Endocrine Disorders in Patients With Inborn Errors of Immunity

Abstract

Background

Human inborn errors of immunity (IEIs) include disorders characterized by aberrant function or development of the immune system. Recently, interest in the immune and endocrine systems has increased. We aimed to investigate endocrine disorders in patients with IEIs.

Methods

Data on patients with IEIs diagnosed from 1994 to 2021 at Samsung Medical Center, Seoul, Korea were reviewed. Each IEI was classified according to the International Union of Immunological Societies classification, and endocrine issues were reviewed.

Results

Of the 169 patients with IEIs, an endocrine evaluation was performed in 130 (76.9%). Thirty-five of the 130 patients (27% of the evaluated group) were diagnosed with at least one endocrine disorder, representing approximately 20% of all IEI patients with cumulative incidence of 32.3% at 20 years and 39.8% at 40 years. Patients with 'diseases of immune dysregulation’ showed the highest proportion of endocrine disorders. Additionally, six of these 35 patients had two distinct endocrine conditions. Thyroid involvement was most commonly observed (n = 15), followed by hypogonadism (n = 8), adrenal insufficiency (n = 7), growth hormone deficiency (n = 6), hypoparathyroidism (n = 3), and diabetes (n = 2).

Conclusion

We described endocrine disorders in patients with IEIs in Korea. About 20% of IEI patients had endocrine problems. Endocrine evaluations should be considered in IEI patients.

Graphical Abstract

INTRODUCTION

Inborn errors of immunity (IEIs) comprise a diverse group of about 485 genetic disorders that are characterized by abnormal immune function or development.1 Despite significant progress in understanding IEIs, there remains a substantial knowledge gap concerning the interaction between the immune and endocrine systems in IEIs. The immune and endocrine systems interact in numerous significant ways; their dysregulation has been linked to various diseases.2 However, the specific role of this interaction in IEIs has not been thoroughly explored.

The endocrine system plays a crucial role in regulating essential processes such as growth, metabolism, and stress response. Patients with IEIs are particularly vulnerable to endocrine disorders, which can significantly impact their health and quality of life. Advances in genetic testing and molecular diagnostics have improved the identification of previously undiagnosed IEIs, and awareness of IEI has increased in Korea and worldwide.3 Despite progress, studies on the co-occurrence of IEI and endocrine disorders are limited. Recognizing its importance, we examined the prevalence and spectrum of endocrine complications in IEI patients from a single center, presenting our findings on their prevalence, clinical presentation, and management in Korean patients.

METHODS

IEI classification and endocrinologic evaluation

Patients diagnosed with IEIs who were followed at Samsung Medical Center, Seoul, Korea from 1994 to 2021 were included. The classification of IEIs was based on the 2022 Update of the International Union of Immunological Societies (IUIS) Phenotypical Classification for Human IEIs,1 as follows: 1) Immunodeficiencies affecting cellular and humoral immunity, 2) Combined immunodeficiencies (CID) with associated or syndromic features, 3) Predominant antibody deficiencies, 4) Diseases of immune dysregulation, 5) Congenital defects of phagocytes, 6) Defects in intrinsic and innate immunity, 7) Autoinflammatory diseases, 8) Complement deficiencies, 9) Bone marrow failure, and 10) Phenocopies of IEIs.

Patients referred to the endocrinology clinic underwent routine evaluations. Laboratory evaluations for serum electrolytes, glucose, hemoglobulin A1c, and thyroid functions were also performed. Depending on the clinical manifestation, additional evaluations for hormonal profiles were applied as needed.

Data collection and measurements

Retrospective review of medical records was performed. The endocrine disorders included thyroid diseases, hypogonadism, adrenal insufficiency, growth hormone deficiency (GHD), diabetes, and hypoparathyroidism. These disorders were diagnosed based on the definitions provided in the Supplementary Data 1.4

Statistics

The cumulative incidence of endocrine disorders was illustrated using Kaplan-Meier curves, and the comparison of each cumulative incidence curve was performed using the log-rank test. The analysis and visualization were performed using GraphPad Prism 10 (GraphPad Software, San Diego, CA, USA).

Ethics statement

This study was approved by the Institutional Review Board (IRB) of Samsung Medical Center and the requirement for informed consent was waived (IRB number 2023-11-100).

RESULTS

Patient characteristics

A total of 169 patients with IEIs was included in the study, among whom 88 (67.7%) were male. The median age of the patients at the time of this analysis was 11.8 years, with a range of 1.9 to 79.1 years. On average, patients were diagnosed with IEIs at a median of 2.8 years (range, 0.0–75.0 years). The median follow-up duration was 5.8 years (range, 0.1–26.0 years).

