Foveal hypoplasia (FH) is a congenital developmental abnormality of the retina in which the foveal pit does not develop or is incompletely formed. It was first described in the early 1900s in association with hereditary nystagmus.
Normal foveal development begins at 12 weeks of gestation. From around 25 weeks of gestation, centrifugal displacement of the inner retinal layers leads to pit formation, which is completed by 15–45 months after birth 1, 2). In FH, this pit formation process is disrupted, and inner retinal layers remain over the fovea.
Epidemiologically, up to 3% of healthy children are reported to have bilateral foveal flattening. In a multicenter study of 907 individuals, the most common genetic cause was albinism (67.5%), followed by PAX6 mutation (21.8%), SLC38A8 mutation (6.8%), and FRMD7 mutation (3.5%) 1).
Major diseases associated with FH are listed below.
Up to 3% of healthy children are reported to have bilateral foveal flattening. Among genetic causes, albinism accounts for 67.5% (most common), followed by PAX6 mutations at 21.8% 1).
Ophthalmoscopy reveals loss of foveal pigmentation and foveal reflex. OCT, FA, and OCTA assess the foveal avascular zone (FAZ) and persistence of inner retinal layers.
Severity classification based on OCT findings is shown below 1).
| Grade | Morphological Features | Visual Acuity (LogMAR) |
|---|---|---|
| Grade 1 | Flat depression + IS elongation + ONL thickening | 0.41–0.65 |
| Grade 2 | Loss of depression + IS elongation + ONL thickening | 0.60 |
| Grade 3 | Loss of depression, no IS elongation + ONL thickening | 0.74 |
| Grade 4 | Loss of depression, no IS elongation, no ONL thickening | 1.01 |
| Atypical | Shallow depression + inner segment disruption | 0.93 |
In Grades 1–2, some cone specialization remains and visual acuity is relatively good. In Grades 3–4, cone specialization is poor and visual acuity is poor 1).
Other major clinical findings are shown below.
In the Leicester grading, visual acuity decreases stepwise from Grade 1 (LogMAR 0.41–0.65) to Grade 4 (LogMAR 1.01) 1). Grades 1–2 retain some cone specialization and have relatively good visual acuity, while Grades 3–4 have poor cone specialization and tend to have poor visual acuity.
Albinism 67.5%
Causative genes: Broadly divided into OCA (autosomal recessive) and OA (X-linked). Seven types (OCA1–7) and six responsible genes are known.
Mechanism: Macular pigment deficiency due to impaired melanin synthesis inhibits foveal development. The OCA2 gene is located on chromosome 15q12-q13 1).
PAX6 mutation 21.8%
Inheritance pattern: Autosomal dominant.
Phenotype: The most common phenotype is aniridia. PAX6 is a major transcription factor for eye development and is involved in overall retinal differentiation 1).
Other genetic causes
SLC38A8 mutations (6.8%): Autosomal recessive. Encodes a glutamine transporter required for retinal development 1).
FRMD7 mutations (3.5%): X-linked. Associated with idiopathic infantile nystagmus 1).
Yes, it can. Maternal rubella infection in the first trimester is thought to spread via the placenta to the fetal vasculature, causing ischemic changes and mitotic inhibition that impair foveal development 2). Prevention is possible with rubella vaccination.
The diagnosis of FH is made by combining multiple examinations. The main examination methods and findings are summarized below.
| Examination method | Main findings |
|---|---|
| Ophthalmoscope | Loss of foveal pigmentation and reflex |
| OCT | Loss of foveal depression, persistence of inner retinal layers (grading) |
| FA / OCTA | Absence or reduction of FAZ |
| Electroretinogram / VEP | Assessment of organic retinal abnormalities |
| Genetic testing | Identification of causes such as albinism, PAX6, etc. |
Details of each examination are shown below.
It is important to differentiate from diseases that present with nystagmus.
Currently, there is no curative treatment for FH itself. Treatment aims to maximize visual function and prevent secondary complications.
Currently, there is no curative treatment. The mainstays of treatment are refractive correction, amblyopia management, and low vision care. Gene therapy research is progressing, and identification of the causative gene (see Diagnosis and Testing Methods) may expand future treatment options 1).
Foveal development begins at 12 weeks of gestation and is completed 15 to 45 months after birth through several stages 1, 2).
In FH, one of these processes—centrifugal displacement, centripetal migration, or outer segment elongation—is impaired, leaving inner retinal layers at the fovea.
The “FAZ hypothesis” proposes that failure to form the foveal avascular zone (FAZ) inhibits pit formation 1). If the FAZ does not form, astrocytes that guide vascular endothelial cells persist across the fovea, preventing pit formation.
However, in achromatopsia, some cases exhibit FH despite a present FAZ, suggesting that the FAZ is necessary but not sufficient for pit formation 1).
In albinism, melanin synthesis deficiency leads to a lack of pigment in the macula. It is inferred that this pigment deficiency interferes with the normal induction of foveal development 1).
In congenital rubella, the virus spreads through the placenta into the fetal vascular system. Chorionic necrosis, induction of apoptosis, mitotic inhibition, and ischemia due to vascular endothelial damage collectively impair foveal development 2).
Viana et al. (2022) reported a case of FH (52-year-old female) with a background of congenital rubella 2). The right eye was microphthalmic and aphakic with no light perception, and the left eye had Leicester Grade 3, BCVA 20/63. Diffuse RPE changes were observed, but the electroretinogram was within normal limits. This case was not diagnosed until adulthood and is notable as a novel report indicating an association between congenital rubella and FH.
For FH associated with albinism, gene therapy targeting OCA-related genes (TYR, OCA2, TYRP1, SLC45A2, etc.) is being studied as a future option. Identification of the causative gene through genetic testing is a prerequisite 1).
Kavalaraki et al. (2023) reported a case of FH (8-year-old girl, Grade 4) with a background of tyrosinase-positive albinism (OCA2), and identified an OCA2 mutation (chromosome 15q12-q13) through genetic testing 1). Visual acuity was BCVA 0.4 in the right eye and 0.5 in the left eye, and +6.50DS hyperopic correction and genetic counseling were provided. OCT grading was shown to be more accurate in predicting visual acuity than iris transillumination or macular transparency.
Leicester grading is becoming established as an objective indicator for predicting visual prognosis in FH. It has higher predictive accuracy for visual acuity than conventional iris transillumination assessment or ophthalmoscopic findings, and is expected to be applied in evaluating treatment effects and genetic counseling 1).
Few cases have reported congenital rubella as a cause of FH, and some are diagnosed in adulthood 2). In regions where rubella outbreaks continue, rubella should be considered as a cause of FH. Widespread rubella vaccination directly contributes to primary prevention of this disease.
Research is investigating the possibility that even without the formation of a foveal pit, cones may undergo morphological changes and increase in density. Elucidating the mechanism of this plasticity is expected to lead to future intervention strategies.
