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Infantile hypophosphatasia(HPPI)

MedGen UID:
75677
Concept ID:
C0268412
Disease or Syndrome
Synonyms: Hypophosphatasia, Infantile; Phosphoethanolaminuria
SNOMED CT: Foetal hypophosphatasia (55236002); Phosphoethanolaminuria (55236002); Rathbun syndrome (55236002); Infantile hypophosphatasia (55236002); Hypophosphatasia, infantile type (55236002); Congenital hypophosphatasia (55236002); Fetal hypophosphatasia (55236002)
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).
 
Gene (location): ALPL (1p36.12)
 
OMIM®: 241500
Orphanet: ORPHA247651

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 descriptions

From OMIM
Hypophosphatasia (HPP) is an inborn error of metabolism characterized clinically by defective bone mineralization and biochemically by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase. Fraser (1957) classified forms of hypophosphatasia according to age of onset: perinatal, infantile, childhood (241510), and adult (146300). Whyte (1988) indicated a fifth form of hypophosphatasia with primarily only dental manifestations, referred to as odontohypophosphatasia (see 146300). All of these forms are allelic.  http://www.omim.org/entry/241500
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 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.  https://medlineplus.gov/genetics/condition/hypophosphatasia

Clinical features

From HPO
Hypercalciuria
MedGen UID:
43775
Concept ID:
C0020438
Finding
Abnormally high level of calcium in the urine.
Nephrocalcinosis
MedGen UID:
10222
Concept ID:
C0027709
Disease or Syndrome
Nephrocalcinosis is the deposition of calcium salts in renal parenchyma.
Elevated urine pyrophosphate
MedGen UID:
871136
Concept ID:
C4025607
Finding
An abnormally increased diphosphate(4-) concentration in the urine. Diphosphate(4-), as ester with two phosphate groups, is also known as pyrophosphate.
Phosphoethanolaminuria
MedGen UID:
1814510
Concept ID:
C5700114
Finding
An increased level of phosphoethanolamine (synonym
Micromelia
MedGen UID:
10031
Concept ID:
C0025995
Congenital Abnormality
The presence of abnormally small extremities.
Short lower limbs
MedGen UID:
98100
Concept ID:
C0426901
Finding
Shortening of the legs related to developmental hypoplasia of the bones of the leg.
Intracranial hemorrhage
MedGen UID:
101799
Concept ID:
C0151699
Pathologic Function
Hemorrhage occurring within the skull.
Disproportionate short-limb short stature
MedGen UID:
342370
Concept ID:
C1849937
Finding
A type of disproportionate short stature characterized by a short limbs but an average-sized trunk.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Anorexia
MedGen UID:
315
Concept ID:
C0003123
Disease or Syndrome
Anorexia, or the loss of appetite for food, is a medical condition.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Craniosynostosis syndrome
MedGen UID:
1163
Concept ID:
C0010278
Disease or Syndrome
Craniosynostosis refers to the premature closure of the cranial sutures. Primary craniosynostosis refers to the closure of one or more sutures due to abnormalities in skull development, and secondary craniosynostosis results from failure of brain growth.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Short ribs
MedGen UID:
