A female manifesting carrier of DMD with exon 45 deletion: a case report

Introduction

Duchenne muscular dystrophy (DMD) is a rare X-linked recessive disorder caused by mutations in the DMD gene, resulting in dystrophin deficiency (1,2). The absence of dystrophin results in the destabilization of the muscle cell membrane, leading to progressive muscle weakness and atrophy. Cardiopulmonary failure exhibits a pronounced male predilection, with an estimated global incidence of approximately 1 case per 5,000 males (3). Female cases are extremely rare and mostly present as manifesting carriers rather than typical DMD patients (4). Children diagnosed with DMD typically manifest an insidious clinical onset between the ages of 2 and 3 years, experience loss of ambulatory capacity by approximately 15 years of age, and ultimately succumb to respiratory or cardiac complications before reaching the age of 30 years (5). This paper presents the clinical characteristics, diagnostic process, and genetic mutation analysis of a female manifesting carrier of DMD, whose initial presentation involved persistently elevated liver enzymes. This case aims to enhance understanding of manifesting carriers of DMD and reduce the likelihood of misdiagnosis. We present this article in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0144/rc).

Case presentation

The patient, a 3-year and 3-month-old female child, was admitted to the Department of Pediatrics at Fenghua District People’s Hospital due to “repeated detection of elevated transaminase levels for more than 2 months”. Two months prior, during a pre-kindergarten physical examination, her liver function tests revealed alanine aminotransferase (ALT) at 71 U/L (normal value 0–40 U/L) and aspartate aminotransferase (AST) at 73 U/L (normal value 0–40 U/L). The child exhibited no symptoms such as cough, sputum, foaming at the mouth, fever, vomiting, or diarrhea. Subsequently, she visited the infectious disease department of our hospital multiple times for treatment, where “liver enzyme elevation” was suspected. During this period, she received minocycline tablets for liver protection and symptomatic treatment for 20 days. Follow-up liver function tests showed persistent and fluctuating elevation of transaminases without obvious improvement, with ALT levels of 102, 82, and 79 U/L, and AST levels of 193, 115, and 93 U/L. Comprehensive testing for hepatitis B and hepatitis series yielded negative results, while CK-myocardium (MB) was measured at 124 U/L and myoglobin at 214.7 U/L. Unfortunately, CK levels were not monitored outside the hospital. The child was a gravida 1, para 1 (G1P1), born at full term (40 weeks) with a birth weight of 3.6 kg and a body length of 50 cm. The Apgar score is unknown. There was no history of ischemia or hypoxia following birth, nor any history of resuscitation. The mother reported no use of special medications or exposure to toxins during pregnancy. The child achieved developmental milestones as follows: looked up at 3 months, sat at 6 months, climbed at 8 months, stood independently at 10 months, walked alone by 12 months, and spoke monosyllabic words such as “father” and “mother” by 12 months. After the age of 1 years, the child’s growth and development lagged behind peers. Currently, at age 3 years, the child exhibits no atypical gait and is able to walk and run steadily, jump on one foot, and ascend and descend stairs using an alternating foot pattern. The child can rise quickly from a lying position and squat without hand support. However, the child cannot jump with both feet (which is typically achieved by ages 2 to 2.5 years), can stand on one foot for approximately 3 seconds (whereas the norm is greater than 3.5 seconds), and can climb steps but is unable to jump down steps. The individual exhibits limited articulation and poor expressive skills, resulting in social neglect by strangers. Nevertheless, the guidance provided to parents can be implemented to facilitate the child’s ability to express their own needs. The Gesell Developmental Diagnostic Scale, administered at 3 years and 1 month, indicated mild abnormalities in gross motor, fine motor, language, and personal social interaction skills, as well as marginal adaptability.

Family history reveals that the child is the only daughter, with both parents in good health, and there is no indication of consanguinity or a family history of genetic disorders.

During the admission physical examination, the child weighed 14 kg [50th percentile (P50)] and measured 94 cm in height (P25), with a head circumference of 46.5 cm (P5–15). The patient was alert with moderate responsiveness, limited verbal fluency, slow speech, and low voice. She was unable to cooperate with the finger-nose test.

Laboratory and auxiliary examinations revealed the following results: blood routine, thyroid function, ceruloplasmin, blood ammonia, venous blood gas, erythrocyte sedimentation rate, and interleukin-6 levels were within normal ranges. Antinuclear antibody, antineutrophil cytoplasmic antibody, cardiolipin antibody, Coombs test, and rheumatoid series results were negative. Tests for TORCH and Epstein-Barr virus were also negative. The myocardial enzyme spectrum, including cTnI, showed elevated levels: CK at 4,293 IU/L (normal value 20–140 IU/L), CK isoenzyme at 164 U/L (normal value 0–25 U/L), myoglobin at 240.7 µg/L (normal value 10–70 µg/L), lactate dehydrogenase at 572 U/L (normal value 110–220 U/L), and AST at 137 U/L (normal value 0–40 U/L). ALT was recorded at 82 U/L (normal value 0–40 U/L). Echocardiography indicated mild tricuspid regurgitation, while the electrocardiogram (ECG) was normal. Lung computed tomography (CT) revealed a few fibrous foci in the right lower lung.

