Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is a skeletal condition that is characterized by rickets, bone pain, bone deformities, increased risk of bone fractures, fatigue, short stature, and calcium deposits in the sites where ligaments and tendons attach to the bones (calcific enthesopathy).
ARHR2 is an extremely rare condition, characterized by low phosphate levels in the blood (hypophosphatemia) resulting from renal phosphate wasting. ARHR2 affects males and females equally and occurs in populations all around the world. ARHR2 can develop at any time in childhood and has been seen in newborn babies. The manifestations of ARHR2 can vary widely, even among members of the same family. The prevalence of ARHR2 is unknown.
Hypophosphatasia is characterized by defective mineralization of bone and/or teeth and reduced serum alkaline phosphatase (ALP). The phenotypic spectrum ranges from stillbirth without mineralized bone at the severe end to pathologic stress fractures of the lower extremities in older adults at the mild end. Intrafamilial clinical variability is common, particularly when some affected family members have a heterozygous ALPL pathogenic variant and other affected family members have biallelic pathogenic variants. Sibs with compound heterozygous variants tend to display less clinical variability at the severe end of the spectrum and more variability at the milder end of the spectrum.
ARHR2 is caused by changes (mutations) in the ENPP1 gene and is thus part of ENPP1 deficiency. Depending on age, ENPP1 deficiency can manifest in two different presentations (phenotypes): ARHR2 and generalized arterial calcification of infancy (GACI) type 1. GACI type 1 causes pathological soft tissue calcification, including mineralization of the arteries, heart, kidneys, and joints. Most infants with ENPP1 deficiency who survive GACI type 1 will develop ARHR2, although ARHR2 can also be seen in patients without a prior history of GACI.
ARHR2 is treated with daily phosphorus and active vitamin D supplementation. The phosphorus is typically taken every four to six hours to maintain proper levels in the body. Regular blood and urine tests are required to ensure the correct balance is achieved. Early diagnosis and prompt treatment can help prevent/correct bone deformities and relieve bone pain.
Types
- Perinatal (severe) hypophosphatasia is typically identified by prenatal ultrasound examination. Pregnancies may end in stillbirth. Small thoracic cavities and short, bowed limbs are seen in both stillborn and live-born infants. A flail chest may be present. Infants with perinatal hypophosphatasia may experience pulmonary insufficiency; restrictive lung disease is the most frequent cause of death. Hypercalcemia is common and may be associated with apnea or seizures. In those treated with asfotase alfa enzyme replacement therapy (ERT), a new phenotype of “treated perinatal and infantile hypophosphatasia” is emerging. However, even when the diagnosis is made expediently, unfavorable outcomes with ERT are possible [rx]. Infants with perinatal (severe) hypophosphatasia started on ERT between age one day and age 78 months showed improvement in pulmonary function and survival. The effect of ERT on fractures remains unclear [rx]. In the past, individuals with severe phenotypes died before dental eruption; emerging data suggest the possibility of dental features in infants treated with ERT.
- Perinatal (benign) hypophosphatasia is typically identified by prenatal ultrasound examination showing short and bowed long bones but normal or slightly decreased mineralization. Postnatally, skeletal manifestations slowly resolve with a less severe hypophosphatasia phenotype [rx].
- Infantile hypophosphatasia. There may be no clinical features apparent at birth. Clinical signs may be recognized between birth and age six months and resemble rickets. Clinical severity depends on the degree of pulmonary insufficiency; the infantile phenotype has a high mortality. Prior to the availability of ERT, 50% of individuals succumbed to respiratory failure caused by under mineralization of the ribs. Other complications include hypercalcemia, irritability, poor feeding, failure to thrive, hypotonia, and more rarely vitamin B6-responsive seizures. Open fontanels and wide sutures may be deceptive, in that the hypo mineralized bone causing this radiographic appearance is prone to premature fusion. Craniosynostosis and intracranial hypertension are potential complications. Older children may have renal damage. Clinical trials with ERT have shown improvement in developmental milestones and pulmonary function[rx].
- Severe childhood (juvenile) hypophosphatasia displays wide variability in initial clinical presentation but often progresses to rickets. More severely affected toddlers have short stature and delay in walking, developing a waddling myopathic gait. Bone and joint pain are typical. Diaphyseal and metaphyseal fractures may occur. Gait, six-minute walk test, and step length improved in individuals treated with ERT. To date, data are insufficient to assess the effect of ERT on fractures in juvenile hypophosphatasia [rx].
