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Autoimmune polyglandular syndrome type I. Features of clinical manifestations, difficulties in diagnosis and methods of correction


Autoimmune polyglandular syndrome (APG) type I is an orphan disease with autosomal recessive inheritance caused by mutations in the autoimmune regulator gene (AIRE); the disease onset typically occurs in childhood. The disease is characterized by a wide variety of clinical manifestations with a certain stage in the manifestation of individual symptoms. The rare occurrence of this pathology determines its late diagnosis, which can lead to the decompensated life-threatening conditions and an unfavorable outcome. Widely informing pediatric specialists will contribute to the development of a diagnostic algorithm for timely verifying the disease from the moment its first clinical manifestations appear, and will improve the quality and life expectancy of the patients.


For citation:

Galkina G.A., Mikhailichenko L.S., Sozaeva D.I., Berezhanskaya S.B., Afonin A.A. Autoimmune polyglandular syndrome type I. Features of clinical manifestations, difficulties in diagnosis and methods of correction. Medical Herald of the South of Russia. 2021;12(4):67-73. (In Russ.)

Polyglandular insufficiency syndrome is based on an autoimmune reaction mediated by the production of specific antibodies, sensitization of immune system cells and their interaction, ultimately leading to autoinflammation, lymphocytic infiltration and partial or complete destruction of the glandular tissue of target organs. As a rule, several endocrine glands are involved in the process, although clinical manifestations of their dysfunction often occur at the same time and cross-autoimmune disorders in non-endocrine tissues may join it while the further development of the pathological process. Under these conditions, several syndromic types of the disease have been identified, depending on the variant of immune pathology.

Polyglandular syndrome of the 1st type (Whitaker syndrome or candidopolyendocrine syndrome; juvenile, juvenile polyendocrinopathy) is a monogenic disease with an autosomal recessive type of inheritance resulting from the AIRE gene mutation encoding the AutoImmune Regulator protein. Its manifestation happens while childhood and is characterized by the presence of a classic triad of diseases – primary chronic candidiasis, primary hypoparathyroidism and primary adrenal gland insufficiency [1][2]. A highly specific symptom is a chronic fungal infection of the skin, respiratory organs, mucous membranes of the oral cavity and gastrointestinal tract, usually preceding the appearance of other components of the syndrome. The development of the disease occurs gradually, over several years or even decades without a strict sequence of clinical syndrome manifestations. In order to make a diagnosis, it is sufficient to prove two or three signs of the classical triad (hypoparathyroidism, adrenal gland insufficiency, candidiasis of the skin and mucous membranes); if the patient has a first-line relative with an established disease, then one component is sufficient for the diagnosis [3][4][5]. Furthermore, other autoimmune disorders may join the patient throughout life, such as alopecia, autoimmune thyroiditis, pernicious anemia, insulin-dependent diabetes mellitus, primary hypogonadism, vitiligo, autoimmune hepatitis, vasculitis [6][7].

There is also the 2nd type of polyglandular syndrome (Schmidt syndrome), characterized by the presence in 100% of cases of primary adrenal insufficiency in combination with an autoimmune thyroid lesion. Hypergonadotropic hypogonadism, vitiligo, alopecia, celiac disease, myasthenia gravis, steatorrhea, pernicious anemia may occur within its course. This disease belongs to the category of multifactorial pathological processes with hereditary predisposition associated with defective expression of antigens of the HLA system (DR/DR4, CTLA-4, HLA-B8, MICA5.1) on the cells of the endocrine glands. The pathological process may be inherited by representatives of the same family for several generations. The disease is more common in women and usually manifests at the age of 20-33 years. At the onset of the disease, there is chronic adrenal insufficiency with the addition of insulin-dependent diabetes mellitus and autoimmune thyroiditis for 10 years, sometimes with the development of diffuse toxic goiter. Patients may have inflammatory processes in the pleura and pericardium, lesions of the optic nerves, celiac disease, tumor processes in the pituitary gland.

Polyglandular syndrome of the 3rd type is a combination of autoimmune diseases of the thyroid gland (autoimmune thyroiditis, diffuse toxic goiter, endocrine ophthalmopathy, idiopathic myxedema) with other endocrine and non-endocrine autoimmune pathologies in the absence of impaired function of the adrenal cortex and hypoparathyroidism. It manifests in adulthood and differs from polyglandular syndromes of the 1st and 2nd type only in the clinical picture. Genetic predisposition to autoimmune thyroid diseases in combination with diabetes mellitus of the 1st type within the framework of this syndrome is determined by the presence of the DR3-DQB1×0201 haplotype, predisposition to the development of celiac disease, autoimmune gastritis and pernicious anemia (which is due to the presence of the DQA1×050 allele [3][5]).

