Lowe Syndrome (Oculocerebrorenal Syndrome)

Updated: Mar 21, 2017
Author: Deborah M Alcorn, MD; Chief Editor: Andrew G Lee, MD 



Lowe syndrome, also called oculocerebrorenal syndrome (OCRS) and oculocerebrorenal syndrome of Lowe (OCRL), is an X-linked recessive metabolic disorder described by Lowe and coworkers in 1952.[1] It is a multisystem disorder that primarily affects the eyes, nervous system, and kidneys. It is characterized by congenital cataracts, infantile glaucoma, neonatal or infantile hypotonia, intellectual impairment, and renal tubular dysfunction (Fanconi syndrome).

Oculocerebrorenal syndrome is so named because of the prominent involvement of the 3 major organ systems; however, involvement of bone, gonads, muscle, skin, and connective tissue, as well as stereotypic behavior, also can occur. Additional manifestations include corneal keloids, growth retardation, areflexia, metabolic acidosis, proteinuria, aminoaciduria, and noninflammatory arthropathy. These patients often exhibit the characteristic facial appearance of frontal bossing, deep set eyes, and full cheeks, although the characteristic phenotype is often difficult to identify in neonates.

Female carriers manifest characteristic lens opacities, but they typically have normal renal and neurologic function. See the image below.

Classic lenticular opacities in a female carrier f Classic lenticular opacities in a female carrier for Lowe syndrome. Note the punctate cortical opacities in radical wedges. Image courtesy of Otis Paul, MD.


Lowe syndrome is caused by a mutation of the OCRL1 gene mapped to the chromosomal locus of Xq26.1.[2] The gene encodes a phosphatidylinositol (4,5) bisphosphate 5 phosphatase, localized to the trans-Golgi complex involved in actin polymerization.[2, 3] It is a key enzyme in the cellular phosphoinositide pathway, important in cellular trafficking. Deficiency of the enzyme causes the protean manifestations of Lowe syndrome. The reduced enzyme activity results in increased enzyme substrate and abnormal actin-binding proteins important in neuronal morphogenesis.[4, 5] Fibroblast activity was found to be decreased by 80%-90% in patients with Lowe syndrome compared to healthy controls.[6]




The estimated prevalence of Lowe syndrome is 1 per 500,000 population. The Lowe Syndrome Association (LSA) reported 190 males living with Lowe syndrome in 2000.[7] As of 2005, the Italian Association of Lowe’s Syndrome reported 34 individuals with Lowe syndrome living in Italy.[6] No cases of Lowe syndrome have been reported in Africa, South America, and parts of Asia.[6, 7]


Ocular: The hallmark feature is congenital cataracts. Left untreated, the cataracts will cause nystagmus and eventual blindness. Glaucoma develops in 50-70% of patients, typically manifesting in the first year of life, but it may present at any age.[8] Patients also may develop corneal leukomas. Amblyopia may occur secondary to poor compliance with treatment and secondary strabismus. Corrected visual acuity is infrequently better than 20/70 despite optimal management. The visual impairment represents a combination of the morphologic changes in the eye, retinal dysfunction, and cortical functioning.

Renal: If untreated, the proximal renal tubular acidosis leads to failure to thrive and metabolic collapse. By the second to third decade, gradual loss of creatinine clearance occurs, with progressive renal failure.

Growth: At birth, these patients are within the normal growth curve but fall off in length, height, and weight in subsequent years.

Neurological: Neonatal hypotonia may contribute to poor feeding and delayed motor development.

Life expectancy: Patients with appropriate therapy may live to be 30-40 years of age, generally dying from renal failure, respiratory distress, status epilepticus, or infection. With improved medical treatment, infection as a cause for death has declined dramatically. The expected life span has not yet been defined.


Lowe syndrome occurs almost exclusively in males. It is an X-linked recessive disorder. The female carrier state is identifiable by characteristic lenticular opacities.

A few cases have been reported in females, often having X-autosome translocations involving the OCRL1 locus, explained by the inactivation of the normal X chromosome by the translocation.[2]


Lowe syndrome is congenital.


