Epileptic seizures and abnormal tooth development as primary presentation of pseudohypoparathyroidism type 1B

Abstract

Pseudohypoparathyroidism (PHP) is a rare genetic disorder characterised by a non-functioning PTH. Usually, the diagnosis is made following (symptomatic) hypocalcaemia. We describe a case in which epileptic seizures and abnormalities in dental development were the main clinical manifestation of PHP type 1B. This case demonstrates the importance of screening for hypocalcaemia in patients with de novo epileptic seizures. In addition, antiepileptic medications themselves may interfere with calcium-phosphate metabolism, causing or aggravating a hypocalcaemia as well. By correcting the calcium level, a resolution of these symptoms could be obtained.

Background

Hypocalcaemia is an infrequent clinical problem, in which patients present with classic symptoms such as paraesthesias, muscle twitching and/or spasm that can be caused by lack of biologically active parathyroid hormone (PTH), that is, hypoparathyroidism (HP) or resistance to PTH, that is, pseudohypoparathyroidism (PHP). However, sometimes it is a coincidental finding. Chronic hypocalcaemia may be associated with cataracts, papilloedema, prolonged Q-T interval, abnormal tooth development and calcifications involving the basal ganglia.¹ We describe an unusual case in which dental and central nervous system complications were the most prominent clinical evidence for hypocalcaemia, which turned out to be caused by an autosomal dominant variant of PHP type Ib (PHP1B), a rare genetic disorder. We would therefore like to raise awareness of the importance of screening for hypocalcaemia in young patients with unexplained epileptic seizures and spastic palsies, especially in the presence of other clinical features such as dental abnormalities that could raise the suspicion of a problem in the calcium–phosphate metabolism.

Case presentation

A patient in his early adolescence was admitted because of severe hypocalcaemia (calcium corrected for albumin was 1.12 mmol/L (normal: 2.10–2.55 mmol/L)), and hyperphosphataemia (2.10 mmol/L; normal: 0.81–1.45 mmol/L) discovered incidentially on routine blood sampling requested by his neurologist. The patient initially did not mention any problems suggestive of low blood calcium level. He was born prematurely at 35 weeks after an uncomplicated pregnancy; delivery was complicated by trauma. His medical history furthermore included an autism spectrum disorder, lactose intolerance and spastic diplegia with incomplete extension of knees since age 6 years, which was thought to be a result of the birth trauma. At the age of 12 years, he was diagnosed with epilepsy for which he was followed through the neurology department and treated with carbamazepin (200 mg two times a day). Growth had been normal. On more thorough questioning, he disclosed frequent cramps of his lower legs as well as his jaws when chewing. The family history was negative for disorders affecting calcium and phosphate regulation. The vital signs were within normal limits, but clinical examination revealed positive Chvostek and Trousseau signs and the ECG showed a prolonged QT-interval.

Investigations

Further laboratory examination revealed an intact PTH level that was three times above the upper limit of the reference range (24.8 pmol/L; normal: 1.59–6.9 pmol/L) with a normal 25-hydroxy-vitamin D3 level (93.6 nmol/L; normal: 50–124.8 nmol/L). Renal function and magnesium level were normal, but alkaline phosphatase was elevated to 244 U/L (normal: 55–149 U/L), and urinary calcium excretion was low at<0.2 mmol/L (with very low urinary calcium/creatinine ratio of 0.003). In addition, TSH was increased slightly (4.8 mU/L; normal: 0.27–4.2 mU/L) with a low-normal free thyroxine (11.3 pmol/L; normal: 11–24.8 pmol/L). MRI of the brain showed prominent hyperintense spots on T1-weighted images at the level of the basal ganglia and thalami (figure 1A, arrows), possibly consistent with calcifications. The orthopantomogram showed small tooth slits as evidence for malocclusion (figure 1B, arrows). Since childhood, he had been treated for orthodontic anomalies and delayed eruption of teeth, particularly his molars. Ultrasonographic examination of the kidneys revealed no evidence for nephrolithiasis or nephrocalcinosis.

Figure 1.

An MRI of the brain showed prominent hyperintense spots on the T1-weighted images at the level of the basal ganglia and thalami (A, arrows), possibly consistent with calcifications. The orthopantomogram showed typical small tooth slits (malocclusion) and delayed tooth eruption, particularly of his molars (B, arrows).

