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Developmental macular disorders: phenotypes and underlying molecular genetic basis
  1. Michel Michaelides1,2,
  2. Glen Jeffery1,
  3. Anthony T Moore1,2
  1. 1UCL Institute of Ophthalmology, University College London, London, UK
  2. 2Moorfields Eye Hospital, London, UK
  1. Correspondence to Dr Michel Michaelides, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK; michel.michaelides{at}


The developmental macular disorders form part of a heterogeneous group of retinal conditions that are an important cause of visual impairment in children. The macular abnormality is present from birth and is usually non-progressive but visual loss may occur as a result of complications such as choroidal neovascularisation. To date, most of the causative genes have not been identified but with the advent of next generation sequencing, it is likely that the genetic basis of these disorders will soon be elucidated. Improved knowledge of the underlying molecular genetics and disease mechanisms will raise the possibility of future treatments for these disorders, for which there are no specific therapies available at the present time.

  • Clinical Trial
  • macula
  • retina
  • ciliary body
  • degeneration
  • pathology
  • macula
  • genetics
  • embryology and development
  • dystrophy
  • visual pathway
  • electrophysiology

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The developmental macular disorders are a heterogeneous group of disorders in terms of both their clinical characteristics and their molecular genetic basis. Although there have been considerable advances made in recent years in our understanding of the clinical phenotypes, natural history and molecular genetics of these disorders, many of the causative genes and underlying mechanisms have yet to be identified. It is anticipated that new genetic technologies, such as next generation sequencing, will soon lead to the discovery of such genes; this new information will result in improved understanding of the biology of macular development and will be the first step in developing new therapies.

In this review, we will briefly describe normal macular embryological and post-natal development, macular structure, and ocular imaging modalities, and then describe current knowledge of the detailed phenotypes associated with disordered macular formation and their underlying molecular genetic basis.



The retina first develops as a hollow evagination of the neural tube, whose outer end becomes indented to form a stalked cup, with the two-walled cup forming the neural and pigmentary layers of the retina. Our knowledge of human retinal and macular development comes from both human and primate studies.1–7

At all stages of development, the presumptive macula is developmentally advanced in relation to all other retinal regions; thereby making it the nodal point for all retinal development. Neuronal precursors first leave the cell cycle at this location and it is the first retinal region to become senescent. All features of retinal development extend out from the presumptive central macula in spatio-temporal waves. Patterns of cell addition and differentiation, laminar formation and connectivity proceed peripherally away from the macular area as development progresses.8 In spite of this, there is no known molecular marker that has been identified uniquely tagging this region. However, this region must have a clear embryological identity, because from the earliest time, temporal retinal axons coursing towards the optic nerve head to leave the retina avoid this region. Within the macula, and subsequently at more peripheral locations, different neuronal populations are generated in overlapping waves, with cones and ganglion cells being the first to leave the cell cycle and differentiate, and rods and bipolar cells being the last. Hence, while cones and ganglion cells are the first cells to be generated in the macular region, the last cells to be produced in the retina are rods and bipolar cells at the retinal margin.8 Because of this pattern, every region of the retina goes through an early developmental phase, where for a period of around a month, it is populated purely by cones. Rods are slowly added to this to produce the adult mosaic pattern.

All retinal mitosis takes place adjacent to the retinal pigment epithelium (RPE), which is the ventricular margin and is developmentally precious, being largely post-mitotic even when early retinal neurons leave the cell cycle centrally.9 The RPE is critical for normal retinal development and mutations impacting on it can have profound consequences for the retina; with its removal resulting in a failure of ocular development.10 The most common among these is albinism, where the lack of pigment results in a range of abnormalities including the failure of foveal development (see below).

