2021 年 68 巻 10 号 p. 1187-1195
Chromosome 22q11.2 deletion syndrome is a multisystem genetic disorder that presents with hypocalcemia due to congenital hypoparathyroidism; cardiovascular, renal, and facial anomalies; and skeletal defects. This syndrome is also associated with an increased risk of autoimmune disease. We report here on a 33-year-old Japanese woman with 22q11.2 deletion syndrome complicated by Graves’ disease. The patient had facial abnormalities and a history of a surgical procedure for a submucous cleft palate at age 3 years. At age 33, the patient was diagnosed with Graves’ disease because both hyperthyroidism and thyroid stimulating hormone receptor antibody were present. The patient’s serum calcium level was within the normal range, but symptomatic hypocalcemia developed 1 month after treatment with methimazole was started for thyrotoxicosis. Methimazole was discontinued because it caused liver dysfunction, so the patient underwent total thyroidectomy to treat her Graves’ disease. We examined longitudinal changes in the number of subsets of CD4 and CD8 lymphocytes, including regulatory T (T reg) cells and PD-1+CD4+ and PD-1+CD8+ T cells, after treatment by total thyroidectomy. A flowcytometry analysis demonstrated that circulating PD-1+CD4+ and PD-1+CD8+ T cells gradually decreased over time, as did circulating T reg cells and circulating CD19+ B cells. These findings suggest that PD-1-positive CD4+ and CD8+ T cells and T reg cells may have been associated with the autoimmunity in our patient with chromosome 22q11.2 deletion syndrome complicated by Graves’ disease.
CHROMOSOME 22q11.2 DELETION SYNDROME is a common microdeletion syndrome that occurs in approximately 1 in 3,000 to 4,000 births [1, 2]. This syndrome is associated with hypocalcemia due to congenital hypoparathyroidism; cardiovascular, renal, and eye anomalies; cleft palate; skeletal defects; and developmental delay [1, 2]. Thymic hypoplasia is observed in more than 80% of patients [1]. Patients with this syndrome also have an increased incidence of autoimmune diseases, including celiac disease and autoimmune thyroid disease [1, 2]; a previous report found concomitant autoimmune diseases in 33% of patients [3]. Although the mechanisms responsible for the causal relationship between 22q11.2 deletion syndrome and autoimmunity remain unclear, thymic hypoplasia may result in a decrease in the number and immune function of T cells, especially regulatory T (T reg) cells, which may contribute to the increased risk of autoimmune diseases in this syndrome [4].
The inhibitory receptor programed cell death protein-1 (PD-1) downregulates the activation and proliferation of T cells and thus helps to maintain peripheral self-tolerance [5]. Recently, several reports described new-onset autoimmune endocrine diseases after administration of PD-1 or PD-1 ligand 1 antibodies to treat cancer [5], suggesting that blockade of the PD-1 pathway may be associated with the development of autoimmune disorders in chromosome 22q11.2 deletion syndrome.
Graves’ disease is a common cause of thyrotoxicosis, which in Graves’ disease is characterized by increased thyroid hormone production due to the presence of thyroid-stimulating hormone receptor antibody (TRAb). Complications of 22q11.2 deletion syndrome and Graves’ disease are relatively rare [6-11].
Here, we report on a 33-year-old Japanese woman with 22q11.2 deletion syndrome complicated by Graves’ disease who presented with symptomatic hypocalcemia after treatment with methimazole for thyrotoxicosis. To obtain information on the effects of treatment on the immune system, we examined longitudinal changes in the number of subsets of CD4 and CD8 lymphocytes, including T reg cells and PD-1+ CD4+ T cells, after treatment by total thyroidectomy.
A 33-year-old Japanese woman presented with breathing difficulties at a nearby hospital. She reported having excessive sweating and finger tremors since about six months before. At this visit, she was diagnosed with Graves’ disease because of the presence of both hyperthyroidism (4.39 ng/dL of free thyroxine [FT4]; >30.0 pg/mL of free triiodothyronine [FT3]; and <0.003 μIU/mL of thyroid-stimulating hormone [TSH]) and TRAb (>40 IU/mL).
