Advance Publication by J-STAGE
Clinical Pediatric Endocrinology
Accepted for publication: March 6, 2024
Advanced Epub: March 25, 2024

Case Report
Pseudohypoparathyroidism type 1B with involuntary movements: a casereport and literature review
Junko Naganuma1, Hiroshi Suzumura1, Satomi Koyama1, Miho Yaginuma1, Yuji Fujita1, Yoshiyuki
Watabe1, George Imataka1, Keiko Matsubara2, 3, Masayo Kagami2, and Shigemi Yoshihara1

1

Department of Pediatrics, Dokkyo Medical University, Tochigi 321-0293, Japan2

Department of Molecular Endocrinology, National Center for Child Health and Development, Tokyo

157-8535, Japan
3

Division of Diversity Research, National Research Institute for Child Health and Development,

Tokyo 157-8535, Japan

Running head: PHP 1B with involuntary movements

Corresponding authors: Junko Naganuma, M.D., Ph.D., Department of Pediatrics Dokkyo Medical
University, 880 Kitakobayashi, Mibu Shimotsuga, Tochigi 321-0293, Japan E-mail: ijunko@dokkyomed.ac.jp; Masayo Kagami, M.D., Ph.D., Department of Molecular Endocrinology,
National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535,
Japan. E-mail: kagami-ms@ncchd.go.jp

1

Highlights
・PHP is characterized by hypocalcemia and hyperparathyroidism due to PTH resistance.
・PHP is rare and unlikely to be accompanied by involuntary movements.
・Patients experiencing exercise-induced involuntary movements may have PHP.

Abstract
Pseudohypoparathyroidism (PHP) is a rare disorder characterized by convulsions, tetany, and sensory
abnormalities caused by hypocalcemia due to parathyroid hormone (PTH) resistance. Only few
patients present with involuntary movements. We report the case of a 7-yr-old girl with PHP and
involuntary movements triggered by running. Initially, she was suspected of having paroxysmal
kinesigenic dyskinesia and was treated with carbamazepine (CBZ). Involuntary movements werereduced. However, 2 months post-treatment, she experienced convulsions during a fever. Blood tests
and brain computed tomography revealed hypocalcemia, hyperphosphatemia, elevated intact PTH,
and calcifications in the frontal cortex and basal ganglia. The patient showed no features of Albright’s
hereditary osteodystrophy. The involuntary movements disappeared after the discontinuation of CBZand initiation of calcium and active vitamin D preparations. Methylation-specific multiplex ligationdependent probe amplification for the GNAS region and microsatellite analysis of chromosome 20 led
to the diagnosis of PHP1B caused by epimutation. In 15 reported cases, with or without intracranialcalcification, PHP-associated involuntary movements disappeared or became less severe withtreatment for hypocalcemia; in eight of 11 cases, they were triggered by exercise or movement. PHPassociated hypocalcemia can trigger exercise-induced involuntary movements owing to lowered
serum ionized calcium levels. In such patients, early blood tests are vital for the differential diagnosis
of PHP.
Key words: involuntary movement, pseudohypoparathyroidism 1B, hypocalcemia

2Introduction

Pseudohypoparathyroidism (PHP) is a genetically heterogeneous condition characterized byhypocalcemia and hyperphosphatemia resulting from end-organ resistance to parathyroid hormone(PTH) (1, 2). However, its exact prevalence remains unknown. Previous studies have estimated theprevalence to be 1.2 per 100,000 in Japan (3) and 1.1 per 100,000 in Denmark (4).
There are two forms of PHP, PHP1 and PHP2 (5). PHP1 is further sub-divided into PHP1A andPHP1B. PHP1A arises from loss-of-function variants that affect maternal GNAS exons 1–13, which
encode the stimulatory G protein α-subunit (1, 2). PHP1B is caused by methylation abnormalities indifferentially methylated regions (DMRs) upstream of the GNAS gene (1, 2) and can follow an
autosomal dominant mode of inheritance or occur sporadically (1, 2). Sporadic-PHP1B presents withbroad methylation changes in two or more DMRs, and its etiology includes paternal uniparental
disomy of chromosome 20 and epimutation (1). PHP1B is less likely to be accompanied by symptomsof Albright’s hereditary osteodystrophy (AHO) (1), and early diagnosis is difficult in the absence ofgeneralized convulsions, tetany, and sensory abnormalities associated with hypocalcemia (1). Only a
few case reports of involuntary movements have been published. We present the case of a patient with
PHP1B-associated involuntary movements and discuss its pathology.

