Meningiomas in Rubinstein-Taybi syndrome: A case report and comprehensive review

Abstract

Rubinstein-Taybi syndrome (RTS) is a congenital disorder with characteristic clinical manifestations. In the vast majority of cases, it is caused by mutations of the gene encoding the transcriptional co-activator cAMP-response element binding protein (CBP)-binding protein (CREBBP). It has been thought to be a tumor predisposition syndrome as RTS patients have an increased risk of developing tumors including meningiomas. However, RTS-associated meningiomas are rarely reported. We report a unique RTS-associated meningioma in which an oncogenic CREBBP mutation is identified. We also comprehensively review the reported RTS-associated meningiomas, from epidemiology and pathogenesis to clinicopathological characteristics and treatment. All RTS patients with meningiomas are female and have the exclusive mutations of CREBBP. In population-based studies RTS-associated meningiomas seem to develop at younger ages. Their pathogenesis may be driven by the CREBBP/CBP alterations resulting in aberrant signal transduction in the CBP-mediated signaling pathways. Meningiomas in RTS patients have common clinicopathological characteristics including comorbidity with other tumors, radiologically intra-osseous growth, and uncommon histopathology such as ossifying and secretory features. Given the genetic nature and rarity of RTS-associated meningiomas, further investigation of their characteristics may define molecular targets for improved therapeutic options for RTS patients.

INTRODUCTION

Rubinstein-Taybi syndrome (RTS) is a congenital disorder that is clinically characterized by features such as growth retardation with short stature, intellectual disability, and multiple congenital anomalies especially of the face and distal limbs.^1–4 It is caused by de novo mutations of the gene encoding the transcriptional co-activator cAMP-response element binding protein (CBP)-binding protein (CREBBP, also known as CBP or RSTS/RTS) in more than 60% of patients.^1,3,5 It may also be caused by a mutation of the gene E1A binding protein p300 (EP300, a CBP homologue) in about 5%-10% of patients.^1,2,6 In a small portion of RTS patients, the diagnosis of RTS is made based on the combination of clinical manifestations with no genetic alteration identified or genetic testing performed.^1,7 There is increasing evidence that given the CBP/CREBBP function, RTS patients have an increased risk of developing tumors particularly benign tumors such as meningiomas and pilomatrixomas.¹

Meningiomas are the most common primary tumor of the central nervous system (CNS), accounting for approximately one third of all primary CNS tumors, and occur in up to 1% of the adult population.^8–10 There is increased risk of meningiomas in several familial syndromes including RTS, providing some mechanistic insight into the pathogenesis of meningiomas.^11,12 The CREBBP mutations have been occasionally found in meningiomas, and have been associated with a significantly increased recurrence and aggressive behavior of meningiomas, although it is unknown if those mutations were somatic or germline as RTS was not described in the examined patients.^13–15 While a detailed study of Dutch population-based RTS data and reported case studies have suggested an increased incidence of meningiomas in RTS individuals, there remain few reported cases of RTS-associated meningiomas.^1,7,16–18 This article adds another RTS-associated meningioma with the molecular finding of a CREBBP mutation in the tumor, and comprehensively reviews RTS-associated meningiomas from their epidemiology, pathogenesis to diagnostics and therapeutics.

Case report

We studied a case of meningioma with en plaque growth and recurrence in a patient with RTS. The patient was a 40-year-old woman who had a history of RTS with characteristic features, including an intellectual developmental delay, short stature, bilateral glaucoma resulting in blindness, scoliosis, left hip dysplasia, severe pelvic obliquity, and a serous cystadenofibroma surgically managed with bilateral salpingo-oophorectomy. She also had multiple pathologically confirmed pilomatrixomas removed from the scalp, neck, left shoulder, arms, face, and back over 40 years. Her family history was remarkable only for a cervical cancer in her grandmother. She presented with an asymptomatic left temporal lesion that was felt to be more invasive than the past lesions that were previously removed. Therefore, she underwent investigation of this lesion involving brain/head computed tomography (CT) and magnetic resonance imaging (MRI). She was found to have a large avidly enhancing, intraosseous tumor (∼3.6 × 4.4 × 4.7 cm) centered within the left sphenoid wing, with intracranial, subgaleal and left orbital extension as well as associated mild intracranial and left intraorbital mass effect but no significant edema (Figure 1A and B).

