Peripheral refraction and ocular shape in children.

PURPOSE: To evaluate the relation between ocular shape and refractive error in children. METHODS: Ocular shape was assessed by measuring relative peripheral refractive error (the difference between the spherical equivalent cycloplegic autorefraction 30 degrees in the nasal visual field and in primary gaze) for the right eye of 822 children aged 5 to 14 years participating in the Orinda Longitudinal Study of Myopia in 1995. Axial ocular dimensions were measured by A-scan ultrasonography, crystalline lens radii of curvature by videophakometry, and corneal power by videokeratography. RESULTS: Myopic children had greater relative hyperopia in the periphery (+0.80 +/- 1.29 D), indicating a prolate ocular shape (longer axial length than equatorial diameter), compared with relative peripheral myopia and an oblate shape (broader equatorial diameter than axial length) for emmetropes (-0.41 +/- 0.75 D) and hyperopes (-1.09 +/- 1.02 D). Relative peripheral hyperopia was associated with myopic ocular component characteristics: deeper anterior and vitreous chambers, flatter crystalline lenses that were smaller in volume, and steeper corneas. Lens thickness had a more complex association. Relative peripheral hyperopia was associated with thinner lenses between refractive error groups but changed in sign to become associated with thicker lenses when analyzed within each refractive error group. Receiver operator characteristics analysis of the ocular components indicated that vitreous chamber depth was the most important ocular component for characterizing the myopic eye, but that peripheral refraction made a significant independent contribution. CONCLUSIONS: The eyes of myopic children were both elongated and distorted into a prolate shape. Thinner crystalline lenses were associated with more hyperopic relative peripheral refractions across refractive error groups, but failure of the lens to thin may account for the association between thicker lenses and more hyperopic relative peripheral refractions within a given refractive group. Increased ciliary-choroidal tension is proposed as a potential cause of ocular distortion in myopic eyes.

Ocular predictors of the onset of juvenile myopia.

PURPOSE: The purpose of this study was to identify reliable predictors of the onset of juvenile myopia. METHODS: The data from 554 children enrolled in the Orinda Longitudinal Study of Myopia (OLSM) as nonmyopes with baseline data from the third grade were evaluated to develop a predictive profile for later onset of juvenile myopia. Myopia was defined as at least -0.75 D of myopia in the vertical and horizontal meridians of the right eye as measured by cycloplegic autorefraction (n = 45 children). Chosen predictors were refractive error and the ocular components: corneal power, Gullstrand crystalline lens power, and axial length. Sensitivity and specificity were calculated. Receiver operating characteristic (ROC) curves were generated to evaluate and compare these predictors singly and combined. RESULTS: Refractive error, axial length, Gullstrand lens and pod corneal power were all significant predictive factors for the onset of juvenile myopia. The best single predictor of future myopia onset in the right eye was the right eye's cycloplegic autorefraction spherical refractive error value (mean sphere across 10 readings) at baseline. For a cut point of less than +0.75 D hyperopia in the third grade, sensitivity was 86.7% and specificity was 73.3%. The area under the ROC curve for this mean sphere was 0.880. Producing a logistic model combining mean sphere, corneal power, Gullstrand lens power, and axial length results in a slight improvement in predictive ability (area under the ROC curve = 0.893). CONCLUSIONS: Onset of juvenile myopia can be predicted with moderate accuracy using the mean cycloplegic, spherical refractive error in the third grade. Measurement of other ocular components at this age improves predictive ability, albeit incrementally. Further improvements in the prediction of myopia onset will require the use of longitudinal data in addition to one-time measurement of refractive error and the ocular components.

A PHEX gene mutation is responsible for adult-onset vitamin D-resistant hypophosphatemic osteomalacia: evidence that the disorder is not a distinct entity from X-linked hypophosphatemic rickets.

Previous investigators described a kindred with an X-linked dominant form of phosphate wasting in which affected children did not have radiographic evidence of rickets, whereas older individuals were progressively disabled by severe bowing. They proposed that this kindred suffered from a distinct disorder that they referred to as adult-onset vitamin D-resistant hypophosphatemic osteomalacia (AVDRR). We recently identified a gene, PHEX, that is responsible for the disorder X-linked hypophosphatemic rickets. To determine whether AVDRR is a distinct form of phosphate wasting, we searched for PHEX mutations in affected members of the original AVDRR kindred. We found that affected individuals have a missense mutation in PHEX exon 16 that results in an amino acid change from leucine to proline in residue 555. Clinical evaluation of individuals from this family indicates that some of these individuals display classic features of X-linked hypophosphatemic rickets, and we were unable to verify progressive bowing in adults. In light of the variability in the clinical spectrum of X-linked hypophosphatemic rickets and the presence of a PHEX mutation in affected members of this kindred, we conclude that there is only one form of X-linked dominant phosphate wasting.

