A Case of Pseudohypoparathyroidism Misdiagnosed as Idiopathic Epilepsy for 5 Years: Clinical Analysis and Follow-up Outcomes

Abstract

We report a 15-year-old Chinese girl who presented with intermittent seizure episodes and had been misdiagnosed as having idiopathic epilepsy 5 years previously. Laboratory testing revealed hypocalcemia, hyperphosphatemia, and a high parathyroid hormone (PTH) concentration. She was subsequently shown to have pseudohypoparathyroidism type Ib (PHPIb) based on the results of methylation analysis of the GNAS gene, which showed a loss of methylation of the differentially methylated regions (DMR) of GNAS-AS1, GNAS-XL, and GNAS-A/B; and a gain of methylation of the DMR of the GNAS-NESP55 region. We adjusted the patient’s medication by prescribing calcium and calcitriol supplements, and gradually reduced the doses of antiepileptic drugs, until they had been completely discontinued. As a result, the patient did not experience any further seizures or epileptiform symptoms; and had normal plasma calcium, phosphorus, and 25-hydroxyvitamin D concentrations and 24-hour urinary calcium excretion. In addition, her PTH concentration gradually normalized over 12 months, and no urinary stones were found on ultrasonographic examination. In conclusion, the clinical presentation of PHP is complex, and the condition is often misdiagnosed. The diagnosis and follow-up of the present patient have provide valuable insights that should contribute to informed clinical decision-making and the implementation of appropriate treatment strategies.

Introduction

Pseudohypoparathyroidism (PHP) is a rare hereditary endocrine disease characterized by resistance to parathyroid hormone (PTH) due to mutations or epigenetic defects of the GNAS gene, which encodes the stimulatory G-protein alpha subunit (Gsα) that binds to the PTH receptor. ¹ Such mutations impair PTH signaling and its effects, leading to disorders of calcium and phosphorus metabolism, specifically hypocalcemia, hyperphosphatemia, and high circulating PTH concentration. The hypocalcemia manifests clinically as greater neuromuscular excitability, in the form of numbness or tingling in the distal extremities or around the mouth, muscle spasms, and in some severe cases, epileptic seizures. In addition, mutations of the GNAS gene cause features of Albright’s hereditary osteodystrophy (AHO), including short stature, obesity, round face, brachydactyly, malformed toes, and ectopic ossification. ² Because defects in the GNAS gene can affect the activity of other G protein-coupled receptors in the thyroid, gonads, and pituitary, patients often develop hormone resistance.^3,4 PHP exists in several types, but PHP types Ia (PHPIa) and Ib (PHPIb) are most common, and the clinical presentations of these types vary. Patients with PHPIa generally present with features of AHO and frequently show resistance to other hormones; whereas those with PHPIb typically lack evidence of skeletal abnormalities and manifestations of hormone resistance, which render it more subject to misdiagnosis. ⁵ Here, we report the clinical findings and outcomes of a 15-year-old girl with PHP that was identified as PHPIb on the basis of methylation analysis of her GNAS gene, but whose disease had been misdiagnosed as idiopathic epilepsy 5 years previously.

Case report

A 15-year-old Chinese girl who presented with general stiffness and twitching of the limbs had been referred to her local hospital several times during the preceding 5 years. Electroencephalography (EEG) revealed benign childhood epilepsy with centro-temporal spikes (BECT) and focal spike-slow waves, but no obvious abnormalities were identified on cranial magnetic resonance imaging (MRI). Cerebrospinal fluid examination revealed no abnormalities, and the patient was negative for antibodies to an epitope that is associated with autoimmune encephalitis. Accordingly, the girl was diagnosed with idiopathic epilepsy and treatment with antiepileptic drugs was instituted. However, the treatment regimen was not effective, and the patient continued to have intermittent seizures. Therefore, she was referred to the Department of Neurology at our hospital in May 2022 for further consultation and treatment.

On physical examination, the patient weighed 46 kg and was 157 cm tall. A neurological examination was unremarkable, and video EEG indicated no interictal epileptiform discharges. Laboratory investigation revealed hypocalcemia (1.83 mmol/L), hyperphosphatemia (1.91 mmol/L), a high circulating PTH concentration (542.1 pg/mL), and a low 24-hour urinary calcium (1.25 mmol/24 hours). However, liver enzyme activities; renal function; and the plasma concentrations of glucose, magnesium, potassium, sodium, vitamin D, sex hormones, thyroid hormones, and growth hormone were all within their normal ranges.

