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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 12 5942-5947
Copyright © 2004 by The Endocrine Society

CLINICAL CASE SEMINAR

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

Elena Laspa, Murat Bastepe, Harald Jüppner and Agathocles Tsatsoulis

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.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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 {alpha}-subunit of the stimulatory G protein (Gs{alpha}). 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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
DIFFERENT FORMS OF pseudohypoparathyroidism (PHP) are caused by heterozygous mutations affecting GNAS, the gene encoding stimulatory G protein (Gs{alpha}). Maternally inherited mutations in one of the 13 GNAS exons encoding Gs{alpha} cause PHP type Ia (PHP-Ia), a disorder characterized by Albright’s hereditary osteodystrophy (AHO), i.e. physical features that include obesity, short stature, brachydactyly, ectopic calcification, and mental retardation. Affected individuals also show resistance to hormones that act through Gs{alpha}-coupled receptors, particularly resistance to PTH and thus hypocalcemia and hyperphosphatemia (1, 2, 3, 4). When the same Gs{alpha} mutations are inherited paternally, affected individuals develop AHO in the absence of hormone resistance; this condition is referred to as pseudopseudohypoparathyroidism (PPHP) (1, 2, 3). Thus, the development of hormone resistance in a patient with a Gs{alpha} mutation is subject to paternal imprinting, i.e. it develops only after maternal transmission (3, 5).

PHP-Ib is another form of PHP, but in contrast to PHP-Ia/PPHP, affected individuals show no features of AHO (1, 6). In most patients with PHP-Ib, Gs{alpha} mutations have not been found, but the autosomal dominant form of the disorder (AD-PHP-Ib) has been genetically linked to the GNAS locus on chromosome 20q13.3 (6, 7, 8), and similar to kindreds with PHP-Ia and PPHP, the pattern of inheritance is consistent with paternal imprinting at this locus (7). Furthermore, all affected individuals with AD-PHP-Ib show a loss of GNAS exon A/B methylation (9, 10), and analysis of multiple unrelated AD-PHP-Ib kindreds has recently led to the identification of a heterozygous, approximately 3-kb microdeletion located within STX16 approximately 220 kb centromeric of GNAS exon A/B (11).

Hormonal resistance in PHP-Ib is usually limited to the PTH-dependent actions in proximal renal tubules and possibly a few other tissues, such as the thyroid, in which Gs{alpha} is paternally imprinted (12, 13, 14, 15). As a consequence of reduced or absent Gs{alpha} expression in the renal proximal tubules, PTH-mediated inhibition of phosphate reabsorption and stimulation of 1{alpha}-hydroxylase activity are usually impaired, explaining the typical biochemical and clinical findings in these patients (1, 6, 16). In contrast, PTH-dependent calcium reabsorption in the distal tubules and the skeletal effects of PTH appear to be normal in PHP-Ib. We now present clinical, biochemical, and genetic aspects of a Greek AD-PHP-Ib kindred, and we demonstrate that this disorder may also be associated with hypouricemia due to impaired tubular urate reabsorption and the consequential increase in fractional urate excretion.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Case presentation

The proband (see also Ref.11 , code T2) was admitted to the emergency room with convulsions as the first presentation of the disease at the age of 26 yr and was found to have hypocalcemia with serum calcium of 6.5 mg/dl [1.62 mmol/liter; normal, 8.2–10.6 mg/dl (2.05–2.65 mmol/liter)] and hyperphosphatemia with serum phosphate of 5.2 mg/dl [1.67 mmol/liter; normal, 2.5–5.0 mg/dl (0.8–1.6 mmol/liter)]. Treatment with iv calcium and subsequently with calcium carbonate (1500 mg/d) and calcitriol (2 µg/d) resulted in symptomatic improvement. It was initially thought that the patient might have primary hypoparathyroidism because his mother had a history of organ-specific autoimmunity, including Hashimoto’s thyroiditis, B12 deficiency, and vitiligo. The diagnosis was refuted, however, after the laboratory report of elevated serum PTH of 470 pg/ml [50.1 pmol/liter; normal, 12–72 pg/ml (1.28–7.68 pmol/liter)]. The patient’s height and weight were 173 cm and 75 kg, respectively, and there were no clinical features of AHO. The serum TSH concentration was 2.53 mIU/liter (normal, 0.5–4.8 mIU/liter) with free T4 of 0.84 ng/dl [10.8 pmol/liter; normal, 0.70–1.85 ng/dl (9.0–23.8 pmol/liter)] and negative antithyroid antibodies. The rest of the routine laboratory tests, including complete blood count, serum creatinine and electrolytes, blood urea nitrogen, and liver function tests, were normal.