A few days after, the patient was referred to the outpatient clinic at our hospital for treatment. The clinic confirmed the presence of hyperthyroidism (FT4: 3.85 ng/dL; FT3: ≥30 pg/mL: and TSH: ≤0.01 μIU/mL). Serum calcium was normal (9.2 mg/dL), but serum phosphate was elevated (4.7 mg/dL) (Fig. 1). Treatment was started with 30 mg/day methimazole for thyrotoxicosis. One month after starting methimazole, laboratory findings showed elevated liver enzymes, ie, 56 IU/L of aspartate aminotransferase (AST) and 57 IU/L of alanine aminotransferase (ALT). Although the dose of methimazole was immediately decreased to 15 mg/day, the patient’s liver dysfunction deteriorated one week later. She also complained of general muscle spasms and tingling in the extremities. She was admitted to our hospital for emergency treatment.
Clinical course: Changes in treatment and thyroid function (F-T4, F-T3, and TSH), serum calcium, and phosphate levels before total thyroidectomy.
On admission, the patient still had finger tremor, and Trousseau sign was present. She was 155.5 cm tall, weighed 50.9 kg, and had a body mass index of 21.2 kg/m2. Her temperature was slightly elevated (37.0°C), her blood pressure was normal (128/63 mmHg), and her pulse was normal and regular (84 beats per minute). She had facial abnormalities, including swelling of the eyelids, narrowing of the palpebral fissure, lower and lateral displacement of both auricles, and expansion of the nasal apex. Her mouth was smaller than normal. She had a diffusely enlarged goiter but no pain. A systolic murmur was heard at the cardiac apex. The patient had a history of a surgical procedure for a submucous cleft palate at age 3 years. She had been diagnosed with a learning disability and was mentally retarded. She had no family history of thyroid or parathyroid disease.
We diagnosed hypocalcemia (serum calcium, 5.5 mg/dL) and hyperphosphatemia (serum phosphate, 4.8 mg/dL). The urinary excretion of calcium was decreased to less than 0.02 g/gCr, and the tubular reabsorption of phosphate (%TRP) was elevated to 92.37%. To treat the hypocalcemia, we administered calcium gluconate intravenously and 0.25 μg/day oral calcitriol and 1,200 mg/day calcium L-aspartate. After about 2 hours, serum calcium had increased to 7.3 mg/dL, serum intact parathyroid hormone (PTH) was 59.7 pg/mL, and 1,25(OH)2D had increased to 145 pg/mL, while 25(OH)D was low (<4.0 pg/mL of 25(OH)D2 and <11.2 ng/mL of 25(OH)D3). Both AST and ALT had normalized; however, ALP was still elevated at 1,079 IU/L. The bone resorption markers urinary N-terminal teropeptide (NTx) and serum tartrate-resistant acid phosphatase 5b (TRACP-5b) were markedly elevated at 206 nmol BCE/mmol and 842 mU/dL, respectively. Bone-specific alkaline phosphatase (ALP) also was increased to 132 μg/L (Table 1). Dual-energy X-ray absorptiometry (DXA) showed an extremely low bone mineral density, with a mean lumber T-score of –3.1 standard deviations (SD).
| Reference range | Reference range | Reference range | Reference range | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Chemistry (On admission: day 1) | Hematology (On admission: day 1) | Urinalysis (day 2) | (day 2) | ||||||||||||
| AST | 94 | IU/L | 13–30 | WBC | 6,300 | /μL | 3,300–8,600 | UN | 365 | mg/dL | Ca | 7.3 | mg/dL | 8.8–10.1 | |
| ALT | 119 | IU/L | 10–42 | Neutro | 65.4 | % | 42.4–75.0 | Na | 125 | mmol/L | IP | 5.7 | mg/dL | 2.7–4.6 | |
| ALP | 1,399 | IU/L | 106–322 | Eosino | 3.8 | % | 0.4–8.6 | K | 19 | mmol/L | Intact PTH | 59.7 | pg/mL | 14–72 | |
