Left Ventricular Systolic Dysfunction Related to Adrenal Insufficiency in a Case due to Autoimmune Polyendocrine Syndrome Type 1 with a Novel Variant

Abstract

Introduction

Primary adrenal insufficiency associated with cardiomyopathy has been rarely reported in children. We report a case of left ventricular (LV) systolic dysfunction related to adrenal insufficiency with autoimmune polyendocrine syndrome type 1 (APS1).

Case Presentation

A 7-year-old girl presented with a loss of consciousness. She had hyperpigmentation over joints and enamel hypoplasia. Laboratory tests showed hypoglycemia, hyponatremia, hypocalcemia, and hyperphosphatemia. Endocrine evaluations revealed low serum parathyroid hormone, low cortisol, and high ACTH. Echocardiography showed moderate to severe mitral regurgitation and LV systolic dysfunction. Serum pro-brain natriuretic peptide (pro-BNP) level was high (2,348 pg/mL). Adrenal insufficiency, hypoparathyroidism, and enamel dysplasia suggested APS1. A novel homozygous variant in the AIRE gene, NM_000383, p.Cys322Arg (c.964T>C) confirmed the diagnosis. Calcium, calcitriol, and hydrocortisone treatments were started. Serum pro-BNP level returned to normal, and LV systolic function improved.

Conclusion

Here, we present a case of adrenal insufficiency and hypoparathyroidism associated with LV systolic dysfunction whose cardiac findings improved completely with hydrocortisone and calcitriol treatments. Our case is the second reported case of APS1 presenting with LV dysfunction.

Established Facts

• Autoimmune polyendocrine syndrome type 1 (APS1) is a rare, autosomal recessive disorder caused by variants in the autoimmune regulator (AIRE) gene.

• Acute adrenal crisis usually presents with hypovolemic hypotension, low cardiac output, and shock.

Novel Insights

• A novel homozygous variant p.Cys322Arg (c.964T>C) in the AIRE gene led to APS1.

• Left ventricular systolic dysfunction completely resolved with hydrocortisone and calcitriol treatments in addition to the known phenotypic features of APS1.

Introduction

Primary adrenal insufficiency (PAI) includes a wide variety of adrenocortical disorders characterized by insufficient glucocorticoid (GC) production, accompanied by mineralocorticoid and adrenal androgen deficiency or excess. Hereditary causes of PAI may be due to abnormalities in adrenal gland development, impaired steroidogenesis, resistance to adrenocorticotropic hormone (ACTH) effect, and progressive adrenal destruction. Congenital adrenal hyperplasia (CAH) is the most common cause of PAI in the pediatric population [Kirkgoz and Guran, 2018]. In developed countries, 80−90% of cases of PAI are caused by autoimmune adrenalitis [Charmandari et al., 2014]. Autoimmune polyendocrine syndrome type 1 (APS1), which is also known as APECED (autoimmune polyendocrinopathy, candidosis, ectodermal dysplasia) syndrome, is a rare, autosomal recessive disorder caused by variants in the autoimmune regulator (AIRE) gene. Dominant AIRE variations typically lead to later-onset milder disease phenotypes than recessive APS1. Other common signs and symptoms of APECED involve dysfunction of the body‧s network of hormone-producing glands (the endocrine system), as well as other organs and tissues [Husebye and Anderson, 2010; Eriksson et al., 2018].

Cardiovascular complications of acute adrenal crisis are generally associated with hypovolemic hypotension, low cardiac output, and shock. Although acute reversible cardiomyopathy and heart failure are rarely reported in children with adrenal insufficiency, hypocortisolemia may develop cardiomyopathy regardless of the etiology. In the literature, acute reversible cardiomyopathy secondary to acute adrenal insufficiency due to Addison‧s disease, CAH (21-hydroxylase and 11β-hydroxylase deficiency), and autoimmune adrenalitis have been reported [Boston et al., 1994; Derish et al., 1996; Conwell et al., 2003; Al Jarallah, 2004; Wiltshire et al., 2004; Wani et al., 2013; Ödek et al., 2017; Alkhateeb et al., 2018]. Herein, we present a case with adrenal insufficiency due to APS1 complicated by left ventricular (LV) dysfunction with a novel homozygous variant of the AIRE gene.

