Idiopathic hypoparathyroidism and systemic sclerosis: An association likely missed.

Hypoparathyroidism in systemic sclerosis is extremely rare with only a single case reported till date. Idiopathic hypoparathyroidism with systemic sclerosis was diagnosed in a 59-year-old gentleman who had presented with recurrent seizures, instability of gait, skin thickening and tightening over both legs and forearms, and arthritis. Examination was significant for positive Trousseau sign and cerebellar ataxia. Evaluation revealed bilateral symmetrical cerebellar and basal ganglia calcification, sensorineural deafness, low serum calcium, elevated serum phosphorus, normal magnesium, normal vitamin D, low plasma parathyroid hormone, high titer of thyroid peroxidase antibody, positive centromere pattern antinuclear antibody, strongly positive anti-topoisomerase-1 (Scl-70) antibody, nonvisualization of parathyroids on neck ultrasonography and skin biopsy suggestive of hyperkeratosis, increased collagen in dermis, and perivascular lymphomononuclear cell infiltration compatible with scleroderma. Last evaluated 10 months after the diagnosis, his ataxia had improved, he remained seizure-free, Trousseau sign was negative, and he had low-normal calcium calcium with calcium carbonate and calcitriol supplementation and switch from phenytoin to valproate. Further studies are warranted to study the use of serum calcium as a screening test for hypoparathyroidism in patients with systemic sclerosis.

INTRODUCTION

Idiopathic hypoparathyroidism is a rare disorder. The etiology is not well known. Autoimmune destruction of the parathyroids is believed to have some role. Idiopathic hypoparathyroidism has been reported with other autoimmune disorders like Addison's disease, autoimmune thyroid dysfunction, and very rarely with systemic lupus erythematosis (SLE).[1-3] Hypoparathyroidism with scleroderma is extremely uncommon with only a single case reported till date.[4]

We present a man with tightening of skin over limbs, recurrent seizures, and ataxia which was diagnosed to be due to idiopathic hypoparathyroidism and systemic sclerosis.

CASE REPORT

A 59-year-old man with episodic generalized tonic-clonic seizures, instability of gait, and recurrent falls since six months was referred from the neurology clinic for endocrine evaluation for low serum calcium level detected during investigation for seizures. There was no history of tingling, numbness, or tetany of hands or feet. He complained of decreased hearing for the past several years. Examination was significant for dry coarse skin and skin thickening and tightening over the legs, thighs, forearms, and hands [Figure 1], which was noticed by the patient two years ago but was not interfering with his routine activities. There was no history of skin rash or Raynaud's phenomenon. He complained of intermittent arthritis mainly involving the small joints of the hand and feet along with elbow, shoulder, and knees, with a history of morning stiffness, which was not severe enough to impair his day-to-day activities or take nonsteroidal anti-inflammatory drugs. Trousseau sign was positive at one minute. Chvostek sign was absent. He had slurring of speech, a wide-spaced gait, impaired tandem walking, and positive cerebellar signs. Pure tone audiometry revealed bilateral moderate sensorineural hearing loss. Biochemical evaluation was significant for persistent hypocalcemia, hyperphosphatemia, normal serum magnesium, 25-hydroxyvitamin D, and low intact parathyroid hormone [Table 1]. Antinuclear antibody (ANA) was positive (titer >1:320) with centromere pattern (indirect immunofluorescence, Hep-2 cells). Anti-topoisomerase-1 (Sci-70) antibody was strongly positive (BlueDOT ENA®, Belgium); anti-U1RNP antibody (RNP: ribonucleoprotein) and rheumatoid factor were negative. Anti-thyroid peroxidase (TPO) antibody was strongly positive [Table 1]. Parathyroid glands could not be visualized on high-resolution ultrasonography and magnetic resonance imaging (MRI) of the neck. Computed tomography (CT) of the brain revealed diffuse symmetric calcification in the basal ganglia and cerebellum [Figure 2]. Skin biopsy from the right thigh revealed hyperkeratosis and increased pigmentation of the basal cell layer, increased collagen in the dermis, and perivascular lymphomononuclear cell infiltration with atrophy of skin appendages compatible with scleroderma [Figure 3].

Figure 1

Skin tightening of both forearms and hand, right greater than left, with swelling of right hand and distal forearm

Table 1

Biochemical evaluation of patient

Figure 2

(a) Computed tomography of the brain showing bilateral cerebellar calcification (black arrows); (b) calcification of bilateral basal ganglia [globus pallidus calcification (black arrows) and caudate nucleus calcification (white arrows)]

Figure 3

Eosin and hematoxylin staining of skin biopsy showing hyperkeratosis, collagen deposition in dermis, and perivascular lymphomononuclear cell infiltration with atrophy of skin appendages

A diagnosis of idiopathic hypoparathyroidism with systemic sclerosis was made in a gentleman who had presented with recurrent seizures and cerebellar ataxia and had diffuse skin tightening of all four limbs with arthritis. Calcium carbonate was started at 2 g/day in divided doses increased to 3 g/day over eight weeks. Calcitriol was started at 0.5 μg/day and increased to 1 μg/day over eight weeks. Phenytoin 300 mg/day was changed to sodium valproate 750 mg/day for seizure prophylaxis. Last evaluated 10 months after the initial diagnosis, his ataxia had improved and he was seizure-free with negative Trousseau sign. Serum calcium was being maintained at low-normal levels and serum phosphorus had normalized.

DISCUSSION

Endocrine abnormalities in systemic sclerosis are common, with thyroid being the most commonly involved gland.[5] The frequency of clinical and subclinical hypothyroidism is 43 and 73%, respectively.[5] The next most common abnormality is osteoporosis occurring in as many as 44% of the patients.[5] Hyperprolactinemia and prolactinomas have also been reported. However, involvement of the parathyroid is extremely rare with only a single case reported till date.[4] The patient in that report had progressive systemic sclerosis and polymyositis with clinically symptomatic hypoparathyroidism, and fibrosis of the parathyroids was found at autopsy.[4] Hypoparathyroidism has also been rarely reported in other autoimmune disease like SLE.[23] The underlying cause of hypoparathyroidism in SLE is not well known. The underlying autoimmunity may have some role in its development.[3]

Autoimmune destruction of the parathyroid can lead to hypoparathyroidism either as a part of autoimmune polyendocrine syndrome-1 (APS-1) or as an isolated entity.[1] Sensorineural deafness is uncommon in hypoparathyroidism. It has rarely been described as a triad of hypoparathyroidism, deafness and renal abnormalities (HDR) syndrome, an autosomal dominantly inherited disorder, the gene for which is located on chromosome 10p.[1] Our patient had normal renal functions and bilateral normal kidneys on imaging.

Our patient was diagnosed to have idiopathic hypoparathyroidism following evaluation for recurrent seizures for six months with features of scleroderma for two years. Likely destruction of parathyroids by fibrosis as well as the underlying autoimmunity may have had some role in this development.

This case report highlights the association of hypoparathyroidism and scleroderma, an association being reported only once previously. Further studies are needed to understand the association between these two rare entities. Further studies are warranted to study the use of serum calcium as a screening test for hypoparathyroidism in patients with systemic sclerosis.