A rare case of Bannayan-Riley-Ruvalcaba syndrome with concurrent arteriovenous malformation

Abstract

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a congenital, autosomal-dominant disorder characterized by a triad of macrocephaly, lipomatosis, and pigmentation of the glans penis. The symptoms of this rare syndrome vary greatly and include multiple hamartomatous polyps, macrocephaly, increased birth weight, developmental delay, and intellectual disability. Vascular abnormalities, including arteriovenous malformations (AVMs), have rarely been reported as part of the vascular manifestations associated with BRRS. Congenital AVMs can rarely progress, resulting in limb- or life-threatening complications. We present the case of a young man with BRRS diagnosed in childhood and presenting with three AVMs involving the right upper extremity and chest. We also provide a brief literature summary of reported cases of BRRS with AVMs. Our paper highlights the importance of recognizing and understanding the vascular manifestations in patients with BRRS. Knowledge of the association between BRRS and AVMs is crucial for guiding patient diagnosis and management, optimizing treatment strategies, and improving overall patient outcomes.

Case report

A 28-year-old White man presented with large bulging veins on his right arm, accompanied by throbbing, swelling, and discomfort that had been noted since childhood. Although the condition has worsened over time, it does not impact his daily activities or work. He was diagnosed with Bannayan-Riley-Ruvalcaba syndrome (BRRS) in childhood based on the presence of diffuse hamartomas, delayed speech, colonic polyps, macrocephaly, and a positive R130X mutation in the PTEN gene. Other than obesity, he had no other significant medical history. The patient has one healthy sister, no children, and no family history of BRRS. The patient provided written informed consent for the report of his case details and imaging studies.

His vital signs included a blood pressure of 120/78 mm Hg, with a heart rate of 82 beats/min. The physical examination revealed large right arm varicosities, associated with bruising and swelling (Fig 1). Furthermore, the patient had scattered hamartomas, mostly involving the upper extremities (Fig 2). The blood workup revealed an unremarkable complete blood count and metabolic profile.

Fig 1.

Right upper extremity arteriovenous malformation (AVM).

Fig 2.

An example of hamartoma lesions on the patient's upper extremities, located on the left palm.

Right upper extremity arterial duplex ultrasound revealed evidence of an arteriovenous malformation (AVM) at the right arm measuring 2.2 × 1.0 cm with a connection between the brachial artery and vein through smaller branches. Another smaller AVM was found at the right proximal forearm, measuring 3.44 × 2.22 cm, with a connection between the proximal radial artery and vein (Fig 3). A computed tomography angiogram of the right upper extremity revealed early venous filling consistent with an AVM at the antecubital fossa level, which involves the distal brachial and proximal radial arteries. The right subclavian, axillary, brachial, radial, and ulnar arteries are otherwise patent (Fig 4). Computed tomography angiography of the chest, abdomen, and pelvis revealed a serpiginous vessel at the left breast and axillary region, measuring >2.5 cm.

Fig 3.

Transverse ultrasound image of the right arm (A) and forearm (B) showing arteriovenous malformations (AVMs) measuring 2.2 × 1.0 cm and 3.44 × 2.22 cm, respectively. Both sampled brachial (A) and radial (B) arteries had low resistive flow consistent with an AVM.

Fig 4.

Transverse computed tomography angiogram of the right arm (A) and forearm (B) showing arteriovenous malformations (AVMs) measuring 2.2 × 1.0 cm and 3.44 × 2.22 cm, respectively. Arrows indicate brachial (A) and radial (B) arteries (at different planes) feeding into the AVMs.

The patient was managed conservatively with intermittent right upper extremity compression and elevation. Furthermore, we plan annual surveillance office visits with repeat imaging studies to follow-up on the current AVM and rule out other new evolving vascular malformations.

Discussion

BRRS is a rare autosomal-dominant overgrowth condition that was first described by Riley and Smith¹ in 1960. The prevalence of BRRS is currently unknown; however, multiple cases have been documented in the medical literature.²

Although specific criteria for a BRRS diagnosis have not been determined, the syndrome is usually diagnosed based on the clinical presentation.³ It is characterized by a triad of macrocephaly, genital lentiginosis, and lipomatosis.⁴ Other manifestations include multiple lipomas, hemangiomas, proximal myopathy, joint hyperextensibility, and scoliosis.⁵ Because hemangiomas are usually asymptomatic with no serious sequela, they do not require specific screening. They are usually discovered via clinical examinations or imaging studies. Infants with BRRS often have a higher weight at birth, >4000 g, although the adult height remains within the normal range.^6,7 Patients usually have a head circumference greater than the 97th percentile.⁸ Approximately one half of the patients experience developmental delays, and mental retardation occurs in 20% to 50% of cases.⁶ Our patient meets the criteria for the diagnosis of BRRS based on the history of macrocephaly, speech delay, hamartomas, genetic test results, and concurrent AVMs.

As an autosomal dominant disorder, BRRS is a subset of the PTEN hamartoma tumor syndrome, marked by alterations in the phosphatase and tensin homolog (PTEN) gene.³ Although BRRS has multiple causes, ∼60% of cases arise from a mutation in the germline PTEN gene that encodes PTEN.^9,10 Our patient falls into this category, as evidenced by the genetic test results, which unveiled an R130X mutation within the PTEN gene. In addition, 10% of BRRS patients without PTEN mutations harbor gene mutations and deletions in the PTEN promoter.¹¹

The pathogenesis of the AVMs in BRRS remains unknown. Although many researchers have argued that AVMs are congenital and not neoplastic, this does not rule out the possibility of a noncongenital process that has undergone development over many years.^12,13 The literature has added AVMs as a part of the spectrum of vascular pathology in BRRS.^12,14

There is, however, ample evidence of the association between AVMs and mutations in PTEN. Déléris et al¹⁵ demonstrated that PTEN's involvement in the normal function of the PI3K–PKB/Akt–PTEN pathway is required for vascular development. PTEN is expressed in vascular smooth muscle cells and induces p53 activity to suppress tumor-induced angiogenesis.^15,16 Therefore, mutations in the PTEN leading to the loss of its mediating effect on the pathway result in abnormal angiogenesis, which might, in turn, explain the incidence of AVMs.¹⁷

A small group of patients with BRRS exhibit vascular malformations, including arteriovenous shunts, anomalies, and fistulas. Vascular malformations are present in ≤10% of BRRS patients.¹⁸ These malformations can range from localized overgrowth of small vessels to the development of large aneurysms.¹⁴ As a form of vascular malformations, AVMs are an even rarer but recognized feature of BRRS. They are “high flow” lesions with the presence of arteries and shunting. Venous-only malformations are “low flow,” consisting of dilated veins without any arterial components.¹⁹ Managing AVMs poses significantly greater challenges compared with managing low-flow venous malformations or other vascular tumors.¹⁴ Surgical treatment of AVMs can be very challenging, because the lesions are generally less anatomically accessible, which can lead to significant bleeding complications. Furthermore, the recurrence rates are high.^14,20 Therefore, endovascular treatment with embolic and sclerosing agents can be considered if intervention is indicated for AVM management.²⁰

In 2001, Naidich et al¹² first documented the association between AVM and BRRS, reporting the case of a 53-year-old man diagnosed with BRRS, who presented with truncal and upper extremity vascular malformations. Intracranial AVMs have also been associated with BRRS.^17,21 AVMs can exhibit rapid angiogenesis that results in vascular remodeling, because they increase in size proportional to the growth of the patient.²² To the best of our knowledge, only 11 studies have reported 26 BRRS cases with AVMs (Table). Most reported cases of AVMs are located in the extremities. Surgical intervention was the most frequent approach for the cases with documented treatment, which might be due to a larger size (≤25 cm) and concurrent chronic symptoms such as pain and swelling.²⁴ After intervention, most patients experienced an improvement in their symptoms.

Table.

Reported cases with Bannayan-Riley-Ruvalcaba syndrome (BRRS) and arteriovenous malformation (AVM)

Pt. No.	Age, years/sex	Investigator	AVM Location	Management	Outcome
1	9/Male	Srinivasa et al17	Right posterior dural	Embolization of AVM on four separate occasions	Reduced periorbital venous congestion and resolved headaches
2	53/Male	Naidich et al12	Trunk and forearm	Excision of lesion	NR
3	59/Male	Rujiwetpongstorn et al23	Duodenum	Band ligation of duodenal AVM	NR
4	4/Female	Kurek et al24	Left thigh and calf	Excision	NR
5	5/Female	Kurek et al24	Right knee	Excision	NR
6	5/Female	Kurek et al24	Left thigh	NR	NR
7	7/Male	Kurek et al24	Left leg	Excision	NR
8	8/Male	Kurek et al24	Right pelvis, thigh, and calf	Debulking	NR
9	8/Male	Kurek et al24	Left foot	Excision	NR
10	8/Male	Kurek et al24	Left hand	NR	NR
11	9/Male	Kurek et al24	Entire right lower extremity and right pelvis	Amputation of right lower extremity	NR
12	10/Female	Kurek et al24	Right leg	Excision	NR
13	11/Female	Kurek et al24	Left thigh and calf	Excision	NR
14	11/Female	Kurek et al24	Left chest wall, left periclavicular region, and right forearm	Excision	NR
15	16/Male	Kurek et al24	Right thoracic paraspinal	Excision	NR
16	17/Female	Kurek et al24	Right knee	Excision	NR
17	18/Female	Kurek et al24	Right face and left knee	Excision	NR
18	14/Male	Kurek et al24	Right flank	Excision	NR
19	19/Male	Kurek et al24	Left face, neck, and left elbow	Excision	NR
20	1/Female	Busa et al25	Face	Conservative speech therapy	Received support for speech delay
21	NR	Palencia et al21	Intracranial AVM	NR	NR
22	24/Male	Anusic et al26	Left forearm and right calf	Multiple transarterial embolization in right calf; contracture in calf treated with physiotherapy; excision of lesion in left forearm	Improved pain, worsened contracture, underwent genetic counseling
23	14/Female	Moon et al27	Dural arteriovenous fistula	Two stages of embolization	Improved symptoms
24	8/Female	Soysal et al28	Through the right buttock to the lower limbs	Amputation of right leg	NR
25	11/Male	Erkek et al29	Right lateral calf and ankle	Imaging and excisional biopsy	Discharged
26	6/Male	Iacobas et al30	Left forearm, hand, and left parietal lobe	Embolization and oral rapamycin	Left upper extremity regained full strength and mobility

NR, not reported; Pt. No., patient number.

Recent literature has sought to expand our knowledge of the spectrum of vascular pathology in patients with BRRS by incorporating AVMs into the existing spectrum. Awareness of the vascular manifestations associated with BRRS has important implications for patient care. Healthcare providers caring for BRRS patients should consider and use appropriate imaging technologies to monitor their patients' vascular health. No guidelines have been established for the best approach to manage patients with AVMs. Based on the current evidence, treatment decisions should consider the severity of symptoms and their impact on patients' quality of life against the potential risks of interventional complications.³¹ Surgical and nonsurgical interventions have been associated with higher morbidity and should be reserved for severely symptomatic or disabled patients with vascular malformations.³² Because our patient remained asymptomatic, conservative treatment with annual follow-up visits and imaging surveillance was offered based on the current literature.³³ If AVMs progress to become symptomatic and disabling, endovascular embolization or surgical resection could be considered. Until further research is reported, we suggest conservative therapy, including compression and elevation, for asymptomatic patients with AVMs, reserving endovascular or surgical intervention for patients with severe symptoms affecting their daily living activities.

Disclosures

None.