Case Presentation

A 7-year-old girl was admitted to the emergency department with a loss of consciousness which was due to hypoglycemia. Parents are third-degree cousins. The family pedigree of the proband is shown in Figure 1. Her anthropometric measurements were in normal ranges (height 123.5 cm, −0.08 SDS; weight 22 kg, −0.52 SDS). She had hyperpigmentation over joints and enamel hypoplasia (Fig. 2a, b). Her heart rate was 92/min, respiratory rate 24/min, and blood pressure was 84/62 mm Hg. Laboratory tests showed hypoglycemia (14 mg/dL), hyponatremia (128 mmol/L), normokalemia (4.4 mmol/L), hypocalcemia (7.1 mg/dL), hyperphosphatemia (7.4 mg/dL), hypoparathyroidism (1.2 pg/mL), hypocortisolemia (0.054 μg/dL), and high ACTH level (1,049 pg/mL). Electrocardiography showed a long QT interval (corrected QT 500 ms). Echocardiography revealed LV systolic dysfunction with an LV end-diastolic dimension of 38 mm, LV end-systolic 27 mm, and fractional shortening (FS) 29%. Brain computerized tomography demonstrated calcifications in the basal ganglia (Fig. 2c). Cardiac biomarkers were elevated (pro-brain natriuretic peptide [pro-BNP] 2,348 pg/mL [<300 pg/mL], troponin-T 0.057 ng/mL [<0.014 ng/mL], and creatine kinase-MB 46 U/L [<25 U/L]) (Fig. 3). For hyponatremia and hypocalcemia, intravenous serum saline replacement and 10% calcium gluconate were administered. PAI was confirmed with low serum cortisol and high ACTH levels. Plasma renin activity was slightly high (150 µIU/mL), and aldosterone level was low (<3.7 ng/dL). Hypoparathyroidism, PAI, and enamel dysplasia suggested APS1. In AIRE exon 8, a novel homozygous missense variant (NM_000383.4: c.964T>C) was detected which had not been reported previously in the database. This variant was classified as a variant of uncertain significance by Varsome. Segregation analysis also revealed that both unaffected parents were heterozygous carriers of this variant. The girl was started with calcium, calcitriol, hydrocortisone, and fludrocortisone treatments. On the third follow-up day, echocardiography demonstrated ongoing mitral regurgitation and LV systolic dysfunction with FS 28%, and pro-BNP increased to 3,169 pg/mL. After 4 weeks of treatment, her clinical and laboratory findings improved, pro-BNP level returned to normal range (Fig. 3). In her fifth month of follow-up, her clinical and laboratory findings were normal, as well as her echocardiographic parameters (FS 35%) (Table 1).

Fig. 1.

Pedigree chart of the family.

Fig. 2.

The patient. a Enamel hypoplasia. b Hyperpigmentation over her joints. c Calcification in the basal ganglia.

Fig. 3.

pro-BNP and troponin T levels of the patient improved with hydrocortisone treatment.

Table 1.

Echocardiographic findings of the cardiac asymptomatic case resolved after temporary worsening with hydrocortisone therapy

	Day 1	Day 3	Day 7	Day 10	Week 4
Echocardiography
EF, %	57	55	54	59	62
FS, %	29	28	27	31	32
pro-BNP, pg/mL	2,348	3,196	3,162	2,515	251

EF, ejection fraction; FS, fractional shortening; pro-BNP, pro-brain natriuretic peptide.

