Congenital hypophosphatasia is associated with poor prognostic expectations, as over 50% of newborns affected by the condition eventually succumb to respiratory defects accompanied by neurological complications, dehydration and fever.

The majority of newborn patients initially display no pathologic symptomatology compatible with hypophosphatasia until the age of 6 months. A given delayed growth, limited appetite and hypotonic characteristics have been reported, but the symptoms remain non-specific during the first months of life. After the age of 6 months, bone abnormalities begin to manifest, including partially or non-ossified bones, irregular vertebral bodies resembling a butterfly in shape and smaller bone size. The ulna or fibula may exhibit the so-called Bowdler spurs, which are essentially osteochondral projections. Pediatric patients experience pain originating from the bones, baby teeth are shed earlier than normal and calcium deposits can be found on the kidneys. Severe complications also include epileptic encephalopathy responsive to vitamin B6 administration [2] and early closure of skull joints which leads to elevated intracranial pressure.

In the case of later-onset hypophosphatasia, patients have usually been completely asymptomatic during the previous years, even though some may report frequent foot or joint pain [3] dating back to their childhood years. The condition is commonly diagnosed incidentally, upon the revelation of diminished alkaline phosphatase levels in a blood test. Many patients may have lost their teeth too early in their childhood. Hypophosphatasia causes the bones to be vulnerable to fractures and stress fractures, due to a defective composition. If an individual suffers from odontohypophosphatasia, the only symptom is an abnormally early loss of adult teeth.

Irrespective of the age of diagnosis, patients with hypophosphatasia may exhibit persisting bone edema (adults), hyperprostaglandinism (children) and osteomyelitis [4]. These findings indicate a close connection of the condition with metabolic disorders.

• Poor Feeding

  The child shows poor feeding, inadequate weight gain and often a clinical picture rickets. Widening of cranial sutures, chest deformities, respiratory compromise, and pneumonia may occur. Calcium levels are elevated in blood and urine. [boneandspine.com]

  A 1-month-old boy visited the clinic because of poor feeding, frequent vomiting, hypotonia, and failure to thrive from birth. [ncbi.nlm.nih.gov]

  Perinatal form presents with a history of poor feeding, failure to thrive, hypotonia, and skin-covered spurs extending from the forearms or legs; it is lethal in 50% of cases. [accessanesthesiology.mhmedical.com]

  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]

  Infants with the disorder have respiratory complications from rickets, as well as high blood calcium levels that may cause: Irritability Poor feeding and loss of appetite Vomiting Low muscle tone Excessive thirst Frequent urination and dehydration Constipation [everydayhealth.com]

• Anemia

  Relatively few conditions are associated with a low serum alkaline phosphatase including Wilson's disease, hypophosphatasia, pernicious anemia and untreated hypothyroidism. [ncbi.nlm.nih.gov]

  Three clinical types are recognized: [1] infantile (symptoms beginning between birth and 6 months and characterized by severe softening of bones, fever, anemia, vomiting, hypercalcemia and high mortality), [2] childhood (symptoms beginning between 6 and [annals.org]

  Retardation Ashkenazi Jewish Atypical Rett Syndrome Autism/Autism Spectrum Disorder Beta Thalassemia Canavan Disease CHARGE Syndrome Chromosomal Microarray Congenital Central Hypoventilation Syndrome Congenital Hyperinsulinism Cystic Fibrosis Diamond-Blackfan Anemia [genetest.org]

  The cause of death is usually severe respiratory compromise, which may occur with fever of unknown origin, anemia, irritability, seizures, and dehydration. [emedicine.medscape.com]

• Fever

  Three clinical types are recognized: [1] infantile (symptoms beginning between birth and 6 months and characterized by severe softening of bones, fever, anemia, vomiting, hypercalcemia and high mortality), [2] childhood (symptoms beginning between 6 and [annals.org]

