Hypoparathyroidism Not Always Seen in APS1, Case Study Suggests

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by Patricia Inacio PhD |

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Impaired activity of the adrenal glands, a condition called Addison’s disease, may be the only typical manifestation of autoimmune polyglandular syndrome type 1 (APS1) to have occurred decades after diagnosis, a case report suggests.

APS1, a rare inherited autoimmune disorder, is typically characterized by at least two of three manifestations: hypoparathyroidism, chronic mucocutaneous candidiasis, and Addison’s disease. However, this study suggests that its symptoms can vary.

The report, “Hypoadrenalism as the Single Presentation of Autoimmune Polyglandular Syndrome Type 1,” was published in the Journal of the Endocrine Society.

APS1 is caused by mutations in the AIRE gene, which contains the instructions for a regulator of the immune system.

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Chronic mucocutaneous candidiasis is caused by the fungus Candida and is characterized by infections of the skin, mucous membranes, and nails. Addison’s disease, also known as primary adrenal insufficiency or hypoadrenalism, is a disorder of the adrenal glands — which sit above the kidneys — and that produce the hormones cortisol and aldosterone.

Usually starting in early childhood, chronic mucocutaneous candidiasis is often the first manifestation of APS1. Hypoparathyroidism is the first endocrine or hormone-related manifestation.

Only 20% of APS1 patients show the full triad of symptoms simultaneously, but around 70% develop the full spectrum of manifestations before they reach age 25.

Late onset of the typical symptoms contributes to a delayed diagnosis, which severely impairs prognosis.

In this report, researchers in Israel describe the case of a 12-year-old boy treated at the emergency department after developing diarrhea, vomiting, weakness, and nausea, all while conscious. He had experienced a constant headache accompanied by abdominal pain for 10 days, followed by five days of diarrhea and vomiting.

The boy was pale when admitted to the hospital, but his breathing was normal. The clinicians noted that his teeth and nails had developed normally, and his abdomen, heart, lungs, and tendon reflexes were normal.

However, within hours, the boy gradually dropped into a coma and was transferred to the pediatric intensive care unit.

A blood analysis analyzed within 20 minutes revealed that his blood levels of sodium dropped from 132 milliequivalents per liter (mEq/L) to 117 mEq/L.

He was given sugar (glucose) and sodium intravenously (into the vein), but this failed to restore consciousness.

The boy’s parents informed his primary care physician that relatives in the family had been diagnosed with APS1, with Addison’s disease as a manifestation.

With this information, the boy was started on intravenous treatment with hydrocortisone (100 mg), which led to a marked and rapid improvement. By the next morning, his blood sodium levels had risen to normal (144 mEq/L). The boy recovered from his coma.

He continued to take sodium but his blood pressure was still lower than normal for his age. Clinicians began a regimen of oral hydrocortisone, a steroid, given at 10 mg every six hours. The dosing was tapered down to 10 mg a day. Oral fludrocortisone acetate — a corticosteroid used to help control the amount of sodium and fluids in the body — was given according to the levels of sodium and potassium in the blood.

After discharge from the hospital, the boy was diagnosed with primary autoimmune adrenalitis based on a lab test.

In 2017, years after this patient had been treated, the Israeli Ministry of Health approved a type of DNA analysis for people suspected of APS1. This patient, then age 37, was the first of his family to undergo this DNA analysis, which revealed he had a mutation — c.47C > T (p.Thr16Met) — affecting both copies of the AIRE1 gene.

By the time of this report, the patient was 39 years old, but no hypoparathyroidism was reported.

Blood and urine levels of calcium were normal, and the man had low levels of vitamin D. No episodes of carpal tetany, or involuntary contraction of muscles in the hand, or abnormal heart rate were reported. His vision was normal and he had no deformities in the nails. Also, no infection by Candida was detected, ruling out mucocutaneous candidiasis.

The additional signs and symptoms of APS1 were ruled out by various lab tests.

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Fludrocortisone treatment was discontinued after two years once the levels of sodium and other minerals were normalized. The treatment was started once again on two more occasions, but stopped after two months when the levels of potassium and sodium were normalized.

The same mutation in the AIRE1 gene also was detected in two other members of the family, ages 21 and 53, both showing all three typical disease manifestations — chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison’s disease. These relatives also showed chronic inflammation of the eye’s cornea, which is the dome-shaped tissue on the front of the eye, and total hair loss.

One member of the family had severe autoimmune liver failure, as well as all three APS1 manifestations. The mutation also was detected in one of the AIRE1 gene copies in eight sisters and four brothers of the three patients with both gene copies mutated. The remaining family members were mutation-free. Of note, six affected patients from the family rejected genetic testing.

Overall, “although the sequence of appearance of the classic features of APS1 is important in the clinical diagnosis of the syndrome, the appearance of AD [Addison’s disease] as the first manifestation in our case was unexpectedly different from the conventional,” the researchers wrote.

“This fact strengthens the idea that diagnosis of APS1 should be considered in all patients who present with one of the classic clinical manifestations,” they concluded.