Methods

AIRE Gene Analysis

A 2-mL venous blood sample was collected in a sterile EDTA vacutainer. Genomic DNA was prepared according to the manufacturer‧s protocols (Blood DNA Kit, GeneAll Biotechnology; South Korea). An AIRE gene analysis was conducted on the patient. Variation was assessed through polymerase chain reaction (PCR). PCR products were analyzed by direct sequencing (DNA Analyzer 3500xl; Applied Biosystems, Foster City, CA, USA). Primers for the PCR and sequence analysis were as follows: Exon1F: 5′CAGTGTCCCGGGACCCAC-3′; Exon1R: 5′-GAGTT­GGGGAAGGCTGGAG-3′; Exon2F: 5′GGAGCTCCACCCTCTAGTCA-3′; Exon2R: 5′-CTCCTCAAACACCACTCCGG-3′; Exon3F: 5′ATCCTAAGAGGCAAAGGGGC-3′; Exon3R: 5′-GG­G­­AAGACTGGAGACCCTGG-3′; Exon4F: 5′ACTCACC­CCC­AC­­TGAGAGG-3′; Exon4R: 5′-TAGGACAGGGTCTCAG­A­GGG-3′; Exon5F: 5′AAGGAAAGGGCTCTGCAGC-3′; Exon5R: 5′-CTACCTGAGCAACAGTCCGG-3′; Exon6F: 5′GGAACTCCACCTGTCTCTGC-3′; Exon6R: 5′-AGGCAACGCTGTT­CCTGG-3′; Exon7F: 5′GTTGCCTCTGGGGGAGTG-3′; Exon7R: 5′-GTTGCCTCTGGGGGAGTG-3′; Exon8F: 5′GGGAGCTGTTTTGGGAAGGA-3′; Exon8R: 5′-CTTGGATGGGAGAGGCTTGG-3′; Exon9F: 5′CGGTTCCCCCTCTGTGAAAA-3′; Exon9R: 5′-CAGGACTCCAGGGGACAGA-3′; Exon10F: 5′GT­CCCAGCAGTCACTGACTC-3′; Exon10R: 5′-TGAA­TTC­AT­CC­GCCCCGTAG-3′; Exon11F: 5′GGTGGTCCC­AGGG­GA­GAG-3′; Exon11R: 5′-GGTGTGGTTGTGGGCTGTAT-3′; Exon12F: 5′CACCCCCATCCCCCACTC-3′; Exon12R: 5′-GTCTGCCCTGAGATGTGCTC-3′; Exon13F: 5′TCTCAGTGTGG­GGGAAACAC-3′; Exon13R: 5′-GAGTGGAGGAGCACCAGGA-3′; Exon14F: 5′GGGAAGGTTGGATGGTGACT-3′; Exon 14R: 5′-TGTCCCCAGAAACACAGAGC-3′. The annealing temperature was 62°C. Additional control data were obtained from 5 pathogenicity prediction software (Polyphen-2, SIFT, Mutation Tester, Panther, and Mutation Assessor) and 4 freely available databases of genetic variants (dbSNP, 1000 Genomes, ExAc, and EVS).

Collection of Clinical Data

Case report forms were designed before data collection, which included demographic and clinical data and were filled in by pediatric endocrinology physicians. Pre-treatment laboratory results were accessed for better analysis.

Discussion

We present a case with adrenal insufficiency due to APS1, complicated by reversible LV dysfunction. Our case is the first case reported with LV dysfunction secondary to APS1 with a novel homozygous variant in AIRE, c.964T>C. Hydrocortisone, calcitriol, and calcium treatments improved clinical and laboratory findings of LV dysfunction in 4 weeks. Over 60 different disease-causing variants have now been described in the AIRE gene [Owen and Cheetham, 2009]. Wani et al. [2013] reported myocardial dysfunction in a case clinically diagnosed as APS1 who had hypocalcemia associated with adrenal insufficiency. In this report, the diagnosis was not confirmed by genetic analysis. Dilated cardiomyopathy secondary to adrenal insufficiency independent of etiology is a rare complication in children [Boston et al., 1994; Derish et al., 1996; Conwell et al., 2003; Al Jarallah, 2004; Wiltshire et al., 2004; Wani et al., 2013; Ödek et al., 2017; Alkhateeb et al., 2018].

In our case, although clinical LV dysfunction findings were absent, laboratory and echocardiographic findings suggested LV dysfunction before the initiation of GC treatment. Oral calcium, calcitriol, and GC treatments improved cardiac dysfunction. Despite low ejection fraction, it has been reported that patients do not show clinical signs of heart failure due to the impaired renin-angiotensin-aldosterone system caused by adrenal insufficiency [Alkhateeb et al., 2018]. Cases that developed congestive heart failure 24−48 h after starting GC therapy have been reported in the literature [Derish et al., 1996; Conwell et al., 2003; Wolff et al., 2007; Ödek et al., 2017]. It is proposed that this is secondary to GC effects such as water and sodium retention [Conwell et al., 2003; Wolff et al., 2007; Shimizu et al., 2011]. Rehydration should be cautious because the myocardium will become more sensitive to inotropic agents with GC therapy [Conwell et al., 2003]. Clinical findings improved in all cases within a few days [Derish et al., 1996; Conwell et al., 2003; Wolff et al., 2007; Shimizu et al., 2011; Ödek et al., 2017].

