In most cases, adrenal insufficiency manifests before dysfunction of other endocrine glands cause clinical symptoms. Consequently, patients presenting with SS often show unspecific symptoms corresponding to Addison's disease upon the first presentation. They usually claim fatigue, weakness, nausea, vomiting, diarrhea, constipation and abdominal pain. Patients tend to lose their appetite and weight, but they may report cravings for salt. Hypotension is often registered. During the physical examination of skin and mucous membranes, hyperpigmented areas of may be recognized, particularly in skin folds and oral cavity. On the other hand, vitiligo may be noted. Vitiligo is considered a comorbidity and a possible marker of autoimmune processes, not a consequence of Addison's disease.

SS develop thyroid disorders and/or diabetes mellitus type 1 either simultaneously or in a delayed manner. Autoimmune thyroiditis and subsequent hypothyroidism are more frequently observed than Graves disease and is associated with fatigue, weakness, intolerance to cold, dry skin, myxedema, constipation and weight gain. Alopecia may be observed in some patients. Graves disease, in contrast, is characterized by symptoms of hyperthyroidism, i.e., restlessness, anxiety, intolerance to heat, arrhythmias, hypertension, diarrhea and weight loss. In some cases, thyroid disorders may manifest before adrenal insufficiency is diagnosed.

Diabetes mellitus type 1 may lead to polydipsia and polyuria.

Additional symptoms may affect parathyroid glands, pituitary gland and gonads, gastrointestinal tract and musculature [9].

• Hypoparathyroidism and hypocalcemic tetany have been reported in SS [1].
• Hypophysitis has been described in SS patients [2].
• A minor share of women suffering from SS claims amenorrhea due to ovarian failure.
• Celiac disease is often observed.
• Myasthenia gravis may be related to SS.
• Pernicious anemia may aggravate fatigue and weakness, cause tachycardia and dyspnea.

• Fatigue

  Pernicious anemia may aggravate fatigue and weakness, cause tachycardia and dyspnea. Due to SS being a genetic disorder, it is important to query the patient regarding a familial history of endocrine disorders. [symptoma.com]

  Abstract A 30 years old man with previous history of asthma complaing to weakness, fatigue, progressive weight loss, nausea, vomiting and increasing darkening of the skin was admited to the hospital. [eprints.ugd.edu.mk]

  Hashimoto thyroiditis that can present with memory problems, myalgia, fatigue, weakness sleepiness, constipation and cold intolerance Addison disease causing nausea and vomiting, loss of appetite, weight loss and fatigue Pernicious anaemia that may present [dermnetnz.org]

• Weight Loss

  note the following: Symptoms - Anorexia, nausea, vomiting, weight loss, weakness, and fatigue Signs - Chronic hyperpigmentation of creases and scars, as well as orthostatic hypotension For celiac disease, symptoms are weight loss, steatorrhea, bloating [emedicine.medscape.com]

  […] with pallor and tiredness Coeliac disease presenting with abdominal pain and cramping, fatty bowel motions, and weight loss. [dermnetnz.org]

  In this case report, Addison's disease had a slow onset in absence of the typical weight loss. In our considerations this is due to the concomitant hypothyroidism that masked some typical signs and also limited acute presentation. [ncbi.nlm.nih.gov]

  Abstract A 30 years old man with previous history of asthma complaing to weakness, fatigue, progressive weight loss, nausea, vomiting and increasing darkening of the skin was admited to the hospital. [eprints.ugd.edu.mk]

• Myxedema

  Polyglandular Type III Autoimmune Syndrome, Diabetes Mellitus-Addisons Disease-Myxedema, Type 2 Multiple Endocrine Deficiency Syndrome, Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy, Autoimmune Polyendocrinopathy with Candidiasis and [xpertdox.com]

