Endocrine Abstracts

JOINT1809

Introduction: Spondyloepiphyseal dysplasia congenita (SEDC) is a rare autosomal dominant skeletal dysplasia (incidence 1:100,000 live births), caused by mutations in the COL2A1 gene, leading to abnormal type II collagen. Reported clinical manifestations include disproportionate short stature, cleft palate, scoliosis, kyphosis, hip deformities, atlantoaxial instability, hearing loss and visual abnormalities. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder (1:250,000) caused by mutations in the SLC4A3 gene, associated with urinary phosphate wasting. While homozygous mutations cause rickets, heterozygous mutations typically cause hypercalciuria without bone disease and potential treatment options include oral phosphate/fluconazole. We report the co-occurrence of SEDC with a heterozygous HHRH mutation in a Sri Lankan adolescent, where extended genetic testing helped clarify the complex clinical picture and guide management.

Case Presentation: A 14-year and 9-month-old boy, the fourth child of healthy non-consanguineous parents, was admitted with exertional dyspnoea and orthopnoea for 3 months. He had multiple congenital anomalies, including cleft palate (surgically repaired), atrial septal defect (spontaneous closure), and congenital talipes equinovarus, with poor growth, kyphoscoliosis, coxa vara, and flat feet. He had normal intelligence. On examination, he had extreme short stature (height age: 6 years) with low BMI, muscle wasting, joint deformities, upper motor neuron signs in upper and lower limbs, and no abnormalities in cardiovascular and respiratory systems. There were no features of rickets. He was peripubertal (Tanner III). His skeletal survey was suggestive of skeletal dysplasia, while cervical spine MRI showed odontoid hypoplasia and atlantoaxial instability. Sleep study showed nocturnal hypoventilation and pulmonary function tests indicated reduced vital capacity. He also had bilateral nephrocalcinosis with hypercalciuria, with normal serum calcium, phosphate, alkaline phosphatase, 25-OH-D and PTH levels. Whole exome sequencing confirmed SEDC, caused by a likely pathogenic heterozygous COL2A1 variant; however, this did not explain nephrocalcinosis. Further analysis revealed another heterozygous likely pathogenic variant in the SLC34A3 gene, with elevated serum 1,25-dihydroxy vitamin D levels, consistent with a mild phenotype of HHRH. He underwent neurosurgical stabilisation, leading to significant improvement in respiratory and neurological complications, while phosphate supplementation was commenced to reduce the hypercalciuria associated with HHRH. Genetic counselling was provided.

Conclusion: This case highlights the value of genetic testing in managing patients with complex clinical features not attributable to a single disorder. While genetic testing is not easily accessible in low-middle-income countries, it can be of great value in diagnosing and managing patients with complex manifestations where diagnosis remains elusive.