Optical and structural development of the crystalline lens in childhood.

PURPOSE: To document the development of key optical and structural parameters of the crystalline lens throughout childhood and examine possible mechanisms by which lens power remains coordinated with the growth of the eye to maintain emmetropia. METHODS: Using cycloplegic autorefraction, video-based phakometry, and ultrasonography, the authors measured refractive error and crystalline lens parameters in 994 children in the first through eighth grades, who participated in the Orinda Longitudinal Study of Myopia, between one and five times from 1989 through 1993. Polynomial growth curves were fit to the data by maximum likelihood estimation. The average annual rates of change in each parameter from each subject's longitudinal data were also estimated. RESULTS: The lens radii of curvature flattened throughout childhood, yet decreases in lens equivalent power stopped after 10 years of age. This indicates that the refractive index of the lens increased during later childhood. Lens thinning in early childhood also ceased after 10 years of age. The spherical volume of the lens showed no appreciable net increase, but the axial length of the eye continued to grow throughout childhood. The prevalence of myopia in our data increased sharply at age 10 years, reaching 21.3% by the age of 14 years. CONCLUSIONS: Concurrent thinning and flattening of the crystalline lens imply that the lens is mechanically stretched by the equatorial growth of the eye during childhood. Changes in the patterns of lens development near the age of 10 years, concurrent with the onset of myopia, suggest that forces arise which interfere with equatorial growth. Such forces might diminish the decreases in lens power and amplify axial elongation to promote myopia.

Corneal changes in schoolchildren.

Videokeratography (TMS-1) data from the right eyes of 788 children between the ages of 6 and 14 years, examined in 1994 as part of the Orinda Longitudinal Study of Myopia, were analyzed using the Fast Fourier Transform (FFT) to quantify corneal power, toricity, and toricity axis. Cross-sectional analysis showed no statistically significant age trend for these parameters. Conversely, longitudinal analysis of data for 387 of these children, first measured in 1991, showed a statistically significant decrease in corneal power. Corneal toricity did not change significantly over this 3-year period, although there was a minute but statistically significant clockwise axis shift. From this we conclude that in the elementary and junior high school years-during which period axial length is known to increase-corneal flattening continues, but corneal toricity is stable.

Quantifying corneal toricity from videokeratography with Fourier analysis.

BACKGROUND: Fourier analysis can be used to quantify corneal toricity from videokeratography data. This study measures the repeatability of Fourier-derived toricity values in normal adult corneas. METHODS: The Topographic Modeling System (TMS) was used to model the corneas of 29 subjects on two occasions, and Fourier analysis applied to the data. Repeatability of Fourier-derived toricity values between sessions was examined, and 95% limits of agreement were established. RESULTS: The 95% limits of agreement between sessions for the Fourier method were -0.02 +/- 0.16 diopters (D) and -0.5 +/- 5.7 degrees for toricity amount and axis, respectively. CONCLUSIONS: The Fourier method yields highly repeatable toricity values and thus provides a sensitive means of detecting longitudinal toricity change in normal corneas.

Repeatability of corneal topography: the "corneal field".

BACKGROUND: The purpose of this study was to determine the interoccasion repeatability of keratometry, photokeratography, and videokeratography and to describe the "corneal field," a scheme for explaining videokeratography results. METHODS: A single examiner obtained corneal curvature measurements with a keratometer, a photokeratoscope, and the TMS-1 in 29 adult patients on two occasions. RESULTS: Estimates for the repeatability of keratometry were +/- 0.49 and +/- 0.65 diopters (D) for the horizontal and vertical meridians respectively. The repeatability of photokeratography was +/- 0.90 and +/- 1.21 D. We presented a rational method for presenting numeric videokeratographic data by temporally and spatially averaging corneal curvature values and grouping them into 24 regions. The repeatability of videokeratography with the TMS-1 was +/- 0.50 D centrally, +/- 0.65 D paracentrally, and +/- 0.80 to +/- 1.00 D in the midperiphery. CONCLUSIONS: Repeatability of the photokeratoscope for central measurements is considerably worse than the keratometer. The repeatability of videokeratography is worse toward the periphery. Refractive surgeons and contact lens investigators need to be aware of these limitations so that true change can be distinguished from measurement error.

Initial cross-sectional results from the Orinda Longitudinal Study of Myopia.

