General HPP Terminology
Alkaline phosphatase (ALP)
Enzyme that controls a chemical that blocks skeletal calcification
Enzyme
A protein that breaks down certain chemicals (substrates)
Hypophosphatasia (HPP)
Hypophosphatasia (HPP) is the rare genetic form of rickets or osteomalacia that features paradoxically low serum alkaline phosphatase (ALP) activity
Bone Biology
Chondrocytes
Cartilage cells found in growth plates of growing children
Collagen
Most abundant protein in bones, skin, muscles, and tendons
Ectopic
“Out of place or position” (for calcium – outside of the skeleton)
Hydroxyapatite
Crystals of calcium and phosphate deposited into collagen to make bones strong
Osteoblasts
Cells that form bone (build up bone)
Osteoclasts
Cells that break down bone (collaspe bone)
Premature Tooth Loss
Loss of a “baby” tooth without trauma before child’s 5th birthday
Doctors and Medical Specialists Involved in HPP Care
Endocrinologist
Diagnoses and treats hormone and metabolic disorders, including HPP
Medical Geneticist
Diagnoses, counsels for, and treats inherited diseases, including HPP
Nephrologist
Treats kidney diseases
Neurologist
Treats brain, seizures, and other nerve problems
Ophthalmologist
Treats eye problems
Orthopedist
Surgeon who manages bone, joint, ligament, muscle, and tendon diseases
Physical Therapist
Provides non-surgical therapy to improve or restore mobility and treat pain
Rheumatologist
Treats inflammation and joint diseases
Genetics and Genetic Terminology
Autosomal Inheritance
Two most common patterns of disease inheritance
Compound Heterozygosity
Presence of two different copies of a gene
Founder Mutation
Genetic defect from distinct geographical regions
Genotype
Genetic make-up of a person
Heterozygosity
One distinctive copy of a gene
Homozygosity
Presence of identical gene copies
Missense (Point) Mutation
Change of a single DNA
Phenotype
Observable traits in a person as a result of how their genes are expressed
Possible Complications of HPP and Other Bone Disorders
Craniosynostosis
Premature fusion of growth plates in the skull; can cause pressure on the brain and require surgery
Hypercalcemia
Elevated blood calcium
Microfractures
Microscopic fractures
Nephrocalcinosis
Calcium-phosphate (mineral) in the kidneys
Osteoarthropathy
Loss of joint cartilage causing arthritis
Osteomalacia
Softening of bones from too little deposited hydroxyapatite crystals
Pseudofractures
X-ray feature of osteomalacia (soft bones) in adults
Rachitic Chest
Pulled-in sternum or “pigeon breast” deformity from rickets (soft bones during growth)
Rickets
Softening and weakening of bones during growth from too little hydroxyapatite deposition
Tests
Alkaline Phosphatase Blood Test
Measures ALP activity in blood serum. Patients with HPP have low ALP levels for their age
ALPL Gene
Mutation (defect[s]), 1 or 2, in this gene underlie HPP
Bone Biopsy
Taking a small sample for microscope examination
Bone Scan
Small amount of radioactive dye injected into a vein that detects where abnormalities are in the skeleton
Chemicals (Substrates) That Accumulate in HPP
- Pyridoxal 5’ phosphate (PLP): a form of Vitamin B6
- Inorganic pyrophosphate (PPi): the blocker of bone mineralization
- Phosphoethanolamine (PEA): often elevated in HPP blood or urine
DXA (DEXA)
X-ray to measure bone mineral density
PTH and 25-Hydroxyvitamin D
Hormones that regulate blood calcium levels
Radiograph
An x-ray
Renal (Kidney) Ultrasound
Sonar method to check for kidney calcification or stones
Serum Calcium
Blood test to diagnose or monitor blood calcium level for many bone diseases
Treatment of HPP
Asfotase Alfa (trade name Strensiq™)
ALP replacement therapy given by injection. Approved to treat pediatric-onset HPP
Supportive
Good dental care, analgesics if sufficient for mild occasional aches or pains
Types of HPP
Adult Hypophosphatasia
Typically presents in middle age; sometimes misdiagnosed as osteoporosis
Benign Prenatal Hypophosphatasia
Common pediatric HPP. Skeletal changes (limb shortening and bowing) in the womb or noted at birth, and then improving spontaneously. Not as severe as perinatal HPP
Childhood Hypophosphatasia
Manifests after age 6 months and before age 18 years
Hypophosphatasia Carrier
Has single HPP mutation, but is healthy
Infantile Hypophosphatasia
Manifests after birth but before age six months
Odontohypophosphatasia
Mildest HPP: Tooth problems only
Perinatal Hypophosphatasia
Most severe HPP; strikingly apparent at birth
Pseudohypophosphatasia
Extremely rare. Like infantile HPP, but blood ALP normal or elevated