Welcome to today's discussion of hypophosphatasia, or HPP. I'm Dr. Eric Rush, a clinical geneticist at Children's Mercy Hospital and the University of Kansas Hospital. HPP is a potentially life-threatening, progressive, multisystemic inherited disorder with life-limiting consequences. Because of this, patients may present with new, recurring, and progressing symptoms to different specialists at any age. You may be thinking that HPP sounds like a challenge to diagnose, but there are key consistent signs and symptoms in patients with HPP that should prompt quick diagnosis. The biologic hallmark of HPP is persistently low tissue nonspecific alkaline phosphatase activity levels, referred to throughout this presentation as low ALP. Today we will focus on three case studies to help us learn to appropriately recognize and diagnose HPP. The first case study is of a 21-year-old college student referred to a rheumatologist for consistent pain and fatigue. She complained that her joints ached and she was tired all the time. Just walking across campus to get to her classes was difficult. Let's take a quick look at her history. The patient describes a recent six-month period of chronic pain that becomes excessive during bouts of activity and is often the most extreme in the morning. During her visit, she reports ankle pain without swelling, as well as general fatigue, and she has been experiencing depressed moods that worsened about one year ago. She denies other joint involvement, rashes, redness, fever, nausea, headaches, or difficulty sleeping. She's a junior in college, does not smoke, drinks socially, and has a relatively sedentary lifestyle. Her medical history reveals a history of non-traumatic fractures occurring at 11 and 17 years of age without any instigating injury. She has normal menses. Family history shows that her mother has fibromyalgia. Finally, she is currently taking ibuprofen for pain. Her physical exam showed that she is a healthy-appearing young female with no acute distress or difficulty standing or walking. Her lab results show low ALP, but the low level is not noted as a concern to the doctor. However, X-ray of the tender ankle reveals chondrocalcinosis and decreased mineralization. Based on the information you just heard about this patient, what would be your initial differential diagnosis? Based on her medical history, her physical exam, the imaging results, and lab values, we can narrow the differential diagnosis. Is there information we have that can narrow the differential further? If you remember, the patient's labs were almost completely normal with the exception of a low ALP value. Low ALP levels, especially if persistently low, should raise the index of suspicion for HPP, particularly in this patient who complains of pain, fatigue, and previous fractures. It's important to note that patients with HPP have persistently low ALP levels in comparison to other conditions, and treatments that can lead to transient decreases in ALP. For this patient, the low ALP was overlooked as insignificant, missing the biochemical hallmark of HPP. High ALP levels often raise red flags and lead to further investigation. However, low ALP levels can often be overlooked. Back to our patient. Her rheumatologist requests additional laboratory tests, which rule out celiac disease and hypomagnesemia, and refers the patient for DEXA scan that is suggestive of low bone density for her age in multiple locations. Because of this, she was told to follow up with her primary care doctor. Supplementation with vitamin D and calcium was not recommended due to slightly elevated calcium levels in the high normal range and normal vitamin D levels. Although in the context of an appropriate clinical history, as well as physical and radiographic findings, a low ALP is clearly consistent with a diagnosis of HPP. It is important to be aware that there are other clinical conditions that are associated with a low ALP. The differential diagnosis of low ALP includes medication-induced reductions in ALP, as may be seen with steroids, chemotherapy, or fibrates, and medical conditions associated with a low ALP, including hypothyroidism, severe malnutrition, scurvy, multiple myeloma, celiac disease, magnesium or zinc deficiency, pernicious or profound anemia, or Wilson's disease. There are a few additional situations in which a patient may experience a low ALP, and those include vitamin D intoxication, improper blood collection in an EDTA-containing tube, and massive blood transfusions. Another challenge to the accurate diagnosis of HPP is transient elevations of ALP. There are certain medical conditions that, when present, may increase circulating levels of ALP, thus masking the normally low levels of ALP in patients with HPP. These conditions include pregnancy, fracture, orthopedic surgery, and liver disease. Additionally, certain medications may transiently elevate ALP levels. HPP is a progressive systemic inherited metabolic disorder. Recall that our patient had low ALP levels. In HPP, loss-of-function mutations in the ALPL gene result in deficient tissue-nonspecific alkaline phosphatase activity. This deficient ALP enzyme activity leads to the biochemical hallmark of HPP, low ALP. It is important to keep in mind that the presentation of HPP can be highly variable depending on genetic, biological, and environmental