Alex V. Levin
BASICS
DESCRIPTION
• Lowe syndrome is a multisystem disorder characterized by anomalies affecting the eye, nervous system, and kidney (1)[B].
• It is also known as oculo-cerebral-renal syndrome of Lowe.
EPIDEMIOLOGY
Incidence
There have been ∼190 known living cases in the United States as of 2000 (1)[B].
Prevalence
1 in 10 affected males in 1,000,000 inhabitants of the United States (1)[B]
RISK FACTORS
X-linked recessive: Female carriers with each pregnancy have a 25% risk of having an affected son, 25% risk of having a carrier daughter, 25% risk of having an unaffected son, and 25% risk of having a noncarrier daughter (2,3)[C,B].
Genetics
• Caused by mutations in OCRL1 gene (Xq24–26); 30% of affected males due to de novo mutations
• Germline and somatic mosaicism in 4.5% of patients
• Rare female affectation due to chromosomal aberration or adverse lyonization (2,3)[C,B]
GENERAL PREVENTION
Genetic counseling
PATHOPHYSIOLOGY
• Cataract: Altered migration of lens embryonic epithelium causes dense cataracts that are present at birth and usually involve the posterior lens.
• Glaucoma due to goniodysgenesis:
– Other manifestations due to accumulation of phosphatidylinositol biphosphate (PiP2) cause a disequilibrium in phosphoinositides.
– Convoluted cytoskeleton remodeling and dysfunctional membrane trafficking cause dysregulation of endocytosis, defective maintenance of tight and adherens junctions, and protein trafficking abnormalities (2)[C].
ETIOLOGY
The OCRL1 gene is an inositol polyphosphate 5 phosphatase (a phosphatidylinositol).
COMMONLY ASSOCIATED CONDITIONS
• Ocular manifestations: Infantile cataract, infantile glaucoma conjunctival cheloids (25% of patients) (4)[C], late-onset retinal dystrophy
• Neurologic manifestations: Hypotonia, absence of deep tendon reflexes, compromised suck reflex, developmental delay behavior disturbances (87%), seizures (50%) (1,5) [B]
• Renal manifestations: Fanconi syndrome (proteinuria, proximal renal tubular acidosis, renal phosphate wasting, hypercalciuria, aminoaciduria, and hypokalemia) with secondary failure to thrive and eventual chronic renal failure (5)
• Renal wasting is associated with the presentation of renal rickets, osteomalacia, and pathological fractures.
• Hypercalciuria is associated with nephrocalcinosis and nephrolithiasis.
• Hyperkaliemia is associated with secondary hyperaldosteronism.
• Cryptorchidism (1)[B]
• Characteristic facies
DIAGNOSIS
HISTORY
• Family history
• Visual deficit due to cataract
• Signs and symptoms of infantile glaucoma (buphthalmus, photophobia, epiphora, corneal clouding)
• Failure to thrive
• Developmental delay, seizures
• Symptoms/signs of renal disease or chronic renal failure (1)[B]
PHYSICAL EXAM
• Facial dysmorphisms are often present and consist of vertically elongated and prominent forehead, fair complexion.
– Plot height, weight, and head circumference on growth curves. Full ocular examination with attention to evidence of cataract, glaucoma (may require sedation or anesthesia for exam), or corneal/conjunctival keloids is required.
– Neurologic assessment for hypotonia with absent deep tendon reflex and poor suck reflexes needs to be done.
– Examine mother for radiating dot lenticular opacities which signify the carrier state. Mother may also have signs of the disease including mild difficulties with mentation, retinal dystrophy, or other signs (1,4) [B,C].
DIAGNOSTIC TESTS & INTERPRETATION
Lab
Initial lab tests
• Renal function studies and urinalysis
• Urine amino acids
• OCRL mutation analysis
Follow-up & special considerations
• Renal function must be monitored over time as worsening will likely occur.
Imaging
Initial approach
• Brain MRI may show mild ventriculomegaly and multiple periventricular cystic lesions (6)[B].
– MRI findings stabilize with time and currently has no clinically significant meaning (6)[B].
Diagnostic Procedures/Other
• B-scan ultrasound if no fundus view
• Photography of optic nerves recommended to allow for monitoring of sequential change due to glaucoma
Pathological Findings
• Cataracts are small and discoid containing posterior lenticonus.