Polyglandular syndrome of the 4th type includes combinations of autoimmune diseases not represented in the above groups: primary chronic adrenal insufficiency in combination with one or more minor autoimmune pathologies (hypogonadism, atrophic gastritis, celiac disease, pernicious anemia, myasthenia gravis, alopecia, vitiligo).

These syndromes are characterized by the fact that firstly one autoimmune disease appears, and subsequent new components are added during life, while one type of polyglandular syndrome can be reclassified into another at a later age (which is important to remember during long-term dynamic monitoring of adolescents with disease of the 1st type). It is known that most often with a combination of pathologies, the clinical symptoms are low, dim, which does not immediately allow one to suspect the addition of a new autoimmune disease.

Taking into account the rare frequency of occurrence, clinical polymorphism, difficulties of diagnosis and interpretation of the obtained clinical and paraclinical data, the authors of this article analyzed the case of a patient G. M-la, born on 08.08.2008, who was staying on inpatient treatment in the pediatric endocrinology department of NIIAP FGBOU IN RostSMU of the Ministry of Health of Russia.

Upon admission, the boy complained of attacks of tonic-clonic tension of the face, trunk and extremities’ muscles, accompanied by the lips stretching, forced characteristic flexion of the fingers, the installation of the hands according to the “main d'accoucheur” type with simultaneous stretching of the hips, shins, bringing the feet inside. Quick muscle pains of the trunk and extremities, lack of respiratory movements and reactions to others without complete loss of consciousness were periodically noted as well. There was the appearance of areas of hyper- and depigmentation of the skin, redness, swelling of the mucous membrane of the gums and oral cavity with a layer of white plaque, itching, burning, pain when eating, congestion in the corners of the mouth, peeling of the lips, episodes of bowel dilution with an admixture of mucus and undigested lumps of food.

Anamnesis of the disease: areas of hyper- and depigmentation of the skin appeared 2 years ago, attacks of muscle tension joined within the last 1.5 years, were provoked by psycho-emotional stress and were of a short-term nature (5-7 minutes), lesions of the oral mucosa in the form of white raids, congestion in the corners of the mouth have occurred over the past year, often recur.

In order to clarify the diagnosis, the boy (10 years old) was hospitalized in the pediatric department of the Regional Children's Clinical Hospital of Rostov-on-Don, where he had repeated attacks of muscle hypertension, episodes of hypoglycemia up to 0.6–1.2 mmol/l, stopped by intravenous administration of 40% glucose solution, periodic vomiting, liquid stool. For diagnostic purposes, the child underwent electroencephalographic examination of the bioelectric activity of the brain, which revealed diffusely pronounced cerebral changes, dysfunction of diencephalic structures, irrigation of the convexital surface of the cerebral cortex with the inclusion of single complexes of the peak-slow wave type and endoscopic examination of the stomach, which determined the signs of widespread superficial gastritis. To exclude Crohn's disease, a colonoscopy was performed under general anesthesia, which revealed the phenomena of catarrhal colitis. In the post-acute period, due to acute cardiovascular insufficiency, the boy was transferred to the intensive care unit to stabilize his condition, where hyponatremia and hypocalcemia were diagnosed for the first time during clinical and laboratory monitoring. To improve the condition, the child was discharged from the hospital with a diagnosis of “Intestinal malabsorption, unspecified. Epilepsy. Chronic superficial gastritis associated with Helicobacter pylori. Catarrhal duodenitis. Reflux-esophagitis. Gastroesophageal reflux. Biliary dysfunction”. The following treatment was recommended: Depakin-chrono 300 mg 2 times a day for a long time, pro-prebiotics and prokinetics in age dosage according to the standard regime. After discharge from the hospital for five months against the background of ongoing therapy, there was no stable positive dynamics of the course of the disease. Attacks of involuntary contraction of the muscles of the face, trunk and extremities became more frequent, rare episodes of hypoglycemia persisted up to 1.1-1.5 mmol / l, abdominal pain and weakness joined (he did not walk on his own, could hardly hold different objects), weight loss progressed, cravings for salty food and darkening of the skin appeared, especially in places of natural folds. The above-mentioned points served as the basis for the patient’s hospitalization in the children's endocrinology department of the NIIAP of the Federal State Budgetary Educational Institution of the Russian Ministry of Health in order to clarify the diagnosis and treatment.

