Oculocerebrorenal Dystrophy (Lowe Syndrome) Clinical Presentation

Updated: Apr 24, 2018
  • Author: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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Presentation

History

Oculocerebrorenal syndrome of Lowe (OCRL), or Lowe syndrome, is most 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 or potential maternal carrier status.

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. About 25% of patients have an IQ greater than 70.

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

Renal dysfunction is not commonly evident at birth but rather noted during the first weeks or months of life and is typically a slowly progressive chronic renal failure that results in end-stage renal disease in the second or third decade of life.

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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. [7]

Seizures may occur.

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. However, severely diminished postnatal growth is typical, and, 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. [8]

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Causes

Lowe syndrome is an X-linked condition caused by mutations in the OCRL1 gene, which encodes inositol polyphosphate 5-phosphatase OCRL-1, which preferentially dephosphorylates phosphatidylinositide 4,5 bisphosphate (PI(4,5)P2). This enzyme appears to play a role in regulating protein trafficking, second messengers, and other aspects of cellular metabolism.

OCRL has been demonstrated to localize to the primary cilium. Recent research has shown that cilia from fibroblasts in patients with Lowe syndrome exhibit increased levels of PI(4,5)P2 and decreased levels of PI4P. Accumulation of ciliary PI(4,5)P2 was pronounced in mouse embryonic fibroblasts (MEFs) derived from a Lowe syndrome mouse model, as well as in Ocrl-null MEFs. Effects to the cilium may explain the multisystem nature of the condition.

Interestingly, OCRL1 mutation has been reported in 23% of kindreds with Dent-2 disease, which is another X-linked renal tubulopathy characterized by hypercalcuria and nephrocalcinosis. [6] 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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Complications

Dental problems may occur.

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