Since the description by Lowe, ' there have appeared approximately one hundred reports of an oculocerebrorenal syndrome characterized by the following abnormalities: congenital cataract, glaucoma, cloudy corneas, craniofacial anomalies, hypotonia and areflexia, aminoaciduria, glucosuria, proteinuria, renal tubular acidosis, reduced ammonia production by the kidneys, bone rarefaction with or without typical rickets and mental retardation.1-5 Although ocular findings are among the earliest, most prominent and constant features of this syndrome, documented pathologic studies of the globe are comparatively rare.6-10 An opportunity to examine the eyes of a 13-year-old boy who had Lowe syndrome prompted us to update the ocular pathologic findings associated with this disorder.
Report of Case
A 40-year-old (gravida 10, para 10) delivered a 3,260 gm white male by Caesarean section after a 36-week gestation. Lowe syndrome had claimed the life of one male sibling at age three and a half years. Three male siblings were born prematurely and died in the neonatal period. Three female and two male siblings are normal. A maternal uncle who had died during infancy was reported to have had ocular abnormalities including small pupils.
At 18 days of age the patient exhibited cloudy corneas, cataracts, generalized hypotonia and frontal bossing. At this time, glucose, protein, proline (25 × normal) and lysine (3 × normal) were present in the urine, but concentrations of all other amino acids were within normal limits. Urine amino acid chromatography was repeated three weeks later, showing an excess of dibasic amino acids (glutamine, lysine and arginine), persistent severe prolinuria and mild general aminoaciduria except for normal levels of branched chain amino acids (leucine, isoleucine and valine), tryptophan and phenylalanine. Blood levels of amino acids were within normal limits.
At three months of age congenital glaucoma was diagnosed. Ocular pressures under general anesthesia were 37.2 and 43.4 mm Hg (Schiotz) right and left respectively. Corneal edema, small, fixed pupils and central cataracts precluded an adequate ophthalmoscopic examination. The anterior chambers were deep. Medical therapy failed to control the glaucoma and he developed a searching nystagmus. The corneas gradually enlarged and became more opaque (Figure 1).
The patient's course was typical of Lowe syndrome. In addition to fluctuating aminoaciduria, proteinuria, glucosuria and hypercalcinuria, he developed renal tubular acidosis and hypophosphatemic renal rickets with rarefaction of bone, severe thoracic scoliosis and multiple fractures of the extremities and ribs. Metaphyseal changes of rickets responded partially to vitamin D therapy, but rarefaction of bone persisted. Seizures developed and were partly controlled with Mebaral and chloral hydrate. Daily oral doses of sodium citrate and calcium phosphate solution maintained serum calcium, but did not correct low serum levels of phosphate or bone density. Psychomotor retardation was so severe that at age 1 1 years he functioned at the level of a 6-month-old infant and at age 12 he weighed thirty pounds. Death at age 13 years occurred at home following a flu-like illness.
The major findings included general skeletal deformity with marked bowing of the lower extremities, thoracic scoliosis and extensive pulmonary atelectasis. The head circumference was 50 cm and the brain weighed 1,137 gm. Although mild diffuse cerebral gyral atrophy was present, microscopy revealed no gliosis or detectable loss of neurone.
Each kidney weighed 50 gm and exhibited numerous punctate calcifications throughout the medullary pyramids. Microscopically, severe tubular and interstitial nephrocalcinosis was limited to the region of the corticomedullary junctions and the pyramids. Except for occasional superficial colloid cysts, the nephrons were largely unaltered.
FIGURE 1: Infant with Lowe syndrome. Note cloudy corneas, particularly on the right side and frontal bossing.
The testes were small, contained immature seminiferous tubules, and were the seat of a marked, uniform interstitial fibrosis. The parathyroid glands were normal.
Microscopy of ribs and several vertebra demonstrated profound accumulations of poorly mineralized lamellar bone and osteoid.
Skeletal muscles were sampled from four sites. In all, there was uniform moderate fiber atrophy, a 10-20 percent expansion of peri-fasicular adipose tissue and a non-diagnostic tendency to grouping of three major fiber types.
Both eyes and attached optic nerves were removed and fixed in 10% formalin. Paraffin sections (5 µ) were stained with hematoxylin and eosin, PAS, PAS diastase, PTAH, orcein, Maseon's trichrome, Holzer's glial, Holmes nerve and congo red amyloid methods.
The right eye measured 26x25x25 mm A-P, H and V respectively with a 1.5-mm stump of optic nerve. A 2-mm pupil was barely visible through a hazy, enlarged (14x13 mm) cornea which was vascularized inferiorly. A horizontal section revealed a small, flattened (4.5x1.5 mm) opaque lens and a liquified vitreous. The retina exhibited a diffuse grayish color most marked peripherally. The pale, cupped optic disc was partly surrounded by a grayish-white pre-retinal membrane. The retinal vessels were diffusely narrowed with foci of apparent obliteration.