  Polyglandular Type III Autoimmune Syndrome [T781325] Autoimmune Syndrome Type III, Polyglandular [T781326] Autoimmune Polyglandular Syndrome, Type 3 [T781327] Polyglandular Autoimmune Syndrome, Type 3 [T781328] Diabetes Mellitus, Addison's Disease, Myxedema [medvik.cz]

  Información en español Title Other Names: Diabetes mellitus, Addison's disease, myxedema; Multiple endocrine deficiency syndrome, type 2; Polyglandular autoimmune syndrome, type 2; Diabetes mellitus, Addison's disease, myxedema; Multiple endocrine deficiency [rarediseases.info.nih.gov]

  […] in familial polyglandular failure. 56 Eisenbarth G...Lebovitz HE 619238 1978 13 Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. 56 Bottazzo GF...Doniach D 4139522 1974 14 DIABETES MELLITUS, ADDISON'S DISEASE AND MYXEDEMA [malacards.org]

• Loss of Appetite

  A 39-year-old woman presented with a 10-day history of epigastric pain accompanied by persistent fatigue and loss of appetite for 3 months. [ncbi.nlm.nih.gov]

  […] of appetite for 1 month and progressive fatigability for the preceding 4 months. [casereports.bmj.com]

  [Case Reports] BMJ Case Rep 2019; 12(2)Arya P V A, Kumar J, … Raj RBC A 24-year-old man with no significant medical history presented to the medical clinic with vomiting and giddiness for 2 days, loss of appetite for 1 month and progressive fatigability [unboundmedicine.com]

  Nine months prior to her referral, she started complaining of various symptoms, among which, weakness, fatigue, alopecia (hair loss), constipation, and loss of appetite resulting in a weight loss of about 12kg within a period of eight months. [austinpublishinggroup.com]

  Hashimoto thyroiditis that can present with memory problems, myalgia, fatigue, weakness sleepiness, constipation and cold intolerance Addison disease causing nausea and vomiting, loss of appetite, weight loss and fatigue Pernicious anaemia that may present [dermnetnz.org]

• Hypotension

  On examination, he was found to be hypotensive and was admitted to the hospital for work-up. [unboundmedicine.com]

  Symptoms - Polyuria, polydipsia, polyphagia, unexplained weight loss, intermittent blurred vision, and lethargy (may present initially with diabetic ketoacidosis and coma) Signs - Depend on the severity; consist of poor skin turgor, orthostasis, and hypotension [emedicine.medscape.com]

  Recent history of her illness revealed the presence of thyroidopathy, hyperpigmentation, hypotensive episodes and various other general signs and symptoms. [austinpublishinggroup.com]

  On examination, he was found to be hypotensive and was admitted to the hospital for work-up. Considering his abnormal labs and physical findings, he was worked up and was diagnosed with primary adrenal insufficiency. [casereports.bmj.com]

  She reported having stopped antihypertensive therapy due to hypotension and presented a glycemic record with frequent hypoglycemia. On physical examination, she had cutaneous hyperpigmentation. [scielo.br]

• Orthostatic Hypotension

  hypotension For celiac disease, symptoms are weight loss, steatorrhea, bloating, cramping, and malnutrition. [emedicine.medscape.com]

  She, frequently experienced symptoms and signs of orthostatic hypotension, with a systolic blood pressure of 80 -100mmHg. Furthermore, the patient began having altered mental status with behavioral changes like apathy, indifference and sleepiness. [austinpublishinggroup.com]

  Despite the fact that hypoadrenalism is characterized by specific symptoms and signs (asthenia, fatigue, orthostatic hypotension, weight loss, nausea, arthralgia, anorexia, skin hyperpigmentation) it is not easy to diagnose at early stages. [journals.sagepub.com]

  Common signs in these patients may include mucosal and cutaneous hyperpigmentation low blood glucose levels and orthostatic hypotension if Addison disease is the diagnosis or polyuria and polydipsia with hyperglycemia if T1DM is present. [statpearls.com]