Ultrasonography and emission computerized tomography of the parathyroid demonstrated no abnormalities, as did ultrasonography of the kidney and urinary tract. Cranial computed tomography (CT) imaging revealed multiple foci of calcification at the cuticomedullary junction and in the basal ganglia in both cerebral hemispheres (Figure 1). After a consultation with an endocrinologist, the patient was transferred to the Department of Endocrinology.

Figure 1.

Cranial computed tomography image, showing the presence of multiple foci of calcification at the corticomedullary junction and in the basal ganglia of both cerebral hemispheres of the patient. A, anterior; P, posterior.

On the basis of this clinical information, the leading causes of hypocalcemia, including rickets, hypomagnesemia, tubulopathies, and gastrointestinal diseases, were excluded and a diagnosis of PHP was considered. The patient had no known family history of similar symptoms, her parents had no features of AHO, and blood testing of her parents showed normal calcium, phosphate, and PTH concentrations.

PHP is a rare hereditary disease that is associated with GNAS gene mutations or epigenetic alterations at the GNAS locus. However, the patient had not undergone electrolyte testing during the preceding 5 years; therefore, we could not confirm whether her epileptiform symptoms were caused by hypocalcemia alone or if they were caused by hypocalcemia in concert with idiopathic epilepsy. Indeed, idiopathic epilepsy is also a genetically determined disorder. Therefore peripheral blood samples from the patient and her parents were sent for the analysis of epilepsy-related genes, the GNAS gene sequence, and GNAS gene methylation. Whole-exon sequencing (WES) analysis revealed no pathogenic mutations in the exons of epilepsy-related genes or the GNAS gene, but abnormalities of GNAS gene methylation were identified, including a loss of methylation (LOM) in the differentially methylated regions (DMRs) of GNAS-AS1, GNAS-XL, and GNAS-A/B; and a gain of methylation (GOM) in the DMR of the GNAS-NESP55 region (Figure 2). Thus, the genetic analysis confirmed the diagnosis of PHP and facilitated a classification of her disease as the PHPIb type. Because no gene mutations were identified, it was not necessary to sequence the epilepsy-related genes or GNAS genes of her parents.

Figure 2.

GNAS gene sequence and GNAS gene methylation map of the patient. (a) The GNAS gene sequence of the patient, showing no mutations and (b) The GNAS gene methylation map of the patient, demonstrating a loss of methylation in the differentially methylated regions (DMRs) of GNAS-AS1, GNAS-XL, and GNAS-A/B (red circle), and a gain of methylation in the DMR of the GNAS-NESP55 region (blue circle). SLC9A2 and FHIT served as non-methylated negative control probes (arrows pointing to the orange and white areas). The blue backgrounds represent the areas of the target sequence, and the gray background indicates the reference sequence. Multiplex ligation-dependent probe amplification and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) were used for the analysis of the GNAS gene sequence and GNAS methylation, respectively. Calculations of the appropriate ratios were made using the strength of the detection signal, and ratios of 0.7 (red horizontal line) to 1.3 (blue horizontal line) are considered to be normal in panels A and B. Ratios >1.3 are suspected to indicate duplication, and those <0.7 are suspected to indicate deletion. In addition, the presence of blue dot annotations (in the blue circle) indicate differences in gene methylation status detected during the MS-MLPA analysis, in comparison to the normal condition, thereby revealing regions of DNA with a high level of methylation.

After the diagnosis of PHPIb had been made, we adjusted the patient’s treatment plan, introducing oral calcium and calcitriol (1, 25-(OH)₂D₃) treatment. In addition, we gradually reduced the doses of her antiepileptic drugs until they had been discontinued. At the time of writing, the progress of the patient has been followed for 12 months, and medication used and the results of her examinations are shown in Table 1. Initially, calcium carbonate was prescribed at a dose of 1.0 g twice a day for calcium supplementation, and calcitriol tablets were provided at a dose of 0.25 μg twice a day to regulate calcium and phosphorus metabolism. One month later, her plasma calcium concentration had increased from 1.83 mmol/L to 2.39 mmol/L, and her 24-hour urinary calcium excretion had increased from 1.25 mmol/24 hours to 2.56 mmol/24 hours. Based on these findings, the dose of calcium carbonate was adjusted to 1.5 g/day, divided into three equal doses of 0.5 g each, while the level of administration of calcitriol was maintained at the same dose. After a further 2 months, her plasma calcium concentration had decreased to 2.25 mmol/L and her 24-hour urinary calcium excretion had decreased to 2.39 mmol/24 hours; therefore, her medication was not further adjusted. After 6 months, the patient’s plasma calcium, phosphorus, and 25-hydroxyvitamin D concentrations, and her urinary calcium excretion, had all returned to normal. Her PTH concentration remained high but showed a gradual decrease, such that it was normal after 12 months, and the other measured parameters remained within their normal ranges. Although data for time points beyond 12 months were not available at the time of writing, the dose of calcitriol (1, 25-(OH)₂D₃) was decreased to 0.25 μg once a day to maintain the patient’s PTH concentration at the upper end of the normal range, or slightly high, to avoid a reduction in calcium reabsorption in the distal renal tubules, which can lead to an increase in urinary calcium excretion and the associated renal complications. During the follow-up period, the patient remained free of seizures. No adverse effects related to the medication were reported and ultrasonographic examination did not reveal any urinary system stones.

