GALNS c.304GA (p.Ala102Thr) variant of uncertain significance (VUS) as a cause of Morquio A disease

Cristobal Colon ¹ Alberto Hernandez-Sanchez ^2,3 Cristina Miguel ^3,4 Sandra Santos ^3,4 Teresa Gonzalez ^2,3 Danylo Palomino ⁵ Francisco Fernandez ⁵ Sandra Gomez ^2,3 Borja Puertas ^2,3 David Alonso ^2,3 Elena Alejo ^2,3 Jose Maria Navarro ^2,3 Carlos Puerta ^2,3 Pablo Garcia ^2,3 Evelyn Gabriela Zapata ^2,3 Alicia Pablos ^2,3 Jesus Hernandez ^2,3 Jose Ramon Gonzalez ^2,3 Emilia Pardal ⁵ Rocio Benito ^3,4 Jose Maria Bastida ^2,3

¹Complexo Hospitalario Universitario de Santiago de Compostela, Spain
²Complejo Asistencial Universitario de Salamanca (CAUSA), Spain
³Instituto de Investigación Biomédica de Salamanca (IBSAL), Spain
⁴Universidad de Salamanca, IBSAL, IBMCC, CSIC, Centro de Investigacion del Cancer, Spain
⁵Hospital Virgen del Puerto, Spain

Background

We present a 35-year-old male patient with functional impotence in both hands for approximately 2 years. He reported pain in the metacarpophalangeal joints of both hands.

Case Study and Results

His personal history includes gait disturbances since the age of 4 years with intermittent limping. At age 11 years, he was diagnosed with Legg-Calvé-Perthes disease, initially receiving orthopaedic treatment. A varicose osteotomy was performed at 14 years and finally, he underwent a bilateral total hip arthroplasty at 25 years old. His younger brother (33 years old) was also diagnosed with Legg-Calvé-Perthes disease in childhood.

The physical examination revealed kyphoscoliosis with short phalanges, bilateral second and third metacarpophalangeal joint pain on palpation and flexion limitation but no signs of inflammatory or connective tissue diseases were observed.

The hemogram showed mild thrombocytosis (475,000/µL) with a discrete elevation of C-reactive protein and erythrocyte sedimentation rate, but all autoimmune markers were negative.

Plain radiographs of both hands showed necrotising osteoarticular lesions in the second and third metacarpophalangeal joints bilaterally.

Genetic analysis revealed a homozygous c.304GA (p.Ala102Thr) mutation in the GALNS gene of the patient and his sibling and it was heterozygosis in both parents.

The galactose-6-sulfate sulfatase concentration was 16 nmol/17h/mg in the index case (reference values 26−174) and 13 nmol/17h/mg in his brother, confirming the diagnostic suspicion of MPS type IV-A.

Discussion and Conclusion

According to ACGM criteria, the variant in this family is classified as VUS. To clarify the pathogenicity of the variant, the whole family together were reevaluated to complete the anamnesis, physical examination and complementary tests, confirming that this variant is causing a mild Morquio phenotype.