Differential diagnosis

Hypocalcaemia is defined as a serum calcium corrected for albumin <2.2 mmol/L or an ionised calcium<1.1 mmol/L.² In this case, the hypocalcaemia was accompanied by an elevated PTH, reflecting a normal response of the parathyroids to the low serum calcium. This rise in PTH is expected to mobilise calcium from the bone and increase calcium reabsorption in the distal renal tubules as well as the formation of active 1,25-dihydroxy vitamin D3 in the proximal tubules. The differential diagnosis of hypocalcaemia with secondary hyperparathyroidism includes chronic kidney disease or vitamin D3 deficiency, vitamin D3 resistance, PTH-resistance, hypomagnesaemia or hypermagnesaemia, calcium malabsorption or calcium precipitation due to hyperphosphataemia (eg, in case of tumour lysis syndrome, rhabdomyolysis). However, our patient had a normal renal function and vitamin D3 levels, there were no signs of tissue breakdown, and hyperphosphataemia made vitamin D3-resistance unlikely. He was known to have lactose intolerance, which might have played a role in aggravating hypocalcaemia because of reduced intake of calcium-rich foods, although lactose intolerance itself does not seem to impair the calcium absorption.³ The combination of hypocalcaemia and hyperphosphataemia seen in our case is consistent with functional hypoparathyroidism (i.e., PTH deficiency or PTH resistance); however, the elevated PTH level made PTH resistance more likely. Absence of PTH can lead to renal calcium loss despite hypocalcaemia as well as decreased intestinal calcium absorption due to reduced 1,25-dihydroxyvitamin D3 production. The hyperphosphataemia results from impaired PTH-dependent downregulation of NPT2a and NPT2c expression and thus impaired renal phosphate excretion, as well as from increased bone resorption which helps maintain blood calcium levels, but causes also excess mobilisation of phosphate. Overt hyperphosphataemia in our patient was the most important clinical clue to differentiate the aetiology of his hypocalcaemia. Since he was taking carbamazepine, a secondary hypocalcaemia caused by his antiepileptics was hereby ruled out. When renal function is normal, the hypocalcaemia is accompanied by a low-serum phosphate if the PTH response is functioning correctly (as would be the case with carbamazepine-induced hypocalcaemia because of enhanced vitamin D3 metabolism), but high in case of deficiency of biologically active PTH. Carbamazepine-induced hypocalcaemia results from induction of CYP3A4-enzyme which accelerates the conversion of vitamin D3 to its inactive metabolites.⁴ Active vitamin D3 deficiency is characterised by a typically decreased serum phosphate because of the decreased intestinal phosphate absorption and the secondary hyperparathyroidism which increases the urinary phosphate excretion.

In conclusion, based on the biochemical findings, the most likely diagnosis in this young patient was a PTH-resistance syndrome. In PHP, there is a failure of PTH to activate cAMP formation at the PTH/PTHrP receptor (PTH1R), which requires the stimulatory G protein.⁵ Also, the imaging findings in our patient were consistent with PHP. The irregular dental malformations seen on the orthopantomogram are typical for an untreated hypocalcaemia during dental development.⁶ Furthermore, Gαs deficiency or a heterozygous PTH1R mutation can lead to delayed tooth eruption.⁷ The calcifications in the basal ganglia are a consequence of a long-standing hyperphosphataemia due to deficiency of functioning PTH. This diagnosis was confirmed by molecular analysis, which revealed the 3-kb STX16 deletion, which is the most frequent cause of autosomal dominant PHP1B (AD-PHP1B).⁵ This deletion upstream of GNAS on chromosome 20q13.3 causes, when located on the maternal allele, a loss-of-methylation at GNAS exon A/B, which is associated with reduced or absent Gαs expression in the proximal renal tubules and few other tissues or cells.⁵ PHP1B can be associated with resistance to TSH and other hormones that mediate their actions through Gαs-coupled receptors.⁸ In our patient, an incipient subclinical hypothyroidism was present, which did not require substitution. Testosterone level was normal, as were the levels for LH and FSH.

Treatment

The patient was admitted to the intensive care unit for cardiac monitoring while correcting the hypocalcaemia, which could be stabilised with parenteral substitution of up to 6 g calcium gluconate as well as 2 g oral calciumcarbonate daily, achieving a total serum calcium concentration of 1.68 mmol/L (ionised calcium 0.88 mmol/L). Calcitriol 0.5 µg one time a day was added to the therapy. During the remainder of the hospitalisation, parenteral substitution of calcium was difficult to taper off. After carefully increasing the calcitriol to a daily dose of 1.5 µg, closely monitoring phosphate levels, the calcium levels could be stabilised. At discharge, the treatment consisted of 3 g of oral calcium carbonate distributed throughout the day, calcitriol 0.5 µg three times a day and cholecalciferol 25.000 IU per week. Since the seizures were possibly secondary to hypocalcaemia and since there is an interaction between carbamazepine and calcitriol (induction of CYP450 enhances the breakdown of calcitriol in the liver), the carbamazepine was discontinued.

