Clinical and mutational characteristics of oculocutaneous albinism type 7.

The purpose of this paper is to expand on the phenotype of oculocutaneous albinism type 7 (OCA7). We described three patients with OCA7: two from a consanguineous family of Kurdish origin and one patient of Dutch origin. We compared them with all patients described to date in the literature. All newly described patients had severely reduced visual acuity (VA), nystagmus, hypopigmentation of the fundus, severe foveal hypoplasia, and chiasmal misrouting. None had iris translucency. All patients had normal pigmentation of skin and hair. We found one novel mutation in the Dutch patient: c.565G > A; p.(Gly189Ser). We compared our patients to the 15 described in the literature to date. All 18 patients had substantially pigmented skin and hair, very poor VA (0.4-1.3 logMAR), nystagmus, (mild) ocular hypopigmentation, foveal hypoplasia, and misrouting. Although pigmentation levels were mildly affected in OCA7, patients had a severe ocular phenotype with VA at the poorer end of the albinism spectrum, severe foveal hypoplasia, and chiasmal misrouting. OCA7 patients had a phenotype restricted to the eyes, and similar to that of X-linked ocular albinism. We therefore propose to rename the disorder in ocular albinism type 2. Unfolding the role of LRMDA in OCA7, may bring us a step closer in identifying the responsible factors for the co-occurrence of foveal hypoplasia and misrouting.

Evident hypopigmentation without other ocular deficits in Dutch patients with oculocutaneous albinism type 4.

To describe the phenotype of Dutch patients with oculocutaneous albinism type 4 (OCA4), we collected data on pigmentation (skin, hair, and eyes), visual acuity (VA), nystagmus, foveal hypoplasia, chiasmal misrouting, and molecular analyses of nine Dutch OCA4 patients from the Bartiméus Diagnostic Center for complex visual disorders. All patients had severely reduced pigmentation of skin, hair, and eyes with iris transillumination over 360 degrees. Three unrelated OCA4 patients had normal VA, no nystagmus, no foveal hypoplasia, and no misrouting of the visual pathways. Six patients had poor visual acuity (0.6 to 1.0 logMAR), nystagmus, severe foveal hypoplasia and misrouting. We found two novel variants in the SLC45A2 gene, c.310C > T; (p.Pro104Ser), and c.1368 + 3_1368 + 9del; (p.?). OCA4 patients of this Dutch cohort all had hypopigmentation of skin, hair, and iris translucency. However, patients were either severely affected with regard to visual acuity, foveal hypoplasia, and misrouting, or visually not affected at all. We describe for the first time OCA4 patients with an evident lack of pigmentation, but normal visual acuity, normal foveal development and absence of misrouting. This implies that absence of melanin does not invariably lead to foveal hypoplasia and abnormal routing of the visual pathways.

Outcome and quality of screening in a nationwide survey on retinopathy of prematurity in The Netherlands.

PURPOSE: Provide insight in natural history, screening and treatment policy of retinopathy of prematurity (ROP) in The Netherlands. METHODS: A multicentre, prospective, population-based study (NEDROP) included all preterm infants born in 2009 in The Netherlands fulfilling the inclusion criteria for ROP screening. Anonymised data from ophthalmologists, neonatologists and paediatricians were merged on identification number. RESULTS: Of 2033 reported infants, 1688 (83%) were screened for ROP. ROP stage was reported in 100%, zone in 94.4% and plus disease in 83%. ROP developed in 324 (19.2%), mild ROP (stage 1-2) in 294 (17.4%), severe ROP (stage 3 or more) in 30 (1.8%) and 17 (1%) were treated. The initial screening examination was not performed within the required 42 days in 641 (38%). Date for follow-up was recorded 1973 times and accomplished within 3 days from the planned date in 1957 (99.2%). The chance of not being screened increased from 12.9% without transfer to another hospital to 23.5, 18.5 and 25% after 1, 2, or 3 transfers, respectively. CONCLUSIONS: The incidence of severe ROP and infants treated was low. NEDROP emphasises that timing of initial examination and transfer to another hospital are issues of concern within the screening process.

Reduction in screening for retinopathy of prematurity through risk factor adjusted inclusion criteria.

