The oculocerebrorenal syndrome is so-named because of the prominent involvement in this disorder of three organ systems: the eye, the central nervous system, and the kidney. However, connective tissue, bone, gonads, muscle, and skin may be involved with what are characteristic and, in some cases, unique clinical features.
The hallmark of this condition is the presence of congenital cataracts, which develop prenatally and are always present prior to birth. Abnormal lens formation in OCRL begins at 7 to 9 weeks’ gestation and is due to disordered migration of the embryonic lens epithelium11 as a primary defect rather than a secondary effect of systemic metabolic imbalance. Pathologic changes in the ocular lens have been described in 20- and 24-week fetuses. In the 20-week fetus, lens size was normal but there was abnormal concavity of the anterior portion of the lens and necrosis of the embryonic lens nucleus with disorganized architecture and swelling of the residual lens cells12 (Fig. 252-1). In the other fetus studied, a cone-shaped opacity at the posterior pole caused loss of light transmission and additional aberrant developmental changes included disorganized nests of epithelial cells directly beneath the anterior lens capsule and swelling of the anterior lens fibers.13 Histologically, the posterior lens capsule was incomplete, with protrusion of lens material and a cellular reaction surrounding the protruding material. It is not known if this histologic appearance results from abnormal formation of the lens capsule with secondary protrusion of material or if it is due to primary dysmigration. No glaucomatous changes were found, and the globes and anterior chambers were otherwise unremarkable in both fetuses.
A. Sagittal section through anterior portion of the eye including cornea, anterior chamber, lens, and ciliary bodies of a 20-week OCRL fetus (×24). B. Higher magnification of lens (×40). Note abnormal anterior concave shape with central fluid-filled space and necrotic cells in the fetal lens nucleus location. Remaining lens cells above and below the fetal nucleus are large, frequently swollen, and disorganized, without a regular parallel distribution. (Courtesy of M.M. Padilla, MD.)
Later in development there is continued protrusion of the posterior polar material through the posterior lens capsule, producing poor demarcation between the lens nucleus and cortex, marked thinning of the lens, and adherence of the vitreous to the posterior pole.11,14,15 Calcification is frequent, with calcific excrescences of both anterior and posterior capsule, and hyperplasia of capsular epithelium. Microphthalmia and enophthalmos secondary to the lens abnormality are often also present.
Glaucoma, either with or without buphthalmos, is quite frequent, occurring in 50 to 60 percent of patients in some series. It is usually bilateral and is a characteristic feature of the disorder rather than a reflection of the surgical technique used for cataract extraction. (16-17). Glaucoma is typically detected in the first year of life, but may appear as late as the second or third decade.
Impaired visual acuity is almost universally present. Corrected visual acuity is rarely better than 20/100 despite optimal management, and the impairment represents both the morphologic changes in the eye caused by congenital cataract and a primary retinal dysfunction caused by the underlying disorder. Nystagmus develops postnatally secondary to the poor visual acuity and is virtually always present in older OCRL patients.
Corneal scarring and keloids are additional features of OCRL that probably develop spontaneously without trauma18 (Fig. 252-2). Keloids may develop in up to 25 percent of OCRL patients, usually after age 5, and are bilateral in about half of affected patients.17 Keloids are often stable and do not interfere with central vision, but they may cause significant visual impairment.
Corneal keloid of the right eye in a 14-year-old boy without known eye-poking behavior or use of contact lenses. The keloid has its densest portion at the limbus and extends centrally to partially obscure central vision in this eye.
Nervous System Abnormalities
Both the central and the peripheral nervous system are involved in OCRL, causing the greatest disease burden of the illness. A prominent feature is cognitive impairment, but neonatal hypotonia with delay in motor milestones is the initial neurologic manifestation and a cardinal feature of the disorder. In addition, areflexia, seizures, neuropathologic and neuroimaging abnormalities, and behavioral disturbances may also be present.
Mental retardation, though common, is not a cardinal feature because the diagnosis of OCRL is compatible with normal intelligence.19 A more accurate description of the cognitive outcome is intellectual impairment; that is, functioning below what would be an individual's predicted intellectual level in the absence of OCRL. Approximately 10 percent of OCRL patients have intelligence within the normal range, typically borderline or low normal. The median IQ is in the moderately retarded range, and one-third of affected individuals appear to be profoundly retarded. These estimates for intelligence suffer from the use of testing techniques that inappropriately penalize OCRL patients for their visual impairment and for behavioral disturbances that may impair accurate testing.19 Socioeconomic status, maternal intelligence, MRI findings, and even the specific mutation causing the disorder appear to have little predictive value for intellectual outcome.20-22 Intelligence appears to be stable over the life span of the individual, and deterioration in cognitive performance, occasionally reported in OCRL,23 most likely represents decline due to progressive renal disease or another intercurrent illness.
