ISSN 1662-4009 (Online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 5.5 | DOI: 10.1530/ey.16.5.5

Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2

Pekkinen M, Terhal PA, Botto LD, Henning P, Mäkitie RE, Roschger P, Jain A, Kol M, Kjellberg MA, Paschalis EP, van Gassen K, Murray M, Bayrak-Toydemir P, Magnusson MK, Jans J, Kausar M, Carey JC, Somerharju P, Lerner UH, Olkkonen VM, Klaushofer K, Holthuis JC & Mäkitie O


Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki Finland


Abstract: JCI Insight. 2019; Apr 4;4(7).

In brief: This study describes a novel autosomal dominant form of primary osteoporosis caused by SGMS2 mutations in six families. A recurrent mutation p.Arg50* led to primary osteoporosis in four families, whereas missense mutations p.Ile62Ser and p.Met64Arg caused a much more severe bone phenotype with spondylometaphyseal dysplasia and neonatal fractures.

Comment: Osteoporosis is characterized by low bone mineral density and deteriorated bone microstructure, leading to increased fragility fractures. Genetic factors play a major role in determining bone mass and risk of fractures, but thus far only few genes underlying familial forms of bone fragility disorders have been described (1). Most commonly such genes relate to type I collagen but other cellular pathways have also been implicated.

Here, an international group of investigators report on a novel form of dominantly inherited osteoporosis with remarkable phenotypic variability. Heterozygous mutations in SGMS2 were identified as the cause of the disease in six unrelated families using next-generation sequencing techniques. SGMS2 encodes sphingomyelin synthase 2, an enzyme involved in sphingolipid metabolism. Mutations led to changes in the enzyme function and disturbed bone metabolism and mineralisation through mechanisms so far partially unknown. Depending on the type of SGMS2 mutation, affected children and adults presented with isolated osteoporosis, osteoporosis associated with sclerotic skull lesions (‘calvarial doughnut lesions’), or severe spondylometaphyseal dysplasia and short stature. Some subjects also had neurological symptoms, transient facial nerve paralysis being a particularly common feature, suggesting that this may be a distinctive marker of this form of osteoporosis.

Bone tissue samples collected from three patients demonstrated significant abnormalities with disturbed bone microarchitecture and defective bone mineralisation. The changes were particularly dominant in the cortical bone, in line with an abundant expression of SGMS2 in cortical bone. The current evidence suggests that sphingomyelin synthase 2 plays an important role in bone matrix mineralisation, the phenotypic variability corresponds to variable enzyme activity, both intracellularly and at the plasma membrane.

These novel findings are of great interest not only in the field of rare bone diseases but also more widely in osteoporosis research, since such new discoveries may uncover novel targets for drug development. Future studies are awaited to learn more about the phenotypic variability and the shared mechanisms behind bone fragility and neurological symptoms.

Reference: 1. Marini JC, Forlino A, Bächinger HP, Bishop NJ, Byers PH, Paepe A, Fassier F, Fratzl-Zelman N, Kozloff KM, Krakow D, Montpetit K, Semler O. Osteogenesis imperfecta. Nat Rev Dis Primers. 2017 Aug 18;3:17052.