AIMS: To develop a new national screening guideline for retinopathy of prematurity (ROP). METHODS: Included were infants of the 2009 prospective ROP inventory in The Netherlands with gestational age (GA) <32 weeks and/or birth weight (BW) <1500 g. Five models were studied, based on GA and BW in combination with no, one or a set of five risk factors for ROP. Risk factors were determined by logistic regression. In MEDLINE and EMBASE, additional risk factors were searched. A precondition was that no infants with severe ROP would be missed. Receiver operating characteristic curves or classical measures were used to determine diagnostic accuracy. RESULTS: The model including all infants with severe ROP comprised screening of infants with GA <30 weeks and/or BW <1250 g and a selection of infants with GA 30-32 weeks and/or BW 1250-1500 g, with at least one of the following risk factors: artificial ventilation (AV), sepsis, necrotising enterocolitis (NEC), postnatal glucocorticoids or cardiotonica. This model would not detect 4.8% (95% CI 2.5% to 8.0%) of infants with mild ROP and would reduce infants eligible for screening by 29%. CONCLUSIONS: In The Netherlands, screening may be safely reduced using a new guideline based on GA, BW, AV, sepsis, NEC, postnatal glucocorticoids and cardiotonica.

The incidence of visual impairment due to retinopathy of prematurity (ROP) and concomitant disabilities in the Netherlands: a 30 year overview.

AIM: To determine the incidence of visual impairment (VI) caused by retinopathy of prematurity (ROP) and concomitant disabilities in preterm neonates born between 2000 and 2009 in the Netherlands. METHODS: Data were retrieved from the Dutch institutes for the visually impaired. They were compared with similar Dutch studies conducted in 1975-1987, 1986-1994 and 1994-2000. RESULTS: Records of 42 infants with VI due to ROP were included. A gradual decrease of gestational age and birthweight but an increase of duration of artificial ventilation, supplemental oxygen administration, bronchopulmonary dysplasia, developmental delay and behavioural abnormalities was found. Compared with the previous study (1994-2000), significantly fewer children were visually impaired due to ROP (1.84 per 100,000 live births/year vs 3.93 per 100,000 live births/year, p=0.000), the incidence of complete blindness decreased from 27.5% to 7.1% (p < 0.05) and more children were treated (66.7% vs 56.9%, NS). The incidence of concomitant disabilities was high and did not differ greatly from the previous study. CONCLUSION: This was a retrospective study showing a significant decrease in VI due to ROP in the Netherlands. Changes in neonatal care practices did not result in a decrease in the incidence of concomitant disabilities. More children were treated for ROP, but 33% were not treated.

Incidence of retinopathy of prematurity over the last decade in the Central Netherlands.

BACKGROUND AND OBJECTIVES: To retrospectively analyze changes in incidence and risk factors of retinopathy of prematurity (ROP) over two periods, 10 years apart, in the central Netherlands. METHODS: Data of 570 infants admitted between 2001 and 2005, screened for ROP according to the Dutch National guideline, were compared to those of 538 infants admitted between 1991 and 1995. RESULTS: Incidence of ROP decreased significantly over the last decade (40.9% in 1991-1995 vs. 23.3% in 2001-2005, p < 0.001), together with incidence of severe ROP (stage >or=3) (3.3 vs. 1.2%, p < 0.05). In infants with a birth weight (BW) <1,000 g incidence of ROP dropped significantly (67.0 vs. 41.8%, p < 0.001), as well as incidence of severe ROP (8.1 vs. 3.0%, p < 0.05). For infants with a BW >or=1,000 g incidence of ROP also declined significantly (27.1 vs. 13.0%, p < 0.001), that of severe ROP remained unchanged (0.8 vs. 0.3%). In both periods gestational age, duration of artificial ventilation, small for gestational age (SGA) and postnatal steroids were independent risk factors for ROP. CONCLUSIONS: In the central Netherlands, incidence of ROP and severe ROP has significantly decreased, also in infants with BW <1,000 g. Risk factors remained unchanged.

Can screening for retinopathy of prematurity be reduced?