Currently, there is no correlation between the genotype and phenotypes, so clinical severity of disease cannot be correlated with certain variants. However, affected males within the same family have similar phenotypes, as intrafamilial variability has not yet been reported.[6]

There is complete penetrance.[7]

The oldest reported patient to live with Lowe syndrome died at age 54 years.[2]




Family history - Family members with congenital cataracts, nystagmus, infantile glaucoma, developmental delay, neurological problems, seizures, or Lowe syndrome. Attempt to identify any potentially affected male relatives through the maternal side.

Pregnancy - Complications, consanguinity, birth weight, and Apgar scores

Medical, as follows:

  • Failure to thrive; recurrent infections
  • Aminoaciduria, phosphaturia, proteinuria, or acidosis
  • Ocular concerns (eg, nystagmus, leukocoria, abnormal globe size, corneal haze, epiphora)
  • Renal problems
  • Neurologic problems; particularly, any hypotonia, areflexia, seizures, neuroimaging abnormalities, or behavioral abnormalities
  • Joint hypermobility, joint contractures, recurrent fractures, tenosynovitis, arthropathy, joint swelling, or genu valgum

Surgery - Previous ocular surgery, cataract extraction, or glaucoma procedure

Developmental - Delay in milestones, particularly motor milestones



Congenital cataracts are the hallmark of Lowe syndrome, also called oculocerebrorenal syndrome (OCRS) and oculocerebrorenal syndrome of Lowe (OCRL). The abnormal lens development begins early (8 weeks' gestation) because of a disrupted migration of the embryonic lens epithelium and not as a result of a systemic metabolic imbalance. Lens abnormalities have been described in 20- to 24-week fetuses by the presence of necrosis and the disorganization of embryonic lens epithelium.

Bilateral leukocoria is evident at birth, often with miosis, shallow chamber, and microphthalmos. These clinically characteristic cataractous lenses are small and discoid. Histopathologically, they show an absence of demarcation between the nucleus and the cortex, indicating a retarded maturation. The anterior capsule may be thickened irregularly, often with anterior subcapsular plaques. The posterior capsule is irregular, with warty excrescences, indicating abnormal function of the posterior lens epithelium.

Glaucoma usually is not present at birth, but it is detected within the first year of life, associated with buphthalmos. Glaucoma develops in 50-70% of patients with Lowe syndrome, usually by age 6 years. It is generally bilateral and is usually the result of a primary developmental filtration angle anomaly rather than secondary to cataract extraction.

The pupils of patients with Lowe syndrome are typically miotic secondary to a hypoplastic dilator muscle.

Nystagmus is usually not noted at birth, but rather it develops shortly thereafter as a sensory nystagmus from poor visual development.

Corneal keloids may develop in up to 25% of patients, usually after age 5 years. They extend through the entire thickness of the cornea. They are progressive and may become visually significant.


A cardinal feature of this disease is infantile hypotonia with a delay in motor milestones. The children may have feeding difficulties. After age 1 year, deep tendon reflexes are absent.

Up to 50% of patients have seizures, but no characteristic seizure type is evident. Infantile spasms, myoclonic seizures, partial complex seizures, and generalized convulsions have been reported. Up to 9% of patients have febrile convulsions.[6] Seizures usually are present by age 6 years.

A poor prognosis exists for intellectual development with early-onset seizures and inadequately controlled seizures. The diagnosis of Lowe syndrome is compatible with normal intelligence. Approximately 10-25% of patients have an intelligence quotient (IQ) in the reference range, although mental deficiency is common. Intelligence appears to be stable over their lifetime, excluding decline due to interceding illness or progressive renal disease.

A high incidence (>80%) of behavioral abnormalities, including tantrums; aggressive and self-injurious behavior; irritability; and repetitive, nonpurposeful movements, occurs.


Abnormal renal function is part of the clinical triad and a cardinal feature of the disease. In Lowe syndrome, impairment of both tubular and glomerular function occurs.[9]

Renal function and histology are apparently normal in utero. Renal function may be normal at birth. Proximal tubular dysfunction usually begins at age 3-12 months. Aminoaciduria, proteinuria, phosphaturia, metabolic acidosis, and impaired urine concentrating ability develop subsequently. The severity and the age of onset of the renal tubular dysfunction may be quite variable.

