Clinical spectrum of hypophosphatasia diagnosed in adults

Berkseth, Kathryn E.<sup>1</sup>; Tebben, Peter J.<sup>2,3</sup>; Drake, Matthew T.<sup>2</sup>; Hefferan, Theresa E.<sup>4,5</sup>; Jewison, Donna E.<sup>4</sup>; Wermers, Robert A.<sup>2,4</sup>

Affiliations

¹Department of Internal Medicine and the Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA, USA

²Department of Internal Medicine and the Division of Endocrinology, Diabetes, Nutrition, and Metabolism, Mayo College of Medicine, Mayo Clinic, Rochester, MN, USA

³Department of Pediatrics and the Division of Pediatric Endocrinology, Mayo College of Medicine, Mayo Clinic, Rochester, MN, USA

⁴Bone Histomorphometry Laboratory, Mayo Clinic, Rochester, MN, USA

⁵Department of Orthopedic Surgery, Mayo College of Medicine, Mayo Clinic, Rochester, MN, USA

Abstract

The presentation of hypophosphatasia (HPP) diagnosed in adults demonstrates a wide range of clinical manifestations, many of which are nonspecific. We sought to assess clinical characteristics of adult HPP by evaluation of Mayo Clinic Rochester adults diagnosed with HPP from 1976 through 2008. Subjects were identified by diagnostic code or medical records. Inclusion criteria were age ≥ 18 years at diagnosis; low serum alkaline phosphatase (AP) without bisphosphonate therapy; and one additional element: elevated pyridoxal 5′-phosphate (PLP) or urine phosphoethanolamine (PEA), evidence of osteomalacia, or family history. We were unable to distinguish manifesting carriers from silent unaffected carriers due to lack of a prospective standardized clinical evaluation and the absence of genetic testing. HPP was diagnosed in 22 unrelated adults (median age 49 years; 68% women). Most patients (68%) were symptomatic at presentation with features including musculoskeletal pain (41%) or incident fracture (18%). A history of fracture was present in 54%: hip/femoral neck (23%), feet (23%, all women), wrist (18%), and spine (9%, all men). Nine patients (36%) had multiple fractures while 4 (all women) had subtrochanteric femur fractures. Radiographic chondrocalcinosis (27%) and documented pyrophosphate arthropathy (14%) were only observed in women. Median minimum serum AP was 43% below the lower normal limit. Urine PEA was elevated in 15/16 patients (94%). PLP median was 68 μg/L (normal, 5–50 μg/L) and all (n = 8) were above normal. Symptomatic subjects had more fractures and chondrocalcinosis, lower median minimum AP and PLP and higher median PEA levels. Clinical features more common in fracture patients included symptoms at presentation, history of childhood rickets, dental abnormalities, lower median minimum AP and PLP, and higher median urine PEA. Four subjects had iliac crest bone biopsies, with 2/4 specimens consistent with osteomalacia.

These results suggest that adult HPP demonstrates a wide spectrum of clinical manifestations including musculoskeletal pain, fractures, chondrocalcinosis and dental anomalies with some overlap in laboratory characteristics in relationship to disease severity. In addition to genetic and environmental factors, gender may influence the clinical expression of HPP.

Links

DOI: 10.1016/j.bone.2013.01.024

PubMed: 23352924

WoS: 000316839800003

History

Received: 2012-11-16

Revised: 2013-01-11

Accepted: 2013-01-14

Online: 2013-01-22

Cited Works (1)

Year	Entry
1987	Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR. Bone histomorphometry: standardization of nomenclature, symbols, and units: report of the ASBMR histomorphometry nomenclature committee. J Bone Miner Res. December 1987;2(6):595-610.