BACKGROUND: Although investigations of human refractive error development and normal ocular growth have been conducted for the last 50 years, no previous study of refractive error and the ocular components has measured all the ocular components. METHODS: The Orinda Longitudinal Study of Myopia was initiated to characterize the development of refractive error and normal eye growth in a sample of predominantly Caucasian children ages 6 to 14 years. RESULTS: Cross-sectional results from 530 children ages 5 to 12 years in the 1st, 3rd, and 6th grades are presented. CONCLUSIONS: This sample's refractive error decreased toward emmetropia with age from an average of +0.73 D at age 6 years to an average of +0.50 D by age 12 years. Between the ages of 6 and 12 years, the vitreous chamber elongated (by 0.52 mm) and the crystalline lens power decreased (by 1.35 D); surprisingly, the crystalline lens thinned by 0.14 mm during this same time period.

Effects of calcitriol and phosphorus therapy on the growth of patients with X-linked hypophosphatemia.

Patients with X-linked hypophosphatemic rickets exhibit clinically evident derangements that include bowed legs and short stature. Although contemporary treatment may result in healing of the rachitic/osteomalacic disorder and straightening of the lower extremities, therapy often does not stimulate growth. Whether such persistent short stature is related to the variable physical manifestations of the disease, the baseline biochemistries, and/or the biochemical response to treatment remains unknown. Therefore, we studied 12 children with X-linked hypophosphatemia to determine if their growth response to calcitriol/phosphorus therapy was dependent upon anthropomorphic characteristics and/or the pre- and posttreatment biochemistries. We observed that growth responsive and resistant youths exhibited similar serum calcium, phosphorus, and creatinine levels at presentation and during therapy. In addition, sexual development was indistinguishable in both groups and growth kinetics appeared independent of physical deformity. In contrast, growth resistant youths presented at less than the 5th percentile whereas growth responsive children were at the 15th percentile or greater. Thus, our data indicate that growth response to calcitriol/phosphate therapy is not a consequence of the biochemical response to therapy or physical deformities. Rather, the criterion that best predicts the growth response is the height percentile at the inception of therapy.

X-linked hypophosphatemic rickets without "rickets".

Wrist and knee radiographs from children with X-linked hypophosphatemic rickets were analyzed and compared with those from normal children and children with established rickets to assess whether radiographically apparent rickets is a consistent abnormality in X-linked hypophosphatemia. The absence or presence of rickets was correctly identified in 94.8% of wrist and knee films from normal and positive controls. In contrast, patients with X-linked hypophosphatemia exhibited rachitic abnormalities in only 5 of 11 wrist and 13 of 15 knee radiographs. As a result, 4 patients within this study group had rickets at the knee and not at the wrist, whereas 5 displayed classic defects at both sites. Perhaps more important, 2 patients, aged 3.8 and 5.2 years, displayed no evidence of rickets in either wrist or knee films, although relatives exhibited demonstrable rachitic abnormalities. Our data indicate that radiographically detectable rickets is a variable abnormality of X-linked hypophosphatemia and does not provide an unambiguous index for the diagnosis of this disease.

Correlations of serum concentrations of 1,25-dihydroxyvitamin D, phosphorus, and parathyroid hormone in tumoral calcinosis.

The inherited metabolic disorder tumoral calcinosis is characterized by elevated serum phosphorus and 1,25-dihydroxyvitamin D [1,25-(OH)2D] levels and paraarticular calcific tumors. The pathogenesis of this disease is obscure, but an elevated renal phosphate reabsorption threshold and increased production of 1,25-(OH)2D are postulated as defects. We studied nine affected patients and found that both serum phosphorus and renal phosphate reabsorption threshold (TmP/GFR) were positively correlated with serum 1,25-(OH)2D levels. Since tumoral calcinosis is a disorder with abnormal renal phosphate transport, we compared the TmP/GFR and serum 1,25-(OH)2D levels to values obtained in patients with two other diseases with renal phosphate transport defects: oncogenic osteomalacia and X-linked hypophosphatemic rickets. We found a significant correlation between TmP/GFR and 1,25-(OH)2D levels in all three diseases, suggesting that in these diseases 1,25-(OH)2D production is regulated in some manner by phosphate transport. Furthermore, previous work indicated that in tumoral calcinosis broad variation exists in serum phosphorus levels. In our patients a negative correlation was found between the serum PTH concentrations and both serum phosphorus levels and TmP/GFR values, respectively. We postulate that although the basic defect in tumoral calcinosis most likely resides in the proximal renal tubular cell, the variation in serum phosphorus levels and possibly disease expression is modulated in part by PTH.