Proteinuria is seen frequently but with variability of age of onset and amount of urinary protein loss. Acidosis is present and of the proximal renal tubular type. This condition may lead to failure to thrive and recurrent infections.

The renal dysfunction may lead to calcium and phosphorus loss, resulting in bone resorption. Bone resorption from long-term loss of phosphorous may lead to rickets and osteomalacia. Nephrocalcinosis and nephrolithiasis may result from hyperphosphaturia and hypercalciuria. Generally, tubular phosphate wasting worsens progressively with age.

In addition to the renal tubular dysfunction, by the second to third decade, impairment of glomerular filtration and gradual loss of creatinine clearance with progressive renal failure occurs.


Patients may exhibit noninflammatory arthropathy, joint swelling, and contractures. Scoliosis is frequently seen. Muscle hypotonic is a contributing factor in the development of contractures and osteopenia.[6]

One half of patients older than 20 years have diffuse swellings of both small and large joints, focal nodules of fingers, and/or bilateral plantar masses, occasionally requiring resection. These manifestations may result from excessive growth of fibroblasts.

Sexual development

The onset of puberty is generally at the appropriate age, but fertility may be reduced secondary to peritubular fibrosis and azoospermia.

Up to 40% of patients may have unilateral or bilateral cryptorchidism.

Other systems

Decreased dentin formation secondary to kidney disease may lead to periodontal disease due to bone loss involving underdevelopment of the maxilla and mandible, constricted dental arches, delayed tooth eruptions, and associated eruption cysts.[6, 7]

Skin manifestations include eruptive hair vellus hair cysts, tricoepithelioma, and excess skin folds.[10, 11, 12]

Impaired hemostasis has been reported in patients with Lowe syndrome. PT, PTT, fibrinogen levels, and Von Willebrand factor were all normal, suggesting impairment of early stages of platelet activation. Twenty percent have mild thrombocytopenia.[2, 6, 7]

Carrier state

Slit lamp examination of the lenses of female carriers of Lowe syndrome is very specific. These carriers manifest multiple (15 to >100) punctate gray-white cortical opacities observed by slit lamp evaluation. They usually are wedge-shaped aggregates located outside the nucleus in anterior cortical wedges. They are seen in increasing numbers with increasing age. The numbers of punctate cortical lenticular opacities are less relevant than their shape and distribution. These lenticular opacities usually have no visual impact.

They also may exhibit subcapsular cataracts, which increase in size and density with age.

The female carriers are otherwise asymptomatic and classically have normal renal and neurologic function.

DNA diagnosis is the most accurate method to identify carriers of Lowe syndrome when the mutation in the family is known.



Lowe syndrome has been mapped to chromosome locus Xq26.1.[2]

The OCRS1 gene has been cloned and encodes the protein product of the OCRS1 gene, a phosphatidylinositol (4,5) bisphosphate 5-phosphatase that is deficient in patients with Lowe syndrome.[2, 13, 14]

To date, more than 70 different mutations have been identified, with most of them being private mutations restricted to one family. A common mutation in the OCRS gene has not been identified among patients with Lowe syndrome.

De novo mutations have been identified in 30% of affected males, and 4.5% of reported cases result from somatic or germline mutations.[2, 6, 7]

The disease typically affects male because of its recessive X-linked inheritance pattern; however, rare cases in females have been reported. In 2005, a female with a normal karyotype but a single 8 base pair mutation with lyonization was reported to have Lowe syndrome.[2, 6, 7]  



Diagnostic Considerations

The differential diagnoses of Lowe syndrome include the following:

  • Dent disease type 2
  • Congenital infections (rubella)
  • Nance-Horan syndrome
  • Smith-Lemli-Opitz syndrome
  • Cystinosis
  • Zellweger spectrum disorders including Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease
  • Myotonic dystrophy type 1
  • Muscle-eye-brain disease (MEB)
  • Mitochondrial disorders
  • Wilson disease
  • Mucopolysaccharidosis 


Laboratory Studies

Laboratory findings associated with Lowe syndrome, also called oculocerebrorenal syndrome (OCRS) and oculocerebrorenal syndrome of Lowe (OCRL), are listed below.

