Lowe Syndrome (Oculocerebrorenal Syndrome) Clinical Presentation

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

History

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

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Physical

Ocular

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.

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. 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.

Renal

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.

Musculoskeletal

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.

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Causes

Genetic

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]  

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