When these 169 patients were grouped according to the IUIS classification, patients in category 2 represented the highest proportion at 30.8% (52/169), followed by category 3 at 20.1% (34/169) category 5 at 18.3% (31/169), category 4 at 14.2% (24/169), category 1 at 9.5% (16/169), category 9 at 4.7% (8/169) category 7 at 1.2% (2/169), and both categories 6 and 8, each with one patient (1/169, 0.6%). The overall survival data for the entire cohort are shown in Fig. 1.

Fig. 1. Overall survival of the cohort. Censoring reflects current ages.

Among these, 130 patients (76.9%) underwent an endocrine evaluation (Fig. 2). A total of 35 patients (20.7% of the IEI cohort) presented with at least one endocrine disorder. The median age was 14 years (range, 2.2–79.1), with 57.1% male (20/35). Six patients had two endocrine disorders. Thyroid disease (n = 15) was the most common, followed by hypogonadism (n = 8), adrenal insufficiency (n = 7), GHD (n = 6), hypoparathyroidism (n = 3), and diabetes (n = 2). The cumulative incidences of any endocrine disorder occurring within the cohort are 15.8% at 10 years, 32.3% at 20 years and 39.8% at 40 years (Fig. 3). The incidence of each individual endocrine disorder is compared with cumulative incidences by age in Fig. 4. Cumulative incidence curves for each endocrine disorder showed significant differences by log-rank test (P = 0.04).

Fig. 2. Diagram of the overall population and study population. Among 169 patients with confirmed IEI, patients with no history of endocrine assessment were excluded (N = 39). Of the patients who underwent endocrine evaluations, 35 had at least one endocrine disorder.

IEI = inborn errors of immunity, SMC = Samsung Medical Center.

Fig. 3. Cumulative incidence of any endocrine disorder by age. Censoring reflects death or current age.

Fig. 4. Cumulative incidence of each endocrine disorder and the comparison of curves.

AI = adrenal insufficiency, GHD = growth hormone deficiency.

The proportion of accompanying endocrine disorders was 12.5% (2/16) in category 1, 26.9% (14/52) in category 2, 14.7% (5/34) in category 3, 29.2% (7/24) in category 4, and 12.9% (4/31) in category 5. Among eight patients in category 9, two (25%) had endocrine disorders.

Clinical data for endocrine disorders

Autoimmune thyroiditis

We observed thyroiditis in three patients (3/130, 2.3%) (Table 1), with a cumulative incidence of 0.9% at 10 years and 3.5% at 20 years (Fig. 4). The underlying IEIs of these patients were agammaglobulinemia, NFkB2 deficiency, and DiGeorge syndrome. Among them, the patients with agammaglobulinemia and DiGeorge syndrome had hypothyroidism and started levothyroxine replacement at the ages of 9 and 15, respectively. Both are currently maintaining a euthyroid state. In the patient with agammaglobulinemia, thyroid ultrasonography revealed decreased parenchymal echogenicity. The thyroid scan demonstrated a relatively increased radioactive technetium uptake in the left thyroid gland, with a corresponding decreased radio uptake in the right thyroid gland. In the patient with DiGeorge syndrome, thyroid ultrasonography exhibited mild enlargement of the thyroid gland accompanied by coarse parenchymal echogenicity. In the patient with NFkB2 deficiency, a microsomal antibody was detected, but the patient maintained a euthyroid state and did not require additional treatment.

Table 1. Clinical data of autoimmune thyroiditis.

Cases		1	2	3
Disease		Agammaglobulinemiaa	CVID (NFkB2 def.)	Di George syndrome
IUIS category		3	3	2
Sex		Male	Female	Female
Diagnosis age of IEI		8 mon	4 yr 8 mon	At birth
Current age		12 yr 11 monb	11 yr 7 mon	20 yr 9 mon
Onset age of thyroiditis		9 yr 2 mon	10 yr 5 mon	15 yr 8 mon
Clinical symptom		None	None	Fatigue
Laboratory data
	Free T4, µIU/mL (0.55–4.78)	0.84	1.4	0.83
	TSH, ng/dL (0.27–4.20)	26.5	1.67	16.3
	Thyroglobulin Ab, IU/mL (0–60)	Positive (63.5)	Negative	Negative
	Microsomal Ab, U/mL (0–60)	Negative	Positive (148.4)	Positive (12,016)
	TSH-receptor-Ab, IU/L (0–1.0)	Negative	Negative	Negative
Treatment
	Age at treatment initiation	9 yr 2 mon	Untreated	15 yr 8 mon
	Medication	LT4		LT4

CVID = common variable immunodeficiencies, def. = deficiency, IUIS = the International Union of Immunological Societies, IEI = inborn errors of immunity, T4 = thyroxine, TSH = thyroid-stimulating hormone, Ab = antibody, LT4 = levothyroxine.