98094
Concept ID:
C0426817
Finding
Reduced rib length.
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.
Decreased calvarial ossification
MedGen UID:
322270
Concept ID:
C1833762
Finding
Abnormal reduction in ossification of the calvaria (roof of the skull consisting of the frontal bone, parietal bones, temporal bones, and occipital bone).
Metaphyseal cupping
MedGen UID:
323062
Concept ID:
C1837082
Finding
Metaphyseal cupping refers to an inward bulging of the metaphyseal profile giving the metaphysis a cup-like appearance.
Platyspondyly
MedGen UID:
335010
Concept ID:
C1844704
Finding
A flattened vertebral body shape with reduced distance between the vertebral endplates.
Widely patent fontanelles and sutures
MedGen UID:
336570
Concept ID:
C1849300
Finding
An abnormally increased width of the cranial fontanelles and sutures.
Vertebral clefting
MedGen UID:
344586
Concept ID:
C1855828
Finding
Schisis (cleft or cleavage) of vertebral bodies.
Unossified vertebral bodies
MedGen UID:
349749
Concept ID:
C1860202
Finding
A lack of ossification of the vertebral bodies.
Rachitic rosary
MedGen UID:
1642285
Concept ID:
C4551565
Disease or Syndrome
A row of beadlike prominences at the junction of a rib and its cartilage (i.e., enlarged costochondral joints), resembling a rosary. Note that rachitic rosary would have one bead per rib (a swelling at the costochondral junction), while beaded ribs in the context of multiple rib fractures have multiple beads (fractures) along the same rib.
Bowing of the legs
MedGen UID:
1807399
Concept ID:
C5574706
Finding
A bending or abnormal curvature affecting a long bone of the leg.
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Sign or Symptom
Lack of breathing with no movement of the respiratory muscles and no exchange of air in the lungs. This term refers to a disposition to have recurrent episodes of apnea rather than to a single event.
Recurrent respiratory infections
MedGen UID:
812812
Concept ID:
C3806482
Finding
An increased susceptibility to respiratory infections as manifested by a history of recurrent respiratory infections.
Fever
MedGen UID:
5169
Concept ID:
C0015967
Sign or Symptom
Body temperature elevated above the normal range.
Hypercalcemia
MedGen UID:
5686
Concept ID:
C0020437
Disease or Syndrome
An abnormally increased calcium concentration in the blood.
Low alkaline phosphatase
MedGen UID:
349734
Concept ID:
C1860130
Finding
Abnormally reduced serum levels of alkaline phosphatase.
Elevated plasma pyrophosphate
MedGen UID:
868752
Concept ID:
C4023157
Finding
An abnormally increased diphosphate(4-) concentration in the blood. Diphosphate(4-), as ester with two phosphate groups, is also known as pyrophosphate.
High-pitched cry
MedGen UID:
116082
Concept ID:
C0239154
Finding
A type of crying in an abnormally high-pitched voice.
Abnormality of the dentition
MedGen UID:
78084
Concept ID:
C0262444
Finding
Any abnormality of the teeth.
Skin dimple over apex of long bone angulation
MedGen UID:
344583
Concept ID:
C1855815
Finding
Polyhydramnios
MedGen UID:
6936
Concept ID:
C0020224
Pathologic Function
The presence of excess amniotic fluid in the uterus during pregnancy.
Blue sclerae
MedGen UID:
154236
Concept ID:
C0542514
Finding
An abnormal bluish coloration of the sclera.

