Hypophosphatasia is a hereditary disorder caused by mutations of the ALPL gene, which encodes for the liver-bone-kidney isozyme of alkaline phosphatase. This enzyme is required for bone and teeth mineralization. If its activity is reduced due to sequence anomalies in the aforementioned genes, skeletal and dental defects as well as hypercalcemia ensue. Childhood-onset hypophosphatasia is a rather mild form of the disease: Symptom onset is delayed until age 6-18 months, skeletal deformities are not life-threatening and mortality is low. The treatment of choice consists in life-long replacement of the missing enzyme by applying asfotase alfa, a recombinant mineral-targeted alkaline phosphatase.
Presentation
While those suffering from early-onset hypophosphatasia present with skeletal malformations at birth - namely a soft or deformed skull, an abnormally shaped thorax, and short limbs - neonates predisposed for childhood-onset hypophosphatasia are apparently healthy. According to the current classification scheme, symptom onset occurs at age 6-18 months in patients affected by this form of the disease [1]. However, first symptoms don't necessarily cause parents to present their child to a physician: Premature loss of deciduous teeth is characteristic of childhood-onset hypophosphatasia, usually occurs in infancy or early childhood, and is often the cause for seeking medical advice [2]. Nevertheless, If explicitly asked, parents may report symptoms that have been observed during the months or even years preceding the initial examination, e.g., irritability, feeding difficulties, vomiting, constipation, polyuria and polydipsia, and respiratory anomalies resulting from rachitic deformities of the chest. These symptoms are more typical of infantile hypophosphatasia, but individual types of hypophosphatasia should be understood as a continuum. There are considerable overlaps between infantile hypophosphatasia (age at onset is less than 6 months), childhood-onset hypophosphatasia (first symptoms at age less than 18 months), and adult hypophosphatasia (onset in adolescence) [1].
Skeletal deformities develop over time. Affected infants and children may present with an abnormally shaped skull - dolichocephalia is most frequently reported -, enlarged joints, bowed legs, genu valgum, and a waddling gait. They may suffer from chronic arthralgia and bone pain and are prone to pathological fractures. In general, they are of relatively short stature and low weight.
Entire Body System
- Short Stature
Commonly, patients have rickets leading to short stature, with delay in walking and a waddling gait, and bone and joint pain. Skeletal deformities may include dolichocephalic skull and enlarged joints. [orpha.net]
Children with HPP may have short stature for additional reasons, and therefore if enzyme replacement therapy is being considered, it is appropriate to evaluate for other causes of short stature prior to treatment, particularly if those causes of short [ojrd.biomedcentral.com]
Signs and symptoms vary but may include delayed motor milestones; low bone mineral density for age; early loss of baby teeth (before age 5); bone and joint pain; short stature ; a waddling gait; skeletal malformations; and/or unexplained broken bones. [rarediseases.info.nih.gov]
- Inflammation
Affected adults may lose their secondary (adult) teeth prematurely and are at increased risk for joint pain and inflammation. The mildest form of this condition, called odontohypophosphatasia, only affects the teeth. [ghr.nlm.nih.gov]
Affected adults may lose their secondary (adult) teeth prematurely and are at increased risk for joint pain and inflammation.[1] The mildest form of this condition, called odontohypophosphatasia, only affects the teeth. [rarediseases.info.nih.gov]
Some affected adults develop joint inflammation and pain near or around certain joints due to the accumulation of calcium crystals (calcific periarthritis) or a condition called chondrocalcinosis, characterized by the accumulation of calcium crystals [rarediseases.org]
- Falling
“Last November, myself and a number of the Foroige… Read more Christina Balsam: My time in Knockree Knockree Hostel in the Wicklow Mountains was the first place that made me fall in love with Ireland. It was also the first hostel I stayed it. [anoige.ie]
Typically, one or more baby teeth fall out earlier than normal. Some children are weak and experience delays in walking, and when they do learn to walk may have a distinct, waddling gait. [rarediseases.org]
- Anemia
It should be noted, though, that low alkaline phosphatase activity may also be observed in those suffering from anemia or hypothyroidism, or even in early pregnancy. Thus, all findings require a contextual interpretation. [symptoma.com]