^aNo pathogenic/likely pathogenic variant in BTK gene.

^bExpired.

Non-autoimmune hypothyroidism

Non-autoimmune hypothyroidism was diagnosed in 12 patients (12/130, 9.2%), with a cumulative incidence of 7.0% at 10 years and 9.2% at 20 years (Fig. 4). Six patients developed hypothyroidism after hematopoietic cell transplantation (HCT) (Table 2). Among these 12 patients, eight had central hypothyroidism, two had subclinical hypothyroidism, and one had primary hypothyroidism. Eleven patients received levothyroxine supplementation, one of whom (patient 12) was diagnosed with subclinical hypothyroidism and remained asymptomatic with stable thyroid levels during follow-up.

Table 2. Clinical data of non-autoimmune hypothyroidism.

Cases		1	2	3	4	5	6	7	8	9	10	11	12
Disease		XL-agamma-globulinemia	CTLA-4 haplo-insufficiency	CVID	Hyper IgM syndrome	IPEX syndrome	Kabuki syndrome	Kabuki syndrome	Osteopetrosis	XL-SCID	Wiskott-Aldrich syndrome	Wiskott-Aldrich syndrome	Wiskott-Aldrich syndrome
IUIS category		3	4	3	1	5	2	2	9	1	2	2	2
Sex		Male	Male	Female	Male	Male	Female	Male	Female	Male	Male	Male	Male
Diagnosis age of IEI		3 yr 6 mon	74 yr 6 mon	5 yr	1 yr 9 mon	7 mon	At birth	1 yr 5 mon	2 yr 8 mon	4 mon	2 yr 6 mon	ND	3 mon
Current age		12 yr 2 mon	79 yr 3 mon	20 yr 1 mona	2 yr 3 mona	14 yr 9 mon	5 yr 8 mon	5 yr 11 mon	14 yr 6 mon	8 yr 3 mon	5 yr 8 mona	8 yr 9 mon	12 yr 5 mon
Age at HCT					2 yr				2 yr 8 mon	10 mon	3 yr 5 mon	9 mon	2 yr 5 mon
Onset age of hypothyroidism		9 yr 11 mon	65 yr	19 yr 2 mon	1 yr 9 mon	7 mon	5 mon	1 mon	8 yr 3 mon	1 yr 1 mon	4 yr 8 mon	1 mon	6 yr 4 mon
	Type	Central	ND	Central	Central	Central	Subclinical	Primary	Central	Central	Central	Subclinical	Central
Clinical symptom		NA	NA	NA	NA	NA	NA	NA	NA	NA	General weakness	NA	NA
											Cold sense
Laboratory data
	Free T4, ng/dL	0.87	ND	0.79	0.58	0.31	1.77	0.4	0.78	0.51	0.39	1.23	0.8
	TSH, µIU/mL	0.082	ND	1.02	1.94	0.8	26	388	2.7	0.103	0.39	10.2	2.92
	T3, ng/dL	83.4		22.6	59.6			78.7	93.9	25.7	29.5	166	149.8
Treatment
	Age at initiation	9 yr 11 mon	65 yr	19 yr 2 mon	1 yr 9 mon	7 mon	5 mon	1 mon	8 yr 3 mon	1 yr 1 mon	4 yr 8 mon	Untreated	6 yr 4 mon
	Medication	LT4	LT4	LT4	LT4	LT4	LT4	LT4	LT4	LT4	LT4		LT4

XL = X-linked, CTLA-4 = cytotoxic T lymphocytic antigen-4, CVID = common variable immunodeficiency, IPEX = immune dysregulation, polyendocrinopathy, enteropathy, X-linked, XL-SCID = X-linked severe combined immunodeficiency, IUIS = the International Union of Immunological Societies, IEI = inborn errors of immunity, ND = not done, HCT = hematopoietic cell transplantation, NA = not applicable, T4 = thyroxine, TSH = thyroid-stimulating hormone, T3 = triiodothyronine, LT4 = levothyroxine.

^aExpired.