Cited By (15)

Year	Entry
2021	Seefried L, Kishnani PS, Moseley S, Denker AE, Watsky E, Whyte MP, Dahir KM. Pharmacodynamics of asfotase alfa in adults with pediatric-onset hypophosphatasia. Bone. January 2021;142:115664.
2021	Desborough R, Nicklin P, Gossiel F, Balasubramanian M, Walsh JS, Petryk A, Teynor M, Eastell R. Clinical and biochemical characteristics of adults with hypophosphatasia attending a metabolic bone clinic. Bone. March 2021;144:115795.
2021	Papadopoulou A, Bountouvi E, Sideri V, Moutsatsou P, Skarakis NS, Doulgeraki A, Karachaliou FE. Parietal aplasia and hypophosphatasia in a child harboring a novel mutation in RUNX2 and a likely pathogenic variant in TNSALP. Bone. May 2021;146:115904.
2022	Hepp N, Folkestad L, Møllebæk S, Frederiksen AL, Duno M, Jørgensen NR, Hermann AP, Jensen J-EB. Bone-microarchitecture and bone-strength in a sample of adults with hypophosphatasia and a matched reference population assessed by HR-pQCT and impact microindentation. Bone. July 2022;160:116420.
2022	Salles Rosa Neto N, Englert D, McAlister WH, Mumm S, Mills D, Veis DJ, Burshell A, Boyde A, Whyte MP. Periarticular calcifications containing giant pseudo-crystals of francolite in skeletal fluorosis from 1,1-difluoroethane "huffing". Bone. July 2022;160:116421.
2022	Shajani-Yi Z, Ayala-Lopez N, Black M, Dahir KM. Urine phosphoethanolamine is a specific biomarker for hypophosphatasia in adults. Bone. October 2022;163:116504.
2021	Jandl NM, Schmidt T, Rolvien T, Stürznickel J, Chrysostomou K, von Vopelius E, Volk AE, Schinke T, Kubisch C, Amling M, Barvencik F. Genotype–phenotype associations in 72 adults with suspected ALPL-associated hypophosphatasia. Calcif Tiss Int. March 2021;108(3):288-301.
2014	McKiernan FE, Berg RL, Fuehrer J. Clinical and radiographic findings in adults with persistent hypophosphatasemia. J Bone Miner Res. July 2014;29(7):1651-1660.
2020	Alonso N, Larraz‐Prieto B, Berg K, Lambert Z, Redmond P, Harris SE, Deary IJ, Pugh C, Prendergast J, Ralston SH. Loss‐of‐function mutations in the ALPL gene presenting with adult onset osteoporosis and low serum concentrations of total alkaline phosphatase. J Bone Miner Res. April 2020;35(4):657-661.
2020	Seefried L, Dahir K, Petryk A, Högler W, Linglart A, Martos‐Moreno GÁ, Ozono K, Fang S, Rockman‐Greenberg C, Kishnani PS. Burden of illness in adults with hypophosphatasia: data from the global hypophosphatasia patient registry. J Bone Miner Res. November 2020;35(11):2171-2178.
2022	Rush ET, Johnson B, Aradhya S, Beltran D, Bristow SL, Eisenbeis S, Guerra NE, Krolczyk S, Miller N, Morales A, Ramesan P, Sarafrazi S, Truty R, Dahir K. Molecular diagnoses of X-linked and other genetic hypophosphatemias: results from a sponsored genetic testing program. J Bone Miner Res. February 2022;37(2):202-214.
2017	Schmidt T, Mussawy H, Rolvien T, Hawellek T, Hubert J, Rüther W, Amling M, Barvencik F. Clinical, radiographic and biochemical characteristics of adult hypophosphatasia. Osteoporos Int. September 2017;28(9):2653-2662.
2020	Bianchi ML, Bishop NJ, Guañabens N, Hofmann C, Jakob F, Roux C, Zillikens MC; Rare Bone Disease Action Group of the European Calcified Tissue Society. Hypophosphatasia in adolescents and adults: overview of diagnosis and treatment. Osteoporos Int. August 2020;31(8):1445-1460.
2020	Martins L, dos Santos EL, de Almeida AB, Machado RA, Lyrio AM, Foster BL, Kantovitz KR, Coletta RD, Nociti FH Jr. A novel de novo heterozygous ALPL nonsense mutation associated with adult hypophosphatasia. Osteoporos Int. November 2020;31(11):2251-2257.
2021	Genest F, Claußen L, Rak D, Seefried L. Bone mineral density and fracture risk in adult patients with hypophosphatasia. Osteoporos Int. February 2021;32(2):377-385.