To further clarify the diagnosis, treatment with calcium and vitamin D was temporarily discontinued, and additional testing was performed. Interestingly, the patient remained eucalcemic, with serum calcium levels of 8.4 mg/dl (2.1 mmol/liter) and 8.3 mg/dl (2.07 mmol/liter) for almost 6 months and delayed his appointment for reevaluation. On reexamination, the patient’s serum calcium had dropped to 7.8 mg/dl (1.95 mmol/liter), serum phosphate was 4.4 mg/dl (1.42 mmol/liter), and PTH was again high at 653 pg/ml (69.6 pmol/liter). Serum 25-hydroxyvitamin D [25(OH)D] was normal at 31.3 ng/ml [78.1 nmol/liter; normal, 10–40 ng/ml (25–100 pmol/liter)], but 1,25-dihydroxyvitamin D [1,25(OH)2D] was low at 7.4 pg/ml [17.7 pmol/liter; normal, 12–40 pg/ml (25–100 nmol/liter)]. Serum alkaline phosphatase was normal at 45 IU/liter (normal range, 30–125 IU/liter). A bone density scan at the lumbar spine revealed a mild degree of osteopenia (T-score, –0.9), and on this occasion, serum uric acid was also measured and was found to be low at 2.6 mg/dl [0.15 mmol/liter; normal, 3.5–7.2 mg/dl (0.2–0.4 mmol/liter)]. A diagnosis of PHP-Ib was made.

Additional screening of the extended kindred (four generations, 13 members; see Fig. 1Go) was undertaken, and blood samples for biochemical and genetic analyses were obtained. The proband’s mother (aged 52 yr), sister (aged 28 yr), and sister’s son (aged 6.5 yr) were asymptomatic, but had evidence of PTH resistance with normal/low normal serum calcium, normal/high normal serum phosphate, and elevated PTH levels (Fig. 1Go). These parameters were normal in the rest of the family members. A bone density scan at the lumbar spine on the proband’s mother also showed mild osteopenia (T-score, –1.35), although she was not yet menopausal.



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  		FIG. 1. The AD-PHP-Ib kindred: age at presentation and laboratory and genetic findings are presented. Circles represent females, and squares represent males. Affected members are indicated by solid black symbols and bold numbers; obligate carriers are shown by striped symbols and bold-italic numbers; unaffected individuals are indicated by solid white symbols and Roman numbers; unaffected individuals carrying disease-associated haplotypes are shown by stippled symbols and italic numbers. The disease-associated haplotype for chromosome 20q13.3 markers is highlighted by shading and bold numbers. Note that based on Southern blot analysis using methylation-sensitive restriction enzymes, GNAS methylation abnormalities in affected individuals are confined to the differentially methylated region at exon A/B. All affected individuals and all obligate carriers revealed the 3-kb deletion 220 kb upstream of exon A/B (21 ). Laboratory results from the affected individuals were obtained at diagnosis. Adult normal laboratory values are shown in parentheses. The pediatric normal range for serum phosphate is 4–7 mg/dl, and that for alkaline phosphatase is 100–320 IU/liter (for comparison of data for subject IV-I). Conversion factor for levels of PTH in picograms per milliliter to picomoles per liter, 0.1067; for serum calcium in milligrams per deciliter to millimoles per liter, 0.25; for serum phosphate in milligrams per deciliter to millimoles per liter, 0.323; for 1,25(OH)2D in picograms per milliliter to picomoles per liter, 2; and for 25(OH)D in nanograms per milliliter to millimoles per liter, 2.496.

 
To further clarify the finding of hypouricemia in the proband and to assess the overall effect of PTH resistance on renal anion handling and acid-base balance, additional tests were undertaken in the affected members of the family under a standardized diet. These tests included the estimation of fractional and 24-h renal excretion of uric acid, fractional excretion, and tubular reabsorption of phosphate (TmP) together with arterial blood gases and a renal ultrasound. Informed consent from the patients and approval from the hospital ethics committee were obtained for the genetic analysis and the biochemical tests.

