Foveal hypoplasia (FH) refers to the absence of foveal depression with presence of inner retinal layers in the presumed foveal area.1–4 Its reported associations include albinism, aniridia, microphthalmus, achromatopsia, and the premature retina.1–3,5 This disease has also been reported as a solitary finding.6 Most reported cases of FH have been accompanied by decreased visual acuity (VA) and nystagmus.7 Fundus imaging is difficult due to nystagmus, and optical coherence tomography (OCT) has been described as a quick and useful tool to confirm the suspected diagnosis.1,2
Dyschromatoses are a group of reticulate pigmentary disorders described mostly in the Japanese population. They are characterized by the presence of both hyper- and hypopigmented macules that are small in size and irregular in shape. This spectrum of diseases includes dyschromatosis universalis hereditaria (DUH), dyschromatosis symmetrica hereditaria (DSH), or acropigmentation of Dohi and a segmental form called unilateral dermatomal pigmentary dermatosis.8,9 Systemic associations of DUH include small stature and high-tone deafness,10 Dowling-Degos disease, X-linked ocular albinism and Tuberous sclerosis.11 Many other associated conditions have been reported, such as ill-defined ocular abnormalities; photosensitivity; learning difficulties; mental retardation; epilepsy; insulin-dependent diabetes mellitus; and erythrocyte, platelet, and tryptophan metabolism abnormalities.12
We present a hitherto unreported association of FH with DUH in a young Indian male. We also hypothesize pigment anomalies to be the reason behind this unique association.
A 32-year-old male presented with poor vision in both eyes accompanied by an involuntary motion of both eyes. The best-corrected VA was 6/36 in right eye and 6/24 in left eye at presentation, both with a myopic spherical error of −1 diopter. He was noted to have a horizontal jerk nystagmus of the manifest latent type without a null position. The anterior segment evaluation was unremarkable. The iris was normal in color and size, with no transillumination defects. Fundus examination was difficult due to the nystagmus but revealed normal pigmentation with an absent foveal reflex in both eyes. Spectral-domain OCT (Cirrus; Zeiss Meditec, Dublin, CA) was done, which confirmed the absence of foveal depression and presence of all the retinal layers in the expected location of the fovea (Figure 1).
Optical coherence tomography images showing absence of foveal contour and continuous inner and middle retinal layers in the locale of the presumed foveal region. The inset infrared images guide the location of the fovea despite the nystagmus.
Clinical photograph demonstrates diffuse interspersed hypopigmented and hyperpigmented macules on trunk and limbs.
Upon detailed workup, he was found to have multiple hyper- and hypopigmented lesions over his trunk, thighs, legs, and arms. The lesions were dense on the trunk and thighs, whereas the palms and soles were not involved. His face showed mild involvement. The hair, nails, teeth, and mucosae appeared normal. There was no apparent atrophy, erythema, or telangiectasia. Additionally, there was no history of photosensitivity, photophobia, or handling any chemical directly. No other systemic anomaly was seen.
Three-generation-linked pedigree analysis was then charted (Figure 3). There was a definite history of nystagmus in the family as presented in Figure 3 (confirmed by the mother of the patient), along with skin lesions exactly similar to that of this patient. Although there was no known record of the first-generation maternal uncle's eye examination, the maternal uncle of the patient was known to have undergone an ocular evaluation and had been diagnosed to have some “retinal disease.” They were not available for eye examination for confirmation with OCT, as they had died due to natural causes in middle to old age (Figure 3). Examination of the rest of the available family members, including siblings and children of the index case, revealed no skin or eye findings. Hence, our case was labelled to have familial FH (FFH) with DUH in an X-linked pattern of inheritance. Visual prognosis was explained to the patient and he was advised a genetic evaluation.
A three-generation pedigree chart depicting the X-linked inheritance pattern.
FH type 1 is associated with mutations in the PAX6 gene (11p13) that are inherited in an autosomal dominant pattern, whereas FH type 2 involves homozygous mutations in the SLC38A8 gene (16q23.3).7 The gene responsible for DUH has been mapped to 6q24.2-q25.2. Other genes associated with DUH or its variants include 12q21-q23 and the ABCB6 gene (605452) on chromosome 2q35. Because the exact biochemical basis of the gene defect is unknown, the diagnosis generally relies on the external phenotype.8,9 Although the majority of cases show autosomal dominant pattern of inheritance with variable penetrance, a few patients have inherited it in an autosomal recessive fashion. In our case, the patient's maternal uncle (MU) and MU's maternal uncle had similar complaints, suggesting an X-linked recessive inheritance. Although the association between DUH and FFH has not been reported earlier, the X-linked pattern of inheritance seen in our case is very rare.
