Hypophosphatasia

Synonyms

4

Overview

Hypophosphatasia (HPP) is a genetic condition that causes abnormal development of the bones and teeth. The severity of HPP can vary widely, from fetal death to fractures that don't begin until adulthood. Signs and symptoms may include poor feeding and respiratory problems in infancy; short stature; weak and soft bones; short limbs; other skeletal abnormalities; and hypercalcemia. Complications can be life-threatening. The mildest form of the condition, called odontohypophosphatasia, only affects the teeth. HPP is caused by mutations in the ALPL (alkaline phosphatase) gene. Perinatal (onset before birth) and infantile HPP are inherited in an autosomal recessive manner. The milder forms, especially adult forms and odontohypophosphatasia, may be inherited in an autosomal recessive or autosomal dominant manner. While treatment has always been symptomatic and supportive, recently an enzyme replacement therapy (ERT) called asfotase alfa has been show to improve bone manifestations people with childhood onset HPP.

Symptoms

The signs and symptoms of hypophosphatasia vary widely and can appear anywhere from before birth to adulthood. The most severe forms of the disorder tend to occur before birth and in early infancy. Hypophosphatasia weakens and softens the bones, causing skeletal abnormalities similar to another childhood bone disorder called rickets. Affected infants are born with short limbs, an abnormally shaped chest, and soft skull bones. Additional complications in infancy include poor feeding and a failure to gain weight, respiratory problems, and high levels of calcium in the blood (hypercalcemia), which can lead to recurrent vomiting and kidney problems. These complications are life-threatening in some cases.

The forms of hypophosphatasia that appear in childhood or adulthood are typically less severe than those that appear in infancy. Early loss of primary (baby) teeth is one of the first signs of the condition in children. Affected children may have short stature with bowed legs or knock knees, enlarged wrist and ankle joints, and an abnormal skull shape. Adult forms of hypophosphatasia are characterized by a softening of the bones. In adults, recurrent fractures in the foot and thigh bones can lead to chronic pain. Affected adults may lose their secondary (adult) teeth prematurely and are at increased risk for joint pain and inflammation.

Below an overview of signs and symptoms:

  • Abnormality of the metaphyses 
  • Abnormality of the ribs
  • Abnormality of the teeth
  • Bowing of the long bones 
  • Craniosynostosis
  • Emphysema 
  • Narrow chest 
  • Sacrococcygeal pilonidal abnormality
  • Short stature
  • Anemia
  • Behavioral abnormality 
  • Hypercalcemia
  • Muscular hypotonia
  • Recurrent fractures 
  • Respiratory insufficiency
  • Seizures

Causes

Hypophosphatasia (HPP) is a genetic condition caused by mutations in the ALPL (alkaline phosphatase) gene.  This gene gives the body instructions to produce an enzyme called alkaline phosphatase, which is needed for mineralization of the bones and teeth.

Mutations in the ALPL gene lead to an abnormal amount of the enzyme alkaline phosphatase, thus affecting the bone mineralization process. A shortage of this enzyme also causes other substances to build up in the body. These abnormalities lead to the features of HPP. ALPL mutations that almost completely eliminate alkaline phosphatase activity generally cause the more severe forms of HPP, while mutations that reduce activity to a lesser extent often cause the milder forms of HPP.

Prevention

Individuals with hypophosphatasia and parents of children with hypophosphatasia are encouraged to seek genetic counseling to understand the likelihood and severity of hypophosphatasia recurring in their families.

Perinatal and infantile hypophosphatasia (HPP) are inherited in an autosomal recessive manner. This means, to be affected, a person must have a mutation in both copies of the ALPL gene in each cell. Affected people inherit one mutated copy of the gene from each parent, who is referred to as carrier. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected).

When 2 carriers of an autosomal recessive condition have children, each child has a:

  • 25% (1 in 4) chance to be affected
  • 50% (1 in 2) chance to be an unaffected carrier like each parent
  • 25% chance to be unaffected and not be a carrier.

The milder forms, especially adult HPP and odontohypophosphatasia, may be inherited in an autosomal recessive or autosomal dominant  manner - depending on the effect the ALPL mutation has on enzyme activity. 

In autosomal dominant inheritance, having a mutation in only one copy of the ALPL gene in each cell is enough to cause features of the condition. When a person with a mutation that causes an autosomal dominant HPP has children, each child has a 50% (1 in 2) chance to inherit that mutation.

