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Last updated:
April 18, 2022
Years published: 2022
NORD gratefully acknowledges Andrew Liu, PhD, Department of Physiology and Functional Genomics, University of Florida College of Medicine; Víctor Martínez-Glez, MD, PhD, Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz; Carlos E. Prada, MD, Division Head, Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children’s Hospital of Chicago; Carolyn Serbinski, MS, CGC, Genetic Counselor, Ann & Robert H. Lurie Children’s Hospital of Chicago; Laurie Smith, MD, PhD; and the Smith-Kingsmore Syndrome Foundation for the preparation of this report.
Summary
Smith-Kingsmore syndrome (SKS) is a rare, neurodevelopmental genetic disorder caused by changes (disease-causing variants) in the MTOR gene. SKS impacts the digestive, endocrine, metabolic and nervous systems.
Patients with SKS have a spectrum of medical, intellectual, and behavioral disabilities resulting in different and variable clinical outcomes. The most common findings in people with SKS are intellectual disability, developmental delay, large brain size (megalencephaly) and seizures. The symptoms vary and largely depend on the type of MTOR gene mutation that the patient has and its distribution in the body. Management of patients with SKS includes treatment of medical concerns, such as seizures as well as speech and physical therapy. Treatment is symptom-driven and there is currently no cure.
Introduction
Genetic changes in the MTOR gene were first noted as a cause of a neurodevelopmental disorder in 2013. Studies are still needed to continue to define the characteristics associated with specific MTOR gene variants. Presently, genetic changes in MTOR can be separated into three clinical types.
The first group includes patients with generalized brain overgrowth (megalencephaly), intellectual disability, autism and hypotonia. These are the patients who have been identified as having SKS.
The second group includes patients with diffuse brain overgrowth, abnormalities of the surface of the brain (polymicrogyria) and skin pigmentation abnormalities.
The third group includes patients with focal changes in the brain (focal cortical dysplasia or hemimegalencephaly) causing early-onset epilepsy.
The distribution and levels of MTOR genetic changes in these three groups vary. The mutations in MTOR in patients with SKS are usually present in all cells of the body. Disease characteristics vary in patients with SKS, even if they have the same MTOR gene mutation. In contrast, genetic changes in MTOR in the second and third groups can be more localized or restricted to certain tissues (mosaic). This may cause these mutations to escape detection if a patient has genetic testing on a blood or saliva sample.
Many symptoms and features are thought to be part of SKS. Some of these characteristics occur more frequently than others. Since there is great variability, not every person with SKS will have all these features. As research progresses, the formal description of SKS will likely change.
Individuals with SKS often show symptoms in very early childhood, sometimes at birth or in the first six months of life. These children often have medical challenges and typically have developmental delays. For example, children with SKS may not reach developmental milestones such as rolling over, sitting up, walking, or talking at the expected time.
Common features of SKS vary but may include:
BEHAVIORAL
• Autism / autistic traits / sensory processing disorder
• ADHD (attention-deficit/hyperactivity disorder)
• Non-verbal /speech anomalies, delayed or absent speech, distorted articulation
• Self-harming behaviors
NEUROLOGIC
• Global developmental delays/intellectual disability
• Macrocephaly / megalencephaly / ventriculomegaly / polymicrogyria / other brain abnormalities on MRI / rapid head growth in the first 6 months
• Low muscle tone (hypotonia)
• Seizures (including nocturnal focal epilepsy)
• Sleep issues (insomnia, waking at night, sleep apnea)
• Hearing Impairment
• Cortical visual impairment
DIGESTION / GASTROINTESTINAL
• Digestive issues (abdominal pain, constipation)
• Hyperphagia (abnormally increased appetite for food)
PHYSICAL
• Curly / wavy hair
• Abnormal facial features
• Frontal bossing, open mouth appearance, prominent and long philtrum, short nose with a flat nasal bridge, macrostomia, hypertelorism
• Macrosomia at birth (large for gestational age)
• Skin pigmentation / Blaschko lines / hypomelanosis/hypermelanosis in vito / Cafe au lait spots
• Decreased perspiration and heat intolerance
• Accelerated growth in first 18 months to 2 years
• Delayed bone age (scan at 2 years like a newborn) or slightly advanced bone age
• Motor skill deficits
SKS is usually an autosomal dominant condition, which means that one copy of the altered MTOR gene in each cell is sufficient to cause the disorder.
