Oculocerebrorenal Dystrophy (Lowe Syndrome) Clinical Presentation

  • Author: Amira Al-Uzri, MD, MCR; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 27, 2012
 

History

Oculocerebrorenal syndrome of Lowe (OCRL), or Lowe syndrome, is often diagnosed at birth or in early infancy based on physical characteristics; therefore, history does not usually contribute to the diagnosis. However, a careful review of history is important in documenting disease manifestations, especially neurological and behavioral abnormalities. Obtaining a detailed family history is essential in order to identify any potentially affected male relatives on the maternal side.

  • Intelligence
    • Although about 10% of boys with Lowe syndrome have intelligence within the low-normal to borderline ranges (intelligence quotient [IQ] of 70 and above), most have more significant intellectual impairment.
    • About one third of patients have profound mental retardation, but most have IQs that fall within the moderate range of 40-54.
    • Socioeconomic status, maternal IQ, OCRL1 mutation, and MRI findings do not correlate with intellectual outcome; thus, prediction of intellectual outcome at birth is not possible. Intelligence is stable over the person's life span.
  • Seizures
    • Seizures occur in about one half of all patients with Lowe syndrome and typically appear in children younger than 6 years. Seizure types vary widely and include myoclonic seizures, generalized tonic-clonic seizures, infantile spasms, partial complex seizures, and atonic seizures.
    • Febrile seizures are more common in persons with Lowe syndrome than in the general population (9% vs 1%).
  • Behavior
    • Although most patients with Lowe syndrome are friendly and sociable, a characteristic pattern of behavioral difficulties is common.
    • Abnormal behavior may include temper tantrums, aggression, unusual repetitive movements, irritability, and rigidity.
    • Individuals may also have unusual preoccupations or obsessions, and self-injurious behavior is not uncommon.
  • GI problems: Constipation is common and may be quite severe; severity typically decreases with age.
  • Renal: Glomerulosclerosis associated with chronic tubular injury usually results in slowly progressive chronic renal failure and end-stage renal disease after age 20 years.
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Physical

The typical facial appearance of patients with Lowe syndrome consists of deep-set small eyes, frontal bossing, and an elongated face.

  • Ophthalmologic examination
    • Cataracts are a hallmark of Lowe syndrome and are always present at birth. Pathologic changes in the ocular lens occur prenatally and have been described in fetuses with Lowe syndrome at 20 weeks' gestation and 24 weeks' gestation.
    • Glaucoma, with or without buphthalmos, occurs in about 50-60% of boys with Lowe syndrome and is usually bilateral. Glaucoma is typically diagnosed in the first year of life but may present at any age.
    • Keloids may spontaneously form over the cornea or the conjunctiva in one or both eyes without preceding trauma. They may cause significant visual impairment. Corneal keloids occur in about 25% of patients, usually develop in children older than 5 years, and are bilateral in about one half of patients.
    • Many children with Lowe syndrome develop strabismus.
    • All boys have impaired vision; corrected acuity is rarely better than 20/100.
  • Examination of the nervous system
    • Neonatal generalized hypotonia due to CNS (brain) dysfunction is a consistent feature of OCRL. Feeding difficulties and delayed motor development may occur.
    • Although tone improves with age, most patients never achieve normal muscular tone and have consequential problems such as scoliosis and hernias.
    • Areflexia may also be present.
    • Decreased motor tone also results in delayed motor milestones. Independent ambulation occurs in approximately 25% of boys aged 3-6 years and in 75% by age 6-13 years. Some never walk and require the use of a wheelchair for mobility.[5]
    • Orthopedic complications include hypophosphatemia and metabolic acidosis, which are causative factors in the development of bone disease. This bone disease includes rickets, osteomalacia, and osteopenia. Osteopenia is a consistent finding despite maintenance of normal serum phosphorus levels with therapy. Aside from osteopenia, the other bone manifestations can be prevented or ameliorated with treatment.
    • Fractures are common in boys with Lowe syndrome and often occur when they are learning how to walk. The femur is most often affected. About one third of patients with Lowe syndrome have more than one fracture. Osteopenia or osteoporosis may play a causative role in this propensity to fracture.
    • Joint swelling, arthritis, and tenosynovitis are common and typically occur in the late teenaged years and early adulthood. Nontender swelling of the small and large joints may occur. Plantar masses have also been reported. The cause of these abnormalities is unknown, and treatment is merely supportive.
    • Scoliosis is frequently present in patients with Lowe syndrome and may progress after puberty.
    • Both joint hypermobility and decreased movement that causes joint contractures have been reported.
  • Growth
    • Patients with Lowe syndrome have normal birth weights and lengths. By age 1-3 years, growth parameters fall below the third percentile.
    • The average final adult height is 5'1".
    • Adult head circumferences are typically within the reference range.
    • Sexual development progresses at a normal pace.
  • Other significant physical examination findings
    • Cryptorchidism occurs in 15-40% of boys with Lowe syndrome.
    • Dermatologic and mucosal cysts may occur in multiple sites including the mouth, teeth (blue dome cysts), buttocks, and lower back. They can be painful and may become superinfected.
    • Delayed eruption of permanent teeth, crowding, hypoplastic enamel, constricted palate, taurodontism of the molars, dental caries, gingival inflammation due to mouth breathing, and excessive calculus deposits on teeth have been reported. Abnormal dentition due to excessive vertical facial length has been described in adult patients with Lowe syndrome. Dental cysts may occur.[6]
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Causes