| LDH | 201 | IU/L | 124–222 | Baso | 1 | % | 0.2–1.4 | Cl | 95 | mmol/L | PTH-rP | <1.1 | pmol/L | <1.1 | |
| γGTP | 99 | IU/L | 9–32 | Moc | 7.6 | % | 3.3–9.0 | Ca | <1 | mg/dL | F-T4 | 0.33 | ng/dL | 0.70–1.48 | |
| T-Bil | 0.7 | mg/dL | 0.4–1.5 | Lympho | 23.1 | % | 18.2–47.7 | P | 41 | mg/dL | F-T3 | 2.03 | pg/mL | 1.71–3.71 | |
| BUN | 7 | mg/dL | 8.0–20.0 | RBC | 473 | 104/μL | 386–492 | Cr | 47 | mg/dL | TSH | 0.01 | μIU/mL | 0.35–4.94 | |
| Cre | 0.42 | mg/dL | 0.46–0.79 | Hb | 13.2 | g/dL | 11.6–14.8 | %TRP | 92.4 | % | TRAb | >40 | IU/mL | <2.0 | |
| eGFR | 135.8 | 60–120 | Hct | 42.4 | % | 35.1–44.4 | TmP/GFR | 4.43 | mg/dL | 2.3–4.3 | TgAb | 571 | IU/mL | –13.6 | |
| CK | 1,202 | U/L | 41–153 | Plt | 25.4 | 104/μL | 15.8–34.8 | TPOAb | 1,020 | IU/mL | –3.2 | ||||
| UA | 4.2 | mg/dL | 2.5–7.0 | Immunology (day 12) | thyroglobulin | 228 | ng/mL | –33.7 | |||||||
| TP | 7.5 | g/dL | 6.6–8.1 | IgG | 1,425 | mg/dL | 861–1,747 | (day 3) | |||||||
| Alb | 4 | g/dL | 4.1–5.1 | Blood gas analysis (day 2) | IgG4 | 32.7 | mg/dL | 4.8–105 | 1,25(OH)2D | 145 | pg/mL | 20–60 | |||
| Na | 141 | mEq/L | 138–145 | pH | 7.409 | 7.350–7.450 | IgA | 291 | mg/dL | 93–393 | 25(OH)D2 | <4.0 | ng/mL | –12.1 | |
| K | 3.8 | mEq/L | 3.6–4.8 | pCO2 | 39.6 | mmHg | 35.0–45.0 | IgM | 122 | mg/dL | 50–269 | 25(OH)D3 | 11.2 | ng/mL | 5.5–41.4 |
| Cl | 104 | mEq/L | 101–108 | pO2 | 96.9 | mmHg | 85.0–105.0 | (day 3) | |||||||
| Ca | 5.5 | mg/dL | 8.8–10.1 | base exess | 0.5 | mmol/L | –2.3–2.3 | GH | 1.2 | ng/mL | <2.1 | ||||
| IP | 4.8 | mg/dL | 2.7–4.6 | HCO3– | 24.6 | mmol/L | 23.0–28.0 | Bone metabolic markers (day 17) | IGF-1 | 89 | ng/mL | 119–283 | |||
| Mg | 1.7 | mg/dL | 1.8–2.6 | U-NTx | 206 | nmol/mmol·Cr | 7.5–16.5 | ACTH | 61.8 | pg/mL | 7.7–63.1 | ||||
| Glu | 173 | mg/dL | 73–109 | TRACP-5b | 842 | mU/dL | 120–420 | cortisol | 18.9 | μg/dL | |||||
| BNP | 386.6 | pg/mL | –18.4 | Bone ALP | 132 | μg/L | 2.9–14.5 | PRL | 14.6 | ng/mL | |||||
| LH | 8.86 | mIU/mL | |||||||||||||
| FSH | 6.8 | mIU/mL | |||||||||||||
| estradiol | 24.5 | pg/mL | |||||||||||||
The electrocardiogram showed a prolonged QT interval (corrected QT interval: 0.53 s). Echocardiography found a low left ventricular ejection fraction of 43%, diffuse hypokinesis of left ventricular wall motion, left ventricular diastolic dysfunction (ratio of early diastolic filling velocity to atrial filling velocity rate: 2.8), and mild tricuspid regurgitation and pulmonary regurgitation. A computed tomography scan of the brain did not reveal calcification in the basal ganglia or brain atrophy. Thyroid ultrasonography showed a markedly diffuse enlargement of the thyroid gland with increased blood flow (Fig. 2a, b).
Thyroid ultrasonography and light microscopic findings of thyroid gland (H-E staining). a)–b) Thyroid ultrasonography showing the markedly diffuse enlargement of both thyroid glands. c) Histological examination of the extracted thyroid tissue showed typical findings of Graves’ disease such as hyperplasia of the follicle epithelium (blue circle), vacuolation of the follicular colloidal cavity (red arrow), and accumulation of lymphocytes around thyroid follicular cells.
On the basis of the patient’s facial appearance, history of submucosal cleft palate, and hypocalcemia, we suspected the presence of 22q11.2 deletion syndrome. A subsequent fluorescence in situ hybridization analysis demonstrated a microdeletion within the 22q11.2 region.
