Microcephaly With Or Without Chorioretinopathy, Lymphedema, Or Mental Retardation

A number sign (#) is used with this entry because of evidence that microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) is caused by heterozygous mutation in the KIF11 gene (148760) on chromosome 10q23.

Description

Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation is an autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes (summary by Ostergaard et al., 2012). Robitaille et al. (2014) found that MCLMR includes a broader spectrum of ocular disease, including retinal detachment with avascularity of the peripheral retina, and noted phenotypic overlap with familial exudative vitreoretinopathy (FEVR; see EVR1, 133780).

Birtel et al. (2017) observed intrafamilial and intraindividual variability in retinal phenotype, and noted that syndromic manifestations in some patients are too subtle to be detected during a routine ophthalmologic evaluation. Variable expressivity and reduced penetrance have also been observed in some families (Jones et al., 2014; Li et al., 2016).

Autosomal recessive forms of microcephaly with chorioretinopathy have been reported (see 251270).

See also Mirhosseini-Holmes-Walton syndrome (autosomal recessive microcephaly with pigmentary retinopathy and mental retardation; 268050), which has been mapped to chromosome 8q21.3-q22.1.

Clinical Features

Microcephaly with chorioretinopathy (of a type that suggests congenital infection) in combination with mental retardation was reported by Tenconi et al. (1981). Warburg and Heuer (1983) presented the cases of 2 brothers and their mother who had the combination of microcephaly and lacunar depigmentation of the retina. Microcephaly was slight and the foreheads were bulging. Mental retardation was mild. A 5-year follow-up demonstrated that visual function was stable (Warburg and Heuer, 1994). Manning et al. (1990) reported the electroretinographic findings in members of a possible third family.

Jarmas et al. (1981) described 2 brothers with severe microcephaly, microphthalmos, retinal folds, and visual deficit. Their mother was also microcephalic and showed mild mental retardation. Young et al. (1987) reported a retarded boy with microcephaly, microphthalmos, and retinal folds. His mother and sister showed microphthalmia and the sister was also microcephalic. Angle et al. (1994) pointed out that the patients of Jarmas et al. (1981) and Young et al. (1987) had lymphedema in addition to microcephaly and chorioretinal dysplasia.

In 5 members of 4 generations of a Chinese family, Leung (1985) described the combination of microcephaly and lymphedema. The lymphedema was present at birth or began soon after birth. Intelligence was normal. Male-to-male transmission was observed.

Crowe and Dickerman (1986) described congenital lymphedema in association with microcephaly in a young boy and his maternal uncle. The mother, maternal grandmother and a sister of the grandmother had microcephaly. The pattern was consistent with X-linkage but may have been indicative of autosomal recessive inheritance with reduced expression in females; the proband's mother, grandmother, and great aunt were microcephalic. In an accompanying editorial, Opitz (1986) made many useful comments. Congenital lymphedema is frequent and represents delay in the maturation of the lymphatics and delay in clearing of the lymphedema regularly present in the fetus. 'Lymphedema nails,' i.e., white nails, especially in the toes, is a persisting sign. Coarseness of the hair follicles over the dorsum of the hands and feet and first phalanges where edema was present earlier is another sign. Unusual persistence of fetal lymphedema is usually associated with congenital hypotonia which clears faster than the lymphedema. Lymphedema in the hands causes thick volar tissues and later numerous white lines seen on palm prints and with a magnifying glass. Change in the pattern of hair may be seen in other areas of the body in addition to the nape of the neck, e.g., in the forearms. Leung (1987) emphasized the intellectual normality in these cases.

Feingold and Bartoshesky (1992) described 2 unrelated boys with microcephaly, lymphedema, and chorioretinal dysplasia. They concluded that their patients had the same entity as the patients reported by Leung (1985), who had an autosomal dominant disorder, and those reported by McKusick et al. (1966), who had an autosomal recessive disorder (see 251270).