  7:Sly Glycoprotein Mucolipidosis - I-cell disease - Pseudo-Hurler polydystrophy - Aspartylglucosaminuria - Fucosidosis - Alpha-mannosidosis - Sialidosis Other Alpha 1-antitrypsin deficiency - Cystic fibrosis - Amyloidosis ( Familial Mediterranean fever [wikidoc.org]

  Other hypersensitivity reactions have also been reported in STRENSIQ ® -treated patients, including vomiting, fever, headache, flushing, irritability, chills, skin erythema, rash, pruritus and oral hypoesthesia. [alexion.com]

• Epilepsy

  Treated Akp2 (-/-) mice grew normally till 4 weeks and appeared well with a minimum skeletal abnormality as well as absence of epilepsy, compared with untreated mice which died by 3 weeks old. [ncbi.nlm.nih.gov]

  Vitamin B6 related epilepsy during childhood. Chang Gung Med J. 2007 Sep–Oct; 30 (5):396–401. 6. Mornet E, Yvard A, Taillandier A, Fauvert D, Simon-Bouy B. [ccmbm.com]

  Pyridoxine dependent epilepsy and antiquitin deficiency: Clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. [naturafoundation.nl]

  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]

• Developmental Delay

  Case: A 6 year old boy visited the clinic because of short stature, intermittent bone pain and mild developmental delay. He was born at 36 weeks via vaginal delivery, weighed 3.02 kg, and had hypoglycemia history after birth. [abstracts.eurospe.org]

  These infants have a history of poor feeding and failure to thrive, developmental delays, and muscle weakness. Hypotonia has also been reported. Affected children often have a history of delayed walking and early loss of deciduous teeth. [emedicine.medscape.com]

  We suggest that treatment of adults with HPP be considered when there is a history of childhood involvement (before age 18 years), such as early loss of primary or secondary teeth, craniosynostosis, gait disturbance, developmental delays, skeletal deformity [asbmr.onlinelibrary.wiley.com]

• Respiratory Insufficiency

  Perinatal HPP is mainly characterized by bone hypomineralization and severe respiratory insufficiency. [ncbi.nlm.nih.gov]

• Respiratory Distress

  A male newborn presented with extreme fontanel gap and respiratory distress. He was diagnosed with perinatal lethal HPP thus AA treatment was started. Serum alkaline phosphatase (ALP) levels increased as high as 12,700 U/L during treatment. [ncbi.nlm.nih.gov]

  At birth, skeletal abnormalities, respiratory distress with pulmonary hypoplasia, hypercalcemia established initial suspicion of bone dysplasia. [journals.lww.com]

• Failure to Thrive

  Two infants with growth retardation and failure to thrive diagnosed as infantile hypophosphatasia are presented. [bone-abstracts.org]

  The infantile case presented with failure to thrive, hypotonia, and radiologic rickets at 4 months old. The adult case had repeated fractures and marked loss of bone density demonstrated by radiographs. [ncbi.nlm.nih.gov]

  Perinatal form presents with a history of poor feeding, failure to thrive, hypotonia, and skin-covered spurs extending from the forearms or legs; it is lethal in 50% of cases. [accessanesthesiology.mhmedical.com]

• Recurrent Vomiting

  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]

  Other complications may include difficulty feeding, poor weight gain, breathing problems and hypercalcemia, which can cause recurrent vomiting and kidney dysfunction. [news-medical.net]

• Tooth Loss

  […] the best preventive measures for slowing the process of premature tooth loss. [decisionsindentistry.com]

  The descriptions include both the manifestations of the disorder and the subsequent patterns of tooth loss. [ncbi.nlm.nih.gov]

  Hypomineralization = Dental Problems Early tooth loss is one of the diagnostic characteristics of hypophosphatasia. [raredr.com]

  Childhood hypophosphatasia may cause a range of bone and tooth issues, including: Repeated fractures and bone pain Enlarged joints Delay in walking Short stature Waddling gait Premature tooth loss, particularly of the incisors The disease may spontaneously [everydayhealth.com]