- Mild childhood hypophosphatasia is characterized by low bone mineral density for age with unexplained fractures. Children may have a premature loss of deciduous teeth (prior to age 5 years), usually beginning with incisors, with the dental root characteristically remaining attached to the lost tooth. Bone and joint pain are atypical.
- Adult hypophosphatasia is sometimes associated with a history of transient rickets in childhood and/or premature loss of deciduous teeth. Early loss of adult dentition is common. Other dental problems in adolescents and adults with hypophosphatasia are more poorly characterized, although enamel hypoplasia and tooth mobility have been described. Adult hypophosphatasia is usually recognized in middle age, the cardinal features being stress fractures and pseudofractures of the lower extremities. Foot pain and slow-to-heal stress fractures of the metatarsals are common. Thigh and hip pain may reflect pseudofractures (“Looser zones”) in the lateral cortex of the femoral diaphysis. Chondrocalcinosis and osteoarthropathy may develop with age. Osteomalacia distinguishes adult hypophosphatasia from odontohypophosphatasia.
- Odontohypophosphatasia can be seen as an isolated finding without additional abnormalities of the skeletal system or can be variably seen in the above forms of hypophosphatasia. Caution should be exercised in citing extra dental manifestations of other forms of hypophosphatasia in individuals with odontohypophosphatasia, in that such features may be common and multifactorial (e.g., low bone density for age). Premature exfoliation of primary teeth and/or severe dental caries may be seen, with the incisors most frequently lost.
Symptoms
Bone deformity, bone pain, increased risk of bone fractures, and short stature are symptoms of ARHR2. The most noticeable bone changes are bowed legs (genu varum) or knock knees (genu valgum), but bone changes in the skull (craniosynostosis), ribs, and other parts of the body can also be the result of ARHR2. All bones in the body can be affected by ARHR2.
ARHR2 doesn’t always present with the typical X-ray features of rickets, and diagnosis can be confirmed by a blood test that shows low levels of phosphate (hypophosphatemia) and elevated alkaline phosphatase and FGF23, in the setting of ENPP1 mutations. Patients also have too much phosphate in their urine (hyperphosphaturia) due to renal phosphate wasting.
Over-retained primary teeth, teeth that don’t fully erupt (infraocclusion), increased cementum, ankylosis, and slow orthodontic movement are also possible symptoms of ENPP1 deficiency.
Calcium deposits that develop in the sites where ligaments and tendons attach to the bones (calcific enthesopathy) can also be a symptom of ARHR2 in later life. This may be inflammatory and can cause pain in the area it affects.
Causes
ARHR2 is caused by mutations in the ENPP1 gene and is also known as ENPP1 deficiency. ENPP1 encodes a protein called ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1), which is a major generator of extracellular pyrophosphate (PPi). Because PPI inhibits calcification, two inactivating mutations in the ENPP1 gene are also responsible for GACI type 1.
In patients with ARHR2, high circulating levels of FGF23 have been described. FGF23 is a secreted protein, which reduces the activity of sodium-phosphate co-transporters NPT2a and NPT2c resulting in renal phosphate wasting, diminishing the renal 1α-hydroxylase, and increasing the 24-hydroxylase activity. Moreover, FGF23 acts at the parathyroid gland to decrease parathyroid hormone synthesis and secretion. Currently, it is unclear how mutations in the ENPP1 gene result in high FGF23 levels.
Some researchers hypothesize that patients with ENPP1 deficiency develop a state of low phosphate in their serum, known as hypophosphatemia, as a compensatory mechanism for the state of low PPI to inhibit or decrease ectopic calcification. This hypophosphatemia leads to rickets in affected patients.
ARHR2 is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier of the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Diagnosis
If a patient with GACI type 1 is having regular blood tests, the signs of ARHR2 may be identified long before any bone abnormalities or bone pain have appeared. A blood test that shows low levels of phosphate and high levels of alkaline phosphatase can be indicators of ARHR2.