[…] fontanelles 0000239 Narrow chest Low chest circumference Narrow shoulders [ more ] 0000774 Short stature Decreased body height Small stature [ more ] 0004322 Skin dimple over apex of long bone angulation 0001024 30%-79% of people have these symptoms Anemia [rarediseases.info.nih.gov]
In addition to her HPP, she had hypertension, hypercholesterolemia, chronic kidney disease stage 4 with renal anemia, and nephrolithiasis, with the latter possibly related to HPP. [academic.oup.com]
Epilepsy (seizures) can occur and can prove lethal.[5] Regions of developing, unmineralized bone (osteoid) may expand and encroach on the marrow space, resulting in myelophthisic anemia. [en.wikipedia.org]
(著者抄録) Mean hemoglobin levels in venous blood samples and prevalence of anemia in Japanese elementary and junior high school students. [researchmap.jp]
- Swelling
This complication can cause headaches, swelling of the optic disk (papilledema), and bulging of the eyes (proptosis). Affected infants have softened, weakened bones that lead to the skeletal malformations of rickets. [rarediseases.org]
Gastrointestinal
- Vomiting
Weakness, arrhythmia, recurrent vomiting and constipation, polyuria, polydipsia and nephrolithiasis may all be encountered in case of hypophosphatasia. Affected families may benefit from genetic counseling. [symptoma.com]
It may result from potassium loss by renal secretion or by the gastrointestinal route, as by vomiting or diarrhea. [mesh.kib.ki.se]
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. [ghr.nlm.nih.gov]
This situation can lead to: headache contracted pupils mild confusion pale, moist, and cool skin vomiting or upset stomach decreased urination or inability to urinate In prolonged periods of a temperature of more than 106.1°F, the following symptoms may [medicalnewstoday.com]
- Nausea
Early symptoms may include: increased thirst extreme sweating dizziness muscle cramps fatigue and weakness nausea light-headedness As the high temperature persists or gets worse, the severity of the symptoms can increase. [medicalnewstoday.com]
Plasma calcium concentrations did not increase (2.4 to 2.8 mmol/L) on this treatment, but because of side effects of nausea and anorexia, the dose was reduced back to 20 µg alternate days. [asbmr.onlinelibrary.wiley.com]
All were injection-site reactions (ISRs), with the exception of nausea and peripheral edema in 1 patient, and all were assessed by the investigators as mild. [insight.jci.org]
- Abdominal Pain
These crises include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Crises can last one to seven days. [ncbi.nlm.nih.gov]
Liver, Gall & Pancreas
- Jaundice
This early phase can progress to liver failure with ascites, jaundice, and gastrointestinal bleeding. Children may have a characteristic odor of "boiled cabbage" or "rotten mushrooms." [ncbi.nlm.nih.gov]
Cardiovascular
- Heart Failure
The causes of heart failure in pediatric patients are significantly different from those in adult patients. Congenital heart disease and primary cardiomyopathy are the main causes in pediatric heart failure patients. [heartj.cn]
- Heart Disease
Incidence and risk distribution of heart failure in adolescents and adults with congenital heart disease after cardiac surgery[J]. [heartj.cn]
Jaw & Teeth
- Tooth Loss
It causes impaired bone mineralisation, fractures, tooth loss, muscle weakness and possibly other adverse health outcomes. The infantile-onset forms are severe, and were often fatal until the recent availability of a treatment (Asfotase Alfa). [hra.nhs.uk]
loss develop, with symptoms first emerging before 6 months of age Childhood, in which rickets, chronic bone/joint pain, fractures and early tooth loss may manifest, with symptoms first emerging after 6 months of age Adult, in which fractures, delayed [pediatricsnationwide.org]
Loss in Children: A Warning Sign of Childhood Hypophosphatasia. 61 Hughes SL...Collard M 29172356 2017 20 Childhood hypophosphatasia with homozygous mutation of ALPL. 61 Ukarapong S...Berkovitz G 25100374 2014 21 Infantile loss of teeth: odontohypophosphatasia [malacards.org]
People with this disorder typically experience abnormal tooth development and premature tooth loss, but do not have the skeletal abnormalities seen in other forms of hypophosphatasia. [ghr.nlm.nih.gov]
However, this cannot be easily predicted, and the postnatal course and severity of ‘benign prenatal’ HPP ranges from that observed in patients with infantile HPP to odonto-HPP.4 While early tooth loss (due to failure of normal cementum production) is [adc.bmj.com]
- Premature Loss of Teeth