Term Hierarchy

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

Professional guidelines

PubMed

Baujat G, Michot C, Le Quan Sang KH, Cormier-Daire V
Arch Pediatr 2017 May;24(5S2):5S61-5S65. doi: 10.1016/S0929-693X(18)30016-2. PMID: 29405934
Stockler S, Plecko B, Gospe SM Jr, Coulter-Mackie M, Connolly M, van Karnebeek C, Mercimek-Mahmutoglu S, Hartmann H, Scharer G, Struijs E, Tein I, Jakobs C, Clayton P, Van Hove JL
Mol Genet Metab 2011 Sep-Oct;104(1-2):48-60. Epub 2011 May 24 doi: 10.1016/j.ymgme.2011.05.014. PMID: 21704546
Greenberg CR, Evans JA, McKendry-Smith S, Redekopp S, Haworth JC, Mulivor R, Chodirker BN
Am J Hum Genet 1990 Feb;46(2):286-92. PMID: 1689104Free PMC Article

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

Wölfel EM, von Kroge S, Matthies L, Koehne T, Petz K, Beikler T, Schmid-Herrmann CU, Kahl-Nieke B, Tsiakas K, Santer R, Muschol NM, Herrmann J, Busse B, Amling M, Rolvien T, Jandl NM, Barvencik F
Calcif Tissue Int 2023 Mar;112(3):308-319. Epub 2022 Nov 21 doi: 10.1007/s00223-022-01041-4. PMID: 36414794Free PMC Article
Whyte MP, Leung E, Wilcox WR, Liese J, Argente J, Martos-Moreno GÁ, Reeves A, Fujita KP, Moseley S, Hofmann C; Study 011-10 Investigators
J Pediatr 2019 Jun;209:116-124.e4. Epub 2019 Apr 9 doi: 10.1016/j.jpeds.2019.01.049. PMID: 30979546
Baujat G, Michot C, Le Quan Sang KH, Cormier-Daire V
Arch Pediatr 2017 May;24(5S2):5S61-5S65. doi: 10.1016/S0929-693X(18)30016-2. PMID: 29405934
Stockler S, Plecko B, Gospe SM Jr, Coulter-Mackie M, Connolly M, van Karnebeek C, Mercimek-Mahmutoglu S, Hartmann H, Scharer G, Struijs E, Tein I, Jakobs C, Clayton P, Van Hove JL
Mol Genet Metab 2011 Sep-Oct;104(1-2):48-60. Epub 2011 May 24 doi: 10.1016/j.ymgme.2011.05.014. PMID: 21704546
Arun R, Khazim R, Webb JK, Burn J
Spine (Phila Pa 1976) 2005 Aug 15;30(16):E471-6. doi: 10.1097/01.brs.0000174277.03526.de. PMID: 16103841

Diagnosis

Whyte MP, Leung E, Wilcox WR, Liese J, Argente J, Martos-Moreno GÁ, Reeves A, Fujita KP, Moseley S, Hofmann C; Study 011-10 Investigators
J Pediatr 2019 Jun;209:116-124.e4. Epub 2019 Apr 9 doi: 10.1016/j.jpeds.2019.01.049. PMID: 30979546
Baujat G, Michot C, Le Quan Sang KH, Cormier-Daire V
Arch Pediatr 2017 May;24(5S2):5S61-5S65. doi: 10.1016/S0929-693X(18)30016-2. PMID: 29405934
Stockler S, Plecko B, Gospe SM Jr, Coulter-Mackie M, Connolly M, van Karnebeek C, Mercimek-Mahmutoglu S, Hartmann H, Scharer G, Struijs E, Tein I, Jakobs C, Clayton P, Van Hove JL
Mol Genet Metab 2011 Sep-Oct;104(1-2):48-60. Epub 2011 May 24 doi: 10.1016/j.ymgme.2011.05.014. PMID: 21704546
Plecko B, Stöckler S
Can J Neurol Sci 2009 Aug;36 Suppl 2:S73-7. PMID: 19760909
Mornet E
Orphanet J Rare Dis 2007 Oct 4;2:40. doi: 10.1186/1750-1172-2-40. PMID: 17916236Free PMC Article

Therapy

Padidela R, Yates R, Benscoter D, McPhail G, Chan E, Nichani J, Mughal MZ, Myer C 4th, Narayan O, Nissenbaum C, Wilkinson S, Zhou S, Saal HM
Orphanet J Rare Dis 2020 Aug 6;15(1):204. doi: 10.1186/s13023-020-01483-9. PMID: 32762706Free PMC Article
Whyte MP, Leung E, Wilcox WR, Liese J, Argente J, Martos-Moreno GÁ, Reeves A, Fujita KP, Moseley S, Hofmann C; Study 011-10 Investigators
J Pediatr 2019 Jun;209:116-124.e4. Epub 2019 Apr 9 doi: 10.1016/j.jpeds.2019.01.049. PMID: 30979546
Rush ET
Orphanet J Rare Dis 2018 Jul 16;13(1):116. doi: 10.1186/s13023-018-0866-7. PMID: 30012160Free PMC Article
Whyte MP, Rockman-Greenberg C, Ozono K, Riese R, Moseley S, Melian A, Thompson DD, Bishop N, Hofmann C
J Clin Endocrinol Metab 2016 Jan;101(1):334-42. Epub 2015 Nov 3 doi: 10.1210/jc.2015-3462. PMID: 26529632Free PMC Article
Stockler S, Plecko B, Gospe SM Jr, Coulter-Mackie M, Connolly M, van Karnebeek C, Mercimek-Mahmutoglu S, Hartmann H, Scharer G, Struijs E, Tein I, Jakobs C, Clayton P, Van Hove JL
Mol Genet Metab 2011 Sep-Oct;104(1-2):48-60. Epub 2011 May 24 doi: 10.1016/j.ymgme.2011.05.014. PMID: 21704546

