Hypophosphatasia Clinical Presentation
- Author: Horacio B Plotkin, MD, FAAP; Chief Editor: Luis O Rohena, MD more...
The most severe form of hypophosphatasia is universally lethal. Review of pregnancy history may reveal polyhydramnios. Skeletal manifestations of the severe cases vary widely among patients. Typical radiographic features include lack of ossification in some bones; marked variability in the degree of bone ossification; unusually dense, round, flattened, and butterfly-shaped vertebral bodies; and generalized smaller ossified bones. Bones are affected to different degrees in the same patient; the bones affected differ among patients. Variability in femoral shape is also observed, and osteochondral projections (Bowdler spurs) of the midshaft of the fibula and ulna may be present. Prognosis is poor, but affected newborns may briefly survive. The cause of death is usually severe respiratory compromise, which may occur with fever of unknown origin, anemia, irritability, seizures, and dehydration.
Initially, affected infants may appear healthy until the onset of signs, which occurs when they are younger than 6 months. These infants have a history of poor feeding and failure to thrive, developmental delays, and muscle weakness. Hypotonia has also been reported.
Affected children often have a history of delayed walking and early loss of deciduous teeth. Bone pain is a frequent symptom. Both infants and children may present with nephrocalcinosis.
Adults usually present with signs and symptoms during middle age, although careful interrogation often reveals signs during childhood or even infancy. As with the childhood form, premature loss of deciduous teeth due to disturbed cementum formation is common. Mineralization of dentin is less likely to be under the influence of the inhibitory action of pyrophosphate than mineralization of cementum. In most cases, diagnosis is made after a low alkaline phosphatase activity level is detected during routine blood work, or when tested after a direct family member was diagnosed with the condition. Adults may also have a history of foot pain due to stress fractures and joint pain due to deposition of calcium pyrophosphate dihydrate. Affected adults may manifest osteomalacia, with slowly healing or nonunion stress fractures (commonly metatarsal) and proximal femur pseudofractures.
Odontohypophosphatasia presents with a premature loss of adult teeth.
Infants with extremely severe hypophosphatasia may be stillborn. Some infants survive a few days but have respiratory complications due to hypoplastic lungs and rachitic deformities of the chest. Other findings include apnea, seizures, craniosynostosis, and marked shortening of the long bones.
Surviving infants may appear healthy at birth; however, the clinical signs of hypophosphatasia appear during the first 6 months. These patients also have respiratory complications due to rachitic deformities of the chest. Despite the presence of an open fontanelle, premature craniosynostosis is a common finding that may result in increased intracranial pressure. Hypercalcemia is also present, and increased excretion of calcium may lead to nephrocalcinosis and renal damage. Infants may also present with severe epileptic encephalopathy that results in death. These seizures respond to vitamin B-6 treatment.
Skeletal deformities (eg, dolichocephalic skull and enlarged joints), a delay in walking, short stature, and waddling gait accompany the childhood form. A history of fractures and bone pain is usually noted. Premature loss of dentition is common; the incisor teeth are often the first affected.
Adults are often diagnosed during middle age. The condition can be completely asymptomatic and is suspected after a low alkaline phosphatase activity level is found during routine laboratory studies, although careful interrogation often reveals signs and symptoms during childhood or infancy. The first symptom may be foot pain, which is due to stress fractures of the metatarsals. Thigh pain, due to pseudofractures of the femur, may also be a presenting symptom. Upon obtaining an in-depth history, many of these patients reveal that they have experienced premature loss of their deciduous teeth.
The only physical finding in odontohypophosphatasia is the premature loss of teeth.
Chronic bone edema in the adult form and chronic hyperprostaglandinism in the childhood form suggest that, in some patients, bone inflammation is present in conjunction with the metabolic defect. Sterile multifocal osteomyelitis could be demonstrated in 2 cases.
A mutation in the gene that codes for tissue-nonspecific alkaline phosphatase is believed to be the cause of hypophosphatasia. The gene has been given the designation ALPL. The ALPL gene is located at band 1p36.1-34.
