Original Article
Clinical and Laboratory Findings in the Oculocerebrorenal Syndrome of Lowe, with Special Reference to Growth and Renal Function
N Engl J Med 1991; 324:1318-1325May 9, 1991
- Abstract
- Abstract
Background.
The oculocerebrorenal syndrome of Lowe is an X-linked disorder whose clinical manifestations include congenital cataracts, mental retardation, and renal tubular dysfunction. We investigated growth, renal function, and serum chemistry values in patients with the oculocerebrorenal syndrome to determine the natural history of the disorder and its heterogeneity with respect to these characteristics.
Methods.
Twenty-three patients with the oculocerebrorenal syndrome, ranging in age from 4 months to 31 years, were examined. Height was compared with bone age. Renal function was assessed by measurements of proteinuria, urinary volume, and fractional excretions of potassium, phosphate, carnitine, and amino acids. Creatinine clearance was determined as a measure of glomerular function.
Results.
In the oculocerebrorenal syndrome, linear growth decreases after one year of age; bone age lies between chronologic age and height age. Renal dysfunction occurs in the first year of life, characterized by proteinuria (mean [±SD], 1.38±0.77 g of urinary protein per square meter of body-surface area per day; normal, ≤0.10), generalized aminoaciduria (mean, 686±505 μmol of urinary amino acid per kilogram of body weight per day; normal, 94±45), carnitine wasting (mean fractional excretion, 0.10±0.05; normal, 0.03± 0.01), and phosphaturia progressing into the third decade. Urinary wasting of individual amino acids is milder than in cystinosis, and branched-chain amino acids are relatively spared. Reciprocal serum creatinine levels fall linearly with age, predicting renal failure in the fourth decade. Concentrations of the muscle enzymes creatine kinase, aspartate aminotransferase, and lactate dehydrogenase, as well as of total serum protein, serum α2-globulin, and high-density lipoproteln cholesterol, are elevated.
Conclusions.
Renal glomerular deterioration is slowly progressive in the oculocerebrorenal syndrome. Renal tubular dysfunction begins early and persists; most patients require alkalinization therapy, and many benefit from supplemental potassium, phosphate, calcium, or carnitine. Serum enzyme elevations suggest muscle involvement in the oculocerebrorenal syndrome. (N Engl J Med 1991; 324:1318–25.)
Media in This Article
Figure 1
Height (Panel A), Weight (Panel B), and Head Circumference (Panel C) of 23 Patients with the Oculocerebrorenal Syndrome, According to Age.Article Activity
- Article
THE oculocerebrorenal syndrome of Lowe is an X-linked recessive disorder mapped to Xq24—261 , 2 and characterized by congenital cataracts, cognitive impairment, and renal tubular dysfunction (Fanconi's syndrome).3 Additional clinical features include areflexia,4 hypotonia, glaucoma and corneal keloid,5 and noninflammatory joint swelling of unknown cause.6 7 8 9 Female carriers can be identified by characteristic lens opacities.10 11 12 13 The primary biochemical defect in the oculocerebrorenal syndrome remains unknown, despite extensive investigations into mitochondrial function,14 proteoglycan synthesis,15 16 17 and nucleotide pyrophosphatase activity.18 Therapy consists of replacement of renal losses and symptomatic treatment of nonrenal complications, such as extraction of cataracts, management of glaucoma, special education, and physical therapy.
Previous studies of the oculocerebrorenal syndrome have investigated several clinical and laboratory manifestations described in isolated case reports and small series of patients.19 20 21 22 23 24 25 26 27 We examined 23 male patients with the syndrome at the National Institutes of Health Clinical Center to determine the natural history of growth and renal impairment in the disorder and to identify clinical abnormalities characteristic of the disease. Our findings provide base lines for diagnosis and therapy and offer insights into previously unrecognized organ-system involvement in the oculocerebrorenal syndrome.