Odontohypophosphatasia refers to children and adults who have only dental, but not skeletal, problems (premature loss of teeth). The x-ray changes are quite distinct to the trained eye. [magicfoundation.org]
Musculoskeletal
- Fracture
[…] and no occurrence of new fractures. [academic.oup.com]
In addition, significant rickets, long bone deformity, and non-traumatic fractures are possible. Fractures may heal poorly and can reoccur. The documents contained in this web site are presented for information purposes only. [orpha.net]
Two patients developed atypical femoral fractures following exposure to bisphosphonates and/or denosumab. [mayoclinic.pure.elsevier.com]
These same patients may also have significant rickets, long bone deformity, and non-traumatic fractures [9]. Fractures which occur in patients with HPP may heal poorly and can reoccur [10]. [ojrd.biomedcentral.com]
- Muscle Weakness
It causes impaired bone mineralisation, fractures, tooth loss, muscle weakness and possibly other adverse health outcomes. The infantile-onset forms are severe, and were often fatal until the recent availability of a treatment (Asfotase Alfa). [hra.nhs.uk]
Physical findings: • A near absence of skeletal mineralization; • Fractures; • Skin-covered spurs of the knees and elbow; • Large fontanels (space between the bones of the skull); • Shortened bones; • Chest deformities; • Muscle weakness; • Hypercalcemia [secure.ssa.gov]
Hypophosphatasia can also lead to chronic debilitating pain, muscle weakness, generalised seizures because of vitamin B6 deficiency, and renal and respiratory complications. [nice.org.uk]
Although the pathogenesis of the muscle weakness of hypophosphatasia is not understood (1, 2), it can be an important complication. [insight.jci.org]
weakness, seizures, impaired renal function, and respiratory failure. [clinicaltrials.gov]
- Decrease in Height
[…] body height Small stature [ more ] 0004322 Skin dimple over apex of long bone angulation 0001024 Waddling gait 'Waddling' gait Waddling walk [ more ] 0002515 Showing of 18 | Last updated: 3/1/2020 Making a diagnosis for a genetic or rare disease can [rarediseases.info.nih.gov]
- Arthritis
Department of Pediatrics, Nippon Medical School Oct 1998 - Mar 2004 Assistant Professor, Department of Pediatrics, Nippon Medical School Jun 1991 - Sep 1998 Member, Department of Pediatrics, Nippon Medical School Jun 1988 - Jun 1991 Research Scientist, Arthritis [researchmap.jp]
Some patients suffer from calcium pyrophosphate dihydrate crystal depositions with occasional attacks of arthritis (pseudogout), which appears to be the result of elevated endogenous inorganic pyrophosphate (PPi) levels. [en.wikipedia.org]
Measurement of health status in children with juvenile rheumatoid arthritis. Arthritis Rheum. 1994;37(12):1761–1769. Version history Version 1 (June 16, 2016): No description Version 2 (June 16, 2016): No description [insight.jci.org]
Neurologic
- Waddling Gait
gait 'Waddling' gait Waddling walk [ more ] 0002515 Showing of 18 | Last updated: 3/1/2020 Making a diagnosis for a genetic or rare disease can often be challenging. [rarediseases.info.nih.gov]
- Confusion
[…] occur: extreme confusion loss of consciousness rapid, shallow breathing dry, hot, and red skin weak, fast pulse widened pupils seizures It is essential to seek treatment for fevers over 106.1°F to help prevent serious long-term complications or death [medicalnewstoday.com]
Because of the inconsistent and confusing nature of its clinical presentation, it is estimated that fewer than 50% of affected individuals are diagnosed while alive. In the general US population, the carrier frequency is estimated at 1:150 to 1:100. [ncbi.nlm.nih.gov]
Workup
Laboratory analyses of blood samples reveal hypercalcemia and this condition may ensue other anomalies, i.e., disturbances of kidney function and consequent blood chemistry findings. Furthermore, elevated serum concentrations of pyridoxal 5'-phosphate are characteristic of hypophosphatasia and represent a sensitive and specific marker of the disease [3]. In urine samples, increased levels of alkaline phosphatase substrates like phosphoethanolamine can be detected [4].
Hypercalcemia, in turn, results from insufficient bone mineralization, which may be detected by means of diagnostic imaging. In images obtained by radiography, characteristic "tongues of lucency" may be recognized extending from growth plates into metaphyses [3]. Irregular, patchy osteopenia and osteosclerosis is frequently observed. Additionally, deposition of minerals may be noted in inner organs. Nephrocalcinosis is not a rare finding in hypophosphatasia patients. With regards to their teeth, enlarged pulp chambers and root canals often cause the appearance of shell teeth [3].
