Atlas of Genetic Diagnosis and Counseling || Hypophosphatasia

Hypophosphatasia

Hypophosphatasia is a heritable metabolic disease,

characterized by impaired ossification of the bones,

reduction in tissue and plasma levels of alkaline phos-

phatase, and the presence of phosphoethanolamine in

the urine. The incidence is estimated to be about 1 in

100,000 live births (Fraser 1957). The incidence of

severe disease is especially high in Canadian Menno-

nites (1 in 2,500 newborns) (Gehring et al. 1999).

Synonyms and Related Disorders

Adult hypophosphatasia (mild hypophosphatasia,

odontohypophosphatasia); Childhood hypophos-

phatasia; Perinatal lethal hypophosphatasia;

Phosphoethanolaminuria

Genetics/Basic Defects

1. Genetic heterogeneity

a. Perinatal lethal hypophosphatasia form: autoso-

mal recessive

b. Prenatal benign hypophosphatasia form: autoso-

mal dominant

c. Infantile hypophosphatasia form: autosomal

recessive

d. Childhood hypophosphatasia form: autosomal

recessive (frequent) and dominant (rare)

e. Adult hypophosphatasia form: autosomal reces-

sive and dominant with variable penetrance

f. Odontohypophosphatasia form: autosomal

recessive and dominant

2. Cause

a. Caused by mutations in the alkaline phosphatase

gene (ALPL) which (Barcia et al. 1997):

i. Codes for tissue nonspecific (“liver/bone/

kidney”) alkaline phosphatase (TNSALP)

ii. Is mapped on chromosome 1p36.1–p34

b. Typically, the other isoenzymes (placental and

intestinal forms) are not affected (Gehring et al.

1999).

3. Pathophysiology

a. Defects in mineralization.

i. Caused by deficiency in TNSALP

ii. Resulting in increased urinary excretion

of phosphoethanolamine and inorganic

pyrophosphate and an increase in serum

pyridoxal 5’-phosphate

b. Osteoclasts, althoughmorphologically normal, lack

membrane-associated alkaline phosphatase activity

on histochemical analysis (Barcia et al. 1997).

i. Impede the proper incorporation of calcium

into newly formed bone matrix

ii. Result in bone demineralization and

hypercalcemia when the impaired matrix

calcification process occurs with a rapid rate

of bone resorption

4. Genotype-phenotype correlations

a. A number of different mutations account for the

clinical heterogeneity.

i. Individuals with recessive hypophosphatasia

with both defective TNSALP alleles.

a) In general, manifest more severe symp-

toms, with many of those affected being

stillborn or expiring shortly after birth.

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_129,# Springer Science+Business Media, LLC 2012

1137

b) Exception when consanguineous marriage

is a factor: the two defective alleles tend

to have distinct pointmutations resulting in

different amino acid substitutions in

the alkaline phosphatase protein.

ii. Individuals with dominant hypophosphatasia

with only one defective TNSALP allele: usu-

ally manifest moderate symptoms, such as the

premature exfoliation of fully rooted primary

teeth.

iii. Division between dominant and recessive

hypophosphatasia sometimes is not well

defined because the heterozygous siblings

with one defective TNSALP allele in kindreds

with recessive hypophosphatasia may show

mild or moderate symptoms of the disease.

b. Missense mutations in the TNSALP gene have

been observed in some hypophosphatasia kin-

dreds, particularly those families with the more

severe perinatal and infantile forms of the disease.

c. Autosomal recessive inheritance has been

observed in most cases of hypophosphatasia

with affected individuals being compound

heterozygotes for two different mutant

hypophosphatasia alleles.

d. Autosomal dominant alleles cause a few rela-

tively mild cases of hypophosphatasia.

e. Mild hypophosphatasia (Fauvert et al. 2009).

i. Can result from either compound heterozy-

gosity for severe and moderate mutations but

also in a large part from heterozygous muta-

tions with a dominant negative effect.

ii. A sequence variation in linkage disequilib-

rium with haplotype E could in addition

play the role of an aggravating factor

resulting in loss of haplosufficiency.

Clinical Features

1. Presence of a wide phenotypic variability ranging

from intrauterine death and extreme hypominera-

lization of the skeleton to lifelong absence of clin-

ical symptoms (Gehring et al. 1999)

a. The following four different forms of the

hypophosphatasia have been defined:

i. Perinatal lethal form

ii. Infantile form

iii. Childhood form

iv. Adult form

b. In general, the earlier the age of presentation, the

more severe the presenting features.