Developmentally, the presumptive macula is also distinguished by the rate of the cell cycle that generates its neuronal population. Throughout central nervous system development, the cell cycle slows gradually as development progresses. In the retina of animal models, this appears to be from around 8 h to approximately 30 h.11 Consequently, retinal cells leaving the cell cycle at the macula leave while the rate is relatively fast, while those leaving later at the periphery are generated from a much slower developmental process. The RPE plays a critical role in the regulation of the rate of the cell cycle in the neuronal retina and in particular acts to slow the rate and may influence cell cycle exit.12

The mechanisms that directly regulate the development of the foveal pit remain obscure. Foveal formation is fundamentally an issue of cell migration. The neuronal population of the central retina and its patterns of connectivity are fully developed prior to the cell migration that gives rise to foveal development. As the fovea is normally avascular, it is possible that there is a relationship between cell migration and blood vessel development. As there is no direct retinal blood supply to the fovea, the migration of cells to form the foveal pit may in part be regulated by a need for a greater blood supply as the retina becomes metabolically more active.

Macular development is far from complete at birth, but is believed to continue until about 4 years of age. Most notable are changes in macular pigmentation, foveal light reflex, cone photoreceptor differentiation and foveal cone density. This normal post-natal development may be disturbed in infants who are born preterm.13–18 Optical coherence tomography (OCT) studies of such infants show increased foveal thickness and an absent or shallow foveal pit.15–18


The central retina in primates is adapted for high acuity vision. The most significant macular adaptations in this respect are: (1) the very high density of L and M cone photoreceptors on the visual axis (and the absence of rod cells and S cones at the fovea), (2) the dominance of midget bipolar synapses with these cones, and (3) the reduction of retinal blood supply at the macula, and complete lack of vascularity of the fovea itself.1–7 The formation of a foveal pit by the lateral displacement of the inner retinal layers is believed to improve light absorption by foveal cones, by reducing light scatter by cells and blood vessels of the inner retina.2 ,3 However, the overall architecture of the fovea can be highly variable between individuals with no obvious correlation with changes in central visual function.

In vivo imaging of the macula

There are multiple imaging modalities that provide information regarding human macular structure, including fundus photography, fluorescein angiography and autofluorescence imaging.19–22

OCT enables non-invasive, high-resolution visualisation of the lamination of the normal and pathological macula. More direct visualisation of the photoreceptor mosaic is afforded by the use of adaptive optics.23–28

Developmental macular disorders

Generalised clinical findings

The developmental macular disorders are usually symptomatic from infancy or early childhood. The majority of these disorders are stationary, but progressive visual loss may occur as a result of complications including choroidal neovascularisation. The level of visual acuity is variable and can range from 20/20 to light perception. Other clinical features include reduced colour vision, central scotomata and fundus abnormalities that are usually confined to the macula. However, there may be evidence of more generalised dysfunction on retinal imaging, detailed electrophysiological assessment or psychophysical testing. Variable degrees of photophobia and nystagmus may be present.

Autosomal dominant and autosomal recessive inheritance have both been reported. Most disorders are completely penetrant but have variable clinical expression.

Specific developmental macular disorders

Foveal maldevelopment (Foveal hypoplasia)

This disorder is characterised by presentation in infancy with reduced vision, nystagmus and a poorly developed fovea; there is no readily recognised foveal pit or luteal pigment and blood vessels may cross the presumed foveal region. These aforementioned changes can be readily demonstrated using OCT and fundus autofluorescence imaging (figure 1).29–33 Foveal hypoplasia may be either an isolated abnormality, or more commonly associated with aniridia, oculocutaneous albinism (OCA) and ocular albinism (OA).34–36

Figure 1

(A) A normal subject is shown for comparison. (B) Foveal hypoplasia. Autofluorescence imaging demonstrating a lack of macular pigment and optical coherence tomography revealing an absence of a foveal pit.

Oculocutaneous albinism and ocular albinism

A recent study of patients with OCA and OA using adaptive optics imaging and spectral domain OCT revealed that foveal specialisation can be measured in vivo on multiple levels—from morphology of the foveal pit to the length of the cone outer segment.33 Varying degrees of foveal maturity and cone specialisation were observed, which were broadly in keeping with proposed normal foveal development based on post-mortem analyses.1 ,4 ,5 ,7 ,37 This supports the concept that, in general, normal foveal development is arrested in individuals with albinism.33 It therefore appears that there is not a single description that captures foveal morphology in albinism; rather there is a continuum of foveal immaturity associated with the condition. This spectrum is likely to be related to a number of factors, including albinism subtype (OA vs OCA), the specific genetic mutation, and the natural pigment background of the patient. Further studies in patients with known genotypes will help to shed light on this phenotypic heterogeneity.