Hypogonadism

Hypogonadism was observed in eight patients (8/130, 6.2%) (Table 3), with a cumulative incidence of 0% at 10 years and 14.2% at 20 years (Fig. 4). All patients had hypogonadotropic hypogonadism. Among them, two male patients developed hypogonadism after HCT. The underlying IEIs included two patients with CHARGE syndrome, two with lipopolysaccharide responsive beige-like anchor protein (LRBA) deficiency, and one each with activated phosphoinositide 3-kinase (PI3K) delta syndrome, common variable immunodeficiencies (CVID), chronic granulomatous disease (CGD), and cytotoxic T lymphocytic antigen-4 (CTLA-4) haplo-insufficiency. All patients received hormone replacement therapy except for one male patient who was diagnosed with hypogonadism at the age of 16 due to low sex hormone levels, bilateral testis volumes of 4 mL, and the absence of secondary sexual characteristics. Notably, this patient exhibited a gradual increase in male hormone levels during follow-up and did not require hormone replacement therapy.

Table 3. Clinical data of hypogonadism.

Cases		1	2	3	4	5	6	7	8
Disease		CHARGE syndrome	CHARGE syndrome	APDS1	CVID	XL-CGD	CTLA-4 haplo-insufficiency	LRBA def.	LRBA def.
IUIS category		2	2	3	3	5	4	4	4
Sex		Male	Female	Female	Female	Male	Female	Male	Female
Diagnosis age of IEI		12 yr 9 mon	17 yr 2 mon	11 yr	5 yr	6 yr 9 mon	14 yr4 mon	10 yr 8 mon	12 yr 9 mon
Current age		19 yr 6 mon	22 yr	18 yr 8 mon	20 yr 1 mona	23 yr	33 yr 7 mon	20 yr 10 mon	23 yr 3 mon
Age at HCT						13 yr		16 yr 7 mon
Detection age of hypogonadism		14 yr	17 yr 2 mon	16 yr 1 mon	18 yr 1 mon	15 yr 1 mon	18 yr 4 mon	15 yr 11 mon	13 yr 3 mon
Type of hypogonadism		Central	Central	Central	Central	Central	Central	Central	Central
Height at onset, cm		142.6	160	148.5	148.6	151	152.6	144	133.3
	SD	−3.8	−0.2	−2.2	−2.6	0	−1.5	−2.6	−3.5
Body weight at onset, kg		36.1	53	38.6	34.6	45.5	35	36.5	25.5
	SD	−2.4	−0.1	−2.5	−4.3	−1.5	−4.2	−2.1	−2.5
Tanner stage		I	I	II	ND	I	ND	II	I
Laboratory data
	LH, mIU/mL	0.7	0.4	0.4	0.07	1.3	1.9	1	0.4
	FSH, mIU/mL	0.6	0.1	1.1	0.43	2.2	1.2	1.5	2.4
	Testosterone, ng/mL	0.16				0.12		0.7
	Estradiol, pg/mL		29	1	74		11		1
Treatment
	Age at initiation	14 yr 6 mon	17 yr 3 mon	16 yr 3 mon	18 yr 1 mon	15 yr 8 mon	19 yr 5 mon	Untreated	15 yr 4 mon
	Bone age at initiation	12 yr	NT	13 yr 6 mon	NT	12 yr	NT		13 yr
Medication		Testosterone	Estradiol progesterone	Estradiol progesterone	Estradiol	Testosterone	Estradiol progesterone		Estradiol progesterone

APDS1 = activated phosphoinositide 3-kinase delta syndrome, CVID = common variable immunodeficiency, XL-CGD = X-linked chronic granulomatous disease, CTLA-4 = cytotoxic T-lymphocyte-associated protein 4, LRBA = lipopolysaccharide-responsive and beige-like anchor protein, def. = deficiency, IUIS = the International Union of Immunological Societies, IEI = inborn errors of immunity, HCT = hematopoietic cell transplantation, SD = standard deviation, ND = not done, LH = luteinizing hormone, FSH = follicle stimulating hormone, NT = not tested.

^aExpired.

Adrenal insufficiency

Adrenal insufficiency was diagnosed in seven patients (7/130, 5.3%) (Table 4), with a cumulative incidence of 2.4% at 10 years, 6.5% at 20 years and 16.8% at 40 years (Fig. 4). No cases of adrenal crisis were observed. Six of seven individuals had a history of long-term glucocorticoid treatment. These patients received prednisolone for durations ranging from as short as 4 months to as long as 9 months (at a dose of 1–2 mg/kg/day) to manage their underlying conditions and control inflammation.

Table 4. Clinical data of adrenal insufficiency.