More than 250 mutations have been described to date. Perinatal and infantile hypophosphatasia have an autosomal recessive mode of inheritance. Both autosomal recessive and autosomal dominant patterns of inheritance have been demonstrated for the childhood, adult, and odontohypophosphatasia forms. Frequently, patients are compound heterozygous.
Nishioka T, Tomatsu S, Gutierrez MA, et al. Enhancement of drug delivery to bone: characterization of human tissue-nonspecific alkaline phosphatase tagged with an acidic oligopeptide. Mol Genet Metab. 2006 Jul. 88(3):244-55. [Medline].
Fraser D. Hypophosphatasia. Am J Med. 1957 May. 22(5):730-46. [Medline].
Balasubramaniam S, Bowling F, Carpenter K, et al. Perinatal hypophosphatasia presenting as neonatal epileptic encephalopathy with abnormal neurotransmitter metabolism secondary to reduced co-factor pyridoxal-5'-phosphate availability. J Inherit Metab Dis. 2010. Epub:[Medline].
[Guideline] Jenny C. Evaluating infants and young children with multiple fractures. Pediatrics. 2006 Sep. 118(3):1299-303. [Medline].
Girschick HJ, Mornet E, Beer M, Warmuth-Metz M, Schneider P. Chronic multifocal non-bacterial osteomyelitis in hypophosphatasia mimicking malignancy. BMC Pediatr. Jan 2007. 7:[Medline].
Rauch F, Greenberg C, Whyte MP, et al. The Bone Tissue Defect in Children with Hypophosphatasia: Histomorphometric Study. Proceedings of the 33 Annual ASBMR Meeting. 2011.
Whyte MP, Greenberg CR, Salman NJ, et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012 Mar 8. 366(10):904-13. [Medline].
Whyte MP, Rockman-Greenberg C, Ozono K, Riese R, Moseley S, Melian A, et al. Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia. J Clin Endocrinol Metab. 2015 Nov 3. jc20153462. [Medline].
Okazaki Y, Kitajima H, Mochizuki N, Kitaoka T, Michigami T, Ozono K. Lethal hypophosphatasia successfully treated with enzyme replacement from day 1 after birth. Eur J Pediatr. 2015 Oct 12. [Medline].
Kishnani PS, Rockman CR, Whyte MP et al. Hypophosphatasia: Enzyme Replacement Therapy (ENB-0040) Decreases TNSALP Substrate Accumulation and Improves Functional Outcome in Affected Adolescents and Adults. Proceedings of American College of Medical Genetics. 2012. 303.
Ozono K. [Biomineralization. Enzyme replacement therapy for hypophosphatasia]. Clin Calcium. 2014. 24(2):257-63. [Medline].
Oda K, Kinjoh NN, Sohda M, Komaru K, Amizuka N. Biomineralization. Tissue-nonspecific alkaline phosphatase and hypophosphatasia. Clin Calcium. 2014. 24:233-239. [Medline].
Gagnon C, Sims NA, Mumm S, et al. Lack of Sustained Response to Teriparatide in a Patient with Adult Hypophosphatasia. J Clin Endocrinol Metab. 2010. Epub:[Medline].
Cahill RA, Wenkert D, Perlman SA, et al. Infantile hypophosphatasia: transplantation therapy trial using bone fragments and cultured osteoblasts. J Clin Endocrinol Metab. Aug 2007. 92:2923-30. [Medline].
Plecko B, Stockler S. Vitamin B6 dependent seizures. Can J Neurol Sci. 2009. 36:S73-7. [Medline].
van den Bos T, Handoko G, Niehof A, et al. Cementum and dentin in hypophosphatasia. J Dent Res. 2005 Nov. 84(11):1021-5. [Medline].
Whyte MP. Enzyme defects and the skeleton. Primer on the metabolic bone diseases and disorders of mineral metabolism. 7th ed. 2008. 454-455.
Whyte MP. Hypophosphatasia. The metabolic & molecular bases of inherited disease. 8th ed. 2001. 5313-29.
Whyte MP, Kurtzberg J, McAlister WH, et al. Marrow cell transplantation for infantile hypophosphatasia. J Bone Miner Res. 2003 Apr. 18(4):624-36. [Medline].