Table 1.

Comparison of the patient’s laboratory results before and after the adjustment of the medication.

	Baseline	1 month	3 months	6 months	12 months	Reference range
Plasma calcium (mmol/L)	1.83	2.39	2.25	2.43	2.50	2.10–2.50
Plasma phosphorus (mmol/L)	1.91	1.72	1.60	1.71	1.57	0.93–1.61
24-hour urinary calcium (mmol/24 hours)	1.25	2.56	2.39	2.50	2.55	2.5–2.7
Parathyroid hormone (pg/mL)	542.1	159.3	189.8	127.0	68.5	18.5–88.0
25-hydroxyvitamin D (nmol/L)	50.54	52.65	53.32	57.08	77.09	<37.5: deficiency, 37.5–50: insufficiency, 50–250: sufficiency
Medication	Calcium carbonate 2.0 g/day; Calcitriol 0.5 μg/day	Calcium carbonate 1.5 g/day; Calcitriol 0.5 μg/day	Calcium carbonate 1.5 g/day; Calcitriol 0.5 μg/day	Calcium carbonate 1.5 g/day; Calcitriol 0.5 μg/day	Calcium carbonate 1.5 g/day; Calcitriol 0.5 μg/day	–

The patient’s family provided their informed consent for her treatment and for the publication of the present case report. All the details of the patient have been de-identified in the manuscript. The reporting of this study conforms to the CARE guidelines. ⁶

Discussion

PTH is secreted by the parathyroid glands and plays a crucial role in calcium homeostasis by having effects in various organs and tissues. It increases plasma calcium concentration by stimulating the release of calcium from bones, enhancing calcium absorption in the intestines, and reducing its excretion by the kidneys. It also promotes the conversion of vitamin D to its active form, which further aids in calcium absorption. Overall, PTH plays a vital role in ensuring a physiologically appropriate supply of calcium.

PHP is a rare endocrine disorder that is characterized by target organ resistance to PTH, which leads to hypocalcemia, hyperphosphatemia, and an increase in circulating PTH concentration, in the presence of normal renal function. The common subtypes of PHP are PHPIa and PHPIb, and the GNAS gene sequence and methylation pattern can be used to determine the subtype of PHP. ⁷ The GNAS gene is the principal gene associated with PHP and is located on chromosome 20q13. Gsα, which is the primary product of the GNAS gene, is a key component of the Gsα-cAMP-PKA signaling pathway, which activates the various biological processes associated with PTH. ⁸ This signaling pathway also regulates the secretion and activity of other hormones, such as thyroid-stimulating hormone, gonadotropins, and growth hormone-releasing hormone.^9,10 Genetic sequence analysis of patients with PHPIa has revealed mutations in the GNAS gene, whereas PHPIb is characterized by abnormalities in the methylation of the GNAS locus. In patients with PHPIb, the expression of Gsα is specifically impaired in the renal cortex, but is normal in other tissues. ¹¹ As a result, patients often show abnormal PTH function but normal bone development. In the present patient, the genetic analysis revealed methylation defects in the GNAS gene in the form of LOMs in the DMRs of GNAS-AS1, GNAS-XL, and GNAS-A/B and a GOM in the DMR of the GNAS-NESP55 region. ¹² On physical examination, she did not exhibit any signs of AHO, and there were no signs of other types of hormone resistance other than PTH resistance. These findings were consistent with the diagnosis of PHPIb.