Several genes involved in melanin biosynthesis have been found to be responsible for albinism.36 OCA is inherited as an autosomal recessive trait. The gene encoding tyrosinase and the P gene are the most common genes associated with OCA type 1 (OCA1; OMIM 203100) and OCA type 2 (OCA2; OMIM 203200), respectively. Other rare forms of OCA type 2 are associated with mutations in tyrosinase related protein1 (OCA3; OMIM 293290) and the MATP gene (OCA4; OMIM 606574). By contrast, OA (OA1; OMIM 300500) is inherited as an X linked recessive trait and is associated with mutations in the gene GPR143. Female carriers usually show mild patchy iris translucency and a typical pigmentary fundus abnormality.

Despite the genetic heterogeneity associated with OCA and OA, each type has foveal maldevelopment as a key feature; with the only common factor being reduced retinal pigment. It is not known why abnormal melanogenesis leads to foveal hypoplasia. However, melanogenesis has been directly linked to other aspects of albinism developmentally, specifically abnormal cell cycle regulation that results in the relative thinning of some retinal layers at maturity. In animal models of this condition, the degree of the deficit present at maturity is linearly related to the amount of melanin present during development.12 ,38

Both Pal et al and Van Genderen et al have described a phenotype of recessively inherited foveal hypoplasia and anterior segment dysgenesis mapping to chromosome 16q23.2-24.2.39 ,40 Affected individuals have evidence of chiasmal misrouting on visual evoked potential studies and it is possible that this disorder represents a mild form of albinism, since mild forms of anterior segment dysgenesis, such as posterior embryotoxon and Axenfeld anomaly, are a recognised feature of albinism.


Aniridia may occur as an isolated ocular abnormality without systemic involvement, caused by mutation of the PAX6 gene or an upstream or downstream regulatory element; or as part of the Wilms tumour, aniridia, genital anomalies, retardation syndrome, with a deletion of 11p13 involving the PAX6 locus and the adjacent WT1 (Wilms tumour) locus.34 ,35 ,41

Isolated aniridia is inherited as an autosomal dominant trait; some individuals having an affected parent, while in others the aniridia occurs as a result of new gene mutation. Interestingly, patients who are haploinsufficient for PAX6 have both anterior segment and retinal abnormalities, whereas patients with missense mutations have a milder phenotype; with missense variants in the N-terminal part of the paired domain associated with isolated anterior segment changes (eg, Peters anomaly) and variants in the C-terminal part associated with isolated foveal hypoplasia; suggesting a possible genotype-phenotype correlation.42 ,43

Isolated foveal hypoplasia

Foveal hypoplasia may also be seen as an isolated abnormality.42 ,44–47 Most cases are sporadic, but two dominant pedigrees have been reported, with a PAX6 missense mutation identified in one of these families.42 ,48 The mutation occurred in the C-terminal part of the paired domain.42 However, PAX6 has been screened in some of the reported isolated cases, with no mutations being identified.47 It is likely that further cases will be identified with the advent of OCT and will allow a more detailed study of the incidence of PAX6 mutations in isolated foveal hypoplasia.

Maculopathy associated with nanophthalmos and posterior microphthalmos

Absence of the foveal pit is also a feature of eyes with nanophthalmos, an uncommon developmental disorder where the anterior and posterior segments are reduced in size but otherwise anatomically normal. In contrast to foveal hypoplasia, there is no nystagmus and OCT imaging demonstrates thickening or crowding of the inner retinal layers thereby filling the foveal pit.49 This highlights the role of ocular expansion in retinal development and adds weight to the notion that development of the overall structure of the eye is separate from that of the neural retina.

