Gauri Dhir1, Dong Li2, Hakon Hakonarson3, Michael A Levine4. 1. Division of Endocrinology Diabetes and Metabolism, Cooper Medical School of Rowan University, Camden, NJ 08103, USA. 2. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. 3. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. 4. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: levinem@chop.edu.
Abstract
OBJECTIVE: To identify a genetic basis for markedly reduced bone density and multiple fractures in an adult patient with hypophosphatemia and hypercalciuria. SUBJECTS: A 54-year-old Vietnamese man, his unaffected two daughters and wife. METHODS: We performed biochemical studies and sequenced the SLC34A3 gene using genomic DNA from peripheral blood mononuclear cells. RESULTS: Biochemical evaluation of the proband revealed hypophosphatemia with increased renal phosphate wasting, hypercalciuria, low serum parathyroid hormone (PTH) and an elevated serum 1,25(OH)2D level. Mutation analysis of SLC34A3 gene revealed that the patient was a compound heterozygote for two nonsynonymous nucleotide substitutions: a novel c.571G>A (p.G191S) damaging mutation and the previously reported c.200G>A (p.R67H) polymorphism, consistent with the clinical diagnosis of late-onset hereditary hypophosphatemic rickets with hypercalciuria (HHRH). His wife and older daughter both carried the p.R67H polymorphism, while his younger daughter was compound heterozygous for p.R67H and p.G191S. CONCLUSIONS: HHRH is an uncommon autosomal recessive disease that generally manifests in childhood as rickets or nephrolithiasis, but an adult onset phenotype may occur in heterozygous carriers of SLC34A3 mutations. The severe presentation of this proband in adulthood with marked nephrolithiasis, multiple fractures and low bone density emphasizes the importance of measuring the serum phosphorus level in patients with suspected but unexplained osteoporosis and/or recurrent renal stones. The recognition of late-onset HHRH facilitates timely institution of appropriate therapy.
OBJECTIVE: To identify a genetic basis for markedly reduced bone density and multiple fractures in an adult patient with hypophosphatemia and hypercalciuria. SUBJECTS: A 54-year-old Vietnamese man, his unaffected two daughters and wife. METHODS: We performed biochemical studies and sequenced the SLC34A3 gene using genomic DNA from peripheral blood mononuclear cells. RESULTS: Biochemical evaluation of the proband revealed hypophosphatemia with increased renal phosphate wasting, hypercalciuria, low serum parathyroid hormone (PTH) and an elevated serum 1,25(OH)2D level. Mutation analysis of SLC34A3 gene revealed that the patient was a compound heterozygote for two nonsynonymous nucleotide substitutions: a novel c.571G>A (p.G191S) damaging mutation and the previously reported c.200G>A (p.R67H) polymorphism, consistent with the clinical diagnosis of late-onset hereditary hypophosphatemic rickets with hypercalciuria (HHRH). His wife and older daughter both carried the p.R67H polymorphism, while his younger daughter was compound heterozygous for p.R67H and p.G191S. CONCLUSIONS:HHRH is an uncommon autosomal recessive disease that generally manifests in childhood as rickets or nephrolithiasis, but an adult onset phenotype may occur in heterozygous carriers of SLC34A3 mutations. The severe presentation of this proband in adulthood with marked nephrolithiasis, multiple fractures and low bone density emphasizes the importance of measuring the serum phosphorus level in patients with suspected but unexplained osteoporosis and/or recurrent renal stones. The recognition of late-onset HHRH facilitates timely institution of appropriate therapy.
Authors: Bettina Lorenz-Depiereux; Murat Bastepe; Anna Benet-Pagès; Mustapha Amyere; Janine Wagenstaller; Ursula Müller-Barth; Klaus Badenhoop; Stephanie M Kaiser; Roger S Rittmaster; Alan H Shlossberg; José L Olivares; César Loris; Feliciano J Ramos; Francis Glorieux; Miikka Vikkula; Harald Jüppner; Tim M Strom Journal: Nat Genet Date: 2006-10-08 Impact factor: 38.330
Authors: Ivan A Adzhubei; Steffen Schmidt; Leonid Peshkin; Vasily E Ramensky; Anna Gerasimova; Peer Bork; Alexey S Kondrashov; Shamil R Sunyaev Journal: Nat Methods Date: 2010-04 Impact factor: 28.547
Authors: Amanda L Tencza; Shoji Ichikawa; Anna Dang; David Kenagy; Edward McCarthy; Michael J Econs; Michael A Levine Journal: J Clin Endocrinol Metab Date: 2009-10-09 Impact factor: 5.958
Authors: Debayan Dasgupta; Mark J Wee; Monica Reyes; Yuwen Li; Peter J Simm; Amita Sharma; Karl-Peter Schlingmann; Marco Janner; Andrew Biggin; Joanna Lazier; Michaela Gessner; Dionisios Chrysis; Shamir Tuchman; H Jorge Baluarte; Michael A Levine; Dov Tiosano; Karl Insogna; David A Hanley; Thomas O Carpenter; Shoji Ichikawa; Bernd Hoppe; Martin Konrad; Lars Sävendahl; Craig F Munns; Hang Lee; Harald Jüppner; Clemens Bergwitz Journal: J Am Soc Nephrol Date: 2014-04-03 Impact factor: 10.121
Authors: Adam Auton; Lisa D Brooks; Richard M Durbin; Erik P Garrison; Hyun Min Kang; Jan O Korbel; Jonathan L Marchini; Shane McCarthy; Gil A McVean; Gonçalo R Abecasis Journal: Nature Date: 2015-10-01 Impact factor: 49.962
Authors: Shu Wang; Yi Jia Ma; Yong Shi Li; Xu Sheng Ge; Chang Lu; Chun Bo Cai; Yang Yang; Yan Zhao; Guo Ming Liang; Xiao Hong Guo; Guo Qing Cao; Bu Gao Li; Peng Fei Gao Journal: Anim Biosci Date: 2022-03-02