Sexual precocity in girls. An association with sexual abuse?

The development of secondary sexual characteristics before 8 years of age in girls is uncommon and little is known of its epidemiology. In a retrospective study of a population of 105 girls 10 years old and younger who were victims of confirmed or suspected sexual abuse, we found a one in 15 prevalence of early development (before 8 years of age) of one or more secondary sexual characteristics. We speculate on possible associations between early development of secondary sexual characteristics and sexual abuse. The data suggest that further research explore this possible association.

Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol.

Although conventional therapy (pharmacologic doses of vitamin D and phosphorus supplementation) is usually successful in healing the rachitic bone lesion in patients with X-linked hypophosphatemic rickets, it does not heal the coexistent osteomalacia. Because serum 1,25-dihydroxyvitamin D levels are inappropriately low in these patients and high calcitriol concentrations may be required to heal the osteomalacia, we chose to treat five affected subjects with high doses of calcitriol (68.2 +/- 10.0 ng/kg total body weight/d) and supplemental phosphorus (1-2 g/d) performing metabolic studies and bone biopsies before and after 5-8 mo of this therapy in each individual. Of these five patients, three (aged 13, 13, and 19 yr) were receiving conventional treatment at the inception of the study and therefore showed base-line serum phosphorus concentrations within the normal range. The remaining two untreated patients (aged 2 and 37 yr) displayed characteristic hypophosphatemia before calcitriol therapy. All five patients demonstrated serum calcitriol levels in the low normal range (22.5 +/- 3.2 pg/ml), impaired renal phosphorus conservation (tubular maximum for the reabsorption of phosphate per deciliter of glomerular filtrate, 2.13 +/- 0.20 mg/dl), and osteomalacia on bone biopsy (relative osteoid volume, 14.4 +/- 1.7%; mean osteoid seam width, 27.7 +/- 3.7 micron; mineral apposition rate, 0.46 +/- 0.12 micron/d). On high doses of calcitriol, serum 1,25-dihydroxyvitamin D levels rose into the supraphysiologic range (74.1 +/- 3.8 pg/ml) with an associated increment in the serum phosphorus concentration (2.82 +/- 0.19 to 3.78 +/- 0.32 mg/dl) and improvement of the renal tubular maximum for phosphate reabsorption (3.17 +/- 0.22 mg/dl). The serum calcium rose in each patient while the immunoactive parathyroid hormone concentration measured by three different assays remained within the normal range. Most importantly, repeat bone biopsies showed that high doses of calcitriol and phosphorus supplements had reversed the mineralization defect in all patients (mineral apposition rate, 0.88 +/- 0.04 micron/d) and consequently reduced parameters of bone osteoid content to normal (relative osteoid volume, 4.1 +/- 0.7%; mean osteoid seam width, 11.0 +/- 1.0 micron). Complications (hypercalcemia and hypercalciuria) ensued in four of these five patients within 1-17 mo of documented bone healing, necessitating reduction of calcitriol doses to a mean of 1.6 +/- 0.2 micrograms/d (28 +/- 4 ng/kg ideal body weight per day). At follow-up bone biopsy, these four subjects continued to manifest normal bone mineralization dynamics (mineral apposition rate, 0.88 +/-0.10 micrometer/d) on reduced doses of 1.25-dihydroxyvitamin D with phosphorus supplements (2 g/d) for a mean of 21.3 +/- 1.3 mo after bone healing was first documented. Static histomorphometric parameters also remained normal (relative osteoid volume, 1.5 +/- 0.4%; mean osteoid seam width, 13.5 +/- 0.8 micrometer). These data indicate that administration of supraphysiologic amounts of calcitriol, in conjunction with oral phosphorus, results in complete healing of vitamin D resistant osteomalacia in patients with X-linked hypophosphatemic rickets. Although complications predictably require calcitriol dose reductions once healing is achieved, continued bone healing can be maintained for up to 1 yr with lower doses of 1,25-dihydroxyvitamin D and continued phosphorus supplementation.

Echocardiographic evidence for impaired myocardial performance in children with type I diabetes mellitus.

Thirty-three children with type I diabetes mellitus and 51 normal children underwent M-mode echocardiography. Abnormalities of myocardial performance were present in many of the diabetic children. The mean end-systolic volume of the left ventricle was greater in diabetics compared to control subjects. Mean ejection fraction, minor axis shortening, and velocity of circumferential fiber shortening were decreased in the diabetics. There was no evidence of increased myocardial mass in these diabetic children. There was no correlation between myocardial dysfunction, clinical assessment of control, or glycohemoglobin in the diabetic children.