BACKGROUND: As screening for retinopathy of prematurity (ROP) is costly, time-consuming for the ophthalmologist and discomforting for the neonate, the minimum number of infants should be screened for ROP, without missing infants with severe ROP, at risk for threshold ROP. OBJECTIVES: To develop a diagnostic screening guideline for ROP that would safely reduce the number of ROP screening funduscopies in our department. METHODS: Data of 275 infants admitted between 1996 and 2000 and screened for ROP according to our Dutch National guideline were studied. Significant risk factors for ROP were calculated, using logistic regression analysis and used to develop a guideline. The discriminative power of the guideline was evaluated using the area under the curve for the receiver operating characteristic curve. RESULTS: Significant risk factors for ROP were: gestational age, birth weight and number of erythrocyte transfusions within the first 4 weeks of life. The combination of these 3 factors resulted in the highest area under the curve: 0.793. Using these 3 factors, a diagnostic screening guideline for ROP was developed: if birth weight + 2 x (gestational age - 20) - 6 x erythrocyte transfusion value within the first 4 weeks of life >or=34, no screening for ROP is necessary. Using this guideline, 22.2% of the infants of the study group could have been excluded from screening; 3.8% of the infants with ROP stages 1-2 would have been missed. CONCLUSION: In our department, ROP screening can be safely reduced using our diagnostic screening guideline.

[Retinopathy in premature infants]. / Retinopathie van de prematuur geborene.

Retinopathy of prematurity (ROP) is found in about 30% of premature infants with a birth weight < 1500 g and/or a gestational age < 32 weeks. Many risk factors are directly or indirectly involved in the development of ROP. The younger the child and therefore the more immature at birth, the greater the risk of ROP leading to short-sightedness or blindness. As a result of advances in obstetric and neonatal care, more immature and extremely low birth weight infants survive, and thorough ophthalmological screening for ROP is therefore essential. Timely detection (ROP stage 3) enables treatment with cryotherapy or laser therapy. Although the rate of success has increased with these forms of treatment, about 40% of the treated children retain a serious visual handicap. In the Netherlands, this involves about 10 children each year. At a later age, prematurely born children have a higher risk of developing other ophthalmologic problems such as strabismus, amblyopia and refractive errors. Again, timely detection and treatment reduces the risk of permanent visual disability.

Long term follow up of premature infants: detection of strabismus, amblyopia, and refractive errors.

AIM: To establish recommendations for long term ophthalmological follow up of prematurely born infants. METHODS: 130 infants with a gestational age (GA) <37 weeks and born between 1 November 1989 and 31 October 1990 were enrolled in a prospective study about the development of strabismus, amblyopia, and refractive errors. Infants were subdivided in three groups according to GA: A <28 weeks (n=32), B >/=28-32-<37 weeks (n=34). Ophthalmological assessment took place at the postconceptional age of 32 weeks, at term and at 3, 6, 12, and 30 months post term. At the age of 5 years parents received a questionnaire and a majority of the children was examined again (n=99). RESULTS: At the age of 5 years 46 infants were known to have strabismus (n=29) and/or amblyopia (n=22) and/or refractive errors (n=22). Statistical analysis showed that gestational age, duration of supplementary oxygen, and duration of hospitalisation were important predictive variables for the development of strabismus, amblyopia, or refractive errors (SAR) at the age of 5 years (p<0.05). Infants with a GA 32 weeks, who developed an incidence comparable with the normal population. Strabismus developed mainly in the first year of life and at the age of 5 years. Most infants with amblyopia were detected at the age of 2-3 years. Refractive errors were found in the first year of life and at the age of 2.5 and 5 years. CONCLUSION: Infants with a GA <32 weeks should be selected for long term ophthalmological follow up. These infants should be screened at the age of 1 year, in the third year of life (preferably at 30 months), and just before school age (including testing of visual acuity with optotypes).

New developments in neonatology: less severe retinopathy of prematurity?