Gene detection was conducted with the informed consent of the child’s parents, involving the extraction of
2 mL of peripheral blood from the child and his parents for full exon genome sequencing. The results (Figure 1) indicate the presence of a heterozygous mutation, exon45del, in the DMD gene (nm_004006.3), which alters the reading frame of the coding protein. According to the American College of Medical Genetics and Genomics (ACMG) rating consensus, this mutation is likely pathogenic (pvs1+PM1+PM2+PP1). Furthermore, this mutation is absent from the population genomic mutation frequency database. A review of the literature reveals that the deletion of exons 45–55 in the DMD gene is a recognized hotspot among Chinese patients with DMD/Becker muscular dystrophy (BMD), and the deletion of exon 45 has been identified in numerous DMD patients (6). Various predictive software tools suggest that this mutation is deleterious. Sanger sequencing confirmed that the parents do not carry the mutation, indicating it is a novel mutation.

Figure 1 Data mining analysis pattern. DMD, Duchenne muscular dystrophy.

Unfortunately, electromyography and magnetic resonance imaging of the lower limb muscles could not be performed due to the children’s age, lack of cooperation, and family preferences. Following the diagnosis and treatment, the patient experienced pain in the right lower limb over the past six months, although the specific onset remains unclear, suggesting a potentially longer duration. Family members reported that the pain could be alleviated through kneading, allowing the patient to move freely without significant gait abnormalities. Symptomatic treatment included the administration of a vitamin C needle, a compound glycyrrhizin needle for liver protection, and coenzyme Q for myocardial nutrition. On the third day of treatment, laboratory and auxiliary investigations revealed that muscle enzyme profiles, although demonstrating a marginal decline, remained substantially elevated throughout the hospitalization period. The detailed results are as follows: CK at 3,807 IU/L (normal value 20–140 IU/L), CK isoenzyme at 147 U/L (normal value 0–25 U/L), myoglobin at 240.7 µg/L (normal value 10–70 µg/L), lactate dehydrogenase at 405.9 U/L (normal value 110–220 U/L), AST at 111 U/L (normal value 0–40 U/L), and ALT at 85 U/L (normal value 0–40 U/L).

There are three isozymes of CK: skeletal muscle (CK-MM), CK-MB, and brain tissue (CK-BB). The level of CK is significantly higher than that of CK-MB. When considered alongside the symptoms and signs observed in children, this elevation suggests myogenic injury. The AST/ALT ratio is greater than 1, while the residual jaundice index, alkaline phosphatase, and gamma-glutamyl transpeptidase (r-GGT) levels remain normal. Color Doppler ultrasound indicates that the liver is not swollen. Hepatitis B and related serologies are normal, regardless of the hepatogenic origin. Based on integrated clinical, laboratory, and genetic assessments, the primary diagnosis was established as manifesting carrier of DMD, complicated by elevated liver enzymes and myocardial injury. The results of full exome sequencing analysis (TRIO) for nm_004006.3 (chrx:31983086-31986639) revealed a heterozygous mutation, exon 45 deletion, which confirms a diagnosis of a manifesting carrier of DMD. A significant limitation of this investigation is the absence of X-chromosome inactivation (XCI) analysis. Skewed XCI is established as the principal mechanism driving clinical symptoms in female manifesting carriers of DMD. Evaluation of XCI status could have fortified the interpretation of genotype-phenotype correlations in this context. Subsequent studies on female manifesting carriers ought to integrate XCI analysis to delineate the underlying molecular mechanisms. Currently, no established curative treatment is available. We have formulated an individualized rehabilitation training regimen for the patient, incorporating physical therapy and exercise therapy, to maximally preserve muscle function and delay the progression of muscle atrophy and weakness. Furthermore, long-term clinical follow-up is imperative for this patient, as most female manifesting carriers of DMD do not exhibit the severe progressive course typically observed in male DMD patients. The patient is currently undergoing close long-term follow-up.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient’s parents for the publication of this case report. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

