INTRODUCTION
Idiopathic hypoparathyroidism (HP) is an induced or inherited condition characterized
by insufficient secretion of parathyroid hormone. The clinical manifestations of this
condition are varied, and pain and stiffness affecting the back and hips resembling
ankylosing spondylitis is an under-recognized symptom in these patients. Here, we
report a case of delayed diagnosis of hypoparathyroidism referred to a rheumatologist
due to progressive inflammatory back pain and myalgia.
Idiopathic hypoparathyroidism is an induced or inherited condition of unknown etiology
and is characterized by insufficient secretion of parathyroid hormone due to atrophy
or absence of parathyroid glands, which leads to hypocalcaemia and hyperphosphatemia.1
Hypoparathyroidism has multiple clinical manifestations, which primarily involve tissues
of ectodermic origin.2 Pain and stiffness affecting the back and hips, limited movement
and posture resembling that seen in patients with ankylosing spondylitis is an under-recognized
feature in patients with this condition.1,3 Muscular complaints by these patients
are common because the concentration of calcium ions is important for the maintenance
and control of several biochemical processes during muscle contraction. Hypocalcaemia
causes hyperexcitability of nerves and muscles, and a sporadic increase in muscular
enzymes.4
Here, we report a case of delayed diagnosis of hypoparathyroidism referred to a rheumatologist
due to progressive inflammatory back pain and myalgia with concomitant elevation of
inflammatory markers and muscle enzymes. The patient was initially erroneously diagnosed
with ankylosing spondylitis (AS) and idiopathic myopathy. This case reinforces the
relevance of investigating the underlying mineral metabolism disturbances in patients
with inflammatory diseases.
CASE REPORT
A 40-year-old man was referred to the Rheumatology Outpatient Clinic with a fifteen-year
history of progressive inflammatory back and neck pain and prolonged (two hours) morning
stiffness. He also complained of diffuse myalgia, muscle cramps, and frequent changes
in bowel habits characterized by chronic diarrhea (intermittent liquid diarrhea without
abdominal pain, mucous or blood, usually occurring after meals). He reported a history
of epilepsy since three months of age and cataracts by age 31. He had no history of
surgical excision or damage to the parathyroid gland, radiation or neoplastic/granulomatosis
infiltration. He also denied consanguinity, Arab ancestry, deafness or recurrent oral
candidiasis.
Upon physical examination, the patient displayed a typical AS posture with decreased
spinal mobility, a neck rotation of 10°, chest expansion of 1.5 cm, and a Schöber
test measurement of 10.5 cm. His hip movement was markedly restricted in all directions,
particularly flexion and rotation. The Fabere test was positive. The patient fulfilled
the modified New York criteria for ankylosing spondylitis.5 Assessment of the patient's
muscle strength revealed Grade IV reduction in all four limbs. Trousseau's and Chvostek's
signs also gave negative results. The patient had dental abnormalities and a cognitive
deficit (two years' education and a Mini-Mental State Examination score of eight),
but cleft palate, growth retardation, microcephaly, microphthalmia, and small hands
and feet were not observed. Dental abnormalities on a panoramic X-Ray revealed few
erupted teeth and the presence of multiple impacted teeth in the maxilla and mandible,
producing a change in anatomical size and shape.
Laboratory investigation revealed hypocalcaemia (calcium 4 mg/dL, ionized calcium
2.3 mg/dl), hyperphosphatemia (5.3 mg/dl), undetectable parathyroid hormone (<3 pg/ml)
and vitamin D levels within the normal range (56.1 ng/ml). Inflammatory markers (CRP
29.9 mg/dl and ESR 31 mm) and muscle enzymes (CPK 2805 U/l, aldolase 8.6 U/l and lactic
dehydrogenase 1397 U/l) were elevated (Table 1). The patient did not express HLA-B27.
Tests for anti-nuclear antibodies and rheumatoid factor were negative. The patient's
thyroid hormones, serum, and urinary cortisol were normal. Blood counts and glucose,
urea and creatinine levels were also within normal ranges. Serology for viral hepatitis,
syphilis, HIV, and HTLV were negative. Echocardiogram and renal ultrasound were normal.
A brain CT scan revealed calcifications in the basal ganglia, thalamus, and cerebellum.
A mandibular panoramic radiograph confirmed hypoplasia and dental malformations. Electromyography
was normal.
Bone fusions in the cervical spine, calcification of ligaments and syndesmophytes
in the lumbar spine were observed through spine radiography (Figure 1), and Grade
II (right)/Grade III (left) sacroiliitis was observed through sacroiliac joint radiography.
Computed tomography (CT) revealed ankylosis foci at the sacroiliac joint (SI) and
bilateral ossification of the iliolumbar ligament (Figure 2B). Similarly, magnetic
resonance imaging demonstrated ossification of the iliosacral ligaments in the lower
portions of the sacroiliac joints and no significant findings in the upper portions
of the SI joint (Figure 2C).
Bone mineral density evaluated by DXA revealed a Z-score of +4.4 SD at the lumbar
spine, -0.2 SD at the total femur and -1.0 SD at the femoral neck.
