Clinical characteristics.

Smith-Kingsmore syndrome (SKS) is characterized by varying degrees of overgrowth, developmental delay / intellectual disability, neurodevelopmental issues (autistic features, ADHD), and congenital anomalies. Developmental delay typically involves all aspects of development (gross motor, fine motor, speech/language). Virtually all individuals have speech delay, although speech abilities over time range from vocalizations to some verbal communication, with about 50% of individuals reportedly able to use verbal communication. Intellectual disability is frequently identified in affected individuals and typically ranges from moderate to severe. Regression in development has been reported in a minority of affected individuals. Other features of SKS include congenital hypotonia, epilepsy, sleep-wake disturbances (including insomnia and obstructive sleep apnea), macrocephaly, hyperphagia, eye anomalies, skeletal anomalies, cardiac findings (including stable aortic root dilatation), and genitourinary anomalies, most commonly in males (undescended testes and hypospadias).

Diagnosis/testing.

The diagnosis of SKS is established in a proband with suggestive findings and a heterozygous constitutional or early postzygotic activating pathogenic variant in MTOR identified by molecular genetic testing. Because a significant subset (20%-25%) of individuals have a pathogenic variant that is postzygotic (and thus mosaic), more than one tissue may need to be tested, such as sequence analysis of DNA derived from a freshly obtained dermal biopsy.

Management.

Treatment of manifestations: Feeding therapy with consideration of gastrostomy tube placement for persistent feeding issues; healthy lifestyle and referral to nutritionist to address obesity; standard treatment for epilepsy, developmental delay / intellectual disability, scoliosis and/or pes planus, mobility issues, vision issues, aortic dilatation, valvar and cardiac septal defects, sleep abnormalities, undescended testes / hypospadias, hypoglycemia, and hearing loss.

Surveillance: At each visit, measure growth parameters, evaluate nutritional status, monitor eating habits, assess for signs of hyperphagia, assess for new neurologic manifestations such as seizures and developmental regression, monitor developmental progress and educational needs, assess mobility and self-help skills, monitor for signs/symptoms of sleep disturbance, and assess for scoliosis clinically (until skeletal maturity). At least annually or as clinically indicated, obtain ophthalmology evaluation. As clinically indicated, monitor for hypoglycemia (typically in infancy), obtain behavioral assessment for anxiety, ADHD, autism, aggression, and self-injury, and perform audiology evaluation.

Therapies under investigation: Off-label sirolimus (rapamycin) has been used in seven individuals with SKS at low-to-moderate doses with parent-reported improvements in some behaviors, including verbal skills, attention span, decreased self-aggression, and improved hyperphagia. Before using mTOR inhibitors (e.g., rapamycin), it is advisable or necessary to assess the biochemical and functional impacts of the pathogenic variant in the affected individual to optimize dosing and timing. Of note, first-generation, second-generation, and third-generation inhibitors may have distinct mechanisms and off-target effects. Any off-label use of drugs should be done at the discretion of the treating physician in conjunction with the affected individual and/or caregiver and is not endorsed by GeneReviews or the authors of this chapter.

Genetic counseling.

SKS is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Approximately 86% of individuals diagnosed with SKS have the disorder as the result of a de novo constitutional or early postzygotic pathogenic variant in MTOR. Some individuals have the disorder as the result of an MTOR pathogenic variant inherited from an unaffected parent with gonadal mosaicism (~11%) or, rarely, an affected parent (~3%). Sib recurrence has been reported in several families with presumed parental gonadal mosaicism. Once the MTOR pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

SKS should be considered in probands with the following clinical and brain MRI findings and family history.

Clinical findings

• Macrocephaly (head circumference that measures 2 standard deviations [SD] or more above the mean for age and sex)
• Large for gestational age (weight and/or length that is more than 2 SD above the mean for age and sex)
• Developmental delays or intellectual disability, typically in the moderate-to-severe range
• Neurodevelopmental disorders, such as autism spectrum disorder and/or attention-deficit/hyperactivity disorder
• Epilepsy, including generalized or focal epilepsy and/or status epilepticus
• Sleep-wake abnormalities
• Hyperphagia
• Hypotonia
• Ophthalmologic involvement, including strabismus, refractory abnormalities, and optic atrophy
• Distinctive facial features (See Figure 1 and Clinical Description, Facial features.)

Figure 1.

