HYPOPHOSPHATASIA:
A 3-month-old white male infant is presented to the pediatric clinic for a routine well-child examination and care.
The birth and perinatal history include a spontaneous vaginal delivery at term to a G3 P2 31-year-old woman
with normal prenatal sonograms and excellent prenatal care. The prenatal history was uneventful. Upon
circumcision at age 4 days, he experienced a choking spell after being restrained, but he recovered without
further incident. He has been breast-feeding since being discharged from the hospital, and at that time he
weighed 6 lb 7 oz. Upon follow-up, he had normal oxygen saturation and his weight was up to 6 lb 12 oz at his
2-week examination. There is no significant family history. He is not currently on any medications and there is
no history of any known allergies.
On examination, the baby, although smiling, appears to be severely malnourished. He has an absence of
subcutaneous fat, and his skin appears wrinkled and tented. He does not seem to be in any acute distress. His
vital signs include a pulse of 130 bpm, respiratory rate of 28 breaths/min, temperature of 98.2° F (36.8° C), and
blood pressure of 127/71 mm Hg. His weight is 6 lb 5 oz, which is below the 3rd percentile for an infant of this
age, and he is measured at 21 in long, which also falls below the 3rd percentile for his age. His head
circumference is 14.75 in (also below the 3rd percentile). He weighs less now than he did at birth. His abdomen
appears bloated, but there is no evidence of any organomegaly. The heart and lung examinations are normal.
Further examination reveals apparently normal hearing and sight. According to the parents, the baby only takes
about 7 oz of baby formula per day (approximately 0.5-1 oz of formula every 2-3 hours and 0.5-1 oz of breast
milk per day). The patient cries when feeding in the office. The child's mother has switched him to a low-flow
nipple as a precaution against choking. The patient is admitted for 10 days in the hospital. When examined
afterwards, the patient is found to still have no appetite, continues to cry when feeding (although his weight has
increased to 8 lb), and appears more hypoxic than normal babies.
Laboratory tests done at the time of hospitalization show that the patient has severe hypercalcemia, with a total
calcium of 18.1 mg/dL (normal range, 9-10.5 mg/dL) and an ionized calcium of 8.8 mg/dL. He also has a low
normal phosphate of 4.4-4.5 mg/dL. The alkaline phosphatase level is 93 mg/dL (normal range, 143-320
mg/dL). His urine phosphoethanolamine level is 2142 nmol/mg of creatinine, and his vitamin B 6 level is >100
µg/dL. A 2-dimensional echocardiogram is normal; however, a radiographic inspection of his bone quality
reveals irregular metaphyses, along with severe metaphyseal flaring and osteopenia. A renal ultrasound
reveals bilateral hydronephrosis that is moderate on the left and mild on the right. There is also a possibility of
an obstruction at the uretero-pelvic junction on the left, with a milder obstruction on the right. A voiding
cystourethrogram (VCUG) is negative. The patient's oxygen saturation is 72%-76% on room air; however, this
measurement is obtained at his home, which is at an elevation of 10,000 feet.
A diagnosis of hypophosphatasia, also known as Rathbun syndrome, was made on the basis of the radiologic
findings and the results of the blood chemistry tests. Initially, several diagnoses were possible; all of the ones
listed in the answer choices above were considered at some point. The typical findings of metaphyseal flaring
and osteopenia, however, pointed to infantile hypophosphatasia. The elevated phosphoethanolamine levels
and below-normal alkaline phosphatase levels also supported the diagnosis. Phosphoethanolamine levels in
urine are usually between 180 and 533 nmol/mg of creatinine. Normal alkaline phosphatase levels are between
143 and 320 mg/dL. The serum calcium level was well above the normal range of 2.25-2.80 mmol/L. The levels
of vitamin B6 were also extremely elevated, the normal range being between 5.3 and 46.7 μg/dL. Other patients
with hypophosphatasia have also presented with what appeared to be an obstruction at the level of the
ureteropelvic junction, although this is not typical in all cases.
Severe hypophosphatasia occurs in approximately 1 in every 100,000 live births in the United States. It is an
autosomal-recessive disorder that is believed to be caused by a molecular defect in the gene encoding tissuenonspecific alkaline phosphatase (TNSALP).[1] TNSALP is an ectoenzyme tethered to the outer surface of
osteoblast and chondrocyte cell membranes. TNSALP normally hydrolyzes several substances, including
inorganic pyrophosphate (PPi) and pyridoxal 5'-phosphate (PLP), a major form of vitamin B6. The less severe
forms that appear later in life may either be autosomal-recessive or -dominant disorders. The main cause of
abnormal bone mineralization is a result of the deficiency of alkaline phosphatase in the bone and liver. The
mechanism is not yet fully understood. Alkaline phosphatase in the intestinal, placental, and germ cells appear
to be unaffected.[1]
There are 6 different forms of hypophosphatasia. They include perinatal, infantile, childhood, adult biphasic,
adult monophasic, and odontohypophosphatasia. Ultrasonography can be used to successfully identify the
disorder in a fetus, and the diagnosis can be confirmed with genetic testing. The most severe perinatal
hypophosphatasia may be identified when a stillborn child is found to have no mineralized bone. However, the
least severe adult form may present simply as a pathologic fracture in an adult.[2] A combination of biochemical
testing for hypercalcemia, decreased levels of alkaline phosphatase, and x-rays to detect findings such as
metaphyseal flaring, abnormally large fontanelle, and abnormally wide sutures can be used to diagnose
infantile hypophosphatasia. In the less severe forms, or those of later onset, often the only sign is the loss of
deciduous teeth.
