Management of Idiopathic Infantile Arterial Calcification (IIAC / GACI)

Key Management points for Idiopathic Infantile Arterial Calcification (IIAC / GACI):

1. Bisphosphonate therapy (etidronate, pamidronate)

2. Management of heart failure

3. Control of severe hypertension

4. Supportive care for end-organ dysfunction

5. Monitoring and management of electrolyte abnormalities

6. Genotype-guided care (ENPP1 vs ABCC6)

7. Treatment of ENPP1-related hypophosphatemic rickets (if develops later)

8. Consider experimental therapies (e.g., ENPP1 enzyme replacement—investigational)

9. Genetic counseling for family

10. Regular imaging follow-up (echo, CT/MRI for

 calcification progression)

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Management of Idiopathic Infantile Arterial Calcification (GACI): A Detailed Review

Idiopathic Infantile Arterial Calcification (IIAC), also known as Generalized Arterial Calcification of Infancy (GACI), is a rare but life-threatening disorder characterized by extensive calcification and stenosis of medium and large arteries. It typically presents in the neonatal period with severe cardiovascular compromise. Management is challenging, largely supportive, and relies on early detection and targeted therapy based on evolving pathophysiological insights.

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Understanding the Disease

IIAC is most often caused by ENPP1 and ABCC6 mutations. ENPP1 deficiency leads to reduced pyrophosphate (PPi), a key inhibitor of vascular calcification, while ABCC6 mutations cause a PXE-like systemic calcification process. Both result in progressive arterial mineralization, hypertension, and high infant mortality if untreated.

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Goals of Management

1. Halt or reduce progression of arterial calcification

2. Improve cardiac function and reduce heart failure burden

3. Control severe hypertension

4. Prevent long-term complications, especially in ENPP1-related disease

5. Provide genetic and long-term multidisciplinary care

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1. Bisphosphonates (Foundation of Therapy)

Bisphosphonates remain the most widely used and supported treatment for GACI. Their mechanism mimics pyrophosphate, reducing vascular calcification.

Commonly Used Agents

Etidronate (most reported; effective in multiple case series)

Pamidronate

Zoledronic acid (rarely used due to potency; limited data)

Mechanism

Bind hydroxyapatite crystals

Prevent further mineral deposition in arterial walls

Reduce vascular stiffness and stenosis progression

Evidence

Case reports and small cohorts have shown:

Improved survival when treatment begins early

Regression of arterial calcification in some infants

Reduction in left ventricular hypertrophy and systemic pressures

Monitoring

Serum calcium, phosphate

Renal function

Skeletal effects, as prolonged etidronate use may cause osteomalacia

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2. Management of Heart Failure

Due to widespread arterial stenosis and increased afterload, infants often present with heart failure.

Therapeutic Components

Diuretics: To reduce preload

ACE inhibitors (if tolerated): Reduce afterload

Beta-blockers: Improve cardiac workload

Inotropes (milrinone/dobutamine): For severe systolic dysfunction

Avoid drugs that worsen hypocalcemia when bisphosphonates are being used

Monitoring Tools

Serial echocardiography

BNP/NT-proBNP

Blood pressure monitoring

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3. Control of Hypertension

Hypertension is nearly universal in IIAC due to:

Narrowed calcified arteries

Renovascular involvement

Management Options

ACE inhibitors / ARBs

Beta-blockers

Calcium channel blockers

Diuretics for volume control

IV antihypertensives (e.g., nitroprusside) for crisis scenarios

Goals

Prevent hypertensive encephalopathy

Reduce cardiac workload

Improve end-organ perfusion

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4. Supportive Management of End-Organ Effects

Arterial calcification can cause:

Renal ischemia

Heart failure

Hepatosplenomegaly

Neurological complications

Supportive Measures

Adequate nutrition and growth monitoring

Management of renal insufficiency

Treat metabolic acidosis

Respiratory support if CHF or pulmonary hypertension develops

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5. Genotype-Guided Care

ENPP1-Associated GACI (Type 1)

ENPP1 mutations lead to lifelong low PPi levels.

Key Considerations

Higher likelihood of early mortality

Survivors may develop autosomal recessive hypophosphatemic rickets (ARHR2)

Requires:

Phosphate supplementation

Active vitamin D (calcitriol) during childhood

Careful monitoring to avoid hyperphosphatemia (worsens calcification)

ABCC6-Associated GACI (Type 2)

Often overlaps with pseudoxanthoma elasticum

Tends to have better long-term survival

No specific targeted therapy yet

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6. Emerging and Experimental Therapies

ENPP1 Enzyme Replacement Therapy

Recombinant ENPP1 therapy (e.g., INZ-701) is under investigation with promising preclinical and early trial results:

Increases plasma PPi

Reduces vascular calcification

Potential to modify long-term outcomes

Phosphate Modulation

Targeted manipulation of FGF23/FGF23 inhibitors is theoretical but not established.

Other Investigational Approaches

Sodium thiosulfate (mineralization inhibitor)—limited neonatal experience

Gene therapy studies (preclinical phase)

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7. Genetic Counseling and Family Planning

Because IIAC is autosomal recessive:

Parents should receive genetic counseling

Families benefit from carrier testing and options for prenatal diagnosis in future pregnancies

Prenatal ultrasound may detect vascular changes

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8. Imaging and Follow-Up Strategy

Initial Evaluation

Echocardiography (myocardial function, LV hypertrophy, pulmonary pressures)

CT scan for arterial calcification

Doppler studies for stenosis

Follow-Up

Serial echocardiograms

Blood pressure checks

Periodic CT/MRI for calcification progression (minimize radiation)

Renal function monitoring

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Prognosis

Historically, mortality was extremely high (70–90% in infancy). Introduction of bisphosphonates has improved outcomes significantly, with many children now surviving into later childhood, especially in ABCC6-related disease.

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Conclusion

Management of Idiopathic Infantile Arterial Calcification is complex and multidisciplinary. Early diagnosis and bisphosphonate therapy remain the cornerstone of improving survival. Supportive management of cardiac function, hypertension, and end-organ complications is essential. Emerging therapies, especially ENPP1 enzyme replacement, offer hope for altering the natural course of this previously fatal condition. Genetic counseling and long-term monitoring are critical for optimizing outcomes.