  She also presented with orthostatic hypotension with blood pressure levels on the supine and sitting position 90/70 mmHg and 70/57mmHg respectively. [ncbi.nlm.nih.gov]

• Arthralgia

  Despite the fact that hypoadrenalism is characterized by specific symptoms and signs (asthenia, fatigue, orthostatic hypotension, weight loss, nausea, arthralgia, anorexia, skin hyperpigmentation) it is not easy to diagnose at early stages. [journals.sagepub.com]

  Indeed, in a restricted number of cases a maculopapular, or morbilliform, or urticaria-like skin rash, eventually accompanied by fever, splenomegaly and arthralgia, has been reported [2, 3, 6–18]. [bmcpediatr.biomedcentral.com]

  The personal history revealed ulcerative colitis and, during the last year, episodes of fever with migrant arthralgia and cutaneous lesions. [link.springer.com]

  Fever, oral ulcerations, arthralgias, neutropenia, and a polycyclic skin eruption in a 14-year-old girl. Pediatr Dermatol. 2009 May-Jun; 26(3):347-8. View abstract Wang CF, Gerner P, Schmidt B, Xu ZZ, Nau C, Wang SY, Ji RR, Wang GK. [childrenshospital.org]

  Familial cold autoinflammatory syndrome 4 is an autosomal dominant disease caused by heterozygous mutation in the NLRC4 gene and characterized by intermittent episodes of rash, arthralgia, and fever after exposure to cold[ 38 ]. [wjgnet.com]

• Hyperpigmentation

  Hyperpigmentation over the dorsum of hands. [ncbi.nlm.nih.gov]

• Dizziness

  We present the case of a 42-year-old woman with a history of total thyroidectomy due to Graves’ disease, type 2 diabetes mellitus, and hypertension, who sought the ED due to asthenia, dizziness, nausea, and vomiting. [scielo.br]

  Four weeks later she presented to our emergency department with dizziness and worsening fatigue. On examination she was conscious, alert, and thin-built with hyper-pigmentation of palms, soles, nail-beds and the tongue [Fig.1]. [casereports.in]

  Other symptoms consistent with adrenal insufficiency include dizziness and orthostasis, anorexia, weakness, nausea, emesis and abdominal pain, salt craving[1]. [hopkinsguides.com]

  Four months later, the patient presented with dizziness, nausea, nonbloody vomiting, and fever without inducing factors. She self-administered antibiotics and acetaminophen, without improvement. [journals.lww.com]

  Fatigue, anorexia, dizziness, muscle and joint pain, decreased libido may be some of the clinical features at the early stages of the disease [8]. Psychiatric manifestations are also well-documented [9]. [ncbi.nlm.nih.gov]

Due to SS being a genetic disorder, it is important to query the patient regarding a familial history of endocrine disorders.

Generally, laboratory analyses of blood samples yield multiple alterations that may be ascribed to the distinct components of this polyendocrinopathy.

• Addison's disease causes hypoglycemia, hyponatremia, hyperkalemia and acidosis.
• Thyroid disorders cause decreased levels of triiodothyronine (T3) and thyroxine (T4) despite high concentrations of thyroid-stimulating hormone (TSH) or vice versa in hypothyroidism and hyperthyroidism, respectively.
• Diabetes mellitus type 1 is associated with insulin-dependent hyperglycemia.

Additional findings may point at the involvement of other organs. Further diagnostic measures don't differ from those applied to determine single endocrinopathies and should be taken if the results of blood sample analyses imply a certain entity. An ACTH stimulation test is recommended to confirm primary adrenal insufficiency. Thyroid function tests, for instance, are indicated if the clinical presentation and serum levels of T3, T4, and TSH suggest hypothyroidism or Graves disease.

Measurement of organ-specific autoantibodies is a sensitive method that allows for an early detection of endocrinopathies before tissue damage suffices to cause symptoms [10].