Cases		1	2	3	4	5	6	7
Disease		XL-agammaglobulinemia	Blau syndrome	XL-CGD	CTLA-4 haploinsufficiency	CVID (NFkB2)	LRBA def.	FHL3 (UNC13D)
IUIS category		3	7	5	4	3	4	4
Sex		Male	Male	Male	Female	Female	Male	Female
Current age		12 yr 2 mon	4 yr 5 mon	12 yr	37 yr 6 mon	11 yr 7 mon	20 yr 10 mon	21 yr 1 mon
Age at HCT							16 yr 4 mon
Diagnosis age of IEI		3 yr 5 mon	1 yr 1 mon	5 yr 7 mon	24 yr 3 mon	4 yr 8 mon	10 yr 8 mon	15 yr
Onset age of adrenal insufficiency		6 yr 3 mon	3 yr 8 mon	10 yr 3 mon	36 yr	6 yr 11 mon	15 yr 11 mon	15 yr
Laboratory data
	ACTH, pg/mL	29.4	107.6	12.4	9.3	10	ND	8.5
	Cortisol basal/peak,a µg/dL	4.7/17.9	8.7/13.3	1.2/3.9	4.2/12.5	0.9/12	0.4/2.1	1.4/5.3
Duration of glucocorticoid use		Untreated	Pd 2.5 yr	Pd 2.7 yr, HCS is ongoing	Pd 8.8 yr	Pd 1 yr, HCS is ongoing	Pd 11 mon	Pd 4 mon

XL = X-linked, CGD = chronic granulomatous disease, CTLA-4 = cytotoxic T-lymphocyte-associated protein 4, CVID = common variable immunodeficiency, LRBA = lipopolysaccharide-responsive and beige-like anchor protein, def. = deficiency, FHL3 = familial hemophagocytic lymphohistiocytosis type 3, IUIS = the International Union of Immunological Societies, HCT = hematopoietic cell transplantation, IEI = inborn errors of immunity, ACTH = adrenocorticotropic hormone, Pd = prednisolone, HCS = hydrocortisone.

^aACTH stimulation test.

GHD

GHD was diagnosed in six patients (6/130, 4.6%) among patients with CHARGE syndrome, CGD, glycogen storage disease (GSD), signal transducer and activator of transcription 3 hyper IgE syndrome (STAT3-HIES), and osteopetrosis (Table 5), with a cumulative incidence of 4.9% at 10 years (Fig. 4). In patients with CGD and osteopetrosis, GHD was diagnosed after HCT. All the patients received growth hormone (GH) therapy except for one CGD patient. One patient discontinued GH therapy due to adherence issues, while others responded well without adverse effects. The therapeutic impact of GH replacement and its clinical outcomes are shown in Table 5.

Table 5. Clinical data of GHD.

Cases		1	2	3	4	5	6
Disease		CHARGE syndrome	CHARGE syndrome	AR-CGD	GSD	STAT3 LOF	Osteopetrosis
IUIS category		2	2	5	5	2	9
Sex		Male	Female	Female	Male	Male	Female
Current age		11 yr 2 mon	11 yr 5 mon	13 yr 8 mon	11 yr 4 mon	20 yr 1 mon	6 yr 1 mon
Age at HCT				3 yr 3 mon			10 mon
Diagnosis age of IEI		2 yr 9 mon	3 yr 1 mon	10 mon	9 mon	5 yr 1 mon	7 mon
Age at the diagnosis of GHD		8 yr 1 mon	7 yr 8 mon	4 yr 8 mon	4 yr 5 mon	9 yr	4 yr 2 mon
Parents' height
	Father/mother, cm	NA/NA	174/167	NA/NA	175/167	177/153	NA/NA
Height at diagnosis, SD		−1.4	−2.6	−2.0	−2.5	−1.6	−1.8
Body weight at diagnosis, SD		−1.5	−1.3	0.5	−0.4	−1.87	−1.3
Laboratory data at diagnosis
	IGF-1, nmol/L	41.7 (50.3–265.9)a	135.6 (102.3–460.1)a	13.9 (29.9–359.4)a	15.8 (8–250)a	86.6 (9.7–30.1)a	67.7 (29.9–359.4)a
	Insulin, µU/mL	12.3	14.15	NT	2.1	NT	NT
	Peak GH production at the provocative tests	Arginine, 2.05; L-dopa, 6.23	Glucagon, 5.36; L-dopa, 2.43	Glucagon, 6.17; L-dopa, 8.93	Glucagon, 5.83; L-dopa, 1.70	Glucagon, 2.68; L-dopa, 4.36	Arginine, 1.21; L-dopa, 1.55
Treatment		GH	GH	Untreated	GH	GH	GH
	Age at the start	8 yr 4 mon	7 yr 8 mon		4 yr5 mon	9 yr 1 mon	4 yr 2 mon
	Bone age at the start	7 yr	6 yr		3 yr 9 mon	4 yr 10 mon	3 yr
	Clinical course	−0.7 SD at 11 yr 2 mon	−1.1 SD at 11 yr 5 mon		Discontinued at 5 yr 1 mon (−2.0 SD) due to poor compliance	Discontinued at 15 yr 11 mon (−0.1 SD)	−1.1 SD at 6 yr 1 mon
	Response	Good	Good		Good	Good	Good