Although these findings surely raise suspicion as to the underlying disease, alkaline phosphatase enzymatic activity has to be determined in order to diagnose hypophosphatasia. And ideally, the diagnosis is further confirmed by sequencing the ALPL gene:
- Residual enzyme activity may be measured and is usually several standard deviations below that obtained in reference groups. However, most techniques don't allow for the isolated assessment of levels of the liver-bone-kidney isozyme, but rather yield the sum of activities of all isoforms of alkaline phosphatase. Furthermore, residual enzymatic activity does not necessarily correlate with the patient's age at symptom onset and the severity of the disease [5]. In any case, results should only be compared to age- and gender-specific reference values. In adults, the physiological range of serum alkaline phosphatase activity is 20 to 140 units per liter, but higher concentrations are to be expected in healthy children and pregnant women [6]. Because liver-bone-kidney alkaline phosphatase accounts for more than 50% of total enzyme activity, values obtained in hypophosphatasia patients are severely and persistently decreased. It should be noted, though, that low alkaline phosphatase activity may also be observed in those suffering from anemia or hypothyroidism, or even in early pregnancy [1]. Thus, all findings require a contextual interpretation.
- Anamnestic, clinical and laboratory findings suffice for diagnosing childhood-onset hypophosphatasia. Still, the diagnosis may be strongly substantiated by the identification of the causal mutation of the ALPL gene. Analysis of the whole gene's coding sequence is generally required to detect anomalies, but the results of genetic analyses conducted to this end may facilitate family planning counseling and prenatal diagnostics and, in some countries, are required before enzyme replacement therapy can be initiated [1]. Mutations of the ALPL gene cannot be identified in all cases, though.
Serum
- Alkaline Phosphatase Decreased
phosphatase Decreased serum alkaline phosphatase 0003282 Myopathy Muscle tissue disease 0003198 Phosphoethanolaminuria High urine phosphoethanolamine levels 0003239 Premature loss of primary teeth Early loss of baby teeth Premature loss of baby teeth [rarediseases.info.nih.gov]
- Alkaline Phosphatase Decreased
phosphatase Decreased serum alkaline phosphatase 0003282 Myopathy Muscle tissue disease 0003198 Phosphoethanolaminuria High urine phosphoethanolamine levels 0003239 Premature loss of primary teeth Early loss of baby teeth Premature loss of baby teeth [rarediseases.info.nih.gov]
- Hypoglycemia
Association of hypoglycemia, hyperglycemia, and glucose variability with morbidity and death in the pediatric intensive care unit. Pediatrics 2006;118:173–179. Dalugama C, Gawarammana IB. [piv.or.kr]
Infants occasionally have persistent hypoglycemia; some have hyperinsulinism [Baumann et al 2005]. Others have chronic low-grade acidosis [CR Scott, unpublished data]. [ncbi.nlm.nih.gov]
- Hyperglycemia
Leukopenia, thrombocytopenia, AST, ALT, LD, CK elevation, and hyperglycemia was observed. Laboratory findings showed gradual improvement. [piv.or.kr]
Treatment
Not long ago, a milestone in hypophosphatasia treatment was achieved when enzyme replacement therapy became available. Asfotase alfa, a recombinant mineral-targeted alkaline phosphatase has been approved for the treatment of childhood-onset disease. Life-long therapy is required, but asfotase alfa has been shown to improve bone mineralization, muscle strength and serum calcium regulation [3]. Motor and pulmonary functions as well as cognitive performance improve within a short period of time in those receiving enzyme replacement therapy [7] [8].
If enzyme replacement therapy is not available, only supportive care can be provided [8]. Supportive measures include, but are not limited to, dietary adjustments, the application of loop diuretics, mechanical ventilation, physical therapy and orthopedic aids [9], surgical interventions, and intensive dental care. Hypophosphatasia patients are recommended to reduce oral calcium intake and may need to take diuretics in order to prevent further increases of serum calcium levels [3].
Prognosis
The overall prognosis for affected individuals has considerably improved since asfotase alfa has been approved for hypophophatasia treatment. Disability and pain may be resolved and to date, serious adverse events related to enzyme replacement therapy have not been reported.
If alternative treatment options are chosen, symptoms of childhood-onset hypophosphatasia generally persist until adolescence. They may, however, improve spontaneously upon growth plate fusion [3]. Nevertheless, recurrent dental and skeletal issues may continue to lower these patients' quality of life.