Serum, as follows:

  • Elevated serum enzyme levels
  • Enzyme test (phosphatidylinositol-4,5-bisphosphate phosphatase; >99% sensitivity) in males who are affected
  • Mild elevations of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK)
  • Increased serum glutamic-oxaloacetic transaminase (SGOT) and lactate dehydrogenase (LDH)
  • Serum protein electrophoresis shows a markedly elevated alpha-2-band, and total serum protein concentration is elevated frequently in patients older than 4 years.
  • Acid phosphatase is elevated in most patients.
  • Increased alkaline phosphatase levels
  • Increased creatinine levels
  • Hypokalemia
  • Decreased plasma carnitine levels [7, 15]

Urinalysis, as follows:

  • Check for reducing substances
  • Low urine osmolality and elevated 24-hour volumes
  • Proteinuria
  • Aminoaciduria
  • Hyperphosphaturia, frequently present, but may be variable
  • Calciuria
  • Check urine ph
  • Check L-carnitine (may be lost in urine)

Blood gas - Metabolic acidosis secondary to urinary loss of bicarbonate

Imaging Studies

Ocular ultrasound: B-scan is indicated if posterior pole cannot be visualized secondary to the cataract.

Ultrasound biomicroscopy of the anterior segment and anterior segment optical coherence tomography (AS-OCT) are helpful in determining the mechanism of glaucoma.[16, 17]

Cranial MRI: Mild ventriculomegaly is evident in about one third of patients. Additionally, in a periventricular and centrum semiovale distribution, increased signal intensity may occur on T2-weighted scans. These areas correspond to cysts of variable size and number and are yet of no known clinical significance.

Proton magnetic resonance spectroscopy exhibits findings consistent with gliosis, such as a prominent myoinositol peak. However, whether the increased signal is due to gliosis or buildup of phosphatidylinositol (4,5) biphosphate cannot be determined.[7, 18, 16, 19]

Other Tests

Ocular evaluation to assess possible carrier status: Slit lamp examination of the biological mother's lenses or females at risk to assess if any lenticular opacities

DNA testing: DNA carrier testing for familial mutation (requires prior identification of unique mutation of OCRL1 gene in that family); ​OCRL1 gene mutation analysis (approximately 90% sensitivity for males who are affected)

Histologic Findings

Renal histology usually is normal in utero and in neonates. However, within the first few months of life, these infants may show tubular abnormalities with dilation, atrophy, and accumulation of proteinaceous material in the tubular lumens. Young infants usually have normal glomeruli, but, after a few years, they may manifest glomerular lesions with sclerosis, focal fibrosis, and thickening of basement membranes.



Medical Care


Patients with Lowe syndrome, also called oculocerebrorenal syndrome (OCRS) and oculocerebrorenal syndrome of Lowe (OCRL), must be monitored for glaucoma. If glaucoma develops, intraocular pressure–lowering agents must be used. Often, these patients require surgical intervention with goniotomy, trabeculotomy, or a drainage filtration device.

Management of the corneal keloids can be very challenging. Unfortunately, no single treatment modality has been found to be uniformly successful. Lubricants, topical steroids, cyclosporine, and antimetabolites have been tried and must be individualized for the patient. Lamellar keratectomy or corneal transplant may be challenging because of the intensive postoperative care required.

Visual development must be monitored, and amblyopia must be treated if detected. Refractions need to be updated as needed. Strabismus may develop, and surgical correction may be required.


Periodic monitoring for renal complications should begin at diagnosis and continue every 3-4 months until age 2 or 3 years. Appropriate treatment for renal tubular wasting should be undertaken. Alkalizing therapy to counter renal bicarbonate losses must be used. Phosphorus supplementation is indicated if bone resorption occurs. If plasma carnitine levels are low, oral supplementation may be required.


Seizures are treated according to type and precipitating factors. Clomipramine, paroxetine, and risperidone appear to show the most promise.