A patient may be diagnosed with SS if they present symptoms of Addison's disease and thyroid disorders or diabetes mellitus type 1, and if autoantibodies are detected that support the tentative diagnosis of an autoimmune disease.

Patients diagnosed with SS (and possibly even those only suffering from Addison's disease) should undergo regular follow-ups in order to identify comorbidities before severe symptoms manifest. Such follow-ups should comprise blood sample analyses and thyroid function tests.

• Hyponatremia

  Severe hyponatremia seems to be found more often in patients with severe hypothyroidism. To our knowledge this is the first case to describe the occurrence of severe hyponatremia with normal thyroid function test and normal baseline cortisol level. [link.springer.com]

  The only blood chemistry abnormalities were hyponatremia (125 mEq/L) and hyperkalemia (6.8 mEq/L). Based on the clinical and biologic picture, adrenal insufficiency was suspected. [ncbi.nlm.nih.gov]

  Blood tests showed hyperkalemia, hyponatremia, elevated creatinine and inadequate response to cosicotropine stimulation test. [austinpublishinggroup.com]

  She was taken to the Emergency Department because she complained of abdominal pain, nausea and vomiting, and her blood analysis revealed a severe hyponatremia. She also had seizures as a consequence of the hyponatremia and frequent hypoglycemia. [hormones.gr]

Treatment regimes correspond to those described for the individual endocrinopathies that form part of SS. Before initiation of treatment, a complete workup needs to be performed. Patients suffering from multiple endocrinopathies may present with adverse events to otherwise well-tolerated drugs. Substitution of thyroid hormones, for instance, may trigger an Addisonian crisis in people suffering from concurrent adrenal insufficiency.

The following drugs are the mainstays of SS therapy:

• So as to compensate for adrenal insufficiency, patients receive hydrocortisone and fludrocortisone to replace glucocorticoids and mineralocorticoids.
• Levothyroxine is the drug of choice in case of hypothyroidism.
• In contrast, anti-thyroid drugs are required by patients presenting with Graves disease. Radiolabeled iodine and surgery constitute therapeutic alternatives.
• Diabetes mellitus type 1 is treated with insulin.

SS patients require life-long treatment. They need to understand that compliance with drug therapy significantly improves their prognosis.

There is no causative treatment for SS; components of this syndrome have to be treated individually and symptomatically. In general, hormone deficits can be compensated for by means of drug therapy and patients are able to lead a relatively normal life. However, Addisonian crisis, thyrotoxic crisis, and diabetic ketoacidosis are life-threatening complications of decompensated endocrinopathies and it is of utmost importance that patients are aware of those risks. Additionally, significant morbidity may arise from long-term decompensation of serum hormone levels, e.g., peripheral neuropathy, nephropathy, and retinopathy in the case of hyperglycemia due to diabetes mellitus type 1.

SS is an autoimmune disorder presumably caused by determined gene patterns. Rather than being triggered by a single mutation, polygenic inheritance seems to lead to this polyendocrinopathy. Consequently, precise inheritance patterns cannot be defined; some genes that contribute to a predisposition for SS may be inherited as an autosomal dominant trait, others in an autosomal recessive manner. Sex chromosomes don't seem to be involved in SS inheritance.

It has been suggested that certain HLA haplotypes may predispose for SS. This hypothesis originates from studies conducted with patients suffering from Addison's disease, a main component of SS. Here, haplotypes comprising HLA-DR3, HLA-DR4, HLA-DQ2, and HLA-DQ8 are associated with a high risk for adrenal insufficiency [3]. Further research is required to confirm that these findings are also applicable to SS.

Of note, SS may also be diagnosed in patients whose family has no medical history of autoimmune disorders. It is not yet clear whether these sporadic cases correspond to recombination, de novo mutation or diseases triggered by environmental factors in a given genetic background.

