Oral Presentation ANZBMS-MEPSA-ANZORS 2022

A RUNX1 germline mutation as a novel cause of previously unexplained severe osteoporosis in a young male (#56)

Tomasz J Block 1 2 , Cat Shore-Lorenti 3 , Roger Zebaze 4 , Peter Kerr 5 , Anna Kalff 6 , Andrew Perkins 6 , Peter R Ebeling 1 4 , Frances Milat 1 3 4
  1. Department of Endocrinology, Monash Health, Melbourne , VIC, Australia
  2. Department of Diabetes, Monash University, Melbourne, Victoria, Australia
  3. Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, Victoria, Australia
  4. Department of Medicine, Nursing & Health Sciences, Monash University, Melbourne, Victoria, Australia
  5. Department of Nephrology, Monash Health, Melbourne, Victoria, Australia
  6. Department of Pathology, Monash Health, Melbourne, Victoria, Australia

A 44-year-old male presented for review of osteoporosis in the setting of several fractures including clavicle (high-impact) at age 16 as well as minimal trauma ankle and wrist fractures in his early twenties. Following a vertebral and elbow fracture sustained from a skateboarding fall at age 38, severe osteoporosis was diagnosed on dual energy x-ray absorptiometry (DXA) with a bone mineral density (BMD) Z-score of -3.6 at the spine and -2.3 at the hip. Family history for osteoporosis was positive for in his mother who had had a minimal trauma ankle fracture in her fifties. He had no glucocorticoid exposure or chronic illness. A spine MRI in July 2017 showed T6 and T7 vertebral fractures. He had also undergone jaw surgery for idiopathic condylysis in the past. He was a non-smoker with minimal alcohol intake.

An extensive screen for secondary causes of osteoporosis was negative, apart from mild vitamin D deficiency, which was promptly treated. Investigations revealed a normal serum tryptase and full blood count. The bone formation marker, serum P1NP, was 56 μg/L (N 15-80 μg/L) (1) and serum CTX was 388 ng/L (N 100-600 ng/L); his serum 25-hydroxyvitamin D had increased to 88 nmol/L. Serum calcium, phosphate, PTH, thyroid function tests, glucose, kidney (eGFR >90 ml/min/1.73m2) and liver function tests were all normal, and his testosterone was normal, as was the ESR. Coeliac disease autoantibodies were negative, as was serum and urine electrophoresis and urine calcium excretion. In addition, a radionuclide bone scan did not demonstrate any abnormal uptake.

Treatment comprised optimising dietary calcium and initiating regular progressive resistance training exercise and commencing weekly 35 mg risedronate. His BMD improved, with a spinal Z-score of -2.8 and -1.9 at the hip within 2 years. In 2021, he had increased lethargy and malaise with associated weight loss of 8 kg over several months, with the diagnosis of a new normochromic and normocytic anaemia with a Hb of 95 g/L (baseline 130 g/L). General examination was unremarkable, he was normotensive with a standing blood pressure of 114/75 mmHg and there were no rashes or arthropathies. Further investigations revealed microscopic haematuria with glomerular RBCs and an elevated creatinine of 117 μmol/L (baseline 78 μmol/L) and mild proteinuria with an albumin/creatinine ratio (ACR) of 4.3. ANCA, a further myeloma screen, ANA, dsDNA, RF and hepatitis serology were negative, and an abdominal ultrasound was normal.

A subsequent renal biopsy confirmed mild IgA nephropathy and he was commenced on candesartan 16 mg daily for long-term renal protection. However, given his ongoing unexplained mild normochromic normocytic anaemia, a haematology review in 2022 recommended a bone marrow biopsy which demonstrated a hypocellular marrow and, in addition, a germline RUNX1 single nucleotide variant mutation (Arg250His) was identified. As this mutation affects osteoblasts and bone formation, risedronate was ceased and the anabolic agent, teriparatide, was commenced. A recent HRpQCT at the tibia and left radius prior to teriparatide commencement demonstrated profound reductions in trabecular vBMD (Tb.vBMD), trabecular number (Tb.N) (<2nd centile for age), as well as increased intra cortical porosity (Ct.Po) (< 2nd centile for age).

A previous high throughput genetic screening study has revealed that RUNX1 is one of the most frequently mutated genes in myelodysplastic syndromes (MDS), found in approximately 10% of cases (2). The patient’s haemoglobin remain has remained stable, with no evidence of neutropenia or thrombocytopenia. The patient will have close clinical follow-up with haematology, as well as ongoing renal and endocrinology review. His response to teriparatide will be monitored with repeat DXA and HRpQCT at 12 months.

Literature review

Runt-related transcription factor 1 (Runx1) and other Runx family proteins including Runx2 and Runx3 play critical roles in cellular differentiation (3) including definitive haematopoiesis during embryonic development (4) and fracture healing (5, 6). A broad range of both germline and somatic RUNX1 mutations have been associated with various myeloid and lymphoblastic malignancies (7, 8). From a bone viewpoint, Runx1 induces mesenchymal stem cells into early stages of chondrogenesis (9, 10), whilst Runx2 in involved in osteoblast differentiation and skeletal development (11) with interactions with multiple co-regulators and transcription factors involved in the osteoblastic lineage (12). The expression of Runx1 has been detected in osteoblast progenitors, pre-osteoblasts, and mature osteoblasts, and our understanding of the role of Runx1 in bone formation is evolving.

A recent study involving Runx1 conditional knockout mice has revealed that Runx1 enhances osteoblast lineage commitment thereby promoting bone formation and inhibiting adipogenesis by up-regulating the Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 and WNT/β-catenin signalling pathways, which are involved in bone formation to maintain postnatal and adult bone homeostasis (13).  Specifically, it was shown that Runx1 deficiency impaired both BMP and TGF-β signalling in the femur, tibia and calvarial cells of the knockout mice, in addition to a down-regulation of active β-catenin protein levels in the trabecular bone due to impaired β-catenin signalling. Interestingly, in an ovariectomised animal model to simulate estrogen depletion-induced osteoporosis, Runx1 overexpression via adeno-associated virus (AAV)-mediated gene expression through calvaria adjacent subcutaneous injection, significantly increased bone volume.

Given the role of Runx1 as a central regulator of osteogenesis, we suggest that the RUNX1 mutation identified in this patient with a normochromic normocytic anaemia and severe osteoporosis is pathogenic. In addition, Runx1 may represent a potential therapeutic pathway for novel treatment strategies for osteoporosis and a range of degenerative bone diseases.

Take Home Points

  • In a young patient with multiple/unusual minimal trauma fractures, it is imperative to consider rarer causes especially when appearing in a constellation with other clinical signs and symptoms.
  • In young patients with fragility fractures, especially multiple ones, impaired bone formation should also be considered.
  • A multidisciplinary approach is often required from a diagnostic and management perspective.
  • In the context of a condition adversely affecting bone formation, together with profound reductions in BMD, an anabolic agent would be the initial treatment of choice.
  • Runx1 has been recently shown to play a key role in the regulation of osteogenesis mediated by the BMP and WNT signalling pathways.
  • The Runx family of proteins represent potential therapeutic targets for novel osteoporosis therapies.
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