  • Lowe syndrome is an inherited condition caused by mutations in the OCRL1 gene, which encodes PtdIns[4,5]P2 5 phosphatase. This enzyme appears to play a role in regulating protein trafficking, second messengers, and other aspects of cellular metabolism.
  • OCRL1 mutation was recently reported in 23% of kindreds with Dent disease-2, which is another X-linked renal tubulopathy characterized by hypercalcuria and nephrocalcinosis.[4] A defect in the OCRL1 protein may cause the mildly elevated creatine kinase and lactate dehydrogenase (LDH) serum levels observed in this subgroup of patients, without the presence of cataract. Mitochondrial encephalomyopathies such as cytochrome oxidase deficiency can present similarly with hypotonia, mental retardation, cataracts, and renal tubular dysfunction.
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Contributor Information and Disclosures
Author

Amira Al-Uzri, MD, MCR  Associate Professor of Pediatrics, Director, Pediatric Clinical Research Office, Director, Pediatric Clinical and Translational Research Center, Department of Pediatrics, Divison of Pediatric Kidney Services and Hypertension, Oregon Health and Science University School of Medicine

Amira Al-Uzri, MD, MCR is a member of the following medical societies: American Society of Nephrology, American Society of Pediatric Nephrology, and American Society of Transplantation

Disclosure: Nothing to disclose.

Coauthor(s)

Robert D Steiner, MD  Credit Unions for Kids Professor of Pediatric Research, Professor of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Faculty, Program in Molecular and Cellular Biosciences, Oregon Health and Science University School of Medicine; Attending Physician, Doernbecher Children's Hospital; Staff Consultant, Director of Metabolic Bone Disease Clinic, Shriners Hospital Portland

Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research

Disclosure: Amicus Honoraria Consulting; Actelion Honoraria Consulting; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Consulting; Genzyme Honoraria Consulting; Shire Honoraria Consulting

Melissa P Wasserstein, MD  Associate Professor, Departments of Genetics and Genomic Sciences and Pediatrics, Mount Sinai School of Medicine

Melissa P Wasserstein, MD is a member of the following medical societies: American Society of Human Genetics

Disclosure: Nothing to disclose.

Cydney L Fenton, MD  Director, Center for Diabetes and Endocrinology, Akron Children's Hospital

Cydney L Fenton, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Ian Krantz, MD  Department of Pediatrics, Assistant Professor, University of Pennsylvania and Children's Hospital of Philadelphia

Ian Krantz, MD is a member of the following medical societies: American Society of Human Genetics

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Leonard G Feld, MD, PhD, MMM, FAAP  Sara H Bissell and Howard C Bissell Endowed Chair in Pediatrics, Chief Medical Officer, Levine Children's Hospital, Carolinas Medical Center

Leonard G Feld, MD, PhD, MMM, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Juvenile Diabetes Foundation International

Disclosure: Nothing to disclose.

Daniel Rauch, MD, FAAP  Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine

Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine

Disclosure: Baxter Honoraria Consulting

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

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The classic lenticular opacities in a female carrier for Lowe syndrome. Note the punctate cortical opacities in radical wedges. (Photo courtesy of Otis Paul, MD)
 
 
 
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