Key Points
Disease summary:
Retinitis pigmentosa (RP) is the commonest “monogenic” form of photoreceptor degeneration affecting 1 in 3000 individuals.
Age of onset varies from early childhood to adulthood.
Patients typically present with night blindness and display a characteristic fundus appearance and constricted visual field (tunnel vision). Legal blindness eventually ensues.
A significant minority of RP patients have evidence of other system involvement, the recognition of which can facilitate specific syndromic diagnosis which has important consequences on the management, molecular diagnosis, and genetic counseling.
Hereditary basis:
RP is one of the most genetically heterogeneous disorders in man. Mutations in any of approximately 50 genes can cause the disease typically in a Mendelian fashion. These mutations account for three quarters of RP cases with the remaining quarter assumed to be caused by mutations in yet unidentified genes.
Autosomal dominant (sometimes with reduced penetrance) and X-linked inheritance (mostly males but sometimes in females with variable severity) are seen each in about 30% and 15% of the cases, respectively, with the remaining 50% likely to be autosomal recessive. This distribution is not simply a reflection of the frequency of the respective loci but rather of the mutation frequency and population characteristics, for example, founder effect and level of consanguinity.
Differential diagnosis:
The significant overlap between the different forms of retinal degeneration means that a patient may have less than classical RP phenotype or even a phenotype typical of a clinically distinct form of retinal degeneration and yet have mutation of a known RP gene. These other forms of retinal degeneration include cone or cone-rod dystrophy and macular dystrophy.
Leber congenital amaurosis (LCA) was previously viewed as a distinct clinical entity in which blindness is observed during infancy but many RP genes are also mutated in LCA patients so LCA can be viewed as a variant of RP with an extremely early onset.
Although RP is typically a rod disease, cones are inevitably lost as the disease progresses, so it is also referred to as rod-cone dystrophy. In cone and cone-rod dystrophies, there is preferential predilection to cones.
Macular dystrophies are a special form of cone dystrophy that is limited in distribution to the macula.
Many syndromes feature pigmentary retinal changes consistent with RP. In fact, some of the genes known to be mutated in these syndromes can be mutated in patients with isolated RP. For example, BBS3 and BBS9 are linked to Bardet-Biedl syndrome (BBS) which is characterized by RP, obesity, polydactyly, renal malformation, and hypogenitalism, but were also found to be mutated in patients with nonsyndromic RP. Other syndromes known to manifest with RP or RP-like lesions include Usher syndrome, Cohen syndrome, Cockayne syndrome, Refsum syndrome, neuronal ceroid lipofuscinosis, and abetalipoproteinemia.
Diagnostic Criteria and Clinical Characteristics
The diagnosis of RP is based on characteristic history and fundus findings. Patients present with night blindness typically in early to late childhood. Physical examination will reveal constricted visual field and the fundus typically displays the classical triad of bone spicule pigmentation, attenuation of arterioles, and optic disc pallor. In early stages, electroretinographic (ERG) findings would show more severe deterioration in scotopic vision (rods) than photopic vision (cones) but as the disease progresses a severely diminished ERG recording in both test conditions is typical.
RP or RP-like lesions (including LCA picture) can be part of various syndromes which, based on the author’s experience, can be missed unless the patient is evaluated by a clinical geneticist or an ophthalmologist who is experienced in the recognition of syndromic RP diagnoses.
Clinical evaluation of a patient with RP should include the following:
Growth parameters: Microcephaly is a primary feature of Cohen syndrome whereas obesity is characteristic of BBS. Obesity is also seen in Alstrom syndrome but this syndrome typically manifests in cone-rod dystrophy rather than RP. Cachectic dwarfism is commonly seen in Cockayne syndrome. This author is aware of a novel form of RP with short stature that maps to a novel locus (unpublished).
Facial features: Prominent upper incisors and a grimacing smile are features of Cohen syndrome whereas sunken eyes with cachectic appearance should point to Cockayne syndrome. Subtle facial dysmorphism can accompany BBS, mainly in the form of round facies.
Skeletal features: Polydactyly is very common in BBS; history of removed extra digits should always be sought and the examiner should thoroughly search for tiny postaxial skin appendages that may be the only manifestation of polydactyly. Even in the absence of polydactyly, brachydactyly (short digits) can be seen, so the digits should be closely inspected.
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