factors. So what impact does low ALP activity have? Low ALP enzyme activity can disrupt bone mineralization and calcium and phosphate homeostasis throughout a person's life. Unwanted bone mineralization can result in a high burden of disease that negatively impacts daily activities and also multisystemic consequences that can be present throughout life. ALP is essential for building a strong foundation with quality bone. Bone strength comes from the formation and deposition of hydroxyapatite crystals. In healthy bone, ALP is crucial in the process that creates those hydroxyapatite crystals. ALP dephosphorylates inorganic pyrophosphate, PPI, releasing inorganic phosphate, PI. Inorganic phosphate then binds to calcium to form hydroxyapatite crystals that mineralize bone. As we previously mentioned, in HPP, loss-of-function mutations in the ALPL gene result in low ALP activity, the biochemical hallmark of HPP. Low ALP enzyme activity disrupts bone mineralization and calcium phosphate homeostasis throughout life. PPI accumulates and is a potent inhibitor of hydroxyapatite formation, thus impairing bone mineralization. Calcium can also accumulate, leading to hypercalcemia, hypercalciuria, ectopic calcifications, and nephrocalcinosis. TNS-ALP also dephosphorylates a number of other substrates, including pyridoxal 5-phosphate, PLP, the active form of vitamin B6, and phosphoethanolamine, PEA. Low ALP enzyme activity leads to poor quality bone and the accumulation of PPI, resulting in an array of multisystemic consequences. In patients with HPP, symptoms can be unpredictable and devastating throughout a lifetime. HPP is a heterogeneous disease that may appear with dental, skeletal, muscular, rheumatologic, or renal symptoms. Signs and symptoms can include premature tooth loss with the root intact and non-traumatic tooth loss with the root intact at any age, defective bone mineralization, leading to rickets, osteomalacia, skeletal deformities, including short stature in bowed legs, and frequent fractures that are often non-traumatic and non-healing, muscle weakness and pain, and bone and joint pain leading to disability, hypercalcemia and hypercalciuria, leading to nephrocalcinosis and renal damage. In patients with HPP, these signs and symptoms are associated with persistently low ALP throughout a person's life. Now let's move on to our second case study, a 7-year-old girl referred to an endocrinologist for evaluation of short stature and fatigue. Her mother complained that she's always been small, but now she's falling behind her friends. The patient's mother reports that she has been of short stature since birth and complained that her daughter was feeling weak and tired over the last three months. The patient also recovered from strep throat treated with penicillin about three weeks ago, and her mother feels like her daughter can no longer keep up with her friends during playtime. The patient had early tooth loss at three years old and a slight delay in walking. The rest of her history is unremarkable. On physical examination, the patient is found to have mild genuvolgum, not knees, but overall the examination is unremarkable. Based on the information we just reviewed about this patient, what would be your initial differential diagnosis? Of note, the ALP values were not flagged as low, as the value is 55 units per liter was within the normal range for adults, and it is important for ALP ranges to be age and sex adjusted. The patient's short stature and slightly knocked knees were deemed a variant of normal development, and her fatigue was thought to be due to a recent strep throat. The patient's primary care physician noted the normal lab values and continued to follow the patient. Let's take a closer look at ALP levels and bone mineral density. As can be seen in the graph, ALP levels are at their highest during puberty when growth is accelerated, but before peak bone mass is achieved. In childhood, rapid bone growth and mass accumulation are essential for strong bone foundation. In comparison to ALP levels, bone mineral density does not reach its peak until over a decade later. In adulthood, bone remodeling repairs microinjury to maintain bone strength. It is important to note that ALP expression increases prior to skeletal and dental mineralization and drops as mineralization progresses. Accordingly, reduced levels of ALP during bone mass development in childhood may impact peak bone mass in adulthood. The graph here shows the changes in ALP and expected bone mass that can be seen in patients with HPP. Early in HPP, such as with the child we were discussing, low ALP activity may cause defective mineralization of bone and teeth. In HPP during adulthood, mineralization deficits can lead to risk for osteopenia, osteoporosis, and increased risk of fracture. Low bone mineral density early in life can potentially lead to consequences later in life. Specifically, decreased bone mass in childhood may lead to a higher rate of fractures in adulthood. In a survey conducted in patients with HPP, it was found that 23%, 7 out of 30, of children ages 5 years and younger had a history of fractures. This percentage increased to 34%, 11 of 32, in children between the ages of 5 and 15 years. The adult population of patients with HPP in this study, 86%, 108 of 125, had a history of fractures. In a retrospective review of