The pit formation of the fovea starts occurring around 25 weeks of gestation, and the complete foveal architecture development occurs in some months after birth.13 This staged process involves centrifugal motion of the inner retinal cells and centripetal migration of cones toward the intended fovea, followed by specialization of the foveal cones. It has been postulated that level of pigmentation in albinism may decide ocular features including foveal maturity and chiasmal decussation.13 Further, adaptive optics and OCT have shown that cone density and outer segment features of the developing fovea can be proportionate to the pigmentary deficiency in albinism.14 It was suggested by McAllister et al. that pigment increment in earlier stages of foveal development may reduce architectural misrouting of cells that happens after birth, as foveal maturity is likely dependent on the overall pigment background of the developing fundus.14 The association of FFH and DUH in this case corroborates such hypothesis as both albinism as well as DUH are characterized by partial or total deficiency of melanin or melanosomes. X-linked albinism is a known association of DUH, and DUH occurs due to an interference with the neural-melanocytic interaction in early embryonic life in those who are genetically susceptible.9
Though it is possible that our patient had two distinct genetic disorders by sheer chance, a genetic linkage must be suspected as the inheritance pattern is uncommon for either of them.7 Due to expenses involved, gene mapping was refused by the patient, which is a limitation of this report. Both previously affected males were not available for examination, which is another important limitation of this report. The history of nystagmus and the skin condition in them was confirmed by another informant (mother), and therefore FFH and DUH were presumed.
To summarize, this report describes a previously unknown association of FH and DUH. OCT proved a useful tool for analysis despite nystagmus and should be employed in management of such cases.
- Holmstrom G, Eriksson U, Hellgren K, Larsson E. Optical coherence tomography is helpful in the diagnosis of foveal hypoplasia. Acta Ophthalmologica. 2010;88(4):439–442. doi:10.1111/j.1755-3768.2009.01533.x [CrossRef]
- Issa PC, Foerl M, Helb HM, Scholl HPN, Holz FG. Multimodal fundus imaging in foveal hypoplasia: Combined scanning laser ophthalmoscope imaging and spectral-domainoptical coherence tomography. Arch Ophthalmol. 2008;126(10);1463–1465. doi:10.1001/archopht.126.10.1463 [CrossRef]
- Vincent A, Kemmanu V, Shetty R, Anandula V, Madhavarao B, Shetty B. Variable expressivity of ocular associations of foveal hypoplasia in a family. Eye (Lond). 2009:23(8);1735–1739. doi:10.1038/eye.2009.180 [CrossRef]
- Querques G, Bux AV, Iaculli C, Noci ND. Isolated foveal hypoplasia. Retina. 2008;28(10):1552–1553. doi:10.1097/IAE.0b013e3181819679 [CrossRef]
- Recchia FM, Recchia CC. Foveal dysplasia evident by optical coherence tomography in patients with a history of retinopathy of prematurity. Retina. 2007;27(9):1221–1226. doi:10.1097/IAE.0b013e318068de2e [CrossRef]
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- Perez Y, Gradstein L, Flusser H, et al. Isolated foveal hypoplasia with secondary nystagmus and low vision is associated with a homozygous SLC38A8 mutation. Eur J Hum Genet. 2014;22(5):703–706. doi:10.1038/ejhg.2013.212 [CrossRef]
- Kantharaj GR, Siddalingappa K, Chidambara MS. Dyschromatosis universalis: Autosomal dominant pattern. Indian J Dermatol Venereol Leprol. 2002;68(1):50–51.
- Bukhari IA, El-Harith EA, Stuhrmann M. Dyschromatosis universalis hereditaria as an autosomal recessive disease in five members of one family. J Eur Acad Dermatol Venereol. 2006;20(5):628–629. doi:10.1111/j.1468-3083.2006.01522.x [CrossRef]
- Rycroft RJ, Calnan CD, Wells RS. Universal dyschromatosis, small stature and high-tone deafness. Clin Exp Dermatol. 1977;2(1):45–48. doi:10.1111/j.1365-2230.1977.tb01536.x [CrossRef]
- Binitha MP, Thomas D, Asha LK. Tuberous sclerosis complex associated with dyschromatosis universalis hereditaria. Indian J Dermatol Venereol Leprol. 2006;72(4):300–302. doi:10.4103/0378-6323.26729 [CrossRef]
- Al Hawsawi K, Al Aboud K, Ramesh V, Al Aboud D. Dyschromatosis universalis hereditaria: Report of a case and review of the literature. Pediatr Dermatol. 2002;19(6):523–526. doi:10.1046/j.1525-1470.2002.00225.x [CrossRef]
- Thomas MG, Kumar A, Mohammad S, et al. Structural grading of foveal hypoplasia using spectral domain optical coherence tomography a predictor of visual acuity?Ophthalmology. 2011;118(8):1653–1660. doi:10.1016/j.ophtha.2011.01.028 [CrossRef]
- McAllister JT, Dubis AM, Tait DM, et al. Arrested development: High-resolution imaging of foveal morphology in albinism. Vision Res. 2010;50(8):810–817. doi:10.1016/j.visres.2010.02.003 [CrossRef]