Figure 1.

MRI of meningioma with secretory features and its recurrence in a patient with Rubinstein-Taybi syndrome. A, B: Axial (A) and coronal (B) post-contrast T1-weighted images demonstrate a large enhancing, intraosseous tumor centered within the left sphenoid wing, with intracranial, subgaleal and left orbital extension. (C-F) Pathological examination of the resected tumor reveals a meningioma with en plaque growth (C, hematoxylin and eosin staining), and bone invasion with frequent positive secretions (D, PAS, staining; *bone) and immunohistochemical positivity for EMA (E) and CEA (F). (G-I) Postoperative MRI exhibits limited focal encephalomalacia with some dural enhancement and suspected residual tumor at 6 months (G) and at 63-month follow-up, enlarged tumor with compression of the orbital contents (H, I). (J-L) Pathological examination of the recurrent tumor shows en plaque meningioma (J) with focally frequent PAS-positive secretions (K) and EMA positivity (L). Scale bars: C, D, J = 20 µm; E, F, K, L = 10 µm.

The patient underwent a left frontotemporal craniectomy for gross total resection of the tumor. Pathological examination of the resected tumor revealed a meningioma with focal en plaque growth, bone invasion, and frequent eosinophilic secretions (Figure 1C-F). The secretions were positive for periodic acid-Schiff ([PAS], Figure 1D) staining and immunohistochemical stains including epithelial membrane antigen (EMA, Figure 1E) and carcinoembryonic antigen ([CEA], Figure 1F). The tumor exhibited low mitotic activity with a Ki-67 proliferation index of 1%. Molecular analysis by the TruSight RNA Pan-Cancer panel showed oncogenic CREBBP (p.Q1031*SNV) gene mutation. DNA methylation profiling classified the tumor as meningioma, subtype benign, subclass 2 Class (Classifier: NIH Bethesda v2; score 0.995), and as meningioma, subclass benign 2 (Classifier: DKFZ CNS v12.8; score 0.9327),^19,20 with no copy number variation alterations identified.

Postoperative MRI at 6-month follow-up showed limited encephalomalacia in the left frontotemporal region with some dural enhancement and suspected residual tumor (Figure 1G). Sequential MRIs or CTs in the following 5 years revealed similar postoperative changes and stable residual tumor in the left sphenoid wing. Serum CEA levels were elevated to 6.3 ug/L (normal, ≤ 3.5 ug/L). On MRI at 63-month follow-up, the tumor was enlarging with compression of the orbital contents (Figure 1H and I). An expanded endonasal and left transorbital resection was then performed to debulk the tumor. Pathological examination of the resection once again demonstrated en plaque meningioma (Figure 1J) with focally frequent PAS-positive secretions (Figure 1K) and EMA positivity (Figure 1L). Following this repeat resection, MRI revealed a residual tumor along the posterolateral orbit into the left sphenoid wing. At 3-month follow-up, the patient was neurologically stable.

Literature search and review

For the systematic literature review, we searched PubMed/MEDLINE, Web of Science, and Scopus for publications from the database inception to August 2024 using the following combinations of keywords: “Rubinstein-Taybi syndrome” and (combined with) “meningioma,” “Rubinstein-Taybi” and “meningioma,” “Rubinstein-Taybi syndrome” and “meningeal tumor,” “Rubinstein-Taybi syndrome” and “CNS tumor,” “CREBBP” and “meningioma,” “CREBBP” and “meningeal tumor,” “CBP” and “meningioma,” “EP300” and “meningioma” or “EP300” and “meningeal tumor.” While a variable number of publications were found from these searches, we excluded publications that did not fit the scope of the topic. Our review identified only 5 RTS patients with 6 or more meningiomas reported previously, although 3 of those patients were later reviewed or further studied with additional genetic information (Table 1).^1,7,16–18

Table 1.

Reported cases of meningiomas in Rubinstein-Taybi syndrome.

