Microcephaly-Lymphedema-Chorioretinopathy Syndrome

Microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) is a rare autosomal dominant condition characterized by variable expression of microcephaly, ocular disorders including chorioretinopathy, congenital lymphedema of the lower limbs, and mild to moderate intellectual disability.

Epidemiology

The exact prevalence of MCLID is not known but the disorder is thought to be rare. Approximately 50 families with clinical features of the syndrome have been described to date with mutations in the KIF11 gene reported in 25 families worldwide. Males and females appear to be affected equally.

Clinical description

MCLID presents with variable expression of the main clinical features (microcephaly, chorioretinopathy, lymphedema and intellectual disability). The microcephaly is primary, and the severity is variable even within families. Mild to moderate learning difficulties are common. A characteristic facial phenotype including upslanting palpebral fissures, broad nose with rounded tip, anteverted nares, long philtrum with thin upper lip, and prominent chin and ears is well recognized. The ocular features include choroidal atrophy and non-progressive dysplasia. Hypermetropic astigmatism, myopic astigmatism, retinal folds, and microphthalmia are also observed. Lymphedema when present, is generally congenital, bilateral and confined to the dorsa of the feet, and resembles the lymphedema seen in Milroy disease (see this term). Congenital heart defects and epilepsy may be rare features of the syndrome.

Etiology

There is likely to be genetic heterogeneity. However, a significant proportion of cases are caused by mutations in the kinesin family member 11 (KIF11) gene (10q24.1). KIF11 encodes EG5, a homotetramer kinesin motor, likely to be important for the development and maintenance of retinal and lymphatic structures. Individuals with pathogenic mutations in KIF11 have been reported without clinical features of the syndrome demonstrating reduced penetrance.

Genetic counseling

Inheritance is autosomal dominant with variable expression and reduced penetrance.