Etiology
The ALPL gene is located on the short arm of chromosome 1, comprises about 70 kbp and 14 exons. It is the only one of four genes encoding for members of the alkaline phosphatase family to be found on this chromosome: Three genes located on chromosome 2 encode for isoforms of alkaline phosphatase expressed in specific tissues only, namely in the intestinal tract, placenta and gonades [6]. By contrast, the ALPL gene encodes for an isoform expressed in a variety of tissues, particularly in bones, liver, and kidney. Consequently, its gene product is called the liver-bone-kidney isozyme of alkaline phosphatase or tissue non-specific alkaline phosphatase.
More than 300 mutations of the ALPL gene have been described to date, and about 40 of those mutations have been related to childhood-onset hypophosphatasia [10]. Most cases result from missense mutations, but nonsense mutations and splicing anomalies have also been reported. Furthermore, the wide variety of known mutations considerably increases the likelihood of disease due to a compound heterozygous genotype [5] [11]. The severity of the disease may be related to the degree of residual enzyme activity and it has been postulated that late-onset hypophosphatasia is provoked by genotypes allowing for significant enzymatic activity [11]. However, in a French study, alkaline phosphatase activity amounted to 45% in a patient suffering from childhood-onset hypophosphatasia, but rised up to 88% in a case of infantile-onset disease [5].
Both autosomal recessive and autosomal dominant patterns of inheritance have been described childhood-onset hypophosphatasia.
Epidemiology
The prevalence of severe hypophosphatasia has been estimated to less than 1 in 100,000 individuals, but milder forms of the disease are more frequently observed. In fact, calculations taking into account the distinct patterns of inheritance (autosomal dominant inheritance has only been reported for less severe forms of the disease), the proportion of dominant mutations (approximately 13%), and the mean penetrance of the genotypes (approximately 32%) yielded estimates of a prevalence of mild hypophosphatasia of 1 in 6,370 inhabitants [12].
Pathophysiology
Tissue non-specific alkaline phosphatase catalyzes the cleavage of inorganic pyrophosphate, a strong inhibitor of mineralization. This reaction yields inorganic phosphate, which is required for the formation of hydroxyapatite crystals, the main component of bone mineral and the matrix of teeth [1]. However, in individuals carrying ALPL mutations, the activity of the liver-bone-kidney isozyme of alkaline phosphatase is significantly reduced. Consequently, inorganic pyrophosphate accumulates and hinders the formation of hydroxyapatite crystals [13]. Insufficient mineralization, rickets and osteomalacia ensue.
At the same time, serum calcium concentrations aren't adequately regulated by means of bone mineral deposition and resorption. Hypophosphatasia patients thus suffer from hypercalcemia. This condition entails a variety of constitutive, cardiac, gastrointestinal, and renal complications. Weakness, arrhythmia, recurrent vomiting and constipation, polyuria, polydipsia and nephrolithiasis may all be encountered in case of hypophosphatasia.
Prevention
Affected families may benefit from genetic counseling. Because mutations of the ALPL gene are widely distributed and many patients suffering from hypophosphatasia have a compound heterozygous genotype, pedigree analysis may pose a real challenge. There may be individuals affected by severe hypophosphatasia, even stillbirths in the same family whose members suffer from childhood-onset hypophosphatasia. It may not be possible to reliably backtrack causal mutations without conducting genetic analyses of the patient at hand and several of their relatives.
Summary
Hypophosphatasia is a hereditary disease associated with insufficient mineralization of bones and teeth as well as further metabolic complications. Hypophosphatasia results from mutations of the gene encoding for tissue non-specific alkaline phosphatase. The clinical spectrum ranges from stillbirth to severe congenital disease to less severe childhood-onset hypophosphatasia and variants only recognized in adulthood. The mildest form of hypophosphatasia is odontohypophosphatasia, which only affects the teeth. Mortality is particularly high in early-onset hypophosphatasia, while late-onset forms of the disease are not usually life-threatening. The wide variety of age at symptom onset, skeletal defects, subsequent complications, and implications for life-expectancy may be explained by the fact that any one of more than 300 known mutations may account for this metabolic hereditary disorder [14].