Anti-thyroid drugs could no longer be administered because methimazole had caused liver dysfunction. Therefore, we made an early decision to treat the patient’s Graves’ disease by total thyroidectomy. It took a few months to obtain the patient’s and relatives’ consent for the surgical procedure, but the patient underwent total thyroidectomy. Pathological examination of the extracted thyroid tissue showed typical findings of Graves’ disease, such as hyperplasia of the follicle epithelium, vacuolation of the follicular colloidal cavity, and accumulation of lymphocytes around thyroid follicular cells (Fig. 2c).
After total thyroidectomy, the patient developed hypothyroidism and was initially administered 25 μg/day levothyroxine sodium; the dose was then gradually increased to 125 μg/day. Just over one year after thyroidectomy, the patient’s serum calcium and phosphate were 8.9 mg/dL and 3.5 mg/dL, respectively. About two years after thyroidectomy, urinary NTx and serum TRACP-5b had normalized to 4.4 nmol BCE/mmol and 116 mU/dL, respectively. Bone-specific ALP had also decreased to 10.3 μg/L. Thus, bone metabolism was improved. DXA showed improved bone mineral density, with a mean lumber T-score of -1.2 SD. And, TRAb was decreased to 1.8 U/L.
Flow cytometry revealed that circulating T reg cells, assessed by measuring CD4+ FoxP3+ CD25+ cells, gradually decreased over time after total thyroidectomy, as did both circulating PD-1+CD4+ and PD-1+CD8+ T cells (Table 2).
| Before thyroidectomy | After thyroidectomy | 2 years after thyroidectomy | Reference range | |
|---|---|---|---|---|
| CD4+PD-1+/CD4+ T cells (%) | 3.52 | 1.64 | 1.19 | 2.00–5.50 |
| CD8+PD-1+/CD8+ T cells (%) | 2.3 | 0.8 | 0.47 | 0.90–5.92 |
| Th1 (IFNγ+IL-4–)/CD4+T cells (%) | 8.4 | 8.1 | 5.7 | 3.9–26.2 |
| Th2 (IFNγ–IL-4+)/CD4+T cells (%) | 1.6 | 0.2 | 0.6 | 0.32–3.24 |
| Th1/Th2 ratio | 5.1 | 44.7 | 9 | 6.34–29.67 |
| CD4+CD25+FoxP3+/CD4+ T cells (%) | 2.33 | 0.6 | 0.22 | 1.44–9.52 |
| WBC count (/μL) | 4,500 | 5,800 | 4,500 | |
| Lymphocyte (%) | 35.4 | 35.5 | 29.8 | |
| Lymphocyte count (/μL) | 1,593 | 2,059 | 1,341 | |
| CD3 (%) | 75.2 | 84.8 | 58.0–84.0 | |
| CD4 (%) | 56.4 | 62.5 | 25.0–56.0 | |
| CD8 (%) | 16.4 | 20.2 | 17.0–44.0 | |
| CD19 (%) | 13.4 | 3.6 | 5.0–24.0 | |
| CD56 (%) | 10.1 | 10.0–38.0 | ||
| CD4/CD8 | 3.44 | 3.09 | 0.60–2.90 | |
| FT4 | 0.59 | 0.45 | 1.45 | 0.70–1.48 |
| FT3 | 2.19 | 0.74 | 1.61 | 1.71–3.71 |
| TSH | 0.01 | 32.21 | 0.48 | 0.35–4.94 |
| TRAb | >40 | 1.7 | <2.0 |
We reported on a 33-year-old Japanese woman with chromosome 22q11.2 deletion syndrome complicated by Graves’ disease who presented with symptomatic hypocalcemia after treatment for thyrotoxicosis. 22q11.2 deletion syndrome is associated with an increased risk for autoimmune diseases, including autoimmune thyroid diseases, which occur in 10% to 33% of patients [3, 12, 13]. However, Graves’ disease is relatively rare in 22q11.2 deletion syndrome. Table 3 summarizes the clinical characteristics of our patient and other patients with both 22q11.2 deletion syndrome and Graves’ disease presented in previous reports [6-11]. Our patient underwent total thyroidectomy for treatment of Graves’ disease once anti-thyroid drugs could no longer be administered because of methimazole-induced liver damage. Upon hematoxylin and eosin staining, the resected thyroid tissue had the typical appearance of autoimmune Graves’ disease.