Treatment with 2 g/day calcium carbonate and 1 µg calcitriol led to evident clinical
and laboratory improvement including normalization of the bowel habits. Increasing
the calcium dose to 4 g/day was recommended. At the following visit, the patient had
stopped taking the medicine, and the laboratory parameters consequently worsened,
particularly inflammatory markers and muscle enzymes (Table 1). The importance of
treatment adherence was reinforced, and calcium supplements were increased to 6 g/day,
normalizing the serum calcium and muscle enzymes and reducing inflammatory markers.
Concomitant improvement of neck and back pain, disappearance of the cramps and muscle
pain and normalization of bowel habits were observed.
DISCUSSION
To our knowledge, this is the first case report of idiopathic HP simulating AS associated
with idiopathic myopathy.
The diagnosis of HP was confirmed by hypocalcemia, hyperphosphatemia, and undetectable
PTH. The chronic development of hypocalcemia may explain the absence of tetany in
this case. In fact, the most prominent symptoms of tetany usually occur in acute forms
of hypocalcemia and the development of tetany symptoms depends on the duration, severity,
and rapidity of hypocalcemia.6
Developmental disorders are unlikely in this case because the patient did not exhibit
the typical characteristics of DiGeorge Syndrome/Catch-22,7 hypoparathyroidism-sensorineural
deafness-renal dysplasia syndrome,8 hypoparathyroidism-retardation-dysmorphism or
Kenny-Caffey syndromes.9 Parathyroid gland destruction was excluded given that the
patient did not have a history of surgical excision or radiation therapy. The patient
had no family history or clinical features suggestive of autoimmune polyendocrinopathy-candidiasis-ectodermal
dystrophy.10 Autoimmune adrenal involvement was also excluded as the serum and urinary
parameters were within normal ranges and clinical symptoms were absent. In addition,
the classic triad of Kearn-Sayres syndrome (KSS) was not observed, and the muscle
complaints began late in life.11 Based on the above evidence, the probable diagnosis
is idiopathic HP, although other rare defects cannot be excluded because specific
genetic analyses were not performed.
Occasionally, patients with HP may have clinical and radiologic characteristics resembling
AS1 due to paravertebral calcification and ossification12. The syndesmophyte in our
HP patient, which exhibited the origination in the vertebral margin and preservation
of disc space characteristic of AS, led to the misdiagnosis of AS. This finding is
distinct from osteoarthritis in which osteophytes are horizontal and there is a significant
reduction in disc space.13 The predominant localization in the lumbar region also
suggested the diagnosis of AS, although any spinal location may be involved in HP.13
Diffuse idiopathic skeletal hyperostosis (DISH) was unlikely, considering the radiologic
spine features, the early appearance of calcifications (before the fourth decade)
and the absence of co-morbidities such as dyslipidemia and diabetes mellitus type
2.12
The radiographic findings in the sacroiliac joint were predominant in the lower portion
with ossification of the iliolumbar ligament, whereas the involvement is more common
in the upper region of the joint in AS. In addition, the evident ossification at the
hip joint with preserved joint space is not characteristic of AS but has been reported
in HP.1 Moreover, the lack of HLA-B27 expression may reduce the likelihood of the
AS diagnosis as over 90% of AS patients are positive for this allele,13 although no
data regarding the frequency of HLA-B27 in the healthy Brazilian population are available.
Of note, the extensive basal ganglia calcification in our case has been reported more
often in HP patients with spine involvement than in those without this complication,13
suggesting a disseminated process of calcification associated with mineral metabolism
disturbance. Reinforcing this possibility, long-term HP disease was more often associated
with spinal involvement,13 which was also observed in the patient evaluated herein.
In addition, there is much in vitro evidence that hyperphosphatemia may have a proinflammatory
role14 that could ultimately contribute to the calcification observed in our patient.
The novel description of concomitant association of HP and spondyloarthritis with
myopathy was supported by the diminished muscle strength and marked muscle enzyme
elevations. Chronic hypocalcemic myopathy secondary to HP and raised serum CK concentration
has rarely been reported15 and is probably an under-recognized condition due to the
patient's adaptation to long-standing hypocalcemia. The most likely explanation of
this condition is that the increased permeability of the muscle membrane induced by
hypocalcemia leads to CK release.16 The inverse correlation between CK and serum calcium
concentrations as well as the normal electromyographic findings observed in this case
support this possibility. Of note, rhabdomyolysis was excluded due to normal urine
analysis, the absence of acute renal failure and the positive response to calcium
treatment.
Idiopathic HP has been described as an unusual cause of diarrhea17 as observed in
the present case. Reinforcing this possibility, the bowel habits were normalized after
hypocalcemia correction.
Importantly, the clinical and laboratory improvements achieved solely with calcium
and calcitriol supplementation confirmed the diagnosis of HP and excluded the associations
with ankylosing spondylitis and idiopathic myopathy, as inflammatory rheumatic diseases
are unresponsive to this therapy.
This case emphasizes the importance of recognizing rheumatic manifestations of HP
to preclude unnecessary treatments. HP should be considered in the differential diagnosis
of spondyloarthropathies and myopathies, and calcium may be included in the diagnostic
workup of these patients.