Anamnesis of life: the boy was born from the first pregnancy, which took place against the background of fetoplacental insufficiency and chronic intrauterine hypoxia of the fetus of the first urgent delivery through the natural birth canal without asphyxia. Birth weight – 2700.0 g, length – 50.0 cm. He has been growing on natural feeding since his birth. He grew and developed up to 1 year according to his age, was vaccinated according to the national calendar of preventive vaccinations, without adverse reactions to the introduction of vaccines. He did not have cases of being ill with childhood infections.

Family background: the grandmother on the mother’s side was suffering from the diabetes mellitus (the 2nd type) for 10 years.

Upon admission to the pediatric endocrinology department, the general condition of the child was severe, weakness, lethargy were expressed, he could not walk independently, was sitting only with support. Weight – 26.2 kg (average), height – 131 cm (-1.6 SDS). On medical examination, an attack of carpopedal cramps was noted, which was stopped independently within 5-7 minutes. The skin was swarthy, dry to the touch, the turgor of soft tissues was preserved. There were areas of depigmentation on the face, in the pelvic area, hyperpigmentation on the skin of the face, elbows, scrotum (Figure 1).


Figure 1. General view of the patient.


Also, visible mucous membranes of the mouth and gums with patches of white plaque, small erosions, congestion in the corners of the mouth, hypoplasia of the gums could be detected (Figure 2).


Figure 2. Gingival hypoplasia.


Musculoskeletal system was without visible deformities, movements in the extremities and joints were painless, not limited. The subcutaneous fat layer was weakly expressed, distributed evenly throughout the body. The thyroid gland was of a soft-elastic consistency, not enlarged. Peripheral and regional lymph nodes were palpable, soft-elastic consistency, painless, were not soldered together and surrounding tissues, the skin above them was not changed. The chest was cylindrical in shape, symmetrically participated in the act of breathing, there was percussive clear pulmonary sound over the entire surface of the lungs, auscultative-vesicular breathing, no wheezing could be detected. The respiratory rate was 20 breaths per minute. The heart tones were clear, rhythmic, pathological noises were not heard. Heart rate – 80 beats per minute, blood pressure – 80/5 0mm Hg. The abdomen was soft, palpation was painless. The tongue was clean, moist. The liver was not enlarged. The stool was frequent, liquefied, without pathological impurities. There was not any peripheral edema. Diuresis was not broken. The genitals were developed according to the male type: Ah1, P1-2, penis 5 cm, testis D = S, 5 ml each in the scrotum. Sexual development was by Tanner 2. The neurological status was without focal symptoms.

Based on complaints, medical history, life history, objective examination, an opinion was expressed in favor of a preliminary diagnosis of “Autoimmune polyglandular syndrome”. As for clinical verification of the type of disease and differential diagnosis with isolated and combined diseases of the endocrine system and non-endocrine disorders, such as primary adrenal insufficiency, secondary hypoparathyroidism, DiGeorge syndrome, Barakat syndrome, Kenny-Caffey syndrome, connective tissue diseases, mitochondrial pathology, hematological diseases, family history and acquired diseases of the gastrointestinal tract with the involvement of instrumental diagnostic methods, a comprehensive clinical and laboratory examination plan was formed.

 The results of general clinical laboratory control revealed a tendency to relative lymphopenia in peripheral blood upon admission, in the absence of pathological changes in urine.

Clinical blood analysis: erythrocytes – 4.32 × 1012/l; hemoglobin – 116 g/l; leukocytes – 4.9 × 109/l; leukocyte formula: segmented – 25%; lymphocytes – 63%; monocytes – 10%; eosinophils – 2%; platelets – 243 × 109/l; ESR – 5 mm/h.

General urine analysis: specific gravity – 1015, pH – 6.0, sugar, acetone, erythrocytes, leukocytes, protein were not determined.

