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Adult hypophosphatasia(HPPA)

MedGen UID:
120636
Concept ID:
C0268413
Disease or Syndrome
Synonyms: Hypophosphatasia, Adult; Hypophosphatasia, Mild
SNOMED CT: Adult hypophosphatasia (20756002); Hypophosphatasia, adult type (20756002)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): ALPL (1p36.12)
 
OMIM®: 146300
Orphanet: ORPHA247676

Disease characteristics

Excerpted from the GeneReview: Hypophosphatasia
Hypophosphatasia is characterized by defective mineralization of growing or remodeling bone, with or without root-intact tooth loss, in the presence of low activity of serum and bone alkaline phosphatase. Clinical features range from stillbirth without mineralized bone at the severe end to pathologic fractures of the lower extremities in later adulthood at the mild end. While the disease spectrum is a continuum, seven clinical forms of hypophosphatasia are usually recognized based on age at diagnosis and severity of features: Perinatal (severe): Characterized by pulmonary insufficiency and hypercalcemia Perinatal (benign): Prenatal skeletal manifestations that slowly resolve into one of the milder forms Infantile: Onset between birth and age six months of clinical features of rickets without elevated serum alkaline phosphatase activity Severe childhood (juvenile): Variable presenting features progressing to rickets Mild childhood: Low bone mineral density for age, increased risk of fracture, and premature loss of primary teeth with intact roots Adult: Characterized by stress fractures and pseudofractures of the lower extremities in middle age, sometimes associated with early loss of adult dentition Odontohypophosphatasia: Characterized by premature exfoliation of primary teeth and/or severe dental caries without skeletal manifestations [from GeneReviews]
Authors:
Mark E Nunes   view full author information

Additional description

From MedlinePlus Genetics
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 known as osteomalacia. 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.

The mildest form of this condition, called odontohypophosphatasia, only affects the teeth. 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.

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.

Hypophosphatasia is an inherited disorder that affects the development of bones and teeth. This condition disrupts a process called mineralization, in which minerals such as calcium and phosphorus are deposited in developing bones and teeth. Mineralization is critical for the formation of bones that are strong and rigid and teeth that can withstand chewing and grinding.  https://medlineplus.gov/genetics/condition/hypophosphatasia

Clinical features

From HPO
Abnormal foot morphology
MedGen UID:
1762829
Concept ID:
C5399834
Anatomical Abnormality
An abnormality of the skeleton of foot.
Recurrent fractures
MedGen UID:
42094
Concept ID:
C0016655
Injury or Poisoning
The repeated occurrence of bone fractures (implying an abnormally increased tendency for fracture).
Pathologic fracture
MedGen UID:
42095
Concept ID:
C0016663
Pathologic Function
A pathologic fracture occurs when a bone breaks in an area that is weakened secondarily to another disease process such as tumor, infection, and certain inherited bone disorders. A pathologic fracture can occur without a degree of trauma required to cause fracture in healthy bone.
Arthropathy
MedGen UID:
7190
Concept ID:
C0022408
Disease or Syndrome
Any disorder of the joints.
Osteomalacia
MedGen UID:
14533
Concept ID:
C0029442
Disease or Syndrome
Osteomalacia is a general term for bone weakness owing to a defect in mineralization of the protein framework known as osteoid. This defective mineralization is mainly caused by lack in vitamin D. Osteomalacia in children is known as rickets.
Rickets
MedGen UID:
48470
Concept ID:
C0035579
Disease or Syndrome
Rickets is divided into two major categories including calcipenic and phosphopenic. Hypophosphatemia is described as a common manifestation of both categories. Hypophosphatemic rickets is the most common type of rickets that is characterized by low levels of serum phosphate, resistance to ultraviolet radiation or vitamin D intake. There are several issues involved in hypophosphatemic rickets such as calcium, vitamin D, phosphorus deficiencies. Moreover, other disorder can be associated with its occurrence such as absorption defects due to pancreatic, intestinal, gastric, and renal disorders and hepatobiliary disease. Symptoms are usually seen in childhood and can be varied in severity. Severe forms may be linked to bowing of the legs, poor bone growth, and short stature as well as joint and bone pain. Hypophosphatemic rickets are associated with renal excretion of phosphate, hypophosphatemia, and mineral defects in bones. The familial type of the disease is the most common type of rickets.
Chondrocalcinosis
MedGen UID:
154303
Concept ID:
C0553730
Disease or Syndrome
Radiographic evidence of articular calcification that represent calcium pyrophosphate depositions in soft tissue surrounding joints and at the insertions of tendons near joints (Entheses/Sharpey fibers) .
Increased susceptibility to fractures
MedGen UID:
234655
Concept ID:
C1390474
Finding
An abnormally increased tendency to fractures of bones caused by an abnormal reduction in bone strength that is generally associated with an increased risk of fracture.
Low alkaline phosphatase
MedGen UID:
349734
Concept ID:
C1860130
Finding
Abnormally reduced serum levels of alkaline phosphatase.
Carious teeth
MedGen UID:
8288
Concept ID:
C0011334
Disease or Syndrome
Caries is a multifactorial bacterial infection affecting the structure of the tooth. This term has been used to describe the presence of more than expected dental caries.
Premature loss of primary teeth
MedGen UID:
585520
Concept ID:
C0399385
Disease or Syndrome
Loss of the primary (also known as deciduous) teeth before the usual age.
Premature loss of permanent teeth
MedGen UID:
409904
Concept ID:
C1969738
Finding
Premature loss of the permanent teeth.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Adult hypophosphatasia in Orphanet.