Angle et al. (1994) presented 2 unrelated boys with microcephaly, lymphedema, and chorioretinal dysplasia.

Kozma et al. (1996) described a sister and brother from a nonconsanguineous Saudi family who, in addition to severe microcephaly (without mental retardation) and lymphedema, had attention deficit disorder. One brother was more severely affected, and X-linked dominant inheritance could not be excluded.

Hordijk et al. (1996) described a father and son with this syndrome. In addition to the usual manifestations, both had microcornea and overgrowth of the conjunctiva over the corneoscleral junction. The father had microphthalmia, and his son was severely mentally retarded. Microphthalmia, microcornea, and severe mental retardation had not been reported in other families with the autosomal dominant form of the syndrome.

Strenge and Froster (1998) described a boy with congenital microcephaly and lymphedema. He also had short stature, a feature that had not been described as part of this syndrome, even though it was present in 1 patient reported by Fryns et al. (1995). Bilateral limb lymphedema with lymphedema toenails was still present at age 2 years. At the age of 4 years, the lymphedema began decreasing. At the age of 8 years, lymphedema was restricted to the surface of the toes and the distal part of both feet. His height was at the 3rd centile; the occipital-frontal circumference was 48 cm (less than 3rd centile). Psychomotor development was normal.

Limwongse et al. (1999) provided follow-up on the family reported by Crowe and Dickerman (1986) which was considered to have the microcephaly-lymphedema syndrome. They found chorioretinal dysplasia with variable visual deficit in multiple relatives, supporting the concept that the combination of microcephaly, lymphedema, and chorioretinopathy constitutes a single autosomal dominant genetic entity with variable expression. In an editorial comment on the report by Crowe and Dickerman (1986), Opitz (1986) had suggested that the facial characteristics of their proband at birth and during childhood resembled those of other patients with disorders associated with congenital lymphedema, i.e., what Opitz (1986) called the 'congenital lymphedema facies' (thick tissues, full cheeks, underdeveloped bridge of nose and supraorbital ridges, thick epicanthal folds, bilateral ptosis with thick lids, and micrognathia). Limwongse et al. (1999) noted a striking similarity between the facial characteristics of their proband at age 14 years and those of the 11-year-old patient of Sadler and Robinson (1993) with microcephaly and chorioretinopathy. Both patients had prominent ears, broad nasal bridge, broad and large nasal tip with anteverted nares, prominent full lips, and pointed chin.

Abdel-Salam et al. (2000) stated that 40 cases of microcephaly with chorioretinopathy, some with additional features such as lymphedema, had been reported. They noted that the facial features in their 2 patients, who had the additional features of severe mental retardation, epilepsy, and spasticity (see 251270), were similar to those described by Limwongse et al. (1999).

Vasudevan et al. (2005) reported 3 unrelated male patients with all of the major features of the microcephaly, lymphedema, chorioretinal dysplasia syndrome. All had a distinct facial appearance involving upslanting palpebral fissures, broad nose with rounded tip, anteverted nares, long philtrum with thin upper lip, pointed chin, and prominent ears. Vasudevan et al. (2005) stated that these cases support the hypothesis of a characteristic facial phenotype in MLCRD syndrome.

Mirzaa et al. (2014) reported 5 unrelated patients with MCLMR. All 5 had severe microcephaly, marked simplification of the gyral pattern on neuroimaging, bilateral chorioretinopathy, and developmental delays. Two patients had normal or mildly small occipitofrontal circumference (OFC) at birth, but all became severely microcephalic with OFCs 4 to 7 SD below the mean. Three patients had transient congenital lymphedema, and one had congenital bilateral sensorineural hearing loss. Two patients had optic nerve hypoplasia, and 1 patient had retinal detachment, glaucoma, and cataract. Neuroimaging in some patients showed mildly enlarged extraaxial space and a thin corpus callosum. Other features included generalized hypotonia and hypertonia of extremities, hand flapping, sleeping difficulties, attention deficit-hyperactivity disorder, seizures, and behavioral abnormalities such as agitation and aggression.