Outcome and follow-up

After 2 months, the cramps and paraesthesias in his legs and jaws were diminished. Our patient was further treated with vitamin D3 (cholecalciferol in addition to calcitriol) and calcium supplements, while monitoring the calcaemia, phosphataemia and urinary calcium excretion every 3 months. After 1 year of follow-up, the calcium carbonate and calcitriol suppletion could gradually be tapered to 1 g calciumcarbonate and 0.25 μg calcitriol daily. During follow-up, serial electroencephalograms were obtained that revealed no focal or epileptiform abnormalities, and there was no need to restart treatment with antiepileptics.

Discussion

This case illustrates the importance of screening for hypocalcaemia in patients diagnosed with epilepsy and stigmata of impaired bone and/or tooth development. Apart from the typical signs of a low extracellular calcium resulting from neuromuscular overexcitability (paraesthesias, spasms, seizures and QTc prolongation), chronic hypocalcaemia can also be associated with abnormal teeth formation or eruption. These dental growth abnormalities lead in this case to widening of the periodontal ligament space (possibly because of increased PTH levels, as this is also well described in primary hyperparathyroidism⁹). Most typical for hypoparathyroidism are hypoplasia of the enamel, hypodontia, as well as a delay of tooth eruption or dental impaction.^{6 10} The hypoplasia of the enamel is thought to be a result of the untreated hypocalcaemia during tooth development.¹⁰ A higher prevalence of enamel hypoplasia and deviation of the root morphology (shortening and blunting of roots) has been described specifically in patients with PHP.¹¹ Seizures in patients with a long-term deficiency of functioning PTH can be caused by hypocalcaemia and basal ganglia calcifications may have contributed to neurocognitive defects.^{12 13} Apart from the cerebral calcifications, extravascular calcium deposits as a consequence of deficient or a non-functional PTH (and resulting hyperphosphataemia and high calcium-phosphate product) can manifest as cataract or papilloedema, as well as renal calcifications.^{1 12}

The diagnostic workup of hypocalcaemia starts with distinguishing aetiology with a high versus low PTH secretion since the regulation of PTH is extremely sensitive for small changes in blood calcium level through the calcium-sensing receptor (CaSR). Secondly alkaline phosphatase and blood phosphate, as well as magnesium level, renal function and 25-hydroxy vitamin D3 need to be measured before starting the calcium supplementation.² Measurement of phosphate is preferably done on a fasting sample since it has a circadian variability and is influenced by food intake.¹⁴ In our case, the hypocalcaemia was accompanied by a high PTH and overtly elevated serum phosphate. Hypocalcaemia with hyperphosphataemia can occur when the phosphate excretion is impaired, in case of impaired renal function or in case of a deficiency in functional PTH. As opposed to hypoparathyroidism, this is accompanied by an elevated (but malfunctioning) PTH in case of end-stage renal disease (when the GFR falls below 15 mL/min/1.73 m²) or PTH resistance. PTH resistance can be caused by pseudohypoparathyrodism, and also severe hypomagnesaemia raises the threshold for PTH secretion at the CaSR.¹⁴ Our patient had an adequate renal function and the plasma magnesium concentration was in the reference range. However, he was chronically treated with carbamazepine, which is known to induce vitamin D3 deficiency thus causing hypocalcaemia.⁴ Long-term therapy with antiepileptic drugs is associated with osteomalacia.¹⁵ A recent meta-analysis¹⁶ found indeed an association between long-term carbamazepine therapy and low-serum calcium, increased alkaline phosphatase, and low vitamin D3level. In addition, some studies suggest that carbamazepine would inhibit the response to PTH and has a direct effect on bone cells and intestinal calcium absorption.^{16 17} In our case, the hyperphosphataemia ruled out a carbamazepine-induced hypocalcaemia as the primary cause, although it is likely that this therapy may have exacerbated the hypocalcaemia and interfered with the initial correction of the serum calcium. Especially since the carbamazepine interfered with calcitriol treatment, a beneficial effect on the serum calcium with discontinuation of the antiepileptics could be expected.

PHP type 1B is a subtype of a group of genetic disorders, characterised by an impaired response to PTH. Sometimes, there are concurrent hormonal resistances leading to hypothyroidism, hypogonadism and growth hormone deficiency.⁵ It is caused by molecular defects that interfere with the signalling of G-protein coupled hormone receptors, mostly at the level of the alpha-subunit of the stimulatory G-protein (Gαs).⁸ The resistance to PTH is most pronounced at the proximal tubule¹⁸ resulting in hypocalcaemia, decreased production of 1,25-dihydroxyvitamin D3 and increased reabsorption of phosphate. PTH resistance is usually not yet present at birth but develops over time, and clinically apparent hypocalcaemia emerges in the teenage years.¹⁸ The molecular cause (de novo or inherited) can be identified in only about 10% of patients with PHP1B.⁵ Our patient was diagnosed with PHP1B, with a mutation in the STX16 gene, a well-known deletion causing the autosomal dominant PHP1B.⁵ PHP1B is an imprinting disorder at the level of the GNAS gene. In most cells, the Gαs protein is transcribed from both the paternal and maternal alleles. However, in the cells of the proximal tubules, the pituitary somatotropic cells, the gonads and the thyroid, transcription of Gαs can occur predominantly from the maternal allele.¹⁹ In these cells, the combination of a STX16 deletion on the maternal allele and paternal silencing of Gαs, results in PTH resistance. In clinical practice, this means that the STX16 deletion leads to PHP1B only if an offspring inherits the mutation from a maternal carrier. If the deletion is passed on by a paternal carrier, the children who inherited the mutation will be unaffected carriers.

