Homozygous variant in <em>Cathepsin K </em>in a family with multiple cases of bilateral atypical femoral fracture but without clinical features of pyknodysostosis — ASN Events
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Homozygous variant in Cathepsin K in a family with multiple cases of bilateral atypical femoral fracture but without clinical features of pyknodysostosis (#87)

Sue Lynn Lau 1 , Aideen M McInerney-Leo 2 , Euphemie Landoa-Bassonga 3 , Daryl Goldman 4 , Thomas Hadwen 5 , Warrick Inder 6 , Matt A Brown 2 , Paul J Leo 2 , Nathan Pavlos 3 , Emma L Duncan 2 7
  1. Dept of Endocrinology, Westmead Hospital, Sydney, NSW, Australia
  2. Queensland University of Technology, Brisbane, QLD, Australia
  3. University of Western Australia, Perth, WA, Australia
  4. School of Medicine, University of Queensland, Brisbane, Qld, Australia
  5. Dept of Endocrinology, Nambour Hospital, Sunshine Coast, Qld, Australia
  6. Dept of Endocrinology, Princess Alexandra Hospital, Brisbane, Qld, Australia
  7. Royal Brisbane and Women's Hospital, Butterfield St, QLD, Australia

Atypical femoral fractures (AFF) are minimal trauma fractures in the subtrochanteric region or femoral shaft, with characteristic radiological appearance. AFF have been reported after bisphosphonate exposure but also occur in bisphosphonate-naïve individuals (e.g. in osteopetrosis, hypophosphotaemic rickets and pyknodysostosis).

We identified a consanguineous family in whom three siblings (two female, one male) sustained bilateral minimal trauma AFF, without bisphosphonate exposure. The proband presented with bilateral AFF aged 48. Her height was 151cm with weight 58.3kg; and she had normal dentition and no dysmorphic features. Bone mineral density showed t-scores of +2.02 at femoral neck and +2.75 at lumbar spine. Skeletal survey showed mild thoracolumbar scoliosis with lumbosacral degeneration (specifically, no evidence of osteopetrosis or pyknodysostosis).

Whole exome sequencing of the two affected sisters demonstrated a homozygous variant in the splice site of exon 6 of Cathepsin K – CTSK(c.784+3A>C). Variant frequency in a control database of 60000 individuals was 0.0000577, with no homozygotes.

Osteoclasts cultured from peripheral blood monocytes were able to form tartrate-resistant acid phosphatase positive osteoclasts equivalent to controls. The proband’s samples exhibited reduced osteoclastic bone resorptive activity (smaller shallower resorption pits, fewer resorption trails). Confocal immunofluorescent analysis showed reduced CTSK expression. Immunoblot demonstrated markedly reduced expression of both the pro-Cath K and mature forms of the CSTK protein expression.

33 CTSK mutations have been identified in 59 families with pyknodysostosis, two thirds occurring in the mature domain, with hotspots in exons 6 and 7. No splice site mutations have been reported previously.

CTSK was sequenced completely in ten further cases with AFF after minimal/no bisphosphonate exposure. No mutations were observed.

These data suggest that CTSK mutations can cause AFF in individuals without other clinical features of pyknodysostosis or other skeletal dysplasia. However, CTSK mutations do not appear to be a common cause of AFF.

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