Patient and Methods

The 7-yr-old female patient was born at 39 wk and 3 d of gestation, with a birth weight of 3,060 g(+0.2 standard deviation [SD]) and a height of 51 cm (+1.2 SD). Her developmental milestones wereunremarkable; however, she had a history of febrile seizures at 1 yr of age. The patient had no family
history of endocrine disorders or epilepsy. At the age of 7 yr and 2 mo, the patient showed involuntary
movements triggered by running, raising her left hand, dropping her right hand behind her, andflexing both wrists. At 7 yr and 4 mo, the involuntary movements of the upper extremities increased
from once every few days to several times a day, and the lower extremities began to jerk when she
3began walking, although she did not present with consciousness-related symptoms. She visited thepediatric neurology outpatient clinic, where an interictal electroencephalogram showed noabnormalities, but no blood or brain imaging was conducted. Carbamazepine (CBZ) was initiated on
the suspicion of paroxysmal kinesigenic dyskinesia (PKD) based on her clinical symptoms andinterictal electroencephalogram results; subsequently, the dyskinesia disappeared.
Two months after CBZ treatment initiation, the patient was transferred to our hospital withfever and convulsions. She was 114 cm tall (–1.4 SD), weighed 19.8 kg (–0.8 SD), had a body massindex of 15 kg/m2, and had no clinical features related to AHO. Her vital signs were as follows:
temperature, 38.6°C; blood pressure, 109/73 mmHg; heart rate, 127 beats/min; and SpO2, 96% (roomair). The generalized tonic convulsions lasted for 3 min, and her level of consciousness was normalwhen she arrived at the hospital. Blood tests revealed no hyponatremia, hypoglycemia, or renal
dysfunction. Serum levels [normal range] of calcium (Ca), phosphorus (P), intact PTH, 1,25dihydroxyvitamin D3, and 25-hydroxyvitamin D were 5.5 [8.7–10.2] mg/dL, 7.6 [3.9–5.8] mg/dL,
343.1 [10–65] pg/mL, 74.3 [20–60] pg/mL, and 13.5 [> 20] ng/mL, respectively. Thyroid function
was normal (thyroid stimulating hormone: 0.881 [0.8–6.0] μIU/mL; free thyroxine: 1.0 [1.0–2.1]
ng/dL; free triiodothyronine: 3.22 [2.73–4.69] pg/mL). Computed tomography (CT) of the brain
revealed multiple bilateral calcifications in the basal ganglia (BG) and frontal cortex (Fig. 1).
Ophthalmological examination revealed pale opacities and bulging of the lens, indicating cataract.
Electrocardiography revealed QT prolongation, with a QTc of 0.496 [0.35–0.43] msec. The patient
was admitted to the hospital for a closer examination and to treat the hypocalcemia. The oral
administration of CBZ was discontinued after hospitalization. Calcium gluconate was administeredintravenously seven times for hypocalcemia, and serum Ca levels were maintained above 7.0 mg/dL
from day 5 after treatment initiation. Furthermore, QT prolongation on electrocardiography improved
with the correction of serum Ca levels. After her general condition improved, the Ellsworth-Howard
test was performed to examine the cause of the hypocalcemia. The urinary phosphate response to PTH
administration was 5 mg/2 h (positive at > 35 mg/2 h), and the urinary cyclic AMP response was 0.99μmol/1 h (positive at > 1 μmol/1 h), both indicating a lack of an increased excretory response to PTH
4and thus a diagnosis of PHP type 1. The patient’s condition stabilized and she was discharged on the
23rd day after admission. Oral administration of an active vitamin D preparation (alfacalcidol 1 μg/d)
was started on the 31st day of illness. Serum Ca levels remained consistently within 8–9 mg/dL, P
levels were stable at approximately 5 mg/dL, and intact PTH levels remained within 200–300 pg/mL.
After treatment initiation, the patient did not experience any symptoms of dyskinesia in the upper orlower extremities.
For molecular analysis of the GNAS region, we employed methylation-specific multiplex
ligation-dependent probe amplification (MS-MLPA) using SALSA ME031 probe mix (MRCHolland, Amsterdam, Netherlands). MS-MLPA revealed abnormal methylation patterns in GNASDMRs, such as hypermethylation of NESP55-DMR and hypomethylation of GNAS-AS, -XL, and A/B-DMR, without copy number changes (Fig. 2). Microsatellite analysis of chromosome 20 using
samples from the patient and her parents showed a biparental origin of the chromosome; therefore,paternal uniparental disomy of chromosome 20 was ruled out. Sequence analysis revealed no
mutation of the GNAS gene (data not shown). We conclude that the etiology of sporadic PHP1B is
epimutation.

Statement of ethics
Written informed consent was obtained from the parent/legal guardian of the patient for the
publication of the details of their medical case and any accompanying images in accordance with the
Declaration of Helsinki.