Tranexamic acid has been documented to successfully treat platelet dysfunction.[6]

Surgical Care


It is imperative to surgically remove the congenital cataracts as soon as possible, ideally in the first 6 weeks of life, to optimize the visual potential. Mechanized vitrector instrumentation is essential. Complete removal of all lens material in conjunction with a primary posterior capsulotomy and an anterior vitrectomy will reduce the chances of a secondary membrane formation. Aphakic correction (eg, contact lenses, intraocular lenses, spectacles) must be initiated immediately following the surgery.

The patient must be monitored closely for possible glaucoma and treated appropriately. Generally, glaucoma in these children is controlled poorly by topical medications and requires surgery. Prior cataract surgery may superimpose a secondary aphakic component that may require glaucoma surgery other than goniotomy.


The ophthalmologist must work in conjunction with the patient's primary care doctor, as well as a pediatric nephrologist, neurologist, and geneticist.


Fluids to replace urinary water losses (if evidence of impaired water-concentrating ability)

Phosphate supplementation

The efficacy of L-carnitine replacement is being studied.

Vitamin D as indicated

The efficacy of a low-protein diet continues to be debated.


Speech, occupational, and/or physical therapy, as indicated by development

Behavioral modification as needed, especially for maladaptive behaviors



Further Outpatient Care

Patients with Lowe syndrome, also called oculocerebrorenal syndrome (OCRS) and oculocerebrorenal syndrome of Lowe (OCRL) should receive follow-up care as needed, such as the following:

  • Ophthalmology: Monitor vision, alignment, IOP, possible glaucoma, optic disc, and refraction. Amblyopia should be vigilantly watched for and treated accordingly.
  • Renal: Monitor renal status. If disease is untreated, progressive renal failure may ensue.
  • Orthopedic: Monitor and treat for joint swelling, arthritis, and tenosynovitis. Fractures are common. Rickets, osteopenia, and osteomalacia may occur.
  • Neurology: Monitor for development, seizures, hypotonia.
  • Physical therapy (motor development)
  • Speech therapy
  • Behavior modification, as needed
  • Genetic counseling

Inpatient & Outpatient Medications

See the list below:

  • Renal loss replacement (essential)

  • Anticonvulsants, if necessary


Prenatal testing, as follows:

  • Chorionic villus sampling or amniocentesis

  • Prenatal enzyme test for male fetuses (>99% sensitivity)

  • DNA - Using linked markers in a family or direct detection of mutant alleles


Ocular, as follows:

  • Blindness, if congenital cataracts are left untreated or if glaucoma (either primary or secondary) is uncontrolled

  • Nystagmus

  • Amblyopia

  • Strabismus

Renal: By the second or third decade, if disease is untreated, progressive renal failure may occur.

Neurologic, as follows:

  • Mental deficiency

  • Seizures

  • Delayed motor development

Orthopedics, as follows:

  • Fractures

  • Joint swelling

  • Tenosynovitis

  • Rickets

  • Osteomalacia

  • Osteopenia


Most patients with Lowe syndrome succumb to renal failure by the third decade of life; however, a patient's life expectancy has been extended with improved medical intervention. The exact expected lifespan with available aggressive medical treatment has not been delineated.

Patient Education

Resources for Lowe syndrome are listed below.

  • Lowe Syndrome Association 18919 Voss Road Dallas, TX 75287 Phone: (972) 733-1338 Internet: http://www.lowesyndrome.org

  • March of Dimes Birth Defects Foundation 1275 Mamaroneck Avenue White Plains, New York 10605 Phone: (914) 997-4488 Internet: http://www.marchofdimes.com

  • NIH/National Human Genome Research Institute Building 31, Room 4B09 31 Center Drive, MSC 2152 9000 Rockville Pike Bethesda, MD 20892 Phone: (301) 402-0911 Internet: http://www.genome.gov

  • The Arc (National Organization on Mental Retardation) 1660 L Street, NW, Suite 301 Washington, DC 20036 Phone: (202) 534-3700 Internet: http://thearc.org/

  • National Organization for Rare Diseases 55 Kenosia Avenue Box 1968 Danbury, CT 06813 Phone: (203) 744-0100 Internet: http://www.rarediseases.org