Dilated cardiomyopathy, extensive subendocardial fibrosis and myocardial non-compaction in a patient with sex development disorder: a rare case of myelin regulatory factor-related cardiac-urogenital syndrome

Introduction

Disorders of sex development (DSDs) are rare congenital conditions. The incidence of ambiguous genitalia is reported as 1/4,500 (1). Previously reported cases of DSDs combined with dilated cardiomyopathy (DCM) involved families with a history of consanguinity and lacked comprehensive imaging data (2,3). We present a novel sporadic case, the first to utilize multimodal imaging and genetic findings to lead to a diagnosis of cardio-genitourinary syndrome (CUGS). Cardiac phenotyping, as defined by cardiac magnetic resonance (CMR), expands the known clinical spectrum of myelin regulatory factor (MYRF)-related disorders.

Case presentation

Patient history

This 13-year-old “girl” was admitted for intermittent palpitations, dizziness (present for >10 days), and an episode of syncope. Physical examination revealed cardiomegaly, weak heart sounds, and the absence of murmurs. Visual acuity was normal. Laboratory findings included: troponinI 0.014 (≤0.1 µg/L). B-type brain natriuretic peptide (BNP) 513.8 pg/mL (normal range, 0–125 pg/mL), and prostate-specific antigen (PSA) 0.06 ng/mL (normal range, 0–4 ng/mL). Electrocardiogram showed sinus arrhythmia and type B ventricular preexcitation (Figure 1). Echocardiography revealed significant left ventricular enlargement (left ventricular diameter 68 mm), thinning of the left ventricular myocardium, excessive trabeculation (Figure 2), severely reduced systolic function. CMR (Figure 3A) revealed spherical left ventricular enlargement [left ventricular end-diastolic volume (LVEDV) 324.3 mL], myocardial thinning, excessive trabeculation of the lateral wall, and an end-diastolic noncompacted/compacted ratio of 4 (>2.3). Left ventricular systolic function was significantly impaired [ejection fraction (EF) 24%] (Video 1), with mild mitral regurgitation and widespread delayed gadolinium enhancement (Figure 3B,3C) involving the endocardium from the left ventricular base to apex, including the interventricular septum. Coronary computed tomography angiography (CTA) (Figure 4A-4C) showed normal coronary arteries origin and no stenosis. Chest radiograph showed cardiomegaly and an anomalous fissure in the right upper lung field (Figure 5). Abdominal computed tomography (CT) was unremarkable.

Figure 1 The 18-lead electrocardiogram demonstrates sinus rhythm with dysrhythmia and B-type ventricular pre-excitation.

Figure 2 The echocardiogram reveals incomplete myocardial densification of the left ventricle, with arrow pointing to non-compaction myocardial tissue.

Figure 3 CMR imaging demonstrates findings consistent with LVNC. The late diastolic four-chamber view (A) shows multiple deep trabeculae (arrows) and a thick spongy myocardium, with a N/C ratio >2.3. Furthermore, four-chamber (B) and short-axis (C) views show delayed gadolinium enhancement demonstrating large, arc-shaped subendocardial enhancement adjacent to the left ventricle, extending from base to apex (arrows). CMR, cardiovascular magnetic resonance; LV, left ventricle; LVNC, left ventricular non-compaction; N/C, non-compacted to compacted myocardium; RV, right ventricle.

Figure 4 Coronary CTA showed no plaque stenosis or abnormal origin. CT coronary MIP (A) and MPR (B,C) show no abnormal origin or atherosclerotic changes were observed in the left and right coronary arteries. CT, computed tomography; CTA, computed tomography angiography; LA, left anterior; LAD, left anterior descending; MIP, maximum intensity projection; MPR, multi-planar reconstruction; RA, right atrium; RCA, right coronary artery.

Figure 5 Chest X-ray anteroposterior view shows cardiomegaly, with significant enlargement of the left cardiac silhouette. A fissure (arrows) is also noted in the right upper lung field.

Although our patient was raised as a girl, he presents with ambiguous genitalia. Physical examination reveals features of both sexes: lack of laryngeal prominence, the presence of armpit hair and breast development, sparse pubic hair, primary amenorrhea, an immature vulva, and penile atrophy. The vagina is a blind-ending pouch accessible only with a small cotton swab. Scrotal dysplasia is present, appearing as separated labia majora. There are no palpable masses in the inguinal regions or labia majora. Pelvic ultrasound (Figure 6A-6C) shows a small uterus (2.8 cm × 2.4 cm × 1.2 cm) and prostate (2.4 cm × 2.2 cm × 1.7 cm), along with two anechoic areas in the left and right inguinal regions suggestive of underdeveloped testicular tissue. The patient’s prior medical history includes a diagnosis of a DSD at another hospital, with a confirmed 46,XY karyotype.