Methods
All patients were admitted to the National institutes of Health Clinical Center and were enrolled in a study of the oculocerebrorenal syndrome approved by the institutional review board, informed consent was obtained from the parents or guardians of all patients. The diagnosis of the oculocerebrorenal syndrome, made by referring geneticists and nephrologists, was confirmed by the findings of congenital cataracts (either present at the time of enrollment or documented by medical records), neurologic involvement (cognitive impairment, areflexia, and a history of infantile hypotonia), and some evidence of renal tubular dysfunction (dilute urine, proteinuria, electrolyte wasting, or aminoaciduria) in male patients with typical facies (deep-set eyes and frontal bossing). Twenty-five patients were referred with the diagnosis; two brothers were excluded from the analysis because their cataracts developed after the age of two years and they had no signs of renal tubular dysfunction. The mean age of the 23 patients studied was 11 years 2 months, with a range of 4 months to 31 years (Table 1Table 1
Renal Function in 23 Patients with the Oculocerebrorenal Syndrome.). This age distribution coincides with that known to the Lowe's Syndrome Association; the mean age of their approximately 82 patients is 13 years 2 months, with a range of 1 year 7 months to 41 years 3 months. Eight of our 23 patients were not members of the Lowe's Syndrome Association; 10 had affected male relatives. None of the patients we examined were institutionalized, but the group had a broad range of cognitive defects. All except the two oldest patients were given a diagnosis before the age of two years.We also studied as controls 8 normal, healthy children (2 to 13 years old) and 30 patients with nephropathic cystinosis (9 months to 29 years old). In the latter group the diagnosis was based on the presence of corneal cystine crystals and an elevated leukocyte cystine content.28 29 30 31
Free and total carnitine in plasma and urine were assayed as previously described,32 , 33 according to a modification of the procedure of McGarry and Foster.34 Fractional excretions of carnitine, potassium, and phosphate were calculated as the urine:plasma ratios of each substance divided by the urine:plasma ratio of creatinine.
Amino acids were measured with a 4151 Alpha Plus analyzer (LKB-Biochrom, Cambridge, United Kingdom), with five lithium buffers. Samples of plasma and urine that had been frozen at — 20°C were thawed and deproteinized by ultrafiltration with Amicon Centrifree micropartition cartridges containing YMT membranes (Amicon, Danvers, Mass.). The ultrafiltrates were analyzed immediately or refrozen until they could be analyzed, which was within one week of filtering.
The amino acid index is a calculation based on the daily urinary excretion of 21 selected amino acids (aspartic acid, hydroxyproline, threonine, serine, asparagine, glutamic acid, glutamine, proline, glycine, alanine, valine, half-cystine, methionine, isoleucine, leucine, tyrosine, phenylalanine, ornithine, lysine, histidine, and arginine). The greater the amino acid index, the more severe the failure to reabsorb amino acids. The amino acid index has been employed as a quantitative measure of renal tubular losses in such disorders as cystinosis28 , 32 , 33 and Salla disease.28 , 35
Lipids were measured with the Gilchem reagent system (Gilford Diagnostics, Cleveland) after an overnight fast. Triglyceride and cholesterol assays were performed with the enzymatic production of a formazan or quinoneimine dye, followed by measurement of absorbance at 500 nm,36 and high-density lipoprotein (HDL) cholesterol levels were determined after precipitation with dextran sulfate.37 The lipoprotein cholesterol levels were then calculated as previously outlined.38 Control values are those established by the Lipid Research Clinics.39
Values are given as means ±SD.
Results
Growth
The mean length of the patients at birth, 51.3±2.1 cm (n=8), exceeded the 50th percentile of normal values.40 Height fell below the third percentile between one and three years of age and continued to fall, relative to normal values, through adolescence (Fig. 1Figure 1
Height (Panel A), Weight (Panel B), and Head Circumference (Panel C) of 23 Patients with the Oculocerebrorenal Syndrome, According to Age.A). Longitudinal growth data for Patients 13, 16, and 17 from one, six, and four years of age, respectively, supported the composite growth curve obtained with cross-sectional data. The mean final height of four adult patients ranging in age from 23 to 31 years was 158±9 cm, which is less than the third percentile of normal values for men. The composite growth curve in the patients did not appear to plateau at 16 to 18 years of age as it does in normal men, suggesting that patients with the oculocerebrorenal syndrome continue to grow in early adulthood. In fact, Patient 23 grew 24 cm between the ages of 15 and 31 (normal growth, 5 to 10 cm).Young boys with the oculocerebrorenal syndrome, with height ages approximating their chronologic ages, also had nearly normal bone ages. As the patients grew older, bone age lagged behind chronologic age and height age fell behind bone age (Fig. 2Figure 2
Bone Age as a Function of Height Age in 21 Patients with the Oculocerebrorenal Syndrome.). The four adult patients had fused epiphyses and adult bone ages. The height ages of patients receiving phosphate supplements were indistinguishable from those of patients not receiving phosphate.The mean birth weight for 14 boys with the oculocerebrorenal syndrome born at term was 3.52±0.34 kg, a value that exceeds the 50th percentile of normal values.40 Patients' weights remained close to or within the normal percentiles for the first three years of life and then fell below the third percentile but paralleled the normal curves (Fig. 1B). As was found for height, weight apparently continued to increase in the patients even after the age of 18; the four adult patients had weights just below the third percentile. In addition, Patient 23 gained 14 kg between the ages of 15 and 31 years.
