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Oculocerebrorenal Syndrome Clinical Presentation

  • Author: Deborah M Alcorn, MD; Chief Editor: Hampton Roy, Sr, MD  more...
 
Updated: Dec 17, 2014
 

History

See the list below:

  • 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
    • 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
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Physical

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  • Ocular
    • Congenital cataracts are the hallmark of this disease. 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 OCRS, 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.
  • Neurologic
    • 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. 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 OCRS 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.
  • Renal
    • Abnormal renal function is part of the clinical triad and a cardinal feature of the disease. In OCRS, impairment of both tubular and glomerular function occurs.[7]
    • 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.
  • Musculoskeletal
    • Patients may exhibit noninflammatory arthropathy, joint swelling, and contractures. Scoliosis is frequently seen.
    • 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.
  • Carrier state
    • Slit lamp examination of the lenses of female carriers of OCRS 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.
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Causes

See the list below:

  • Genetic
    • OCRS 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 OCRS patients.[2, 8, 9]
    • 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 OCRS patients.
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Contributor Information and Disclosures
Author

Deborah M Alcorn, MD Associate Professor, Departments of Ophthalmology and Pediatrics, Stanford University School of Medicine; Director of Pediatric Ophthalmology and Strabismus, Lucile Packard Children's Hospital

Deborah M Alcorn, MD is a member of the following medical societies: American Academy of Ophthalmology, International Society for Genetic Eye Diseases and Retinoblastoma, American Association for Pediatric Ophthalmology and Strabismus

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Hampton Roy, Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Hampton Roy, Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, Pan-American Association of Ophthalmology

Disclosure: Nothing to disclose.

Additional Contributors

Andrew W Lawton, MD Neuro-Ophthalmology, Ochsner Health Services

Andrew W Lawton, MD is a member of the following medical societies: American Academy of Ophthalmology, Arkansas Medical Society, Southern Medical Association

Disclosure: Nothing to disclose.

Acknowledgements

Brian R Younge, MD Professor of Ophthalmology, Mayo Clinic School of Medicine

Brian R Younge, MD is a member of the following medical societies: American Medical Association, American Ophthalmological Society, and North American Neuro-Ophthalmology Society

Disclosure: Nothing to disclose.

References
  1. Lowe CU, Terrey M, MacLachlan EA. Organic-aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation. Am J Dis Child. 1952. 83:164-184.

  2. Loi M. Lowe syndrome. Orphanet J Rare Dis. 2006 May 18. 1:16. [Medline].

  3. Luo N, Kumar A, Conwell M, Weinreb RN, Anderson R, Sun Y. Compensatory Role of Inositol 5-Phosphatase INPP5B to OCRL in Primary Cilia Formation in Oculocerebrorenal Syndrome of Lowe. PLoS One. 2013. 8(6):e66727. [Medline]. [Full Text].

  4. Kim HK, Kim JH, Kim YM, Kim GH, Lee BH, Choi JH, et al. Lowe syndrome: a single center's experience in Korea. Korean J Pediatr. 2014 Mar. 57(3):140-8. [Medline]. [Full Text].

  5. Sugimoto K, Nishi H, Miyazawa T, Fujita S, Okada M, Takemura T. A novel OCRL1 mutation in a patient with the mild phenotype of lowe syndrome. Tohoku J Exp Med. 2014. 232(3):163-6. [Medline].

  6. Walton DS, Katsavounidou G, Lowe CU. Glaucoma with the oculocerebrorenal syndrome of Lowe. J Glaucoma. 2005 Jun. 14(3):181-5. [Medline].

  7. Topaloglu R, Ludwig M, Çelebi Tayfur A. Selective proximal renal tubular involvement and dyslipidemia in two cousins with oculocerebrorenal syndrome of Lowe. Turk J Pediatr. 2013 May-Jun. 55(3):331-4. [Medline].

  8. Pirruccello M, De Camilli P. Inositol 5-phosphatases: insights from the Lowe syndrome protein OCRL. Trends Biochem Sci. 2012 Apr. 37(4):134-43. [Medline]. [Full Text].

  9. Kühbacher A, Dambournet D, Echard A, Cossart P, Pizarro-Cerdá J. Phosphatidylinositol 5-phosphatase oculocerebrorenal syndrome of Lowe protein (OCRL) controls actin dynamics during early steps of Listeria monocytogenes infection. J Biol Chem. 2012 Apr 13. 287(16):13128-36. [Medline]. [Full Text].

  10. Attree O, Olivos IM, Okabe I, Bailey LC, Nelson DL, Lewis RA. The Lowe's oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase. Nature. 1992 Jul 16. 358(6383):239-42. [Medline].

  11. Cibis GW, Waeltermann JM, Whitcraft CT, Tripathi RC, Harris DJ. Lenticular opacities in carriers of Lowe's syndrome. Ophthalmology. 1986 Aug. 93(8):1041-5. [Medline].

  12. Kenworthy L, Charnas L. Evidence for a discrete behavioral phenotype in the oculocerebrorenal syndrome of Lowe. Am J Med Genet. 1995 Nov 20. 59(3):283-90. [Medline].

  13. Kruger SJ, Wilson ME Jr, Hutchinson AK, Peterseim MM, Bartholomew LR, Saunders RA. Cataracts and glaucoma in patients with oculocerebrorenal syndrome. Arch Ophthalmol. 2003 Sep. 121(9):1234-7. [Medline].

  14. Lavin CW, McKeown CA. The oculocerebrorenal syndrome of Lowe. Int Ophthalmol Clin. 1993 Spring. 33(2):179-91. [Medline].

  15. Lin T, Lewis RA, Nussbaum RL. Molecular confirmation of carriers for Lowe syndrome. Ophthalmology. 1999 Jan. 106(1):119-22. [Medline].

  16. Nussbaum RL, Orrison BM, Janne PA, Charnas L, Chinault AC. Physical mapping and genomic structure of the Lowe syndrome gene OCRL1. Hum Genet. 1997 Feb. 99(2):145-50. [Medline].

  17. Suchy SF, Nussbaum RL. The deficiency of PIP2 5-phosphatase in Lowe syndrome affects actin polymerization. Am J Hum Genet. 2002 Dec. 71(6):1420-7. [Medline]. [Full Text].

  18. Tripathi RC, Cibis GW, Tripathi BJ. Pathogenesis of cataracts in patients with Lowe's syndrome. Ophthalmology. 1986 Aug. 93(8):1046-51. [Medline].

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