Microscopic: The sclera exhibited a moderate, diffuse thickening posteriorly as well as an endophytic nodular thickening near the nasal ora region. Hypertrophy of the peripheral corneal stroma was accompanied by superficial scarring and vascularization and broad breaks in Bowman's membrane. Descemet's membrane was markedly thickened peripherally and exhibited numerous tiny cracks. Over half of the endothelium was absent or severely degenerated but slight proliferation was noted peripherally. A few erythrocytes and mononuclear leucocytes were scattered in the unusually deep anterior as well as in the posterior chamber. The iris exhibited diffuse stromal thinning, a hypertrophied sphincter, and scattered plasma cells and lymphocytes (Figure 2). Several tiny protuberances of the pigment epithelium projected into the stroma as well as posteriorly. The iris root and longitudinal ciliary musculature attached directly to the trabecular mesh work which comprised a poorly organized syncytium of thin fibers interspersed with endothelial cells, large capillaries, pigment granules and mononuclear leucocytes (Figure 3). In some areas, particularly nasally, iris adhesions compressed the meshwork and extended slightly anterior to Schwalbe's line. Schelmm'e canal and the scleral spur were unidentifiable. Anomalous ciliary processes, mostly underdeveloped, but occasionally hyperplastic, arose from or reached the iris root, the trabecular meshwork or the pars plana. Both layers of the ciliary epithelium were partly absent over the processes. The nonpigmented portion exhibited a small (75-100 µ) cyst adjacent to the iris and a cystoid appearance in the pars plana. In the temporal pars plana the pigmented layer was hyperplastic. The lens had a "bar-bell" configuration due to the loss of substance centrally in relation to a defective capsule (Figure 4). It was diffusely cataractous with poor differentiation between nucleus and cortex although most of its substance appeared to be nuclear. There was a small anterior lentiglobus. Metaplastic fibrous tissue comprised much of the central portion of the lens and adjacent anterior cortical area (Figure 4). Large, swollen, irregularly-shaped, degenerating fibers, some with retained nuclei, were present throughout the nucleus and cortex. Calcification was widespread (Figure 4). In addition to a marked variation in thickness, the lens capsule exhibited a few-PAS-positive excrescences anteriorly and equatorially (Figure 5). The capsular epithelium had proliferated anteriorly and also posteriorly up to the site of capsular dehiscence and contained PASpositive material. A moderate number of mono- and polymorphonuclear leucocytes presented in the iris, ciliary body and anterior hyaloid which appeared slightly adherent to the posterior lens capsule. Retinal neuronal atrophy affected mainly the ganglion cell layer and was accompanied by a marked collagenous thickening of vessel walls and exuberant gliosis (Figure 6). The latter involved mainly the inner half of the retina, but occasionally affected the full thickness. Early cystoid edema occurred in the outer plexiform layer at the macula. In many areas the markedly irregular retinal pigment epithelium appeared to be sloughing, in poor coaptation or have small breaks. A pre-retinal gliotic membrane presented along the temporal edge of the deeply cupped optic disc (Figure 7). There was marked fibrogliosis of the optic nerve.
FIGURE 2: Right eye. Sphincter (arrow) is hypertropkied. Note slight ectropion uveae and scattered inflammatory cells in atrophic stroma (hematoxylin and eosin X 80).
FIGURE 3: Right eye. Trabecular meshwork is vascularized and composed of thin sheets interspersed with inflammatory cells and pigmentary debris. Longitudinal ciliary muscle (large arrow) and iris (small arrow) insert directly on meshwork (hematoxylin and eosin X 325).
FIGURE 4: Right eye. Lens has a bar-bell configuration. Central portion exhibits metaplastic fibrous tissue (large arrow) anda small anterior lentiglobus (small arrow). Note extensive calcification (double arrows) (trichrome X 34).
FIGURE 5: Right eye. Lens exhibits thickened capsule and excrescences (large arrow). Note inflammatory cells (small arrows) adjacent to capsule (PAS X 100).
FIGURE 6: Right eye. Normal retinal architecture is replaced by exuberant gliosis. Note marked collagenous thickening of vessels (arrows/ (hematoxylin and eosin X 250).
FIGURE 7: Right eye. Pre-retinal gliotic membrane (arrow) is present at temporal margin of cupped optic disk (hematoxylin and eosin X 42).
