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Hypophosphatasia

MedGen UID:
43799
Concept ID:
C0020630
Disease or Syndrome
Synonym: Phosphoethanol-aminuria
SNOMED CT: Hypophosphatasia (190859005); Alkaline phosphatase deficiency (190859005); Deficiency of alkaline phosphatase (360792001)
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)
 
Monarch Initiative: MONDO:0018570
Orphanet: ORPHA436

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
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.

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.

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 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.  https://medlineplus.gov/genetics/condition/hypophosphatasia

Professional guidelines

PubMed

Charoenngam N, Nasr A, Shirvani A, Holick MF
Genes (Basel) 2022 Oct 17;13(10) doi: 10.3390/genes13101880. PMID: 36292765Free PMC Article
Mornet E, Taillandier A, Domingues C, Dufour A, Benaloun E, Lavaud N, Wallon F, Rousseau N, Charle C, Guberto M, Muti C, Simon-Bouy B
Eur J Hum Genet 2021 Feb;29(2):289-299. Epub 2020 Sep 24 doi: 10.1038/s41431-020-00732-6. PMID: 32973344Free PMC Article
Whyte MP
Nat Rev Endocrinol 2016 Apr;12(4):233-46. Epub 2016 Feb 19 doi: 10.1038/nrendo.2016.14. PMID: 26893260

Recent clinical studies

Etiology

Khan AA, Brandi ML, Rush ET, Ali DS, Al-Alwani H, Almonaei K, Alsarraf F, Bacrot S, Dahir KM, Dandurand K, Deal C, Ferrari SL, Giusti F, Guyatt G, Hatcher E, Ing SW, Javaid MK, Khan S, Kocijan R, Linglart A, M'Hiri I, Marini F, Nunes ME, Rockman-Greenberg C, Roux C, Seefried L, Simmons JH, Starling SR, Ward LM, Yao L, Brignardello-Petersen R, Lewiecki EM
Osteoporos Int 2024 Mar;35(3):431-438. Epub 2023 Nov 20 doi: 10.1007/s00198-023-06844-1. PMID: 37982857Free PMC Article
Charoenngam N, Nasr A, Shirvani A, Holick MF
Genes (Basel) 2022 Oct 17;13(10) doi: 10.3390/genes13101880. PMID: 36292765Free PMC Article
Fenn JS, Lorde N, Ward JM, Borovickova I
J Clin Pathol 2021 Oct;74(10):635-640. Epub 2021 Apr 30 doi: 10.1136/jclinpath-2021-207426. PMID: 33931563
Wilson MP, Plecko B, Mills PB, Clayton PT
J Inherit Metab Dis 2019 Jul;42(4):629-646. Epub 2019 Mar 20 doi: 10.1002/jimd.12060. PMID: 30671974
Whyte MP
Nat Rev Endocrinol 2016 Apr;12(4):233-46. Epub 2016 Feb 19 doi: 10.1038/nrendo.2016.14. PMID: 26893260

Diagnosis

Schini M, Vilaca T, Gossiel F, Salam S, Eastell R
Endocr Rev 2023 May 8;44(3):417-473. doi: 10.1210/endrev/bnac031. PMID: 36510335Free PMC Article
Cianferotti L
Int J Mol Sci 2022 Nov 28;23(23) doi: 10.3390/ijms232314896. PMID: 36499221Free PMC Article
Charoenngam N, Nasr A, Shirvani A, Holick MF
Genes (Basel) 2022 Oct 17;13(10) doi: 10.3390/genes13101880. PMID: 36292765Free PMC Article
Fenn JS, Lorde N, Ward JM, Borovickova I
J Clin Pathol 2021 Oct;74(10):635-640. Epub 2021 Apr 30 doi: 10.1136/jclinpath-2021-207426. PMID: 33931563
Whyte MP
Nat Rev Endocrinol 2016 Apr;12(4):233-46. Epub 2016 Feb 19 doi: 10.1038/nrendo.2016.14. PMID: 26893260