• Osteoporosis

  Adult forms are milder, often missed by doctors or confused with osteoporosis. This is important because the usual osteoporosis treatments may be harmful in HPP, and increase the risk of broken bones. [clinicaltrials.gov]

  KEYWORDS: ALKALINE PHOSPHATASE; ASFOTASE ALFA; HYPOPHOSPHATASIA; OSTEOMALACIA; OSTEOPOROSIS [Indexed for MEDLINE] Free full text [ncbi.nlm.nih.gov]

  Impaired bone quality like osteoporosis, osteopenia and osteomalacia are commonly found in clinical practice. In particular, vitamin D deficiency-related deterioration of bone quality leading to the development of stress fractures is well known. [osteoporosi.it]

  […] hypophosphatasia: lethal in ~50% of cases 3 childhood hypophosphatasia adult hypophosphatasia: relatively mild odontohypophosphatasia Skeletal manifestations Some of the skeletal features are common across subtypes and include 4: generalized (usually irregular) osteoporosis [radiopaedia.org]

  Greenberg, Hypophosphatasia: Canadian update on diagnosis and management, Osteoporosis International, 10.1007/s00198-019-04921-y, (2019). [doi.org]

• Bone Pain

  In conclusion, hypophosphatasia must not be forgotten as an aetiological factor of repetitive fractures or bone pain in children and AP activity should be checked accurately. [ncbi.nlm.nih.gov]

  The mother of the patient were confirmed to have same variant with bone pain and relatively low ALP level. [abstracts.eurospe.org]

  Childhood form often presents as delayed walking, early loss of deciduous teeth, and bone pain. Adult form has mild symptoms (foot pain as a result of spontaneous fractures of metatarsal bones). [accessanesthesiology.mhmedical.com]

• Muscle Weakness

  The PPi excess can cause tooth loss, rickets or osteomalacia, calcific arthropathies, and perhaps muscle weakness. Severely affected infants may seize from insufficient hydrolysis of pyridoxal 5'-phosphate (PLP), the major extracellular vitamin B 6. [ncbi.nlm.nih.gov]

  It causes impaired bone mineralisation, fractures, tooth loss, muscle weakness and possibly other adverse health outcomes. [clinicaltrials.gov]

• Foot Pain

  Adults may also have a history of foot pain due to stress fractures and joint pain due to deposition of calcium pyrophosphate dihydrate. [emedicine.medscape.com]

  Childhood form often presents as delayed walking, early loss of deciduous teeth, and bone pain. Adult form has mild symptoms (foot pain as a result of spontaneous fractures of metatarsal bones). [accessanesthesiology.mhmedical.com]

  The first symptom may be foot pain, which is due to stress fractures of the metatarsals. Premature loss of deciduous teeth due to disturbed cementum formation is common. Mineralization of dentin is less likely. [boneandspine.com]

  Other features of the condition include premature loss of secondary (adult) teeth and thigh, hip and foot pain. This condition is sometimes associated with a history of rickets in childhood and premature loss of primary teeth. [news-medical.net]

• Rachitic Rosary

  The shape of the chest in infancy is similar to other forms of severe rickets with a narrow inlet, flaring of the costal margin and a rachitic rosary. [ccmbm.com]

  Chest x-ray was showed Rachitic rosary appearance of the ribs. Left humeral head ossification center is not aligned with metaphysis Left perihilar consolidation with blunting of both costophrenic angles. Craniosynostosis was not observed. [oatext.com]

  Features can include growth failure, craniotabes, craniosynostosis, blue sclerae, costochondral enlargement ("rachitic rosary"), scoliosis, thickening of wrists and ankles, bowing of long bones, lax ligaments, and hypotonia. [ncbi.nlm.nih.gov]

• Seizure

  In PRS, seizures resist standard anticonvulsants apart from PN, yet have a good prognosis. [ncbi.nlm.nih.gov]

  Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. [analesdepediatria.org]

• Waddling Gait

  Childhood hypophosphatasia may cause a range of bone and tooth issues, including: Repeated fractures and bone pain Enlarged joints Delay in walking Short stature Waddling gait Premature tooth loss, particularly of the incisors The disease may spontaneously [everydayhealth.com]

