Year : 2021 | Volume
: 7 | Issue : 1 | Page : 62--65
Hypophosphatasia: A missed diagnosis
Tess Chamakkala1, Thomas Gallagher2,
1 Department of Internal Medicine, St. Luke's University Health Network, Bethlehem, Pennsylvania, USA
2 St. Luke's Center for Diabetes and Endocrinology, St. Luke's University Health Network, Bethlehem, Pennsylvania, USA
Dr. Tess Chamakkala
801 Ostrum Street, Bethlehem, PA 18015
Hypophosphatasia is a disorder of bone metabolism due to defective tissue nonspecific alkaline phosphatase (ALP). It is most severe in early life but can present at any age, leading to a likely underdiagnosis of its adult, and commonly less severe, forms. This is the case of a 42-year-old female who presented to endocrinology asking about her low ALP levels in the setting of prior bilateral metatarsal fractures and was diagnosed with hypophosphatasia. This case report aims to highlight the importance of making this diagnosis in order to avoid commonly prescribed therapies that can be harmful. Antiresorptive therapies as well as supplementation with calcium or Vitamin D can potentially worsen the disease. There are no Food and Drug Administration-approved treatments for adult hypophosphatasia, but asfotase alfa and teriparatide are two promising therapies currently being studied.
The following core competencies are addressed in this article: Practice-based learning and improvement, Medical knowledge.
|How to cite this article:|
Chamakkala T, Gallagher T. Hypophosphatasia: A missed diagnosis.Int J Acad Med 2021;7:62-65
|How to cite this URL:|
Chamakkala T, Gallagher T. Hypophosphatasia: A missed diagnosis. Int J Acad Med [serial online] 2021 [cited 2022 Jan 22 ];7:62-65
Available from: https://www.ijam-web.org/text.asp?2021/7/1/62/311885
Hypophosphatasia (HPP) is an inherited disorder predominantly of bone metabolism caused by a deficiency of tissue nonspecific alkaline phosphatase (ALP). A defective ALP leads to an accumulation of its substrates, including inorganic pyrophosphate, which interferes with bone formation.
HPP has a variable presentation and is notably most severe in its infantile form with a mortality rate of approximately 50%. Although less severe in adulthood, it should be recognized in order to avoid potentially harmful therapies. This is the case of a 42-year-old female who presented to endocrinology, inquired about her persistently low ALP values, and was diagnosed with hypophosphatasia.
A 42-year-old Caucasian female with a history of hypothyroidism treated with levothyroxine presented to establish care with endocrinology. She asked about her ALP levels, noted again at a level of 20 (33–115 U/L) on her most recent labwork with her primary care provider. On chart review, this patient's ALP had been noted to be below reference range at least 4 years prior at a value of 19 and had remained between 16 and 20 leading up to her presentation. On further discussion, the patient reported approximately six nontraumatic metatarsal stress fractures in bilateral feet throughout her life as well as a skull fracture at the age of two. She reported the first fracture occurred around the age of 7 while walking. She reported additional metatarsal stress fractures while younger but could not recall further details on these fractures. She reported her two most recent fractures were in her 20 s, the last of which was a fifth digit metatarsal fracture. There was no family history of similar bone disease or hypophosphatasia. This patient denied premature loss of deciduous teeth. She reported good compliance with her prescribed levothyroxine and denied taking any daily vitamins. Physical examination was generally unremarkable with no acute bony abnormalities noted. At this juncture, ALP was repeated and remained below the normal range at 19 (39–117 IU/L). Vitamin B6 was evaluated and was elevated at 64.1 (2–32.8 mcg/L). Vitamin D and calcium were within the normal range. This patient was evaluated for other causes of low ALP such as pernicious anemia, celiac disease, heavy metal toxicities, Wilson's disease, hypothyroidism, and hypomagnesemia; this labwork was all within the normal range. Thyroid-stimulating hormone was 2.04 uIU/mL on levothyroxine. Given the prior unusual fracture history and the persistently low ALP in the setting of elevated B6, the diagnosis of HPP was made.
Adult HPP is a disorder primarily of bone but with a wide range of clinical presentations. It is due to a deficiency in tissue-nonspecific ALP which leads to the accumulation of multiple substrates, including phosphoethanolamine, inorganic pyrophosphate, and pyridoxal-5'-phosphate. There are more than 240 TNSALP defects reported worldwide in patients with hypophosphatasia, approximately 80% of which are missense mutations. The more severe forms of the disease, the perinatal and infantile forms of HPP, are associated with autosomal recessive inheritance of the gene mutation. However, the more mild forms of childhood or adult HPP have been found to be inherited as either autosomal dominant or autosomal recessive traits. Perinatal hypophosphatasia can emerge during pregnancy with polyhydramnios and intrauterine death. During infancy, HPP can manifest with signs of failure to thrive, seizures, rachitic deformities, craniosynostosis, and flail chest with a mortality rate of about 50%. Prognosis improves after 6 months of age; presenting symptoms are less severe in childhood but can still include rickets, frontal bossing, and short stature. On the other hand, adult HPP has usually been associated with metatarsal fractures or thigh pain from femoral pseudofractures in middle-aged adults. However, it has been shown to present with a number of other signs and symptoms including musculoskeletal pain, pseudogout, chondrocalcinosis, and vertebral fractures. The prevalence of this disease in its mild-to-moderate forms is difficult to discern given this wide clinical presentation. One study estimates the prevalence of moderate HPP in Europe to be 1/6370, while the severe, autosomal recessive, forms have been estimated at 1/100,000–1/300,000.
