Case Report: Marfan’s Syndrome with Neurofibromatosis Type-2

Introduction

Marfan syndrome (MFS) is an autosomal dominant hereditary connective tissue disease (CTD) with significant presentations in the skeletal, ophthalmic, and cardiovascular systems that are age-related and is caused due to mutation in the protein gene Fibrillin-1 (FBN1) and affects about 1 in 5,000 people worldwide.^1–3 De novo variants can be present in up to 25% of patients with MFS,⁴ which means that the affected person has a new mutation. It has been shown that MFS is caused by FBN1 missense variations, insertions, deletions, and mutations linked to loss of expression from one allele,^1,5 which is released and integrated into the extracellular matrix (ECM). Microfibrils, which are also known as FBN1, play a crucial role in ECM structures and are found in tissues or in close proximity to elastin fibres.¹

Aortic root aneurysms that are asymptomatic, aortic dissections, ocular lens dislocations, and musculoskeletal anomalies with bone overgrowth are the most notable characteristics of MFS. It is not always necessary to perform genetic testing to validate the existence of FBN1 for diagnosis of MFS but can aid in differentiating MFS from other inherited disease syndromes that can demonstrate skeletal characteristics identical to MFS.^6,7 Acute aortic dissections, which can be fatal, can develop from untreated aortic root aneurysms. Medical treatment is necessary for MFS to reduce the risk of dissection and slow aneurysm progression. The formation of an aneurysm must be routinely monitored with imaging methods such as echocardiography, Computed Tomography (CT), or Magnetic Resonance Imaging (MRI) in order to determine when precautionary repair surgery should be performed to prevent an acute aortic dissection.¹

The other autosomal dominant disease seen in this case report is Neurofibromatosis type 2 (NF-2), which is marked by schwannomas, meningiomas, and ependymomas.⁸ The majority of adult patients with NF-2 have bilateral vestibular schwannomas, which are indicative of NF-2. They typically appear as an augmenting mass that extends from the internal acoustic canal into the cerebellopontine cistern.^8,9 These tumours, however, may not always be present or may be too small to be seen on a routine CT or MRI scan. When this occurs, the development of non-tumoral calcifications, either with or without tumoral calcifications, indicate that NF-2 is a probable diagnosis.⁸ There may also be other cancers of the neurological system, such as tumours of the intrinsic spinal cord, spinal nerve root schwannomas and intracranial and spinal meningiomas.⁹ The coexistence of these two diseases is rare and therefore, this report highlights a rare case of a young boy having MFS along with NF-2.

Case report

The case report was amended according to the CARE guidelines.

Clinical findings

Physical examination revealed thin built with the swelling at different sites. The musculoskeletal and anthropometric findings were evaluated based on Revised Ghent Criteria for MFS.¹ Anthropometric measurements indicated height of 162 cm and weight of 36 kg, head circumference was found to be 55 cm and arm span was 170 cm. Additionally, upper and lower segment heights were measured separately, which were 65 cm and 97cm, respectively. The thoracic expansion from axillary perimetry was 80.5 cm and xyphoid perimetry was 78.77 cm. Musculoskeletal abnormalities included laxity of joints, a positive Walker-Murdoch wrist test, in which the patient was asked to encircle the wrist with the contralateral hand during which the thumb and the little finger superimposed while encircling the wrist, along with positive Steinberg thumb sign test in which the patient adducted the thumb and flexed the fingers showing distal phalanx of the thumb exceeding the palmar area,as illustrated in Figure 1. Dolichostenomelia and arachnodactyly were observed. A dense cataract with subluxation of lens, previous detachment of retina, minimal light perception, and iridodonesis were detected during ophthalmology examination in the left eye whereas in the right eye only myopia-related iridodonesis was visible. The results of the laboratory investigations were within normal limits.

Figure 1. Walker-Murdoch wrist test.

Diagnostic assessment

The diagnostic assessment involved X-ray in lateral and posterior-anterior position that was performed for spine, chest, and sternum that revealed pectus carinatum (PC). The degree of scoliosis that was analysed by the Cobb’s angle was 20.76 cm describing moderate scoliosis. The MRI scan revealed multiple meningioma, heterogeneous lesions in bilateral cerebellopontine angle, which were ruled out as bilateral schwannoma of size 3.4×2.8×1.2 cm on the right side and 5.2×5.0×3.8 cm on the left side,as shown in Figure 2A, however bilateral vestibular schwannoma and mass effect caused in the form of compression of cerebellum is shown in Figure 2B. Echocardiogram showed minimal mitral regurgitation. The multiple swellings were diagnosed as NF-2. Based on the above findings he was diagnosed with MFS along with NF-2 for which he was referred for neurosurgeon’s opinion.

Figure 2. A: Axial T1 contrast image showing the evidence of enhanced bilateral cerebellopontine angle mass lesion, left yellow arrow showing widening of internal auditory canal, right yellow arrow shows extra-axial enhancing mass with dural tail.

B: Coronal T1 contrast image in which both yellow arrows pointing towards bilateral vestibular schwannoma and orange arrow indicating mass effect caused in the form of compression of cerebellum.

