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.
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 . 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 . 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) .
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
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]
Conversely, a patient with poor growth velocity would appear to be at risk of future growth deceleration, which arguably constitutes its own functional consequence. [ojrd.biomedcentral.com]
Disproportionate Short Stature
Fernando Cassorla Aim: Léri-Weill dyschondrosteosis (LWD) is a mesomelic dysplasia with disproportionate short stature associated with short stature homeobox-containing gene (SHOX) haploinsufficiency. [researchgate.net]
rosary 0000897 Seizures Seizure 0001250 Short stature Decreased 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: [rarediseases.info.nih.gov]
(ERT) called asfotase alfa has been show to improve bone symptoms in people with childhood hypophosphatasia and has been approved by the FDA. 0002979 Carious teeth Dental cavities Tooth cavities Tooth decay [ more ] 0000670 Craniosynostosis 0001363 Dolichocephaly [rarediseases.info.nih.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 often [rarediseases.info.nih.gov]
Face, Head & Neck
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 . In urine samples, increased levels of alkaline phosphatase substrates like phosphoethanolamine can be detected .
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 . 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 .
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 . 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 . 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 . 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 . Mutations of the ALPL gene cannot be identified in all cases, though.
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]
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 . Motor and pulmonary functions as well as cognitive performance improve within a short period of time in those receiving enzyme replacement therapy  .
If enzyme replacement therapy is not available, only supportive care can be provided . Supportive measures include, but are not limited to, dietary adjustments, the application of loop diuretics, mechanical ventilation, physical therapy and orthopedic aids , 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 .
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 . Nevertheless, recurrent dental and skeletal issues may continue to lower these patients' quality of life.
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 . 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 . 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  . 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 . 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 .
Both autosomal recessive and autosomal dominant patterns of inheritance have been described childhood-onset hypophosphatasia.
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 .
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 . 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 . 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.
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.
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 .
In detail, the following types of hypophosphatasia are distinguished in current classification schemes :
- Perinatal hypophosphatasia, also called perinatal severe hypophosphatasia
- Prenatal benign hypophosphatasia, also called non-lethal hypophosphatasia
- Infantile hypophosphatasia
- Childhood-onset hypophosphatasia
- Adult hypophosphatasia
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.
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