| Case | age (yrs) | sex | diagnosis | facial anomalitis | mental/learning disabilities | cardiovasculer anomalitis | thyroid gland | Ca (mg/dL) | IP (mg/dL) | intact PTH (pg/mL) | TRAb | TSAb | TgAb | TPOAb | thyrod test | mycrosome test | References No. |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 19 | F | GD at 11 years-old/Hypocalcemia at 19 years-old | telecanthus/nasal apex/fish mouth | completed high school education | diffuse enlargement | 6.7 | 4.8 | 34 | 2,080 IU/L | 1,072% | 8 IU/mL | 1,012 IU/mL | [6] | |||
| 2 | 68 | F | GD and hypocalcemia simultaneously at 68 years-old | telecanthus/prominent nose with a large tip/hypoplastic nose/small mouth | scizopherenia at 20 years-old | mild diffuse enlargement | 6.9 | 3.5 | 7.0 | N/A | 164% | 30.2 IU/mL | 581.5 IU/mL | [6] | |||
| 3 | 18 | F | December 1996: diagnosed with GD followed by hypocalcemia a few months later | small auriculas/low position of ears | mantal development was normal | diffuse enlargement | 5.4 | 8.1 | ×6,400 | ×6,400 | [7] | ||||||
| 4 | 19 | F | GD at 17 years-old/Hypocalcemia at 18 years-old | submucosal cleft palate/hypernasal speech/hooded eyelids/short palpebral fissures/boxlike nose/hypoplastic alae nasi | speech delay/mental retardation (borderline) | diffuse goitor | 4.2 | 39% | NA | 3.2 U/mL | ×100 | [8] | |||||
| 5 | 20 | F | GD and hypocalemia at 10 years-old | velopharyngeal incompetence/hooded eyelids/boxlike nose/hypoplastic nasi/small mouth | IQ 70 | tetralogy of Fallot | 35.1% | NA | NA | <×100 | <×100 | [8] | |||||
| 6 | 15 | F | Hypocalcemia at 2 years-old/GD at 7 years-old | velopharyngeal incompetence/hooded eyelids/boxlike nose/malar hypoplasia | IQ 60 | 13.7% | 4.0 μU/mL | NA | <×100 | ×1,600 | [8] | ||||||
| 7 | 17 | M | Hypoparathyroidism at 12 years-old/GD at 16 years-old | hooded eyelids/short palpebral fissures/boxlike nose/strabismus | schizophrenia | tetralogy of Fallot | smoothly enlarged | 5.3 | 3.4% | 110% | NA | <×100 | ×400 | [8] | |||
| 8 | 5 | F | Hypocalcemia by hypoparathyroidism at 3 months-old/GD at 2 years-old | conoseptal hypoplasia type ventricular septal defect/bicuspid aortic valve/interrupted aortic arch type B with aberrant right subclavian artery/bilateral hydronephoresis | diffusely and symmetrically enlarged | 62% | NA | NA | negative | negative | [8] | ||||||
| 9 | 16 | M | DiGeorge syndrome at 1.5 years-old/GD at 13 years-old | hypertelorism/hypoplastic auricles/high-arch palate/superficial midline cleft of nose | mild aortic stenosis at 4 years-old | diffusely enlarged | negative | not detectable | [9] | ||||||||
| 10 | 17 | F | GD at 17 years-old/Hypocalcemia at after 5 month later | mild learning difficulties | bicuspid aortic valve and minor aortic regurgitation (AR) | small diffuse goitor | 1.72 mmol/L | 1.28 mmol/L | 4.8 ng/L | 6.9 U/L | 582 IU/mL | [10] | |||||
| 11 | 3 | M | Hypocalcemia at 6 days/GD at 3 years-old | posteriorly rotated ears/mild hypertelorism/wide mouth with downturned corners/rounded nose | interrupted aortic arch/atrial septal defect/ventrcular septal defect | [11] | |||||||||||
| 12 ours | 33 | F | GD at 33 years-old/Hypocalcemia at after 1 month later | submucosal cleft palate/eyelid swelling/narrowing of palpebral fissure/lower and lateral displacement of both auricles/expansion of nasal apex/small mouth | a learning disability | diffuse hypokinesis of left ventricular wall motion/left ventricular diastolic disfunction/mild tricuspid regurgitation (TR), trivial pulmonary regurgitation (PR) | diffusely enlarged | 5.5 | 4.8 | 59.7 | 40 U/L | 571 IU/mL | 1,020 IU/mL |
Patients with 22q11.2 deletion syndrome have an immune deficit caused by thymic hypoplasia, which is associated with reduced thymic T cell diversity or number. Several studies demonstrated that both the absolute counts and the percentage of circulating T reg cells (CD4+ CD25+ cells) are decreased in patients with 22q11.2 deletion syndrome [14-16]. Moreover, a recent study showed a significant decrease in both the number and the proportion of CD4+ FoxP3+ natural T reg cells in these patients [4]. Because T reg cells may play a role in establishing and maintaining self-tolerance and immune homeostasis, a decrease in the number of T reg cells may be associated with an increased incidence of autoimmune diseases, including Graves’ disease, in 22q11.2 deletion syndrome. On the other hand, some studies demonstrated that the frequency and absolute counts of circulating T reg cells were reduced in patients with untreated Graves’ disease and that circulating T reg cells were increased after treatment with anti-thyroid drugs [17, 18]. Unexpectedly, in our patient both the number and the percentage of CD25+ FoxP3+ CD4+ Treg cells gradually decreased after total thyroidectomy.