Individuals with Smith-Kingsmore syndrome

Brain MRI findings

• Cortical malformations, including polymicrogyria, focal cortical dysplasia, and hemimegalencephaly
• Other brain abnormalities, such as atypical corpus callosum and ventriculomegaly

Family history. Because SKS is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Occasionally, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations) or gonadal mosaicism (e.g. affected males and females in the same generation with unaffected parents) [Liu et al 2024].

Establishing the Diagnosis

The diagnosis of SKS is established in a proband with suggestive findings and a heterozygous constitutional or early postzygotic activating pathogenic (or likely pathogenic) variant in MTOR identified by molecular genetic testing (see Table 1). Because a significant subset (20%-25%) of individuals have a pathogenic variant that is postzygotic (and thus mosaic), more than one tissue may need to be tested, such as sequence analysis of DNA derived from a freshly obtained dermal biopsy (see Molecular Genetics).

Note: (1) Per American College of Medical Genetics and Genomics (ACMG) / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous MTOR variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

To date, at least 100 individuals have been identified with a pathogenic variant in MTOR leading to SKS [Smith et al 2013, Baynam et al 2015, Lim et al 2015, Mroske et al 2015, Mirzaa et al 2016, Møller et al 2016, Moosa et al 2017, Gordo et al 2018, Handoko et al 2019, Lee et al 2019, Rodríguez-García et al 2019, Besterman et al 2021, Carli et al 2021, Carmignac et al 2021, Poole et al 2021, Resta et al 2021, Liu et al 2024]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delays and intellectual disability. The majority of affected individuals exhibit developmental delays, which are often the first noticeable feature, typically presenting before the age of two years.

• Developmental delay involving all aspects of development (gross motor, fine motor, speech/language) is commonly observed, but some individuals can present with more significant and specific language delays.
  • Most individuals are able to walk independently at an average age of 2.5 years (typically ranging from about age 18 months to up to age 5 years).
  • About one third of affected individuals do not achieve independent ambulation.
  • Virtually all individuals have speech delay.
  • Speech abilities over time range from vocalizations to some verbal communication, with about 50% of individuals reportedly able to use verbal communication.
• Intellectual disability is frequently identified in affected individuals and typically ranges from moderate to severe.
• There is a significant lack of longitudinal follow-up data, limiting understanding of the long-term developmental trajectory and outcomes in affected individuals.
• Regression in overall development has been reported in about 18% of affected individuals.
  • Most of the individuals with regression also had autism or autistic behaviors.
  • A few individuals with developmental regression also had epilepsy.

Neuromuscular concerns are observed in 79% of individuals.

• Congenital hypotonia is present in 46% of individuals. It is most often mild to moderate and is not progressive.
• Hypertonia is less common but has also been noted.

Epilepsy. About 60% of affected individuals have epilepsy, with seizures first presenting in childhood for many.

• Both generalized and focal seizures have been described.
• While there is limited data available, status epilepticus in general tends to be more common in individuals with brain malformations.
• EEG may demonstrate a combination of midline rhythmic waveforms and asynchronous spike-and-wave discharges with anterior fast activity in sleep and wake, which is a possible hallmark feature, although further data is needed to improve our understanding [Simonelli et al 2024].

Neurobehavioral/psychiatric manifestations

• Autism spectrum disorder (ASD) or autistic behaviors are reported in 46% of affected individuals. ASD is common in individuals with regression, but not all those with ASD have regression.
• Attention-deficit/hyperactivity disorder (ADHD) or hyperactivity/impulsivity is reported in 22% of affected individuals. More than half of individuals with ADHD have a co-occurring ASD diagnosis.
• Self-injurious behaviors or aggression toward others are reported in 27% of affected individuals.
• Anxiety is reported in about 15% of affected individuals and may be present starting in early childhood. However, there is a significant lack of natural history data in adolescents and adults, limiting understanding of the likelihood of anxiety presenting across the life span.

Sleep disturbances. About 75% of affected individuals have sleep-wake disturbances, including insomnia and obstructive sleep apnea.

• Sleep onset and sleep maintenance difficulties have both been reported, although sleep maintenance difficulties are more common.
• Circadian rhythm sleep-wake disorders have also been described.