The left eye measured 27x26x25 mm in the three principal meridians and its optic nerve stump was 3-mm long. An unusually deep anterior chamber was poorly visualized through a cloudy cornea that measured 14.5x14.5 mm. Patchy atrophy of the iris accompanied a 2-mm ovoid pupil. A horizontal section revealed essentially the same appearance as that of the right eye (Figure 8).
Microscopic: The findings were generally similar to those of the right eye; a few differences were noted. Cracks in Descemet's membrane were more prominent and corneoscleral trabeculae were virtually nonexistent in some areas (Figure 9). The iris exhibited more collagenous tissue than in the right eye and a break in the pigment epithelium was associated with hyalinized material. In the lens, capsular thickening, folding and excrescences were more striking than in the right eye. There was slight perivascular accumulation of pigment in the retina. The wall of the central retinal artery was moderately thickened by muscular hyperplasia.
With the exception of the eyes, pathologic alterations in Lowe syndrome are not diagnostic and may correlate poorly with clinical manifestations. The eye exhibits a greater variety of morphologic change (Table) than any other organ in this disorder. The characteristic constellation of lens and other anterior segment changes includes incomplete or virtually no differentiation of the anterior chamber angle, a small, deformed cataractous lens with marked capsular changes, and anterior displacement of the ciliary body and at times of the retina.
The most striking ocular finding in Lowe syndrome is a bizarre type of cataract characterized by reduced A-P and equatorial measurements and malformations ranging from a discoid configuration to a giant posterior lentiglobus.10 Some form of cataract is virtually always present, and though it may be predominantly nuclear or posterior polar initially it tends to become total. In addition to being markedly thinned or defective posteriorly, the capsule exhibits focal thickening and excrescences and prominent hyperplasia of the associated epithelium. In relation to capsular defects there may be a mild inflammatory reaction and an intermixing of proliferated aberrant lens cells with condensed fibrils of the anterior vitreous which may include a hyaloid artery remnant. The causal relationship between capsular defects, adjacent cellular reaction and vitreous alterations is debatable. A leakage of lens material through a defective capsule could initiate an inflammatory reaction or enhance an already existing one. Dystrophic calcification of nuclear-cortical material is more prominent than in other forms of congenital cataract.
FIGURE 8: Left eye. Pre-retinal membrane (large arrow) partly obscures cupped optic disk. Note thickened blood vessels (small arrows) gross photograph X 7).
FIGURE 9: Left eye. A markedly thickened Descemet's membrane contains many cracks (small arrows) some of which contain inflammatory cells. Trabecular meshwork (large arrow) is extremely atrophic (hematoxylin and eosin X 200).
OCULAR PATHOLOGIC FINDINGS IN LOWE SYNDROME
Electron microscopic studies of the lens have not been carried out in a typical case of Lowe syndrome. In a presumed case involving a 24-week fetus, there was marked swelling of the mitochondria, endoplasmic reticulum and lens fibers.11
Glaucoma, with or without buphthalmos, occurs in about 60% of individuals with Lowe syndrome and is usually congenital. It is ascribed to an anomalous development of the anterior chamber angle, although a clinically normal angle with congential glaucoma has been noted in Lowe syndrome. '" Pathologically, the angle resembles that usually encountered in other primary infantile glaucomas including those associated with other syndromes such as Sturge-Weber and rubella embryopathy. In our patient, however, there seemed to be more involvement of the trabecular meshwork than in other cases of Lowe syndrome. The hypoplastic trabecular sheets were vascularized, studded with inflammatory cells and pigmentary debris and exhibited iris adhesions. These findings may represent secondary changes which further compromised an already defective angle. The scleral spur and Schlemm's canal are usually ill-defined or unidentifiable as in our patient.
Iridociliary anomalies comprise a variety of hypoplasias, hyperplasias and abnormal attachments. The ciliary processes in our patient attached abnormally to the trabecular meshwork. An absolute or relative hypertrophy of the iris sphincter may be the basis for the characteristically small pupil that reacts weakly to mydriatics.
Corneal opacities, present in at least 50% of cases of Lowe syndrome, are probably related mainly to congenital and chronic glaucoma. The alterations of the peripheral stroma and Descemet's membrane, as seen here, may reflect a dystrophy which is occasionally suspected clinically in the OCR syndrome. Breaks in Bowman's membrane with superficial vascularized scarring probably represent a healed trophic ulcer similar to that seen in another patient with Lowe syndrome.7
Documented retinal alterations in Lowe syndrome involved mainly the peripheral portion and included hamartoma and anterior displacement or heterotopia on the pars plana.7 The most striking retinal changes in our patient were the exuberant gliosis and marked collagenous thickening of vessels. Their pathogenesis is unknown. Sloughing or breaks of the RPE may be a primary developmental defect or secondary to other retinal alterations. The parapapilliary membrane appeared to be of retinal glial origin.
