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Research Notes: Ocular Problems in Prader-Willi SyndromeFrom Management of Prader-Willi Syndrome 3rd edition (2006), pp 133-134: Esotropia has been reported in 43% of 15 infants and 66% of 65 older individuals with PWS, and was included as a supportive finding for clinical diagnosis. However, there are surprisingly few published studies characterizing ocular abnormalities and their treatment in PWS, and documentation of opthalmologic findings is lacking in many descriptive series of the syndrome.
Esotropia is a type of strabismus (dysconjugate eye movement) in which one eye turns inward (toward the nose) while the other is fixated in a forward gaze. In a series of 46 patients clinically diagnosed with PWS, 22 were found to have esotropia, while 7 had exotropia, or outward turning of the eye. Additional defects included myopia (15%), significant astigmatism (oblong deformation of the eye leading to blurred vision, 41%), amblyopia (decreased visual acuity in one eye, 24%), and iris transillumination defects (33%). In a detailed study of 12 patients with PWS, Roy et al. found only 1 patient with esotropia, 2 with exotropia, and 9 with orthophoria (normal conjugate eye movements). One patient had myopic chorioretinal degeneration, 1 had disc atrophy and foveal hypoplasia, and 5 (42%) were noted to have telecanthus (increased distance between the inner corners of the eyes without orbit displacement).
A later series of Fox et al. compared 20 PWS patients with deletion and 7 with uniparental maternal disomy with 16 controls matched for age, body composition, and intelligence. Strabismus was found in 6 deletion subjects (30%), 4 disomy subjects (57%), and 4 controls (25%) - not significantly different between groups. Abnormal iris transillunimation was found in 4 deletion and none of the disomy or control subjects. Foveal hypoplasia was not identified in any of the groups, while findings of astigmatism, amblyopia, and amisometropia were not significantly different between the PWS and control groups. Stereopsis differed (p<0.002) between the PWS (45% deletion, 43% disomy) and controls (81%), indicating an increased defect in 3-D perception in the PWS group. The mean level of myopia was also different (P=0.01) between control (refractive error -2.23+_165SD) and PWS (-5.56 +- 5.38) subjects.
Ocular hypopigmentation has also been noted in PWS. Generalized skin hypopigmentation is a well-known feature of PWS (~50% of cases) and may be associated with deletion of the P (pink-eyed dilution) gene, a nonimprinted gene located within the PWS deletion boundaries. Mutations of the P gene are the cause of oculocutaneous albinism type 2 (OCA2) in humans, in which there is hypopigmentation of the eyes, skin, and hair. Associated findings include strabismus, loss of steropsis, nystagmus, and foveal hypoplasia, apparently due to abnormal routing of the optic nerve pathways. The similarity of these eye findings along with skin hypopigmentation to features of PWS suggested a similar pathogenesis. An initial study of 6 patients with PWS and strabismus found abnormal visual-evoked potentials (VEP) in 3 of 4 hypopigmented patients and in neither of the 2 normally-pigmented patients. The VEP abnormality was indistinguishable from that observed in OCA2, suggesting a similar abnormality in optic nerve pathways in PWS. However, the presence of strabismus in those patients with normal VEP was unexplained and subsequent studies failed to confirm these initial findings.
Overall, the data suggest strabismus, both esotropia and exotropia, is not uncommon in PWS, and may be related to ocular muscle hypotonia. A variety of other ophthalmologic disorders may also be present, including ocular hypopigmentation. These disorders could be related to deletion of the P gene, which is also associated with skin hypopigmentation. However, this link is far from certain because misrouting of optic nerve pathways, such as observed in OCA2, has not been confirmed in PWS.
Evaluation and treatment of eye conditions in PWS requires consultation with an experienced ophthalmologist. Treatment of congenital strabismus has been noted to have variable outcome in non-PWS cases and there are limited data in PWS.