Facial features. Distinctive facial features have been observed but may not be specific enough to this condition to be able to make a clinical diagnosis without confirmatory molecular genetic testing (see Figure 1). The features are more evident in early childhood but not present in all individuals. In older individuals some features can be more subtle and difficult to diagnose. In general, the distinctive facial features include:

• Macrocephaly
• Broad forehead
• Widely spaced eyes
• Downslanted palpebral fissures
• Long philtrum
• Thin vermilion of the upper lip
• Wide mouth
• Open-mouth posture

The above describable facial features are more consistently present in individuals with pathogenic variants in the kinase and FAT domains (see Genotype-Phenotype Correlations).

Growth. Onset of generalized overgrowth has been noted at birth and early postnatally in 47% of affected individuals.

• Macrocephaly (head circumference >2 standard deviations [SD] above the mean for age and sex) is a hallmark feature, present in 90% of affected individuals.
• Limited prenatal growth data is available, but in at least one report fetal macrocephaly was noted during pregnancy [Everett et al 2022].
• Height may normalize in adulthood, but final adult height data is scarce.

Gastrointestinal/feeding issues

• There has been at least one individual with a PEG tube placement [Szczałuba et al 2021] and at least two individuals with dysphagia [Besterman et al 2021].
• Hyperphagia has been described in 41% of affected individuals. This typically presents in early childhood. There is one affected adult reported with obesity [Bonnet et al 2024].
• Constipation has also been observed.
• One adult with SKS has been reported with intestinal polyps, but ongoing natural history studies are needed to help clarify if this is related to the diagnosis of SKS [Moosa et al 2017].

Ophthalmologic involvement is noted in 71% of affected individuals and includes cortical visual impairment, strabismus, refractory abnormalities, optic atrophy, enlarged retinal vessels, iris coloboma, and drusen pigmentation.

Skeletal features. Abnormal gait, pes planus, and scoliosis have been described.

Cardiovascular abnormalities. About 40% of individuals who have undergone cardiac imaging have abnormalities. Described findings include mitral valve dysplasia and stenosis, septal defects, bicuspid aortic valve, and stable aortic root dilatation.

Neuroimaging. About 80% of individuals who have undergone neuroimaging have abnormalities.

• A range of cortical malformations have been reported, including polymicrogyria, focal cortical dysplasia, and hemimegalencephaly.
• Other abnormalities include ventriculomegaly, abnormal corpus callosum, white matter abnormalities, and brain atrophy.

Other associated features

• Hearing impairment. Sensorineural hearing loss has been reported in a few affected individuals but is not common.
• Genitourinary abnormalities. Undescended testes and hypospadias have been described in males.
• Ectodermal findings
  • Hyperpigmented nevi are a common finding in individuals with a mosaic pathogenic variant.
  • Hair can be curly/wavy in some individuals.
  • Dry skin and pigmentary mosaicism have also been described.
• Endocrinologic. Infantile hypoglycemia has been observed in a few individuals [Poole et al 2021, Szczałuba et al 2021].

Prognosis. A few individuals have been reported with early death, including one individual who succumbed due to hypoxic respiratory failure in the setting of viral pneumonia [Smith et al 2013; C Prada, D Krueger, & C Raski, personal observations]. However, survival to adulthood is common. One reported individual with a pathogenic variant in the FIT domain of MTOR is alive at age 70 years [Møller et al 2016], demonstrating that survival into late adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported. Additional studies are needed to better understand the life span and health span in individuals with Smith-Kingsmore syndrome.

Genotype-Phenotype Correlations

Protein domain-related correlations

• Kinase domain. The following are more common in individuals who have pathogenic variants in the kinase domain:
  • Hearing problems
  • Distinctive facial features
• FAT domain. The following are more common in individuals who have pathogenic variants in the FAT domain:
  • Autistic behavior
  • Distinctive facial features

Pathogenic variant-related correlations

• c.5395G>A (p.Glu1799Lys) is the most prevalent pathogenic variant, reported in close to 50% of individuals with SKS. Affected individuals with this pathogenic variant have more uniform neurodevelopmental outcomes, including developmental delay involving all aspects of development (gross motor, fine motor, and speech/language), intellectual disability, and autistic behaviors (see Molecular Genetics).

Prevalence

The prevalence of this condition is unknown.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SKS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for SKS.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Off-label sirolimus (rapamycin) has been used in seven individuals with SKS [Liu et al 2024] at low-to-moderate doses (0.5-2 mg/day) with parent-reported improvements in some behaviors, including verbal skills, attention span, self-aggression, and hyperphagia.