Genetic analysis

DNA was extracted from peripheral blood leukocytes for genetic analysis. The methods used for genotyping and genetic linkage analysis to the 20q13.3 region, methylation analysis of GNAS, detection of the 3-kb microdeletion within STX16, and sequence analysis of the region were described previously (10, 11).

Biochemical methods

Serum calcium, phosphate, uric acid, creatinine, and electrolytes and urinary calcium, phosphate, creatinine, and urate were measured with an Olympus Clinical Chemistry Analyzer (Olympus Diagnostics, Hamburg, Germany). A standard formula was used for calculating fractional excretion of uric acid, calcium, and phosphate. Normal excretion of uric acid in adults is less than 750 mg/d in woman and less than 800 mg/d in man (17). In hypouricemic subjects, a fractional urate excretion of more than 10% was considered inappropriate uricosuria (18). Fractional excretion of calcium and phosphate more than 3% and 20%, respectively, were considered as indications of inappropriate urinary wasting of these two minerals (19). The tubular maximum reabsorption of phosphate over the glomerular filtration rate (TmP/GFR) was calculated according to the nomogram of Walton and Bijvoet (20) after obtaining a 2-h fasting urine measurement for phosphate and creatinine with simultaneous serum phosphate and creatinine determinations. The normal adult range for TmP/GFR is 2.5–4.2 mg/dl (0.16–1.35 mmol/liter) (20). Intact PTH in serum was measured by a solid phase, two-site chemiluminescent enzyme-labeled immunometric assay with IMMULITE 2000 Analyzer (Diagnostic Products Corp., Los Angeles, CA). The intra- and interassay coefficients of variation of this method were 4.2% and 8.8%, respectively. The serum concentrations of the vitamin D metabolites 25(OH)D and 1,25(OH)2D were measured by radioligand assays using human D-binding protein for 25(OH)D and calf thymus receptor (Incstar, Inc., Stillwater, MN) for 1,25(OH)2D. Before the assay determinations, the metabolites were partially purified by Sep-Pak C18 chromatography and then separated by HPLC. Tritiated (3H) labels from Amersham Biosciences (Little Chalfont, UK) were used for the assays. The unlabeled vitamin D metabolites were donated by Hoffmann-La Roche (Basel, Switzerland). The methods used were adapted from those of Shepard et al. (21) and Reinhardt et al. (22). The intra- and interassay coefficients of variation were 7.8% and 10.5% for 25(OH)D and 6.5% and 8.7% for 1,25(OH)2D, respectively. Serum TSH and free T4 were determined by a microparticle enzyme immunoassay using the AXSYM system (Abbott Laboratories, Inc., Chicago, IL). The reference range for TSH was 0.5–4.8 mIU/liter. Bone mineral density was measured at the lumbar spine (L2–L4) by dual energy x-ray absorptiometry using a Norland XR26 Mark II instrument (Norland Medical Systems, Inc., Fort Atkinson, WI).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Genetic analyses

Genetic linkage analysis of the extended kindred using previously described microsatellite markers (10, 11) suggested linkage to the GNAS locus on chromosome 20q13.3 (Fig. 1Go). Consistent with this finding, genomic DNA for affected individuals showed loss of methylation at GNAS exon A/B, but no abnormalities at the promoters of this locus (data not shown). Furthermore, the previously identified heterozygous 3-kb microdeletion within STX16 was present in all affected members and obligate carriers (11).

Biochemical findings

The results for serum calcium, phosphate, vitamin D metabolites, and PTH concentrations, which were obtained for most members of the kindred, are shown in Fig 1Go. Apart from the proband, the other three affected members had low normal or normal serum calcium, normal serum phosphate, low serum 1,25(OH)2D with normal 25(OH)D, and elevated serum PTH levels. All healthy family members had normal values for these parameters. Urinary fractional excretion of calcium and phosphate, TmP/GFR, and acid-base balance in the affected family members are shown in Table 1Go. Fractional excretion of calcium was at the low normal range, as was the fractional excretion of phosphate, whereas the TmP/GFR was normal. Arterial pH and bicarbonate levels were also normal. Renal function and morphology, as assessed by serum creatinine levels and renal ultrasound (in the adult affected members), and serum chloride levels were also normal (results not shown).


