Microcephaly, Short Stature, And Polymicrogyria With Or Without Seizures

A number sign (#) is used with this entry because of evidence that microcephaly, short stature, and polymicrogyria with or without seizures (MSSP) is caused by homozygous or compound heterozygous mutation in the RTTN gene (610436) on chromosome 18q22.

Clinical Features

Kheradmand Kia et al. (2012) reported a consanguineous Turkish family in which 2 sibs were demonstrated to have diffuse asymmetric polymicrogyria extending from the frontal to the temporal, parietal, and occipital lobes on brain MRI. Other imaging findings included mild ventricular enlargement and thin or short corpus callosum. One patient had mild cerebellar atrophy. The patients were 12 and 14 years old at the time of the report. Both had microcephaly, moderate to severe mental retardation, poor speech, dysarthria, and seizures. One had pyramidal signs. Another family member had moderate mental retardation and seizures, but detailed clinical features were not available. An unrelated 16-year-old boy with diffuse polymicrogyria had microcephaly, severe mental retardation with lack of speech, seizures, and spastic tetraparesis. Two of the patients had normal abdominal ultrasound with situs solitus; 1 had small kidney volume.

Shamseldin et al. (2015) described 3 unrelated families segregating microcephaly, short stature, and polymicrogyria without seizures. In the first family, 3 brothers, born to consanguineous parents from Yemen, had intrauterine growth retardation (IUGR), severe short stature, primary microcephaly, and severe intellectual disability. Brain MRI in the oldest brother, aged 12 years, showed few sulcations, bilateral pachygyria, and shallow Sylvian fissures. He also had a single kidney and mild bilateral hearing loss. His 11-year-old brother had a sacral lesion cephalad to the gluteal crease without abnormality of the spinal cord, a right pelvic ectopic kidney, hypospadias, and an undescended testis. His 6-year-old brother had a sacral lesion cephalad to the gluteal crease. In another family, a 5-year-old male, born to consanguineous Saudi Arabian parents, had severe IGUR, severe short stature, primary microcephaly, mildly delayed motor development, noticeable delay in cognitive and speech development, typical microcephaly-related craniofacial dysmorphism, and increased tone. Brain MRI showed simplified gyration, and a 3D computed tomography scan revealed secondary craniosynostosis. In the third family, 2 Canadian brothers were affected. One boy had severe microcephaly, a sloping forehead, a high and broad nasal bridge, multiple joint contractures, and severe failure to thrive. MRI showed severe cerebral and cerebellar hypoplasia, incomplete separation of the cerebral hemispheres, dysgenesis of the corpus callosum, an abnormal ventricular system, a large posterior cyst, multiple areas of lissencephaly and/or pachygyria and polymicrogyria, and multiple subependymal gray matter heterotopias. He died at 2 months of age of a cardiorespiratory arrest. His brother had severe, prenatal-onset growth restriction characterized by microcephaly, and a sloping forehead. His MRI showed microcephaly with gross brain parenchymal abnormalities affecting the cerebral hemispheres and the cerebellum, both of which were extremely small, agenesis of the corpus callosum, reduced sulcation, deformed ventricles, and large cerebrospinal fluid intensity areas occupying the majority of supratentorial compartments bilaterally. He also had cryptorchidism and required urgent surgical intervention for duodenal atresia. He died at 19 days of age.

Grandone et al. (2016) reported a brother and sister, born of first-cousin Moroccan parents, with MSSP. At birth, the sibs had severe microcephaly, 28 cm (-5.5 SD) in the boy and 27 cm (-5.3 SD) in the girl. Birth weights and lengths were -1.47 SD and -2.3 SD in the boy and -1.7 SD and -2.9 SD in the girl, respectively. Both sibs presented with diffuse eczema at birth. Facial dysmorphisms included receding forehead and chin, protruding nose, hypotelorism with prominent eyes, slightly upturned palpebral fissures, and simple helices. Both sibs showed severe growth failure and developmental delay. The boy started to walk at age 20 months and speech was absent at his last examination at age 35 months; the girl could sit and crawl at 21 months but could not yet walk and had no speech. Skin remained diffusely pruritic, scaled, and dry in both patients, but dermatitis had begun to improve spontaneously in the boy. Brain MRI showed lissencephaly, periventricular gray matter heterotopia, pons hypoplasia, and a quadigeminal cistern arachnoid cyst extending into the right occipital region.