In contrast to nanophthalmos, in posterior microphthalmos reduction in the size is confined to the posterior segment; the anterior segment is normal. There is usually an elevated papillomacular fold with or without cysts and with variable yellow deposits in the macular region (figure 2).50–52

Figure 2

Posterior microphthalmos. Colour fundus photography (A) showing the characteristic elevated papillomacular fold, which can also be seen on optical coherence tomography (B) and autofluorescence imaging (C). Cysts can be seen within the thickened redundant retinal fold on optical coherence tomography (B), with hyperfluorescent deposits seen along the fold on autofluorescence imaging (C). Ultrasonography (D) demonstrates normal anterior segment depths with a reduction in size of the posterior segment resulting in reduced axial lengths of 16.5 mm in the right eye and 16.4 mm in the left eye.

Nanophthalmos may be inherited as an autosomal dominant (NNO1; OMIM 600165 and NNO3; OMIM 611897) or autosomal recessive trait (NNO2; OMIM 609549). NNO1 has been mapped to chromosome 11p, with NNO2 associated with mutations in the MFRP gene.53–55

Congenital-onset central chorioretinal dystrophy associated with high myopia

Iqbal and Jalili in 1988 reported congenital macular atrophy associated with progressive high myopia in six siblings from a consanguineous Palestinian family.56 The siblings ranged from 6 months to 19 years and presented with central visual loss, with the best corrected visual acuity ranging from 1/60 to 6/36. Myopia ranged from −3.00 dioptres in the youngest to −10.50 dioptres in the second-eldest subject. The maculopathy was characterised by a well-defined area of atrophy of the choriocapillaris and RPE. These lesions progressed over time, both in terms of size and depth.56 The underlying molecular genetic basis of this disorder has not to date been established. We have identified a cohort of seven unrelated patients with a phenotype in keeping with that described by Iqbal and Jalili (unpublished data) (figure 3). Full-field electroretinograms (ERGs) have been normal in the four patients in whom testing has been undertaken, consistent with the retinal dysfunction being confined to the macular region.

Figure 3

Congenital-onset central chorioretinal dystrophy associated with high myopia. RetCam fundus images at 5 months (A,B) and 12 months (C,D) of age of a boy with a −10 DS refractive error in both eyes. Progressive chorioretinal atrophy can be seen over this 7-month period. Images courtesy of Ms Jane Marr, FRCOphth, Sheffield Childrens Hospital, UK.

North Carolina macular dystrophy

North Carolina macular dystrophy (NCMD; MCDR1) is an autosomal dominant disorder characterised by a variable macular phenotype and a non-progressive natural history (when first described it was believed to be progressive and hence called a ‘dystrophy’, which has with time proven to be a misnomer). The disorder shows complete penetrance but variable expressivity. Presentation is usually during the 1st or 2nd decade but mildly affected family members may remain asymptomatic. The disorder is believed to represent a failure of macular development.57–63

Bilaterally symmetrical fundus appearances in MCDR1 range from a few small (<50 um) yellow drusen-like lesions in the central macula (grade 1) to larger confluent lesions (grade 2) and well demarcated macular chorioretinal atrophy (grade 3). The severity of visual loss is dependant upon the grade of retinal phenotype, with vision being poorest in association with grade 3 lesions. Colour vision is usually normal. Occasionally MCDR1 is complicated by choroidal neovascular membrane (CNVM) formation. The electro-oculogram (EOG) and ERG are normal, indicating that there is no generalised retinal dysfunction.

Linkage studies have mapped MCDR1 to a locus on chromosome 6q16.57–63 The disease interval has been recently refined to 3 cM (1.8 mb), with no mutations identified in the screened positional candidates.63 The identification of the gene responsible for this disorder is keenly awaited, as it will help to improve our understanding of the pathogenesis of drusen and CNVM in MCDR1 and will provide new insights into the biology of human macular development.

Progressive bifocal chorioretinal atrophy

Progressive bifocal chorioretinal atrophy (PBCRA) is an early-onset autosomal dominant disorder characterised by infantile onset nystagmus, myopia, poor vision and slow progression.64 A large atrophic macular lesion and nasal subretinal deposits are present soon after birth. An atrophic area nasal to the optic nerve head appears in the 2nd decade of life, and enlarges progressively (figure 4). Marked photopsia in early/middle age and retinal detachment extending from the posterior pole are recognised complications.