In the literature, cardiomyopathy associated with CAH was first described in 21-hydroxylase deficiency and then in 11β-hydroxylase deficiency [Boston et al., 1994; Al Jarallah, 2004]. Minette et al. [2013] showed that GC deficiency directly affected cardiac functions in newborns with CAH, and cardiac functions in echocardiography improved following GC replacement therapy.

In cardiomyopathy associated with hypocortisolemia and hypocalcemia, hydrocortisone, calcitriol, and calcium treatments are sufficient without need to intervene on management of cardiac dysfunction. The improvement of heart failure symptoms with the replacement of oral calcium, calcitriol, and hydrocortisone has proven that myocardial dysfunction is caused by hypocalcemia and hypocortisolemia [Wani et al., 2013].

Although cortisol deficiency is associated with cardiomyopathy, exact mechanisms are not known. Studies in adrenal ectomized rats have shown that GC deficiency causes changes in membrane Ca²⁺ transport, myocardial contractile protein ATPase activity, and calmodulin-dependent protein kinase II activation that would affect cardiac contractility [Narayanan, 1983; Bhaskar et al., 1989; Rao et al., 2001]. Allolio et al. [1994] have demonstrated the importance of normal GC levels for β2-adrenoceptor function and helped to explain the decreased responsiveness to catecholamines and the impaired cardiac performance in adrenal crisis. It is speculated that GC deficiency may cause a loss of protective mechanisms against catecholamines. Catecholamines can cause myocardial damage through reperfusion, oxidative damage, and mitochondrial dysfunction after ischemia in GC deficiency. GCs protect myocardial catecholamines from toxic effects by immune modulation and free radical scavenging [Kassim et al., 2008]. Due to the mechanisms mentioned, profound hypotension is also resistant to catecholamines, as it is also associated with secondary volume reduction due to adrenal insufficiency [Conwell et al., 2003; Shimizu et al., 2011]. They suggest that initial vasopressor treatment without GC may cause myocardial damage and heart failure in adrenal insufficiency. Therefore, GC replacement simultaneously with vasopressor treatment is crucial in these patients [Ödek et al., 2017]. However, persistent heart failure and severe hypotension often respond to GC replacement therapy [Wani et al., 2013; Alkhateeb et al., 2018].

Elevated levels of NT-pro-BNP have been suggested to be associated with myocardial cell damage and LV dysfunction [Ödek et al., 2017]. NT-pro-BNP may be considered a valuable biomarker for myocardial dysfunction in children, adolescents, and adults. NT-pro-BNP levels in pediatric heart failure patients strongly correlate with both impaired heart function on echocardiogram and clinical status. Serial BNP levels in the pediatric heart failure clinic follow the clinical course [Favilli et al., 2009].

Conclusion

Adrenal insufficiency may be more common in the etiology of LV dysfunction. Failure to identify the etiology leads to ineffective treatment of heart failure with diuretics. The results of this report expand the known phenotypic and genetic spectra of APS1.

Statement of Ethics

The authors declare that for the publication of the reported patient‧s details and accompanying images, her parents have given their written informed consent in accordance with the Declaration of Helsinki. Ethical approval was not required for this study in accordance with local/national guidelines. The authors have no ethical conflicts to disclose.

Conflict of Interest Statement

The authors declare that there is no conflict of interest.

Funding Sources

The authors declare that this paper received no financial support.

Author Contributions

Surgical and medical practices: Yavuz Özer, Hande Turan, Aydilek Dağdeviren Çakır, Selman Gökalp, Zeynep Ocak, Oya Ercan, Olcay Evliyaoğlu. Concept: Yavuz Özer, Selman Gökalp, Zeynep Ocak, Olcay Evliyaoğlu. Design: Yavuz Özer, Selman Gökalp, Zeynep Ocak, Olcay Evliyaoğlu. Data collection or processing: Yavuz Özer, Hande Turan, Aydilek Dağdeviren Çakır, Selman Gökalp, Zeynep Ocak, Oya Ercan, Olcay Evliyaoğlu. Analysis or interpretation: Yavuz Özer, Selman Gökalp, Zeynep Ocak, Olcay Evliyaoğlu. Literature search: Yavuz Özer, Selman Gökalp, Zeynep Ocak, Oya Ercan, Olcay Evliyaoğlu. Writing: Yavuz Özer, Selman Gökalp, Zeynep Ocak, Olcay Evliyaoğlu.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

Funding Statement

The authors declare that this paper received no financial support.