Wambach et al. (2018) identified a boy with primary microcephaly, simplified gyri, pontocerebellar hypoplasia, contractures, and intractable epilepsy. The boy had a head circumference within normal limits (-1.5 SD) at birth, but by 6 weeks of age, he was severely microcephalic (-4.9 SD). On physical exam, he had microcephaly with metopic ridging, occipital prominence, bilateral microphthalmia, microstomia, microretrognathia, smooth philtrum, relatively large cupped low-set ears, bilateral contractures of knees and ankles, mild camptodactyly with contractures of the interphalangeal joints, and bilateral syndactyly of fourth and fifth fingers and second to fifth toes, microphallus, cryptorchidism, and appendicular hypertonia with normal deep tendon reflexes. Brain MRI showed cerebral hypoplasia with simplified gyral pattern, pontocerebellar hypoplasia, bilateral frontal cortical dysplasia, agenesis of the corpus callosum, thinning of the periventricular white matter, misshapen orbital globes, and optic nerve hypoplasia. Ophthalmologic evaluation showed rudimentary retinal vasculature, hypoplastic optic nerves, and pale optic discs. The patient also had gracile appearing bones with thin ribs on skeletal survey. He had bilateral pyelocaliectasis on renal ultrasound. He had intractable seizures and died at age 4 months of acute, progressive respiratory failure. Wambach et al. (2018) noted that this patient's ophthalmologic and skeletal findings had not previously been reported in patients with MSSP.

Cavallin et al. (2018) reported a boy with severe microcephaly, polymicrogyria, and growth restriction, consistent with MSSP. Concerns were initially raised prenatally because of a small head circumference (-4.5 SD) and other abnormalities of the brain. Birth length and weight were also abnormal (-4 SD and -2 SD, respectively). The boy showed microcephaly-related craniofacial dysmorphism, axial hypotonia, and limb spasticity. He began to develop hyperkinesia, with agitation and crying, and severe sleep disorders by the age of 6 months. At last evaluation at age 5 years 9 months, his height and weight were both -4 SD and his head circumference was -10 SD. Development was severely delayed. He had hyperkinetic movement disorders, with self-injurious behavior and motor stereotypies. Neurologic examination showed pyramidal signs. Brain MRI showed microcephaly with extremely reduced frontal lobes, bilateral generalized dysgyria with areas of polymicrogyria, and posterior corpus callosum agenesis. The patient did not develop seizures. EEG showed a rapid alpha-like rhythm with frontotemporal spikes.

Inheritance

The transmission pattern of polymicrogyria in the family reported by Kheradmand Kia et al. (2012) was consistent with autosomal recessive inheritance.

Mapping

By autozygosity mapping on the basis of a while-genome search of 3 affected members of a family segregating polymicrogyria with seizures, Kheradmand Kia et al. (2012) found shared homozygous regions on chromosomes 14q24.3-q31.1 and 18q22.

Molecular Genetics

In 3 members of a consanguineous Turkish family with polymicrogyria with seizures, Kheradmand Kia et al. (2012) identified a homozygous mutation in the RTTN gene (L932F; 610436.0001). The mutation was identified by autozygosity mapping followed by candidate gene sequencing. Another unrelated patient with a similar disorder carried a different homozygous mutation (C27Y; 610436.0002). Mutant L932F RTTN correctly localized to the basal bodies in patient fibroblasts, but there was a higher percentage of ciliary abnormalities, including short cilia with bulbous tips, compared to control. No ciliary abnormalities were apparent in cells from the patient with the C27Y mutation. However, gene expression profiling in patient fibroblasts with both mutations showed deregulation of several genes involved in brain development and/or known to be regulated at the cilium compared to control fibroblasts. Such genes included SHH (600725), HHIP (606178), WNT5A (164975), and BMP4 (112262). The polymicrogyria was primarily a postmigratory cortical organization defect, consistent with the localization of rotatin to the marginal zone in mouse embryonic brain. The findings supported the involvement of rotatin in the pathogenesis of this cortical malformation, and suggested that aberrant ciliary function contributes to abnormal development and organization of the cortex in humans.

In affected members of 3 unrelated families with microcephaly, short stature, and polymicrogyria, Shamseldin et al. (2015) identified homozygous or compound heterozygous mutations in the RTTN gene (610436.0003-610436.0006).

In a brother and sister, born of first-cousin Moroccan parents, with MSSP, Grandone et al. (2016) identified a homozygous missense mutation in the RTTN gene (R985G; 610436.0007). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the gnomAD database.

Using trio-based whole-exome sequencing, Cavallin et al. (2018) identified homozygosity for the R985G mutation in the RTTN gene in a boy with MSSP. The boy's consanguineous Moroccan parents were heterozygous for the mutation.

In a male infant with MSSP, Wambach et al. (2018) identified compound heterozygous mutations in the RTTN gene: V64F, which was not present in the ExAC database, and an intronic variant (c.32-3C-T), which was present at a frequency of 0.0073 in the ExAC database. Cultured fibroblasts from the infant showed abnormal cilia with reduced length and number of primary cilia. The authors suggested that functional characterization of primary cilia length and number could be used to determine RTTN variant pathogenicity.