medical records in 22 adult patients with HPP, 54% had a history of fractures. In another retrospective study of 38 adult patients with HPP, a history of fractures was present in 15 patients, or 39%. Lifetime fracture prevalence is lower in the general population than in patients with HPP, with less than 45% of healthy women and 55% of healthy men ever experiencing a fracture. It is important to keep in mind that other manifestations of HPP may occur before the development of fractures. Our final case study is of a 42-year-old mother referred to an endocrinologist for evaluation of fatigue. She complains that she is having a tough time walking and keeping up with her two young daughters. This mother also has longstanding low bone mineral density for her age. She uses a cane to assist her in walking and has had to cut back working at a hair salon due to the difficulty standing and walking. She also reports consistent fatigue and difficulty keeping up with her seven and nine-year-old daughters. Her medical history includes low bone density for age and previous fractures in her teenage years. Her mother has osteoporosis and fibromyalgia, and her father passed away from myocardial infarction at age 67 years. She takes naproxen for pain, as well as calcium and vitamin D supplements. Imaging of her leg showed reduced bone mineral density and a poorly healed fracture. Recent lab results show low ALP levels, and further review of her chart shows a history of low ALP values, fractures, low bone density, and short stature. Based on the symptoms and the persistently low ALP level, the endocrinologist diagnoses the patient with HPP. Because HPP is genetic, her two daughters and mother are tested for the disorder as well. Performing a thorough family history can aid in the diagnosis of HPP and counseling of family members. Key elements for taking a family history include the following. The first step is to assess key patient data, including demographics like age, sex, and ethnic background. Additionally, reviewing the health status of the patient, the age of diagnosis, and the circumstances around any deceased family members can provide important information. All this information should be recorded in a pedigree of the family to lay out the relationship between any of the affected family members. Here's a hypothetical pedigree developed for the patient in case three. Finally, the pedigree can be used to recognize the high-risk individuals within the family based on the number of first and second degree relatives with the disorder, as well as the severity of disease in those relatives. It is important to remember that HPP is a single genetic disease that may be inherited in an autosomal dominant or autosomal recessive mode with deviations from Mendelian inheritance, including a variable expressivity, interfamilial variability, and incomplete penetrance. Signs and symptoms of HPP may delay development and cause significant burden of disease. Patients with the presence of any one of the key clinical signs or symptoms shown on this slide and low ALP should be diagnosed with HPP. Patients with HPP in both childhood and adulthood can experience these signs and symptoms, but not all signs and symptoms need to be present for a patient to be diagnosed with HPP. In particular, tooth loss with the root intact is an early sign of future skeletal and systemic complications in HPP. In our case studies, recall that each presentation demonstrated at least one of these symptoms as well as low ALP. Patients with the presence of any one of the clinical signs or symptoms and low ALP should be diagnosed with HPP. I have been mentioning that low ALP is an important sign for diagnosis of HPP. Ensuring that your laboratory is correcting for age and sex when reporting ALP levels is critical to ensure that you are working with the correct data in evaluating your patients for HPP. Let's go back to the second case study for a minute. Before correcting for the age and sex of this child, we saw that the ALP of 55 units per liter was noted as normal because the adult reference range was used. Once we correct for her age and sex, we see that the value of 55 units per liter should have been flagged as low. Low ALP activity levels and applicable signs and symptoms should raise suspicion for HPP and prompt a referral to a specialist with HPP experience. When managing patients with HPP, misdiagnosis and delayed diagnosis can lead to ineffective management. In order to minimize risk for exacerbation of disease in patients, ensure a correct diagnosis by ruling out HPP before initiating any of these treatments for disorders with overlapping symptoms. These treatments may have negative impact to patients with HPP. For example, bisphosphonate treatment for osteoporosis may worsen skeletal hypomineralization. Teriparatide and denosumab treatment do not address the underlying cause of HPP. High-dose vitamin D and calcium for rickets or osteomalacia can exacerbate the hypercalcemia and hypercalciuria in HPP. Treatment with analgesics for pain and fibromyalgia also do not address the underlying cause in HPP. Therefore, it is critical to eliminate the possibility of HPP prior to starting these treatments. Additional assessments can allow a physician to comprehensively monitor and manage a patient who has been diagnosed with HPP. PLP, the active form of