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Lowe’s syndrome - also known as the cerebrooculorenal syndrome, the oculocerebrorenal syndrome of Lowe, and phosphatidylinositol-4,5-bisphosphate-5-phosphatase deficiency - represents a very rare multisystem disorder that affects the eye, the central nervous system, and the kidneys.
The condition was initially described in 1952 by Lowe and his colleagues as a potpourri of hydrophthalmos, mental retardation, organic aciduria, and decreased renal ammonia production. The estimated prevalence of Lowe's syndrome is 1 in 500 thousand people.
Lowe’s syndrome is a result of mutations in a gene called the OCRL gene, which codes for an enzyme that helps modify fat molecules known as membrane phospholipids. By controlling the levels of these specific phospholipids, this enzyme helps in transport regulation to and from the cell membrane, but is also involved in signal transduction and actin polymerization.
The gene resides on the X chromosome, hence Lowe’s syndrome is inherited in an X-linked pattern. In this type of inheritance, fathers will not be able to pass on X-linked characteristics to their male progeny.
The clinical manifestations differ among affected individuals, but also according to their age. The hallmark of this disorder is the appearance of congenital bilateral cataracts (thick clouding of the lenses) that are usually deemed visually significant at birth. Other ocular defects that appear are infantile glaucoma (increased pressure in the eye) and searching nystagmus (involuntary eye movements).
Renal involvement is another major clinical feature of Lowe’s syndrome, usually occurring during the initial years of life with varying degrees of severity. Affected patients can present with renal tubular acidosis, loss of salt, proteins, amino acids, minerals and other nutrients, but also life-threatening renal failure and end-stage renal disease later in life.
Children that are affected usually present with a weak muscle tone and the absence of reflexes since birth (also known as neonatal hypotonia and areflexia), which causes problems with feeding and breathing. There is also a common onset of behavioral problems with pronounced stereotypic behaviors (such as aggressiveness and temper tantrums), and sometimes seizures may be observed.
Patients with Lowe’s syndrome often exhibit typical facial determinants such as deep-set eyes, frontal bossing, chubby cheeks, as well as a fair complexion with a blonde hair. Dental findings include protracted retention of primary teeth, enlarged pulp chambers, but also dysplastic dentin formation.
A triad of eye, nervous system, and kidney involvement is absolutely necessary for the diagnosis of Lowe’s syndrome. The diagnosis is initially suggested by uniformly present congenital cataract, while the recognition of cerebral manifestations is based on a comprehensive neurological examination.
In order to detect kidney involvement, non-invasive biochemical procedures are usually employed – namely spot urine test for low-molecular-weight proteinuria and hypercalciuria, as well as detection of the presence of other proximal tubular dysfunctions. The cost effectiveness of the aforementioned clinical examination when combined with an ophthalmological investigation and simple biochemical tests is quite high.
For final confirmation of Lowe’s syndrome, measurement of the activity of the inositol polyphosphate-5-phosphatase can be done in skin fibroblasts, although genetic testing for the OCRL gene is also an option. Prenatal identification is sometimes pursued using signs such as increased fetal nuchal translucency and bilateral lenticular opacities in the second trimester of pregnancy.
In differential diagnosis, we have to bear in mind that bilateral cataracts of the eyes and hypotonia are also found in congenital infections (such as rubella), congenital myopathies, mitochondriopathies and some other syndromes. Nevertheless, with the appearance of renal involvement within the first months of life we can safely exclude these alternative diagnoses.
Management of Lowe’s syndrome includes early cataract surgery in order to avoid amblyopia, while ocular tone has to be tested repeatedly in order to diagnose glaucoma. Furthermore, targeted rehabilitation therapy as early as possible is warranted to treat hypotonia, while seizures require treatment with symptom-specific drugs.
Renal tubular acidosis necessitates timely recognition and prompt treatment with alkali supplements in order to maintain the level of bicarbonates in the serum at around 20 milliequivalents per liter. Potassium citrate is remarkably useful for this indication, as it can also help to prevent nephrocalcinosis and reduce the excretion of calcium by the kidneys.
In conclusion, the possibility of the oculocerebrorenal syndrome of Lowe should always be considered in boys with cataracts on both eyes and glomerular disease. Increased survival of these patients has been attributed to the administration of aggressive medical care with subsequent gains in the quality of life.