The head circumferences of the patients approximated normal values in the first three to four years of life, then fell to the third percentile in mid-childhood, and eventually reached the normal range (Fig. 1C). The four adults had a mean head circumference of 56 cm (50th percentile).
Glomerular Filtration Rate
Among the 10 boys under the age of 10, the highest serum creatinine value was 53 μmol per liter (0.6 mg per deciliter) (Table 1 ). Values were higher in patients older than 10, and the linear relation between the reciprocal serum creatinine level and age that is typical of progressive renal failure41 42 43 44 was observed (Fig. 3Figure 3
Reciprocal Serum Creatinine Level as a Function of Age in 13 Patients with the Oculocerebrorenal Syndrome Who Were Older Than 10 Years.). This relation reflects substantial variation among patients, similar to that observed in the patients with cystinosis when the reciprocal serum creatinine level was plotted cross-sectionally against age45 (Fig. 2). As for cystinosis, the data for the oculocerebrorenal syndrome credibly predict the age at which renal failure (a serum creatinine level of more than 880 μmol per liter [ 10 mg per deciliter] ) will occur; in the case of the oculocerebrorenal syndrome, it is approximately 36 years of age. However, a biphasic pattern of renal failure, with relatively rapid deterioration from 11 to 16 years of age followed by slow deterioration up to the age of 31, cannot be ruled out (Fig. 3). Creatinine clearances in the patients varied widely, with a mean of 0.84±0.27 ml per second per 1.73 m2 of body surface area (50.4± 16.1 ml per minute per 1.73 m2) (Table 1).Other Measures of Renal Function
The renal dysfunction associated with the oculocerebrorenal syndrome was assessed by measurements of urine volume and osmolality, urinary protein excretion, and reabsorption of electrolytes, amino acids, and other small molecules. The 24-hour urine volume was moderately elevated, reaching a maximum of 4.7 liters in Patient 21 (Table 1). This reflects impaired water reabsorption, manifested by low urine osmolality in 21 of the 23 patients (mean, 401 ±125 mmol per kilogram of body weight; normal, 600 to 900). Urine osmolality did not increase significantly with the age of the patients (Table 1).
Excessive urinary excretion of protein occurred from infancy to adulthood but was highly variable in older patients. Fifteen of the 23 patients had urinary protein concentrations in the nephrotic range (>1.0 g per square meter per day)46 but no other features of the nephrotic syndrome. Only one patient had physiologic levels of protein excretion (≤0.1 g per square meter per day).
Tubular reabsorption of small molecules was impaired to various degrees in the patients. Potassium wasting was mild and did not vary with age. Eight patients required potassium supplementation, but 13 patients who were not receiving potassium supplements had a mean fractional excretion of potassium of 0.29±0.09 (normal, ≤0.15) (Table 1). Individual fractional excretions of potassium were elevated even though serum potassium concentrations determined at the same time were normal or below normal (for example, in Patients 20, 21, 22, and 23). Seven patients required oral phosphate supplements (3 received vitamin D as well), but 14 patients who were not receiving phosphate supplements had fractional excretions of phosphate that averaged 0.24±0.16 (normal, ≤0.20) (Table 1) and increased with age (Fig. 4Figure 4
Fractional Excretion of Phosphate as a Function of Age in 14 Patients with the Oculocerebrorenal Syndrome Who Were Not Receiving Oral Phosphate.). Only eight patients had normal fractional excretions of phosphate, and even patients with normal or low serum phosphate concentrations (Patients 17, 18, 20, 21, 22, and 23) had elevated fractional excretions (Table 1). Free carnitine, which normally has a mean (±SD) fractional excretion of 0.028±0.009 in both children and adults,32 was poorly reabsorbed in 17 of the 21 patients who were not receiving L-carnitine supplements, including all patients over 15 years of age. Consequently, plasma free carnitine concentrations were low (Table 1), and plasma total carnitine averaged 36 μmol per liter (normal, 33 to84).32 Urinary glucose excretion was absent on the basis of dipstick results (<100 mg per deciliter) in 19 of 21 patients tested; 2 had trace amounts of glucose. Quantitative determinations of urinary glucose excretion verified the low degree of glucosuria in the oculocerebrorenal syndrome.