Jpn J Ophthalmol. 2001 Sep-Oct. BACKGROUND: The association of oblique palpebral fissures and A- or V-pattern has not been clarified. We report two cases of A-pattern esotropia with marked mongoloid slanting palpebral fissures associated with vertical displacement of the horizontal rectus muscle. CASES: Case 1 was a boy with Prader-Willi syndrome. He showed A-pattern esotropia with upward slanting palpebral fissures. Severe superior oblique muscle overaction was observed. Case 2 was a girl with meningocele. She also showed A-pattern esotropia with upward slanting palpebral fissures. OBSERVATIONS: In case 1, weakening surgery of the superior oblique muscles did not improve the A-pattern. Coronal images of computed tomography showed one-half-muscle-width upward displacement of both lateral rectus muscles. After downward transposition surgery of the lateral rectus muscles, the preoperative A-pattern of 25 prism diopters (PD) was successfully corrected to 10 PD. In case 2 also, upward displacement of both lateral rectus muscles was shown by computed tomography. The preoperative A-pattern of 26 PD was corrected to 4 PD postoperatively after upward transposition surgery of the medial rectus muscles. CONCLUSIONS: The vertical displacement of horizontal rectus muscles was considered the principal cause of A-pattern in these cases associated with marked mongoloid slanting palpebral fissures. J Pediatr Ophthalmol Strabismus. 1999 Nov-Dec. PURPOSE: Prader-Willi syndrome (PWS) refers to a genetic disorder induced by an anomaly on chromosome 15 occurring with a frequency of one in 10,000 to 20,000. It is characterized by a unique set of features including infantile hypotonia, obesity in childhood, small hands and feet, hypogonadism, and mental retardation. Reported here are the results of ophthalmic examinations of persons with PWS, together with results from controls comparable in age, percentage of body fat, and intelligence. These data bear on the hypothesis that the ocular anomalies in PWS are unique to this syndrome. METHOD: A comprehensive investigation of PWS brought children and adults to Vanderbilt University for extended testing, which included an ophthalmic examination. Genetic analysis determined unequivocally the PWS diagnosis and identified subgroups-deletion and maternal disomy. A group of persons without PWS but generally comparable in age, body composition, and intelligence served as controls. RESULTS: Significant differences between the deletion and disomy subgroups were not found for the clinical ophthalmic measures. The incidence of anomalies in the combined PWS was similar to those reported in previous studies. A similar pattern was present in the control group except for myopia and stereopsis. An effect of genetic subgroup, however, was observed for random element stereopsis with the maternal disomy group having a greater degree of impairment. CONCLUSION: The overall similarity between the PWS and control groups on all measures except myopia and stereopsis suggest that many of the anomalies in PWS found in prior studies are due to factors inherent in a general dysfunctional population, rather than reflective of an ocular signature unique to PWS. Am J Med Genet. 1997 Jul 11. The Prader-Willi syndrome (PWS) usually results from a paternal deletion of 15q11-q13 or maternal disomy for chromosome 15. Reduced pigmentation of skin, hair, and eyes is common in PWS and was suggested previously to be associated with the 15q11-q13 deletion. The P gene, located in this same region, is associated with OCA2, an autosomal recessive disorder that is the most frequent form of tyrosinase-positive oculocutaneous albinism. We studied 28 individuals with PWS and found that hemizygosity for the P gene was significantly correlated with the occurrence of hypopigmentation among PWS patients. However, we found little or no relationship between the occurrence of hypopigmentation and the polymorphism haplotype of the intact P allele. Thus, our results indicate that hypopigmentation is likely the result of deletion of the P gene in the context of PWS but do not support the linked hypothesis that hypopigmentation results from hemizygosity for variant P alleles with reduced function. Jpn J Ophthalmol. 