Patients with infantile hypophosphatasia, such as the patient described in this case study, may show signs at
birth or the signs and symptoms may manifest within the first 6 months of life. Respiratory complications are
typical due to a rachitic chest, a finding which may lead to the misdiagnosis of vitamin D deficiency (rickets),
especially when coupled with some of the findings on blood chemistry. Hypercalcemia is also typical of patients
with hypophosphatasia. Infantile hypophosphatasia usually presents with early failure to thrive, hypotonia,
seizures, irritability, anemia, hypercalciuria, and phosphoethanolaminuria. Patients may exhibit blue sclerae,
bowed short limbs, metaphyseal cupping, bony spurs on the ulna and fibula, lack of skeletal ossification, easy
fracturing, craniosynostosis, and poorly formed teeth.[3] Hypercalcemia and hypercalcuria can cause vomiting
and compromise the kidneys. Nephrocalcinosis and seizures may also be present in a patient affected with
infantile hypophosphatasia.[4]
Childhood hypophosphatasia is usually diagnosed by a dentist when premature loss of deciduous
teeth is seen. As stated, this may be the only symptom, and other symptoms may be ascribed to other
bone diseases. Those affected may also have stunted growth, a waddling gait, and learn to walk later
than normal.
Adult hypophosphatasia presents in 2 forms: a biphasic type, which appears during childhood and is often not
diagnosed until it becomes much more active during middle age; and a monophasic form, which appears later
in life with milder symptoms. Both of these forms are generally not diagnosed until the fourth decade of life.
Tooth loss, metatarsal stress fractures, and femur fractures which cause hip and thigh pain in adults are
indicative of this diagnosis.
Odontohypophosphatasia presents only as through the loss of deciduous teeth and does not appear with any
other symptoms of decreased mineralization.[4]
Overall, hypophosphatasia is considered quite similar to osteogenesis imperfecta. Many of the symptoms are
common to both diseases, such as the blue sclera and the pathologic fractures. Unlike hypophosphatasia,
however, osteogenesis imperfecta does not correlate with a decreased alkaline phosphatase level concomitant
with an increase in other endogenous substances, such as vitamin B 6 and phosphoethanolamine. This patient's
endocrinologist also suggested hypervitaminosis D, subcutaneous fat necrosis, Bartter syndrome, Williams
syndrome, Jansen syndrome, and embryonal renal tumor as possible causes for the patient's symptoms.
Hypervitaminosis D was ruled out because it was not supported by any of the laboratory findings.
Subcutaneous fat necrosis did not account for the radiologic findings. None of the other diagnoses could
account for the combination of symptoms seen in this 3-month-old. Hypophosphatasia was indicated clinically,
biochemically, and radiologically. The severe failure to thrive, blue sclera, and flaring at the wrists are all typical
of the condition. Laboratory analysis showed the expected decreased alkaline phosphatase activity, elevated
urinary phosphoethanolamine levels, and high serum levels of vitamin B6. In addition, a fluorescent in situ
hybridization (FISH) test for the Williams syndrome deletion was negative. The radiology report that showed
metaphyseal flaring and osteopenia further pointed towards a diagnosis of hypophosphatasia.
Several experimental treatments are available for infantile hypophosphatasia, although none have provided a
definitive clinical course of action. Bone quality has improved after a bone marrow transplant in some patients,
but it has not reversed the course of the hypophosphatasia. Improvement in technique, such as multiple
administration sites, shows promise. Older patients have had some relief using parathyroid hormone therapy,
but this may worsen skeletal growth in young patients. Enzyme replacement therapy has been suggested, and
when tried it has been shown to help reverse the alkaline phosphatase deficiency, but it does not reverse the
hypomineralization of bone and has yet to be of clinical significance.[4] Some patients have benefited from
calcitonin injections to control the hypercalcemia, in association with hydrochlorothiazide treatment (a diuretic
that increases the absorption of calcium).[1] It appears that some patients who survive infantile
hypophosphatasia experience a spontaneous improvement in their clinical condition. It is possible that this is
due to the decrease in growth velocity experienced after infancy. Bisphosphonates have been ineffectual and
may be contraindicated.
The prognosis for the patient discussed here was poor, at best. The condition is considered to be lethal, with
death resulting usually secondary to respiratory insufficiency or severe infection. If a patient survives the first
few months, it is possible that the condition will spontaneously improve.[5] Initially, the infant in this case was
hospitalized to treat the severe failure to thrive, and once his weight had increased slightly, the patient was
referred to an endocrinologist. It was at this point that the patient was diagnosed. The family relocated to an
area that is relatively lower in elevation above sea level, as compared with their previous residence. The patient
was put on a low-calcium formula to control the hypercalcemia, although this cannot reverse the damage
already done by the decreased mineralization of his bones. If necessary, hydrocortisone or salmon calcitonin
could be added to this treatment. The patient's parents were informed of the possibility of using bone-targeted
enzyme replacement therapy to treat the condition as part of a clinical trial, but they have yet to decide whether
to exercise this option.
Hypophosphatasia is the only one of these clinical entities that is associated with low alkaline phosphatase.
Williams syndrome is characterized by cardiac, chromosomal, and facial abnormalities. Bartter syndrome
typically presents with hypokalemia and low blood pressure. Radiologic findings similar to those seen in rickets
(with decreased mineralization) differentiate hypophosphatasia from hypervitaminosis D (which is associated
with increased mineralization). Osteogenesis imperfecta presents with high alkaline phosphatase levels.