AR-CGD = autosomal recessive chronic granulomatous disease, GSD = glycogen storage disease, STAT3 LOF= signal transducer and activator of transcription 3 loss-of-function, IUIS = the International Union of Immunological Societies, HCT = hematopoietic cell transplantation, IEI = inborn errors of immunity, GHD = growth hormone deficiency, NA = not applicable, SD = standard deviation, IGF-1 = insulin-like growth factor-1, NT = not tested, GH = growth hormone.

^aNormal reference range may vary depending on the assay and age-specific standards.

Diabetes

Diabetes was identified in two patients (2/130, 1.5%), both having type 2 diabetes mellitus (T2DM) (Table 6), with a cumulative incidence of 2.1% at 20 years and 9.7% at 40 years (Fig. 4). One patient had ataxia telangiectasia, with no notable family history of diabetes, and was diagnosed with diabetes at the age of 18 during routine endocrine evaluations. After about 6 years of metformin treatment, glimepiride was added due to inadequate glycemic control. After maintaining this combination for approximately one year, linagliptin was additionally included. Currently, the patient's blood sugar levels were relatively well managed. Continuous monitoring for diabetes complications revealed no nephropathy or retinopathy. Another patient with CTLA-4 haplo-insufficiency was diagnosed with diabetes at the age of 31 years during regular follow-up. After the diagnosis, she began treatment with linagliptin, and glipizide was added due to inadequate glycemic control. Despite these interventions, her hemoglobin A1c remained at 11%. Consequently, at the age of 33, she started subcutaneous insulin therapy. Currently, she has no evidence of diabetes complications such as neuropathy, nephropathy, or retinopathy.

Table 6. Clinical data of diabetes.

Cases		1	2
Disease		Ataxia telangiectasia	CTLA-4 haplo-insufficiency
IUIS category		2	4
Sex		Male	Female
Current age		25 yr 9 mon	33 yr 7 mon
Diagnosis age of IEI		13 yr	14 yr 5 mon
Onset age of diabetes		18 yr 4 mon	31 yr 8 mon
Clinical symptom		Polydipsia, polyuria	Polydipsia, polyuria
Laboratory data
	Fasting blood glucose, mg/dL (ref. 74–109)	164	125
	HbA1c, % (ref. 4.0–6.0)	7.2	8.3
	C–peptide, ng/mL (ref. 0.69–3.59)	5.53	0.86
	Insulin, µU/mL (ref. 1.0–9.6)	30.2	2.6
	Anti-GAD II Ab, U/mL (ref. 0–1.0)	Negative (0.2)	Negative (0.36)
	Anti-insulin Ab, % (ref. 0–7.0)	Negative (5.3)	Negative (4.1)
	Neuropathy	Early autonomic dysfunction	NT
	Nephropathy	No	No
	Retinopathy	No	No
Treatment
	Age at initiation	18 yr 4 mon	31 yr 8 mon
	Medication	Metformin, linagliptin, glimepiride	Subcutaneous insulin

CTLA-4 = cytotoxic T-lymphocyte-associated protein 4, IUIS = the International Union of Immunological Societies, IEI = inborn errors of immunity, ref. = reference, HbA1c = hemoglobulin A1c, GAD = glutamic acid decarboxylase, Ab = antibody, NT = not tested.

Hypoparathyroidism

Three patients had hypoparathyroidism (3/130, 2.3%), all of whom also had DiGeorge syndrome and were diagnosed within the first month of life. The first patient developed seizures on the 3rd day after birth. Subsequent evaluations revealed hypocalcemia, which was managed with calcium supplementation. The symptoms subsided with the medication. By one month of age, the patient maintained normal calcium levels without medication. The second patient was transferred to our center on the 6th day after birth for surgery due to a cardiac anomaly (truncus arteriosus) and diagnosed with hypocalcemia during preoperative tests. Calcium supplementation was administered to the patient. The patient received calcium supplementation until 2 years and 5 months of age. The third patient, diagnosed with hypocalcemia during perioperative test, had interrupted aortic arch and a ventricular septal defect 13 days after birth. Calcium supplementation continued until the 3 years 4 months, after which the calcium level was well maintained without intervention.