Amino acid excretion, which is not influenced by oral replacement therapy, was quantitated with the amino acid index. This represents the composite amount of 21 amino acids excreted daily; the mean normal value reported for nine children and adults was 94±45 μmol per kilogram per day.32 Patients with the oculocerebrorenal syndrome had an amino acid index that was 2 to 20 times the normal value, with a mean of 686 ±505 μmol per kilogram per day (Table 1). The amino acid index did not vary with age in the patients.
The pattern of amino acid excretion in the oculocerebrorenal syndrome was investigated by calculating the mean fractional excretion of 19 individual amino acids. Normal fractional excretions, determined in eight children, ranged from negligible for proline and 0.002 for valine and arginine to 0.065 for histidine and 0.07 for half-cystine (Fig. 5Figure 5
Mean Fractional Excretion of 19 Amino Acids in 8 Normal Children (2 to 13 Years Old) (Solid Bars), 23 Patients with the Oculocerebrorenal Syndrome (4 Months to 31 Years Old) (Hatched Bars), and 30 Children with Nephropathic Cystinosis (1 to 13 Years Old) (Stippled Bars).). Published results for children and adults47 closely resemble these values. Mean fractional excretions for the 23 patients with the oculocerebrorenal syndrome ranged from nearly normal for isoleucine to 26 times normal for lysine and arginine (Fig. 5). The lowest mean fractional excretions in the patients were for the branched-chain amino acids valine (0.038), isoleucine (0.02), and leucine (0.032). By way of comparison, 30 patients with cystinosis who had renal tubular dysfunction had mean fractional excretions ranging from 0.10 for arginine to 0.71 for histidine (Fig. 5). For every amino acid, the mean fractional excretion in patients with cystinosis was greater than that in patients with the oculocerebrorenal syndrome.Blood Chemistry Analysis
Abnormalities of blood chemistry values were mitigated by replacement therapy for renal tubular losses. Serum electrolyte levels were maintained in the normal range (Table 2Table 2
Blood Chemistry and Hematologic Values in Patients with the Oculocerebrorenal Syndrome.*), although 8 patients received oral potassium supplements and 15 took oral bicarbonate or citrate as alkalinization therapy.Serum calcium concentrations varied around a normal mean (Table 2), with three patients receiving calcium supplements and seven receiving oral phosphate supplements. Seven of the 23 patients had serum alkaline phosphatase levels of more than 8.3 μkat per liter (500 U per liter) (Table 2); 3 of these were not receiving phosphate supplements. One patient had a history of rickets, which healed with phosphate supplementation, but no cases of active rickets were seen. On the other hand, demineralization was observed on knee or wrist x-ray films in 13 of 21 patients studied (ages, 8 months to 31 years). Bone densitometry, performed in six patients, confirmed the clinical diagnosis of osteomalacia.
The total serum protein concentration was eleva-ed in 9 of the 15 patients over four years of age. The serum albumin concentration was generally no-mal, but serum protein electrophoresis, performed in 15 patients, revealed an elevated concentration of α2gglobulin in 10 patients. For Patients 1, 3 through 9, 12, and 21, the meanα2-globulin level was 1±1 g per liter (normal, 4 to 9).
Mean levels of serum thyroxine and thyroid-stimulating hormone were 14±41 nmol per liter (normal,48 64 to 154) and 3.7±2.1 μU per milliliter (normal,48 0 to 5.5), respectively. The mean value for thyroxine-binding globulin in 16 patients was 373±77 nmol per liter (normal,48 , 49 180 to 415 nmol per liter). The mean hemoglobin level and the mean hematocrit were in the lower range of normal (Table 2), whereas the mean erythrocyte sedimentation rate was slightly elevated.
Serum Enzyme Levels
Alanine aminotransferase activity was normal or very slightly elevated in the patients (Table 2). In contrast, aspartate aminotransferase activity was elevated twofold to threefold and was within the normal range in only one patient. The mean lactate dehydrogenase activity was twice the mean value in normal subjects, again with only one patient having a value within the normal range. Lactate dehydrogenase isoenzyme fractionation in eight patients revealed a prominent lactate dehydrogenase I component (0.32± 0.04; normal, 0.13 to 0.25) and a ratio of isoform I to isoform II of nearly 1. Creatine kinase was variably elevated, and increased concentrations were observed in 17 of 23 patients. Creatine kinase isoenzyme fractionation revealed elevated concentrations of MB bands (0.01 to 0.06; normal, 0) in 14 patients and of BB bands (0.02 to 0.08; normal, 0) in 9 patients.