In 4 of 28 probands who had been diagnosed with FEVR and who did not have a mutation in known FEVR genes, Robitaille et al. (2014) identified heterozygous mutations in the KIF11 gene (see MOLECULAR GENETICS) as well as features suggestive of MCLMR such as microcephaly. At least 1 patient in each pedigree manifested one or more of the following features that are usually associated with FEVR: macular dragging, partial retinal detachment, falciform folds, or total retinal detachment. The authors recommended that children presenting with partial or complete retinal detachments at a young age be examined for mild to moderate microcephaly, which could lead to a more precise diagnosis and accurate genetic counseling.

Jones et al. (2014) reviewed the phenotype associated with KIF11 mutations in 37 patients from 22 families, including 9 previously unreported families. In this cohort, 32 (86%) of the patients had microcephaly; 29 (78%) had an ocular abnormality consistent with the diagnosis, including 22 (59%) with chorioretinopathy; 17 (46%) had lymphedema; 27 (73%) had mild to moderate learning difficulties; 3 (8%) had epilepsy; and 3 (8%) had a cardiac anomaly, including congenital thickened pulmonary valve, atrial septal defect, and patent foramen ovale. A majority of patients exhibited the characteristic facial dysmorphism, consisting of upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, and prominent large ears. Parents did not have the same dysmorphic features seen in their children, suggesting that facial dysmorphism may become less obvious with age. In addition, 3 (8%) of the 37 patients with KIF11 mutations showed no clinical features of MCLMR, demonstrating reduced penetrance.

Hu et al. (2016) evaluated 7 Chinese patients from 4 families diagnosed with FEVR in whom mutations in KIF11 were identified. Six of the patients had severely reduced visual acuity, ranging from 20/250 to no response to light, but the father of 1 proband was asymptomatic with 20/20 vision. Fundus changes also varied significantly and showed intrafamilial variation, ranging from an avascular zone in the peripheral retina (in the asymptomatic father) to severe ocular changes, including temporal dragging of the optic disc, falciform retinal folds, retinal detachment, and/or retrolenticular fibrotic masses. Microcephaly was present in 4 of the 7 patients, with OFCs ranging from -4.1 to -6.4 SDS, and a fifth patient was reported by his parents to be microcephalic and to have mental retardation. None of the patients had lymphedema.

Li et al. (2016) reported 7 probands with FEVR and mutations in KIF11. All 7 had advanced FEVR (stage 4 or above), 3 showed unilateral microphthalmia, and 1 had chorioretinopathy; in addition, 3 of the probands had microcephaly. Variable expressivity and reduced penetrance were observed.

Birtel et al. (2017) retrospectively studied 4 patients from 3 families with KIF11 mutations, including a patient previously reported by Jones et al. (2014). Obvious syndromic disease was present only in 1 patient, but minor signs, such as reduced head circumference, were present in the other 3 patients. After analysis of these and previously reported patients, the authors proposed 4 distinct types of KIF11-related retinal changes: type 1, with subclinical retinal changes that may include retinal thinning or decreased full-field electroretinographic (ERG) responses; type 2, showing retinal dystrophy with characteristic findings on optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging; type 3, in which there is sharply demarcated chorioretinal atrophy, primarily outside the vascular arcades; and type 4, an FEVR-like phenotype with retinal folds. Birtel et al. (2017) observed intrafamilial and intraindividual variability with occurrence of more than 1 retinal subtype, and also noted that syndromic manifestations in some patients are too subtle to be detected during routine ophthalmologic evaluation.

Inheritance

Alzial et al. (1980) reported cases of microcephaly and chorioretinopathy with autosomal dominant inheritance.

Male-to-male transmission was observed for the first time in a family reported by Sadler and Robinson (1993), suggesting autosomal dominant inheritance; also see Robinson and Sadler (1993). A father and 2 sons were affected. Polycystic kidney disease was segregating in the family, apparently independently of the microcephaly syndrome.

