Hipofosfatazia Infantila

A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia (printer-friendly)
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Author(s)
Christine A. Ebert-Santos, MD
Christine A. Ebert-Santos, MD, Associate Professor of Pediatrics, University of Colorado School of Medicine; Staff Physician, Summit, Medical Center, Frisco, CO Disclosure: Christine A. Ebert-Santos, MD, has disclosed no relevant financial relationships. Dr. Ebert-Santos does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Dr. Ebert-Santos does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.
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Anicia Santos
Anicia Santos, PreMedical Student, University of Colorado, Boulder, CO Disclosure: Anicia Santos has disclosed no relevant financial relationships. Anicia Santos does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Anicia Santos does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.
Editor(s)
Craig A Goolsby, MD
Craig A. Goolsby, MD, Director, eMedicine Case of the Week; Staff Physician, Department of Emergency Medicine, Wilford Hall Medical Center, Lackland Air Force Base, San Antonio, TX Disclosure: Craig A. Goolsby, MD, has disclosed no relevant financial relationships.
Usama Basit, MD, MBBS
Usama Basit, MD, MBBS, Reviewer, eMedicine Interactive Case Studies (CME Case of the Week), Rawalpindi, Pakistan Disclosure: Usama Basit, MD, MBBS, has disclosed no relevant financial relationships.
Bruce Buehler, MD
Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology; Executive Director, Hattie B. Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska Disclosure: Bruce Buehler, MD, has disclosed no relevant financial relationships.
Luis M. Soler, BA
Luis M. Soler, BA, Associate Editor, eMedicine/Medscape, New York, NY Disclosure: Luis M. Soler, BA, has disclosed no relevant financial relationships.
CME Reviewer(s)
Laurie E. Scudder, DNP, NP
Accreditation Coordinator, Continuing Professional Education Department, Medscape, LLC; Clinical Assistant Professor, School of Nursing and Allied Health, George Washington University, Washington, DC; Nurse Practitioner, School-Based Health Centers, Baltimore City Public Schools, Baltimore, Maryland Disclosure: Laurie E. Scudder, DNP, NP, has disclosed no relevant financial relationships.
From Medscape CME Case Presentations
A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia CME

Christine A. Ebert-Santos, MD; Anicia Santos
5/14/2011
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CME Released: 05/18/2010; Reviewed and Renewed: 05/11/2011; Valid for credit through 05/11/2012
A 3-Month-Old Boy With Severe Failure to Thrive and Hypercalcemia

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 B6 level is >100 g/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.
What is the diagnosis? Hint: Keep in mind the severe hypercalcemia, alkaline phosphatase, and radiology results. Osteogenesis imperfecta Hypophosphatasia Bartter syndrome Vitamin D deficiency (rickets) Save and Proceed
Discussion
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Figure 1.
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Figure 2.
Figure 3.
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 g/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 tissue-
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Figure 1.
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Figure 2.
Figure 3.
nonspecific 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
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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 B6 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
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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.
CME
Test
You are caring for a pregnant woman with a family history of hypophosphatasia. She would like her baby to be tested for the disease. Which of the following is most appropriate? Abdominal CT scanning Ultrasonography Maternal serum calcium level Maternal alkaline phosphatase level You examine a 3-month-old infant with failure to thrive and suspect that this patient has hypophosphatasia. What laboratory or physiologic abnormalities would support this conclusion? High alkaline phosphatase levels Hypokalemia and low blood pressure Hypercalcemia and decreased alkaline phosphatase Increased mineralization Save and Proceed
References
1. Deeb AA, Bruce SN, Morris AAM, Cheetham, TD. Infantile hypophosphatasia: disappointing results of treatment. Acta Paediatr. 2000;89:730-743. 2. Mornet E, Nunes ME. Hypophosphatasia. GeneReviews. November 20, 2007. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hops Accessed May 7, 2010. 3. Hypophosphatasia, infantile. CTGT Connective Tissue Gene Tests. 2009. Available at: http://ctgtstaging.net/tests/hypophosphatasia-infantile Accessed May 7, 2010. 4. Gurenlian JR. Hypophosphatasia. Access. 2001;15:38-41. Available at: http://www.library.nhs.uk/booksandjournals/details.aspx?t=Osteomalacia% 2fpathology&stfo=True&sc=bnj.ovi.amed,bnj.ovi.bnia,bnj.ebs.cinahl,bnj.ovi.emez,bnj.ebs.heh,bnj.ovi.hmic,b Accessed May 7, 2010.
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5. Mochizuki H, Saito M, Michigami T, et al. Severe hypercalcaemia and respiratory insufficiency associated with infantile hypophosphatasia caused by two novel mutations of the tissue-nonspecific alkaline phosphatase gene. Eur J Pediatr. 2000;159:375-379.
Disclaimer The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on www.medscape.org. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity. Medscape CME Case Presentations 2010 MedscapeCME
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A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia (printer-friendly)

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A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia (printer-friendly)

Authors and Disclosures

A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia (printer-friendly)

From Medscape CME Case Presentations

A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia CME

A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia (printer-friendly)

A 3-Month-Old Boy With Severe Failure to Thrive and Hypercalcemia

A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia (printer-friendly)

A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia (printer-friendly)

A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia (printer-friendly)

A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia (printer-friendly)

A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia (printer-friendly)

A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia (printer-friendly)

A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia (printer-friendly)

A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia (printer-friendly)

A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia (printer-friendly)

A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia (printer-friendly)

A 3-Month-Old With Severe Failure to Thrive and Hypercalcemia (printer-friendly)

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