Behavioral disturbances may be the most troublesome feature for caregivers. Studies confirmed a high incidence of stereotypic behavioral disturbances including self-injury, episodic outbursts (Lowe tantrum), aggression, irritability, and repetitive nonpurposeful movements that interfered with function.19,24,25 A specific behavioral phenotype for OCRL consisting of stubbornness, temper tantrums, rigidity of thought, and unacceptable stereotypic behavior emerged when age, gender, visual impairment, and cognitive function were controlled for.25 This behavioral phenotype is reminiscent of the obsessive-compulsive disorder spectrum and warrants further study.
Neonatal or infantile hypotonia are cardinal manifestations of OCRL and may persist into childhood. A neuromuscular cause of hypotonia is suggested by the mildly elevated creatine kinase values and areflexia, but the improvement with age and the absence of reproducible and significant nerve or muscle pathology in most patients is more consistent with a central nervous system origin. Other than the deep tendon reflex, nerve conduction and motor amplitudes are normal. These data do not support the presence of a progressive peripheral neuropathy in OCRL.
Central Nervous System Abnormalities.
Seizures occur in up to 50 percent of patients with OCRL.10 There is no characteristic seizure type, and infantile spasms with hypsarrhythmia, myoclonic seizures, partial complex seizures, and generalized convulsions have all been reported or observed in the series of OCRL patients studied at the NIH. “Febrile” seizures appear to occur at a higher frequency than in the general population (9 percent versus 1 percent), and approximately one-third of these patients will progress to a true seizure disorder. Most seizures occur before age 6, although some patients have developed seizures as late as age 19. Severe, early onset seizure disorders carry a poor prognosis for intellectual development and seizure control, as they do in the general population.
Neuropathology and Neuroimaging.
Cranial MRI demonstrates mild ventriculomegaly in approximately one-third of patients, as well as areas of increased signal intensity on T2-weighted scans (which are particularly sensitive for water) in a periventricular and centrum semiovale distribution, without involvement of other myelinated areas (corpus callosum, cortical U-fibers, brainstem, or cerebellum).24,26 These areas correspond to cysts of variable size and number27,28 (Fig. 252-3). The signal is undetectable until cerebral myelination is well advanced, but it is uncertain whether cysts are present at birth and not detectable or whether they develop as myelination proceeds. Cysts appear to be stable in size and location over a several-year observation period, and their size, location, and number have no clinical significance.
Multiple periventricular cysts and ventriculomegaly in an 18-year-old boy with OCRL, more prominent in the left hemisphere in this section.
Results of neuropathologic examination of the brain in OCRL were normal in some reports, while in others, a number of different abnormalities were found. These abnormalities include diffuse or focal myelin pallor without myelin breakdown; ventriculomegaly; mild cerebral abnormalities; isolated cases of subependymal cysts; mesencephalic proencephaly; postencephalitic changes; blunted and foreshortened frontal lobes; acute pontine necrosis; cerebellar hypoplasia; and aberrant neuronal migration.10,23,27,29,30 Multiple tiny cysts without inflammatory changes were found in the cerebral white matter of one patient with typical evidence of such cysts on MRI (Wendy Shertz, MD, personal communication).
Abnormal kidney function is part of the clinical triad on which the diagnosis of OCRL is based.31,32 Renal function and histology are apparently normal in utero, although the observation that amniotic fluid and maternal serum α-fetoprotein levels are elevated in some affected pregnancies with a male fetus suggests that there may be a defect in the fetal kidney with resulting leakage of serum protein.33 The most striking renal abnormality is found postnatally, with the onset of proximal tubular acidosis, aminoaciduria, phosphaturia, and proteinuria.31,34 The renal tubular dysfunction, in contrast to the cataracts, is not always present at birth and may require a few weeks to months to become apparent. Renal tubular dysfunction is quite variable in severity and clinical significance and may not require medical intervention, but is usually stable in older patients once established.
