532 532 Hypophosphatasia is a heritable metabolic disease, charac- terized by impaired ossification of the bones, reduction in tis- sue and plasma levels of alkaline phosphatase, and the presence of phosphoethanolamine in the urine. The incidence is estimated to be about 1 in 100,000 live births. The incidence of severe disease is especially high in Canadian Mennonites (1 in 2500 newborns).
GENETICS/BASIC DEFECTS
1. Genetic heterogeneity
a. Perinatal lethal hypophosphatasia form: autosomal recessive
b. Infantile hypophosphatasia form: autosomal recessive c. Childhood hypophosphatasia form: autosomal reces-
sive and dominant
d. Adult hypophospatasia form: autosomal recessive and dominant with variable penetrance
e. Odontohypophosphatasia form: autosomal recessive and dominant
2. Cause
a. Caused by mutations in the gene (ALPL) which:
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 intes- tinal forms) are not affected
3. Pathophysiology
a. Defects in mineralization
i. Caused by deficiency in TNSALP
ii. Resulting in increased urinary excretion of phos- phoethanolamine and inorganic pyrophosphate and an increase in serum pyridoxal 5′-phosphate b. Osteoclasts, although morphologically normal, lack membrane-associated alkaline phosphatase activity on histochemical analysis
i. Impede the proper incorporation of calcium into newly formed bone matrix
ii. Result in bone demineralization and hypercal- cemia 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 symptoms, with many of those affected being stillborn or expiring shortly after birth
b) Exception when consanguineous marriage is a factor: the two defective alleles tend to have distinct point mutations resulting in
different amnio acid substitutions in the alkaline phosphatase protein
ii. Individuals with dominant hypophosphatasia with only one defective TNSALP allele: usual- ly 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 defec- tive 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 kindreds, partic- ularly 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 individ- uals being compound heterozygotes for two different mutant hypophosphatasia alleles
d. Autosomal dominant alleles causes a few relatively mild cases of hypophosphatasia
CLINICAL FEATURES
1. Presence of a wide phenotypic variability ranging from intrauterine death and extreme hypomineralization of the skeleton to lifelong absence of clinical symptoms a. The following four different forms of the hypophos-
phatasia 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 ii. Skin-covered spurs extending from the forearms
or legs (skin dimples)
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: lethal in utero or within a few days of birth
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
c. Associated with progressive bony demineralization i. Abnormal skull with apparent wide separation of
the cranial sutures and a wide, bulging 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 one 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 5 years): the
most consistent clinical sign e. Frequent bone pain
f. Defective bone mineralization presenting clinically as rickets in children
g. Respiratory complications due to rachitic deformities of the chest
h. Premature craniosynostosis despite open fontanelle 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 radiograph- ically 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 clinically 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 pyrophos- phate dihyrate
DIAGNOSTIC INVESTIGATIONS
1. Laboratory tests
a. Low serum alkaline phosphatase levels in all types of hypophosphatasia
b. Increased levels of urinary phosphoethanolamine 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 var-
ious forms of hypophosphatasia reported 2. Skeletal survey
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: rectangular, round, flattened, sagitally 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 metaph- ysis: 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 metaph-
ysis giving a ‘frayed’ or ‘tufted’ appear- ance: a distinguished feature in hypophos- phatasia. In rickets, the decalcification 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 craniosynos- tosis 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 radiographic 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 histochemical testing, dis- rupting incorporation of calcium into the matrix b. Teeth
i. A decrease in cementum ii. Enlarged pulp chamber iii. Incisors tend to be affected
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Autosomal recessive: 25%
ii. Autosomal dominant: not increased unless a par- ent is affected in which case the recurrence risk is 50%
b. Patient’s offspring
i. Autosomal recessive: not increased unless a spouse is a carrier in which case the recurrence risk is 50%
ii. Autosomal dominant: 50%
2. Prenatal diagnosis a. Fetal radiography b. Prenatal ultrasonography
i. Failure to visualize a well-defined skull
ii. Other fetal skeletal structures not readily dis- cernable
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. Mutation analysis of fetal DNA from amniocentesis or CVS where 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 hypophos- phatasia has not been successful
i. Nonsteroidal anti-inflammatory drugs for con- trol of the bone pain
ii. Large dose of Vitamin D: reversal of improve- ment in the bony architecture upon withdrawal of the drug
iii. Oral cortisone: reversal of improvement in serum alkaline phosphatase level and radi- ographic appearance of the bones upon with- drawing of the drug
iv. Avoid saline solution, fluosemide diuresis, steroid therapy, or a low calcium diet because these approaches may actually worsen bone min- eralization and nephrocalcinosis
v. Inhibition of osteoclastic activity with calcitonin:
continued demineralization despite returning of normal serum calcium concentration
vi. Plasma infusions designed to supplement alka- line phosphatase activity or induce alkaline phosphatase production: not consistently improve bone mineralization
b. A clinical trial of marrow cell transplantation for infantile hypophosphatasia
i. A significant, prolonged clinical and radiographic improvement followed soon after receiving a boost of donor marrow cells
ii. Biochemical features of hypophosphatasia, how- ever, 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 form functional osteoblasts and perhaps chondrocytes, to amelio- rate 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 mid- shaft fractures
c) Anticipate delayed union of fractures
REFERENCES
Anadiotis GA: Hypophosphatasia. 2002. http://www.emedicine.com Anderton JM: Orthopaedic problems in adult hypophosphatasia: a report of two
cases. J Bone Joint Surg Br 61:82–84, 1979.