If there is no history of GACI type 1, ARHR2 should be considered in patients presenting with bone deformities, frequent bone fractures, and bone pain. ARHR2 doesn’t always present with the typical X-ray features of rickets, and diagnosis can be confirmed by a blood test that shows low levels of phosphate (hypophosphatemia) and elevated alkaline phosphatase and FGF23 in the setting of ENPP1 deficiency. Patients also have too much phosphate in their urine (hyperphosphaturia) due to renal phosphate wasting.
To confirm an ARHR2 diagnosis the patient (and sometimes parents) may be genetically tested for mutations in the ENPP1 gene.
Laboratory features
- Hypercalciuria particularly during the first year of life with or without hypercalcemia
- Typically normal serum calcium and ionized calcium. Note: May be elevated, particularly in the first year of life.
- Typically normal serum and urine inorganic phosphate. Note: May be elevated.
- Normal serum vitamin D (25-hydroxy and 1,25-dihydroxy) and parathyroid hormone
- Elevated plasma vitamin B6 without oral supplementation
- Elevated serum pyridoxal 5′-phosphate (PLP), a biologically active metabolite of vitamin B6. Note: (1) Reference laboratories may measure PLP and report it as “vitamin B6.” (2) Use of multivitamin or calcium supplements containing vitamin B6 within a week of assaying serum PLP may lead to false-positive results.
- Elevated urine phosphoethanolamine (PEA) and proline on urine amino acid chromatogram. Note: (1) Urine PEA may be elevated with other metabolic bone diseases. (2) Urine PEA may be normal in affected individuals and can be elevated in asymptomatic heterozygotes.
- Elevated urine inorganic pyrophosphate (PPi). Note: (1) Assay is not available in North American clinical laboratories. (2) Asymptomatic heterozygotes can have elevated urine PPi.
- Reduced serum unfractionated alkaline phosphatase (ALP) activity. Note: (1) Transient increases in serum ALP activity can occur during pregnancy, with liver disease, and after acute fracture or surgery. Thus, serial measurements may be necessary for toddlers with unexplained fractures. Quantitation of the activity of the bone isoform of ALP in serum may be necessary for the setting of liver disease. The bone isoform is heat-labile; the liver isoform is heat stable. (2) Asymptomatic heterozygotes can have reduced serum ALP activity.
Radiographic features
- Prenatal long bone bowing with osteochondral spurs
- Infantile rickets: under mineralized bones, widened-appearing sutures, brachycephaly, rachitic costochondral rib changes, flared metaphyses, poorly ossified epiphyses, and bowed long bones
- Focal bony defects of the metaphyses resembling radiolucent “tongues” are fairly specific for childhood hypophosphatasia.
- Defective mineralization of growing/remodeling bone and/or teeth. Bone mineral content increases with age, and there may be improved mineralization during adolescence with decreased mineralization in middle age.
- Alveolar bone loss results in premature loss of deciduous teeth typically involving the anterior mandible, with the central incisors lost first. However, any tooth may be affected.
- Pathologic fractures. Growing children may have a predilection to metaphyseal fractures; however, epiphyseal and diaphyseal fractures are also seen. In adults, metatarsal stress fractures and femoral pseudofractures prevail.
- Osteomalacia with lateral pseudofractures (“Looser zones”) in adult hypophosphatasia
Medical Monitoring
Ongoing monitoring of ARHR2 includes ultrasounds, X-rays, frequent lab and urine work, orthopedic evaluation/ intervention, and physical therapy. Significant improvement in symptoms can be achieved if corrective action is taken while the bones are still actively growing. Early diagnosis and prompt treatment can help prevent/correct bone deformities and relieve bone pain.
- Molecular genetic testing. Once the ALPL pathogenic variant(s) have been identified in an affected family member, prenatal testing and preimplantation genetic testing for hypophosphatasia are possible.
- Fetal ultrasonography. Recurrence of perinatal hypophosphatasia may reliably be identified by prenatal ultrasound examination. Undermineralization, small thoracic cavity, shortened long bones, and bowing are typical features of autosomal recessive and severe hypophosphatasia. Long bone bowing has been reported prenatally in affected sibs and in children of individuals with childhood (juvenile) or adult hypophosphatasia, but the finding is not diagnostic of perinatal severe hypophosphatasia, since it may also be seen in perinatal benign hypophosphatasia, a clinical form that can improve during later stages of pregnancy and result in nonlethal hypophosphatasia [rx]. Established information on the functional effect of some ALPL pathogenic variants can assist in distinguishing lethal and nonlethal hypophosphatasia prenatally [rx].