Professional guidelines

PubMed

Martins L, de Almeida AB, Dos Santos EJL, Foster BL, Machado RA, Kantovitz KR, Coletta RD, Nociti FH Jr
Bone 2019 Aug;125:128-139. Epub 2019 May 8 doi: 10.1016/j.bone.2019.05.005. PMID: 31077853

Curated

Mornet E, Beck C, Bloch-Zupan A, Girschick H, Le Merrer M
Eur J Hum Genet 2011 Mar;19(3) Epub 2010 Oct 27 doi: 10.1038/ejhg.2010.170. PMID: 20978533Free PMC Article

Recent clinical studies

Etiology

Calmarza P, Lapresta C, Martínez García M, Ochoa J, Sienes Bailo P, Acha Pérez J, Beltrán Audera J, González-Roca E
J Bone Miner Metab 2023 Sep;41(5):654-665. Epub 2023 Jun 23 doi: 10.1007/s00774-023-01440-z. PMID: 37351650
Weider M, Schlagenhauf U, Seefried L
J Clin Periodontol 2022 Dec;49(12):1253-1261. Epub 2022 Sep 7 doi: 10.1111/jcpe.13718. PMID: 36054522
Genest F, Claußen L, Rak D, Seefried L
Osteoporos Int 2021 Feb;32(2):377-385. Epub 2020 Sep 2 doi: 10.1007/s00198-020-05612-9. PMID: 32879991Free PMC Article
Schmidt T, Mussawy H, Rolvien T, Hawellek T, Hubert J, Rüther W, Amling M, Barvencik F
Osteoporos Int 2017 Sep;28(9):2653-2662. Epub 2017 May 25 doi: 10.1007/s00198-017-4087-z. PMID: 28547134
Barvencik F, Beil FT, Gebauer M, Busse B, Koehne T, Seitz S, Zustin J, Pogoda P, Schinke T, Amling M
Osteoporos Int 2011 Oct;22(10):2667-75. Epub 2011 Jan 26 doi: 10.1007/s00198-011-1528-y. PMID: 21267545

Diagnosis

Calmarza P, Lapresta C, Martínez García M, Ochoa J, Sienes Bailo P, Acha Pérez J, Beltrán Audera J, González-Roca E
J Bone Miner Metab 2023 Sep;41(5):654-665. Epub 2023 Jun 23 doi: 10.1007/s00774-023-01440-z. PMID: 37351650
Feurstein J, Behanova M, Haschka J, Roetzer K, Uyanik G, Hadzimuratovic B, Witsch-Baumgartner M, Schett G, Zwerina J, Kocijan R
Orphanet J Rare Dis 2022 Dec 14;17(1):435. doi: 10.1186/s13023-022-02572-7. PMID: 36514157Free PMC Article
Briot K, Roux C
Arch Pediatr 2017 May;24(5S2):5S71-5S73. doi: 10.1016/S0929-693X(18)30018-6. PMID: 29405936
Schmidt T, Mussawy H, Rolvien T, Hawellek T, Hubert J, Rüther W, Amling M, Barvencik F
Osteoporos Int 2017 Sep;28(9):2653-2662. Epub 2017 May 25 doi: 10.1007/s00198-017-4087-z. PMID: 28547134
Sorensen E, Flodgaard H
Acta Med Scand 1975 May;197(5):357-60. doi: 10.1111/j.0954-6820.1975.tb04934.x. PMID: 167553