1995. A 25-year-old woman is described whose clinical features included infantile hypotonia, obesity after infancy, intellectual impairment, dysmorphic facial features, short stature, small hands and feet, and abnormal dentition, which are typical of the Prader-Willi syndrome. The patient had almond-shaped eyes, spot-like hypopigmentation under the retina, and a polychromatic luster in the anterior and posterior subcapsular regions of both lenses. Using fluorescence fundus angiography, we identified choroid-transmitted fluorescence in the areas of spot-like hypopigmentation. Recordings of both electroretinogram and visual evoked potential were normal. Ophthalmologists should be aware of the characteristic features of Prader-Willi syndrome because some of the ocular disorders associated with this syndrome can be treated. Pigment Cell Res. 1994 Dec. Mutations at the mouse pink-eyed dilution locus, p, cause hypopigmentation. We have cloned the mouse p gene cDNA and the cDNA of its human counterpart, P. The region of mouse chromosome 7 containing the p locus is syntenic with human chromosome 15q11-q13, a region associated with Prader-Willi syndrome (PWS) and Angelman syndrome (AS), both of which involve profound imprinting effects. PWS patients lack sequences of paternal origin from 15q, whereas AS patients lack a maternal copy of an essential region from 15q. However, the critical regions for these syndromes are much smaller than the chromosomal region commonly deleted that often includes the P gene. Hypopigmentation in PWS and AS patients is correlated with deletions of one copy of the human P gene that is highly homologous with its mouse counterpart. A subset of PWS and AS patients also have OCA2. These patients lack one copy of the P gene in the context of a PWS or AS deletion, with a mutation in the remaining chromosomal homologue of the P gene. Mutations in both homologues of the P gene of OCA2 patients who do not have PWS or AS have also been detected. J Am Optom Assoc. 1994 May. BACKGROUND: First described in 1956, Prader-Willi syndrome is a neurogenetic condition characterized by infantile hypotonia, hypogonadism and obesity. Mental deficiency, behavioral abnormalities, and obvious dysmorphic features are frequently found as well. It is a relatively common condition, with an incidence estimated to be between 1 in 10,000 to 25,000 live births. Few studies have been published that investigated the ocular defects associated with this syndrome. METHODS: This case report discusses the systemic and oculo-visual abnormalities of a 34-year-old white male enrolled in the Easter Seal Society of Metropolitan Chicago/Illinois College of Optometry Eye Care and Treatment Program. Examination techniques commonly used for patients with cognitive/developmental dysfunctions were utilized. RESULTS: Our findings include ocular hypopigmentation with reduced visual acuity, a myopic refractive error, exotropia, corneal abnormalities, glaucoma, and other ocular and systemic health abnormalities. CONCLUSIONS: Reported ocular findings for patients with Prader-Willi syndrome include iris hypopigmentation with depressed visual acuity, moderate to high refractive error, and strabismus. Individual patients with this syndrome have also been reported with cataracts, congenital ocular fibrosis syndrome, diabetic retinopathy, and congenital ectropion uveal. The numerous ocular, systemic, and functional abnormalities of patients with Prader-Willi syndrome make it mandatory that all routinely receive primary optometric vision care. N Engl J Med. 1994 Feb 24. BACKGROUND. Type II (tyrosinase-positive) oculocutaneous albinism is an autosomal recessive disorder that has recently been mapped to chromosome segment 15q11-q13. The frequency of this disorder is greatly increased in patients with Prader-Willi or Angelman syndrome, both of which involve deletions of chromosome 15q. The P protein is a transmembrane polypeptide that may transport small molecules such as tyrosine, the precursor of melanin. The P gene is located in chromosome segment 15q11-q13. METHODS. We studied the tyrosinase and P genes in three patients with type II oculocutaneous albinism, one of whom also had Prader-Willi syndrome, and in one patient with a milder syndrome known as autosomal recessive ocular albinism. Individual exons of these genes were amplified from the DNA of each patient by the polymerase chain reaction and screened for mutations by simultaneous analyses of single-stranded conformation polymorphisms and heteroduplexes and subsequent DNA sequencing. RESULTS. Mutations of the P gene were identified in all four patients. These included one frame shift, three missense mutations that result in amino acid substitutions, and one mutation that affects RNA splicing. The patient with Prader-Willi syndrome plus albinism had a typical deletion of the paternal chromosome 15, rendering him hemizygous for a maternally inherited mutant allele of the P gene. The child with ocular albinism was heterozygous for two different mutations in the P gene. CONCLUSIONS. Abnormalities of the P gene are associated with a wide range of clinical phenotypes, including type II oculocutaneous albinism, albinism associated with the Prader-Willi syndrome, and at least some cases of autosomal recessive ocular albinism. Can J Ophthalmol. 