DISCUSSION

In our study, 35 of 169 IEI patients (20.7%) showed at least one endocrine disorder, with cumulative incidences of 32.3% at 20 years and 39.8% at 40 years. We also found significant differences in cumulative incidence curves for endocrine disorders. These findings highlight the need for regular evaluations, including annual checks of growth velocity and key hormone levels, to aid early detection of endocrine disorders in IEI patients. Extra attention during puberty, with monitoring of gonadal hormones and staging, is crucial for timely management. The endocrine assessment parameters and schedule implemented during the follow-up of IEI patients at our center are detailed in Supplementary Table 1.

Endocrine disorders were more prevalent in IUIS categories 4 (‘Disease of immune dysregulation’ [29.2%, 7/24]), and 2 (‘CIDs with associated or syndromic feature’ [26.9%, 14/52]) than in the other categories.1 Among the diseases in category 4, CTLA-4 haplo-insufficiency (75%, 3/4), LRBA deficiency (100%, 2/2), familial hemophagocytic lymphohistiocytosis (FHL), and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome (50%, 1/2) were all associated with endocrine disorders. Among the category 2 diseases, the types of IEIs and the proportions of accompanying endocrine disorders were as follows: CHARGE syndrome (21.1%, 4/19), DiGeorge syndrome (30%, 3/10), Wiskott-Aldrich syndrome (37.5%, 3/8), and Kabuki syndrome (25%, 2/8).

So far, few prior studies have investigated the endocrine disorders associated with IEIs. A Japanese study5 showed key differences from ours: they reported a lower 5.3% prevalence of endocrine disorders compared to our 20.7% (with cumulative incidence of 32.3% at 20 years), likely due to differences in patient selection. Their study did not provide detailed information on the proportion of patients undergoing endocrinological evaluations or HCT and excluded treatment-related endocrine disorders after HCT. While hypoparathyroidism was most common in Japanese cohort, thyroid disorders were more prevalent in our study. In 2019 Netherlands study,6 focused on adult CVID and antibody deficiencies, found anterior pituitary dysfunction to be a prominent issue, with central hypothyroidism and hypogonadism frequently observed, possibly due to chronic disease-related hormone suppression. In contrast, our study on younger IEI patients observed broader endocrine disorders, suggesting that age and immune disorder type influence endocrine disorders. The variations in endocrine disorders across the studies suggest that genetic, environmental, and immunological factors must be considered to develop effective, regionally adapted management approaches.

The vulnerability to endocrine disorders in IEIs is likely attributed to two main pathophysiological factors: autoimmune reactions and the potential direct influence of genes implicated in IEIs.2 Certain types of IEIs are associated with autoimmunity, which is known to involve the production of autoreactive B and T cells, dysregulated innate immune cells, and autoantibodies.7,8 Endocrine organs are common targets of autoimmune diseases, and these autoimmune endocrine diseases involve autoantibodies and/or autoreactive lymphocytes, arising from interactions between environmental factors and genetic predispositions, often linked to specific MHC/HLA molecules such as HLA-DR3, HLA-DR4, HLA-DQ2, HLA-DQ8, HLA-B8, and HLA-DR5.9 Some endocrine disorders in IEI are directly linked to genetic defects such as STAT5b,10 HAX1,11 SAMD9/SAMD9L,12 ATM,13 STAT1,14 and CHD7.15 In addition, treatment modalities such as glucocorticoid, HCT for IEI may increase endocrine susceptibility.

Autoimmune thyroiditis manifests frequently in individuals with IEIs.16,17 In our cohort, there were three cases of autoimmune thyroiditis observed among individuals with agammaglobulinemia, DiGeorge syndrome, and NFKB2 deficiency. There is a report of an association between X-linked agammaglobulinemia (XLA) and autoimmune thyroiditis.8 According to a US registry study,18 about 5% of patients with XLA exhibited hypothyroidism or goiter with no information on the presence of autoantibodies.19 In our study, among the 18 patients with agammaglobulinemia (mostly XLA), 2 had central hypothyroidism and autoimmune thyroiditis. A recent long-term study involving 73 children with DiGeorge syndrome revealed that 21.9% of them developed autoimmune thyroiditis before the age of 18 years. This suggests that inflammation may trigger thyroid autoantibody production in DiGeorge syndrome patients predisposed to autoimmunity, though the mechanism remains unclear.20 NFKB2 deficiency, a form of CVID, is associated with adrenal insufficiency, ectodermal dysplasia, and autoimmunity.21 A previous study describing the clinical presentation of NFKB2 patients reported that 40% of patients with NFkB2 have autoantibodies, with more than half having TPO-Ab.22 In our study, one patient with NFKB2 was included and also had autoimmune thyroiditis caused by TPO-Ab. The production of TPO-Ab is thought to be related to the immune dysregulation associated with the underlying IEI.

