Benign lobular inner nuclear layer proliferations (BLIPs)

Key points at a glance

Key points of this condition

• Benign lobular inner nuclear layer proliferation (BLIPs) is a benign, extremely rare intraretinal tumor arising from the inner nuclear layer of the retina.
• It is a new disease concept, first reported in four cases by the BLIP Consortium in 2022.
• Patients are almost always asymptomatic and do not cause vision loss.
• Optical coherence tomography (OCT) is the most important test for diagnosis, showing a homogeneous, highly reflective lobulated lesion located in the inner nuclear layer.
• It has no intrinsic blood vessels, and OCT angiography (OCTA) shows no blood flow signal.
• It is a benign, stable tumor, and only follow-up observation is needed; no treatment is required.
• Cases have been reported to remain stable even with long-term follow-up over 30 years.

1. What are benign lobular inner nuclear proliferations (BLIPs)?

Benign lobular inner nuclear proliferations (BLIPs) are benign retinal tumors that arise from the inner nuclear layer of the retina. They may be associated with congenital hypertrophy of the retinal pigment epithelium (CHRPE).

This is a disease concept first reported in 2022 by the BLIP Consortium, based on four cases, including Dr. Aaron Nagiel, Dr. Christian J. Sanfilippo, and Dr. Michael Javaheri. ¹⁾ Later, one case reported by Pastor-Idoate et al. (2016) as “Diagnostic and Therapeutic Challenge” was found to retrospectively fit this disease. ²⁾

It has hamartomatous features and is considered benign with no effect on visual function. ¹⁾ No sex predominance has been reported. The cause is unknown, and only a few cases have been reported so far, making it an extremely rare condition.

Q When was BLIPs discovered and named?

A

This disease concept was first reported in 2022 by the BLIP Consortium in four cases and published in Ophthalmology in 2023. ¹⁾ Some cases previously reported as a different disease were later found to fit this condition. ²⁾

2. Main symptoms and clinical findings

Subjective symptoms

Patients are usually asymptomatic. Visual impairment is not seen in most cases. Although lesions may be present in the macula, they typically do not cause symptoms.

Q Does BLIPs affect vision?

A

Visual impairment is not seen in most cases. Even when a lesion is present in the macula, it is usually asymptomatic, and one case was reported to have no decrease in vision even after 30 years of follow-up. ³⁾

Clinical findings

Multimodal imaging shows the following characteristic findings.

• Fundus photography: A lobulated white intraretinal tumor with thin, arcing protrusions. It is usually seen in the macula, but may extend to the ora serrata. Lesions of congenital hypertrophy of the retinal pigment epithelium may also be seen from the macula to the ora serrata.¹⁾
• Fundus autofluorescence (FAF): Mild hypoautofluorescence in areas corresponding to the BLIPs lesion. Marked hypoautofluorescence in areas of congenital hypertrophy of the retinal pigment epithelium.¹⁾
• Fluorescein angiography (FA): No leakage is seen because the BLIPs area has no intrinsic vasculature.¹⁾
• Optical coherence tomography: Multiple homogeneous, hyperreflective lobulated lesions located in the inner nuclear layer. On en face OCT, the “ball and spike” appearance is emphasized. The lesions compress the adjacent outer and inner retinal layers, but there is no infiltration, cavitation, or hyperreflective foci. They do not cause intraretinal fluid, hemorrhage, or exudates.¹⁾
• OCT angiography (OCTA): Shows absence of flow signal.¹⁾

3. Causes and risk factors

The cause is unknown, and no specific risk factors have been identified. No sex predilection has been reported. It is considered a hamartoma in nature, and genetic testing (whole-exome sequencing) has been performed, but no correlation has been identified.¹⁾

About congenital hypertrophy of the retinal pigment epithelium, which may be seen with BLIPs, the following is known. Congenital hypertrophy of the retinal pigment epithelium is a flat, well-defined, solitary pigmented lesion that is often seen in the mid-peripheral fundus and has depigmented spots called lacunae. It enlarges very slowly, and enlargement is seen in 80% of cases over 5 years. There is no sex or racial difference, and the retina over the lesion shows marked thinning because the outer layers are lost. When this lesion is multiple, it may be associated with familial adenomatous polyposis (FAP) or Gardner syndrome.

Specialist note

BLIPs are thought to be a hamartomatous benign proliferation, and there have been no reports of malignant transformation. At present, many aspects of its genetic background and mechanism of onset remain unclear.

4. Diagnosis and examination methods

The diagnosis of BLIPs is made by combining multimodal imaging. In particular, optical coherence tomography is the most important test.

Fundus photograph

Findings: lobulated white intraretinal tumor with arched protrusions

Features: often found in the macula, but may extend to the ora serrata. Lesions of congenital hypertrophy of the retinal pigment epithelium may be seen from the macula to the ora serrata.

Fundus autofluorescence

BLIPs area: mild hypoautofluorescence

Area of congenital hypertrophy of the retinal pigment epithelium: marked hypoautofluorescence. The difference in degree between the two helps with diagnosis.

Optical coherence tomography

Findings: homogeneous hyperreflective lobulated lesion in the inner nuclear layer

Features: ball-and-spike appearance on en face OCT. There is compression of the adjacent layers, but no infiltration.

OCT angiography

Finding: absence of blood flow signal

Significance: indicates that it has no intrinsic vascular network. Useful for distinguishing it from malignant tumors with neovascularization.