- Biochemical testing. The concentration of alkaline phosphatase in amniotic fluid, amniocytes, and chorionic villous samples is prone to misinterpretation (particularly in distinguishing unaffected heterozygotes); molecular genetic testing is the preferred method in confirming the prenatal diagnosis [rx].
- Fetal ultrasonography. Although perinatal hypophosphatasia may be distinguished from other skeletal dysplasias by prenatal ultrasonography, care must be taken in the interpretation of bowed long bones. Undermineralization, small thoracic cavity, shortened long bones, and bowing are typical features of autosomal recessive and severe hypophosphatasia.
Treatment
ARHR2 is treated with daily phosphorus and active Vitamin D supplementation which maintains proper levels in the body as determined by regular blood and urine tests. Phosphorus is typically taken every four to six hours to maintain proper levels in the body. Even with treatment, patients will continue to waste phosphate through their urine, but the frequent medication administration replaces the lost phosphate.
Pharmacologic treatment
In children, treatment generally begins at the time of diagnosis and continues until long bone growth is complete. Treatment for most children consists of oral phosphate administered three to five times daily and high-dose calcitriol, the active form of vitamin D. Two different regimens have been used, but have not been compared:
- Low dose. Treatment is generally started at a low dose to avoid the gastrointestinal side effects of diarrhea and gastrointestinal upset. The doses are then titrated to a weight-based dose of calcitriol at 20 to 30 ng/kg/day administered in two to three divided doses and phosphate at 20 to 40 mg/kg/day administered in three to five divided doses [rx].
- High dose. Some clinicians favor a high-dose phase of treatment for up to a year. The high-dose phase consists of calcitriol at 50-70 ng/kg/day (up to a maximum dose of 3.0 µg daily) along with the phosphate [rx] [rx]. The calcitriol doses that are frequently employed in adults are in the range of 0.50 to 0.75 µg daily; the phosphate is given as 750 to 1000 mg/day in three to four divided doses. As with children, the phosphate dose is slowly titrated to avoid gastrointestinal side effects, starting at 250 mg/day and titrating up by 250 mg/day each week until the final dose is reached.
- Orthopedic treatment. Despite what appears to be adequate pharmacologic therapy (see following Note), some individuals have persistent lower-limb bowing and torsion, which may lead to misalignment of the lower extremity. In these individuals, surgical treatment is frequently pursued. No control trials of the different surgical techniques have been undertaken; the literature consists of case series. Note: Poor compliance with pharmacologic therapy during childhood and the teen years may be one factor for persistent lower-limb deformities.
- Craniofacial treatment. Although hypophosphatemic rickets is a rare condition, a recent review from three neurosurgical centers reported on ten patients treated over twenty years and recommended prompt referral to a craniofacial specialist when head shape abnormalities are seen in patients with this disorder [rx].
- Dental treatment. Because individuals with XLH are susceptible to recurrent dental abscesses which may result in premature loss of decidual and permanent teeth, good oral hygiene with flossing and regular dental care and fluoride treatments are the cornerstones of prevention. Pit and fissure sealants have been recommended but have not been well studied. A recent study has suggested that the treatment of adults with phosphate and calcitriol can improve the severity of dental disease [rx].
- Sensorineural hearing loss has been reported in persons with XLH; individuals with this complication are treated in a standard manner.
Surgery
There are two possible options for surgery to correct deformities of the legs – eight-plate surgery (also known as guided growth) and bone realignment surgery (osteotomy). Patients with ARHR2 are usually followed by a team of specialists which may include endocrinology, nephrology, orthopedics, physical therapy, dental, and audiology.
Investigational Therapies
In 2015, Demetrios Braddock, MD, Ph.D., a pathologist and professor from Yale University along with his team published an article in Nature Communications demonstrating the reduction of calcification and prevention of mortality in a mouse model of GACI given a replacement version of the enzyme ENPP1. This discovery has led to the establishment of a biotechnology company developing new medicines to treat rare disorders of calcification including GACI. These medicines may also be used to treat ARHR2.
References
