Bone Abstracts

Background: 3M syndrome is a primordial growth disorder caused by mutations in CUL7, OBSL1 or CCDC8. Affected individuals have severe short stature for which growth hormone (GH) therapy may have a role¹. We present a 10-year-old girl from Sri Lanka with 3M syndrome-2 due to a mutation in OBSL1 gene, with good short-term response to growth hormone therapy.

Presenting Problem: The only child of second-degree consanguineous parents, both themselves children of second cousin marriages presented with severe short stature. She was born at 35 weeks of gestation with a birth length of 43 cm (<3rd centile), birth weight of 2.2 kg (10th centile) and head circumference of 33 cm (50th–90th centile). At 9 years of age her height was −5.5S.D., well below the mid-parental height range, and height velocity was 3 cm/y. She had features suggestive of 3M syndrome including upturned fleshy tipped nose, frontal bossing, triangular face, prominent heels, short chest and lumbar lordosis with mild scoliosis.

Clinical management: On investigation, basic biochemistry, Insulin-like Growth Factor-1 (IGF-1), stimulated peak growth hormone (GH) level, karyotype and mucopolysaccharidosis screening test results were normal. 3M syndrome was suspected, and genetic testing identified a homozygous splice site mutation in the Obscurin-like protein 1 (OBSL1) gene (c.2134+1G>A (chr2:220431551), associated with 3M syndrome². Both parents were heterozygous for the same mutation. After counselling, she was commenced on GH therapy (5 mg/m² per week). In the first 6 months of therapy her HV increased to 4.8 cm/year, and height improved by +0.6 S.D. As IGF-1 level was within normal range, GH dose was increased to 5.5 mg/m² per day. Height gain and serum IGF-1 levels will be monitored regularly.

Discussion: This Sri-Lankan girl with 3M syndrome-2 due to OBSL1 gene mutation showed a reasonable short-term response to growth hormone therapy with height S.D. score improving from −5.5S.D. to −4.9S.D. after 6 months of therapy.

References: 1. Hanson, Dan, et al., ‘Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling.’ Journal of molecular Endocrinology, 49.3(2012):267–275.

2. Guo, Michael H., et al., ‘Whole exome sequencing to identify genetic causes of short stature’, Hormone Research in Paediatrics, 82.1(2014):44–52.

Disclosure: The authors declared no competing interests.