According to the results of a biochemical blood test, a decrease in the level of total protein to 64.4 g/l (normal – 66-87 g/l) was revealed, against the background of a slight increase in conjugated bilirubin — 4.0 mmol/l (normal – 0-3.4 mmol/l) and aspartate aminotransferase — 42.3 mmol/l (normal – 0-37 mmol/l). There was a significant decrease in blood calcium levels: total calcium — 1.26 mmol/l (normal – 2.02–2.6 mmol/L), ionized calcium — 0.6 mmol/l (normal – 1.0–1.5 mmol/L) against the background of hyperphosphatemia to 3.6 mmol/l (normal – 0.87–1.45 mmol/l), electrolyte disorders were characterized by a tendency to hyponatremia — 126.5 mmol/l (normal – 135-146 mmol/l), hypochloremia – 90 mmol / l (normal – 98-106 mmol /l). In the study of the hormonal spectrum of blood serum before the start of therapy, there was a reduced content of parathyroid hormone in the blood — 6.2 pg/ml (normal – 8.8–76.6 pg/ml), a slight increase in prolactin levels to 982 mlU/ml (normal – 105-540 mlU/ml), a decrease in cortisol 110-98-76 nmol / l (normal – 150-660 nmol/ml) according to daily monitoring, aldosterone up to 15 pg/ml (normal – 25-315 pg/ml), as well as an increase in the level of ACTH to 624 pg/ml (normal – 18.3—57.8 pg/ml), which indicated in favor of hypoparathyroidism, hypocorticism. An increase in the level of thyroid-stimulating hormone to 6.8 micro IU/ml (normal – 0.23-3.4 micro IU/ml) with a normal free thyroxine content of 11.9 pmol/ml (normal – 10.3-24.0 pmol/ml) was a confirmation of subclinical hypothyroidism.

In the hospital, the child underwent therapy aimed at relieving the main symptoms of polyglandular insufficiency, namely intravenous drip administration of 10% calcium gluconate 10.0–15.0 ml, intramuscular administration of hydrocortisone 25 mg, followed by a transition to oral administration of 1 tablet (10 mg) 3 times a day, intravenous drip administration of a solution (5% glucose with calcium gluconate), in connection with the identified clinical and laboratory signs of subclinical hypothyroidism, it was recommended to take levothyroxine sodium 25 mcg / day. Further, the boy is recommended oral administration of alfacalcidol 1 mcg (1000 units) 3 times a day, complivit SaD3 500 mg 3 times a day, anticonvulsant therapy (prolonged form of valproic acid 600 mg / day.) with gradual cancellation for 3 months under the control of continued EEG monitoring and determination of its level in the blood.

On the background of the therapy was noted a distinct improvement in the general condition of the child: muscle weakness decreased significantly, he became active and started to walk independently, his appetite increased, stool became normal, hyperpigmentation on the face and extremities decreased, with a 4-day stay in the hospital the attacks of muscular-tonic seizures stopped, there was a stabilization of blood pressure in the range of 90/60 – 100/70 mm Hg.

The results of dynamic laboratory monitoring revealed normalization of the parameters of the peripheral blood:

General blood analysis: erythrocytes – 3.65 × 1012/l; hemoglobin – 98 g/l; leukocytes – 9.3 × 109/l; leukocyte formula: rod – 4%; segmented – 74%; lymphocytes – 18%; monocytes – 3%; platelets – 177 × 109/l; ESR – 3 mm/h.

A biochemical blood test revealed a positive dynamics of indicators characterized by a decrease in blood phosphorus levels to 2.67–2.07 mmol/l (normal –0.87–1.45 mmol/L), an increase in sodium levels to 136.7 mmol/l (normal –135-146 mmol/L), chlorine — to 94 mmol/l (normal – 98-106 mmol/L), total calcium — to 1.56 mmol/l (normal – 2.02–2.6 mmol / l), ionized calcium — 0.78 mmol / l (normal –1.0–1.5 mmol/l). The study of the hormonal spectrum of blood serum showed normalization of parathyroid hormone content – 18.2 pg/ml (normal – 8.8-76.6 pg/ml), the parameters of daily dynamics of cortisol – 206-463-460 nmol/ml (normal – 150-660 nmol/ml) and a decrease in the level of ACTH to 589 pg/ml (normal – 18.3-57.8 pg/ml).

According to the results of the instrumental examination of the internal organs of the abdominal cavity and retroperitoneal space, cardiovascular system, thyroid gland, no pathological changes were determined.

Functional research methods also did not reveal disorders of the cardiovascular and nervous systems, including the absence of paroxysmal and epileptiform graphoelements during routine and three-hour EEG video monitoring, which made it possible to doubt the presence of one of the forms of epilepsy in the examined child. The boy was also consulted by a neurologist, an optometrist, an ENT doctor and a dermatologist.

