Poster Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Six cases of ENPP1 gene mutations causing Autosomal Recessive Hypophosphatemic Rickets Type 2 and Generalised Arterial Calcification of Infancy (#354)

Lucy Collins 1 2 , Jessica Sandy 3 4 , Stephanie Ly 3 , Kate Lomax 5 6 , Sarah Black 5 , Fiona McKenzie 7 8 , Eadaoin Hayes 5 , Cathryn Poulton 7 , Craig Jefferies 9 10 , Wendy Hunter 11 , Peter J Simm 2 12 13 , Christine Rodda 13 14 , Andrew Biggin 3 4 , Craig Munns 15 16 , Aris Siafarikas 5 6 8 17
  1. Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Victoria
  2. Department of Endocrinology, Royal Children's Hospital, Melbourne, Victoria
  3. Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales
  4. Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales
  5. Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia
  6. Telethon Kids Institute, University of Western Australia, Perth, Western Australia
  7. Genetic Health Western Australia, King Edward Memorial Hospital, Perth, Western Australia
  8. Medical School - Paediatrics, University of Western Australia, Perth, Western Australia
  9. Te Whatu Ora , Starship Children's Health, Auckland, New Zealand
  10. Department of Paediatrics and Liggins Institute, University of Auckland, Auckland, New Zealand
  11. Te Whatu Ora, Nelson Marlborough, Nelson, New Zealand
  12. Hormone Research, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria
  13. Department of Paediatrics, University of Melbourne, Melbourne, Victoria
  14. Australian Institute for Musculoskeletal Research, Melbourne, Victoria
  15. Child Health Research Centre, Faculty of Medicine, The University of Queensland, Brisbane, Queensland
  16. Department of Endocrinology and Diabetes, Queensland Children's Hospital, Brisbane, Queensland
  17. Institute for Health Research, Notre Dame University, Perth, Western Australia

ARHR2 and GACI occur secondary to biallelic ectonucleotide pyrophosphate/phosphodiesterase 1 (ENPP1) loss-of-function mutations. GACI is a life-threatening condition, often presenting in the neonatal period with heart failure and hypertension, caused by calcification of large- and medium-sized arteries. ARHR2 typically manifests later in life with short stature, rachitic skeletal changes, lower limb deformities, skeletal fragility and bone/muscle pain. We present six cases of homozygous pathogenic variants in the ENPP1 gene causing ARHR2 and/or GACI (Table 1). These cases add to the phenotypic spectrum of this exceedingly rare condition and highlight diagnostic and therapeutic challenges faced by clinicians.

Case 1: Presented with lower limb deformities and pain with radiological evidence of rickets. Subsequent investigations displayed aortic and pulmonary arterial calcification.

Case 2: Presented with lower limb deformities and knee pain. Confirmatory genetic testing was undertaken following her brother’s (Case 1) diagnosis.

Case 3: The diagnosis was made antenatally. Bisphosphonate treatment was instituted in both the pre- and post-natal periods due to the presence of extensive arterial calcifications. Rickets were noted by two years of age.

Case 4: Presented with lower limb deformities and pain. There is no current evidence of arterial calcification nor hypertension. 

Case 5: Presented at three months of age in cardiogenic shock with widespread calcification of large and medium-sized arteries. Bisphosphonate treatment was instituted. 

Case 6: Presented at two weeks of age with right shoulder discomfort, with evidence of pericapsular calcification of the glenohumeral joint. Further imaging revealed aortic, mediastinal and vertebral calcification.

Case 1 and 2 were also found to have a heterozygous pathogenic ALPL variant consistent with hypophosphatasia.

Clinical features, biochemistry, imaging and genetic analyses assist in the diagnosis of ARHR2 and GACI. Treatment to date includes phosphate and calcitriol for ARHR2 and bisphosphonates for GACI. Clinical trials of ENPP1 replacement treatment are currently underway.

 

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