Late-onset familial cerebral cavernous malformation without a family history: a case description

Introduction

Cerebral cavernous malformation (CCM) is a vascular anomaly characterized by clusters of abnormally dilated, thin-walled capillaries (1). The gold standard for diagnosis is brain magnetic resonance imaging (MRI), particularly with susceptibility-weighted imaging (SWI), which effectively visualizes the characteristic hemosiderin deposition (2). According to the Zabramski classification, CCMs can be categorized into four types based on brain MRI (3). Among these, Type II is the most common, characterized by a popcorn-like lesion with a mixed reticulated signal due to repeated microhemorrhage and hemosiderin deposition (4).

Although it has been established that familial cases (~20%) result from autosomal dominant mutations in one of the CCM1 (KRIT1), CCM2 (MGC4607), or CCM3 (PDCD10) genes (5,6), the majority of sporadic CCM cases (~80%) are thought to arise through distinct genetic mechanisms (7-10), which remain an active area of investigation. Lesion distribution patterns differ between familial and sporadic CCM (6,11). Familial CCM is characterized by multiple lesions scattered throughout the brain, attributable to germline mutations, whereas typical sporadic CCM most often presents with a single lesion located within the drainage territory of a developmental venous anomaly (DVA) (11). However, atypical sporadic cases may exhibit multiple clustered lesions surrounding the collecting vein associated with a DVA (11). Compared with sporadic CCM, familial CCM tends to have a more aggressive disease course, and thus genetic testing and family screening in suspected hereditary cases are critical (12).

This case report presents an older adult patient with familial CCM, initially identified through brain MRI and later confirmed via genetic testing. The unique aspect of this case is the late-onset presentation of familial CCM in the absence of a known family history, which could have led to a misdiagnosis of cerebral amyloid angiopathy (CAA) or hypertensive arteriopathy. This report highlights the need to consider familial CCM even in older adult patients without an apparent family history. A thorough imaging analysis is crucial for differential diagnosis.

Case presentation

A 76-year-old woman presented with a 1-month history of headache and memory loss. She experienced intermittent, pulsating headache primarily in the frontal and temporal regions, accompanied by short-term memory loss and abnormal psychiatric behaviors. The headache, aggravated by exercise, lasted 1–2 hours per day and was not accompanied by fever, altered consciousness, nausea, vomiting, visual disturbances, or seizures. The visual analogue scale score was 6. She had no personal history of hypertension and no family history of CCM. Apart from short-term memory loss, the neurological examination was unremarkable. No suspicious vascular lesions were observed in the head and neck region.

Cerebrospinal fluid (CSF) analysis revealed no evidence of bacterial, fungal, or viral infection. Additionally, tests for anti-cell surface antigen antibodies and anti–intracellular antigen antibodies in the CSF associated with autoimmune encephalitis were negative. Brain MRI identified a Zabramski Type II lesion adjacent to the left lateral ventricle, characterized by mixed signals on T1-weighted and T2-weighted fluid-attenuated inversion recovery imaging, with a surrounding hypointense rim indicative of hemosiderin deposition. SWI confirmed hypointensity within the lesion. Furthermore, diffuse hemosiderin deposition was observed in the bilateral frontal and parietal lobes, periventricular regions, and pons. These hemosiderin deposits were more extensive and irregular compared to those typically seen in CAA and hypertensive arteriopathy, suggesting the presence of Zabramski Type IV lesions (Figure 1). Imaging showed no evidence of vertebral, hepatic, or renal hemangiomas. After CAA and encephalitis were ruled out, familial CCM was considered as the potential diagnosis due to the presence of multiple hemosiderin deposits on SWI despite the absence of a documented family history. We performed whole-exome sequencing for the patient. Raw data were aligned to the human reference genome (hg18), and variant calling and annotation were performed via the standard bioinformatics pipelines. By analyzing the data of whole-exome sequencing, we identified a heterozygous nonsense mutation in exon 19 of the KRIT1 gene (NM_194456.1:c.2092C>T; p.Q698*). This c.2092C>T variant has not been reported in the Exome Aggregation Consortium or the 1000 Genomes Project databases. The Q698* mutation introduces a premature stop codon, which is predicted to result in a truncated KRIT1 protein. A previous study reported that this variant cosegregates with the disease in affected family members (13). Based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology 2015 guidelines (14), this mutation is classified as pathogenic. This finding confirmed the diagnosis of autosomal dominant familial CCM Type 1. Her son’s genetic testing results were normal, with no KRIT1 gene mutations, and his brain MRI showed no CCM lesions. The patient received symptomatic treatment, including pain management, which led to gradual symptom relief over the course of 1 month.

Figure 1.

