Lowe Syndrome

Clinical characteristics: Lowe syndrome (oculocerebrorenal syndrome) is characterized by involvement of the eyes, central nervous system, and kidneys. Dense congenital cataracts are found in all affected boys and infantile glaucoma in approximately 50%. All boys have impaired vision; corrected acuity is rarely better than 20/100. Generalized hypotonia is noted at birth and is of central (brain) origin. Deep tendon reflexes are usually absent. Hypotonia may slowly improve with age, but normal motor tone and strength are never achieved. Motor milestones are delayed. Almost all affected males have some degree of intellectual disability; 10%-25% function in the low-normal or borderline range, approximately 25% in the mild-to-moderate range, and 50%-65% in the severe-to-profound range of intellectual disability. Affected males have varying degrees of proximal renal tubular dysfunction of the Fanconi type, including low molecular-weight (LMW) proteinuria, aminoaciduria, bicarbonate wasting and renal tubular acidosis, phosphaturia with hypophosphatemia and renal rickets, hypercalciuria, sodium and potassium wasting, and polyuria. The features of symptomatic Fanconi syndrome do not usually become manifest until after the first few months of life, except for LMW proteinuria. Glomerulosclerosis associated with chronic tubular injury usually results in slowly progressive chronic renal failure and end-stage renal disease between the second and fourth decades of life.

Diagnosis/testing: The diagnosis of Lowe syndrome is established in a male proband with typical clinical and laboratory findings and a hemizygous pathogenic variant in OCRL identified by molecular genetic testing. The diagnosis of Lowe syndrome is rare in females but can be established in a female proband who demonstrates the same clinical and laboratory findings as a male proband and who is found to have a heterozygous pathogenic variant in OCRL by molecular genetic testing.

Management: Treatment of manifestations:

1. Early removal of cataracts with postoperative glasses; management of glaucoma; early infant therapy, preschool intervention program and individualized education program throughout schooling; behavior modification plan; anticonvulsant therapy if seizures are present.

2. Treatment of renal tubular dysfunction includes oral supplements of sodium and potassium bicarbonate or citrate to correct acidosis and hypokalemia, and oral phosphate and oral calcitriol (1,25-dihydroxyvitamin D₃) to correct hypophosphatemia and renal rickets; treatment of ESRD with chronic dialysis and renal transplant in selected individuals.

3. Consider human growth hormone therapy to improve growth velocity; tube feedings may be needed to treat infant feeding problems associated with hypotonia; standard treatment for gastroesophageal reflux if present. Bracing or surgery for severe or progressive scoliosis or joint hypermobility; resection of fibromas and cutaneous cysts if painful or impairing function.

Surveillance: Intraocular pressure monitoring every six months for life, other eye evaluations at intervals determined by specialist; at least annual assessment of kidney function, growth, developmental progress; annual evaluation for scoliosis and joint problems; semiannual dental examinations.

Circumstances to avoid: Corneal contact lenses because of associated risk of corneal keloid formation and complexities of contact lens care; artificial lens implants because of probable increased risk of glaucoma.

Genetic counseling: Lowe syndrome is inherited in an X-linked manner. De novo pathogenic variants have been reported in 32% of males affected with Lowe syndrome. A high risk of germline mosaicism (4.5%) has been identified. When a mother is a heterozygous, each pregnancy has a 25% chance of an affected son, a 25% chance of a heterozygous daughter, a 25% chance of an unaffected son, and a 25% chance of a daughter who is not heterozygous. No affected male is known to have reproduced. Approximately 95% of heterozygous females older than age 15 years have characteristic findings in the lens of the eye on slit lamp examination by an experienced ophthalmologist using both direct and retroillumination. Once the OCRL pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.