  “In contrast, with severe childhood HPP there is muscle weakness often with a waddling gait, sometimes obvious rachitic deformities of the skeleton such as bowed legs or knocked knees, bony aches and pains, sometimes fracturing, and an increased likelihood [endocrinenews.endocrine.org]

  Some children are weak and experience delays in walking, and when they do learn to walk may have a distinct, waddling gait. [centogene.com]

  gait bone pain/fractures Dental: premature loss of deciduous teeth Adult (AR or AD) Bone: Stress fractures: metatarsal, tibia Osteoarthritis Dental: Symptoms may be present or absent Odontohypophosphatasia (AR or AD) Bone: loss of alveolar bone Dental [ada.org]

• Irritability

  Severe forms may present with many neurological problems such as seizures, hypotonia, irritability. [ncbi.nlm.nih.gov]

  Other hypersensitivity reactions have also been reported in STRENSIQ ® -treated patients, including vomiting, fever, headache, flushing, irritability, chills, skin erythema, rash, pruritus and oral hypoesthesia. [alexion.com]

  Infants with the disorder have respiratory complications from rickets, as well as high blood calcium levels that may cause: Irritability Poor feeding and loss of appetite Vomiting Low muscle tone Excessive thirst Frequent urination and dehydration Constipation [everydayhealth.com]

  About 15% of people in the studies had allergic reactions, including emesis, fever, headache, flushing, irritability, chills, skin erythema, and rash. [managedcaremag.com]

• Encephalopathy

  To our knowledge, this is the first MRI-based report of a deleterious neurological clinical outcome due to a progressive encephalopathy in an infant harboring a functional human ALPL "knock out". [ncbi.nlm.nih.gov]

  Infants may also present with severe epileptic encephalopathy that results in death. [emedicine.medscape.com]

• Neonatal Seizures

  Altogether, these findings suggest that the purinergic signalling regulates the neurodevelopmental alteration and the neonatal seizures associated to HPP. © The Author 2016. Published by Oxford University Press. [ncbi.nlm.nih.gov]

  Neonatal seizures may occur Deformities and gait abnormalities may require surgical correction. Prognosis The perinatal form is considered lethal and the cause of death is often respiratory complication. [boneandspine.com]

  Vitamin B-6 may be indicated to treat neonatal seizures. [25] [emedicine.medscape.com]

The first step towards evaluating a case of potential hypophosphatasia is laboratory testing, including levels of the following:

Blood tests

• Alkaline phosphatase: low levels are consistent with the condition that the patient does not need to have fasted prior to the examination.
• Phosphate analysis: the patient needs to have fasted.
• Phosphorus
• Magnesium
• Calcium
• Parathyroid hormone
• Vitamin D
• Creatinine
• PLP: elevated. Its levels may be affected by vitamin B6 supplementation.
• PPi

Urine tests

• PEA: elevated levels are consistent with the condition but are not pathognomonic.

The next diagnostic step involves radiologic examining of the skeleton. Adults usually exhibit multiple pseudofractures and partially healed stress fractures. Pediatric patients exhibit incomplete mineralization, rachitic abnormalities and spurs in the elbows and knees. Early synostosis of the skull can also be observed. The radiologic findings depend on the severity of each case.

Ultrasonography can be used to detect kidney calcinosis. Patients who are affected by odontohypophosphatasia solely display diminished maxillary density.

A biopsy sample ban be obtained from a bone, but this procedure is mainly carried out for research purposes. A histological analysis is expected to reveal increased osteoid indices, such as thickness and osteoid surface per bone surface, inadequate mineralizing surface and a decreased bone formation rate. Regional cartilage calcification can also be observed. Osteoblasts and osteoclasts are functional but membrane ALP activity is absent, as illustrated by a histochemical analysis.