In detail, the following types of hypophosphatasia are distinguished in current classification schemes [1]:
- Perinatal hypophosphatasia, also called perinatal severe hypophosphatasia
- Prenatal benign hypophosphatasia, also called non-lethal hypophosphatasia
- Infantile hypophosphatasia
- Childhood-onset hypophosphatasia
- Adult hypophosphatasia
Patient Information
Hypophosphatasia is a hereditary disorder caused by DNA sequence anomalies that result in a reduction of the activity of an enzyme called alkaline phosphatase. This enzyme is required for mineral deposition in bones and teeth and consequently, individuals suffering from hypophosphatasia show skeletal deformities and dental problems. Because serum calcium levels cannot be adequately regulated by means of bone mineral deposition and resorption, hypophosphatasia patients also develop hypercalcemia. This condition entails a variety of constitutive, cardiac, gastrointestinal, and renal complications, namely weakness and irritability, arrhythmia, recurrent vomiting and constipation, polyuria, polydipsia and nephrolithiasis.
In severe forms of hypophosphatasia, skeletal anomalies may cause stillbirth or chest deformities incompatible with lung function and life. Fortunately, childhood-onset hypophosphatasia is associated with less severe symptoms. In fact, parents may note any of the aforementioned symptoms during the first or second year of their child's life, but don't usually seek medical advice until they lose their primary teeth months or even years later. Clinical examination, laboratory analyses of blood and possibly urine samples, and diagnostic imaging typically yield results that substantiate a tentative diagnosis of hypophosphatasia. This suspicion may be confirmed if persistently low levels of alkaline phosphatase are measured and, ideally, if the causal mutation is identified. Even though genetic analyses are not indispensable for the diagnosis of childhood-onset hypophosphatasia, they are highly recommended to facilitate the familial workup, future genetic counseling and prenatal diagnostics.
The mainstay of treatment is the replacement of the missing alkaline phosphatase by a recombinant analog called asfotase alfa. This agent has only recently been approved for hypophosphatasia treatment, but has been shown to significantly improve bone and teeth mineralization, serum calcium regulation, and consequently motor and cognitive performance.
References
- Mornet E. Hypophosphatasia. Metabolism. 2017.
- Mori M, DeArmey SL, Weber TJ, Kishnani PS. Case series: Odontohypophosphatasia or missed diagnosis of childhood/adult-onset hypophosphatasia? - Call for a long-term follow-up of premature loss of primary teeth. Bone Rep. 2016; 5:228-232.
- Whyte MP. Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016; 12(4):233-246.
- Schmidt T, Amling M, Barvencik F. [Hypophosphatasia : What is currently available for treatment?]. Internist (Berl). 2016; 57(12):1145-1154.
- Taillandier A, Cozien E, Muller F, et al. Fifteen new mutations (-195C>T, L-12X, 298-2A>G, T117N, A159T, R229S, 997+2T>A, E274X, A331T, H364R, D389G, 1256delC, R433H, N461I, C472S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in patients with hypophosphatasia. Hum Mutat. 2000; 15(3):293.
- Sharma U, Pal D, Prasad R. Alkaline phosphatase: an overview. Indian J Clin Biochem. 2014; 29(3):269-278.
- Bowden SA, Adler BH. Asfotase alfa treatment for 1 year in a 16 year-old male with severe childhood hypophosphatasia. Osteoporos Int. 2017.
- Hofmann C, Seefried L, Jakob F. Asfotase alfa: enzyme replacement for the treatment of bone disease in hypophosphatasia. Drugs Today (Barc). 2016; 52(5):271-285.
- Phillips D, Case LE, Griffin D, et al. Physical therapy management of infants and children with hypophosphatasia. Mol Genet Metab. 2016; 119(1-2):14-19.
- Mornet E. The Tissue Nonspecific Alkaline Phosphatase Gene Mutations Database. http://www.sesep.uvsq.fr/03_hypo_mutations.php. Accessed November 27th, 2017.
- Brun-Heath I, Taillandier A, Serre JL, Mornet E. Characterization of 11 novel mutations in the tissue non-specific alkaline phosphatase gene responsible for hypophosphatasia and genotype-phenotype correlations. Mol Genet Metab. 2005; 84(3):273-277.
- Mornet E, Yvard A, Taillandier A, Fauvert D, Simon-Bouy B. A molecular-based estimation of the prevalence of hypophosphatasia in the European population. Ann Hum Genet. 2011; 75(3):439-445.
- Whyte MP. Hypophosphatasia: Enzyme Replacement Therapy Brings New Opportunities and New Challenges. J Bone Miner Res. 2017; 32(4):667-675.
- Whyte MP. Hypophosphatasia: An overview For 2017. Bone. 2017; 102:15-25.