Changes in the MTOR gene are usually random events (sporadic or de novo) that happen in the egg or sperm prior to conception and are not inherited from either parent. This type of change is present in all cells of the affected individual and is called a germline variant.
There are also some SKS patients who have an altered MTOR gene in some, but not all of their cells, and this is called somatic mosaicism. This type of change is also de novo (not inherited) and occurs at some point while a baby is developing during pregnancy. MTOR gene mutations in these SKS patients can only be detected in samples of affected tissues and might not be detected in a blood or saliva sample.
Rarely, people with SKS inherit the altered gene from an unaffected parent who has a MTOR gene mutation only in their sperm or egg cells (germline tissues). This is called germline mosaicism and, although rare, it has been seen more frequently in SKS than in other diseases.
The MTOR gene encodes the MTOR protein which plays a central role in the cell’s nutrient/energy sensing pathway. This pathway provides a way for cells to communicate information such as when to grow and how quickly to grow. Changes in the MTOR gene may change the instructions for the body and how the MTOR pathway works.
Changes in MTOR can cause the pathway to become hyperactive (i.e., gain of function). As a result of pathway hyperactivation, the affected nerve cells (neurons) grow unusually large and misshapen, leading to brain malformations, cognitive delays and epilepsy.
MTOR-related disorders are extremely rare. The total patient population is still unknown, but it is estimated that there are about 10 people with MTOR gene disorders (with some MTOR mutations causing SKS) in every 10,000 individuals. However, SKS may go undiagnosed or misdiagnosed, making it extremely difficult to determine the true frequency in the general population. Based on the current understanding of this condition, SKS occurs worldwide in people of all ethnic groups.
SKS is a rare condition that many physicians are not familiar with. A diagnosis of SKS is suspected based upon the identification of characteristic features, a detailed patient and family history and a thorough clinical evaluation.
A diagnosis of SKS is confirmed with the detection of a germline or mosaic mutation in the MTOR gene. A genetic test performed on a sample of blood or saliva will detect a mutation that is present in all cells of the body (germline variants). To detect a mutation only present in some cells (somatic mosaicism), the genetic test must be performed on a sample of affected tissue.
Some individuals with SKS may be diagnosed with a molecular genetic test that covers a subset of genes related to the individual’s symptoms (gene panel testing) while others may have whole exome sequencing (WES) or whole genome sequencing (WGS). These methods rely on new technologies that allow rapid sequencing of large amounts of genetic material known as next-generation sequencing (NGS).
The appropriate testing should be discussed with the care team.
Currently, there is no cure for SKS, and no treatments approved by the U.S. Food and Drug Administrations (FDA). Treatment is based on a child’s specific symptoms. Patients and their families typically visit one or more of the following medical specialists:
Pediatrics
• Annual visits to monitor growth and development
• Medical management of constipation is often needed
• Monitoring for illness due to abnormal immune cell function
Developmental Pediatrics
• Developmental and behavioral evaluations to assess for challenges and recommend treatments
• Evaluate for appropriate therapies including physical, occupational, speech/feeding, behavioral, vision therapy
• Guide individualized education plans (IEPs)
Pediatric Genetics and Genetic Counseling
• Review genetic testing and results
• Provide information about recurrence risk
• Provide coordination of care
Neurology
• If seizures are suspected, an EEG (measurement of the brain’s
electrical activity) is recommended
• An MRI should be considered to identify any brain malformations
Ophthalmologist/Neuro-ophthalmologist
• Screening for cortical visual impairment (CVI)
Audiology
• Routine hearing screening (newborn and annually)
Endocrinology
• Consider a referral if hypoglycemia develops or if premature (precocious) puberty is suspected
Orthopedics/Physical Rehabilitation
• Evaluate the need for assistive devices due to hypotonia, motor deficits and/or bone abnormalities
Neuropsychology
• For school-age children, this assessment can help identify the most
appropriate educational support and schooling
Routine dental and/or orthodontic care is also recommended as well as speech and language therapy, physical and occupational therapy and behavior therapy/psychological counseling.
