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Childhood hypophosphatasia(HPPC)

MedGen UID:
65089
Concept ID:
C0220743
Congenital Abnormality; Disease or Syndrome
Synonym: Hypophosphatasia, Childhood
SNOMED CT: Childhood hypophosphatasia (30174008); Hypophosphatasia, childhood type (30174008); Juvenile hypophosphatasia (30174008)
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®: 241510
Orphanet: ORPHA247667

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 (see 241500), infantile (241500), childhood, and adult (146300). Whyte (1988) indicated a fifth form of hypophosphatasia with primarily only dental manifestations, referred to as odontohypophosphatasia (see 241500). All of these forms are allelic.  http://www.omim.org/entry/241510
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
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
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
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.
Waddling gait
MedGen UID:
66667
Concept ID:
C0231712
Finding
Weakness of the hip girdle and upper thigh muscles, for instance in myopathies, leads to an instability of the pelvis on standing and walking. If the muscles extending the hip joint are affected, the posture in that joint becomes flexed and lumbar lordosis increases. The patients usually have difficulties standing up from a sitting position. Due to weakness in the gluteus medius muscle, the hip on the side of the swinging leg drops with each step (referred to as Trendelenburg sign). The gait appears waddling. The patients frequently attempt to counteract the dropping of the hip on the swinging side by bending the trunk towards the side which is in the stance phase (in the German language literature this is referred to as Duchenne sign). Similar gait patterns can be caused by orthopedic conditions when the origin and the insertion site of the gluteus medius muscle are closer to each other than normal, for instance due to a posttraumatic elevation of the trochanter or pseudarthrosis of the femoral neck.
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.
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Dolichocephaly
MedGen UID:
65142
Concept ID:
C0221358
Congenital Abnormality
An abnormality of skull shape characterized by a increased anterior-posterior diameter, i.e., an increased antero-posterior dimension of the skull. Cephalic index less than 76%. Alternatively, an apparently increased antero-posterior length of the head compared to width. Often due to premature closure of the sagittal suture.
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.
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.
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.
Skin dimple over apex of long bone angulation
MedGen UID:
344583
Concept ID:
C1855815
Finding
Proptosis
MedGen UID:
41917
Concept ID:
C0015300
Disease or Syndrome
An eye that is protruding anterior to the plane of the face to a greater extent than is typical.

Term Hierarchy

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

Professional guidelines

PubMed

Girschick HJ, Seyberth HW, Huppertz HI
Bone 1999 Nov;25(5):603-7. doi: 10.1016/s8756-3282(99)00203-3. PMID: 10574582

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

Held CM, Guebelin A, Krebs A, Sass JO, Wurm M, Lausch E, van der Werf-Grohmann N, Schwab KO
J Pediatr Endocrinol Metab 2022 Feb 23;35(2):169-178. Epub 2021 Sep 22 doi: 10.1515/jpem-2021-0104. PMID: 34551461
Girschick HJ, Haubitz I, Hiort O, Schneider P
Joint Bone Spine 2007 May;74(3):263-9. Epub 2007 Mar 15 doi: 10.1016/j.jbspin.2006.06.017. PMID: 17420150
Girschick HJ, Seyberth HW, Huppertz HI
Bone 1999 Nov;25(5):603-7. doi: 10.1016/s8756-3282(99)00203-3. PMID: 10574582
Beumer J 3rd, Trowbridge HO, Silverman S Jr, Eisenberg E
Oral Surg Oral Med Oral Pathol 1973 May;35(5):631-40. doi: 10.1016/0030-4220(73)90028-5. PMID: 4512507

