Introduction:
The other names for childhood hypophosphatasia are hypophosphatasia, Rathbun disease, and phosphoethanol-aminuria. It is caused due to the suppression of the activity of tissue-nonspecific alkaline phosphatase (TNSALP) enzyme. Since this condition is very rare, it is difficult to be diagnosed. To present, about 190 mutations (change in the basic genetic structure) have been identified that cause the deficiency of the enzyme. It is a hereditary condition.
What Are the Different Types of Hypophosphatasia?
Based on the age and severity of the disease, hypophosphatasia can be classified into:
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Perinatal Hypophosphatasia: This type develops before birth inside the mother’s womb and the babies are mostly stillborn. Surviving infants can die due to respiratory failure. There is a complete absence of mineralization and the babies are born with short limbs and unusual bony projections (bone spurs) in the long bones. In benign prenatal hypophosphatasia, the unborn infant may develop skeletal defects that transform into a less severe form. Lethal perinatal hypophosphatasia is characterized by death, either before birth in the womb or after the baby is stillborn.
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Infantile Hypophosphatasia: There is poor weight gain in these infants within six months of age due to difficulty in feeding. Other symptoms include a flail chest, blue sclera (white layer of the eyeball), and pneumonia (inflammation of the air sacs in one or both lungs). Cranial (head) sutures and fontanelles (soft spots) appear wide.
An increase in pressure inside the skull (intracranial pressure) and hypertelorism (increased distance between the eye orbits) can result in proptosis (abnormal protrusion or displacement of the eye). There can be renal (kidney) issues.
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Childhood Hypophosphatasia: Children with this condition usually consult the dental surgeon as there can be a loss of primary teeth and horizontal bone loss without root resorption (the process in which the structures around the root are destroyed) may be noticed.
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Adult Hypophosphatasia: This condition is usually identified in middle age and the individual can have a previous history of primary or adult tooth loss. Premature tooth loss affects the six teeth present in the front of the upper and lower jaw. There can be a history of profuse caries in adults. Liver metabolism and foot and ankle pain can be affected in a few cases.
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Odontohypophosphatasia: This is the least severe form of hypophosphatasia and is characterized by dental abnormalities like the delayed eruption of primary dentition, early decay of primary and adult teeth, and so on but other signs of skeletal disease are absent.
How Common Is Hypophosphatasia?
Different forms of hypophosphatasia affect about one in 1,00,000 newborns. Mild cases that occur in childhood or adulthood may have a more frequent occurrence. Though this condition affects people of different ethnic backgrounds, the white population is commonly affected.
How Is Childhood Hypophosphatasia Caused?
The teeth and bones are predominantly made up of minerals like calcium, and phosphorous (mineralization) to keep these strong. Too much build-up of calcium and phosphorous is not good. This is checked by the enzyme, tissue-nonspecific alkaline phosphatase (TNSALP) which plays a pivotal role in the mineralization of the teeth and skeleton.
The ALPL gene is responsible for the production of tissue-nonspecific alkaline phosphatase enzyme (TNSALP) and mutations in this gene cause childhood hypophosphatasia as a result of a build-up of mineral-blocking chemicals like inorganic pyrophosphate (PPi). Severe forms of this condition are caused due to complete elimination of the activity of TNSALP due to ALP gene mutations. In less severe forms, there is a decreased but not complete elimination of the activity of the enzyme.
What Are the Symptoms of Childhood Hypophosphatasia?
The disease is severe if the symptoms present at a young age. Symptoms include:
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Premature loss of primary teeth (mostly before five years of age) but the roots remain intact. This is the classical sign of this condition.
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Skeletal abnormalities due to poor mineralization.
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Short stature with bowed legs or knock knees.
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Skeletal abnormalities.
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Decreased movement or mobility.
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Bone and joint pain.
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Enlarged wrist or ankle joints.
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Abnormal shape of the skull.
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Early loss of primary teeth.
The symptom differs with each individual ranging from mild, serious, to even fatal.
How Is Childhood Hypophosphatasia Diagnosed?
The healthcare professional will ask for a complete family history and proceed by taking X-rays and blood tests. Diagnostic tests are as follows:
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A chorionic villus sampling (CVS) is a procedure in which placental tissues are obtained and analyzed to confirm the presence of the condition before delivery.
