Generalised arterial calcification of infancy

Clinical features of generalised arterial calcification of infancy (GACI) are outlined below.

Antenatal period

• Polyhydramnios, fetal hydrops and pericardial effusion.
• Hyperechogenicity of major arteries and kidneys.

Neonatal period

• Heart failure symptoms, such as:
  • increased work of breathing;
  • hepatomegaly;
  • feeding difficulties; and
  • failure to thrive.
• High blood pressure.
• Reduced or absent pulses.
• Scan findings (echocardiogram or vascular ultrasound) of arterial calcification (mainly coronary and pulmonary arteries, ascending aorta and aortic arch) or calcification of the cardiac valves.
• Joint calcifications (found in about 30% of babies with GACI), most frequently in the hip, ankle, wrist, shoulder, elbow, knee, foot and/or sternoclavicular joints.

Infancy

• Gastrointestinal complications such as gut wall inflammation or intestinal obstruction due to stenosis, presenting with irritability and/or bloody stools.
• Hearing loss (conductive, sensorineural or mixed) caused by calcification of the arteries supplying the inner ear and/or immobility of the ear bone (stapedovestibular ankylosis).
• Dental issues such as teeth that don’t fully erupt (infraocclusion), over-retained primary teeth, ankylosis, slow orthodontic movement and an excessive build up of normal cementum on the roots of the teeth.
• Hypophosphataemia and rickets or osteomalacia (found in GACI type 1, caused by variants in ENPP1).

Older patients

• Pseudoxanthoma elasticum (skin changes and retinal angioid streaks).
• Cervical spine fusion.

• GACI type 1 is the most common form, occurring in two thirds of patients and caused by compound heterozygous or homozygous variants in the ENPP1 gene on chromosome 6q23.2.
• GACI type 2 is caused by compound heterozygous or homozygous variants in the ABCC6 gene on chromosome 16p13.11.
• There can be considerable intrafamilial variability in phenotype.

GACI has an autosomal recessive pattern of inheritance. This means that a child whose parents are both carriers of an associated genetic variant has a 25% chance of developing the condition.

• GACI is a rare condition. There are currently no dedicated national guidelines, but management requirements (monitoring and treatment) will need to be individualised to the features present and will need to address likely future complications.
• Input from a multidisciplinary team with experts from cardiology, endocrinology, renal, ENT, orthopaedics and other specialties is likely to be required to manage and pre-empt complications.

Gene-directed therapies and clinical trials

Several clinical trials into ENPP1 replacement therapy for GACI are currently underway, though they are unlikely to be able to reverse established cases.

For clinicians

• GeneReviews: Generalised arterial calcification of infancy
• National Organization for Rare Disorders: Generalized arterial calcification of infancy
• NHS England: National Genomic Test Directory
• OMIM: #208000 Arterial calcification, generalized, of infancy, 1; GACI1
• OMIM: #614473 Arterial calcification, generalized, of infancy, 2; GACI2
• Orphanet: Generalized arterial calcification of infancy

For patients

• Children’s Hospital of Philadelphia: Generalized arterial calcification of infancy (GACI)
• GACI Global
• Genetic and Rare Diseases Information Center: Generalized arterial calcification of infancy
• Nicklaus Children’s Hospital: Generalized arterial calcification of infancy