Most people with autosomal dominant HPP have inherited the mutation from a parent who may or may not have symptoms. Not all people with a mutation that causes autosomal dominant HPP develop symptoms of the condition. While it is possible to have autosomal dominant HPP due to a new mutation that was not inherited ( de novo mutation), this has never been reported in HPP.

Diagnosis

Dental findings

Often, one of the first symptoms of hypophosphatasia is early loss of deciduous (baby or primary teeth) with root intact. Researchers have recently documented a positive correlation of dental abnormalities to clinical phenotype. Poor dentition is noted in adults.

Laboratory testing

The pathognomonic symptom is subnormal serum activity of alkaline phosphatase (ALP). In general, clinical severity mirrors the degree of enzyme deficiency. The most sensitive substrate marker for hypophosphatasia is an increased pyridoxal 5’-phosphate (PLP) plasma level, which often correlates with disease severity. And, although it remains only a research technique, quantification of urinary inorganic pyrophosphate (PPi) levels, which are elevated in most hypophosphatasia patients, has been reported to accurately detect carriers. In addition, increased urinary levels of phosphoethanolamine (PEA) are observed in most patients. Availability of the age-adjusted serum ALP test is widespread and included on many CHEM20 panels.

Radiography

Despite patient-to-patient variability and the diversity of radiographic findings, the X-ray is diagnostic in infantile hypophosphatasia, and can reveal the characteristic abnormalities found in other forms.[7]Radiologic evidence of skeletal defects is found in nearly all patients and includes hypomineralization, rachitic changes, incomplete vertebrate ossification and occasionally, lateral bony spurs on the ulnae and fibulae. Availability of XRAYs are widespread.

In newborns X-rays readily distinguish perinatal HPP from even the most severe forms of osteogenesis imperfecta and congenital dwarfism. Some stillborn skeletons show almost no mineralization; others have marked bony undermineralization and severe rachitic changes; and occasionally, there can be peculiar complete or partial absence of ossification in one or more vertebrae. In the skull, individual membranous bones may calcify only at their centers, making it appear that areas of the unossified calvarium have cranial sutures that are widely separated, when in fact they are functionally closed. Tongues of radiolucency often protrude from the metaphyses into the bone shaft.

In infants, radiographic features of infantile HPP are striking though generally less severe than those found in perinatal HPP. In some newly diagnosed patients, an abrupt transition from relatively normal-appearing diaphyses to uncalcified metaphyses appears suggesting an abrupt metabolic change has occurred. Serial radiography studies may reveal the persistence of impaired skeletal mineralization (i.e. rickets), instances of sclerosis and gradual generalized demineralization.

In adults, x-rays may reveal bilateral femoral pseudofractures in the lateral subtrochanteric diaphysis. These pseudofractures may remain for years or worsen, but they may not heal until they break completely or the patient receives intramedullary fixation. These patients may also experience recurrent metatarsal fractures.

 

 

Prognosis

The outcome following a diagnosis of hypophosphatasia is very variable. In general, the earlier the diagnosis is made the more severe the skeletal manifestations. Cases with severe, not mild, deformity at birth almost always have a lethal outcome within days or weeks. When the diagnosis is made before six months of age, some infants have a downhill and fatal course, others survive and may even do well.

The perinatal form is considered lethal, whereas the infantile form has a mortality rate of 50%. Individuals with the other forms can reach adulthood, although often with increased morbidity.

Treatment

Until recently, management of hypophosphatasia (HPP) has mostly been aimed at addressing symptoms of the condition. For example:

  • Hydration, restriction of dietary calcium, vitamin D, and sometimes thiazide diuretics for hypercalcemia
  • Ventilatory support for severely affected infants, some of which need a tracheostomy, which can lead to problems with speech and language development and tolerance of oral feeds
  • Physiotherapy, occupational therapy and chronic pain management for pain and motor difficulty
  • Surgery for fractures that fail to heal

More recently, research has shown positive effects of human recombinant enzyme replacement therapy (ERT), called asfotase alfa, on people who began having symptoms before 6 months of age. There reportedly have been significant improvements in the X-ray appearances of bone tissue, along with improvements in growth, respiratory function, motor development and calcium homeostasis after 6–12 months of treatment. The children in the original study have now received more than three years of treatment, without apparent major side effects, and with continuing improvement in affected systems. 

In October 2015 the FDA approved asfotase alpha (Strensiq)- For the treatment of patients with perinatal/infantile-and juvenile-onset hypophosphatasia (HPP).
Bone marrow and stem cell transplantation in infancy and childhood have improved the severity of the disease, but have not provided long term improvement.

Resources

Refer to research Publications.