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  		TABLE 1. Fractional renal excretion of calcium (%FE-Ca), phosphate (%FE-P), TmP/GFR, HCO3–, and arterial pH values in several patients with AD-PHP-Ib

 
Serum uric acid levels in affected members, obligate carriers, and healthy members together with fractional and 24-h renal urate excretion in the affected members are shown in Table 2Go. All four affected members had low serum uric acid levels compared with the obligate carriers and healthy family members, in whom uric acid levels were within the normal range. In addition, the affected members had increased fractional urate excretion (>10%), which is inappropriate uricosuria for the prevailing serum uric levels; however, absolute 24-h uric acid excretion was within the normal range. Hypouricemia in the affected members was consistently observed in several measurements and was not affected by treatment (results not shown).


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  		TABLE 2. Serum uric acid concentrations and fractional renal excretion of urate (%FE urate) in the affected and unaffected members of the PHP-Ib kindred compared with normal laboratory values

 
The results of thyroid function indexes are shown in Table 3Go. The proband’s mother had autoimmune hypothyroidism and was therefore receiving replacement therapy with L-T4 (150 µg/d); all other affected members had high normal serum TSH levels, whereas free T4 levels were normal/low normal in the absence of antithyroid antibodies and thyroid enlargement.


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  		TABLE 3. Serum thyroid function indexes in AD-PHP-Ib patients

 

   Discussion
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Similar to previous reports, the severity of the disorder in this Greek family with AD-PHP-Ib varied among the affected members, who all showed the recently identified 3-kb deletion within STX16 (6, 11, 16). In fact, the proband was the only affected member with clinical symptoms. This is indicative of variation in the onset of symptomatic hypocalcemia among PHP-Ib patients, which is probably related to unimpaired PTH actions in kidney and bone that contribute importantly to mineral ion homeostasis. For example, PTH acts on the distal portions of the nephron, where it minimizes urinary calcium losses (23), as was observed in the AD-PHP-Ib family presented. Furthermore, PTH acts on bone, where it increases osteoblast activity and, through the RANKL/RANK (receptor activator of NF-{kappa}B ligand/receptor activators of NF-{kappa}B) system, osteoclastic bone resorption, thus leading to mobilization of calcium (and phosphate) (24). Data from animal studies and human cell lines indicate that Gs{alpha} signaling is intact in distal nephron and bone (13, 25). Thus, distinct mechanisms involving bone and distal renal tubules can compensate, at least partially, for the impaired proximal tubular actions of PTH, thereby delaying the development of symptomatic hypocalcemia. The importance of these mechanisms is underlined by observations in the proband, who had remained eucalcemic for almost 6 months after discontinuation of treatment with calcium and vitamin D.

In the proximal renal tubules, PTH normally limits phosphate reabsorption by regulating sodium phosphate cotransporter type IIa expression and degradation through cAMP-dependent and -independent pathways (26, 27). In addition, it increases 1{alpha}-hydroxylase activity, thereby facilitating the synthesis of 1,25(OH)2D, which, in turn, enhances intestinal calcium (and phosphate) absorption (28). Interestingly, in most affected members of our AD-PHP-Ib kindred, serum phosphate levels remained at the upper limit of the normal range. Furthermore, fractional phosphate excretion was maintained within the normal/low normal range, and TmP was not detectably altered (Table 1Go.). This suggests that diminished expression of other sodium phosphate cotransporters (29) may result in increased renal phosphate excretion through PTH-independent mechanisms, thus compensating, to some extent, for the lack of PTH-dependent mechanisms involving sodium phosphate cotransporter type IIa.

In contrast to the lack of readily detectable major changes in renal phosphate handling, serum 1,25(OH)2D concentrations were low in all affected individuals despite normal/high normal 25(OH)D levels, confirming that PTH is indeed an important regulator of the 1{alpha}-hydroxylase in the proximal renal tubules, and that these actions are cAMP mediated (30). It remains uncertain whether other hormones, such as FGF-23, a recently identified phosphaturic factor that reduces 1{alpha}-hydroxylation of 25(OH)D through as yet unknown mechanisms (31), is elevated in AD-PHP-Ib and thus may contribute to the diminished concentrations of 1,25(OH)2D in this disorder.