The ocular alterations in Lowe syndrome essentially comprise a mesoectodermal dysgenesis with superimposed secondary changes related mainly to chronic glaucoma and to iritis induced by leakage of lens material through a thin or dehiscent capsule. The chronic nephropathy and associated serum abnormalities may well contribute to ocular structural and functional changes. Considerably more pathologic study is required to separate the obviously congenital ocular lesions from those induced secondarily. At the present time the most characteristic ocular changes in the OCR syndrome seem to involve the lenticular basement membrane (capsule). Lowe syndrome may be the only known disease in which an anterior and posterior segment dysgenesis includes both a prominent thickening and thinning (or dehiscence) of lens capsule.
The embryologie timing of ocular lesions in Lowe syndrome is debatable. An unknown chemical or genetic defect is already operational by the 7-9 mm stage (horizon XV) when the capsule and early fibers of the lens are forming. Damage to the developing ocular structures through the 13-17 mm stage (horizon XVIII) could explain virtually all of the known anomalies in Lowe syndrome even those involving the anterior uvea, trabecular meshwork and Schlemm's canal which differentiate at the 55-65 mm stage. Some of the alterations in the anterior segment may be secondary to major defects in adjacent structures. As an example, a stunted growth of the lens could result in excessive zonular tension and anterior displacement of the retina and ciliary body preventing normal differentiation of the anterior chamber angle.
The extraocular findings in our patient were consistent with those usually found in Lowe syndrome. In the kidney diffuse tubular alterations with cystic dilation and eosinophilic casts, and fibrotic glomeruli have been most common. In our patient the nephrons were structurally intact; nephrocalcinosis was the principal morphological abnormality.
The pathogenesis of Lowe syndrome is the least understood of all the proximal renal tubular syndromes associated with systemic disease. The basic biochemical defect is unknown although it seems likely that at least some of the symptoms may be secondary to accumulation of polyamines, a class of compounds that includes cytotoxic byproducts of faulty dibasic amino acid metabolism." The minor histological changes in the kidney, brain and skeletal muscle of our patient and in many reported patients with this syndrome do not reflect the degree of associated dysfunction. Moreover, the cataracts and glaucoma were established during gestation at a time when fetal renal function is inconsequential compared to normal maternal homeostasis. Therefore a biochemical defect is likely to exhibit a tissue distribution that encompasses all involved organs, rather than being limited to the kidney.
The brain undergoes enormous growth during the 1114 mm stage (horizon XVII), the period during which some of the earliest ocular changes appear to have been established, thus providing the opportunity for simultaneous disturbance of growth in both organs. Yet, if an injury to the developing brain occurred at this early stage, one might expect major structural anomalies, rather than normal head size at birth and mild cerebral atrophy at death. In fact histological study of the brain in patients with the OCR syndrome has not resulted in definition of a lesion comparable to the ocular lesion in specificity or complexity. It remains to be determined if there is a deficit of neurons or a qualitative defect in brain organization in Lowe syndrome.
Although generally thought to be transmitted as an Xlinked recessive disorder, a disease resembling or indistinguishable from classical Lowe syndrome has been reported in girls.10,14-16 The OCR syndrome could theoretically occur in homozygous females but this is unlikely since male patients do not, as a rule, reach reproductive age.17 A specific diagnostic test to identify carriers is lacking although some features of the syndrome (cataracts, aminoaciduria after ornithine loading) have been described in a few mothers.18
The prominent findings in the eye and kidney in the OCR syndrome reflect the increasing recognition of an association between ocular and renal anomalies. Specifically, keratopathy and cataracts are common features of other aminoacidurias including Wilson's disease, galactosemia, tryosinemia and Fanconi's syndrome.
We studied the eyes of a 13-year-old boy with Lowe syndrome and updated the microscopic ocular findings. These are interpreted as a mesoectodermal dysgenesis involving the anterior and posterior segment. The eye exhibits a greater variety of morphologic change than any other organ in Lowe syndrome. The microscopic findings, particulary in the lens, are highly suggestive of this disorder.
The pathogenesis of the ocular and extraocular lesions in Lowe syndrome is unknown. Most of the ocular abnormalities are probably determined in the first two months of gestation and there is no apparent embryologie relation to extraocular abnormalities. Some manifestations of Lowe syndrome may be secondary to accumulation of polyamines, a class of compounds that includes cytotoxic byproducts of faulty dibasic amino acid metabolism.
We are indebted to Drs. A. James McAdams and Josef Warkany for review of manuscript. Amy Kay Kinkier, Tina Link, Maureen McCarthy, Dan McMullen and Philanthy K. Bruning provided photographic and other technical assistance.
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OCULAR PATHOLOGIC FINDINGS IN LOWE SYNDROME