Endocrine Abstracts

Mutations in GHR, STAT5B and IGF1 lead to GH-insensitivity but often the cause of reduced GH-sensitivity remains unknown. We describe the identification of a mutation in the MVK gene encoding mevalonate kinase (MK) in a pedigree investigated for STAT5B-deficiency.

A 15-year-old male born to consanguineous parents was referred for short stature (height 125.8 cm; −5.6 SDS) and arthritis. He presented, aged 2 years, with fever and poly-arthritis, and continued to have episodes of fever, hepatosplenomegaly and gastritis/duodenitis, and developed cataracts. A liver biopsy showed sclerosing cholangitis. He was on steroid treatment for presumed auto-immune disease. Pubertal development was delayed. The peak GH in response to provocation was 6 μg/l. Plasma IGF1-concentration was 27 μg/l (140–887) and IGFBP3 1.05 mg/l (3–8 mg/l). GH-treatment (6–10 mg/m² per week) had little effect on growth and IGF1-concentration. One affected sister died of peritonitis. Two sisters had short stature, poly-arthritis and delayed puberty; one received GH-treatment with little effect. Six siblings were unaffected.

Microsatellite analysis and homozygosity screening of three affected and four unaffected family members pointed to a region on chromosome 12q24, not containing STAT5B. Candidate gene sequencing excluded SOCS2 mutations and detected a novel homozygous missense mutation (p.Val310Leu) in MVK in all three affected siblings, affecting a highly conserved valine; a previously described p.Val310Met mutation resulted in severe MK-deficiency. The mother and two unaffected siblings were heterozygous. The third unaffected sibling and 100 controls did not carry the mutation. MK is the enzyme following HMG-CoA in isoprenoid and cholesterol biosynthesis, important for several cellular processes. MK-deficiency leads to mevalonic aciduria, characterised by short stature, developmental delay, hepatosplenomegaly, arthritis, cataract and periodic inflammation, or the milder hyperimmunoglobulinaemia D. In conclusion, mevalonic aciduria was revealed in a pedigree with presumed GH-insensitivity. Growth failure is likely due to a combination of liver dysfunction, inflammation, steroid treatment and possibly MK-deficiency directly.