Some patients with SKS have been prescribed sirolimus (rapamycin) or everolimus to treat intractable seizures (seizures that cannot be controlled completely by other medications). There is currently no published data about how well this works (efficacy) and these drugs are not currently approved by the FDA to treat SKS. Studies are pending to determine the long-term effects of rapamycin on neurocognitive development in people with SKS and clinical trials are needed to clarify potential effectiveness of rapamycin.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Besterman AD, Althoff T, Elfferich P, et al. Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity. PLOS Genetics. 2021; 17(7): e1009651
Szczałuba K, Rydzanicz M, Walczak A, et al. Brain Tissue Low-Level Mosaicism for MTOR Mutation Causes Smith-Kingsmore Phenotype with Recurrent Hypoglycemia-A Novel Phenotype and a Further Proof for Testing of an Affected Tissue. Diagnostics (Basel). 2021;11(7):1269. Published 2021 Jul 15.
Poole RL, Curry PDK, Marcinkute R, et al. Delineating the Smith-Kingsmore syndrome phenotype: Investigation of 16 patients with the MTOR c.5395G > A p.(Glu1799Lys) missense variant. Am J Med Genet A. 2021 Aug;185(8):2445-2454.
López-Rivera JA, Pérez-Palma E, Symonds J, et al. A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants. Brain. 2020;143(4):1099-1105. doi:10.1093/brain/awaa051.
Zhang B, Guo D, Han L, et al. Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complex. Neurobiology of Disease 2020 Feb;134:104615.
Rodríguez-García ME, Cotrina-Vinagre FJ, Bellusci M, et al. A novel de novo MTOR gain-of-function variant in a patient with Smith-Kingsmore syndrome and antiphospholipid syndrome. European Journal of Human Genetics. 2019 Sep;27(9):1369-1378. Epub 2019 May 3.
Lee D, Jang J, Lee C. Smith–Kingsmore syndrome: The first report of a Korean patient with the MTOR germline mutation c.5395G>A p.(Glu1799Lys). Journal of Genetic Medicine. 2019;16:27-30.
Gordo G, Tenorio J, Arias P, et al. mTOR mutations in Smith-Kingsmore syndrome: Four additional patients and a review. Clin Genet. 2018;1–14.
Ramanathan C, et al. mTOR signaling regulates central and peripheral circadian clock function. PLoS Genet. 2018;14:e1007369.
Sabatini DM. Twenty-five years of mTOR: uncovering the link from nutrients to growth. Proc Natl Acad Sci USA. 2017; 114:11818–11825.
Moosa S, Bohrer-Rabel H, Altmuller J, et al. Smith-Kingsmore syndrome: a third family with the MTOR mutation c.5395G-A p.(Glu1799Lys) and evidence for paternal gonadal mosaicism. J. Med. Genet. 2017: 173A: 264-267.
Moller RS, Weckhuysen S, Chipaux M, et al. Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy. Genet. 2016; 2: e118.
Mirzaa GM, Campbell CD, Solovieff N, et al. Association of MTOR mutations with developmental brain disorders, including megalencephaly, focal cortical dysplasia, and pigmentary mosaicism. JAMA Neurol. 2016;73:836–845.
Baynam G, Overkov A, Davis M, et al. A germline MTOR mutation in aboriginal Australian siblings with intellectual disability, dysmorphism, macrocephaly, and small thoraces. J. Med. Genet. 2015; 167A: 1659-1667.
Mroske C, Rasmussen K, Shinde DN, et al. Germline activating MTOR mutation arising through gonadal mosaicism in two brothers with megalencephaly and neurodevelopmental abnormalities. BMC Med. Genet. 2015;16: 102.
Smith LD, Saunders CJ, Dinwiddie DL, et al. Exome sequencing reveals de novo germline mutation of mammalian target of rapamycin (MTOR) in a patient with megalencephaly and intractable seizures. Genomes Exomes 2013;2: 63-72.
Lee JH, Huynh M, Silhavy JL, et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nature Genet. 2012; 44: 941-945.
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