– Fetal nucleus may show retention of the lens nuclei with lens capsular excrescences.
• Patients show embryonic anterior chamber angle with anterior displacement of rudimentary ciliary processes.
– Histology may show segmental hypoplasia of the iris dilator muscle.
• Retina shows Lange’s folds with peripheral retinal cystoid changes.
• Some cases may show hyalinized retinal vessels and mild gliosis.
• The anterior lens of carrier females has many small, irregular, punctate spots, clustered in zones or wedges.
• Carrier females may also present with round, conical, white plaque in the central portion just inside the back capsule (or shell) of the lens (7)[B].
DIFFERENTIAL DIAGNOSIS
• Congenital rubella
• Peroxisomal disorders
• Mitochondriopathies
• Numerous syndromes combine developmental delay and cataract but the renal and glaucoma features will help to narrow differential diagnosis.
TREATMENT
MEDICATION
• Antiseizure medication as needed
• Psychoactive medication for behavior issues:
– Renal management often includes sodium or potassium citrate and sodium bicarbonate. Renal rickets is treated with phosphate supplementation and vitamin D. Treatment should be targeted toward maintaining serum calcium and parathyroid hormone within the normal range.
– Glaucoma management may involve medical control unless infantile presentation and gonioscopy indicate surgery (see the Infantile Glaucoma chapter)
ADDITIONAL TREATMENT
General Measures
• Aphakic/pseudophakic rehabilitation
• Low vision intervention as indicated
• At risk for amblyopia – treat as indicated
Issues for Referral
• Consult medical genetics
• Genetic counseling (3)[B]
• Nephrology
• Neurology:
– Developmental pediatricians, occupational therapists, physical therapists, speech therapists
– Psychology/psychiatry for behavioral issues or general surgery if cryptochidism
SURGERY/OTHER PROCEDURES
• Glaucoma surgery as indicated (see the Infantile Glaucoma chapter) (1)[B]. Usually initial surgery is goniotomy or trabeculotomy.
• Cataract surgery as indicated
• Renal transplantation may be needed.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
• Periodic examination for glaucoma and cataract assessment
• Renal monitoring
• Patients should follow up with a neurologist for appropriate treatment of seizures (1)[B]
• Developmental support
DIET
As indicated for renal issues
PATIENT EDUCATION
Lowe’s Syndrome Association: 972-733-1338 (http://www.lowesyndrome.org/)
PROGNOSIS
• Death usually occurs between the end of second decade and the beginning of fourth decade.
• In first years of life, death occurs as a consequence of renal disease, hypotonia, or susceptibility to infectious disease.
– Respiratory or gastrointestinal infections are common.
• Most frequent causes of death are respiratory disease, epileptic seizures, and sudden death while sleeping.
• Longest reported survival is 54 years old (1)[B].
• Visual prognosis limited by ultimate retinal dystrophy
• Early response to cataract and glaucoma intervention can be positive.
COMPLICATIONS
• Amblyopia
• Glaucoma
• Cataract
• Retinal dystrophy
• Seizure disorders
• Renal insufficiency
• Developmental delay
• Respiratory issues
REFERENCES
1. Loi M. Lowe syndrome. Orphanet J Rare Dis 2006;1:16.
2. Monnier N, et al. OCRL1 mutation analysis in French Lowe syndrome patients: Implications for molecular diagnosis strategy and genetic counseling. Hum Mutat 2000;16(2):157–165.
3. Cau M, et al. A locus for familial skewed X chromosome inactivation maps to chromosome Xq25 in a family with a female manifesting Lowe syndrome. J Hum Genet 2006;51(11):1030–1036.
4. Tripathi RC, Cibis GW, Tripathi BJ, Pathogenesis of cataracts in patients with Lowe’s syndrome. Ophthalmology 1986;93(8):1046–1051.
5. Scriver CR. The metabolic & molecular bases of inherited disease, 8th ed. New York: McGraw-Hill, 2001;4v:6338.
6. Demmer LA, Wippold FJ, 2nd, Dowton SB. Periventricular white matter cystic lesions in Lowe (oculocerebrorenal) syndrome. A new MR finding. Pediatr Radiol 1992;22(1):76–77.
7. Tripathi RC, Cibis GW, Tripathi BJ. Lowe’s syndrome. Trans Ophthalmol Soc UK 1980;100(Pt 1):132–139.
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