1992 Oct. It has recently been suggested that aberrant misrouting of retino-geniculate-cortical (RGC) projections, a finding previously noted only in albinism, may be an additional feature of the Prader-Willi syndrome. To determine the prevalence of ocular abnormalities in patients with the syndrome and to look for evidence of misrouted RGC projections by means of testing of the pattern-onset visual evoked potential (VEP) response, we examined 12 patients with Prader-Willi syndrome, 8 albino subjects and 5 healthy control subjects. Ocular findings in the first group included telecanthus (in five subjects), strabismus, nystagmus, foveal hypoplasia, visual field defects and cataract. However, the VEP asymmetry typically seen in albinism was not noted in any of the patients with Prader-Willi syndrome. Our findings do not support previous claims of abnormal optic nerve fibre decussation in Prader-Willi syndrome. Am J Hum Genet. 1989 Jul. In order to determine the frequency and characterization of hypopigmentation in Prader-Labhart-Willi syndrome (PLWS), clinical, cytogenetic and biochemical findings are reported in 56 PLWS individuals. Forty-eight percent of the individuals with PLWS met the criteria for hypopigmentation. Hypopigmentation in PLWS individuals appears to be as common as previously recognized features such as behavioral problems and dental abnormalities. Significant differences in hair color, sun sensitivity, and complexion were found between those PLWS patients with the chromosome 15 deletion and those with normal chromosomes. Individuals with the deletion frequently had lighter hair color, more sun sensitivity, and fairer complexion than did either other family members or nondeletion PLWS patients. No significant differences in biochemical findings (phenylalanine, tyrosine, catecholamines, or beta-melanocyte-stimulating hormone) were found between deletion and nondeletion PLWS patients or between hypopigmented and normally pigmented patients. The data suggest that a gene(s) controlling the activity of tyrosinase or other enzymes required for melanin production is located on proximal 15q. From the full text article: Decreased oculocutaneous pigmentation has been observed in clinical studies in several individuals with PLWS (Hittner et al. 1982; Butler et al. 1986; Wiesner et al. 1987; Phelan et al. 1988). ... Recently, Wiesner et al. (1987) studied 29 PLWS patients and found decreased cutaneous and ocular pigmentation in 48% of their patients. They also reported abnormal melanosomes in one PLWS patient. Misrouting of optic fibers, a finding consistent with oculocutaneous or ocular albinism, was also found in several PLWS patients reported by Creel et al. (1986). [...] There was no difference in strabismus, nystagmus, or iris translucency between deletion PLWS patients and nondeletion PLWS patients. Strabismus was found in 64% of deletion PLWS patients and in 75% of nondeletion PLWS patients. ... [...] There also was no significant difference in biochemical findings (beta-melanocyte-stimulating hormone, phenylalanine, tyrosine, or catecholamine levels), strabismus, nystagmus, or consistent iris translucency or retinal abnormalities between the hypopigmented PLWS patients and the normally pigmented PLWS patients. Strabismus was found in 75% of hypopigmented PLWS patients and in 62% of normally pigmented PLWS patients. The average hair-color rating was 2.0 (dark blond) for the hypopigmented PLWS patients and 4.1 (light brown) for those judged to have normal pigmentation. The average eye-color score was 2.8 (dark blue) for the hypopigmented PLWS patients and 4.5 (light green-medium green) for those with normal pigmentation. ... [...] In summary, the clinical and biochemical data in both this study and other reports indicate that there is decreased pigment in approximately one-half of the PLWS patients-a finding that correlates with the chromosome 15 deletion, although the hypopigmentation is not as severe as in individuals with oculocutaneous albinism. ... Doc Ophthalmol. 