Brain MRI showed multiple cerebral cavernous malformations. Brain MRI revealed a Zabramski Type II lesion (arrows) adjacent to the left lateral ventricle, characterized by a mixed signal on (A) T1-weighted and (B) T2-weighted FLAIR imaging, along with marked hypointensity on SWI (C). Additionally, multiple Zabramski Type IV lesions (arrowheads) were observed in the (A-C) bilateral frontal and parietal lobes, periventricular region, and (D-F) pons, characterized by significant hemosiderin deposition; this was not visible on (A,D) T1-weighted or (B,E) T2-weighted FLAIR imaging but was distinctly visible on (C,F) SWI. FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; SWI, susceptibility-weighted imaging.

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 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

Familial CCM follows an autosomal dominant inheritance pattern, typically manifests with symptomatic onset in early-to-middle adulthood, and is often accompanied by a positive family history (15,16). However, clinical recognition can be challenging in older adult patients without a documented family history. This case report presents an older adult patient diagnosed with familial CCM despite the absence of a known family history, underscoring the potential value of imaging-based differentiation and genetic testing in selected cases to support diagnostic accuracy.

Brain MRI plays a crucial role in the diagnosis and differential diagnosis of familial CCM. In this case, the patient exhibited the characteristic multifocal lesions of familial CCM, including a Zabramski Type II lesion with hemosiderin deposition and multiple Zabramski Type IV lesions. In older adult patients, the imaging findings can be confused with those of other common cerebrovascular disorders, such as CAA and hypertensive arteriopathy. However, subtle differences exist between these conditions on MRI. CAA-related microbleeds predominantly occur in the cortical and subcortical regions, particularly in the parietal or occipital lobes (17). In contrast, hypertensive arteriopathy-related microbleeds are typically located in the deep gray-matter nuclei and exhibit a more symmetrical distribution (18). Familial CCM lesions, however, tend to be asymmetrically and diffusely distributed throughout the brain, affecting the subcortical white matter, deep brain structures, and brainstem (19). A key distinguishing feature of familial CCM on MRI is the characteristic “popcorn-like” appearance with surrounding hemosiderin deposition, which is frequently observed on SWI (6). On the other hand, CAA and hypertensive arteriopathy typically present with microbleeds appearing as homogeneous, punctate hypointensities without complex structural features, which are markedly different from those of familial CCM.

Several key aspects distinguish this case from typical familial CCM, including the late-onset clinical presentation and the absence of a family history. These differences illustrate the phenotypic variability of familial CCM and suggest that genetic testing may be helpful in atypical presentations, particularly when clinical or imaging findings raise suspicion for hereditary disease. Familial CCM typically manifests between 30 and 40 years old (6,20), with the most common presentations being hemorrhagic stroke, seizures, or focal neurological deficits. However, our patient developed nonspecific symptoms, such as headaches and memory impairment, at the age of 76 years, which contrasts sharply with the early-onset phenotype. Familial CCM follows an autosomal dominant inheritance pattern, and more than 50% of cases have a positive family history (21,22). The absence of a family history in this case may have several possible explanations. First, familial CCM exhibits incomplete penetrance, with up to 20% of KRIT1 mutation carriers remaining asymptomatic (23). Second, although rare, a de novo KRIT1 mutation might have occurred. Finally, older family members may have harbored undiagnosed lesions due to the lack of MRI screening, which could have precluded genetic evaluation and contributed to underdiagnosis.

Recent studies have significantly expanded our understanding of the genetic heterogeneity underlying familial CCM (24-26). Although KRIT1 remains the most frequently mutated gene, a wide range of pathogenic variant types have been identified, including nonsense, frameshift, splice-site, and in-frame mutations. For instance, Chen et al. reported a novel KRIT1 frameshift mutation (c.1119dupT) in a large Chinese family with both intracranial and spinal cavernous malformation, thereby broadening the mutational spectrum observed in the Chinese population (24). Li et al. identified a KRIT1 splice-site mutation (c.1255-1G>T) co-occurring with a NOTCH3 variant in a Chinese family, suggesting a potential synergistic pathogenic mechanism (25). Furthermore, Szczygieł-Pilut et al. described a PDCD10 splice-site mutation (c.395+1G>A) in a young Polish woman, underscoring the contribution of non-KRIT1 genes to familial CCM pathogenesis (26). Through this case report, we add to the existing body of evidence by documenting a well-characterized KRIT1 nonsense mutation (c.2092C>T; p.Q698*) in a patient with a late-onset phenotype, thereby emphasizing the broad genotypic and phenotypic heterogeneity of familial CCM and underscoring the clinical value of genetic testing, especially in atypical cases.

In conclusion, this case underscores the need to consider familial CCM in older adult patients with multiple hemosiderin deposits on SWI, even when no family history is reported. Comprehensive MRI evaluation remains essential, and genetic testing may provide additional diagnostic insight, particularly in cases in which familial CCM is suspected.

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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 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.