Introduction
Laminopathies are inherited genetic disorders caused by mutations in the LMNA gene, which encodes for lamins A and C, crucial nuclear envelope proteins. These conditions exhibit remarkable clinical diversity, including dilated cardiomyopathy, arrhythmias, Emery–Dreifuss muscular dystrophy, and familial partial lipodystrophy. Reference Bertrand, Chikhaoui, Yaou and Bonne1–Reference Garg, Vinaitheerthan, Weatherall and Bowcock4 Beyond muscular and cardiac issues, altered lamin A/C expression is linked to metabolic conditions like obesity and type 2 diabetes, as well as ageing. Reference Magno, Ceccarini and Pelosini5 Emerging evidence also connects LMNA mutations to tumorigenesis and cancer progression, with inconsistent expression patterns observed across various tumour types. Reference Zhao, Zhang, Pan, He, Zheng and Tang6
Case presentation
We report the case of a 17-year-old boy, asymptomatic, incidentally diagnosed with left ventricular dilation at age 11, during cardiological screening. Cardiac features of the patients were previously reported: basal electrocardiogram (ECG) was normal; echocardiography revealed mildly dilated ventricles, with slightly reduced biventricular systolic function, a patent foramen ovale, and a mild dilated aortic root and ascending aorta. Reference Baban, Cicenia and Magliozzi3 A 24-hour ECG Holter monitoring showed an ectopic atrial rhythm with sporadic supraventricular and ventricular and ectopic beats. Cardiac MRI confirmed the presence of left ventricular hypertrabeculation, with slightly dilated ventricles and mildly reduced ejection fraction, mildly dilated aortic root and ascending aorta, and no tissue characterization anomalies. At blood tests, cardiac biomarkers and creatine kinase levels were normal.
The patient underwent genetic testing that revealed a heterozygous mutation in the LMNA gene, c.598A>G, leading to the variant p.Met200Val. Segregation analysis revealed paternal inheritance, with variable expressivity among the family: the patient’s father (48 years old) and paternal grandmother showed positive genotype and negative phenotype; the younger brother (13 years old) with the same LMNA mutation presented biventricular dilatation with normal systolic function and no extracardiac findings. Paternal relatives showed a history of dilated cardiomyopathy in the grandfather, implanted with a pacemaker, and in the great-uncle. Reference Baban, Cicenia and Magliozzi3
During follow-up, at the age of 15 years old, the patient developed bilateral sensorineural hearing loss and recurrent hemicrania. Brain MRI revealed the presence of pontine cavernous angiomas and venous drainage anomalies, requiring annual monitoring by a neurosurgeon. Moreover, at the age of 16 years old, he developed a low-grade osteogenic sarcoma of the third finger of the left hand, successfully treated with surgical resection.
Therapeutic interventions included the use of angiotensin-converting-enzyme (ACE) inhibitors for the cardiac status, bilateral hearing aids for hypoacusia, conservative management for the pontine angioma, and surgical excision alone for the osteosarcoma.
Discussion
Our case significantly broadens the known clinical spectrum associated with laminopathies, establishing the first documented association between LMNA mutations and extracardiac findings such as bilateral sensorineural hearing loss, pontine cavernous angiomas, and osteosarcoma.
While cardiac involvement has been highly described in literature, Reference Bertrand, Chikhaoui, Yaou and Bonne1–Reference Baban, Cicenia and Magliozzi3 these features are of new interest.
Bilateral sensorineural hearing loss has not been previously reported as a classic manifestation of laminopathies in humans. A recent study of Magno et al. Reference Magno, Ceccarini and Pelosini5 described three patients carrying the LMNA p.R349W mutation, all presenting with atypical progeroid syndrome and bilateral sensorineural hearing loss. Pillers et al. Reference Pillers, Kempton, Duncan, Pang, Dwinnell and Trune7 revealed cochlear pathology and bilateral sensorineural hearing loss in a mouse model of congenital muscular dystrophy (laminin α2 deficiency), suggesting the critical role of extracellular matrix proteins, like laminin, in maintaining auditory system integrity. Furthermore, in adult-onset congenital muscular dystrophy type 1J, mapped to chromosome 6q23–24, the occurrence of dilated cardiomyopathy and hypoacusia has been described, indicating shared vulnerability pathways between the heart and inner ear. Reference Schönberger, Levy and Grünig8
On the other hand, pontine cavernous angiomas are vascular malformations that were not previously linked to LMNA mutations. Recent molecular insights showed that a novel FOS-LMNA fusion gene was detected in an index case affected by epithelioid haemangioma, a benign vascular tumour, suggesting a potential connection between LMNA gene dysregulation and vascular tumorigenesis, possibly through altered transcriptional regulation or endothelial cell signalling. Reference Huang, Zhang and Sung9
Recent advances in LMNA research have also illustrated its potential involvement in tumour biology. In 2024, a comprehensive review by Zhao et al. Reference Zhao, Zhang, Pan, He, Zheng and Tang6 extensively discussed how LMNA mutations, dysregulation, and misprocessing might contribute not only to classical laminopathies but also to neoplastic processes. Altered LMNA expression, in fact, has been observed across various tumour types, where it can influence proliferation, apoptosis, and metastatic behaviour through interactions with various signalling pathways. Reference Zhao, Zhang, Pan, He, Zheng and Tang6
Finally, the association of LMNA with sarcomas, an aggressive malignant tumour originating from mesenchymal cells, has been investigated. Reference Cheng, Li, Li, Yang and Fan10 In particular, proteomic research identified a strong correlation between CCR4-NOT transcription complex subunit 1 (CNOT1) and osteosarcoma cell growth. It has been demonstrated how CNOT1’s activity is LMNA-dependent, suggesting an oncogenic role for this signalling pathway in osteosarcoma progression. Reference Cheng, Li, Li, Yang and Fan10
Given this emerging evidence, it is clinically prudent to consider neoplastic surveillance in patients with LMNA mutations, especially in individuals with multi-system involvement.
Conclusions
This case report significantly expands the known clinical spectrum of clinical manifestations in laminopathies, revealing a unique combination of multiorgan involvements in one patient: dilated cardiomyopathy, bilateral sensorineural hearing loss, pontine cavernous angiomas, and low-grade osteogenic sarcoma. These features, alongside different clinical phenotypes in the genotype-positive relatives, highlight the broad and complex multisystemic findings correlated to LMNA mutations. Moreover, the emerging link between laminopathies and neoplastic risk suggests that multidisciplinary evaluation, including an oncological surveillance, may be considered for these patients from a young age.
Acknowledgements
This work was supported by the Italian Ministry of Health through “Current Research Funds.”
Financial support
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Competing interests
None.
Ethical standard
This study complies with the Declaration of Helsinki and was approved by the local ethics committee. Informed consent was obtained from the patient.