1989 Apr. Oculocutaneous, electrophysiological, and cytogenetic factors were evaluated in 14 patients with Prader-Willi syndrome and in three controls, two albinos and a normal observer. In a substantial number of PW patients chromosomal anomalies, particularly deletions of the long arm of chromosome 15 as well as hypopigmentation of hair, skin, and eye have been identified. In the genetic condition of albinism, hypopigmentation related to neural ectoderm derivatives is associated with reduced visual acuity, foveal hypoplasia, and aberrant retinogeniculocortical projections. The latter can be observed by visual evoked potential (VEP) assessment of hemispheric response symmetry. To determine the possible neural ectodermal origin of hypopigmentation and its involvement in ocular development and optic pathway integrity, the potential distributions of the pattern onset/offset VEP were examined. Our results show hypopigmentation in 13 of our 14 PW patients and a chromosome abnormality in 6; no correlation between these two features was found. None of the PW patients showed the characteristic contralateral hemispheric asymmetry seen in albinism. On the other hand their VEP profiles were found to be atypical, rendering waveform and cortical topography difficult to interpret. Analysis suggests that in the absence of VEP evidence for optic pathway misprojection, PW hypopigmentation is probably of neural crest origin. J Pediatr Ophthalmol Strabismus. 1988 May-Jun. Forty-six patients with Prader-Willi syndrome were examined to determine the incidence and character of ocular abnormalities. All patients met clinical criteria for this syndrome including infantile hypotonia, hypogonadism, truncal obesity, intellectual impairment, dysmorphic facies, and short stature. Thirty-two patients had best corrected visual acuities between 6/6 and 6/9 in each eye. Seven patients (15%) had myopia greater than -3.75 diopters. Nineteen (41%) patients had astigmatism of 1.25 diopters or greater. Amblyopia of strabismic, anisometropic, or ametropic etiology was present in 11 (24%) of the patients. Strabismus was present in 25 (54%) patients: 22 (48%) patients had esotropia and three (7%) had exotropia. Nine patients either received or required strabismus surgery. Thirty-three percent of the patients examined for iris transillumination defects had this finding. This study represents the first large series of patients with Prader-Willi syndrome to undergo detailed ophthalmologic evaluation. Recognition of this syndrome is important because of the high incidence of potentially treatable ocular problems. Wiad Lek. 1987 May 15. Am J Hum Genet. 1987 May. Cutaneous and ocular pigmentation were evaluated in 29 individuals with the Prader-Willi syndrome (PWS). Criteria for hypopigmentation included the presence of type I or II skin, the lightest skin type in the family by history, and iris translucency on globe transillumination. On the basis of these criteria, 48% of the PWS individuals were hypopigmented. The presence of hypopigmentation correlated with a small interstitial deletion on the proximal long arm of chromosome 15; however, this deletion was also found in individuals who did not meet the full criteria for hypopigmentation. Hairbulb tyrosinase activity and glutathione content, as well as urine cysteinyldopa excretion, were low in PWS individuals with and without hypopigmentation and did not separate these two groups. We conclude that hypopigmentation is found in a significant proportion of individuals with PWS and that the hypopigmentation may be associated with a deletion of the long arm of chromosome 15. The mechanism for the hypopigmentation is unknown. From the full text article: Fundus pigmentation was normal for both groups [i.e., both hypo- and normally pigmented]. Strabismus either was or had been present in the majority of individuals in each group, including 8 HPWS [hypopigmented] and 10 NPWS [normal pigmentation]. Several individuals had undergone successful surgical correction. [...] Hittner et al. (1982) suggested that a defect in neural crest-cell migration may be the mechanism for the hypopigmentation, but our data do not support this interpretation. We did not carry out quantitative analysis of hairbulb and skin melanocytes, but we had no difficulty in finding adequate numbers of melanocytes in these tissues in six individuals. Furthermore, abnormalities in the central visual system have been demonstrated in PWS individuals with hypopigmentation, indicating an embryologic defect in retinal and optic-tract pigmentation (Creel et al. 1974, 1978, 1986; Strongin and