2. Perinatal lethal form

a. Often stillborn

b. Skeletal deformities: presenting features

i. A profound lack of skeletal mineralization

in utero.

ii. Skin-covered spurs extending from

the forearms or legs (skin dimples)

(Shohat et al. 1991): these spurs are often

diagnostic for hypophosphatasia.

iii. Markedly shortening and bowing of the

long bones (short-limbed dwarfism).

iv. Fractures (perinatal).

v. Rickety rosary.

vi. Metaphyseal swelling.

vii. Soft, pliable cranial bones (“vault like

a balloon”).

viii. Bulging anterior fontanelle.

c. Respiratory distress due to hypoplastic lungs and

rachitic deformities of the chest

d. Other features

i. Hypotonia

ii. High-pitched cry

iii. Vomiting

iv. Constipation

v. Unexplained fever

vi. Apnea

vii. Cyanosis

viii. Irritability

ix. Seizures

e. Prognosis

i. Lethal in utero or within a few days of birth.

ii. In the rare prenatal benign form, despite

prenatal symptoms, there is a spontaneous

improvement of skeletal defects (Pauli et al.

1999; Moore et al. 1999; Wenkert et al.

2007).

3. Infantile form

a. Appears normal at birth

b. Onset of symptoms

i. Before 6 months of age

ii. Poor feeding

iii. Failure to thrive (growth failure)

iv. Hypotonia

v. Convulsions

1138 Hypophosphatasia

c. Associated with progressive bony

demineralization

i. Abnormal skull with apparent wide separa-

tion of the cranial sutures and a wide, bulg-

ing anterior fontanelle

ii. Tendency toward developing craniosynostosis

a) Formation of a sagittal ridge

b) A bony prominence at the position of the

anterior fontanelle

iii. Rachitic skeletal deformities manifesting by

age 6 months

iv. Flail chest

v. Pulmonary insufficiency

d. Late in walking

e. Development of genu valgum

f. Short stature

g. Complications

i. Recurrent pneumonia

ii. Increased intracranial pressure

iii. Renal compromise secondary to:

a) Hypercalcemia

b) Hypercalcinuria

c) Nephrocalcinosis

h. Prognosis:

i. Fatal in approximately 50% of cases by the

age of 1 year

ii. Survivors

a) Tend to improve symptomatically.

b) Deformities persist and often become

worse.

4. Childhood form

a. Appears normal at birth.

b. Often present after 6 months of age.

c. History of delayed walking and waddling gait.

d. Early loss of deciduous teeth (before age of

5 years): the most consistent clinical sign.

e. Frequent bone pain.

f. Defective bone mineralization presenting clini-

cally as rickets in children.

g. Respiratory complications due to rachitic defor-

mities of the chest.

h. Premature craniosynostosis despite open fonta-

nelle resulting in increased intracranial

pressure.

i. Dolichocephalic skull.

j. Enlarged joints.

k. Short stature.

l. Bone fractures.

m. Presence of hypercalcemia causes increased

excretion of calcium resulting in renal damage.

n. Prognosis: improving both clinically and radio-

graphically with age in some childhood

hypophosphatasia patients.

5. Adult form

a. Variable age of onset and severity.

b. Onset usually during middle age.

c. Defective bone mineralization presents clini-

cally as osteomalacia in adults.

d. Premature loss of deciduous teeth.

e. Usually presents clinically with loss of adult

teeth.

f. Multiple fractures secondary to osteomalacia,

often after minimal fractures.

g. Foot pain due to stress fractures of the

metatarsals.

h. Thigh pain due to pseudofractures of the femur.

i. Delay in healing after a fracture.

j. Joint pain due to deposition of calcium pyro-

phosphate dihydrate (chondrocalcinosis).

