Microcephaly and chorioretinopathy are a group of rare genetic disorders primarily characterized by abnormal development of the head and eyes during the fetal period. Microcephaly is defined as a head circumference more than 2 standard deviations (SD) below the mean for age and sex. Chorioretinopathy is observed on fundus examination as punched-out lesions and may be associated with rod-cone dysfunction.
This group of disorders is classified into the following four types based on the causative gene:
The prevalence of MCLMR due to KIF11 mutation is estimated to be less than 1 in 1,000,000 2). KIF11 mutations account for all familial cases and about half of sporadic cases, with up to 40% arising from de novo mutations 2). ClinVar lists 140 pathogenic or likely pathogenic KIF11 mutations, comprising 72 frameshift, 39 nonsense, 22 splice site, and 7 missense mutations 3).
MCCRP (types 1-3) are autosomal recessive, occurring when both parents are carriers. MCLMR is autosomal dominant, potentially caused by a mutation from one parent, but de novo mutations are also common. In the dominant type MCLMR, incomplete penetrance and variable expressivity are prominent.
Ocular findings vary depending on the genetic type. Ocular abnormalities are present in approximately 72% of patients3).
MCCRP1–3 (Recessive type)
Chorioretinal atrophy: Punched-out lesions with pigmentary changes and atrophy are characteristic.
Rod-cone dystrophy: Electroretinography shows reduced amplitude and delayed responses in both photopic and scotopic conditions. Some cases may be non-recordable.
Retinal folds and retinal detachment: May present with posterior pole lesions similar to familial exudative vitreoretinopathy.
Microphthalmia and microcornea: Reported in several types.
MCLMR (Dominant type, KIF11)
Chorioretinal lacunae: Accompanied by extramacular pigment clumping and vascular attenuation. Extensive posterior pole atrophy has also been reported.
FEVR-like findings: Incomplete retinal vascular development, retinal folds, and tractional retinal detachment may occur2).
Others: Cataracts, optic disc pallor or dysplasia, hyperopia or myopia, and keratoconus (rare)3).
Microcephaly is the most common finding, present in approximately 91% of patients, with severity ranging from -2 SDS to -9.5 SDS3). Lymphedema occurs in 47%, usually congenital and limited to the lower limbs3).
Systemic comorbid findings are shown below.
In a parent support group survey (n=63), 20% of children with KIF11 mutations had ASD, 25% had ADHD, and 15% had both diagnoses1). This is significantly higher than the general population prevalence of ASD (approximately 1%) and ADHD (5–7%).
Electroretinography shows diffuse retinal dysfunction. In one case, using skin electrodes, both rod and cone signals were abnormally low and delayed2).
This group of disorders is caused by mutations in four genes. All encode proteins involved in microtubule dynamics and mitotic spindle function (see “Pathophysiology” section).
| Genetic type | Gene | Inheritance pattern |
|---|---|---|
| MCCRP1 | TUBGCP6 (22q13) | Autosomal recessive |
| MCCRP2 | PLK4 (4q28) | Autosomal recessive |
| MCCRP3 | TUBGCP4 (15q15) | Autosomal recessive |
| MCLMR | KIF11 (10q23.33) | Autosomal dominant |
In MCLMR, incomplete penetrance and variable expressivity are major features. Even individuals with the same mutation within the same family can have significantly different phenotypes1)3).
Apuhan et al. (2025) reported 7 individuals from 2 families and showed that among a mother, sisters, and an aunt with the same mutation (c.2946dup), the presence of ocular findings, intellectual disability, and lymphedema varied markedly3).
Because KIF11 mutations have incomplete penetrance and variable expressivity, the clinical picture can vary greatly among individuals even with the same mutation3). Modifier genes and environmental factors are suspected to be involved, but a clear genotype-phenotype correlation has not been established.
The combination of microcephaly and chorioretinopathy is also seen in congenital infections (TORCH infections), so it is important to first rule out infection.
The mainstay of definitive diagnosis is identification of genetic mutations by whole exome sequencing (WES). Targeted genetic testing is also possible when clinically strongly suspected. The causative gene is currently included in standard gene panels for inherited retinal diseases.
The main diseases to be differentiated are listed below.
| Disease | Key Points for Differentiation |
|---|---|
| TORCH infections | Accompanied by jaundice, hepatosplenomegaly, and intracranial calcifications |
| FEVR | No microcephaly. Phenotype overlaps with KIF11-related disorders. |
| Aicardi syndrome | X-linked. Characterized by infantile spasms and agenesis of the corpus callosum. |
Congenital cytomegalovirus infection may present with microcephaly, hepatosplenomegaly, jaundice, intracranial calcifications, and chorioretinitis. Congenital toxoplasmosis is characterized by necrotic scar lesions centered on the macula. Both are differentiated by serological and virological tests.
There is currently no curative treatment for this group of diseases. Management focuses on symptomatic intervention for ocular complications and systemic follow-up.
Yaskanich et al. (2025) reported a 20-year follow-up of MCLMR due to KIF11 mutation2). At age 11, the left eye developed retinal detachment with macular detachment, and vitrectomy, scleral buckling, and cataract surgery were performed, but final visual acuity in the left eye was no light perception. At age 32, scleral buckling was performed on the right eye, and visual acuity improved from 20/400 to 20/200.
Scleral buckling or vitrectomy may be performed, but the prognosis depends on the stage of the disease and the timing of surgery 2). While there are reports of preserving vision in one eye, vision recovery may be difficult in severe cases. Early detection and regular retinal examinations are important.
Primary microcephaly results from defects in neurogenesis. Most identified microcephaly-related genes encode centrosomal proteins. All four genes in this disease group are involved in microtubule dynamics and mitotic spindle function.
Microtubules are nucleated by centrosomes during mitosis. Centrosomes consist of a pair of centrioles surrounded by pericentriolar material, where γ-TuRC is scattered. γ-TuRC is composed of γ-tubulin and GCP2–6.
KIF11 encodes the homotetrameric kinesin motor protein EG53). EG5 is essential for bipolar spindle formation and maintenance during mitosis, and contains microtubule-binding, ATP-binding, and motor domains3).
Inhibition of KIF11 leads to monopolar spindle formation and chromosome misalignment, inducing apoptosis in neural progenitor cells and embryonic retinal neurons. This is thought to cause microcephaly and chorioretinopathy.
Most reported pathogenic mutations produce truncated proteins, suggesting a haploinsufficiency mechanism3). However, predicting clinical phenotype from mutation type or location is difficult, and a clear genotype-phenotype correlation has not been established3).
KIF11 also plays an important role in retinal vascular development, and its pathogenic mutations are associated with a FEVR-like phenotype. Overlap between MCLMR and FEVR phenotypes has been recognized in recent years2).
Apuhan et al. (2025) identified craniosynostosis in two patients with KIF11 mutations, reporting it as a novel phenotype of this syndrome for the first time3). Additionally, the first case of detecting lymphedema as dorsal foot edema on prenatal ultrasound has been reported.
These findings suggest that the clinical spectrum of KIF11-related disorders is broader than previously recognized.
Marcelis et al. (2024) showed in a survey of parent support groups that the prevalence of ASD in children with KIF11 mutations is 20%, and ADHD prevalence is 25%1). These rates are significantly higher than in the general population. Elucidating the link between KIF11 mutations and neurodevelopmental disorders may provide new insights into the genetic mechanisms of neurodevelopment.
Phenotypic overlap between MCLMR and FEVR has been reported in multiple studies2). It has been proposed that both should be treated under the same classification system, and efforts are underway to develop an integrated management approach.