Guillery 1981). Since the retinal melanocytes are neuroectodermal in origin, the abnormality of the central visual system in PWS is evidence that the change in pigment formation is not limited to neural crestderived melanocytes (Rawles 1947; Mintz 1967; Moore 1973). The results of this study suggest that the definition of oculocutaneous albinism may not be precise. The usual criteria for albinism include hypopigmentation of the skin, hair, and eyes associated with the ocular features of nystagmus, photophobia, reduced visual acuity with hypoplasia of the fovea, and misrouting of the retinal ganglion fibers at the chiasm associated with an alternating strabismus (King 1986). We excluded from this study one individual with PWS who met these criteria but had other family members with oculocutaneous albinism without PWS. Several individuals in the study had nystagmus or strabismus, but the characteristics of these eye findings were not typical of albinism: the nystagmus was not sustained, and the strabismus was not alternating. Furthermore, we have demonstrated misrouted retinal ganglion fibers at the chiasm in HPWS without sustained nystagmus (Creel et al. 1986). There appears to be a continuum between hypopigmentation that meets the criteria of oculocutaneous albinism and that which we have found in HPWS. J Pediatr Ophthalmol Strabismus. 1986 Jul-Aug. We report an 11-year-old boy with both the congenital ocular fibrosis and the Prader-Willi syndromes. Since birth he has had bilateral blepharoptosis and fixed ocular misalignment in downward gaze. Pathological examination of the extraocular muscles showed replacement by fibrous tissue. Additionally, the child had the typical clinical features of the Prader-Willi syndrome including mental retardation, hypotonia, short stature, hypogonadism, and obesity. The Prader-Willi syndrome has been consistently associated with interstitial deletions of the long arm of chromosome 15. Although our patient appeared to have normal chromosomes, he may indeed have an undetectable deletion which may be responsible for both syndromes. We believe that the gene(s) for the congenital ocular fibrosis syndrome may be located near the gene(s) for the Prader-Willi syndrome on the long arm of chromosome 15. JAMA. 1986 Jun 20. A patient with Prader-Willi syndrome and unilateral congenital ectropion uveae with glaucoma was found to have factor XI deficiency and reduced levels of serum luteinizing hormone, follicle-stimulating hormone, and testosterone. Administration of gonadorelin (LH-RH) increased serum levels of luteinizing hormone and follicle-stimulating hormone, while clomiphene citrate had no effect, suggesting a primary hypothalamic defect. Patients with congenital ectropion uveae should be followed up for the development of both glaucoma and neural crest disorders. N Engl J Med. 1986 Jun 19. Patients with oculocutaneous or ocular albinism have misrouting of optic fibers, with fibers from 20 degrees or more of the temporal retina crossing at the chiasm instead of projecting to the ipsilateral hemisphere. Misrouting can result in strabismus and nystagmus. Because patients with the Prader-Willi syndrome may also have hypopigmentation and strabismus, we wondered whether they too might have misrouting of optic fibers. We therefore studied six patients with Prader-Willi syndrome selected for a history of strabismus, using pattern-onset visually evoked potentials with binocular and monocular stimulation to look for evidence of misrouted retinal-ganglion fibers. Four had hypopigmentation, and three of these four had abnormal evoked potentials indistinguishable from those recorded in human albinos. The two with normal pigmentation had normal responses. These findings indicate that patients with Prader-Willi syndrome who have hypopigmentation have a brain abnormality characterized by misrouting of retinal-ganglion fibers at the optic chiasm--a finding previously reported only in forms of albinism. Aust N Z J Ophthalmol. 1985 Feb. Congenital ectropion uveae is a rare condition which may be present in one or both eyes. If the patient is followed glaucoma will always be found to be present. Associated features which have been described are ptosis, Rieger's anomaly, Prader Willi syndrome, facial hemiatrophy and neurofibromatosis. This paper describes a patient followed for 18 years who had bilateral congenital ectropion uveae, bilateral ptosis, asthma and late onset of a dental defect. Am J Ophthalmol. 1973 Feb. No abstract available. Orv Hetil. 1971 Jul 18. No abstract available. |