vitamin B6, is typically elevated in patients with HPP. However, values may be borderline or within the normal range. B6 laboratory results may vary due to differences in reference ranges, vitamin B6 supplementation, and improper sample handling. Improper sample handling for PLP testing can artificially result in a lower test result. Vitamins should be collected in a collection tube with heparin or EDTA, protected from light, and stored properly. Before measuring PLP, patients should discontinue vitamin supplements containing vitamin B6 at least one week prior to testing to avoid a falsely high reading. Patients with HPP are also at increased risk for developing ectopic calcifications. Patients should be assessed at diagnosis and monitored routinely. Detection of an ALPL mutation can support diagnosis when biochemical and clinical data are not clear. But failure to find an ALPL gene mutation or a finding of a variant of unknown significance cannot be used to exclude a diagnosis of HPP. Depending on the type of sequencing conducted, there is the potential to miss mutations in the ALPL gene. Because many patients are compound heterozygotes and because most of the genotypes are only found in direct relatives, it is almost impossible to predict the genotype-phenotype relationship. Physical therapy can also serve an important role in the evaluation and ongoing management of a patient with HPP. Now let's take a moment to review the cases we covered today. We covered three case studies, a 21-year-old college student, a 7-year-old girl, and a 42-year-old mother of two. Based on the information initially presented, would you have diagnosed HPP in each of these patients? Would your answer change if I revealed that, in fact, we have been reviewing the same patient at different points in her life? So the better question is, when would you have diagnosed HPP? Our patient's experience highlights that for patients presenting in childhood, low ALP activity can lead to limited mobility, delayed development, pain, and significant functional disability that continues throughout life. Throughout life, the burden of disease and multisystemic consequences for HPP for adult patients may progress. Diagnosing patients with key signs and symptoms and a persistently low ALP with HPP is critical. Today we have reviewed the progressive and systemic consequences of HPP as highlighted in a patient case. Loss-of-function mutations in the ALPL gene result in low ALP enzyme activity, the biochemical hallmark of HPP. Low ALP enzyme activity disrupts bone mineralization and calcium and phosphate homeostasis throughout life. Disrupted bone mineralization can result in high burden of disease that negatively impact daily activities and causes multisystemic consequences throughout life. Diagnosing patients with key signs and symptoms and low ALP with HPP is critical. Age and sex-adjusted ALP reference intervals must be used to correctly diagnose HPP, especially in childhood. Let's take a moment to discuss HPP in infants. HPP is fatal in infants by five years of age. In a natural history study of 48 infants and neonates with HPP, survival was only 27% at five years of age. Respiratory failure resulting from severe hypomineralization and ricketic chest is the most common cause of death in infants and neonates with HPP. Early and accurate diagnosis of HPP in neonates and infants is critical. The systemic manifestations of HPP, especially respiratory and neurologic complications, pose a serious mortality risk to neonates. Severe hypomineralization of the ribcage resulting in ricketic chest can lead to fatal respiratory complications in patients with HPP. In a natural history study of patients with severe perinatal and infantile onset HPP, the majority of patients less than five years of age required respiratory support. Key signs and symptoms of HPP during infancy are life-threatening. Infants with the presence of any one clinical sign or symptom and low ALP should be diagnosed with HPP. Infants may present with skeletal symptoms, including skeletal dysplasia, severe hypomineralization, craniosynostosis, fractures, ricketic chest, or rickets. Additionally, they may have delays in development and growth, such as failure to thrive, poor feeding, or short limbs. Respiratory insufficiency or failure are also common in infants with HPP. Other symptoms to be aware of in infants are vitamin B6 responsive seizures, renal consequences related to hypercalcemia and hypercalceria, and muscular signs such as hypotonia. Remember that not all signs and symptoms need to be present for a patient to be diagnosed with HPP. Let's take a moment to summarize what we have learned about infants with HPP. HPP in infants can have life-threatening consequences, including respiratory failure and vitamin B6 responsive seizures. In infants with HPP, there is an elevated risk of mortality, with the most common cause being respiratory failure. The mortality rate for HPP, which manifests in utero or soon after birth, is high, 75% within the first 1 and 1⁄2 years. Therefore, infants with the presence of any one or more clinical signs or symptoms and low ALP should be diagnosed with HPP. We hope that this presentation was informative to you and your practice. Thank you.

hypophosphatasia

inherited disorder

symptoms

diagnosis

case studies

persistently low ALP levels