Case [ref]	Sex	Age at Dxa (yrs)	Clinical presentation (meningioma)	PMH; comorbidity	Imaging (pre-OR)	Location; size (mm)	OR	Meningioma subtype	Grade (WHO)	Genetics/Molecular profiling	Treatment (for meningioma)	F-U (post-OR)
Bilir et al. (1990)7; Siraganian et al. (1989)16; Boot et al. 20181	F	39	Headache, increasing somnolence & anorexia	Recent otitis media, gingivitis; RTS: severe mental retardation, short stature, unusual face with prominent nose, broad thumbs, and broad first toes	CT: contrast-enhancing bifrontal mass; cerebral angiography: a mass with hypervascular channels	Bifrontal attached to the sagittal falx; large	Excision	Angioblastic meningioma	Grade 1	Not tested	F-U (no chemotherapy/radiation)
Hennekam et al. (1990)17; Boot et al. (2018)1	F	41		RTS; hemangioma						CREBBP c.1011dupA
Verstegen et al. (2005)18; Boot et al. (2018)1	F	36 (1st), 37 (2nd)	(1st) progressive bonelike swelling of the forehead; 4 yrs later, (2nd) progressive bradyphrenia, proptosis, & a mild left-sided hemiparesis.	RTS	(1st) CT: bifrontal hyperostosis of the skull; 1 yr later, MRI: multiple de novo enhancing intracranial masses	Metachronous, independent foci: (1st) bifrontal; multiple, including (2nd) an enlarged right frontoparietal mass	Partial resection (after a biopsy, for the 1st); decompressive resection (2nd)	Ossifying meningioma (1st); chordoid meningioma (2nd), focally en plaque growing	Grade 1 (1st) & 2 (2nd)	CREBBP, microdeletion 9-13	local radiotherapy (for the 1st)	Died of respiratory complications 6 weeks post-OR
Boot et al. 20181	F	29		RTS; breast carcinoma, non-small cell lung carcinoma						CREBBP, microdeletion
Boot et al. (2018)1	F	46		RTS: fibroadenoma of breast						CREBBP, exonic duplication 4-23
Present case	F	40	Left temporal subcutaneous lesion, followed by CT & MRI finding of a large intraosseous, expansile tumour centered within the left sphenoid wing	RTS; intellectual developmental delay, short stature, bilateral glaucoma/blindness, scoliosis, left hip dysplasia, severe pelvic obliquity, & serous cystadenofibroma with bilateral salpingo-oophorectomy; multiple pathologically-confirmed pilomatrixomas	MRI: avidly enhancing, intraosseous tumor (approximately 3.6 × 4.4 × 4.7 cm)	Left sphenoid wing, with intracranial, subgaleal & left orbital extension	Near total resection	Meningioma with secretory features (methylation classification: subclass benign 2 [19,20])	Grade 1	CREBBP, p. Q1031aSNV, identified in meningioma	F-U with serial CTs/MRIs after OR	3 mo, neurologically stable; post-OR MRI: a residual tumor along the posterolateral orbit into the left sphenoid wing

^aAge at the histopathological diagnosis of meningiomas.

Abbreviations: &, and; Dx, diagnosis; F, female; F-U, follow-up; M, male; OR, operation/surgery; RTS, Rubinstein-Taybi syndrome; CT, computerized tomography; mo, month; MRI, magnetic resonance imaging; yr, year.

Epidemiology

The incidence of RTS-associated meningiomas is extremely low, with only 6 RTS patients (including our present case) reported with meningiomas (Table 1), although an increased incidence of meningiomas was found in the Dutch population-based study (with cumulative meningioma incidence of 1/34 in 20-29 year-old to 1/13 in 40-49 year-old RTS individuals vs <0.1% in general Dutch population).¹ All reported RTS patients with meningiomas were female, in keeping with the female predominance of meningiomas but of no statistical difference between this small RTS series (6 female; 0 male) and a population-based study of the French Brain Tumor Database (19 622 female; 5734 male; analyzed by Chi-squared test with Yates’ correction)¹⁰ or another population-based study of The Central Brain Tumor Registry of the United States (111 724 female; 41 032 male).¹⁹ The ages when meningiomas were found in RTS patients ranged from 29 to 46 years with the median of 39 years. This age median of RTS-associated meningiomas at diagnosis is younger than that of population-based studies with the median of 58-66 years,^8,10,21 which may imply earlier development of meningiomas in RTS patients with genetic predisposition for tumors.

