title: Neuromuscular symptoms in a patient with familial pseudohypoparathyroidism type Ib diagnosed by methylation-specific multiplex ligation-dependent probe amplification.
abstract: Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare genetic disorder characterized by hypocalcemia and hyperphosphatemia due to imprinting defects in the maternally derived GNAS allele. Patients with PHP-Ib are usually identified by tetany, convulsions, and/or muscle cramps, whereas a substantial fraction of patients remain asymptomatic and are identified by familial studies. Although previous studies on patients with primary hypoparathyroidism have indicated that hypocalcemia can be associated with various neuromuscular abnormalities, such clinical features have been rarely described in patients with PHP-Ib. Here, we report a 12-year-old male patient with familial PHP-Ib and unique neuromuscular symptoms. The patient presented with general fatigue, steppage gait, and myalgia. Physical examinations revealed muscular weakness and atrophies in the lower legs, a shortening of the bilateral Achilles' tendons and absence of deep tendon reflexes. Laboratory tests showed hypocalcemia, hyperphosphatemia, elevated serum intact PTH level, and impaired responses of urinary phosphate and cyclic AMP in an Ellsworth-Howard test, in addition to an elevated serum creatine kinase level. Clinical features of the patient were significantly improved after 1 month of treatment with alfacalcidol and calcium. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and subsequent PCR analyses identified a methylation defect at exon A/B of GNAS and a microdeletion involving exons 4-6 of the GNAS neighboring gene STX16 in the patient and in his asymptomatic brother. The results suggest that various neuromuscular features probably associated with hypocalcemia can be the first symptoms of PHP-Ib, and that MS-MLPA serves as a powerful tool for screening of GNAS abnormalities in patients with atypical manifestations.
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan. nagasaki@med.niigata-u.ac.jp
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nagasaki
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tsuchiya
authors.forename: Akihiko
authors.initials: A
authors.lastname: Saitoh
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
mesh_terms: D002136:Calcium, Dietary / Q000627:therapeutic use; D002648:Child; D002864:Chromogranins; D019175:DNA Methylation; D019587:Dietary Supplements; D005091:Exons; D005192:Family Health; D005221:Fatigue / Q000209:etiology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics* / Q000378:metabolism; D020233:Gait Disorders, Neurologic / Q000209:etiology / Q000517:prevention & control; D017353:Gene Deletion; D006801:Humans; D006887:Hydroxycholecalciferols / Q000627:therapeutic use; D006996:Hypocalcemia / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D060885:Multiplex Polymerase Chain Reaction; D059352:Musculoskeletal Pain / Q000209:etiology / Q000517:prevention & control; D009468:Neuromuscular Diseases / Q000209:etiology* / Q000517:prevention & control; D011547:Pseudohypoparathyroidism / Q000097:blood / Q000178:diet therapy / Q000235:genetics / Q000503:physiopathology*; D051438:Syntaxin 16 / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D002136:Calcium, Dietary; D002864:Chromogranins; D006887:Hydroxycholecalciferols; C496118:STX16 protein, human; D051438:Syntaxin 16; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; C008088:alfacalcidol