Retinal Dystrophy, Iris Coloboma, And Comedogenic Acne Syndrome

A number sign (#) is used with this entry because of evidence that retinal dystrophy, iris coloboma, and comedogenic acne syndrome (RDCCAS) can be caused by homozygous or compound heterozygous mutation in the RBP4 gene (180250) on chromosome 10q23.

Clinical Features

Seeliger et al. (1999) reported 2 German sisters, aged 17 and 13 years, respectively, who had night vision problems since early childhood but were otherwise well, except for severe comedogenic acne with densely aggregated open and closed comedones, mostly of the sandpaper type, which was more intense in the younger sister; both sisters also exhibited widespread follicular keratosis. Visual acuities were slightly reduced: 20/40 in the 17 year old and 20/25 in the 13 year old. Anterior segments were normal except for a discrete inferior iris coloboma, most prominent in the right eye of 1 sister, but present to a lesser extent in the left eyes of both girls. Although they did not exhibit corneal dryness, both patients showed a typical 'fundus xerophthalmicus,' involving patchy atrophy of the retinal pigment epithelium (RPE), with small white dots in the periphery representing a more focal loss of RPE. The optic discs were prominent, with irregular capillaries; macular reflexes were irregular and no foveal reflexes were seen. Dark adaptation thresholds were elevated, and scotopic electroretinogram (ERG) responses were reduced or undetectable, whereas photopic responses were reduced in the older sister and normal in the younger sister. Both affected sibs had no detectable serum RBP, retinol levels less than 20% of normal, and normal retinyl esters. Biesalski et al. (1999) restudied the German sisters and found that absorption of fat and vitamin A was normal, and beta-carotene and zinc levels were within the normal range.

Cukras et al. (2012) described a 63-year-old Caucasian man and his 55-year-old sister, born of second-cousin parents, who had early-onset, progressive, severe retinal dystrophy. The man reported impaired night vision and loss of visual acuity since childhood. He also had a history of hypercholesterolemia and underwent repair of patent ductus arteriosus at age 46 years. Ocular examination revealed anterior segment dysgenesis with a small (9-mm) cornea, inferiorly displaced pupil, and inferior coloboma of the iris. There was evidence of conjunctival and corneal limbal neovascularization, which appeared to be secondary to exposure. The view of the posterior pole was limited due to the presence of significant nuclear sclerotic cataract. Fundus examination revealed inferior coloboma of the retina and choroid, in addition to retinal degeneration. Vision was reduced to light perception in both eyes. His 55-year-old sister reported peripheral vision abnormalities beginning at age 10 years. She also had hypercholesterolemia, as well as acne beginning at a young age and extending into her 50s. Ocular examination showed normal anterior segments; funduscopy revealed retinal degeneration in both eyes, with peripheral retinal atrophy, intraretinal 'bone spicule' pigmentation, and attenuated retinal arterioles. An island of relatively intact retina remained in the central few degrees of the macula surrounding the fovea. Testing showed severely constricted visual fields bilaterally. There was evidence for progression in retinal disease, as visual fields were smaller than on previous examination 17 years earlier, and ERG responses had worsened: scotopic rod-driven responses were not detectable at either visit, and cone photopic single-flash responses were approximately 80% reduced at age 38 years, and these residual cone responses were now reduced to the level of noise. Neither sib had signs of xerophthalmia, keratomalacia, or Bitot spots (see 277350).

Molecular Genetics

In 2 German sisters with night blindness and retinal dystrophy, who had had no detectable serum RBP, retinol levels less than 20% of normal, and normal retinyl esters, Seeliger et al. (1999) identified compound heterozygosity for missense mutations in the RBP4 gene (180250.0001 and 180250.0002). Their unaffected mother, who had a low-normal retinol level and a plasma RBP level that was approximately 50% of normal, was heterozygous for 1 of the mutations.

Using exome capture and next-generation sequencing in a brother and sister with early-onset progressive severe retinal dystrophy, who were born of second-cousin parents, Cukras et al. (2012) identified homozygosity for a splice site mutation in the RBP4 gene (180250.0003). Lack of other classic symptoms of vitamin A deficiency in these patients suggested that some dietary vitamin A was being delivered to organs independently of RBP4, but that RBP4 was required to deliver sufficient levels of vitamin A to prevent retinal degeneration. Cukras et al. (2012) noted that the retinal pathology associated with RBP4 mutations is indistinguishable from the recessive retinal dystrophy phenotype due to mutations in other genes (see 268000); however, the additional presence of acne or developmental abnormalities is unique to patients with RBP4-associated retinal dystrophy.

History

Matsuo et al. (1987) described a family in which the mother and 2 children had about half-normal levels of plasma RBP. Familial hypo-RBP predisposed the proband child to keratomalacia during measles infection, despite good nutrition. Measles has been thought to lower serum retinol by decreasing vitamin A absorption. Thuluvath (1987) suggested that protein-calorie malnutrition may have been responsible for the low levels of serum RBP. Thuluvath (1987) suggested that Matsuo et al. (1987) should have measured serum RBP after high-protein intake for a few days, followed by an injection of retinol. Matsuo (1987) defended their conclusion concerning RBP deficiency.