Smith-Kingsmore Syndrome
A number sign (#) is used with this entry because of evidence that Smith-Kingsmore syndrome (SKS) is caused by heterozygous mutation in the MTOR gene (601231) on chromosome 1p36.
DescriptionSmith-Kingsmore syndrome is a rare autosomal dominant syndromic intellectual disability syndrome characterized by macrocephaly, seizures, umbilical hernia, and facial dysmorphic features including frontal bossing, midface hypoplasia, small chin, hypertelorism with downslanting palpebral fissures, depressed nasal bridge, smooth philtrum, and thin upper lip (Smith et al., 2013; Baynam et al., 2015).
Clinical FeaturesSmith et al. (2013) described a girl with megalencephaly and intractable seizures. The pregnancy was complicated by maternal hypothyroidism and preeclampsia, and the patient was born at 35 weeks' gestation by cesarian section for breech presentation. She had macrocephaly, poor feeding, hypoglycemia, thrombocytopenia, and hypotonia. Brain imaging showed callosal dysgenesis and mild dilatation of the posterior horns of the lateral ventricles. At age 2 months, she developed apneic seizures and EEG showed high voltage spike and slow wave activity. Treatment with antiepileptic medication was unsuccessful. The patient also had dysmorphic features including large anterior fontanel, frontal bossing, midface hypoplasia, small chin, hypertelorism with downslanting palpebral fissures, depressed nasal bridge, smooth philtrum, and thin upper lip. Other features included narrow thorax, umbilical hernia, rhizomelic limb shortening, and short proximal phalanges. She died of pneumonia at age 19 months.
Baynam et al. (2015) described 3 Aboriginal Australian sibs with intellectual disability, macrocephaly, seizures, umbilical hernia, cafe-au-lait lesions, and craniofacial features including macrostomia, an open mouth posture, hypertelorism, short nose with a depressed nasal bridge, downslanting palpebral fissures, curly or wavy hair, long philtrum, and tall forehead. A cerebral MRI of sib 1 at 2 years 5 months of age showed mild prominence of the ventricular system, hypogenesis of the body and the splenium of the corpus callosum, and generalized white matter loss, particularly in the peritrigonal regions. The mesencephalon, pons, and medulla were small. The cerebellum was normal. A cranial MRI of sib 2 at 2 years 6 months of age showed megalencephaly, perisylvian polymicrogyria, mild prominence of the lateral ventricles, moderate hypogenesis of the corpus callosum, 3 small areas of heterotopic gray matter within the right frontal lobe, and a small left middle cranial fossa arachnoid cyst.
Mroske et al. (2015) reported 2 brothers, aged 6 and 23 years, with SKS. The patients were large for gestational age, had progressive macrocephaly (+5 SD), mildly delayed psychomotor development with intellectual disability and autistic features, and hypotonia. They had mild dysmorphic features, including prominent forehead, deep-set eyes, and strabismus. Both also had iris coloboma and cryptorchidism. Linear growth and weight normalized with age. The older brother had more severe intellectual disability with significant delays in speech and motor skills, whereas the younger brother had more significant asthma and persistent food allergies. Neither had seizures.
Moosa et al. (2017) reported a brother and sister, born of unrelated German parents, with SKS. The patients had progressive macrocephaly from birth (up to +6 SD) and delayed psychomotor development with learning disabilities. Both attended a special-needs school. Dysmorphic features included prominent forehead, frontal bossing, downslanting palpebral fissures, depressed nasal bridge, open mouth, small chin, narrow chest, and short distal phalanges of the hands and feet. The older sister had cystic kidneys, although there was a history of cystic kidneys in the paternal line associated with mutation in the PKD1 gene (601313). She also had multiple polyps in the ileum, cecum, and colon, but it was unclear whether or not the intestinal polyps were related to the disorder.
Clinical Variability
Moller et al. (2016) reported 8 patients, including a mother and daughter and a pair of monozygotic twin sisters, with germline mutations in the MTOR gene and a phenotype consistent with SKS. Seven of the 8 patients had epilepsy, including 6 with focal epilepsy and 1 with generalized epilepsy. The age of seizure onset ranged from 8 months to 10 years. Seizure types were variable, and all patients with seizures showed EEG abnormalities. About half of patients had delayed development, cognitive impairment, intellectual disability, and/or autistic features. Five patients had macrocephaly, and 6 had dysmorphic features, such as frontal bossing, low-set ears, micrognathia, and depressed nasal root. Moller et al. (2016) noted that the phenotypic spectrum associated with germline MTOR variants included milder phenotypes than previously reported; none of the patients had a malformation of cortical development apparent on brain imaging, although some had enlarged ventricles or thin corpus callosum, and at least 3 had near-normal cognitive development. One patient had macrocephaly and intellectual disability without seizures.
Molecular GeneticsIn a girl with megalencephaly and intractable seizures, Smith et al. (2013) identified a de novo heterozygous missense mutation in the MTOR gene (C1483F; 601231.0001). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Smith et al. (2013) noted that Lee et al. (2012) had previously identified a somatic mutation at the same residue in the MTOR gene (C1483Y) in brain cells derived from a patient with hemimegalencephaly and seizures and had postulated a gain-of-function effect.
In 3 Aboriginal Australian sibs with intellectual disability, dysmorphism, macrocephaly, and small thoraces, Baynam et al. (2015) identified a de novo heterozygous missense mutation in the MTOR gene (E1799K; 601231.0001). Peripheral blood cells derived from 1 of the patients showed increased mTOR activity when stimulated, and the increased response was inhibited by coincubation with rapamycin. The findings were consistent with a gain-of-function effect at the cellular level. Because the 3 sibs had different fathers and the mutation was not detected in the mother's peripheral blood, Baynam et al. (2015) suggested that the mother was gonadal mosaic for the mutation.
Mroske et al. (2015) identified a de novo heterozygous E1799K mutation in 2 brothers with SKS. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the peripheral blood of either parent, suggesting it originated as a consequence of gonadal mosaicism. Based on molecular modeling, Mroske et al. (2015) noted that the E1799K mutation occurs in the FAT domain, which clamps onto the kinase domain and negatively regulates MTOR activity. Disruption of this residue may destabilize the protein and shift it to a more active state. Mroske et al. (2015) suggested that increased MTOR activity could cause exaggerated protein synthesis during brain development, or that this increased activity could trigger inflammation in the brain.
In 8 patients, including a mother and daughter and a pair of monozygotic twins sisters, with variants of SKS, Moller et al. (2016) identified de novo heterozygous germline missense mutations in the MTOR gene (see, e.g., 601231.0009 and 601231.0010). The mutations were found by exome sequencing of a custom gene panel and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed.
In 2 sibs, born of unrelated German parents, with SKS, Moosa et al. (2017) identified a de novo heterozygous E1799K mutation in the MTOR gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not detected in the parents' peripheral blood. Additional sequencing indicated that the mutation was located on the paternal chromosome, which Moosa et al. (2017) suggested was consistent with paternal gonadal mosaicism. Functional studies of the variant and studies of patient cells were not performed.