Etiology and pathogenesis

The etiology of meningiomas remains elusive. There are a few risk factors for developing meningiomas, which include exposure to ionizing radiation, endogenous/exogenous hormone use, body mass index, and current smoking.^8,22 It has been noted that several other syndromes, most notably neurofibromatosis type 2 (NF2) caused by a de novo mutation in the NF2 gene, increase the risk of meningioma development. A few germline defects, such as neurofibromatosis type 1 (NF1) and CREBBP, have been also reported in association with meningiomas.^1,8,11,12 The CREBBP mutations are exclusively reported in RTS patients with meningiomas, and a pathogenic variant (p.Q1031*SNV) of CREBBP is found in the present case of meningioma with secretory features (Table 1). Germline loss-of-function mutations of CREBBP in RTS tumor predisposition syndrome has suggested a tumor-suppressor role of CREBBP.^2,23,24

The CREBBP gene encodes the CREB binding protein which itself binds the cAMP- response element binding protein (CBP). CREBBP is a general transcriptional coactivator expressed in all nucleated cells, responsible for many cellular functions including acetylation of histones to aid in gene expression, regulation of histone methyltransferase allowing gene silencing, de-condensing chromatin to allow for transcription, recruiting transcriptional RNA polymerase II, and acetylation of p53 that is a tumor suppressor pathway deregulated in many tumors.^5,24–26 The CREBBP alterations including chromosomal translocations and somatic mutations have been seen to lead to CBP overexpression in multiple solid and hematologic tumors including lymphomas, leukemias, melanomas, gastric, colorectal, and squamous cell carcinomas.^24,27–29 As CBP is a highly homologous lysine acetyltransferase, its overexpression in tumors gives rise to aberrant signal transduction in multiple signaling pathways. This may cause deregulated expression of downstream genes that control tumorigenesis, which includes a defect of CBP-mediated p53 acetylation and activation to play its tumor suppressive functions.^24,30,31

The PI3K/AKT pathway has also been thought to be involved in the pathogenesis of meningiomas.^8,32,33 A mutation of PIK3CA or AKT1 has been found in up to one-third of meningiomas.^32–34 While activated AKT controls multiple cellular functions including cell proliferation, survival, metabolism, and angiogenesis in both normal and tumor cells, oncogenic PIK3CA mutations activate several proliferation-associated signaling pathways in meningiomas.^8,32,34,35 There is interaction between the PI3K/AKT and Wnt/β-catenin pathways.^36,37 The Wnt/β-catenin pathway can similarly regulate cell proliferation, migration, differentiation, and apoptosis, which is also involved in the development and progression of meningiomas.³⁸ CBP with intrinsic lysine acetyltransferase activity acetylates ß-catenin protein, a central component of the Wnt signaling pathway, and inhibits the Wnt signaling pathway that is heavily implicated in a variety of human tumors.^39,40 A few studies targeting the Wnt/β-catenin signaling pathway have shown promising results in meningioma treatment.⁴¹ The pathogenesis of RTS-associated meningiomas may be driven by CREBBP mutations resulting in CBP alternations and leading to aberrant signal transduction in the CBP-mediated signaling pathways such as p53, PI3K/AKT, and/or Wnt/β-catenin pathways.