Barcia JP, Strife CF, Langman CB: Infantile hypophosphatasia: treatment options to control hypercalcemia, hypercalciuria, and chronic bone dem- ineralization. J Pediatr 130:825–828, 1997.
Brock DJ, Barron L: First-trimester prenatal diagnosis of hypophosphatasia:
experience with 16 cases. Prenat Diagn 11:387–391, 1991.
Fallon MD, Teitelbaum SL, Weinstein RS, et al.: Hypophosphatasia: clinico- pathologic comparison of the infantile, childhood, and adult forms.
Medicine (Baltimore) 63:12–24, 1984.
Fraser D: Hypophosphatasia. Am J Med 22:730–746, 1957.
Gehring B, Mornet E, Plath H, et al.: Perinatal hypophosphatasia: diagnosis and detection of heterozygote carriers within the family. Clin Genet 56:313–317, 1999.
Henthorn PS, Whyte MP: Missense mutations of the tissue-nonspecific alkaline phosphatase gene in hypophosphatasia. Clin Chem 38:2501–2505, 1992.
Hu JC, Plaetke R, Mornet E, et al.: Characterization of a family with dominant hypophosphatasia. Eur J Oral Sci 108:189–194, 2000.
James W, Moule B: Hypophosphatasia. Clin Radiol 17:368–376, 1966.
Kozlowski K, Sutcliffe J, Barylak A, et al.: Hypophosphatasia. Review of 24 cases. Pediatr Radiol 5:103–117, 1976.
Leroy JG, Vanneuville FJ, De Schepper AM, et al.: Prenatal diagnosis of con- genital hypophosphatasia: challenge met most adequately by fetal radiog- raphy. Prog Clin Biol Res 104:525–539, 1982.
Maxwell DJ, Blau K, Johnson RD, et al.: Activities of alkaline phosphatase in first trimester chorion biopsy tissue. Prenat Diagn 5:283–286, 1985.
Mornet E, Muller F, Ngo S, et al.: Correlation of alkaline phosphatase (ALP) determination and analysis of the tissue non-specific ALP gene in prenatal diagnosis of severe hypophosphatasia. Prenat Diagn 19:755–757, 1999.
Mulivor RA, Mennuti M, Zackai EH, et al.: Prenatal diagnosis of hypophos- phatasia; genetic, biochemical, and clinical studies. Am J Hum Genet 30:
271–282, 1978.
Rathbun JC: “Hypophosphatasia”, a new developmental anomaly. Am J Dis Child 75:822–831, 1948.
Shohat M, Rimoin DL, Gruber HE, et al.: Perinatal lethal hypophosphatasia;
clinical, radiologic and morphologic findings. Pediatr Radiol 21:
421–427, 1991.
Tongsong T, Pongsatha S: Early prenatal sonographic diagnosis of congenital hypophosphatasia. Ultrasound Obstet Gynecol 15:252–255, 2000.
Wendling D, Jeannin-Louys L, Kremer P, et al.: Adult hypophosphatasia.
Current aspects. Joint Bone Spine 68:120–124, 2001.
Whyte MP: Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. Endocr Rev 15:439–461, 1994.
Whyte MP, McAlister WH, Patton LS, et al.: Enzyme replacement therapy for infantile hypophosphatasia attempted by intravenous infusions of alka- line phosphatase-rich Paget plasma: results in three additional patients.
J Pediatr 105:926–933, 1984.
Whyte MP, Kurtzberg J, McAlister WH, et al.: Marrow cell transplantation for infantile hypophosphatasia. J Bone Miner Res 18:624–636, 2003.
Fig. 1. A neonate with perinatal lethal form of hypophosphatasia showing severe shortening of limbs. Radiograph shows markedly defi- cient ossification and abnormal bone development similar to achon- drogenesis type I.
Fig. 2. Radiograph of another neonate with hypophosphatasia shows rickets-like metaphyseal cupping and poor mineralization of cranial bones.
Fig. 3. Photomicrograph of a rib. Broad columns of hypertrophic chondrocytes with osteoid seams are present in the metaphysis. These columns are poorly mineralized and ossified.
Fig. 4. Radiographs of another neonate with perinatal lethal form of hypophosphatasia showing marked deficient skeletal mineralization, prenatal fracture of the left femur, and abnormal metaphyseal ossifica- tion of the proximal femurs.
Fig. 5. Childhood hypophosphatasia in two brothers showing short stature and bowed legs.