Therapy

Mannes I, Rothenbuhler A, Merzoug V, Di Rocco F, Linglart A, Adamsbaum C
Pediatr Radiol 2022 May;52(5):998-1006. Epub 2021 Dec 2 doi: 10.1007/s00247-021-05232-3. PMID: 34854966
Falsaperla R, Sciuto L, La Spina L, Sciuto S, Praticò AD, Ruggieri M
Metab Brain Dis 2021 Dec;36(8):2195-2203. Epub 2021 Aug 17 doi: 10.1007/s11011-021-00798-1. PMID: 34403026Free PMC Article
Fenn JS, Lorde N, Ward JM, Borovickova I
J Clin Pathol 2021 Oct;74(10):635-640. Epub 2021 Apr 30 doi: 10.1136/jclinpath-2021-207426. PMID: 33931563
Wilson MP, Plecko B, Mills PB, Clayton PT
J Inherit Metab Dis 2019 Jul;42(4):629-646. Epub 2019 Mar 20 doi: 10.1002/jimd.12060. PMID: 30671974
Linglart A, Biosse-Duplan M
Curr Osteoporos Rep 2016 Jun;14(3):95-105. doi: 10.1007/s11914-016-0309-0. PMID: 27084188

Prognosis

Reis FS, Lazaretti-Castro M
Arch Endocrinol Metab 2023 May 25;67(5):e000626. doi: 10.20945/2359-3997000000626. PMID: 37249457Free PMC Article
Fenn JS, Lorde N, Ward JM, Borovickova I
J Clin Pathol 2021 Oct;74(10):635-640. Epub 2021 Apr 30 doi: 10.1136/jclinpath-2021-207426. PMID: 33931563
Del Angel G, Reynders J, Negron C, Steinbrecher T, Mornet E
Hum Mutat 2020 Jul;41(7):1250-1262. Epub 2020 Mar 18 doi: 10.1002/humu.24010. PMID: 32160374Free PMC Article
Cormier C
Joint Bone Spine 2019 Jul;86(4):459-466. Epub 2018 Oct 6 doi: 10.1016/j.jbspin.2018.10.001. PMID: 30300686
Briot K, Roux C
Arch Pediatr 2017 May;24(5S2):5S71-5S73. doi: 10.1016/S0929-693X(18)30018-6. PMID: 29405936

Clinical prediction guides

Falsaperla R, Sciuto L, La Spina L, Sciuto S, Praticò AD, Ruggieri M
Metab Brain Dis 2021 Dec;36(8):2195-2203. Epub 2021 Aug 17 doi: 10.1007/s11011-021-00798-1. PMID: 34403026Free PMC Article
Vimalraj S
Gene 2020 Sep 5;754:144855. Epub 2020 Jun 6 doi: 10.1016/j.gene.2020.144855. PMID: 32522695
Del Angel G, Reynders J, Negron C, Steinbrecher T, Mornet E
Hum Mutat 2020 Jul;41(7):1250-1262. Epub 2020 Mar 18 doi: 10.1002/humu.24010. PMID: 32160374Free PMC Article
Mornet E
Metabolism 2018 May;82:142-155. Epub 2017 Sep 20 doi: 10.1016/j.metabol.2017.08.013. PMID: 28939177
Briot K, Roux C
Arch Pediatr 2017 May;24(5S2):5S71-5S73. doi: 10.1016/S0929-693X(18)30018-6. PMID: 29405936

Recent systematic reviews

Falsaperla R, Sciuto L, La Spina L, Sciuto S, Praticò AD, Ruggieri M
Metab Brain Dis 2021 Dec;36(8):2195-2203. Epub 2021 Aug 17 doi: 10.1007/s11011-021-00798-1. PMID: 34403026Free PMC Article
Zhou W, van Rooij JGJ, Ebeling PR, Verkerk AJMH, Zillikens MC
Curr Osteoporos Rep 2021 Apr;19(2):123-130. Epub 2021 Feb 15 doi: 10.1007/s11914-021-00658-y. PMID: 33587247Free PMC Article
Szabo SM, Tomazos IC, Petryk A, Powell LC, Donato BMK, Zarate YA, Tiulpakov A, Martos-Moreno GÁ
Orphanet J Rare Dis 2019 Apr 25;14(1):85. doi: 10.1186/s13023-019-1062-0. PMID: 31023354Free PMC Article
Bloch-Zupan A
Int J Paediatr Dent 2016 Nov;26(6):426-438. Epub 2016 Mar 31 doi: 10.1111/ipd.12232. PMID: 27030892
Faruqi T, Dhawan N, Bahl J, Gupta V, Vohra S, Tu K, Abdelmagid SM
Biomed Res Int 2014;2014:670842. Epub 2014 Oct 22 doi: 10.1155/2014/670842. PMID: 25530967Free PMC Article

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