Acid phosphatase levels were elevated in 13 of 14 patients tested, averaging 23.3± 13.3 nkat per liter (1.4±0.8 U per liter). This was significantly greater than the mean value of 13.3±3.3 nkat per liter (0.8±0.2 U per liter) (two-tailed P<0.01) in 20 patients with cystinosis, who ranged in age from 9 months to 29 years.
Cholesterol and Triglyceride Levels
The mean serum triglyceride concentration of patients with the oculocerebrorenal syndrome was normal, but the mean total cholesterol level was elevated (Table 2). Triglyceride levels were within the normal age-adjusted range in 11 of 15 patients, whereas 15 of 23 patients had elevated total cholesterol levels. This was not due to increases in very-low-density lipoprotein or low-density lipoprotein cholesterol levels, but was largely accounted for by increased HDL cholesterol levels (Table 2). The mean HDL cholesterol level was 1.55±0.54 mmol per liter (60±21 mg per decil-ter), as compared with a median value of 1.11 mmol per liter (43 mg per deciliter) for the patients who were less than 19 years old. The range of HDL cholesterol values in the patients was 0.83 to 2.48 mmol per liter (32 to 96 mg per deciliter) (10th and 90th percentiles of normal values, 0.78 and 1.50, respectively). Seven of 15 patients tested had HDL cholesterol values above the 90th percentile for age.
Discussion
The investigation of many patients with the same rare disease often allows the disorder's accepted characteristics to be either documented or denied. In the case of the oculocerebrorenal syndrome, early diagnosis in affected persons and their reduced longevity because of renal disease20 have been confirmed. The oldest patient we examined is now 33 years old, and we are aware of only one older patient, who is 41. This is consistent with the age at which renal failure occurs in the oculocerebrorenal syndrome — the mid-30s — as predicted by a plot of reciprocal serum creatinine level against age (Fig. 3).
On the other hand, some previous conclusions regarding renal involvement in the oculocerebrorenal syndrome have not been borne out. Previous studies have suggested that there are three phases of renal disease.20 Phase I, present in utero and throughout infancy, had no specific clinical manifestations and minimal morphologic changes. Phase II, which lasted from infancy through childhood, involved predominantly tubular dysfunction with little glomerular damage. During Phase III (adulthood), renal glomerular disease predominated and the tubular dysfunction improved as a result of decreased glomerular filtration. In contrast to this scheme of events, Phase I in our patients included clinically apparent proteinuria, aminoaciduria, and low urine osmolality within the first year of life (Table 1). Moreover, these findings persisted with aging (Fig. 4), with the fractional excretion of phosphate increasing even into adulthood, or Phase III. The pattern of tubular and glomerular worsening in the oculocerebrorenal syndrome resembled that in nephropathic cystinosis, in which tubular dysfunction occurs early and persists despite the inexorable progression of glomerular damage, resulting in renal failure by the age of 10 years.28 29 30 31 In the oculocerebrorenal syndrome, glomerular dysfunction becomes obvious much later in life, although it may be present even in early childhood. Its progress appears more variable than in cystinosis, a disease whose renal tubular dysfunction makes its comparison with the oculocerebrorenal syndrome appropriate.