Discussion

We reported the case of a 7-yr-old girl presenting with involuntary movements of lifting her upper
limbs triggered by running. She was initially suspected to have PKD and was treated with CBZ. After
convulsions during a high fever, she was diagnosed with PHP1B based on the results of blood tests
5and molecular analyses. The involuntary movements disappeared after normalization of Ca levels
following the administration of Ca and active vitamin D preparations.
Only a few cases of PHP-associated involuntary movements have been reported (Table 1) (6–17). Our patient was initially suspected of having PKD because her symptoms met the clinicaldiagnostic criteria for PKD, such as seizures triggered by motor movements, no pain or loss of
consciousness during the seizure, age of onset under 20 years, no other organic diseases, normal
neurological examination during seizures, and effectiveness of CBZ (18, 19). She was diagnosed with
PHP1B based on blood tests and molecular analysis following convulsions during a high fever.
Considering that the diagnostic criteria for PKD include the exclusion of other organic diseases (18,19), it was not a suitable diagnosis.
The patient did not undergo blood tests when CBZ treatment was initiated for involuntary
movements. Considering the patient’s clinical course, we speculated that she had hypocalcemia at theonset of the involuntary movements. Furthermore, the involuntary movements disappeared after
initiating treatment for hypocalcemia, despite the discontinuation of CBZ. To the best of ourknowledge, only 15 patients with PHP-related involuntary movements have been reported (Table 1)(6–17). In all cases, with or without intracranial calcification, the involuntary movements disappearedor became less severe with hypocalcemia treatment. These findings suggest that the involuntary
movements were caused by hypocalcemia. In eight of the previously reported 11 patients with PHPassociated involuntary movements and intracranial calcification, the involuntary movements were
triggered by exercise or movement, similar to the current case (7, 8, 10, 11, 12, 14, 15). Additionally,
Parkinsonism was observed in three cases of adult PHP (13, 16, 17). Early blood tests to detect
hypocalcemia in patients with exercise-induced involuntary movements should be considered in the
differential diagnosis of PHP. Furthermore, for adult patients with parkinsonism, blood tests to detect
hypocalcemia may be needed for the differential diagnosis of PHP.
The mechanism underlying hypocalcemia-induced involuntary movements remains unclear.
Voluntary movements are regulated through the cerebral cortex- BG-thalamus loop with thecoordination of excitatory and inhibitory neurons (20). In inhibitory neurons, Ca influx into the6presynaptic terminus releases synaptic vesicles containing gamma-aminobutyric acid (GABA), a
crucial inhibitory neurotransmitter transmitted to the postsynaptic membrane (21). Hypocalcemia may
suppress the functions of GABAergic inhibitory neurons, cause excitatory neurons to become
dominant, and trigger involuntary movements. In a previous study, cases of PHP with involuntary
movements together with hypocalcemia showed significant hypometabolism in the ventral putamen
and inferior caudate on [18F]- fluorodeoxyglucose-positron emission tomography, altered BG
metabolism, and resolution of clinical symptoms following Ca/calcitriol treatment (22). Furthermore,
exercise can decrease serum ionized Ca levels (23), and decreased ionized Ca levels may further
suppress the function of GABAergic inhibitory neurons and cause involuntary movements in patientswith PHP-related hypocalcemia. Not all patients with PHP-associated hypocalcemia experience
exercise-induced involuntary movements. Individual differences may exist in the susceptibility ofGABAergic inhibitory neurons to hypocalcemia. CBZ was temporarily effective for the involuntary
movements in our patient. CBZ suppresses glutamatergic excitatory projections and partiallydecreases involuntary movements (24). However, the association between brain calcification andinvoluntary movements remains unclear. Damage due to calcification in the cerebral cortex-BGthalamus pathway can lead to involuntary movements; however, some patients do not show
intracranial calcification (9, 13). Intracranial calcifications in the patient in the present case did notchange after Ca levels normalized; nonetheless, involuntary movements were not observed. Thesefindings suggest that the involuntary movements were caused by hypocalcemia rather thanintracranial calcification.

Conclusion

This study showed that exercise-induced involuntary movements associated with PHP can be causedby hypocalcemia, with or without intracranial calcification. Based on this study and literature review,
early blood tests to detect hypocalcemia in patients experiencing exercise-induced involuntary
movements should be considered in the differential diagnosis of PHP.
7

Conflicts of interests: The authors have no conflicts of interest to declare.
Data availability statement: All data generated or analyzed during this study are included in thisarticle. Further inquiries can be directed to the corresponding authors.

Acknowledgements
This work was supported by grants from the National Center for Child Health and Development(2022B-5) and the Japan Agency for Medical Research and Development (AMED)(23ek0109587h0002).

8

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14. Kwon YJ, Jung JM, Choi JY, Kwon DY. Paroxysmal kinesigenic dyskinesia in
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Fig. 1. Computed tomography scan of the head showing multiple calcifications in the basal ganglia and thefrontal cortex.

