Lucy Collins, Jessica Sandy, Stephanie Ly, Kate E. Lomax, Sarah Black, Fiona McKenzie, Eadaoin Hayes, Cathryn Poulton, Craig Jefferies, Wendy Hunter, Peter Simm, Christine Rodda, Andrew Biggin, Craig Munns, Aris Siafarikas
Royal Children’s Hospital. Monash University. Children’s Hospital at Westmead. University of Sydney. Perth Children’s Hospital. University of Western Australia. King Edward Memorial Hospital. Starship Children’s Health. University of Auckland. Nelson Marlborough. Murdoch Children’s Research Institute. Australian Institute for Musculoskeletal Research. University of Queensland. Queensland Children’s Hospital. Notre Dame University.
Australia and New Zealand
Journal for Bone and Mineral Research Plus
JBMR Plus 2025; 9(Suppl 5): v47-v57
DOI: 10.1093/jbmrpl/ziae174
Abstract
Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) and generalized arterial calcification of infancy (GACI) occur secondary to biallelic ectonucleotide pyrophosphate/phosphodiesterase 1 (ENPP1) loss-of-function pathogenic variants. GACI is a life-threatening condition, often presenting in the neonatal period with heart failure and hypertension, caused by calcification of the media in large- and medium-sized arteries. ARHR2 typically manifests later in life. Children with ARHR2 commonly exhibit short stature, rachitic skeletal changes, progressive deformities of the lower limbs, skeletal fragility and bone/muscle pain. We present six cases of homozygous pathogenic variants in the ENPP1 gene causing ARHR2 and/or GACI. 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 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 neither any current evidence of arterial calcification nor hypertension. Case 5: Presented at 3 mo of age in cardiogenic shock with widespread calcification of large and medium-sized arteries. Bisphosphonate treatment was instituted. Case 6: Presented at 2 wk of age with right shoulder discomfort, with evidence of glenohumeral joint calcification. Further imaging revealed aortic, mediastinal, sternoclavicular joint and vertebral spinous process 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. Conventional therapy, oral phosphate and calcitriol for ARHR2 and bisphosphonates for GACI, have been utilized for many years. ENPP1 replacement treatment remains an exciting prospect for future management of ARHR2 and GACI secondary to loss of function of ENPP1.
Category
Segmental Pulmonary Arterial Disease
Genetic Factors Associated with Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes