Familial Retinal Arterial Macroaneurysm (FRAM)

Key Points at a Glance

Highlights of this disease

• FRAM is a rare autosomal recessive disease caused by mutations in the IGFBP7 gene.
• The official name is RAMSVPS (Retinal Arterial Macroaneurysms with Supravalvular Pulmonic Stenosis) syndrome.
• Bilateral retinal arterial macroaneurysms and arterial beading are present in 100% of patients. ¹⁾
• Persistent hyaloid artery is associated in 88–90% of cases. ¹⁾
• Life-threatening systemic vascular complications such as pulmonary artery stenosis (65%) and coronary artery aneurysms are present. ¹⁾
• Reported only in consanguineous families from the Arabian Peninsula. ¹⁾
• Laser photocoagulation can control exudation from leaking macroaneurysms. Systemic management of the cardiovascular system directly affects prognosis. ¹⁾

1. What is Familial Retinal Arterial Macroaneurysms (FRAM)?

Familial Retinal Arterial Macroaneurysms (FRAM) is a rare autosomal recessive disease caused by mutations in the IGFBP7 gene. It was first reported in 2002 by Dhindsa & Abboud. ¹⁾

Subsequently, after identification of IGFBP7 mutations and confirmation of supravalvular pulmonic stenosis by echocardiography, it is now renamed as RAMSVPS (Retinal Arterial Macroaneurysms with Supravalvular Pulmonic Stenosis) syndrome. ¹⁾

This disease is characterized by progressive bilateral multiple retinal arterial macroaneurysms. The causative mutation is a splicing mutation c.830-1G>A (homozygous) in IGFBP7 (4q12), leading to upregulation of the BRAF/MEK/ERK pathway. ¹⁾

Reported cases are limited to 15 families and 30 individuals, mainly from Saudi Arabia and the UAE. ¹⁾ The mean age at initial diagnosis is 12.5 years (range 1–34 years), with no sex predilection.

Disease Overview

Official name: RAMSVPS syndrome

Former name: FRAM

Inheritance pattern: Autosomal recessive

Causative gene: IGFBP7 (c.830-1G>A)

Epidemiology

Number of reported patients: 30 (15 families)

Mean age at first visit: 12.5 years (range 1–34 years)

Sex predilection: None

Ethnicity: Arabian Peninsula origin

Q Are FRAM and RAMSVPS the same disease?

A

They are the same disease. First reported as FRAM in 2002, an IGFBP7 mutation was identified in 2011, and after echocardiography confirmed supravalvular pulmonary stenosis, it was renamed RAMSVPS. ¹⁾

2. Main symptoms and clinical findings

Familial Retinal Arterial Macroaneurysms FRAM image

Kenan Sonmez; Pehmen Y Ozcan. Nd:YAG Laser Photodisruption for Multilevel Premacular Hemorrhage due to Isolated Retinal Venous Macroaneurysm. Case Rep Ophthalmol Med. 2017 Oct 4; 2017:4630187. Figure 2. PMCID: PMC5646296. License: CC BY.

One month after laser treatment, (a) fundus photography of the right eye shows only small amount of residue blood at the lower edge of the detached ILM. (b, c) Fluorescein angiography shows a round area of hyperfluorescence which is prominent in venous phase and corresponds to a macroaneurysm of the macular branch of the superotemporal vein at the bifurcation site. (d) Optical coherence tomography demonstrates the detached and wrinkled ILM (white arrow) extending from the site of the macroaneurysm (yellow arrow) to the inferior margin of the residual sub-ILM blood causing a shadowing effect (star) in the macula.

Subjective symptoms

The main complaint is decreased visual acuity due to hemorrhage and exudation from the macroaneurysm into the macula. In reported cases, the best-corrected visual acuity (BCVA) at initial visit was 20/300 in the right eye and 20/60 in the left eye. ¹⁾

Some asymptomatic patients with a family history are detected through screening examinations.

Clinical Findings

Arterial beading and macroaneurysms are the most characteristic findings, observed in all patients (100%). ¹⁾ Persistent hyaloid artery is present in 88–90% of cases. ¹⁾ Recurrent hemorrhage/exudation (vitreous/subretinal) occurs in 71%, and submacular gliosis in 35%. ¹⁾

Macroaneurysms with leakage are clearly visualized on fluorescein angiography (FA). Peripheral telangiectasia, dropout, and arterial beading are also observed simultaneously. ¹⁾

Characteristic Ocular Findings

Arterial beading + macroaneurysms: 100%

Persistent hyaloid artery: 88–90%

Recurrent hemorrhage/exudation: 71%

Other Ocular Findings

Retinal artery narrowing/sheathing: 42%

Coats-like findings: 42%

Submacular gliosis: 35%

In severe cases, macroaneurysms with leakage lead to intraretinal/subretinal exudates and progress to exudative retinal detachment. Coats-like findings (peripheral telangiectasia/nonperfusion) are observed in 42%. ¹⁾

3. Causes and Risk Factors

The causative gene is IGFBP7 (4q12), and homozygosity for the splicing mutation c.830-1G>A has been confirmed in all reported cases. ¹⁾ The inheritance pattern is autosomal recessive, and it is frequently observed in families with consanguineous marriage. ¹⁾

IGFBP7, also called angiomodulin, is a vascular secretory factor. ¹⁾ In the retina, it is specifically expressed in the endothelium of large smooth muscle vessels, but not in capillaries. ¹⁾ This expression pattern is thought to explain why beading and macroaneurysms are confined to the major arterial trunks.

Histologically, multiple linear breaks are observed in the retinal artery wall. The frequencies of systemic complications are shown below.

Systemic complication	Frequency	Outcome
Pulmonary artery stenosis	65%	47% surgery, 13% death
Supravalvular aortic stenosis	22%	—
Cerebrovascular lesions	3 cases	Stroke/hemorrhagic death

Systemic management

If FRAM is diagnosed, screening for pulmonary artery stenosis by echocardiography is essential. Since coronary artery aneurysms and systemic arterial lesions may be present, collaboration with a cardiologist is important.

Q Is FRAM inherited?

A

It is an autosomal recessive disorder, and definitive diagnosis is possible by identifying IGFBP7 c.830-1G>A. ¹⁾ It is more common in families with consanguineous marriage, and carriers (heterozygotes) are asymptomatic.

4. Diagnosis and Testing Methods

Fundus Examination and Fluorescein Angiography

Arterial beading and macroaneurysms of the major arterial trunks are observed in all patients (100%). ¹⁾ FA reveals macroaneurysms with leakage, peripheral telangiectasia, and dropout. ¹⁾

Genetic Testing

Identification of IGFBP7 c.830-1G>A is essential for definitive diagnosis. This mutation was not found in 300 healthy controls. ¹⁾

Systemic Examination

Echocardiographic screening for pulmonary artery stenosis is essential (65% have cardiac disease). ¹⁾ For detection of coronary artery aneurysms and systemic arterial stenosis, systemic vascular evaluation including cardiac catheterization is performed. ¹⁾

Differential Diagnosis

FRAM must be differentiated from diseases with similar fundus findings.

Disease Name	Main Features	Points of Differentiation from FRAM
Coats disease	Unilateral, idiopathic	Telangiectasia is predominant
IRVAN	Non-familial, inflammatory	Vasculitis, anterior chamber cells present
Takayasu arteritis	Large vessel vasculitis	Differentiated by genetic testing

Q How is FRAM distinguished from Coats disease and IRVAN?

A

FRAM is bilateral and familial, characterized by beading of major arterial trunks and aortic aneurysms. Coats disease is unilateral and idiopathic, primarily involving telangiectasia. IRVAN is non-familial and associated with vasculitis and anterior chamber inflammation. Persistent hyaloid artery (88–90%) is also an important distinguishing feature of FRAM. ¹⁾

5. Standard Treatment

Laser Photocoagulation

For leaking macroaneurysms, retinal grid laser photocoagulation is performed to stop lipid exudation. Multiple sessions may be required. ¹⁾

In reported cases, multiple laser photocoagulation sessions over two years in the right eye resulted in cessation of leakage and regression of exudates. ¹⁾

Note that after spontaneous rupture of a macroaneurysm, the aneurysm becomes naturally occluded and fibrotic, so laser treatment is unnecessary. ¹⁾

Panretinal Photocoagulation (PRP)

Panretinal photocoagulation is performed for ischemic areas. ¹⁾

Vitrectomy

Performed in cases with vitreous hemorrhage or submacular hemorrhage. ¹⁾ In reported cases, a combination of cataract surgery, vitrectomy, membrane peeling, and SF6 gas tamponade improved BCVA to 20/80. ¹⁾

Anti-VEGF Agents

Reports exist for bevacizumab and others, but their role in RAMSVPS is not established. ¹⁾

Systemic Management

Cardiovascular evaluation and management are essential; coronary artery bypass surgery has been performed in some cases. ¹⁾ Collaboration with cardiology affects life prognosis.

Treatment Considerations

• Laser photocoagulation is effective for leaking macroaneurysms, but multiple sessions are needed due to recurrence.
• If repeated bleeding leads to submacular gliosis, visual recovery becomes difficult.
• Cardiovascular complications directly affect life prognosis, so collaboration with cardiology is essential.

Q What is the visual prognosis for FRAM?

A

It varies by case. Laser photocoagulation for leaking macroaneurysms can control exudation, but if repeated bleeding and exudation cause submacular gliosis, visual recovery becomes difficult. ¹⁾ Systemic management (cardiovascular) is also important as it directly affects life prognosis.

6. Pathophysiology and Detailed Mechanism

IGFBP7 mutations impair normal IGFBP7 production. ¹⁾ IGFBP7 (angiomodulin) is a CNS vessel-specific angiocrine factor that blocks VEGF-induced angiogenesis when VEGF-A signaling drives brain angiogenesis. ¹⁾

Experiments in zebrafish show that blocking angiomodulin leads to defects in vessel sprouting and patterning. ¹⁾

In the retina, IGFBP7 is specifically expressed in the endothelium of large smooth muscle vessels and is not expressed in capillaries. ¹⁾ This expression distribution is the pathological basis for beading and aneurysms occurring only in the main arterial trunks. Aortic aneurysms form at sites of reduced mechanical integrity of the vessel wall where pressure is highest. ¹⁾

Three parallels are observed between retinal findings and systemic arterial findings. ¹⁾

1. Correspondence of location: Aneurysms form in the proximal portions of the retinal, coronary, and carotid arteries.
2. Correspondence of stenosis/sheath formation: Sheath formation in retinal arteries corresponds to segmental stenosis in systemic arteries.
3. Correspondence of nonperfusion: Retinal capillary nonperfusion corresponds to disappearance of cerebral artery branches.

Regarding the pathogenesis of Coats disease-like findings, disruption of the inner blood-retinal barrier (iBRB) due to pericyte loss is thought to cause abnormal capillary dilation. ²⁾

7. Latest Research and Future Perspectives

For patients: Please read this

The following content is currently under research or has limited reports, and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments. Please consult your physician for actual medical care.

New Findings on the Extent of Systemic Vascular Lesions

Reports of RAMSVPS cases with coronary artery aneurysms are revealing that systemic vascular lesions are more extensive than previously recognized. ¹⁾ Additionally, the similarity of arterial findings between Takayasu arteritis and RAMSVPS may suggest the existence of an undiscovered common pathological basis. ¹⁾

Diagnostic Expansion and Misdiagnosis Issues

All reported cases to date are limited to individuals from the Arabian Peninsula, but there may be undiagnosed or misdiagnosed cases outside the Arabian Peninsula. It has been suggested that some cases diagnosed as Coats disease or IRVAN may include FRAM. ¹⁾

Potential of Anti-VEGF Therapy

The efficacy of anti-VEGF drugs for RAMSVPS has not been established, and further investigation is awaited. ¹⁾

Positioning as a background disease of retinal aneurysm formation

Retinal macroaneurysm formation secondary to retinal vein occlusion has also been reported, ³⁾ and pathophysiological studies of FRAM may provide clues to elucidate the mechanism of aneurysm formation.

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8. References

1. Jomar DE, Albakri AS, Abu Safieh L, Nowilaty SR. Retinal arterial macroaneurysms with supravalvular pulmonic stenosis syndrome can be associated with coronary and major systemic arterial disease. Am J Ophthalmol Case Rep. 2022;26:101514.
2. O’Leary F, Campbell M. The blood-retina barrier in health and disease. FEBS J. 2023;290(4):878-891.
3. Flaxel CJ, Adelman RA, Bailey ST, et al. Retinal Vein Occlusions Preferred Practice Pattern. Ophthalmology. 2020;127(2):P288-P320.