The pathogenesis of non-autoimmune hypothyroidism in IEIs remains unclear. Among the 12 cases in our cohort, half developed non-autoimmune hypothyroidism post-HCT, suggesting it as a potential complication.23,24,25 The IEIs associated with non-autoimmune hypothyroidism were CVID, CTLA-4 haploinsufficiency, IPEX syndrome, and Kabuki syndrome. It is well-known to be associated with thyroid abnormalities including hypothyroidism, hyperthyroidism, and thyroiditis.26 This correlation highlights the need to consider thyroid dysfunction in diagnosing and managing IPEX syndrome, particularly as these issues can arise in the neonatal stage.27 Additionally, several case reports have documented the occurrence of thyroid disease in patients with Kabuki syndrome.28,29

Adrenal insufficiency was observed in seven patients, mostly after prolonged glucocorticoid treatment for underlying immune dysregulations (including Blau syndrome, CGD, CTLA-4 haplo-insufficiency and LRBA deficiency, NFkB2 deficiency, and FHL). For patients with autoimmune or auto-inflammatory characteristics requiring long-term glucocorticoid administration, it is important to be aware of the potential risk of secondary adrenal insufficiency.

In our cohort, GHD was identified in 6 patients. Notably, two of these patients developed GHD after undergoing HCT, suggesting it was a potential complication of HCT.30 Additionally, GHD was observed in patients with CHARGE syndrome, CGD, GSD type 1b, and STAT3-HIES. Patients with CHARGE syndrome and GSD type 1b can experience growth failure.2 The patient with CHARGE syndrome had a good response to GH therapy. The GSD type 1b patient initially responded positively to treatment, but due to poor adherence, therapy was discontinued after 8 months. Although STAT3 is involved in the GH signaling pathway, normal growth is maintained with heterozygous STAT3 loss-of-function.31,32 However, we reported a patient with STAT3-HIES was diagnosed with GHD at age 9 with a positive response to GH therapy without side effects. IEIs can cause growth failure through pathways like the JAK-STAT signaling pathway,33 particularly defects in STAT5b, leading to GH insensitivity.34 Growth failure in IEI patients results from various factors, including medication effects, recurrent infections, chronic inflammation, and the nature of the IEI. GH therapy should be used cautiously, particularly in patients with malignancy risk.

A literature review of 133 patients with a CTLA-4 haplo-insufficiency phenotype found that 1/3 had endocrine disorders.35 In our study, three of four individuals (75%) with CTLA-4 haplo-insufficiency had an endocrine disorder, including one with adrenal insufficiency after long-term glucocorticoid treatment, one with hypothyroidism, and one with T2DM and hypogonadism. The emerging literature suggests that specific variations in CTLA-4 polymorphisms may be associated with T2DM as well as autoimmune T1DM.36,37 In addition, T1DM manifestations in IEIs are frequently associated with mutations in genes that affect regulatory T cell development, function, and survival, such as FOXP3, IL2RA23 and AIRE, as well as STAT mutations, PI3K p110δ, and LRBA deficiency.38 Moreover, some IEIs caused by DNA repair defects, such as ataxia telangiectasia or Bloom syndrome, are reported to be associated with DM. In such IEIs, markedly increased insulin resistance is thought to contribute to DM development.39 Given the potential risk of glucose intolerance, caution is needed with prolonged glucocorticoid use for autoimmune/autoinflammatory symptoms or graft-versus-host disease following HCT.40

This retrospective, single-center study has limitations, including a small sample size for each IEI and incomplete endocrine evaluations. The prevalence of endocrine issues may be underestimated due to the exclusion of patients managed elsewhere or not tested. Nonetheless, this is the first study to analyze endocrine disorders in the largest Korean IEI cohort, presenting the cumulative incidence while considering the follow-up period. Further investigations using the national IEI registry is needed.

Regular and tailored endocrine evaluations for IEI patients are necessary, because endocrine disorders can become another morbidity of IEIs. Therefore, collaboration between immunologists and endocrinologists is crucial to provide multidisciplinary care to patients with IEIs. Early detection and individualized management of endocrine disorders are crucial for improving long-term outcomes in IEI patients.

SUPPLEMENTARY MATERIALS

Supplementary Data 1

Definitions of endocrine disorders

Supplementary Table 1

Endocrine assessment schedule for IEI patients during follow-up