Prognosis

Whyte MP, Leung E, Wilcox WR, Liese J, Argente J, Martos-Moreno GÁ, Reeves A, Fujita KP, Moseley S, Hofmann C; Study 011-10 Investigators
J Pediatr 2019 Jun;209:116-124.e4. Epub 2019 Apr 9 doi: 10.1016/j.jpeds.2019.01.049. PMID: 30979546
Baujat G, Michot C, Le Quan Sang KH, Cormier-Daire V
Arch Pediatr 2017 May;24(5S2):5S61-5S65. doi: 10.1016/S0929-693X(18)30016-2. PMID: 29405934
Park EG, Cho SY, Lee J, Kim J, Cho H, Kim J, Huh R, Ki CS, Kim OH, Jin DK
Ann Clin Lab Sci 2016 May;46(3):302-7. PMID: 27312557
Stockler S, Plecko B, Gospe SM Jr, Coulter-Mackie M, Connolly M, van Karnebeek C, Mercimek-Mahmutoglu S, Hartmann H, Scharer G, Struijs E, Tein I, Jakobs C, Clayton P, Van Hove JL
Mol Genet Metab 2011 Sep-Oct;104(1-2):48-60. Epub 2011 May 24 doi: 10.1016/j.ymgme.2011.05.014. PMID: 21704546
Mornet E
Orphanet J Rare Dis 2007 Oct 4;2:40. doi: 10.1186/1750-1172-2-40. PMID: 17916236Free PMC Article

Clinical prediction guides

Kim I, Noh ES, Kim MS, Jang JH, Jeon TY, Choi HW, Cho SY
Medicine (Baltimore) 2023 Feb 10;102(6):e32800. doi: 10.1097/MD.0000000000032800. PMID: 36820543Free PMC Article
Wölfel EM, von Kroge S, Matthies L, Koehne T, Petz K, Beikler T, Schmid-Herrmann CU, Kahl-Nieke B, Tsiakas K, Santer R, Muschol NM, Herrmann J, Busse B, Amling M, Rolvien T, Jandl NM, Barvencik F
Calcif Tissue Int 2023 Mar;112(3):308-319. Epub 2022 Nov 21 doi: 10.1007/s00223-022-01041-4. PMID: 36414794Free PMC Article
Padidela R, Yates R, Benscoter D, McPhail G, Chan E, Nichani J, Mughal MZ, Myer C 4th, Narayan O, Nissenbaum C, Wilkinson S, Zhou S, Saal HM
Orphanet J Rare Dis 2020 Aug 6;15(1):204. doi: 10.1186/s13023-020-01483-9. PMID: 32762706Free PMC Article
Whyte MP, Simmons JH, Moseley S, Fujita KP, Bishop N, Salman NJ, Taylor J, Phillips D, McGinn M, McAlister WH
Lancet Diabetes Endocrinol 2019 Feb;7(2):93-105. Epub 2018 Dec 14 doi: 10.1016/S2213-8587(18)30307-3. PMID: 30558909
Halling Linder C, Narisawa S, Millán JL, Magnusson P
Bone 2009 Nov;45(5):987-93. Epub 2009 Jul 22 doi: 10.1016/j.bone.2009.07.009. PMID: 19631305Free PMC Article

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