• Nephrolithiasis

  Last Update: 2012-04-11 Usage Frequency: 2 Quality: Lithuanian -Nefrokalcinoz, nefrolitiaz English -Nephrocalcinosis, nephrolithiasis Last Update: 2008-03-04 Usage Frequency: 1 Quality: Warning: This alignment may be wrong. [mymemory.translated.net]

  Kidney impairment was also observed with reduced creatinine clearance, nephrolithiasis, and nephrocalcinosis. [ncbi.nlm.nih.gov]

• Shortened Long Bone

  After birth, infants with the disorder typically have apnea, seizures, and shortened long bones. They may survive for a few days after birth, but ultimately die from respiratory issues stemming from lack of development of the lungs and chest. [everydayhealth.com]

  Undermineralization, small thoracic cavity, shortened long bones, and bowing are typical features of autosomal recessive and severe hypophosphatasia. [ncbi.nlm.nih.gov]

No cure is available for hypophosphatasia and the rarity of the condition affects the prospects of thorough clinical studies in a negative way. Possible conservative treatment plans include the administration of non-steroidal anti-inflammatory drugs which seemed to relieve pediatric patients from pain [5] [6] and reduce the subsequent metabolic inflammation [4]. Phosphate intake should be also reduced. Teriparatide further seemed to improve the healing of recurrent stress fractures [7].

An experimental treatment was attempted in 1997: a patient aged 8 months old received a bone marrow transplant as treatment for hypophosphatasia and displayed considerable clinical improvement [8]. Another treatment that was carried out in another pediatric patient involved the use of bone fragments and osteoblasts derived from a culture [9]; the patient grew up to exhibit a milder clinical picture than expected. Lastly, researchers inactivated the plasma cell membrane glycoprotein-1 (PC-1) gene in laboratory mice [10], something which actually restored the characteristics of affected rodents. Both genetic therapy and enzyme supplementation therapy are currently being under research, with the aim of developing an adequate hypophosphatasia treatment.

The congenital type of hypophosphatasia is a fatal condition and only half of the pediatric patients who develop the disease during infancy eventually survive. Individuals affected by the later-onset, adult type, as well as those exhibiting odontohypophosphatasia exhibit the same mortality rate as the rest of the population.

Hypophosphatasia has been genetically mapped; the ALPL gene responsible for all the disease types, both early and adult, is found at the 1p36.1-34 band. ALPL encodes for tissue nonspecific alkaline phosphatase. Hundreds of variants have been detected over the years and regardless of the type of hypophosphatasia, it can be passed down to offspring via both an autosomal dominant and a recessive pattern.

The most severe type of hypophosphatasia is particularly observed amongst some specific populations, like the Canadian Mennonites with a frequency of around 1 in 2,500 births. Generally, the condition is believed to affect approximately 1 in 100,000 newborns in the USA [1]. Data regarding its incidence on a worldwide scale are not available.

Occurrences of hypophosphatasia that arise within 6 months after birth are extremely severe, with half of the newborns succumbing to complications affecting the respiratory tract. In the cases of later onset usually patients reach the age of 18; however, frequent and troubling complications arise. Rachitic deformities are common amongst hypophosphatasia patients, as are frequent fractures, delayed or incomplete healing, calcium deposits on the kidneys, seizures and elevated intracranial pressure. Skeletal weakness and softness renders an individual unstable, as the bones fail to support their weight and are fractured. Therefore, approximately 1/4 of the patients move with the aid of a wheelchair or other walking device.

In general, hypophosphatasia exhibits no racial predilection and affects both genders and age groups.

The human organism functions with the aid of distinct isoforms of alkaline phosphatase, one of which is TNSALP. TNSALP stands for tissue nonspecific alkaline phosphatase and although its function has yet to be fully understood by the medical community, it is believed to mediate matrix mineralization and hydrolyze pyridoxal phosphate (PLP), phenethylamine (PEA) and diphosphate (PPi). The genetic location of the TNSALP gene is known to be 1p36.1.