Our report is the first to investigate longitudinal PD-1 expression of circulating CD4+ and CD8+ T cells in a patient with 22q11.2 deletion syndrome complicated by Graves’ disease after treatment by thyroidectomy. A recent study demonstrated significantly higher frequencies and absolute counts of PD-1+ CD4+ T cells and PD-1+ CD8+ T cells in untreated patients with Graves’ disease than in healthy volunteers [19]. In our case, we found that the proportion of circulating PD-1+ CD4+ and PD-1+ CD8+ T cells did not increase before treatment and it decreased over time after thyroidectomy. Again, the mechanisms remain unclear. Although the frequencies and absolute counts of circulating PD-1+ CD4+ T cells and PD-1+ CD8+ T cells in 22q11.2 deletion syndrome have not been studied in detail, they may be reduced in this syndrome, which may contribute in part to the increased risk of autoimmune diseases. Identically to T reg cells, the proportion of circulating PD-1+ CD4+ and PD-1+ CD8+ T cells may have returned to the original low level.
In our case, we also found a reduction in circulating CD19+ B cells after total thyroidectomy. A previous study demonstrated a significant increase in CD19+ B cells in the peripheral blood of adolescents with newly diagnosed Graves’ disease and a positive correlation between CD19+ B cells and the titer of TSH antibodies [20], suggesting that CD19+ B cells might play a role in producing autoantibodies in autoimmune thyroid disease. In our case, however, CD19+ B cells were within the reference range. It has been reported that patients with chromosome 22q11.2 deletion syndrome show a progressive decrease in switched memory B cells with hypogammaglobulinemia [15]. In our case, we speculate that the increase of CD19+ B cells was attenuated before treatment and the decreased proportion of CD19+ B cells after thyroidectomy may have reflected the original low level.
Serum calcium was within the normal range at our patient’s first visit to our outpatient clinic, but she developed symptomatic hypocalcemia 1 month after administration of methimazole for thyrotoxicosis associated with Graves’ disease. Another case report described hypocalcemia after treatment for thyrotoxicosis in a patient with 22q11.2 deletion syndrome complicated by hyperthyroidism [10]. The authors speculated that the hypercalcemic effect of hyperthyroidism may mask underlying hypoparathyroidism during the period of untreated Graves’ disease [10, 21]. Although hypocalcemia is considered a typical feature of 22q11.2 deletion syndrome, its prevalence in this syndrome has been found to range from 32.8% to 64.1% [22]. The main mechanism responsible for hypocalcemia is considered to be hypoparathyroidism or a decreased reserve of PTH caused by congenital aplasia or hypoplasia of the parathyroid glands.
In our patient, when serum calcium was low (7.3 mg/dL), intact PTH was within its normal range. Although the ability of the parathyroid glands to compensate for the low serum calcium levels may have been reduced, the thyrotoxicosis-mediated increase in serum calcium may have canceled out the latent hypocalcemia, resulting in normocalcemia. We suggest that treatment of the hyperthyroidism caused symptomatic hypocalcemia because the parathyroid glands could not compensate for the treatment-related decrease in calcium levels. Another possible explanation for development of hypocalcemia after treatment for hyperthyroidism is hungry bone syndrome, which is known to be a cause of postoperative hypocalcemia after total thyroidectomy in patients with long-standing thyrotoxicosis [23]. Clinicians should be aware of the risk for symptomatic hypocalcemia after treatment of thyrotoxicosis in 22q11.2 deletion syndrome complicated by Graves’ disease. And, in our case, we found that Treg cells, PD-1+ CD4+ T cells and PD-1+ CD8+ T cells were decreased after thyroidectomy for Greaves’ disease. These findings may contribute to the increased risk of developing autoimmune disease in 22q11.2 deletion syndrome.
