Decoding Infantile Hypophosphatasia: Understanding, Diagnosing, and Harnessing the Power of Genetic Testing

Expert Reviewed By: ⁠Dr. Brandon Colby MD

Understanding Infantile Hypophosphatasia

Infantile hypophosphatasia (HPP) is a rare inherited metabolic disorder that affects bone mineralization, leading to skeletal abnormalities and systemic manifestations1. This condition is caused by mutations in the ALPL gene, which encodes the tissue-nonspecific alkaline phosphatase (TNSALP) enzyme. TNSALP plays a crucial role in bone formation and mineralization, and its deficiency results in the clinical manifestations of HPP2.

HPP can present with varying degrees of severity, ranging from life-threatening perinatal forms to milder adult-onset forms. Infantile HPP typically presents within the first six months of life, with symptoms such as poor weight gain, respiratory complications, and skeletal abnormalities like rickets and fractures1.

Diagnosing Infantile Hypophosphatasia

Diagnosing infantile HPP can be challenging due to its rarity and overlapping symptoms with other metabolic disorders. A combination of clinical findings, biochemical markers, and radiographic imaging is often used to establish a diagnosis. Biochemical markers include low serum alkaline phosphatase (ALP) activity and elevated levels of substrates like phosphoethanolamine and pyridoxal-5’-phosphate1. Radiographic imaging may reveal characteristic skeletal abnormalities such as undermineralization, rickets, and fractures1.

Role of Genetic Testing in Diagnosis

Genetic testing plays a crucial role in confirming the diagnosis of infantile HPP by identifying mutations in the ALPL gene2. This can be particularly helpful in cases with atypical clinical presentations or inconclusive biochemical and radiographic findings. Genetic testing can also help differentiate HPP from other genetic causes of neonatal and infantile hypercalcemia, such as Williams syndrome, idiopathic infantile hypercalcemia, and familial hypocalciuric hypercalcemia4.

Using Genetic Testing for Infantile Hypophosphatasia

Genetic Counseling and Family Planning

Genetic testing is essential for providing accurate genetic counseling to families affected by infantile HPP. Since HPP is an autosomal recessive disorder, parents of an affected child have a 25% chance of having another affected child in future pregnancies3. Identifying the specific ALPL gene mutations in affected individuals can help determine the risk of recurrence and inform family planning decisions.

Understanding Disease Variability and Prognosis

Genetic testing can also provide insights into disease variability and prognosis. For example, a study investigating the TNSALP defect causing transiently reversible and variably lethal infantile HPP in a kindred of black ancestry revealed that homozygosity for the mutation 1348c>T (Arg433Cys) was responsible for the observed clinical manifestations3. Understanding the specific genetic defects and their associated clinical outcomes can help clinicians tailor treatment and management strategies for affected individuals.

Potential for Future Therapies

As our understanding of the genetic basis of infantile HPP continues to grow, so does the potential for the development of targeted therapies. Current treatment options for HPP are limited and primarily focused on managing symptoms and complications. However, advances in genetic research could pave the way for novel therapeutic approaches, such as gene therapy or enzyme replacement therapy, to directly address the underlying genetic defects and improve patient outcomes.

In conclusion, genetic testing is a valuable tool for understanding, diagnosing, and managing infantile hypophosphatasia. By identifying the specific ALPL gene mutations responsible for this rare metabolic disorder, clinicians can provide accurate genetic counseling, tailor treatment strategies, and potentially contribute to the development of targeted therapies for affected individuals.

About The Expert Reviewer

Dr. Brandon Colby MD is a US physician specializing in the personalized prevention of disease through the use of genomic technologies. He’s an expert in genetic testing, genetic analysis, and precision medicine. Dr. Colby is also the Founder of  and the author of ⁠⁠Outsmart Your Genes.

Dr. Colby holds an MD from the Mount Sinai School of Medicine, an MBA from Stanford University’s Graduate School of Business, and a degree in Genetics with Honors from the University of Michigan. He is an Affiliate Specialist of the American College of Medical Genetics and Genomics (⁠⁠ACMG), an Associate of the American College of Preventive Medicine (⁠⁠ACPM), and a member of the National Society of Genetic Counselors (⁠NSGC)