Acidosis is clearly of the proximal renal tubular type with bicarbonate wasting4,5,31 and leads to the failure to thrive, recurrent infections, and metabolic collapse seen in early case reports when the disease was poorly recognized and untreated. Water resorption is also defective, as reflected in elevated 24-h volumes and low urine osmolality.31 Clinically significant hypokalemia or hypocalcemia requiring replacement therapy occurs in a minority of patients and may be part of a preterminal exacerbation of tubular dysfunction.
The aminoaciduria is generalized, with greater elevations of basic amino acids and cysteine and relative sparing of branched-chain residues, but the profile is variable, with the degree of aminoaciduria (amino acid index) ranging from just above the upper limit of normal to 15 times the upper limit of normal.4,31 In OCRL, as in other forms of the renal Fanconi syndrome, the pattern of aminoaciduria is not diagnostic of any particular etiology of the renal tubular dysfunction.35
Proteinuria is very frequently seen, but the amount of urinary protein loss and age of onset are both highly variable. Proteinuria is usually present in infancy but can occur first later in childhood. When present, protein losses can be substantial (1.38 to 10.77 g/m2 /day; normal <0.1 g/m2 /day) and are composed of roughly equal proportions of tubular proteinuria (molecular mass <40 kDa) and albuminuria, with little to no protein of higher molecular weight. Glycosuria is generally not a feature of the renal tubular dysfunction seen in OCRL.
Hyperphosphaturia is also frequent but variable, and may lead to osteomalacia, renal rickets, and pathologic fractures if untreated. It probably does not contribute significantly to the short stature seen in the syndrome.31 In approximately half of patients, fractional excretions of phosphate are elevated despite low-normal serum phosphate levels, and there appears to be a progressive worsening of tubular phosphate wasting with age. Severe hypophosphatemia has been detected preterminally in several patients and may have contributed to their demise. Nephrolithiasis and nephrocalcinosis may occur in OCRL either because of hyperphosphaturia and hypercalciuria or as a complication of calcium and vitamin D therapy for rickets.36 The frequency with which these complications occur is unknown.
Progressive Renal Failure.
In addition to renal tubular dysfunction, gradual loss of creatine clearance reflecting progressive renal failure is a feature seen in OCRL patients in the second and third decades of life. The rate and extent of deterioration of renal function is, however, open to interpretation. In a series of 13 OCRL patients ranging in age from 10 to 31 years of age, there was a statistically significant linear correlation between the reciprocal of the serum creatinine concentration and age, similar to what is seen in many forms of chronic renal failure in children.37,38 However, with the small sample size, it remains possible that the rate of loss of renal function was actually biphasic, with more rapid loss in children under age 15 and relative stability of function after that. Thus, although gradual loss of glomerular filtration has been seen in OCRL, the average age of onset of renal insufficiency and its severity have not been clearly defined in a large enough population of patients.
Results of histologic examination by light microscopy are usually normal in very young infants, but dilatation, atrophy, loss of brush border, and accumulation of proteinaceous material in the tubule lumen appear in the first few months of life.4,5,34,39 These tubular abnormalities have been documented in a number of studies, including some in which serial biopsy specimens from the same patients were examined, and affect predominantly the proximal tubules; some involvement of Henle's loop, the distal tubules, and the conducting system is occasionally reported as well. Glomeruli are frequently normal in young children, even when proximal tubular lesions are present. After the first few years of life, however, glomerular lesions can be seen. These include thickening of basement membranes, focal fibrosis, and sclerosis. By electron microscopy, swelling of mitochondria in renal tubules was reported in a 22-month-old who showed no glomerular abnormalities.4 When the same child was biopsied 7 years later, distinctive glomerular changes, including podocyte fusion and basement membrane thickening, were apparent.34
While in most patients, renal tubular pathology precedes glomerular pathology, several patients have been reported with glomerular pathology and minimal or no evidence of renal tubular dysfunction. This indicates that in some patients, glomerular disease may coincide with or precede tubular abnormalities, rather than result from them (Gropman et al, 2000; Pueschel et al, 1992).32
Musculoskeletal complications of OCRL can occur either as complications of cardinal features of the illness—that is, hypotonia and renal disease—or as specific and possibly unique manifestations of the underlying disorder. Reported complications include joint hypermobility; recurrent fractures; genu valgum; joint contractures; scoliosis; kyphosis; platyspondylia; dislocated and/or subluxated hips; and cervical spine anomalies; as well as tenosynovitis and a nonspecific arthropathy.40-44 Hypotonia contributes to joint hypermobility, decreased movement fosters the development of contractures, and inadequately treated rickets can lead to genu valgum deformities. Coxa valga deformity and hip contractures were found in a 16-year-old, profoundly retarded male who lost the ability to walk at age 13 years, but the hips were neither subluxated nor dislocated.26 Joint laxity leading to varus deformity or hyperextension of the knee has also been seen. Osteopenia can be worsened by untreated renal phosphate wasting, but it is almost always present, with variable severity, despite adequate phosphate replacement, and it appears to be a specific manifestation of OCRL. Some of the patients studied in the NIH series had mildly increased cervical spine mobility without subluxation, and three had asymptomatic bone cysts,24 but platyspondylisis, hip dislocation or subluxation, and cervical spine anomalies are quite uncommon in most series.24 In contrast, scoliosis is widely reported in OCRL10,17,24,41 and may be progressive postpubertally, suggesting that it is a specific feature of OCRL.