Another proximal tubular function that is at least partially PTH-dependent includes inhibition of bicarbonate reabsorption (32), and this was apparently not affected because none of our AD-PHP-Ib patients had obvious changes in acid-base balance and serum chloride levels. In contrast, primary hyperparathyroidism is associated with hyperchloremic acidosis (33). The lack of such a response to increased PTH in our patients provides indirect evidence for the conclusion that Gs{alpha} imprinting may also involve those cells in the proximal renal tubules mediating PTH-dependent inhibition of bicarbonate reabsorption.

Recent studies have shown that Gs{alpha} expression from the maternal allele alone occurs not only in the proximal renal tubules, but also to some extent in the thyroid gland (14, 15). Consequently, Gs{alpha} mutations or impaired expression of this maternally derived mRNA may lead to the development of mild or moderate TSH resistance in patients with PHP-Ia or PHP-Ib (10, 14, 34, 35). Consistent with these observations, affected members of our AD-PHP-Ib kindred had evidence for TSH resistance, which, however, remained subclinical and therefore did not require treatment. Consistent also with the previous report (14), TSH levels on consecutive measurements were intermittently elevated, indicating that subtle TSH resistance might be missed on single TSH measurements.

In addition to changes in the regulation of calcium and phosphate homeostasis discussed above, PTH resistance in the AD-PHP-Ib kindred we studied appears to have led to perturbations in uric acid excretion, which have not been previously reported. Hypouricemia is a term that has been arbitrarily defined without physiological or clinical correlates and is usually considered to be a serum uric acid concentration between 1.5 and 4 mg/dl (0.08–0.23 mmol/liter) (17). In humans, uric acid is the end product of purine metabolism, and the kidneys play a predominant role in its elimination. Uric acid is secreted and reabsorbed along the proximal tubules, with little or no transport in the distal tubules. Most of the filtered uric acid is reabsorbed, and its fractional excretion approximates only 10% (18, 36).

Little is known about the role of PTH in renal urate handling. Primary hypoparathyroidism has been reported as a disease associated with increased fractional excretion of urate (37). Consistent with this finding, patients with primary hyperparathyroidism show hyperuricemia, which is corrected after successful parathyroidectomy (38, 39). These findings together with those observed in the AD-PHP-Ib kindred we studied suggest that PTH may affect uric acid excretion in the proximal renal tubules. A urate-anion exchanger (URAT1, encoded by SLC22A12) that is predominantly expressed in epithelial cells of the proximal renal tubules and involved in the regulation of the serum uric acid concentration has been recently identified (40), and based on our findings, it appears plausible that PTH could have a role in regulating URAT1 activity and/or its expression.

In conclusion, because of the variability in clinical and biochemical findings, particularly with regard to calcium-phosphate homeostasis, mildly affected members in AD-PHP-Ib kindreds may not be readily identified. Epigenetic analysis of the differentially methylated GNAS exon A/B and search for the 3-kb microdeletion upstream of this region can help in establishing the diagnosis of AD-PHP-Ib. Documenting the presence of this deletion in a patient’s mother and then extending the molecular investigations to all family members could be helpful in preventing potentially harmful, hypocalcemia-related complications in other, not yet clinically affected members. Hypouricemia due to inappropriately increased fractional excretion of urate appears to be a novel finding in AD-PHP-Ib, which suggests that the renal handling of uric acid excretion is at least partially PTH- and cAMP-dependent. However, the clinical relevance of this latter finding remains uncertain and requires additional investigations.


   Footnotes
 
Abbreviations: AD, Autosomal dominant; AHO, Albright’s hereditary osteodystrophy; GFR, glomerular filtration rate; Gs{alpha}, {alpha}-subunit of the stimulatory G protein; 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)2D, 1,25-dihydroxyvitamin D; PHP-Ia, pseudohypoparathyroidism type Ia; PPHP, pseudopseudohypoparathyroidism; TmP, tubular reabsorption of phosphate.

Received February 12, 2004.

Accepted September 15, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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