Differential diagnosis

BLIPs need to be differentiated from the following retinal tumors.¹⁾

• Retinoblastoma: a malignant tumor common in children. It is accompanied by calcification and neovascularization. BLIPs are homogeneous, show no blood flow signal, and have a benign, stable course.
• Retinocytoma: a benign variant of retinoblastoma. Calcification is characteristic.
• Retinal astrocytoma / astrocytic hamartoma: may be associated with tuberous sclerosis. The layer of origin and morphology differ on OCT.
• Simple retinal pigment epithelial hamartoma / combined hamartoma: involves proliferation of glial cells from the retinal pigment epithelium. It is often congenital and nonhereditary, but may be associated with neurofibromatosis type 1 or type 2. It often occurs near the macula or optic disc.
• Retinal pigment epithelial adenoma / adenocarcinoma: acquired tumors characterized by the presence of feeding vessels and hard exudates. BLIPs have no vascular component, so they can be distinguished.

Q What is the most important test for diagnosing BLIPs?

A

Optical coherence tomography is the most important test and shows a homogeneous, hyperreflective lobulated lesion located in the inner nuclear layer.¹⁾ The ‘ball-and-spike’ shape on en face OCT and the absence of blood flow signal on OCT angiography further support the diagnosis. The combination of no leakage on FA and hypoautofluorescence on fundus autofluorescence makes for characteristic imaging findings.

5. Standard treatment

BLIPs are benign, do not cause visual impairment, and remain stable, so no intervention is needed. Observation alone is recommended.¹⁾

There is no drug therapy or surgery. Short-term follow-up has shown lesion stability¹⁾, and Shah & Charbel Issa reported a case that remained stable even after 30 years of long-term follow-up.³⁾

About follow-up

At present, only a very small number of cases have been reported. The optimal follow-up interval has not been established, and more case accumulation is needed to build evidence.

Q Do BLIPs need treatment?

A

As a benign, stable tumor, no intervention is needed and observation alone is recommended.¹⁾ Stability for up to 30 years has been reported, and it has been confirmed not to cause vision loss or complications.³⁾

6. Pathophysiology and detailed mechanism of development

BLIPs are thought to be a hamartomatous proliferation arising from the inner nuclear layer. The imaging features are summarized below.

Examination	Findings	Clinical significance
Optical coherence tomography	Homogeneous hyperreflective lobules in the inner nuclear layer	Identification of the site of origin
OCT angiography	Absence of blood flow signal	No neovascularization
FA	No leakage	Lack of intrinsic vasculature

The lesion has no intrinsic vasculature (no leakage on FA, no blood flow signal on OCT angiography). ¹⁾ The lesion is homogeneous and does not have cavitation or hyperreflective spots. It compresses the adjacent retinal layers but does not infiltrate them. It does not cause intraretinal fluid, bleeding, or exudates. ¹⁾

Whole-exome analysis has not identified a genetic association. ¹⁾ An association with congenital hypertrophy of the retinal pigment epithelium has been suggested, but the mechanism is unknown.

7. Latest research and future outlook (reports at the research stage)

For patients: Please read carefully

The following information is still at the research stage or under clinical trial and is not standard treatment available at ordinary hospitals. It is reference information for specialists about future medical developments.

BLIPs was first reported in 2022, and case collection and understanding of the disease are still ongoing. The reported cases are as follows.

Reported by	Year	Number of cases
Sanfilippo et al.	2023	4 cases
Pastor-Idoate et al.	2016 (retrospective)	1 case
Shah & Charbel Issa	2024	1 case (30-year follow-up)

In 2022, Sanfilippo CJ et al. reported four cases as the BLIP Consortium. ¹⁾ Lesions were characterized by multimodal imaging, and whole-exome analysis of blood was performed in 3 of the 4 patients. They were judged to be hamartomatous in nature, and stability on short-term follow-up was shown.

Shah M & Charbel Issa P (2024) reported a case with 30 years of long-term stability. ³⁾ The lack of vision loss or lesion enlargement over the long term is an important finding supporting the benign and static nature of BLIPs.

Future challenges are to clarify the cause, identify the genetic background, and elucidate the mechanism linking it to congenital hypertrophy of the retinal pigment epithelium. As more case reports accumulate, the overall picture of BLIPs is expected to become clearer.

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8. References

1. Sanfilippo CJ, Javaheri M, Handler S, Berry JL, Cobrinik D, Deardorff MA, Sun M, Schmidt RJ, Barkmeier AJ, Nagiel A.. Benign Lobular Inner Nuclear Layer Proliferations of the Retina Associated with Congenital Hypertrophy of the Retinal Pigment Epithelium. Ophthalmology. 2023;130(3):265-273. doi:10.1016/j.ophtha.2022.10.011. PMID:36270406; PMCID:PMC9974858.

2. Salvador Pastor-Idoate, Heinrich Heimann, Pearse A. Keane, Konstantinos Balaskas, Brandon J. Lujan. Diagnostic and Therapeutic Challenges. Retina. 2016;36(9):1796-1801. doi:10.1097/iae.0000000000000979.

3. Shah M, Charbel Issa P.. Long-Term Stability of Benign Lobular Inner Nuclear Layer Proliferations. JAMA Ophthalmol. 2024;142(6):e236065. doi:10.1001/jamaophthalmol.2023.6065. PMID:38900199.