Discussion

The most prevalent inherited CTD, which is MFS, has a wide range of clinical symptoms.¹² MFS is strongly linked to mutations in the FBN1 gene.¹² The pathophysiological effects of the elastic fibres’ deterioration in MFS seem to account for the majority of its symptoms. The most significant effect of elastin degeneration is stiffness and impaired aortic distensibility in response to elevated pulse pressure.¹³ Another theory has recently surfaced in an effort to explain the pathophysiology of MFS, which states that the cytokine Transforming Growth Factor β (TGFβ), which controls cell morphogenesis, is thought to contribute to the MFS phenotype. Abnormal fibrillin prevents the latent TGFβ precursor from being sequestered, which causes excessive TGFβ activation, thus eliciting the MFS-specific symptoms as a result.^1,12,14

The prognosis for these patients is driven by the cardiovascular abnormalities. Therefore, regular cardiovascular monitoring is necessary to increase these patients’ chances of survival. If untreated, people with MFS have a 32-year median life expectancy.³ The elastic and collagen fibres that give ligaments their flexibility and resistance are connected to the connective tissue, and therefore any alterations in the musculoskeletal system occur if the connective tissue is impaired. Hence, this case report illustrated anthropometric and musculoskeletal changes that occur in patients with MFS.¹⁵ According to histopathological analysis, patients with MFS who underwent muscular biopsy showed fragmentation of fibrillin, which would result in musculoskeletal symptoms.^15,16

One of the most frequent MFS symptoms involving changes to the chest wall is the pectus, which is defined by an imbalance in the development of the costochondral cartilages and the cartilaginous plates of the sternum. An earlier study found a high prevalence of PC in this population, which may conclude that PC could occur throughout the growth phase and deteriorate, especially in people with a genetic susceptibility. According to PC’s severity and its relationship to other thoracic abnormalities including kyphosis and scoliosis, respiratory issues related to PC may occur. Because of this, it’s essential to recognize musculoskeletal changes early in order to avoid complications.¹⁵

A genetic disease known as NF-2 is marked by malignancies such as meningiomas, schwannomas, and ependymomas.⁸ NF-1 and NF-2 are two independent types of diseases of neurofibromatosis with different diagnostic and clinical findings that result from discrete chromosomes. Inactivation of a tumour suppressor gene that occurs due to mutation on chromosome 17 causes NF-1. However, mutation in the gene on chromosome 22 that encodes a tumour-suppressor protein “Merlin” causes NF-2. The diagnosis of NF-2 is strongly influenced by radiographic examination. The diagnosis is relatively simple when bilateral vestibular schwannomas with the usual appearance of progression into the cerebellopontine cisterns from the internal acoustic canals are observed. However, schwannomas of other nerves, meningiomas, ependymomas, and ocular abnormalities can emerge in some people, particularly children and young adults. Therefore, screening for NF-2 should begin when a young patient presents with one or more schwannomas, as well as numerous extra-axial brain or spine tumours. Small intracanalicular tumours may get easily ignored on MRI in such instances. For this reason, small schwannomas of the vestibular or other cranial nerves should be looked for using axial and coronal thin slice contrast enhanced T1-weighted sequences.⁸ In our case, in axial T1 contrast image there is evidence of enhancing bilateral cerebellopontine angle mass lesion along with internal auditory canal with extra axial enhancing mass and dural tail, as shown in Figure 2A,whereas coronal T1 contrast image is pointing towards bilateral vestibular schwannoma and mass effect caused in the form of compression of cerebellum, as shown in Figure 2B, that confirmed NF-2.

The coexistence of these two diseases suggests either a chance occurrence or that the two diseases are etiologically or genetically related. The chances of both the diseases occurring in the same patient is one in 60 million.¹⁷ Mutation in the gene FBN1 on chromosome 15q21 causes MFS, whereas mutation in the gene on chromosome 22 causes NF-2. As a result, both conditions must be considered as different mutations, since the position of the two genes are unrelated, it is most probable that two independent mutations have taken place. Additionally, the diagnosis was reliant on clinical standards as the genetic analysis was not performed for the reason that the patient denied for the test. This was considered as a big limitation of reporting this case.

Conclusions

This report highlights a rare case of a young boy having coexistence of Marfan’s syndrome along with Neurofibromatosis Type-2 and concludes that when compared to acquired CTD, MFS is rare and inheritable. Since genetic testing is non-specific, the diagnosis is reliant on clinical standards. Despite the morbidity and mortality linked to MFS, lives of many patients can be enhanced or lengthened through appropriate surgical and medical interventions along with future advancements in research. By contrast, NF-2 is a genetic neurocutaneous disease that causes anomalies in the skin and serves as a potential for a variety of brain and spinal cord tumours. MFS is caused due to mutation in chromosome 15, whereas, NF-2 is caused due to mutation in chromosome number 22, since the position of the two genes are unrelated, it concludes that two distinct mutations have taken place hence, this report highlights a rare coexistence of both the mutations, which will prove beneficial for medical profession in enhancing future studies.

Consent

Written informed consent for publication of clinical details and images was obtained from the parents of the patient.