When a persistently low ALP is noted, a comprehensive history and physical should be performed to evaluate for causes including hypophosphatasia, hypothyroidism, starvation/malnutrition, Wilson's disease, zinc deficiency, Vitamin C deficiency, profound anemia, hypomagnesemia, (recent exposure to drugs such as glucocorticoids, chemotherapy, clofibrate, Vitamin D toxicity, and milk-alkali syndrome), or massive blood or plasma transfusion. In this patient, recurrent metatarsal fractures in the setting of low ALP should have prompted further evaluation for HPP which can be diagnosed with clinical history/findings and radiographic changes that are consistent with the diagnosis as well as a persistently low ALP. Radiographic studies of the involved bones are often performed, and these studies can be diagnostic in the earlier and more severe forms of HPP (perinatal, infantile, or childhood HPP). However, in adult HPP, where there is less skeletal disease, the findings are not diagnostic. One of the substrates of ALP, pyridoxal-5'-phosphate (PLP) which is the active form of Vitamin B6, is usually elevated in HPP and can further support the diagnosis. In vitamin B6 metabolism, the multiple dietary forms of Vitamin B6 are converted in the liver to PLP which cannot cross plasma membranes without extracellular dephosphorylation. Tissue nonspecific ALP acts in this extracellular dephosphorylation, and so serum levels of PLP rise when ALP is defective. Vitamin B6 containing supplements should be discontinued 1 week before measuring levels of Vitamin B6 or PLP. HPP originates from loss-of-function TNSALP mutations, and genetic testing can additionally be pursued to confirm the diagnosis.
This case report aims to bring awareness to this diagnosis in order to assist primary care providers in accurate diagnosis of the condition and to further evaluate the effects of different treatment therapies. This case is unique in that this patient had shown signs and symptoms of HPP for many years before appropriate diagnosis. The current expert consensus is that antiresorptive therapy with bisphosphonates and potentially denosumab in patients with HPP may lead to adverse effects including atypical fractures, and should be avoided. These antiresorptives can further lower serum ALP. Some emerging evidence does suggest that in patients with mild/asymptomatic HPP (with a single TNSALP mutation and no evidence of osteomalacia) who are additionally diagnosed with osteoporosis, the risks of treatment with bisphosphonates may be low. Calcium or Vitamin D supplements may exacerbate hypercalcemia and hypercalciuria and should be used on a case-by-case basis with caution in these patients. Currently, there are no Food and Drug Administration-approved treatments for adult hypophosphatasia, and treatment consists of a multidisciplinary approach with nutrition, laboratory monitoring if needed, dental monitoring, physical therapy, and continued follow-up. Teriparatide has been used off-label for fracture healing with some evidence of improvement in the mild forms of HPP. Recently, in 2015, enzyme replacement therapy with asfotase alfa was approved by the US Food and Drug Administration to treat perinatal, infantile, and juvenile HPP. Asfotase alfa is a recombinant glycoprotein containing the catalytic domain of TNSALP, replacing the defective TNSALP enzyme to prevent the accumulation of substrates which, in hypophosphatasia, inhibit effective bone mineralization. There is one published case of a patient with adult HPP and chronic musculoskeletal complaints who was treated with asfotase alfa and had improvement in her symptoms as well as objective improvement in whole-body bone scan uptake and pedometer count. Of note, during treatment with asfotase alfa, ALP levels have been noted to be markedly elevated, even as high as 24,000 U/L; at this time, these markedly elevated levels do not appear to be harmful. More research would be needed to investigate the role of asfotase alfa in adults with HPP and to further evaluate if bisphosphonates would be definitively contraindicated. The ability to perform this much-needed research is limited by the missed diagnosis of hypophosphatasia.
One of the limitations of this case report is the lack of TNSALP mutation testing in this patient; it was discussed with the patient but ultimately, she could not afford to have it performed.
Persistent low ALP levels should prompt further clinical investigation into a cause. Adult HPP is one diagnosis that can present with a wide range of symptoms but usually centers on fractures and skeletal abnormalities. This disorder is likely much more prevalent than currently reported. In this case, a 42-year-old female with recurrent metatarsal fractures was diagnosed many years later when the connection was finally made to her low ALP levels. Making the diagnosis is important so as to avoid therapies that are suspected to worsen the risk of fractures or other manifestations as well as to pursue treatments as they become available in the future. Asfotase alfa and teriparatide are two therapies that may soon prove promising in the treatment of adult hypophosphatasia.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initial will not be published and due efforts will be made to conceal the identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
Research quality and ethics statement
The authors of this manuscript declare that this scientific work complies with reporting quality, formatting, and reproducibility guidelines set forth by the EQUATOR Network. The authors also attest that this clinical investigation was determined to not require the Institutional Review Board/Ethics Committee review, and the corresponding protocol/approval number is not applicable. The authors certify that they have obtained appropriate patient consent. The patient has given her consent for their clinical information to be reported in the journal. The patient understands that her name and initials will not be published, and due efforts will be made to conceal the identity, but anonymity cannot be guaranteed.
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