Figure 6 Pelvic ultrasound reveals a tiny uterus (2.8 cm × 2.4 cm × 1.2 cm) (A), a tiny prostate (2.4 cm × 2.2 cm × 1.7 cm) (B) respectively (arrows), and an anechoic area in the groin suggestive of underdeveloped testicular tissue (arrows) (C). P, prostate; TS, testicular; UB, urinary bladder; UT, uterus.

Family history and genetic analysis

The patient, an only child born to healthy parents without consanguinity, was diagnosed with a DSD at an outside facility (karyotype 46,XY). The patient’s family history includes cardiovascular disease (coronary artery disease in the paternal grandfather and hypertension/unspecified heart disease in the maternal grandmother). Genetic testing (total exome sequencing) revealed no pathogenic variants for DCM, but identified two variants of uncertain significance (VUS) in genes associated with DSD. One of which is in MYRF, a gene linked to cardio-genitourinary syndrome [CUGS (cardiac and urogenital anomalies)], encoding a membrane-bound transcription factor expressed in tissues relevant to CUGS (4). Parental genetic testing was recommended but declined due to financial limitations.

A donor heart was allocated through the Chinese Organ Donation and Sharing Computer System; however, the patient and his family declined transplantation for personal reasons.

All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

This case report details a 46,XY female with reproductive system anomalies and DCM. Although similar to previously reported cases (2,3), this case presents several key differences. Notably, the absence of familial or intellectual disability in the parents distinguishes it as a sporadic case, unlike previously reported cases within consanguineous families.

In addition, our case presents comprehensive imaging data, including echocardiography, X-ray, CT, and CMR. Significantly, we are the first to report the CMR characteristics of this type of DCM. The patient exhibited marked cardiac enlargement with extensive subendocardial late gadolinium enhancement (LGE). While left ventricular enlargement, wall thinning, and fibrosis are typical features of DCM, subendocardial or transmyocardial LGE is observed in approximately 13% of DCM cases. Although the precise mechanism of this LGE remains unclear (5), hypotheses include reperfusion injury following myocardial infarction, certain types of DCM, or reperfusion related to DSDs. However, given the normal coronary CTA and the patient’s young age without a history of myocardial infarction, the CMR findings strongly suggest a genetic etiology for the cardiomyopathy, which appears linked to urogenital anomalies.

Genetic testing identified a novel heterozygous MYRF gene variant (chr11:61773979) as a likely cause of the patient’s combined urogenital and cardiovascular abnormalities. With the advent of exome sequencing, pathogenic MYRF variants have been implicated in CUGS (6). This finding supports the association between MYRF variants and CUGS, previously linked to various congenital heart defects, including aortic coarctation, left heart hypoplasia syndrome, tetralogy of Fallot, atrial and ventricular septal defects, dextrocardia, aortic arch hypoplasia, aortic stenosis, bicuspid aortic valve, mitral stenosis and atresia, aortic valve hypoplasia and atresia, and patent ductus arteriosus (6-10). While MYRF variants are known to impact cardiac development through their role in regulating epithelial cell proliferation and migration, this patient presented with atypical features including incomplete myocardial compaction, DCM, and subendocardial scarring. We hypothesize that the MYRF mutation affects epicardium-derived cell (EPDC) differentiation via epithelial-mesenchymal transition (EMT), potentially leading to myocardial non-compaction, DCM, and fibrosis. This novel MYRF mutation expands the known phenotypic spectrum associated with MYRF variants and contributes to a better understanding of this gene’s phenotypic spectrum.

DSD with cardiomyopathy are common features of both Malouf syndrome (11) and Turner syndrome (TS) (12,13), necessitating differential diagnosis. Malouf syndrome, first described in 1985 in two 46,XX sisters, is characterized by hypergonadotropic hypogonadism, DCM, ptosis, and hypertelorism. In contrast, TS is defined by the absence or partial absence of one or more sex chromosomes (45,X), frequently presenting with cardiovascular anomalies, including bicuspid aortic valve, mitral valve prolapse, ventricular septal defect, and patent ductus arteriosus. Left ventricular dysfunction and hypertrophy are more prevalent in TS. Furthermore, other genetic variations, such as mutations in LMNA TTN and GATA-4, can also cause DSD and cardiomyopathy (14,15), highlighting the importance of genetic testing for accurate diagnosis.

This is the first report of integrating multimodal imaging with genetic results, ultimately leading to a diagnosis of CUGS. CMR findings of this case report have broadened the known clinical spectrum of MYRF-related diseases, highlighting the effective demonstration of CUGS disease phenotypes through the combination of multimodal imaging and genetic analysis.

Acknowledgments

None.

Footnote

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2728/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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