Little is known about the autoimmune response that causes symptom onset. It has been proposed that SS may manifest in patients who suffered from congenital rubella syndrome. The latter has been related to adult-onset hypothyroidism, diabetes mellitus, growth hormone deficiency and autoimmune disorders [4]. Dietary factors may also alter the individual susceptibility for SS.

In developed countries, the overall incidence of SS has been estimated to be less than 5 per 100,000 inhabitants [5]. The risk of developing SS may be increased 50-fold in people who inherited one of the aforementioned HLA haplotypes and is highest in those patients previously diagnosed with Addison's disease. These estimates are based on the following observations:

• Addison's disease is the most frequently observed initial manifestation of SS.
• The overall incidence of Addison's disease is 10 per 100,000 inhabitants and 500 per 100,000 carriers of determined HLA haplotypes [3].
• People suffering from an autoimmune disease are more prone to develop another, similar disorder than their healthy peers [6]. In the case of Addison's disease, up to 50% of affected individuals will develop another autoimmune disorder, e.g., thyroid disorders or diabetes mellitus [7].

With regards to SS, women are affected about three times as often as men. Symptom onset typically occurs during the third or fourth decade of life, but this type of polyendocrinopathy has also been diagnosed in pediatric and elder patients [5].

The pathogenesis of SS is poorly understood and only general statements can be made regarding the pathophysiological events leading to dysfunction of multiple endocrine glands and other organs in this pathology.

As has been indicated above, SS is primarily considered a genetic disorder. With regards to HLA haplotypes and polymorphisms related to SS, penetrance and expressivity seem to vary widely. Symptom onset rarely occurs in childhood and the patient's immune system works just fine until well into adulthood. Thus, environmental, dietary or intrinsic factors are assumed to trigger an autoimmune response in patients predisposed to this type of polyendocrinopathy. In this context, SS may likely be classified as a multifactorial disease.

The nature of SS trigger(s) is not clear; they induce an autoimmune response and production of distinct, organ-specific autoantibodies. Their target structures, namely adrenal glands, thyroid cells and the endocrine pancreas, are progressively destroyed by the patient's own immune system. Symptom onset does not occur until considerable shares of hormone-producing cells are destructed.

Histopathological analysis of affected glands shows focal or generalized infiltration with lymphocytes and extensive tissue damage [8].

Medical bracelets may identify SS patients in case of emergency and guide their treatment.

First degree relatives of SS patients should undergo genetic testing to diagnose this autoimmune disorder before symptom onset. Additionally, affected families may benefit from genetic counseling.

Despite being the most common polyendocrinopathy, Schmidt syndrome (SS) is a rare disorder. Alternative denominations for that same disease are autoimmune polyendocrine syndrome type 2 or polyglandular autoimmune syndrome type 2.

SS is considered a genetic disorder, but the disease has not been related to determined polymorphisms or mutations. According to current knowledge, polygenic inheritance and environmental factors contribute to predisposition and symptom onset. First symptoms typically manifest in adulthood, but patients pertaining to all age groups may be affected. Women are affected significantly more often than men.

As per definition, SS may be diagnosed if a patient presents with Addison's disease and thyroid disorders and/or diabetes mellitus type 1. With regards to thyroid dysfunction, both primary hypothyroidism and Graves disease may be associated with SS, but the former is more common. Additionally, parathyroid glands, pituitary gland, and gonads may be compromised by the autoimmune response occurring in SS patients [1] [2]. Celiac disease, myasthenia gravis, pernicious anemia and vitiligo may also be observed.

Of note, the diagnosis of autoimmune polyendocrine syndromes is based on the presence or absence of certain symptoms. Types 1, 3 and 4 are defined as follows:

• Type 1 is characterized by hypoparathyroidism, Addison's disease, and chronic mucocutaneous candidiasis. It is typically diagnosed in childhood; two out of three symptoms are required for diagnosis.
• Type 3 is marked by those symptoms described for SS except for adrenal insufficiency.
• Type 4 is a polyendocrinopathy that does not fulfill the criteria for either types 1, 2 or 3.

