Welcome to the hypophosphatasia section of the Endocrine Society's fellow training series. This is a picture of a girl with hypophosphatasia who wore braces starting at age 3. Objectives of this talk are to diagnose hypophosphatasia, identify the genetic mutation, and select appropriate therapy. Hypophosphatasia, or low serum alkaline phosphatase, is an inborn error of metabolism. It results from loss-of-function mutations in genes that encode tissue-nonspecific isoenzyme of alkaline phosphatase, I will call it TN-SALP for short. These are located on the cell membranes of osteoblasts and chondrocytes. Inheritance pattern can be autosomal dominant or recessive. The highest prevalence is in Mennonites, such as in this picture. It occurs more in Caucasian than African American populations, but can also occur in Hispanics and Asians. Bone marrow biopsy shows osteomalacia with excessive osteoid. As you can see in this picture, the mineralized bone is green and the osteoid is in red. People with hypophosphatasia would have an excess amount of this area coated in red. TN-SALP normally splits inorganic pyrophosphate and allows bone mineralization. It also converts pyridoxal 5-phosphate, the active form of vitamin B6, into pyridoxal, allowing it to cross the plasma membrane into the CNS. It then rephosphorylates back into pyridoxal 5-phosphate for neurotransmitter synthesis. When TN-SALP is low, inorganic pyrophosphate accumulates outside of cells and inhibits formation of hydroxyapatite, one of the main components of bone, causing rickets and osteomalacia. Resulting labs show elevated pyridoxal 5-phosphate, inorganic pyrophosphate, and phosphoethanolamine. Furthermore, low TN-SALP prevents pyridoxal 5-phosphate from entering the CNS, resulting in seizures. Question. A mutation in which of the following causes hypophosphatasia? A. COL1A1 B. GNAS C. FEX D. TN-SALP Please pause the video if you need more time. The best answer is D. GNAS mutations cause Albright's hereditary osteodystrophy and McCune-Albright syndrome. FEX mutations cause hypophosphatemia. COL1A1 mutations cause osteogenesis imperfecta. There are several types of hypophosphatasia. We're going to start with the least severe and progress on to the most severe. The least severe variety is called odontohypophosphatasia because it predominantly causes dental problems. It's the mildest form with premature loss of baby teeth. Adult hypophosphatasia presents in middle age with early loss of adult teeth, recurrent metatarsal stress fractures, femoral pseudofractures, osteomalacia, and calcific periarthritis. High extracellular pyrophosphate causes pseudogout and pyrophosphate arthropathy. This femur x-ray shows osteopenia throughout the bone and a pseudofracture at the arrow. Childhood hypophosphatasia presents after six months of age with a wide range of severities. Patients have premature loss of baby teeth, bone deformities, costochondral junction beating, short stature, muscle weakness causing stiffness, delayed ambulation, a waddling gait, rickets, and premature closure of the skull sutures. Picture A is an x-ray showing tongues of radiolucency at these arrows. I'll draw a circle around it. Here in the wrist, here in the knee. They project from the growth plate into the metathesis. It also shows hypomineralization of the distal ulna and proximal fibula. Picture B is an x-ray showing an elongated skull with the beaten copper appearance characteristic of suture closure. A craniectomy site is located between these two arrows with bones starting to fill in. Infantile hypophosphatasia presents before age six months with poor feeding, failure to thrive, weakness, delays in motor milestones, rickets, peroptosis, widely spaced eyes, flattening of the back of the head, increased intracranial pressure causing papilledema. Minerals blocked from entering bone result in hypercalcemia and hypercalceria. This results in vomiting and kidney stones. Patients get vitamin B6 dependent seizures. They get thoracic deformities, rib fractures, and tracheomalacia causing pneumonia. About half die from respiratory complications. This picture shows a prominent anterior fontanel, proptosis, scaphoid chest, and ricketic changes in the costochondral junction. Perinatal hypophosphatasia is usually fatal. Patients present with skeletal hypomineralization, vitamin B6 dependent