Thus, based on the conducted clinical and laboratory examination, the final clinical diagnosis was made: “Autoimmune polyglandular syndrome of the 1st type: adrenal cortex dysfunction, hypoparathyroidism, subclinical hypothyroidism, vitiligo, oral mucosal candidiasis, intestinal malabsorption” and the concomitant diagnosis “Secondary paroxysmal dyskinesia by type of focal motor seizures. Autonomic dysfunction. Violation of refraction and accommodation of both eyes. Retinal angiopathy of both eyes of the 1st stage”.

Within the framework of telemedicine technologies (according to the “doctor – doctor” system), the child was consulted at the Federal State Budgetary Institution “National Medical Research Center of Endocrinology of the Ministry of Health of the Russian Federation (ENC)”.

Medical conclusion: ICD-10 code: E31.8

Diagnosis – autoimmune polyglandular syndrome of the 1st type: adrenal cortex dysfunction, hypoparathyroidism, vitiligo, candidiasis, intestinal malabsorption.


There is no doubt that the patient is suffering from autoimmune polyglandular syndrome of the 1st type. Taking into account the presence of signs of deficiency of not only glucocorticoids, but also mineralocorticoids, the patient is to be treated with fludrocortisone at a starting dose of 0.1 mg per day, followed by the correction of the level of blood electrolytes and renin.

In the case of the effect absence of alfacalcidol therapy, the patient may initiate calcitriol therapy (rocaltrol).

The patient is to undergo an AIRE gene study. It is necessary to study the frequent mutation of R257X. In the absence of this mutation, complete sequencing of the AIRE gene is to be conducted. The study is being conducted at the National Medical Research Center of Endocrinology of the Ministry of Health of the Russian Federation within the framework of the Alpha-endo program.

Thus, this clinical case very clearly demonstrates the development of autoimmune polyglandular syndrome of the 1st type in a child with its inherent phasing of clinical manifestations. It is noteworthy that the development of oral candidiasis did not take place at the onset, but after the development of other main signs of the disease (hypoparathyroidism and hypocorticism). It is important to note that, despite the characteristic feature of the appearance of symptoms of the disease, the time from their manifestation to the final diagnosis took a long interval. In these conditions, informing a wide range of general practitioners and specialists of a narrow profile will undoubtedly help to increase their awareness. The latter, in turn, will make it possible to form a circle of differential diagnostic search as early as possible, build an examination plan and correct the detected violations, which will make it possible to prevent the development of life-threatening conditions, improve the quality and life expectancy of this category of patients.

Further monitoring of these patients should be carried out on a regular basis with laboratory monitoring of the parameters of the main components of the syndrome. Children with rare hereditary variants of hypoparathyroidism should be observed not only at the place of residence, but also in specialized medical centers with experience in monitoring patients with rare endocrine pathology.


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About the Authors

G. A. Galkina
Rostov State Medical University
Russian Federation

Galina A. Galkina, Dr. Sci. (Med.). Head. Department of Pediatric Endocrinology, Research Institute of Obstetrics and Pediatrics, Professor of the Department of Endocrinology with the Course of Pediatric Endocrinology, Rostov State Medical University; Chief freelance pediatric endocrinologist of the Southern Federal District and Ministry of Health RO


L. S. Mikhailichenko
Rostov State Medical University
Russian Federation

Lilya S. Mikhaylichenko, doctor of the pediatric endocrinology department of the Research Institute of Obstetrics and Pediatrics


D. I. Sozaeva
Rostov State Medical University
Russian Federation

Diana I. Sozaeva, Dr. Sci. (Med.), Researcher, Pediatric Department, Research Institute of Obstetrics and Pediatrics


S. B. Berezhanskaya
Rostov State Medical University
Russian Federation

Sofya B. Berezhanskaya, Dr. Sci. (Med.), Professor, chief officer of the Pediatric Department, Research Institute of Obstetrics and Pediatrics


A. A. Afonin
Rostov State Medical University
Russian Federation

Alexander A. Afonin, Dr. Sci. (Med.), chief officer of the Pediatric Department, Research Institute of Obstetrics and Pediatrics



For citation:

Galkina G.A., Mikhailichenko L.S., Sozaeva D.I., Berezhanskaya S.B., Afonin A.A. Autoimmune polyglandular syndrome type I. Features of clinical manifestations, difficulties in diagnosis and methods of correction. Medical Herald of the South of Russia. 2021;12(4):67-73. (In Russ.)

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