DMD is a rare X-linked recessive genetic disorder and is among the most severe and prevalent of the rare diseases (7). The principal clinical manifestations comprise impaired stair-climbing ability, gait instability, recurrent falls, difficulty squatting, gastrocnemius pseudohypertrophy, a positive Gower’s sign, and intellectual disability of varying severity (8). According to the meta-analysis conducted by Crisafulli et al. (8), the pooled prevalence of DMD was estimated at 7.1 cases per 100,000 males, while the pooled birth prevalence was reported as 19.8 cases per 100,000 live male births (equivalent to approximately 1 in 5,050 live male births). The same study indicated an overall prevalence of 2.8 cases per 100,000 individuals (including both males and females); however, a separate pooled estimate specifically for live female births was not provided. Cases of DMD in female infants are exceptionally rare, with documented incidence rates in the literature as low as approximately 1 in 1,000,000 live births (9). This condition results from mutations in the DMD gene present in affected tissues. The DMD gene is located at chromosome Xp21.2–p21.1, consists of 79 exons, and spans approximately 2,400 kb, accounting for about 1% of the entire X chromosome (10). As one of the largest known genes, it exhibits a high mutation rate. The DMD gene encodes dystrophin, which interacts with a series of skeletal proteins to form the dystrophin-associated protein complex (DAPC). This complex plays a critical role in preserving the stability and integrity of the muscle cell membrane and foreign regulating cellular signal transduction pathways. Mutations in the DMD gene, disrupt the structure and function of the encoded dystrophin protein, which in turn compromises membrane stability, ultimately leading to calcium influx and oxidative stress—a key pathological cascade in cellular damage. Subsequently, the release of pro-inflammatory cytokines, along with the pathological processes of inflammation, degeneration, necrosis, and fibrosis of muscle fibers, impairs muscle cell regeneration. This impairment initiates a cycle of inflammation, during which damaged muscle cells are replaced by proliferating adipose tissue and fibrous connective tissue. Ultimately, this process results in a decline in muscle function and a series of pathophysiological mechanisms. Concurrently, mitochondrial dysfunction or vascular ischemia may occur, leading to metabolic damage that exacerbates muscle dysfunction and ultimately contributes to muscle atrophy. Among the mutations associated with DMD, deletion mutations represent the predominant type, comprising approximately 55% to 65% of cases. In contrast, duplication mutations account for 5% to 10%, while point mutations constitute approximately 25%. The remaining minor deletion mutations comprise approximately 8%. Deletion mutations were primarily concentrated in two hotspots: exon 2–20, which accounted for 30% of deletion mutations, and the central deletion hotspot, located in exons 44-51, which accounted for 70% of deletion mutations. The severity of most DMD symptoms can be assessed according to the “open reading frame (ORF) principle” of gene mutation (11). The severity of clinical manifestations correlates with the extent of disruption to the reading frame structure of the gene. However, approximately 10% of DMD phenotypes deviate from this established principle, which complicates the diagnostic process. It is anticipated that future research will elucidate the mechanisms underlying the genotype-phenotype relationship in DMD. A summary of data from 42 children with DMD indicated that parents observed reduced exercise ability in 67.6% of cases, while 32.4% were identified through physical examinations in kindergarten that revealed elevated muscle enzyme levels. Patients diagnosed solely due to leg hypertrophy constituted only 3.8% of those with DMD. Consequently, the diagnostic accuracy for this condition based on characteristic clinical signs—such as diminished exercise tolerance, pseudohypertrophy of the gastrocnemius muscle, and a positive Gower sign—remains suboptimal. Missed diagnoses and misdiagnoses frequently occur among pediatric patients with DMD. Serum levels of CK, ALT, AST, and lactate dehydrogenase (LDH) are markedly elevated due to skeletal muscle fiber damage (12). Any factor that alters the permeability of the muscle fiber membrane can result in increased serum concentrations of these enzymes. Muscle diseases that do not present with significant muscle weakness or atrophy are frequently misdiagnosed as myocarditis or hepatitis. In the early stages of this case, recurrent elevated liver enzymes were the primary manifestation, while other characteristic symptoms and signs were not prominent, complicating clinical diagnosis. Unfortunately, electromyography and magnetic resonance imaging of the lower limb muscles could not be performed due to the young age of the patients. Additionally, in atccordance with the family’s wishes, a muscle biopsy was deferred, and the diagnosis of DMD was definitively established through molecular genetic analysis of the DMD gene. Therefore, when children present with elevated liver enzymes as the principal symptom, the potential for DMD should be considered, emphasizing the importance of CK monitoring. Currently, clinical drug trials have indicated that casimersen can alleviate clinical symptoms by enhancing dystrophin levels in patients with DMD resulting from a skip mutation in exon 45 of the DMD gene (13). The efficacy of casimersen in the treatment of DMD associated with exon 45 skip-amenable mutations in the DMD gene has not been definitively established. Although the U.S. Food and Drug Administration (FDA) anticipates potential clinical benefits, it remains unclear whether this therapeutic intervention can lead to improvements in motor function or slow the progression of muscular atrophy.

Conclusions

In summary, this study conducted a comprehensive clinical and genetic analysis of a female manifesting carrier of DMD. The findings indicate that the clinical phenotype of manifesting DMD carriers in pediatric populations, which may predominantly present with elevated liver enzymes, can be atypical and is susceptible to misdiagnosis. Systematic monitoring of CK levels is crucial in such cases. Persistent elevation in CK warrants early genetic testing, which can facilitate the identification of the disease’s etiology, standardize therapeutic interventions, ameliorate symptomatic progression, and ultimately improve patient prognosis and quality of life.

Acknowledgments

We thank the patient and her parents for participating in this study.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0144/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0144/prf

Funding: This work was supported by the Key Medical Discipline Construction Program of Fenghua District (No. 2025ZD03).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0144/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 and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient’ s parents for the publication of this case report. 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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