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Challenging arterial calcification disease associated with rare NT5E gene mutation
  1. Giampiero Avruscio1,
  2. Mauro Massussi2,
  3. Angelo Adamo1 and
  4. Alfredo Brusco3,4
  1. 1Department of Cardiac, Thoracic and Vascular Sciences, Angiology Unit, University of Padua, Padova, Italy
  2. 2Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padova, Italy
  3. 3Department of Medical Sciences, University of Turin, Torino, Italy
  4. 4Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, Italy
  1. Correspondence to Professor Alfredo Brusco; alfredo.brusco{at}unito.it

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Description

A 47-year-old woman has been suffering from intermittent claudication since she was 33 years old. The symptoms have slowly worsened during the following years and the patient was unable to walk more than 200 m without leg pain (Leriche-Fontain IIb) at admission. She had a history of hydroxyapatite crystal calcification disease diagnosed at the age of 19 years, after the onset of bilateral symmetric hand arthritis and Raynaud phenomenon.

On physical examination, peripheral pulses were weak at palpation and ankle–brachial index (ABI) measurement was markedly decreased (0.59 on the right and 0.38 on the left leg). Echocolour Doppler ultrasounds of the lower limbs documented severely calcified arteries (figure 1A,B), while no calcification of the carotid walls was found. The patient underwent coronary CT scan, abdominal and thoracic aorta CT scan and lower limbs artery CT scan and X-ray to accurately assess the systemic calcium deposit and to determine the global cardiovascular risk. The images revealed severe calcific arterial disease limited to femoral and popliteal arteries bilaterally with developed collateral neovascularisation (figure 1C,D); coronary arteries and the whole aorta were free from vascular wall calcification. Hands X-ray displayed pericapsular calcification of the finger joints. A wide panel of laboratory examination, including serum calcium and phosphate, vitamin-D, parathyroid hormone, antinuclear antibodies, antiextractable nuclear antigen antibodies were unremarkable.

Figure 1

Imaging panel showing wide calcification of the common femoral artery with signs of partial demodulated blood flow on echocolour Doppler scan (A) with distal evidence of poststenotic flow (B); X-ray (C) and CT scan (D) of both legs displaying the typical pattern of massive arterial calcification with several collateral vessels.

We performed Sanger sequencing of the coding exons of the NT5E gene (table 1) and identified the homozygous c.1608dupA–p.Val537SerfsTer7 variant, consistent with the diagnosis of ‘arterial calcification due to deficiency of CD73’ also known as ‘calcification of joints and arteries’ (CALJA) syndrome (MIM211800). The variant is predicted loss-of-function, described in another case with the disease1 and reported in ClinVar database (VCV000029689.1). Segregation analysis showed both parents were heterozygotes (figure 2).

Table 1

PCR primers used for Sanger sequencing of NT5E gene

Figure 2

Family pedigree and electropherograms of the pathogenic NT5E gene variant in exon 9.

Arterial calcification due to deficiency of CD73 is a rare syndrome defined by arterial calcification that targets vessels below the diaphragm, notably the large lower extremity arteries, and spares coronary circulation. Mutations in NT5E gene, encoding for the plasma membrane enzyme CD73 which hydrolyses adenosine monophosphate (AMP) to adenosine and inorganic phosphate (Pi), were identified in adults from three different families affected with the disease.1 From this first description, only four other families have been described worldwide.2–5

In vitro assays demonstrated that CD73-deficient fibroblasts reduced extracellular adenosine levels and enhanced the activity of tissue non-specific alkaline phosphatase, which generates procalcifying extracellular Pi. CALJA is an adult-onset disease, with the first symptoms occurring during the second decade of life. The pathogenetic calcification progresses for years, possibly leading to neoangiogenic vascular remodelling and development of small collateral vessels. This fact could explain the marked decrease of ABI index with a mild functional impairment of our patient.

An approved therapy for patients affected by arterial calcification due to deficiency of CD73 has not yet been available, however, an ongoing clinical trial is testing the effectiveness and the safety of etidronate as a standard treatment for this syndrome.

Learning points

  • Arterial calcification due to deficiency of CD73 is a rare genetic syndrome secondary to NT5E gene mutation characterised by arterial calcification which selectively targets vessels below the diaphragm together with periarticular calcification.

  • A complete imaging evaluation with duplex ultrasounds, CT scan and X-ray is of utmost importance to identify the typical arterial and articular calcification pattern.

  • Arterial calcification due to deficiency of CD73 treatment is still a challenge with bisphosphonates as the only pharmacological therapy under evaluation by clinical trials.

Acknowledgments

We would like to thank the patient for participating in this study.

References

Footnotes

  • Contributors GA, MM and AA performed and interpreted clinical evaluation and drafted the manuscript. AB performed and interpreted genetic analyses. All authors revised the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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