Schmidt syndrome (SS) is a rare autoimmune disorder characterized by multiple endocrinopathies. The disease may also be referred to as autoimmune polyendocrine syndrome type 2.

Causes

SS is a genetic disorder, i.e., inheritance of certain genomic pattern predisposes patients for this disease. However, penetrance and expressivity vary largely and neither do all patients that carry those patterns develop SS nor do all SS patients present the same symptoms.

Symptom onset usually occurs in adulthood and is caused by the induction of an autoimmune response. Here, the body's immune system produces antibodies against its adrenal and thyroid glands, against the pancreas that secretes insulin and sometimes also against other endocrine glands.

Symptoms

SS patients suffer from Addison's disease and thyroid disorders and/or diabetes mellitus type 1. Commonly observed symptoms may be ascribed to those endocrinopathies and may comprise the following:

• Fatigue, weakness
• Loss of appetite, nausea, vomiting, diarrhea, constipation and abdominal pain
• Weight fluctuations
• Hyperpigmented skin and mucous membranes
• Altered blood pressure
• Vitiligo
• Intolerance to cold or heat
• Excessive thirst and frequent urination

Diagnosis

Clinical examination and laboratory analyses of blood samples allow for a tentative diagnosis of polyendocrinopathy. Special tests have to be carried out to confirm adrenal insufficiency, thyroid malfunction or diabetes mellitus, though.

Measurement of autoantibodies is required to proof that observed symptoms are provoked by an autoimmune response.

Treatment

Treatment mainly consists in the substitution of lacking hormones. Lifelong therapy is required.

Glucocorticoids and mineralocorticoids are prescribed in case of Addison's disease; levothyroxine is required if SS patients suffer from hypothyroidism. In the case of Graves disease - a form of hyperthyroidism - excess production of thyroid hormones needs to be limited by means of medication, radiolabeled iodine or surgery. Diabetes mellitus type 1 is treated with insulin.

Compliance with drug therapy significantly affects the patient's prognosis since decompensation of hormonal levels may cause the Addisonian crisis, thyrotoxic crisis or diabetic ketoacidosis, which are life-threatening events.

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2. Hrubiskova K, Jackuliak P, Vanuga P, Pura M, Payer J. [Autoimmune polyendocrine syndrome type 2 associated with autoimmune hypophysitis and coeliac disease]. Vnitr Lek. 2010; 56(11):1169-1176.
3. Robles DT, Fain PR, Gottlieb PA, Eisenbarth GS. The genetics of autoimmune polyendocrine syndrome type II. Endocrinol Metab Clin North Am. 2002; 31(2):353-368, vi-vii.
4. Forrest JM, Turnbull FM, Sholler GF, et al. Gregg's congenital rubella patients 60 years later. Med J Aust. 2002; 177(11-12):664-667.
5. Metwalley KA, Farghaly HS. Hepatitis C virus infection in a child with autoimmune polyendocrine syndrome type 2: a case report. J Med Case Rep. 2012; 6:221.
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7. Meyer G, Neumann K, Badenhoop K, Linder R. Increasing prevalence of Addison's disease in German females: health insurance data 2008-2012. Eur J Endocrinol. 2014; 170(3):367-373.
8. Kahaly GJ. Polyglandular autoimmune syndrome type II. Presse Med. 2012; 41(12 P 2):e663-670.
9. Betterle C, Lazzarotto F, Presotto F. Autoimmune polyglandular syndrome Type 2: the tip of an iceberg? Clin Exp Immunol. 2004; 137(2):225-233.
10. Falorni A, Laureti S, Santeusanio F. Autoantibodies in autoimmune polyendocrine syndrome type II. Endocrinol Metab Clin North Am. 2002; 31(2):369-389, vii.