Therapy

Polyzos SA, Tournis S, Goulas A, Kollia P, Whyte MP
J Musculoskelet Neuronal Interact 2021 Dec 1;21(4):584-589. PMID: 34854399Free PMC Article
Genest F, Claußen L, Rak D, Seefried L
Osteoporos Int 2021 Feb;32(2):377-385. Epub 2020 Sep 2 doi: 10.1007/s00198-020-05612-9. PMID: 32879991Free PMC Article
Righetti M, Wach J, Desmarchelier R, Coury F
Joint Bone Spine 2018 May;85(3):365-367. Epub 2017 Dec 12 doi: 10.1016/j.jbspin.2017.12.001. PMID: 29246529
Bhattacharyya T, Jha S, Wang H, Kastner DL, Remmers EF
BMC Musculoskelet Disord 2016 Aug 9;17:332. doi: 10.1186/s12891-016-1191-8. PMID: 27507156Free PMC Article
Sorensen E, Flodgaard H
Acta Med Scand 1975 May;197(5):357-60. doi: 10.1111/j.0954-6820.1975.tb04934.x. PMID: 167553

Prognosis

Xu L, Pang Q, Jiang Y, Wang O, Li M, Xing X, Xia W
Biosci Rep 2018 Aug 31;38(4) Epub 2018 Aug 29 doi: 10.1042/BSR20171377. PMID: 29724887Free PMC Article
Righetti M, Wach J, Desmarchelier R, Coury F
Joint Bone Spine 2018 May;85(3):365-367. Epub 2017 Dec 12 doi: 10.1016/j.jbspin.2017.12.001. PMID: 29246529
Taillandier A, Domingues C, Dufour A, Debiais F, Guggenbuhl P, Roux C, Cormier C, Cortet B, Porquet-Bordes V, Coury F, Geneviève D, Chiesa J, Colin T, Fletcher E, Guichet A, Javier RM, Laroche M, Laurent M, Lausch E, LeHeup B, Lukas C, Schwabe G, van der Burgt I, Muti C, Simon-Bouy B, Mornet E
J Bone Miner Metab 2018 Nov;36(6):723-733. Epub 2017 Dec 13 doi: 10.1007/s00774-017-0888-6. PMID: 29236161
Briot K, Roux C
Arch Pediatr 2017 May;24(5S2):5S71-5S73. doi: 10.1016/S0929-693X(18)30018-6. PMID: 29405936
Camacho PM, Mazhari AM, Wilczynski C, Kadanoff R, Mumm S, Whyte MP
Endocr Pract 2016 Aug;22(8):941-50. Epub 2016 Apr 4 doi: 10.4158/EP15890.OR. PMID: 27042741

Clinical prediction guides

Feurstein J, Behanova M, Haschka J, Roetzer K, Uyanik G, Hadzimuratovic B, Witsch-Baumgartner M, Schett G, Zwerina J, Kocijan R
Orphanet J Rare Dis 2022 Dec 14;17(1):435. doi: 10.1186/s13023-022-02572-7. PMID: 36514157Free PMC Article
Weider M, Schlagenhauf U, Seefried L
J Clin Periodontol 2022 Dec;49(12):1253-1261. Epub 2022 Sep 7 doi: 10.1111/jcpe.13718. PMID: 36054522
Genest F, Claußen L, Rak D, Seefried L
Osteoporos Int 2021 Feb;32(2):377-385. Epub 2020 Sep 2 doi: 10.1007/s00198-020-05612-9. PMID: 32879991Free PMC Article
Briot K, Roux C
Arch Pediatr 2017 May;24(5S2):5S71-5S73. doi: 10.1016/S0929-693X(18)30018-6. PMID: 29405936
Schmidt T, Mussawy H, Rolvien T, Hawellek T, Hubert J, Rüther W, Amling M, Barvencik F
Osteoporos Int 2017 Sep;28(9):2653-2662. Epub 2017 May 25 doi: 10.1007/s00198-017-4087-z. PMID: 28547134

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