Clinical features

Clinical data of RTS-associated meningiomas are scant, as only 3 patients including our present case (Table 1), have detailed clinical information. As aforementioned, all reported RTS patients with meningiomas were female aged 29-46. While the patients all had RTS manifestations, meningiomas occurred with symptoms and signs dependent on tumor location: compression of adjacent structures in two patients, and a nonspecific presentation in another patient (Table 1). One patient had metachronous, independent foci of meningiomas.^1,18 These reported RTS patients with meningiomas often had comorbid tumors including hemangioma in one patient, breast and lung carcinomas in one patient, and breast fibroadenoma in another patient; the present case had an ovarian serous cystadenofibroma and multiple pathologically confirmed pilomatrixomas associated with RTS. While pilomatrixomas are thought to be increased in RTS patients,¹ the comorbidity of pilomatrixomas and meningioma is found only in the present case (Table 1). Another common feature of RTS is the development of keloids (excessive scar tissue), seen in 24% of RTS patients, but interestingly, has not been found in RTS patients with meningiomas,¹ which may be due to different pathogenic mechanisms between keloids and meningiomas, and warrants further investigation.

Radiological features

Radiological data of RTS-associated meningiomas are similarly scant. All reports described meningiomas with typical enhancement CT and/or MR images. At least 2 of 4 reported meningiomas were radiologically intra-osseous, with their extension to the adjacent structures (Table 1). One RTS patient was reported to have an “ossifying” meningioma with associated bifrontal hyperostosis of the skull; 4 years later, the same patient was found to have multiple homogenously enhancing dural lesions.¹⁸ She underwent resection of one of these lesions (a large right frontoparietal mass with associated perilesional edema), and the resected lesion turned out to be a chordoid meningioma. In the present case of meningioma with secretory features (Figure 1), MRI with contrast demonstrated an expansile, enhancing lesion centered within the left sphenoid bone with both subgaleal and intracranial components, a dural tail and smooth pachymeningeal enhancement extending partially along the left frontal convexity, involving the posterolateral aspect of the left orbit, and associated mass effect. The lack of edema associated with this meningioma is likely due to the tumor en plaque growth and/or intraosseous location, as en plaque meningiomas with osseous involvement typically show no or minimal edema on radiological images.^42,43

Pathological features

RTS-associated meningiomas may appear more frequently as uncommon subtypes; 4 of 7 reported tumors were described as angioblastic meningioma, ossifying meningioma, chordoid meningioma, and meningioma with secretory features, respectively, while the pattern of other meningiomas was not specified (Table 1). One of them is a World Health Organization (WHO) grade 2 chordoid meningioma with a higher likelihood of recurrence, and another meningioma with secretory features (despite WHO grade 1) recurred 5 years after the first resection. Two RTS-associated meningiomas with detailed pathology demonstrated at least focal en plaque growth. En plaque meningiomas are a rare variant/subtype of meningiomas that are frequently encountered in the spheno-orbital region as seen in these 2 RTS-associated meningiomas (patients 3 and 6 in the Table 1) and characterized by a hyperostotic and dural invasive architecture, which require a careful diagnostic and treatment approach.⁴³

As molecular diagnostic testing in meningiomas has been advancing in recent years, the molecular profile of RTS-associated meningiomas may be worth noting.^8,9,14 Although all reported RTS patients (except one without genetic testing) with meningiomas had germline CREBBP mutations (exclusively, with no EP300), molecular information of RTS-associated meningiomas was not described in the previously reported cases (Table 1). It seems that somatic CREBBP mutation are occasionally found in meningiomas of non-RTS patients.^13–15 A recent study case found a clinically aggressive, recurrent meningioma with both NF2 and CREBBP mutations detected by next-generation sequencing.¹⁵ Our present case is the first demonstrating an oncogenic CREBBP mutation (p.Q1031*SNV) in a meningioma of an RTS patient. Interestingly, the present meningioma shows secretory features, histologically compatible with secretory pattern (Figure 1), which is traditionally thought to be genetically characterized by KLF4 with or without combined TRAF7 mutations.^8,9 The DNA methylation classification of this meningioma is subclass benign 2 that is typically associated with AKT1/TRAF7, KLF4/TRAF7, or SMO mutations.^19,20 However, no mutation of KLF4 or others including AKT1 and NF2 (tested in the RNA sequencing of more than thousand genes) was found in this RTS-associated meningioma with secretory features. This molecular/genetic profile may suggest that RTS-associated meningiomas likely develop in association with the mutation of CREBBP, rather than NF2 or KLF4 even in secretory meningiomas.^8,9 Molecular characteristics of RTS-associated meningiomas warrant further investigation.