Limwongse et al. (1999) concluded that the combination of microcephaly, lymphedema, and chorioretinopathy constitutes a single autosomal dominant genetic entity with variable expression.

Molecular Genetics

In 5 unrelated probands with microcephaly, lymphedema, and mild learning difficulties, only 1 of whom had eye abnormalities (hypermetropic astigmatism and chorioretinopathy), Ostergaard et al. (2012) performed whole-exome sequencing and identified heterozygosity for truncating mutations in the KIF11 gene (148760) in 3 of the probands (see, e.g., 148760.0001 and 148760.0002). Sequencing of the KIF11 gene in 9 additional unrelated probands revealed 7 more independent heterozygous KIF11 variants (see, e.g., 148760.0003-148760.0005). Each of the 10 identified KIF11 variants was assessed in all available relatives; 2 were shown to have arisen de novo, and 8 demonstrated cosegregation with microcephaly, variable in its severity, and with a spectrum of eye and lymphatic abnormalities. Noting the substantial phenotypic overlap between MLCRD (microcephaly, primary lymphedema, and chorioretinal dysplasia) syndrome and CDMMR (chorioretinal dysplasia, microcephaly, and mental retardation) syndrome, Ostergaard et al. (2012) analyzed the KIF11 gene in 6 unrelated CDMMR families and identified heterozygous mutations in 5 of them (see, e.g., 148760.0006); 1 mutation was the same nonsense mutation previously found in a family with microcephaly and lymphedema (148760.0001). Ostergaard et al. (2012) concluded that the MLCRD and CDMMR syndromes should be considered a single entity with variable clinical features.

In 5 of 12 patients with features suggesting MCLMR, Mirzaa et al. (2014) identified 5 different de novo heterozygous mutations in the KIF11 gene (see, e.g., 148760.0007-148760.0008).

In 5 patients with MCLMR, who were originally diagnosed with FEVR and who did not have mutations in any of the known FEVR genes, Robitaille et al. (2014) identified 4 different heterozygous mutations in the KIF11 gene (see, e.g., 148760.0009-148760.0010). The first mutation (E470X; 148760.0009) was found by whole-exome sequencing, and the others were found by Sanger sequencing. In addition, the authors screened 3 probands with a likely diagnosis of MCLMR for mutations in the KIF11 gene, and in the proband from a family of Acadian descent with 4 affected members, they identified heterozygosity for a missense mutation.

Hu et al. (2016) analyzed potential pathogenic variants in the KIF11 gene resulting from whole-exome sequencing in 814 Chinese probands with various eye diseases, including 34 diagnosed with FEVR. They identified 4 probands with FEVR who had heterozygous truncating variants in KIF11 (see, e.g., Q744X, 148760.0011). Three of the 4 probands were found to be microcephalic and the fourth had a small head (OFC -1.3 SDS); 1 had mental retardation, and none exhibited lymphedema.

In 142 probands diagnosed with FEVR, Li et al. (2016) analyzed 6 FEVR-associated genes and identified 7 probands with heterozygous mutations in the KIF11 gene. All 7 had advanced FEVR (stage 4 or 5), 3 showed unilateral microphthalmia, and 1 had chorioretinopathy; in addition, 3 of the probands had microcephaly. Five of the mutations occurred de novo; the remaining 2 families demonstrated variable expressivity and incomplete penetrance of missense and frameshift mutations, respectively, with 1 heterozygous parent exhibiting only a mild clinical phenotype and the other carrier parent being unaffected.

In 31 Chinese pedigrees clinically diagnosed with FEVR, Rao et al. (2017) analyzed 6 FEVR-associated genes and identified mutations in 12 probands. They identified a de novo 4-bp deletion in the KIF11 gene in a 2-year-old boy who also exhibited microcephaly.

Associations Pending Confirmation

For discussion of a possible association between MCLMR and haploinsufficiency of the CDK19 gene, see 614720.