6. Odontohypophosphatasic form: premature loss of

adult teeth; the only physical finding in this form

7. Craniosynostosis

a. Considered a known feature in the infantile and

childhood types of hypophosphatasia (Whyte

1995; Mornet 2007; Collmann et al. 2009),

while it is missed in the adult and odontohypo-

phosphatasia forms

b. Often progressively involves all cranial sutures

and poses significant functional risks to the optic

nerves, as well as the spinal cord

Diagnostic Investigations

1. Laboratory tests.

a. Low serum alkaline phosphatase levels in all

types of hypophosphatasia

b. Increased levels of urinary phosphoetha-

nolamine levels

c. Elevated plasma levels of pyridoxal 5’-

phosphate

d. Normal serum calcium, except in infantile cases

where hypercalcemia can be seen due to renal

failure

e. Normal serum phosphate: hyperphosphatemia in

various forms of hypophosphatasia reported

Hypophosphatasia 1139

2. Skeletal survey (Kozlowski et al. 1976).

a. Lethal perinatal form

i. Near absence of skeletal mineralization

ii. Skull: tiny ossification of occipital and/or

frontal bones or complete absence of

ossification

iii. Teeth: very poorly formed

iv. Spine

a) Some vertebrae frequently unossified

b) Occasionally unossified vertebrae

c) Abnormally shaped vertebrae: rectangu-

lar, round, flattened, sagittally cleft, or

butterfly-shaped vertebrae

v. Shortening and bowing of the long and

tubular bones

vi. Diaphyseal spurs

vii. Skin-covered spurs extending from the

medial and lateral aspects of the knee and

elbow joints

viii. Fractures

ix. Rachitic changes

a) Pathology most evident at metaphyses

as in rickets where growth is most

rapid, namely the wrists, knees, hips,

and proximal humeri.

b) Defective, irregular ossification of the

metaphysis: the most diagnostic feature

of the disease.

c) Nearly absent provisional zone of

calcification.

d) Irregular widening of the epiphyseal

plate.

e) Grossly irregular ossification of

metaphysis giving a “frayed” or “tufted”

appearance: a distinguished feature in

hypophosphatasia. In rickets, the decal-

cification is usually regular and may

give a “ground glass” effect to the

affected metaphysis (metaphyseal

cupping).

b. Infantile form

i. Deficient skeletal mineralization.

ii. Congenital bowing of the long bones.

iii. Bands of decreased density in metaphyses.

iv. Widened cranial sutures.

v. Later craniosynostosis: premature cranio-

synostosis occurs despite an open

fontanelle.

vi. Asymmetrical, moderate to severe rickets-

like metaphyseal changes.

vii. Metaphyseal and epiphyseal ossification

defects.

viii. Distorted bone trabeculation with areas of

decreased and increased transradiancy.

ix. Thin cortical bone.

x. Diaphyseal spurs.

c. Childhood form

i. Mild, asymmetrical, metaphyseal changes

resembling rickets or metaphyseal dysplasia

ii. Distorted bone trabeculation with areas of

decreased and increased transradiancy

iii. Thin cortical bone

iv. Hypotubulation and bowing of long bones

v. Stress fractures

vi. Radiolucent projections from the epiphyseal

plate into the metaphysis

d. Adult form

i. Pseudofractures often occur in the lateral

aspect of the proximal femur: a hallmark of

this form

ii. Osteomalacia

iii. An increased incidence of poorly healing

stress fractures, especially of the metatarsals

e. Odontohypophosphatasic form: normal radio-

graphic findings

3. Radiography and ultrasound screening for

nephrocalcinosis.

4. Histology.

a. Growth plates

i. Rachitic abnormalities

ii. Poorly mineralized and ossified columns

with broad osteoid seams in metaphysis

iii. Osteoblasts lacking membrane-associated

alkaline phosphatase activity on histochemi-

cal testing, disrupting incorporation of cal-

cium into the matrix

b. Teeth

i. A decrease in cementum

ii. Enlarged pulp chamber

iii. Incisors tend to be affected

5. Molecular genetic diagnosis: ALPL, the gene-

encoding alkaline phosphatase, tissue nonspecific

isozyme (TNASALP), is the only gene known to

be associated with hypophosphatasia.

a. Targeted mutation analysis

b. Sequence analysis


Genetic Counseling

1. Recurrence risk: genetic counseling is complicated

by the inheritance that may be autosomal dominant

or autosomal recessive, the existence of the uncom-

mon prenatal benign form, and the variable expres-

sion of the disease (Simon-Bouy et al. 2008).