Tenosynovitis, joint swelling, and arthritis or arthropathy appear to be frequent and striking primary complications of OCRL and probably represent the same underlying disorder of excessive growth of fibroblasts. This manifestation was initially reported as palmar and plantar fibrosis43 and later as thickened articular joint surfaces with nonspecific tenosynovitis, flexion contractures of the digits, and swelling of the interphalangeal and metacarpophalangeal joints;44 the first detailed investigation described four additional patients with similar joint manifestations and varying degrees of nontender swelling of multiple joints. In some cases, the periarticular areas and joints of the fingers and wrist were involved, with erosion of the carpal bones. Results of laboratory studies were normal. A synovial biopsy found rubbery tissue with loss of the normal glistening surface, sparse synovial lining cells, no inflammatory cell infiltrate, fibrous connective tissue containing mature collagen and thin fibrils, and large amounts of finely fibrillar material and a granular basement membrane-like substance around the small vessels.44 Similar diffuse swellings of the fingers, wrists, ankles, and feet without evidence of an inflammatory arthritis and similar joint changes are reported in 50 percent of OCRL patients over 20 years of age.17 The spectrum of joint involvement is quite broad, presenting as nontender joint swelling involving both small and large joints, focal nodules (Fig. 252-4) on the finger, or bilateral plantar masses (Fig. 252-5). On occasion, these masses become painful and require resection.24 It seems likely that these changes are the manifestation of abnormal, excessive growth of fibroblasts from periarticular tissue or tendons.
Hand of a 7-year-old boy showing nontender, diffuse swelling of the second and third proximal interphalangeal joints and a subcutaneous nodule on the second digit over the distal interphalangeal joint. There was no history of trauma to this area.
Bilateral plantar masses (arrows) in a 12-year-old boy. The masses are firm and are attached to underlying connective tissue, but they are nontender and do not interfere with ambulation.
The onset and progression of puberty occur at a normal age in OCRL patients, producing Tanner V genitalia and axillary and facial hair. Testosterone levels are normal. Sexual interest among older males varies, but there is a notable lack of a strong sexual drive in comparison with other similarly intellectually compromised adults. Fertility may also be reduced owing to the peritubular fibrosis and azoospermia associated with OCRL.23
Other Clinical Manifestations
Cryptorchidism is a common occurrence in OCRL, up to 40 percent in one report16 and 15 percent in a more comprehensive survey.17 Dental cysts during primary tooth eruption and enamel hypoplasia have been reported45 and, in older individuals, sebaceous cysts on the buttocks and perineum appear to occur frequently.17 Constipation of variable severity is frequent in OCRL and usually improves with age,17 although it may persist and cause a protuberant abdomen or diarrhea with stooling around a fecal impaction.
The mean length and weight are within the normal range at birth, typically above the 50th percentile, but fall from the normal curve with age. Mean height falls to the third percentile by 3 years of age, and continues to show a relative fall throughout adolescence. Mean final height is less than the third percentile, but OCRL patients continue to grow into early adulthood. Bone age lags slightly behind height age, and epiphyses fuse at adult height. Mean weight shows a similar profile, with a late plateau phase into the early twenties and a final weight less than the third percentile. Head circumference of OCRL patients is within the normal range, with a mean adult head circumference at the 50th percentile.31
OCRL patients have been reported to succumb to renal failure or infection in their second or third decade16 but infection as a cause of death has become infrequent with more aggressive medical intervention. Other causes of death include status epilepticus, refractory renal tubular wasting of electrolytes, respiratory compromise from scoliosis, and sudden, unexplained death. The oldest OCRL patient in the United States expired at age 41. The expected life span with current medical practice has not been defined.