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Ultrasounds during pregnancy can reveal short and bowed long bones.
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A genetic test may be suggested to identify any mutations in the ALP-producing gene. This test is not easily available and can be expensive. The hallmark diagnostic test is the identification of low alkaline phosphatase (ALP) activity. Interpretation of these measurements must use the appropriate age and gender-related reference values.
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Other supportive findings that aid in diagnosis include hypercalcemia (elevated levels of calcium in the blood), hyperphosphatemia (elevated levels of phosphate in the blood), and hypercalciuria (excretion of more than 250 mg of calcium in a day through urine).
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X-rays show tongue-shaped radiolucencies that project from the epiphyseal (the rounded end of a long bone at the point where it combines with another bone) plate into the metaphysis (the neck portion of the long bone situated between the epiphysis and the diaphysis).
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The upper, domelike, or convex portion of the skull called the calvarium has a ‘beaten copper’ appearance.
How Is Childhood Hypophosphatasia Inherited?
If one or both parents carry the mutated ALPL gene, the child is at risk of acquiring the condition. Inheriting two copies of the mutated gene can result in severe forms of this condition while mild forms are inherited through a single mutated copy from one parent.
How Is Childhood Hypophosphatasia Treated?
Childhood hypophosphatasia is treated in the following ways:
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A drug called Asfotase alfa is used to treat the infant or childhood forms of the condition. This is given as a shot under the skin, and it replaces the enzyme alkaline phosphatase (ALP) in the bones.
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Prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) like Ibuprofen, or Acetaminophen to relieve pain in bones and joints.
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Skull surgery or placing shunts to relieve the pressure in the brain.
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Vitamin B6 can help control the sudden, involuntary bursts of electrical activity in the brain (seizures).
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Calcium levels in the blood can be lowered through diet or calcitonin injections as these hormones regulate calcium levels.
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Frequent dental care.
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Insertion of metal rods into the bones that fracture frequently.
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Physical therapy (a therapy to treat injury, disease, or deformity by physical methods like exercise, massage, and so on).
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Using a foot orthotic device or ‘boot’ in kids to help them with stability.
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Bisphosphonate drugs are used to treat other disorders of the bone like osteoporosis. This should be avoided as it can worsen hypophosphatasia.
Can Childhood Hypophosphatasia Be Prevented and What Are the Associated Complications?
Childhood hypophosphatasia cannot be prevented as it occurs due to genetic reasons. Associated complications are:
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Respiratory problems can lead to pneumonia (inflammation of the air sacs in one or both lungs).
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Hypercalcemia (elevated levels of calcium in the blood).
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Premature or early closure of one or more bones of the skull in babies (craniosynostosis) can increase the pressure in the skull (intracranial pressure).
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Increased deposition of calcium in the kidneys (nephrocalcinosis).
What Is the Long-Term Outlook of Childhood Hypophosphatasia?
Childhood hypophosphatasia is a lifelong condition. The U.S. Food and Drug Administration (FDA) approved Asfotase alfa in the treatment for this hypophosphatasia in 2015. This drug is the first, and only prescription treatment available for perinatal, infantile, and childhood types of hypophosphatasia. It is based on alkaline phosphatase enzyme replacement therapy (ERT). This therapy improves skeletal mineralization, and respiratory infection, and reduces mortality.
What Are the Differential Diagnoses for Hypophosphatasia?
Other conditions that resemble hypophosphatasia are:
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Osteogenesis Imperfecta: This is a group of rare diseases that affect connective tissues resulting in brittle and fragile bones that can fracture easily.
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Rickets: A bone disorder that can be inherited or caused due to calcium and Vitamin D deficiencies, inadequate exposure to the sun, or improper absorption of these nutrients during pregnancy.
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Campomelic Dysplasia: A rare, inherited disorder that affects the development of the reproductive system, skeleton, and face.
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Achondrogenesis: Severe inherited disorders that affect the development of bone and cartilage.
Conclusion:
Childhood hypophosphatasia is a very rare inherited disorder that occurs due to gene mutations that affect the levels of the enzyme alkaline phosphatase responsible for the growth of bones and teeth. It can be difficult for these individuals to live with pain, bone fractures, and other symptoms. With the available treatment options, supportive management can be provided.