seizures, apnea, cyanosis, bradycardia, fever, anemia, and intracranial hemorrhage. Picture A shows a stillborn neonate with accordion like skin folds of the arm from lack of underlying bone structure. You can see that right here. Picture B is an x-ray showing almost no skeletal mineralization. This is the worst type overall. Question. A child presents with rickets and premature loss of baby teeth. Which of the following is most consistent with hypophosphatasia? A. High alkaline phosphatase. B. Low inorganic pyrophosphate. C. High pyridoxal 5-phosphate. D. Low phosphoethanolamine. Please pause the video if you need more time. The correct answer is C. Patients have low alkaline phosphatase levels, high inorganic pyrophosphate, high pyridoxal 5-phosphate, and high phosphoethanolamine. Supportive therapy includes mechanical ventilation, dental care, NSAIDs, and surgical fracture repairs. Treatment options with limited success included bone marrow transplant, vitamin B6 for seizure, craniotomy for early suture closure, PTH for pain, and fractures. Hypercalcemia responds somewhat to restricting calcium in the diet, hydration, loop diuretics, and glucocorticoids. In 2012, there was an open-label study of asphatase alpha, which is a recombinant human TN-SALP. 11 very young children received a loading dose of this substance and then continued it at 1-3 mg per kg, subcutaneously, 3 times a week. At baseline, patients had failure to thrive, fracture, motor delays, none of them could weight-bear because of skeletal abnormalities and weakness. Alkaline phosphatase was low and pyridoxal 5-phosphate was elevated. The parents of one participant withdrew him from the study because of fever and respiratory difficulty after the IV infusion. The rest of the patients continued the study and had minimal side effects consisting mainly of injection site reactions. After 4 years of asphatase alpha therapy, most patients were mobile and could breathe independently. Pyridoxal 5-phosphate and inorganic pyrophosphate lowered into normal ranges. There were no changes in the rate of early skull suture closure, however. This striking radiograph shows hypomineralization of bone at baseline and how they improved with treatment. Here you can see the bones of the fingers. There have been similar results in older children and even benefits for adults with this medication. In 2015, FDA approved asphatase alpha for treating pediatric hypophosphatase because it improves survival, muscle strength, pain, bone mineralization, pulmonary, cognitive, and motor functions. This graph from the manufacturers shows the survival benefit of asphatase alpha in the green line on the top. Compared to untreated patients on the black line below. Adults and adolescents with hereditary hypophosphatase treated with asphatase alpha had improvements in gross motor function, proximal muscle strength, ambulation, and functional disability. As you can see in the graph, there was reduction in pyridoxal 5-phosphate levels by 6 months, which was sustained for 5 years on treatment. This table summarizes the variable presentations of hypophosphatasia, which range from mild forms that involve only teeth to lethal forms. Typically, the earlier patients present, the worse their prognosis. Adults often present with skeletal problems and you can diagnose them biochemically. Children additionally present with poor growth and mobility. Infants may have kidney stones, seizure, many die of respiratory problems. Perinatal forms often die in utero. Question What is the most effective therapy for hypophosphatasia? A. Asphatase alpha B. Bone marrow transplant C. Teriparatide D. Vitamin B6 Please pause the video if you need more time. The best answer is A. The other choices have had limited success. In summary, hypophosphatasia results from loss of function mutations in genes that encode TN-SALP. The result is an increase in extracellular pyrophosphate resulting in defective mineralization, tooth loss, and osteomalacia. Diagnose this with a low serum alkaline phosphatase for age and gender. Additionally, a high pyridoxal 5-phosphate level. Check the TN-SALP gene to diagnose prenatal forms and predict risk in future pregnancies. Asphatase alpha is an effective treatment for this condition. Thank you for your attention.

hypophosphatasia

alkaline phosphatase

TN-SALP gene

bone mineralization

asfotase alfa