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ELECTRONIC ARTICLE |
* Department of Pediatric Endocrinology and Metabolism, Mayo Clinic, Rochester, Minnesota
Endocrine and Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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ABSTRACT |
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Key Words: pseudohypoparathyroidism type Ib • paroxysmal dyskinesia • genetics (molecular)
Abbreviations: PHP, pseudohypoparathyroidism • PTH, parathyroid hormone • AHO, Albright's hereditary osteodystrophy • AD-PHP-Ib, autosomal dominant form of pseudohypoparathyroidism type Ib • PKC, paroxysmal kinesigenic choreoathetosis • Gs
, subunit of the stimulatory G protein
Pseudohypoparathyroidism (PHP) is a rare condition characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) levels caused by end-organ resistance to PTH. The main clinical types of PHP include PHP types Ia (PHP-Ia) and Ib (PHP-Ib). PHP-Ia is characterized by the classic laboratory findings and features of Albright's hereditary osteodystrophy (AHO), including short stature, developmental delay, brachydactyly, and heterotopic calcifications. Patients with PHP-Ib present with the typical laboratory findings but lack features of AHO. Recently, a microdeletion on chromosome 20q13.3 was identified as a plausible cause of an autosomal dominant form of PHP-Ib (AD-PHP-Ib).1
Many individuals affected by PHP-Ib have no apparent clinical symptoms and may show only a mild PTH elevation as evidence of PTH resistance.2 However, some patients with this disorder may present with symptomatic hypocalcemia leading to abnormal movements suggestive of a primary neurologic etiology. This report describes the clinical presentation and molecular diagnosis of 2 siblings with AD-PHP-Ib who were initially diagnosed as having a paroxysmal movement disorder.
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CASE REPORTS |
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Her parents (II-1 and II-2) are healthy and not related. They have 9 children; 6 girls and 3 boys. The elder sibling (III-4) started experiencing similar events at 10 years of age. Investigations included a normal electroencephalogram and magnetic resonance imaging of the head. Based on the clinical features of these attacks, she was diagnosed with PKC and treated with carbamazepine (100 mg daily), which significantly reduced the frequency of these attacks. However, by 14 years old, symptoms were worsening progressively, and her dose of carbamazepine was increased (200 mg of sustained release daily). In addition, elemental calcium (600 mg daily) was added, which resulted in a mild improvement in her symptoms.
On examination, our index patient had a stature of 146.7 cm (40th percentile) and weighed 36 kg (50th percentile). She had discolored teeth with poor dental enamel. There were no features of AHO. Her neurologic examination revealed accentuated deep tendon reflexes and positive Chvostek's and Trousseau's signs.
Laboratory testing revealed low calcium (7.4 mg/dL; reference: 9.5–10.5 mg/dL) and elevated phosphorus (8.2 mg/dL; reference: 3.5–5.0 mg/dL) concentrations, with elevated intact PTH (37 pmol/L; reference: 1-5.2 pmol/L) indicative of PTH resistance and PHP.
This diagnosis prompted reevaluation of her elder sibling, who was found also to be hypocalcemic and hyperphosphatemic, with elevated PTH levels (Ca: 5.7 mg/dL; P: 7.4 mg/dL; intact PTH: 34 pmol/L). Her skeletal survey showed a brown tumor in the proximal humerus consistent with hyperparathyroid bone disease (Fig 1). Both siblings also had elevated thyroid-stimulating hormone levels (6.3 and 5.3 mIU/L, respectively; reference: 0.3-5.0 mIU/L), with normal free thyroxine levels and undetectable thyroperoxidase antibodies.
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DISCUSSION |
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subunit of the stimulatory G protein (Gs), an essential signaling protein that couples a large variety of cell-surface receptors, including the PTH/PTHrP receptor, to the stimulation of adenylyl cyclase.3 Defects in this signaling pathway result in renal PTH resistance and thus hypocalcemia, hyperphosphatemia, and elevated PTH concentrations despite otherwise normal renal function. However, the skeleton remains sensitive to the calcemic actions of PTH, maintaining blood calcium concentrations at the expense of bone. Because of the prolonged PTH-dependent bone resorption, changes in bone that are characteristic of long-standing hyperparathyroidism were observed in the elder sister.
The PHP-Ib variant is different from other PHP types, because mutations in Gs-encoding GNAS exons have not been found in most cases.2,4 Our patients carry the same 3-kb deletion upstream of GNAS, which has been found in numerous other unrelated kindreds with AD-PHP-Ib.1,5,6 It is currently postulated that this deletion affects, in cis, directly or indirectly, the establishment or maintenance of exon A/B methylation on the maternal GNAS allele, which then silences Gs expression in the proximal renal tubules and possibly few other tissues.1 Thus, the genetic defect leads to resistance to PTH only if the deletion is inherited by a female carrier. In our case, the mother shared the same deletion as her 2 affected daughters, but she is an asymptomatic carrier, because she inherited her deletion from her father, who presumably inherited the mutation paternally as well.
Our patients also had elevated thyroid-stimulating hormone levels, which is consistent with recent reports indicating that Gs expression is also paternally imprinted in the thyroid.7
The elder sister described in this report was treated initially for presumed PKC with carbamazepine, which partially masked her symptoms putatively through sodium-channel inhibition and neuronal membrane stabilization.8 PKC is a rare condition characterized by brief episodes of chorea or dystonic spasms precipitated by sudden movement and can be sporadic or familial.9 A favorable response to antiepileptic medications is often a diagnostic criterion for PKC; thus, no other investigations were pursued after treatment was initiated.8,9
Although reports of PKC caused by hypocalcemia and hypoparathyroidism have been described in adults,10–13 our review of the literature found only 2 cases involving children with PHP.14,15 These 2 patients had intracranial calcifications on computerized tomographic imaging and features more consistent with a hypocalcemic disorder.14,15
Our cases describe a unique diagnosis of AD-PHP-Ib in 2 siblings with a neurologic presentation of a metabolic derangement illustrative of a specific genetic defect: a 3-kb microdeletion centromeric of GNAS, which seems to be directly or indirectly involved in silencing Gs expression from the maternal allele. This case also reinforces that metabolic evaluations should be conducted in all patients with dystonia and choreoathetotic movements, which may be mimicked by symptomatic hypocalcemia.
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FOOTNOTES |
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Address correspondence to Aida N. Lteif, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail: lteif.aida{at}mayo.edu
No conflict of interest declared.
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This article has been cited by other articles:
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  H. JUPPNER, A. LINGLART, L. F. FROHLICH, and M. BASTEPE Autosomal-Dominant Pseudohypoparathyroidism Type Ib is Caused by Different Microdeletions Within or Upstream of the GNAS Locus Ann. N.Y. Acad. Sci., April 1, 2006; 1068(1): 250 - 255. [Abstract] [Full Text] [PDF]
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 M. Bastepe and H. Juppner Pseudohypoparathyroidism, Gs{alpha}, and the GNAS Locus IBMS BoneKEy, December 1, 2005; 2(12): 20 - 32. [Full Text] [PDF]
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