Diagnosis

Martins L, Lessa LGF, Ali TM, Lazar M, Kim CA, Kantovitz KR, Santamaria MP, Araújo CF, Ramos CJ, Foster BL, Franco JFS, Bertola D, Nociti FH Jr
Int J Mol Sci 2022 Dec 23;24(1) doi: 10.3390/ijms24010282. PMID: 36613725Free PMC Article
Held CM, Guebelin A, Krebs A, Sass JO, Wurm M, Lausch E, van der Werf-Grohmann N, Schwab KO
J Pediatr Endocrinol Metab 2022 Feb 23;35(2):169-178. Epub 2021 Sep 22 doi: 10.1515/jpem-2021-0104. PMID: 34551461
Haliloglu B, Guran T, Atay Z, Abali S, Mornet E, Bereket A, Turan S
Eur J Pediatr 2013 Jun;172(6):851-3. Epub 2012 Oct 24 doi: 10.1007/s00431-012-1868-4. PMID: 23093139
Silva I, Castelão W, Mateus M, Branco JC
Acta Reumatol Port 2012 Jan-Mar;37(1):92-6. PMID: 22781519
Collmann H, Mornet E, Gattenlöhner S, Beck C, Girschick H
Childs Nerv Syst 2009 Feb;25(2):217-23. Epub 2008 Sep 4 doi: 10.1007/s00381-008-0708-3. PMID: 18769927

Therapy

Rush ET
Orphanet J Rare Dis 2018 Jul 16;13(1):116. doi: 10.1186/s13023-018-0866-7. PMID: 30012160Free PMC Article
Bowden SA, Adler BH
Osteoporos Int 2018 Feb;29(2):511-515. Epub 2017 Oct 18 doi: 10.1007/s00198-017-4267-x. PMID: 29046930
Girschick HJ, Haubitz I, Hiort O, Schneider P
Joint Bone Spine 2007 May;74(3):263-9. Epub 2007 Mar 15 doi: 10.1016/j.jbspin.2006.06.017. PMID: 17420150
Girschick HJ, Schneider P, Haubitz I, Hiort O, Collmann H, Beer M, Shin YS, Seyberth HW
Orphanet J Rare Dis 2006 Jun 28;1:24. doi: 10.1186/1750-1172-1-24. PMID: 16803637Free PMC Article
Girschick HJ, Seyberth HW, Huppertz HI
Bone 1999 Nov;25(5):603-7. doi: 10.1016/s8756-3282(99)00203-3. PMID: 10574582

Prognosis

Martins L, Lessa LGF, Ali TM, Lazar M, Kim CA, Kantovitz KR, Santamaria MP, Araújo CF, Ramos CJ, Foster BL, Franco JFS, Bertola D, Nociti FH Jr
Int J Mol Sci 2022 Dec 23;24(1) doi: 10.3390/ijms24010282. PMID: 36613725Free PMC Article
Girschick HJ, Haubitz I, Hiort O, Schneider P
Joint Bone Spine 2007 May;74(3):263-9. Epub 2007 Mar 15 doi: 10.1016/j.jbspin.2006.06.017. PMID: 17420150
Girschick HJ, Seyberth HW, Huppertz HI
Bone 1999 Nov;25(5):603-7. doi: 10.1016/s8756-3282(99)00203-3. PMID: 10574582
Beumer J 3rd, Trowbridge HO, Silverman S Jr, Eisenberg E
Oral Surg Oral Med Oral Pathol 1973 May;35(5):631-40. doi: 10.1016/0030-4220(73)90028-5. PMID: 4512507

Clinical prediction guides

Martins L, Lessa LGF, Ali TM, Lazar M, Kim CA, Kantovitz KR, Santamaria MP, Araújo CF, Ramos CJ, Foster BL, Franco JFS, Bertola D, Nociti FH Jr
Int J Mol Sci 2022 Dec 23;24(1) doi: 10.3390/ijms24010282. PMID: 36613725Free PMC Article
Bowden SA, Adler BH
Osteoporos Int 2018 Feb;29(2):511-515. Epub 2017 Oct 18 doi: 10.1007/s00198-017-4267-x. PMID: 29046930
Haliloglu B, Guran T, Atay Z, Abali S, Mornet E, Bereket A, Turan S
Eur J Pediatr 2013 Jun;172(6):851-3. Epub 2012 Oct 24 doi: 10.1007/s00431-012-1868-4. PMID: 23093139
Girschick HJ, Schneider P, Kruse K, Huppertz HI
Bone 1999 Sep;25(3):361-7. doi: 10.1016/s8756-3282(99)00164-7. PMID: 10495141

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