Discussion
Here, we present a patient with SOS that is caused by a known pathogenic maternal variant and another paternal novel variant in XYLT2 that is assessed as likely pathogenic in the clinical context. This is the first case of aortic dilatation and the second case of congenital corneal clouding observed in SOS. This report underscores the clinical significance of the neonatal presentation of SOS.

Conclusion
Our report enriches the genotypic and phenotypic description of SOS. Furthermore, the description of aortic dilatation reflects the importance XYLT2 gene in connective tissue homeostasis and can be an important consideration when developing surveillance strategies for this ultra-rare syndrome.

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