Individuals suffering from hypophosphatasia display low levels of TNSALP; as a result, the levels of PPi increase, and this impairs the formation of hydroxyapatite crystals and disrupts the equilibrium between phosphate and calcium.

As a genetic condition, hypophosphatasia cannot be prevented.

Hypophosphatasia is a condition which causes inadequate deposition of minerals on bone tissue and teeth during their formation.

There are various degrees of severity; the types associated with the severer symptomatology are early onset (arising during the first years of life) or congenital. Similar to rickets, hypophosphatasia does not allow for a normal composition of bones and teeth, leading to soft, weak bones that are susceptible to fractures and teeth that tend to fall prematurely. Children who are born with hypophosphatasia exhibit shortened extremities, soft bones on the skull, abnormally bent knees and chest structural abnormalities; later on in life they show poor feeding habits and hypercalcemia, which greatly impairs renal function in addition to frequent vomiting. In many cases, the first symptom indicating the presence of hypophosphatemia in children is the premature loss of baby teeth.

Late onset hypophosphatemia regards cases which appear during the adult life and are typically not as severe as early onset disease types. Osteomalacia is the prevalent symptom, which means "soft bones" and is a term derived from the Greek "osto= bone + malakos= soft". Adults are very susceptible to bone fractures and early teeth loss, as well as persistent pain due to the frequent fractures.

Lastly, there is a sub-type of Hypophosphatasia which solely impairs teeth formation, called "odontohypophosphatasia". Adult individuals suffer only dental problems and early teeth loss but no other bone abnormalities.

Hypophosphatasia is a rare hereditary bone disease that is caused by abnormally low levels of alkaline phosphatase (ALP). ALP is an enzyme which greatly contributes to the formation of a strong skeleton and correctly developed bones and teeth. Individuals who suffer from hypophosphatasia have weak bones which lack in density and subsequently defective teeth. The disease exhibits various degrees of severity and there are individuals who merely have low levels of ALP in their blood, without any other symptoms.

A person can be born with hypophosphatasia or be diagnosed with it during their infancy, childhood, or adult life. Individuals who are affected by odontohypophosphatasia only experience teeth problems and no skeletal deformities.

Patients with this condition suffer frequent fractures and stress fractures. Their skeleton is not properly developed and various abnormalities can occur, either visible or not. Teeth are usually lost quite early in childhood. When the chest structure is too damaged, pneumonia is bound to occur in a more frequent manner as in healthy individuals.

As for treatment options, there is no treatment for hypophosphatasia. Patients have in the past been treated with various medications which were conservative and not able to cure the disease. Bone marrow transplant and bone donors have been used, but no definitive treatment plan has been developed yet.

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3. Jenny C. Evaluating infants and young children with multiple fractures. Pediatrics. 2006 Sep; 118(3):1299-303. 
4. Girschick HJ, Mornet E, Beer M, Warmuth-Metz M, Schneider P. Chronic multifocal non-bacterial osteomyelitis in hypophosphatasia mimicking malignancy. BMC Pediatr. 2007 Jan 23;7:3.
5. Girschick HJ, Seyberth HW, Huppertz HI. Treatment of childhood hypophosphatasia with nonsteroidal antiinflammatory drugs. Bone 1999; 25:603-7
6. Girschick HJ, Schneider P, Haubitz I, et al. Effective NSAID treatment indicates that hyperprostaglandinism is affecting the clinical severity of childhood hypophosphatasia. Orphanet J Rare Dis 2006; 1:24.
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8. Whyte MP, Kurtzberg J, McAlister WH, et al. Marrow cell transplantation for infantile hypophosphatasia. J Bone Miner Res 2003; 18:624-36. 
9. Cahill RA, Wenkert D, Perlman SA, et al. Infantile Hypophosphatasia: Transplantation Therapy Trial Using Bone Fragments and Cultured Osteoblasts. J Clin Endocrinol Metab. 2007 Aug;92(8):2923-30.
10. Hessle L, Johnson KA, Anderson HC, et al. Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization. Proc Natl Acad Sci USA 2002; 99:9445-9.