Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations

Abstract

Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR) (MIM No.152950) is a rare autosomal dominant condition for which a causative gene has recently been identified. Mutations in the kinesin family member 11 (KIF11) gene have now been described in 16 families worldwide. This is a review of the condition based on the clinical features of 37 individuals from 22 families. This report includes nine previously unreported families and additional information for some of those reported previously. The condition arose de novo in 8/20 families (40%). The parental results were not available for two probands. The mutations were varied and include missense, nonsense, frameshift, and splice site and are distributed evenly throughout the KIF11 gene. In our cohort, 86% had microcephaly, 78% had an ocular abnormality consistent with the diagnosis, 46% had lymphoedema, 73% had mild-moderate learning difficulties, 8% had epilepsy, and 8% had a cardiac anomaly. We identified three individuals with KIF11 mutations but no clinical features of MCLMR demonstrating reduced penetrance. The variable expression of the phenotype and the presence of mildly affected individuals indicates that the prevalence may be higher than expected, and we would therefore recommend a low threshold for genetic testing.

Figure 1

(a) Clinical photographs showing facial features of the probands with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Pedigree no. (Left—Right) Row 1—I, II, III, V, VI, VIII; Row 2—IX, XI, XII, XIII, XIV, XV; and Row 3—XVII, XVIII, XIX, XXI, XXII. (b) Parents with less obvious dysmorphism. Pedigree no. (Left—Right) Row 1—II, IX, XII, XIV, XV, XVII.

Figure 2

(a) Lymphoedema is typically congenital, bilateral, and confined to the dorsa of the feet. (b) Lymphoedema of the feet detected by antenatal ultrasound scan. (c) Fundal images demonstrating characteristic changes of chorioretinal dysplasia.