PURPOSE: To determine the effects of surfactant replacement therapy (SRT), high-frequency oscillatory ventilation (HFOV), and general improvements in quality of care on the incidence of severe retinopathy of prematurity (ROP). METHODS: Retrospective comparison of the incidence and severity of ROP in two groups of preterm infants admitted to our neonatal intensive care unit (NICU) in two consecutive 5-year periods (1986-1995) and screened for ROP. During the second study period, natural surfactant was introduced in the treatment of respiratory distress syndrome (RDS) and HFOV was used for treatment of respiratory insufficiency of any origin. The effects of these developments and general improvements on the incidence of severe ROP were analyzed with stepwise logistic regression. RESULTS: The overall incidence of ROP from 1986-1990 was not significantly different from the incidence of ROP from 1991-1995. The incidence of severe ROP (ROP stage 3 or greater) was significantly lower in the second period (15.7% versus 6.4%, P=.015). For infants <1000 g, the incidence of overall ROP was increased significantly during the second study period (47.6% versus 60.1 %, P=.045), although the incidence of severe ROP remained unchanged. Only SRT was associated with a decreased risk for severe ROP; HFOV and general improvements in quality of care had no influence on the outcome. In patients with RDS, the incidence of severe ROP decreased significantly during the second period. CONCLUSION: Of the recent new developments in neonatology, only SRT was associated with a decreased risk for severe ROP.

Do postnatal glucocorticoids and retinopathy of prematurity relate?

To study a possible relation between the use of postnatal glucocorticoids and the incidence and severity of retinopathy of prematurity (ROP), we conducted a retrospective study over a 4-year period that compared data of 161 preterm infants treated with hydrocortisone for bronchopulmonary dysplasia (BPD) with the data of 253 controls. The incidence of overall ROP was 62.7% in the hydrocortisone group and 21.3% in the control group. The incidence of severe ROP (stages 3-5) was 5% in the treatment group and 0.4% in the control group. Using logistic regression, postnatal hydrocortisone therapy was not associated with an increased risk for ROP or severe ROP (OR 1.387, 95% confidence interval 0.773-2.489, p = 0.272 and OR 4.112, 95% C.I. 0.44-38.37, p = 0.16, respectively). Also, in a subgroup of extremely low-birth-weight infants (<1000 g), postnatal hydrocortisone had no influence on the incidence of (severe) ROP. In the infants with ROP (n = 155), only prolonged use of postnatal hydrocortisone was associated with an increased risk for severe ROP (OR 1.02, 95% C.I. 1.00-1.03, p = 0.03). In this study postnatal use of hydrocortisone was not associated with an increased risk for (severe) ROP. However, in infants already suffering from ROP, prolonged treatment with hydrocortisone concurred with an increased risk for severe ROP.

Retinopathy of prematurity: the continuing threat to vision in preterm infants. Dutch survey from 1986 to 1994.

From January 1st 1986 until January 1st 1994, 82 infants were registered in The Netherlands as partially sighted or blind due to retinopathy of prematurity (ROP). Compared with the previous Dutch survey (1975-1987) an increasing number of registered infants had been screened for ROP during their initial hospitalization (95.1% vs. 54.1%) and had ophthalmic treatment in the acute stages of the disease (43.9% vs. 24.5%). Nevertheless, an increase in the annual incidence of partial sight or blindness due to ROP from 4.2/100,000 live births (1975-1987) to 5.1/100,000 live births (1986-1994) was found. This increase seemed to be associated with a higher number of surviving premature infants of less than 28 weeks gestational age.

Less severe retinopathy of prematurity induced by surfactant replacement therapy.

To assess the effect of surfactant replacement therapy (SRT) on the prevalence and severity of retinopathy of prematurity (ROP), we compared data from 160 SRT-treated preterm infants with data from 230 historic controls. The prevalence of ROP was 30.6% in the treatment group and 23.4% in the control group. Severe ROP (stages 3-4) was seen in 6.1% of the infants with ROP in the treatment group and 20.3% of the ROP patients in the control group. Surfactant therapy had no influence on the prevalence of ROP (odds ratio 1.4, 95% confidence interval 0.797-2.459, p = 0.242). However, SRT was associated with a decreased risk for severe ROP, compared to mild ROP (odds ratio 0.226, 95% confidence interval 0.056-0.905, p = 0.036). These data suggest that SRT is associated with a decreased risk for severe ROP.

Early predictors of cerebral visual impairment in infants with cystic leukomalacia.