Figure 4

Progressive bifocal chorioretinal atrophy. Colour fundus photographs showing extensive macular atrophy and atrophy nasal to the optic nerve head.

Unlike MCDR1, both ERG and EOG are abnormal, reflecting widespread abnormality of photoreceptors and RPE.64

PBCRA has also been linked to 6q14-q16.2 and the disease locus overlaps with the established MCDR1 interval.65 These two autosomal dominant macular disorders have some phenotypic similarities and both are thought to result from a failure of normal macular development. However, PBCRA differs significantly from MCDR1 in several important respects, including slow progression, abnormal colour vision, extensive nasal and macular atrophy and abnormal ERG and EOG. Therefore, if allelic, it is likely that different mutations are involved in their aetiology. An alternative explanation is that PBCRA and MCDR1 are caused by mutations in two different adjacent developmental genes.

North Carolina macular dystrophy-like phenotypes

NCMD-like phenotypes mapping to different genetic loci than MCDR1 have been described, suggesting further genetic heterogeneity in the MCDR1 phenotype.

Autosomal dominant macular dystrophy (MCDR3) resembling NCMD

A British and Danish pedigree have been described with an early onset autosomal dominant macular dystrophy (MCDR3).66 ,67 Visual acuity ranged from 6/5 to 6/60. The retinal changes were confined to the macular region and vary from mild RPE pigmentary change to atrophy. Drusen-like deposits were present to varying degrees and were characteristic of the phenotype (figure 5). CNVM formation was an established complication. The EOG and ERG were normal indicating that there is no generalised retinal dysfunction. The only significant differences between this phenotype and MCDR1 is that in MCDR3 colour vision is abnormal in the majority of affected individuals and there was evidence of disease progression, albeit in a single case.

Figure 5

Autosomal dominant macular dystrophy (MCDR3) resembling North Carolina macular dystrophy. Colour fundus photographs showing bilateral typical fine macular drusen-like deposits (above), which are associated with increased autofluorescence (middle) and bilateral macular retinal pigment epithelium atrophy and pigment clumping, with surrounding drusen-like deposits (below).

Genetic linkage analysis in both the British and Danish families established linkage to chromosome 5p13.1-p15.33, and excluded the MCDR1 locus.66 ,67 The gene has not to date been identified.

North Carolina-like macular dystrophy and progressive sensorineural hearing loss (MCDR4)

A British family characterised by a non-progressive MCDR1-like macular dystrophy in association with progressive sensorineural hearing loss has been reported (MCDR4).68 Visual acuity ranged from 6/9 to hand movements. In keeping with MCDR1 and MCDR3, the EOG and full-field ERG were normal. Progressive sensorineural deafness was present in all affected individuals over the age of 20 years.

Genotyping excluded linkage to the MCDR1 locus and established linkage to chromosome 14q.

North Carolina-like macular dystrophy and digital anomalies (Sorsby Syndrome)

A British and a French family have been described with a dominantly inherited condition characterised by bilateral macular dysplasia in association with apical dystrophy or brachydactyly (figure 6).69–71 Visual acuity ranged from 6/12 to 4/60. The maculopathy was non-progressive and variable in severity, ranging from mild RPE pigmentary changes to excavated chorioretinal atrophic lesions. There was no evidence of generalised retinal dysfunction.

Figure 6

North Carolina-like macular dystrophy and digital anomalies (Sorsby Syndrome). Colour fundus photographs showing the typical bilateral macular dysplasia. In this individual there is shortening and deformity of the fingers and toes due to aplasia and hypoplasia of middle and terminal phalanges. There is skin syndactyly in association with bifurcation of the terminal phalanx of the hallux causing severe deformity of the feet.

The MCDR1, MCDR3 and MCDR4 loci have all been excluded in these two families on the basis of linkage, providing evidence of further genetic heterogeneity associated with the NCMD-like phenotype.71



  • Funding This work was supported by grants from the Foundation Fighting Blindness (USA), Moorfields Special Trustees, Fight for Sight, and the National Institute for Health Research UK to the Biomedical Research Centre for Ophthalmology based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. MM is supported by an FFB Career Development Award.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.