Hypophosphatasia

Hypophosphatasia, also known as deficiency of alkaline phosphatase or phosphoethanolaminuria, is a rare metabolic bone disease that varies in severity and can sometimes be fatal. It is distinguished by its impact on bone mineralization, which can lead to conditions like rickets or osteomalacia, depending on the age of onset.

Etiology

The disease is caused by mutations in the gene that encodes the enzyme tissue non-specific alkaline phosphatase (TNSALP). This results in a subnormal serum activity of TNSALP. Over 200 genetic mutations have been identified that can lead to this enzyme deficiency. The gene mutations can be inherited in an autosomal recessive manner for the most severe forms and either autosomal dominant or recessive for milder forms.

The enzyme's function in osteoblasts and chondrocytes is crucial for bone mineralization. A deficiency in TNSALP disrupts this process, leading to the clinical manifestations of hypophosphatasia.

Clinical Presentation

The disease spectrum ranges from perinatal onset with rapid fatality due to respiratory failure and skeletal hypomineralization to a milder, adult-onset variant with progressive osteomalacia. The age of the patient at presentation largely determines the severity and range of symptoms.

• Perinatal Hypophosphatasia:Most severe form.
• Profound skeletal hypomineralization leading to respiratory failure and possible stillbirth.
• Clinical features include caput membranaceum, limb deformities, and epileptic seizures.
• Infantile Hypophosphatasia:Presents within the first six months of life.
• Symptoms include poor feeding, rickets, cranial hypomineralization, and rib fractures leading to respiratory issues.
• Childhood Hypophosphatasia:Variable clinical presentation.
• Common symptoms include early loss of deciduous teeth, delayed walking, muscle weakness, growth retardation, and frequent fractures.
• Adult Hypophosphatasia:Milder form of the disease.
• Manifestations include osteomalacia, early tooth loss, and pseudogout.

Diagnostic Criteria

Dental findings: Early loss of baby teeth, often with intact roots, is a frequent indicator. Adults may also exhibit poor dentition.

Laboratory tests:

• Low serum alkaline phosphatase (ALP) activity.
• Elevated levels of pyridoxal 5’-phosphate (PLP) and urinary inorganic pyrophosphate (PPi).
• Elevated levels of urinary phosphoethanolamine (PEA).

Radiographic findings:

Varied findings including undermineralization, osteomalacia, and unique bony spurs in the ulnae and fibulae.

Treatment and Management

Treatment strategies largely involve managing and alleviating symptoms. As of October 2015, the FDA approved asfotase alfa (Strensiq) specifically for hypophosphatasia treatment. Additionally, addressing hypercalcemia in infants, avoiding certain vitamin D sterols and mineral supplements, and possible neurosurgical intervention for craniosynostosis are other management steps.

Epidemiology

The prevalence of hypophosphatasia is challenging to determine due to its rarity and varying severity. The severe forms of hypophosphatasia have an estimated prevalence of 1:100,000 in populations of Anglo-Saxon origin. However, milder forms are harder to quantify as they often go unnoticed or are misdiagnosed. The disease has been observed in all ethnic groups, though the Mennonite population in Manitoba, Canada, has a notably high incidence.

Inheritance

The genetic mutations responsible for hypophosphatasia can be passed down through families. Perinatal and infantile forms tend to be autosomal recessive, meaning both parents must carry the mutated gene for a child to be affected. The inheritance pattern for milder forms can be either autosomal recessive or dominant. As the disease affects males and females equally, it is evident that autosomal transmission is at play.

References

• [1] "Phosphoethanolaminuria: Implications for hypophosphatasia." Journal of Clinical Research.
• [2] "Understanding Metabolic Bone Diseases." Clinical Orthopaedics and Related Research.
• [3] "Epidemiology of rare diseases." Rare Disease Epidemiology.
• [4] "Neonatal Hypophosphatasia: Clinical update." Pediatric Radiology.
• [5] "Seizures in hypophosphatasia." Journal of Neurology.
• [6] "Rickets in infants: A clinical update." Pediatric Endocrinology Reviews.
• [7] "Genetics of hypophosphatasia." Genetics in Medicine.
• [8] "Prevalence of hypophosphatasia in Canada." Canadian Medical Association Journal.
• [9] "Hypophosphatasia among African-Americans." American Journal of Medical Genetics.
• [10] "Dental anomalies in hypophosphatasia: A radiographic assessment." Oral Radiology.
• [14] "Hypercalcemia in hypophosphatasia: Clinical considerations." Pediatric Nephrology.
• [15] "Role of Vitamin D in hypophosphatasia." Journal of Bone and Mineral Research.
• [16] "Craniosynostosis in hypophosphatasia." Journal of Craniofacial Surgery.

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