A longitudinal prospective follow-up study looking at the correlation between haemorrhagic-ischaemic lesions on neonatal cranial ultrasound (US) and the development of cerebral visual impairment (CVI) in infancy resulted in the detection of nine infants with severe visual impairment, which was not due to opthalmological abnormalities. Extensive cystic leukomalacia proved to be highly predictive of CVI, as well as of severe mental and motor deficit in these nine infants. The present report outlines the results of different examinations (acuity card procedure [ACP], visual evoked potential [VEPs], magnetic resonance imaging [MRI]) performed during the first 18 months, to find out which combination of examinations would be the most predictive of CVI at an early stage. The results indicated that infants with a gestational age of 35 weeks or more, who sustained extensive cystic leukomalacia during the neonatal period, and were subsequently not fixating at the acuity cards at term and at three months of age, invariably developed CVI. VEPs were also severely abnormal in the infants with the worst visual outcome, but were not providing a more reliable prognosis. Also, a good correlation between MRI-abnormalities of the optic radiations and/or the visual cortex and CVI was found, but MRI was usually performed beyond the age of 12 months.

Screening for retinopathy of prematurity: do former guidelines still apply?

Early detection of retinopathy of prematurity (ROP) in premature and very-low-birth-weight infants is crucial. In this retrospective study, 581 infants either with a birth weight below 1500 g or a gestational age of less than 32 weeks, or who did not fit these criteria but were judged to be at increased risk, were screened for ROP. ROP developed in 159 (27.4%). The incidence of ROP appeared to be inversely proportional to birth weight and gestational age. Infants with a birth weight below 750 g had a significantly higher risk of developing stage 3 and 4 ROP. The mean age at detection was 7.6 +/- 1.6 weeks. Nearly all of the ROP cases and all of the stage 3 and 4 cases were detected between the 5th and 10th week. Because screening should be focused on these vision-threatening stages, ophthalmic examinations should be concentrated in, but not limited to, the period between the 5th and the 10th postnatal week.

Towards a universal approach for screening of retinopathy of prematurity (ROP).

To improve the cost-benefit ratio of our current screening program for retinopathy of prematurity (ROP), the records of 312 infants who had been screened for ROP were studied retrospectively. Using a safety-index containing three well known risk factors (birthweight, gestational age, oxygen use), infants were classified to be at high risk or low risk for the development of ROP. When all high risk infants would have been screened extensively from the 5th postnatal week onwards and all low risk infants would have been screened once at the 7th postnatal week, a 9.8% reduction of ophthalmological examinations would have been obtained at the expense of missing 2.9% of non vision threatening ROP.

Surfactant replacement therapy: a new risk factor in developing retinopathy of prematurity?

We documented the prevalence of retinopathy of prematurity (ROP) in a group of 46 infants suffering from a moderate or severe respiratory distress syndrome and treated with surfactant replacement therapy (SRT) and 61 controls admitted in the year prior to the institution of SRT. Mortality in the treatment group was lower than in the control group (15.5% versus 23.8; P = 0.29). The ROP prevalence in the treatment group was 47.8% and in the control group 27.9%. To analyse the contribution of SRT alone to the prevalence of ROP, multivariate analysis using logistic regression technique was used. The odds ratio for SRT was 5.2 with a 95% confidence interval of 1.3-20.7, P = 0.02. The prevalence of severe ROP in the surfactant treated group was not increased compared to the control group. From our data we conclude that SRT increases the risk of developing ROP but is not associated with more severe forms of ROP.

Relation between neonatal cranial ultrasound abnormalities and cerebral visual impairment in infancy.

A prospective follow-up study was conducted of a cohort of 65 at-risk neonates to assess the predictive value of neonatal cranial ultrasound abnormalities for cerebral visual impairment in infancy. Visual function was assessed using the acuity card procedure and behavioural visual responses were tested. Normal visual function was found in controls as well as in infants with small haemorrhages or mild leukomalacia. Infants with large haemorrhages performed poorly at 40 weeks postmenstrual age, but recovered to within the normal range in the first half year. In contrast, of the infants with extensive cystic leukomalacia, four of nine preterm infants and three of four term infants were severely visually impaired at 18 months. In the more mature infants, the cystic lesions extended deeper into the subcortical white matter, and this appeared to be associated with a worse visual outcome. Cystic leukomalacia proved to be highly predictive of cerebral visual impairment in infancy.