Based on expert opinion, the acute management of hypocalcaemia comprises calcium and vitamin D3 supplementation. In case of neuromuscular symptoms or hypocalcaemia <1.9 mmol/L, as in our patient, treatment with parenteral calcium is indicated under electrocardiographic monitoring. Blood calcium levels should be monitored initially every 4 hours. Unlike patients with hypoparathyroidism, whose serum calcium levels should be maintained in the low-normal range (between 2.0 and 2.2 mmol/L),¹⁴ calcium levels in PHP patients should be increased to the normal range. In parallel, oral calcium substitution is started, with a dosage interval of 6 hours.² Hypomagnesaemia should be corrected.² In this case of PTH resistance, the conversion to 1,25-dihydroxyvitamin D3 is impaired, and calcitriol (or calcidiol) should be started in addition to cholecalciferol, typically starting with 0.5–1 µg calcitriol daily, increased every 4–7 days until the calcium is on target.² On a dose increment of calcitriol, one must watch out for hyperphosphataemia and an increased calcium-phosphate product, which may need temporary treatment with a phosphate binder, such as sevelamer. In PHP, the consensus guideline defines a therapeutic goal of a stable normal plasma calcium with a normal phosphate.⁸ The PTH level is ideally maintained in the upper normal range or up to two times the upper limit of normal (ULN) to maximise calcium reabsorption in the distal renal tubules and to reduce the negative effects of PTH on bone resorption, since chronically high PTH can increase bone turnover and can evolve into tertiary hyperparathyroidism.¹⁸ The cornerstone of therapy for PHP is the lifelong treatment with calcitriol. As opposed to hypoparathyroidism, recombinant parathormone is not a treatment option. Mostly, the calcium carbonate supplementation is necessary in the beginning, but often this can be stopped if dietary intake is sufficient.²⁰ However, in our patient, the calcium supplements were still needed during long-term treatment, probably because he had a low dairy consumption because of lactose intolerance. If the PTH rises above two times ULN, calcitriol should be increased even if the calcaemia is normal.¹⁸ The level of 25-hydroxy vitamin D3 should be kept in the normal range with appropriate supplementation.¹⁸ Overdosing with calcitriol should be avoided since it can reduce PTH levels below the normal range, thus preventing distal calcium reabsorption resulting in renal calcium losses (because of deficient PTH activity in this part of the nephron) with the risk of hypercalciuria and nephrocalcinosis. However, this risk is low in patients with PHP1B, if PTH levels are maintained in the upper end of normal or slightly elevated to preserve its actions on the distal tubule. Once the calcaemia is stabilised, biochemical follow-up should be continued every 3–6 months.² If the calciuria becomes too high, the dose of active vitamin D3 should be reduced, and imaging of the kidneys is advised. Relative dietary salt restriction is recommended as this helps lower calciuria.

The management of patients with PHP includes the screening for associated problems such as TSH resistance, hypogonadism, skeletal and dental abnormalities, glucose intolerance or type 2 diabetes mellitus, hypertension, neurocognitive decline, as well as genetic counselling.⁸ Given that the patient has the frequent 3-kb STX16 deletion, which was probably maternally inherited, the following recommendations can be given for the genetical screening of his family: first, his mother should be investigated to determine whether she is an unaffected carrier of the mutation, which would indicate that she had inherited the mutation from her father. In that case, the patient’s siblings should be investigated as they may have inherited also the STX16 deletion. The patient would need to be advised that he would pass the mutation to half of his children, who would be unaffected carriers; if daughters are carriers, their children could again be affected. A multidisciplinary approach is thus preferred.

Learning points.

• Pseudohypoparathyroidism is more than a problem of hypocalcaemia. In this case report, we focused on the possible dental and cerebral complications.

• Importance of screening for hypocalcaemia as a cause of new-onset epileptic seizures.

• Antiepileptics can interfere with the calcium–phosphate metabolism, causing a hypocalcaemia accompanied by a hypophosphataemia.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).