Other findings include a growth rate that declines only after infancy (Fig. 1) and a bone age that lies between height age and chronologic age (Fig. 2). Patients with the oculocerebrorenal syndrome have more pronounced proteinuria (which includes both albumin and low-molecular-weight proteins typically seen in tubular proteinuria50 , 51) and less severe aminoaciduria (Table 1) than patients with cystinosis (686 vs. 1085 μmol per kilogram per day).32 These patients also have a curious, unexplained sparing of the excretion of branched-chain amino acids (Fig. 5). Many have elevated serum protein concentrations (not seen in cystinosis) and increased levels of acid phosphatase (greater than those in cystinosis), as well as increased serum concentrations of the α2-globulin fraction on serum electrophoresis. The finding of an elevated high-density lipoprotein cholesterol fraction may be a metabolic effect due to renal losses, or it may reflect direct regulation by the kidney. Finally, the elevation of serum creatine kinase concentrations in conjunction with the frequent occurrence of substantial concentrations of MB isoenzymes, the elevated aspartate aminotransferase and lactate dehydrogenase concentrations in the setting of normal liver function, and the ratio of lactate dehydrogenase isoform I to isoform II of close to 1 suggest muscle involvement in the oculocerebrorenal syndrome. Minor anomalies in the ratios of fiber types and elevated creatine kinase levels suggest that there may be both muscular and central contributions to the hypotonia seen in these patients.14 , 52
Many physical and laboratory indexes, such as head circumference, hemoglobin, hematocrit, and serum calcium, albumin, alanine aminotransferase, and triglyceride levels, are normal in patients with the oculocerebrorenal syndrome. Abnormal values for these indexes in an individual patient are not typical features of the disorder, and appropriate investigations to find an alternative medical diagnosis should be undertaken. Conversely, the routine elevation of the erythrocyte sedimentation rate in this disorder diminishes the usefulness of this measurement as a marker for active joint inflammation, which commonly occurs late in the disease.9
Some of the laboratory abnormalities associated with the oculocerebrorenal syndrome may be amenable to medical therapy. One third of the patients examined had plasma free carnitine concentrations below 20 μmol per liter, a concentration associated with depletion of carnitine in tissues.53 Since the value of Lcarnitine supplementation in renal tubular dysfunction remains unproved,33 its use in the oculocerebrorenal syndrome should be addressed by a controlled clinical trial. However, the progressive phosphaturia seen in this disorder (Fig. 4) suggests that early intervention with phosphate supplementation, before the development of hypophosphatemia or active rickets, may prevent continued bone resorption. In addition, the use of vitamin D preparations may enhance the intestinal absorption of phosphate in younger patients and may counter the vitamin D deficiency of renal failure in older patients. The need for cholesterol-lowering therapy in the oculocerebrorenal syndrome appears unwarranted, given that the elevation is largely in the HDL fraction, considered protective against atherosclerosis.54
A portion of the variability in the clinical and laboratory features of the oculocerebrorenal syndrome probably reflects the number of different mutations of the oculocerebrorenal-syndrome gene in our patient population, representing 20 separate kindreds. The heterogeneity is also consistent with the expectation that one third of severe X-linked disorders in each generation result from new mutations.55 Steady progress continues toward the identification of the gene for the oculocerebrorenal syndrome, and the isolation of the X chromosome translocation breakpoint from an affected female patient raises hopes that this will occur in the near future.56 The use of current molecular biologic techniques should allow analysis of the specific types of mutations causing the syndrome, elucidation of the relation between the phenotype and the abnormal genotype in this disorder, and a clearer understanding of the pathophysiology underlying the oculocerebrorenal syndrome.
We are indebted to Drs. M. Batshaw, N. Buist, A. DiGeorge, P. Fernholf, D.K. Grange, R. Gray, T. Lake, C. Langman, R. Pagon, B. Powell, W. Purdy, D. Rowland, J. Scheinman, B. Waldo, R. Wappner, R. Weismann, and R. Weiss for referrals of patients to participate in our study; to the Lowe's Syndrome Association for their vigorous recruitment effort and support of clinical research; to the excellent and dedicated 9 West nursing staff, without whom this project could not have been accomplished; and to Carol Becker and Jacqueline Sharkey for editorial assistance in the preparation of this manuscript.
Source Information
From the Unit on Neurogenetics (L.R.C.) and the Section on Human Biochemical Genetics {LB., W.A.G.), Human Genetics Branch, National Institute of Child Health and Human Development, National Institutes of Health, and the Molecular Disease Branch (D.R., J.M.H.), National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Md. Address reprint requests to Dr. Gahl at the Human Genetics Branch, NICHD, NIH, Bldg. 10, Rm. 9S242, 9000 Rockville Pike, Bethesda, MD 20892.
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Attree
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Scott J. Schurman, Steven J. Scheinman. (2009) Inherited cerebrorenal syndromes. Nature Reviews Nephrology 5:9, 529-538
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Arend Bökenkamp, Detlef Böckenhauer, Hae Il Cheong, Bernd Hoppe, Velibor Tasic, Robert Unwin, Michael Ludwig. (2009) Dent-2 Disease: A Mild Variant of Lowe Syndrome. The Journal of Pediatrics 155:1, 94-99
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Robert L Stamper, Marc F Lieberman, Michael V Drake. 2009. Developmental and childhood glaucoma. , 294-329.
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