a. Patient’s sib

i. Autosomal recessive: 25%

ii. Autosomal dominant: not increased unless

a parent is affected in which case the recur-

rence risk is 50%

b. Patient’s offspring

i. Autosomal recessive: not increased unless

a spouse is a carrier in which case the recur-

rence risk is 50%

ii. Autosomal dominant: 50%

2. Prenatal diagnosis.

a. Fetal radiography

b. Prenatal ultrasonography

i. 2D-ultrasonography

a) Failure to visualize a well-defined skull

b) Other fetal skeletal structures not readily

discernable

ii. 3D-ultrasonography: can demonstrate specific

osseous spurs in a lethal form (Sinico et al. 2007)

c. Assay of the alkaline phosphatase activity: a

useful complementary and independent method,

especially when a mutation is unidentified

and DNA from the index case is unavailable

i. Assay of the tissue nonspecific alkaline phos-

phatase activity in chorionic villus samples in

the first trimester

ii. Absent alkaline phosphatase activity in the

amniotic fluid and cultured amniotic fluid

cells in the second trimester

d. Prenatal diagnosis and preimplantation genetic

diagnosis: mutation analysis of fetal DNA from

amniocentesis or CVSwhere the disease-causing

mutation has been identified in the family

3. Management.

a. No specific treatment available: efforts to effect

improved mineralization in patients with

hypophosphatasia have not been successful

(Barcia et al. 1997).

i. Nonsteroidal anti-inflammatory drugs for

control of the bone pain.

ii. Dietary phosphate restriction may be help-

ful (Wenkert et al. 2007).

iii. Large dose of vitamin D: reversal of

improvement in the bony architecture upon

withdrawal of the drug (Anderton 1979).

iv. Oral cortisone: reversal of improvement in

serum alkaline phosphatase level and radio-

graphic appearance of the bones upon with-

drawal of the drug (Anderton 1979).

v. Avoid saline solution, furosemide diuresis,

steroid therapy, or a low-calciumdiet because

these approaches may actually worsen bone

mineralization and nephrocalcinosis.

vi. Inhibition of osteoclastic activity with cal-

citonin: continued demineralization despite

returning of normal serum calcium

concentration.

vii. Plasma infusions designed to supplement

alkaline phosphatase activity or induce

alkaline phosphatase production: not con-

sistently improve bone mineralization.

viii. Pyridoxine and/or pyridoxal phosphate in

neonates with intractable seizures

(Balasubramaniam et al. 2010).

b. A clinical trial of marrow cell transplantation for

infantile hypophosphatasia.

i. A significant, prolonged clinical and radio-

graphic improvement followed soon after

receiving a boost of donor marrow cells.

ii. Biochemical features of hypophosphatasia,

however, remain unchanged to date.

iii. The most plausible hypothesis for the

patient’s survival and progress: transient

and long-term engraftment of sufficient

numbers of donor marrow mesenchymal

cells forms functional osteoblasts and

perhaps chondrocytes, to ameliorate the

skeletal disease.

c. Surgical care.

i. Rachitic deformities

ii. Gait abnormalities

iii. Adult form

a) Rod placement for pseudofractures of the

adult type results in the union and relief of

the pain.

b) Primary bone grafting and plating for

midshaft fractures.

c) Anticipate delayed union of fractures.


References

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http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hops




http://emedicine.medscape.com/article/945375-overview

a b c

Fig. 1 (a–c) A neonate with perinatal lethal form of hypophosphatasia showing severe shortening of limbs. Radiograph shows

markedly deficient ossification and abnormal bone development similar to achondrogenesis type I

Fig. 2 Radiograph of another neonate with hypophosphatasia

shows rickets-like metaphyseal cupping (spurs) and poor miner-

alization of cranial bones

Fig. 3 Photomicrograph of a rib. Broad columns of hypertro-

phic chondrocytes with osteoid seams are present in the

metaphysis. These columns are poorly mineralized and ossified


a

c d

bFig. 4 (a–d) Radiographs ofanother neonate with perinatal

lethal form of

hypophosphatasia showing

marked deficient skeletal

mineralization, prenatal

fracture of the left femur, and

abnormal metaphyseal

ossification of the proximal

femurs


Fig. 5 Childhood hypophosphatasia in two brothers showing

short stature and bowed legs


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Atlas of Genetic Diagnosis and Counseling || Hypophosphatasia