12

Fig. 2. Methylation-specific multiplex ligation-dependent probe amplification.
A: Copy number analysis. No copy number variants were detected within the pseudohypoparathyroidism related regions.
B: Methylation analysis. Calculated ratios are reported on the y-axis and probes on the x-axis. The analysis
revealed hypermethylation of the NESP55 DMR and hypomethylation of GNAS-AS, -XL, and -A/B DMRs.
DMR, differentially methylated region; TSS, transcription start site; NESP, GNAS-NESP:TSS-DMR; AS,
GNAS-AS1:TSS-DMR; XL, GNAS-XL:Ex1-DMR; A/B, GNAS A/B:TSS-DMR.

13

Table 1. Reported PHP cases with involuntary movements
Age
(yr)

Sex

Diagnosis

Involuntary
movements

Trigger

Serum Calevel

Treatment
Neuroradiological imaging

Ref.

Genetic analysis results(mg/dL)

Pre-DxPost- Dx

CBZ

Ca and Vit D

CT: calcification in BG
5.5

Hypermethylation of NESP55
DMR and hypomethylation
MRI: high signal coincident of GNAS-AS, -XL, -A/B
DMR
with calcified area in T2−

6.7

CT: calcification in bilateral Multiple changes insubcortical, lens nuclei, and methylation pattern of DMRs
thalamuson the GNAS locus without
mutation in GNAS

Ca and Vit D

6Running

6.6

CT and MRI: predominantcalcification in BG−

Ca and Vit D

7

7.5

CT: calcification in BG and
frontal lobe white matter−

Ca and Vit D

8

−

7.4

MRI: normal

A 3-kb deletion upstream of
the GNAS locus on 20q13.3
inherited from the mother

CBZ

Ca and Vit D

9

−

5.7

MRI: normal

A 3-kb deletion upstream of
the GNAS locus on 20q13.3
inherited from the mother−

Ca and Vit D

97.7

CT and MRI: bilateral
calcification in frontal and Methylation abnormalities ofparietal cortex and thalamus the DMR(s) without copy
number change on the GNAS
locus

CBZ

Ca and Vit D

10F

Sporadic
PHP1B

Raising the upper limbs

9

M

Sporadic
PHP1B

Ocular motor tics, throat
tightness, and eye
mutation

10

F

PHP

Dystonia of the lower
extremities

11

F

PHP

Writhing and shaking ofPlaying sport
both upper limbs

12

F

Forward fall seizures,
AD PHP1B facial convulsions, andtremor of limbs

14

F

AD PHP1B

Paroxysmal kinesigenic
dyskinesia

Sporadic
PHP1B

Dystonia of the shoulder Upper andjoint, wrist, knee, andlower limb
metacarpophalangeal
extension
joint
exercises

7

15

M

Running

This
case

14

Dystonic movements
Writing andinvolving mainly the left physicalhandexercise

16

M

Sporadic
PHP1B

M

PHP

Dystonia of upper andlower limbs, facial
rigidity

Activity

17

−

20

F

PHP

Parkinsonism including
tremor, rigidity,
bradykinesia, stooped
posture

25

M

PHP

Dystonia of the neckand extremities

Physical
exercise

25

M

PHP

Dystonia of the arm,
open mouth, generalankylosis

Running andexercise

27

F

PHP

Dystonia of upper andlower limbs

Physical
exercise

52

58

F

F

AD PHP1A

PHP1Parkinsonism including
bradykinesia andmuscular rigidity

Parkinsonism including
immobility, mask-likefacies, pill-rolling
tremor, cogwheel
rigidity

5.5
7.7

Ca and Vit D

11

CT: Calcification in BG,
thalamus, cortical arcuate
fiber

−

CT: normal

−

−

13

5.3

CT: Nonspecific findings (noBG calcification)

−

Ca

14

4.9

MRI: symmetriccalcifications on the bilateralputamen and dentate nucleus.

−

Ca and Vit D

15

4.4

CT: bilateral calcification in
the BG

−

Ca

14

7.4

CT: calcification in BG

Ca and Vit D

16

Ca and Vit D

17

CBZ

Ca and Vit D

12

9.8

−

4.9
−

CT: Multiple subcortical and Methylation defects of the
diffuse BG calcifications
A/B DMR without deletion
involving STX16

Loss-of-function mutation in
GNAS
MRI (T1WI and T2WI):
NM_000516.5:c.343C>Tincreased signal intensity in (NP_000507.1:p.Pro115Ser)
bilateral caudate nucleus andthalamusCT: BG calcification−

Dx, diagnosis; AD, autosomal dominant; PHP, pseudohypoparathyroidism; CT, computed tomography; MRI, magnetic resonance imaging; T1WI, T1-weighted image; T2WI, T2weighted image; BG, basal ganglia; CBZ, carbamazepine; Ca, calcium; Vit D, vitamin D.

15