Fundus coloboma 743.52
Other congenital anomalies of posterior segment 743.59
Other congenital anomalies of posterior segment of eye Q14.8
Foveal hypoplasia is an ocular abnormality in which the foveal pit either fails to develop, or does not completely develop, and is associated with poor visual acuity and nystagmus.  It may present in isolation or be associated with other conditions such as albinism, coloboma, optic nerve hypoplasia, retinopathy of prematurity, and aniridia.  Risk factors that affect foveal development, such as prematurity, can lead to foveal hypoplasia.
Although the foveal pit does not fully develop in foveal hypoplasia, there is developmental plasticity in the retina that allows cone cells in the foveal area to change its own shape to allow for a higher cone cell density in the fovea. This, in the most basic sense, allows for the central area of the eye and brain to increase the sampling rate of each photon that enters the retina.
Early descriptions of foveal hypoplasia in the early 1900’s were in association with other diseases, particularly hereditary nystagmus, while assessing for retinal abnormalities with ophthalmoscopy. Other conditions were later discovered to be associated with foveal hypoplasia, including macular aplasia, macular coloboma, and albinism. Later use of imaging techniques such as fundus fluorescein angiography to identify absent foveal avascular zones (FAZ) have found cases of isolated foveal hypoplasia without associated nystagmus or comorbidities.
A cross-sectional study by Noval et al with 286 healthy children found that up to 3% of children had an anatomically underdeveloped foveal pit bilaterally on OCT. Because foveal hypoplasia is commonly associated with a number of ocular diseases, there does not seem to be a widely accepted standalone statistic on its prevalence or incidence in isolation. However, many studies show frequency of foveal hypoplasia occurrence in associated diseases.
Risk Factors and Associations
There are numerous risk factors associated with foveal hypoplasia including those that are developmental and genetic in nature. It is hypothesized that fetal endothelial cell and macular pigmentary development are key to proper development of the foveal pit. Prematurity is a significant risk factor due to the associated abnormal development of retinal vasculature and deficiency of macular pigmentation in these patients. Prior studies have shown a small FAZ in patients with a history of prematurity. Foveal hypoplasia is also associated with albinism, aniridia, incontinentia pigmenti, achromatopsia, optic nerve hypoplasia, familial exudative vitreoretinopathy and Stickler syndrome. 
A multicenter observational study of 907 patients found that the most common genetic etiology for typical foveal hypoplasia was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) gene variants. Multiple gene mutations have been linked to ocular albinism, with and without cutaneous involvement.
PAX6 variants can cause autosomal dominant foveal hypoplasia and affect embryonic eye development, resulting in a range of phenotypes, the most common being aniridia.
SLC38A8 variants are responsible for an autosomal recessive form of foveal hypoplasia. SLC38A8 codes for a glutamine transporter mainly expressed in the photoreceptor layer of the retina. Missense mutations of SLC38A8 can cause defects in the sixth transmembrane domain of photoreceptors, resulting in underdevelopment of the retina.
FRMD7 variants are often associated with idiopathic infantile nystagmus and have an X-linked inheritance pattern. The role of FRMD7 is not well understood, but knockdown models in mice suggest that it regulates neuronal outgrowth and development.
There are other genes that cause ocular diseases that are associated with foveal hypoplasia as a symptom of the main disease. For example, several genes cause achromatopsia, which is partial or total agenesis of cone cells in the retina and associated with foveal hypoplasia. Melanin synthesis genes, retinal vascularization genes, and procollagen genes which cause albinism, familial exudative vitreoretinopathy and stickler syndrome respectively, all also have a high association with also having foveal hypoplasia as an ocular symptom of their disease.
There are hypotheses on why the foveal fails to develop in these diseases, although the mechanism is not certain. One theory is that in fetal development, the foveal avascular zone does not develop, and instead astrocytes induce retinal endothelial cell migration across the fovea which inhibits the foveal pit to form. The concentration of vessels is thought to cause the retinal tissue to have a fragile and stiff quality, reducing malleability for the formation of the foveal pit. However, in disease conditions such as congenital achromatopsia, the foveal avascular zone is present while the patient still presents with foveal hypoplasia, suggesting that the foveal avascular zone is necessary for normal foveal development, but not sufficient to prevent foveal hypoplasia all together.
Other hypotheses for the development of foveal hypoplasia suggest cellular disruption in the mechanical development of retinal neurons forming the foveal pit. The ganglion cell layer and inner nuclear layer are displaced centrifugally while cone cells in the outer nuclear layer are migrated centrally to the fovea during foveal development. During this process, Muller cells aid in vertical traction of the Henle fibers causing vertical stability of the foveal pit, and astrocytes retract laterally, causing widening of the pit. This suggests that if there is cellular disruption to this mechanical process in specific diseases, it may lead to foveal hypoplasia.
Signs and Symptoms
Foveal hypoplasia is commonly seen with other conditions such as albinism, nystagmus, achromatopsia, iris abnormalities like aniridia, cataracts and other ocular abnormalities. Histologic analysis and OCT studies have revealed that the structure of the macula resembles peripheral retinal tissue with persistence of ganglion and nuclear layers. Ophthalmoscopy shows absence of the foveal pit and FAZ. Most patients with foveal hypoplasia have poorer than normal visual acuity ranging between 20/50 to 20/200.
Diagnostic Procedures/ Testing
Historically, the diagnosis of foveal hypoplasia was made in evaluation of nystagmus with ophthalmoscopic examination of the fundus. Findings commonly included absence of foveal pigmentation and the foveal reflex. Introduction of fluorescein angiography allowed for visualization of the FAZ, and a small or absent FAZ coupled with ophthalmoscopy support the diagnosis of foveal hypoplasia. Non-invasive imaging such as OCT and OCT-A are now commonly used to evaluate the morphology and vasculature of the retina, respectively. In foveal hypoplasia, OCT evaluation reveals absence of the foveal pit and persistence of inner retinal layers through the area where the foveal center is expected. OCT-A evaluation of the FAZ shows an absence at the superficial capillary plexus and variable decrease in the deep capillary plexus.
A summary of diagnostic test findings is described below:
|Ophthalmoscopy||Absent foveal pigmentation and foveal reflex|
|Fluorescein angiography||Absence or decreased foveal avascular zone|
|Optical coherence tomography||Absence of foveal pit
Persistence of inner retinal layers through expected area of fovea
|Optical coherence tomography angiography||Absence of FAZ at the superficial capillary plexus
Absence or decrease of FAZ at the deep capillary plexus
OCT provides high-resolution images of the retinal layers and has aided in morphologic characterization of foveal hypoplasia. In 2020, a study by Rufai et al described the Leicester Grading System for Foveal Hypoplasia based on morphologic features detected on OCT. The OCT results from 81 eyes of 42 patients were then correlated with future best corrected visual acuity (BCVA), demonstrating worsening BCVA with higher grades of foveal hypoplasia. Their grading system is described below:
|Grade||Morphologic features||Associated BCVA (LogMAR)|
There are no known treatments for this disorder. Instead, only management exists with visual aid devices.
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