Hypocalcemia can cause epileptic seizures because it increases the excitability of the neuromuscular system. Theoretically, any type of epileptic seizure can be recorded using EEG during seizure episodes or interictal periods. On the basis of the EEG conducted at the patient’s local hospital during the preceding 5 years, which showed childhood epilepsy with BECT, she was prescribed antiepileptic medication. The negative EEG findings at subsequent examinations conducted at our hospital may be explained by her use of antiepileptic drugs, which suppress epileptic discharges in the brain.

Chronic hypocalcemia with hyperphosphatemia can cause the aberrant deposition of calcium and phosphorus in the form of ectopic calcification. ¹³ Previous studies have shown that ectopic calcification occurs in the majority of patients with PHP, and that intracranial calcification of the nervous system, particularly in the bilateral basal ganglia, is the most common manifestation. ¹⁴ Cranial CT imaging showed multiple foci of calcification in the cuticomedullary junction and basal ganglia of both cerebral hemispheres, which is consistent with the manifestations of the disease.

PHP is an incurable genetic disorder that requires lifelong treatment with calcium and vitamin D preparations, which is similar to the therapy of hypoparathyroidism except that the doses required are usually higher than those for true hypoparathyroidism. ¹⁵ This is because the defect in PHP is partial and distal renal tubular function is not affected. ¹⁶ The objectives of treatment are to control symptoms and to normalize or near-normalize plasma calcium concentrations to prevent the formation of urinary stones secondary to hypercalciuria and avoid vitamin D toxicity.

If acute symptoms of hypocalcemia develop, such as tetany, laryngospasm, convulsions, or epileptic seizures, 10% calcium gluconate should be administered intravenously at a dose of 10 to 20 mL to alleviate these symptoms. During asymptomatic episodes of hypocalcemia, the oral administration of calcium supplements and vitamin D preparations is recommended. Calcium supplements should be taken over the long term, and calcium carbonate is the preferred form. Calcitriol (1, 25-(OH)₂.D₃) is the most commonly used vitamin D preparation because there is a deficiency in renal 1α-hydroxylase activity in patients with PHP, which impairs the conversion of 25-(OH)-D₃ to the active form, 1, 25-(OH)₂.D₃. ¹⁷ Calcitriol promotes calcium absorption from the intestines, thereby increasing the plasma calcium concentration, and inhibits PTH release. When the plasma calcium concentration increases, the renal phosphate threshold decreases, leading to an increase in urinary phosphate excretion and a subsequent decrease in the plasma phosphate concentration. Therefore, phosphorus-lowering treatments are generally unnecessary. In addition, some patients with PHP1b may develop overt hyperparathyroid bone disease owing to chronically high PTH concentrations. ¹⁸ Therefore, it is recommended that PHPIb is treated using appropriate doses of calcium and vitamin D preparations with the intention of achieving PTH concentrations within or as close to the normal range as possible. The maintenance of a PTH concentration below the upper limit of the reference range is also important to enhance calcium reabsorption in the distal renal tubule, thereby helping to prevent hypercalciuria. ¹⁵ If patients with PHP also demonstrate hypofunction of other hormones, the corresponding hormone replacement therapy should also be provided. ¹⁹

In the present patient, after a diagnosis of PHPIb had been made, calcium carbonate and calcitriol supplementation were commenced, her antiepileptic drugs were gradually discontinued, and no more epileptiform seizures occurred. Her plasma calcium, phosphorus, PTH, and 25-hydroxyvitamin D concentrations; 24-hour urinary calcium excretion; and urinary ultrasonographic findings were regularly reviewed and the drug dosage was adjusted accordingly. By the time of the 12-month follow-up examination, the patient’s plasma calcium, phosphorus, 25-hydroxyvitamin D, and PTH concentrations had all normalized. This may be attributed to the patient’s relatively mild condition and indicates the potential reversibility of the abnormal PTH concentration that characterizes this disease. However, it should be noted that these findings do not imply a complete cure but rather appropriate control of the condition. Finally, no stones were identified on urinary tract ultrasonography.

In summary, it is essential for clinicians to recognize the significance of symptoms associated with hypocalcemia, hyperphosphatemia, and high PTH concentrations in young patients. A diagnosis of PHP can be confirmed, and the specific subtype identified, through analysis of the GNAS gene sequence and its methylation status. By identifying and managing the symptoms promptly, clinicians can help enhance the overall well-being of patients with PHP. However, the patient had only been followed for 1 year at the time of writing, and therefore the subsequent effects of treatment require monitoring.