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Phenotypic and Molecular Genetic Aspects of Pseudohypoparathyroidism Type Ib in a Greek Kindred: Evidence for Enhanced Uric Acid Excretion Due to Parathyroid Hormone Resistance

Department of Medicine, Division of Endocrinology, University of Ioannina (E.L., A.T.), 45110 Ioannina, Greece; and Endocrine Unit, Department of Medicine, Massachusetts General Hospital (M.B., H.J.), and Pediatric Nephrology (H.J.), MassGeneral Hospital for Children, and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Dr. Agathocles Tsatsoulis, Department of Medicine, Division of Endocrinology, University of Ioannina, Ioannina 45110, Greece. E-mail: atsatsou{at}cc.uoi.gr.

The predominant feature of pseudohypoparathyroidism (PHP) is renal resistance to PTH. Pseudohypoparathyroidism type Ia (PHP-Ia) is caused by maternally inherited heterozygous mutations in the GNAS exons encoding the -subunit of the stimulatory G protein (G_s). Besides PTH resistance, PHP-Ia patients have Albright’s hereditary osteodystrophy and often display resistance to additional hormones. Patients with PHP-Ib lack features of Albright’s hereditary osteodystrophy, and PTH resistance is associated with loss of methylation at the maternal GNAS exon A/B. Most individuals with the autosomal dominant form of PHP-Ib have a 3-kb microdeletion within STX16 approximately 220 kb upstream of exon A/B. Here we report on the clinical and genetic aspects of a Greek PHP-Ib kindred with four affected members and three obligate carriers, who had the 3-kb deletion within STX16. Symptomatic hypocalcemia was present only in the proband, but PTH was elevated in all members who had inherited the 3-kb deletion maternally. In all affected family members, urinary phosphate excretion was normal, but 1,25-dihydroxyvitamin D levels were diminished. These findings confirm previous data regarding patient to patient variation in disease severity for autosomal dominant PHP-Ib. Furthermore, affected individuals displayed hypouricemia with increased fractional excretion of uric acid, suggesting possible involvement of PTH in the renal handling of this metabolite.

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