Pregnancy-Associated Plasma Protein-A2 (PAPP-A2) Deficiency

Pregnancy-Associated Plasma Protein-A2 deficiency is a rare genetic condition that affects how your body regulates growth hormones. People with this condition lack a specific enzyme called PAPP-A2, which normally helps release insulin-like growth factor 1 from its carrier proteins in the blood. Without this enzyme, IGF-1 remains bound and cannot work properly in the body.

This creates an unusual pattern in blood tests. Total IGF-1 levels appear extremely high, but the free or bioavailable IGF-1 that your cells can actually use stays very low. This mismatch explains why people with PAPP-A2 deficiency often experience growth problems despite high IGF-1 readings on standard blood panels.

The condition is inherited in an autosomal recessive pattern. This means both parents must carry a gene mutation for a child to develop the deficiency. PAPP-A2 deficiency was only identified in recent years, so doctors are still learning about its full range of effects on health throughout life.

• Short stature or slowed growth in childhood
• Delayed bone age compared to chronological age
• Low bone mineral density or thin bones
• Normal intelligence and cognitive function
• Paradoxically high IGF-1 on blood tests
• Low free or bioavailable IGF-1 levels
• Normal or low-normal growth hormone levels

Many people with mild PAPP-A2 deficiency may not realize they have the condition until blood work shows unusual IGF-1 patterns. Some individuals are diagnosed only when investigating unexplained short stature or bone health concerns in childhood or adolescence.

PAPP-A2 deficiency is caused by mutations in the PAPPA2 gene. This gene provides instructions for making the PAPP-A2 enzyme, which normally cleaves or cuts the proteins that bind IGF-1 in your bloodstream. When both copies of the gene are mutated, the body cannot produce functional PAPP-A2 enzyme. IGF-1 stays trapped in its bound form and cannot reach cells to promote normal growth.

The condition runs in families and follows an autosomal recessive inheritance pattern. Parents who each carry one mutated gene typically show no symptoms but have a 25 percent chance with each pregnancy of having a child with the deficiency. Consanguinity, or having children with a close relative, increases the risk of recessive genetic conditions like PAPP-A2 deficiency.

Doctors diagnose PAPP-A2 deficiency by looking at a specific pattern in blood tests. Standard hormone panels show very high total IGF-1 levels, which might initially suggest excess growth hormone. However, when doctors measure free or bioavailable IGF-1, those levels come back low. This paradox is the hallmark of PAPP-A2 deficiency and prompts genetic testing to confirm mutations in the PAPPA2 gene.

Rite Aid offers IGF-1 testing through our partnership with Quest Diagnostics at over 2,000 locations nationwide. If your IGF-1 results show unusual patterns, your doctor can order additional specialized tests to measure free IGF-1 and evaluate for PAPP-A2 deficiency. Early detection helps families understand growth patterns and plan appropriate monitoring.

• Regular monitoring of growth patterns and bone health
• Calcium and vitamin D supplementation to support bone density
• Weight-bearing exercise and strength training for bone strength
• Nutritious diet rich in protein and essential nutrients
• Genetic counseling for affected families
• Endocrinology follow-up to track hormone levels
• Research into IGF-1 replacement therapy is ongoing

There is currently no specific cure for PAPP-A2 deficiency. Treatment focuses on supporting healthy bone development and monitoring for complications. Some researchers are exploring whether free IGF-1 therapy could help, but this remains experimental. Most people with the condition lead normal lives with appropriate monitoring and bone health support.