Treatment and prognosis

As recommended by the commonly used guideline on the management of meningiomas,⁹ a significant proportion of meningiomas (particularly in asymptomatic and/or elderly patients) may be managed by a watch-and-scan strategy; symptomatic meningiomas typically require surgical intervention with the goal of gross total resection; inoperable or recurrent tumors may be treated with radiosurgery or fractionated radiotherapy. It is unclear if or how many asymptomatic meningiomas occur in RTS patients. Treatment has only been reported for four meningiomas in three RTS patients, with total resection of 2 tumors and subtotal resection of 2 tumors in the same patient (Table 1). One patient received local radiotherapy after a partial resection of an ossifying meningioma but died of respiratory complications 6 weeks following the second resection of a chordoid meningioma.¹⁸ A challenge in the treatment of RTS-associated meningiomas appears to be the en plaque growth pattern. While the growth rate of en plaque meningiomas appears overall comparable to that of other benign meningiomas, those tumors may typically involve the orbit and cavernous sinus. Therefore, they are more likely to become symptomatic.⁴³ For en plaque meningiomas, early and aggressive surgical resection is the mainstay of treatment with the goal of maximally safe resection, and adjuvant radiation therapy may be offered for subtotal resections or recurrence.⁴³ This therapeutic approach may be favored for RTS-associated meningiomas, as the mutations of CREBBP in those tumors may be associated with increased risk of recurrence and aggressive behavior.^10,11 The prognosis of RTS-associated meningiomas is minimally described (Table 1) and warrants further investigation.

Molecular analysis and targets in the diagnostics and therapeutics of meningiomas are emerging. There have been a few potential molecular targets with promise for individualized therapy.^9,44 Given the genetic nature of RTS, meningiomas in RTS patients are of particular interest for potential genetic or molecular targeted therapy. This is borne out in some other genetic diseases, such as NF2-associated meningiomas. A large cohort study of NF2-mutant meningiomas found an association between low Merlin expression and proliferation of meningioma with poor clinical outcomes. ICG-001, a CBP inhibitor, selectively suppressed tumor growth in cells with low Merlin expression and mediated a meningioma cell line growth inhibition primarily through robust induction of the G1 cell-cycle arrest suggesting the targetable potential of the CBP/CREBBP inhibitor through antagonizing Wnt/β-catenin signaling pathway.⁴¹ A few other studies have also targeted the Wnt/β-catenin signaling pathway, which is normally inhibited by CBP though β-catenin acetylation, which is of importance in the pathogenesis of multiple tumors including meningiomas.^{36,38–40,45,46} A study of medicinal plant derivatives against human meningioma cells in vitro demonstrated the therapeutic potential of those agents acting through suppressing the Wnt/β-catenin signaling pathway.⁴⁵ Another recent study examined histone deacetylase 6 (HDAC6) inhibitors in conjunction with radiation therapy to treat meningiomas and found the inhibition of β-catenin followed by the inhibition of c-myc oncogenic expression in tumors, which suggests the therapeutic potential of HDAC6 to improve the radiosensitization in the treatment of meningiomas.⁴⁶ Further investigation of clinicopathological characteristics of RTS-associated meningiomas may similarly define molecular targets for improved therapeutic options for these patients.

CONCLUSION

RTS-associated meningiomas are extremely rare, although a population-based RTS study has suggested an increased incidence of meningiomas in RTS individuals. Despite scant data, the reported meningiomas in RTS patients have some common clinicopathological characteristics including the comorbidity with other tumors, bifrontal location, radiologically intra-osseous growth with extension to the adjacent structures, and uncommon histopathology such as ossifying and secretory features. All reported RTS patients with meningiomas are female, and genetically, have exclusive mutations of CREBBP. RTS-associated meningiomas seem to develop at a younger age, in keeping with genetic predisposition for tumors in those RTS patients. The present case has demonstrated the mutation of CREBBP in a RTS-associated meningioma with secretory features. Molecular diagnostics and therapeutics of RTS-associated meningiomas warrant special consideration and further investigation.

FUNDING

None declared.

CONFLICTS OF INTEREST

The authors have no duality or conflicts of interest to declare.