Persistent Hypoparathyroidism May Merit APS-1 Diagnosis

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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The presence of persistent hypoparathyroidism should prompt physicians to consider a possible diagnosis of autoimmune polyglandular syndrome type 1 (APS-1), a rare genetic disorder, even in the absence of other typical symptoms, according to a case report.

The study, “Hypoparathyroidism as the single major component for decades of autoimmune polyglandular syndrome type 1,” was published in the journal Endocrinology, Diabetes & Metabolism.

APS-1, also known as Whitaker syndrome, is caused by mutations in the AIRE gene, which plays a key role in immune tolerance. The disease typically manifests with at least two of three core features, including chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and Addison’s disease.

CMC refers to recurring fungal infections in the skin, nails, and mucous membranes (membranes that surround the body’s internal cavities). Hypoparathyroidism causes calcium levels to drop due to the lack of parathyroid hormone (PTH). Addison’s disease, also known as adrenal insufficiency, is a condition in which the adrenal glands, which sit on top of the kidneys, become unable to produce two key hormones, called cortisol and aldosterone.

APS-1 usually manifests with CMC during childhood.

Here, a group of Portuguese researchers described the rare case of a patient who had an atypical disease presentation, in which hypoparathyroidism was the first and only manifestation of APS-1 for decades.

The 50-year-old man was diagnosed at age 7 with primary hypoparathyroidism, and was referred to an outpatient endocrinology clinic to have his condition regularly monitored.

Analysis of previous lab tests showed his calcium and phosphate levels in the blood often fluctuated, while his calcium levels in the urine remained consistently high (hypercalciuria).

He also had other medical conditions. He developed cataracts in both eyes at age 25, and then glaucoma at age 47. Glaucoma is a condition in which the optic nerve becomes damaged  due to increased eye pressure, potentially causing blindness. He also had beard and hair loss, and was diagnosed with chronic gastritis at age 46.

Analysis of family history revealed the patient’s parents were second cousins, and his younger brother, 40, also had been diagnosed with primary hypoparathyroidism at age 16.

Persistent complaints of fatigue, gastrointestinal discomfort, and weight loss led physicians to perform additional examinations.

A physical assessment revealed onychomycosis — a fungal infection that causes nail discoloration — in several fingers and toes, along with mucocutaneous hyperpigmentation, or patches of dark skin and mucous membranes, which were consistent with CMC. Blood tests also indicated he had low levels of cortisol and aldosterone, indicating the presence of adrenal insufficiency.

He was started on antifungal and hormonal replacement therapy to treat both disorders, and his overall health condition improved. He also was instructed to continue taking his regular calcium and vitamin D supplements to keep hypoparathyroidism under control, and prescribed hydrocortisone and fludrocortisone for adrenal insufficiency.

The patient remained stable two years after his first visit to the outpatient clinic. However, he still needs to have the dosage of his calcium and vitamin D supplements adjusted often to keep hypoparathyroidism under control and to avoid gastrointestinal issues.

The coexistance of hypoparathyroidism, CMC and adrenal insufficiency led physicians to order a genetic test to assess if the patient could have APS-1. This test revealed he had a disease-causing mutation in both copies of the AIRE gene, which had been found in two Asian siblings, confirming the diagnosis of APS-1.

“This case highlights the broad phenotypic spectrum [disease manifestations] of APS-1 and … clarifies the need for regular long-term follow-up,” the researchers wrote.

The patient said “The doctors have never clarified the root cause of my hypoparathyroidism and I feel that my manifestations have never been valued enough.”

“At a time when I felt more exhausted and misunderstood than ever, my General Practitioner referred me to an Endocrinology outpatient clinic,” he added. “At that moment, I felt little energy to travel several kilometres, but my wife convinced me and helped me to go there. And it was really worth the effort!”.