Dissecting a Family History

Presentation Number: SAT 336
Date of Presentation: April 1st, 2017

Rachel Coleman-Pierron* and Kathryn McCrystal Dahir
Vanderbilt University Medical Center, Nashville, TN


Hypophosphatasia (HPP) is a rare inherited disorder caused by the loss of function mutation in the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP), resulting in low alkaline phosphatase (AP) activity and elevated extracellular inorganic pyrophosphate and pyridoxal 5’-phosphate. Presentation of HPP is variable, ranging from no deformity to lethal during the perinatal period.

39 year old woman presented for evaluation of osteoporosis. Medical history included traumatic bimalleolar fracture at age 17 and loss of deciduous teeth prior to age 5. She reported migraines, menorrhagia, balance difficulty and arthralgia of bilateral ankles and left hip. When pregnant with her first child 7 years prior, routine prenatal ultrasonography detected extreme skeletal hypomineralization. After birth, genetic testing revealed C119C>T and C1231A>G. Newborn was diagnosed with HPP and started on asfotase alfa, recombinant bone targeted TNSALP. Bone mineralization substantially improved, but death occurred from infectious cause at 8 months of life. Her sister was diagnosed with osteoporosis at age 49. Patient and two other sisters, age 59 and 45, were then diagnosed with osteoporosis. Their father had cracked teeth, collar bone fracture and feet deformities. Suspicion that the family’s bone mineralization disorders could be related to her late child’s diagnosis prompted genetic testing. The patient did not undergo mutational analysis, but screening of 4 siblings revealed C1231A>G. Musculoskeletal examination demonstrated mild thoracolumbar scoliosis and left hand grip weaker than right. AP was 38 (40-15) units/L with bone specific AP 5.2 (4.5-16.9)mcg/L and vitamin B6 92.4 (20-125) nmol/L. Bilateral lower extremity, spine and skull radiographs showed normal mineralization. Diagnosis of HPP was made. Screening for disease complications included renal ultrasound, dental films, ophthalmology examination and physical therapy evaluation.

Prevalence of severe forms of HPP is estimated at 1 in 100,000. At least 300 TNSALP mutations have been detected. Autosomal dominant and autosomal recessive transmission typically leads to mild versus severe HPP. The natural history of adults with likely dominant negative mutations is largely unknown given that it is under or misdiagnosed. Adult symptoms are premature loss of deciduous teeth, arthropathy without bone disease, femoral pseudofractures and failure to heal metatarsal stress fractures. Extracellular accumulation of inorganic pyrophosphate can lead to pseudogout, calcific periarthritis and ossification of ligaments causing debilitating pain and muscle weakness. Laboratory testing typically reveals low AP and elevated vitamin B6 levels. Diagnosis does not require mutation analysis and can be made clinically with medical history, physical examination, routine laboratory studies and radiographic findings.


Disclosure: KMD: Clinical Trial Investigator, Alexion. Nothing to Disclose: RC