Note: Individuals with SKS have experienced sleep-wake cycle abnormalities when sirolimus trough levels exceeded 3 ng/mL, suggesting that a lower dose with target levels of <3 ng/mL should be considered for individuals with SKS. While further controlled and objective clinical studies are warranted to evaluate the efficacy and safety of the use of sirolimus in this population, it is recommended to monitor sleep-wake behavior closely in individuals with SKS treated with sirolimus and adjust the dose accordingly for optimal benefit and overall health.

Before using mTOR, it is advisable or necessary to assess the biochemical and functional impacts of the pathogenic variant in the affected individual to optimize dosing and timing. Additionally, it is noted that first-generation, second-generation, and third-generation inhibitors may have distinct mechanisms and off-target effects.

Rx-Matcher is a free web platform established at the University of Washington that enables clinicians and researchers to share experiences with off-label drug treatments in genetic diseases. The system supports submission and browsing of treatment reports and facilitates optional connections between users who have tried similar therapeutic approaches.

Note: Any off-label use of drugs should be done at the discretion of the treating physician in conjunction with the affected individual and/or caregiver and is not endorsed by GeneReviews or the authors of this chapter.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Smith-Kingsmore syndrome (SKS) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Approximately 86% of individuals diagnosed with SKS have the disorder as the result of a de novo constitutional or early postzygotic pathogenic variant in MTOR [Liu et al 2024].
• Some individuals diagnosed with SKS have the disorder as the result of an MTOR pathogenic variant inherited from an unaffected parent with gonadal mosaicism (~11%) or, rarely, an affected parent (~3%) [Liu et al 2024].
• If the proband has a constitutional MTOR pathogenic variant and appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. (If the proband is known to have a postzygotic [mosaic] pathogenic variant in MTOR, it is presumed that neither parent has an MTOR pathogenic variant.) Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members. Therefore, de novo occurrence of an MTOR pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the MTOR pathogenic variant.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for an MTOR pathogenic variant may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the MTOR pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the MTOR pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the significant possibility of parental gonadal mosaicism. Sib recurrence has been reported in several families with presumed parental gonadal mosaicism [Mroske et al 2015, Moosa et al 2017].

Offspring of a proband. Each child of an individual with SKS has a 50% chance of inheriting the MTOR pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

Prenatal Testing and Preimplantation Genetic Testing

Once the MTOR pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Smith-Kingsmore syndrome (SKS) is typically caused by gain-of-function pathogenic variants in MTOR, the gene encoding serine/threonine-protein kinase mTOR (also called mammalian or mechanistic target of rapamycin; mTOR), a serine/threonine kinase that serves as a central regulator of cell growth, proliferation, metabolism, and autophagy. These pathogenic variants result in hyperactivation of the mTOR signaling pathway, particularly within the mTOR complex 1 (mTORC1), leading to dysregulated cellular homeostasis [Shimobayashi & Hall 2014, Saxton & Sabatini 2017].

Signals from nutrients, energy status, and growth factors are integrated by mTOR to regulate anabolic and catabolic processes. In the central nervous system, mTOR plays a critical role in neurodevelopment, synaptic plasticity, and circadian rhythm regulation. Dysregulated mTOR activity is believed to underlie the neurodevelopmental features, epilepsy, macrocephaly, and sleep disturbances characteristic of SKS.

Mechanism of disease causation. Gain of function

MTOR-specific laboratory technical considerations. Because of the possibility of an affected individual having a mosaic MTOR pathogenic variant, use of deep sequencing (e.g., deep next-generation sequencing, amplicon sequencing, or droplet digital PCR) on an appropriate sample may be necessary. Standard-depth exome sequencing can miss mosaic MTOR variants, especially if performed on blood-derived DNA.

Author Notes

Carlos E Prada, gro.snerdlihceirul@adarpc

• Clinical work: neurofibromatosis, RASopathies, lysosomal storage disorders, metabolic disorders, and implementation of genomics in clinical care
• Research interests: development of biomarkers for rare disease, clinical trials, and gene discovery
• Web page: www.luriechildrens.org

Carolyn R Raski, gro.snerdlihceirul@iksarc

• Clinical work: RASopathies, neurofibromatosis, neurodevelopmental disorders, and implementation of genomics in clinical care
• Research interests: development of biomarkers for rare disease, clinical trials, and gene discovery
• Web page: www.luriechildrens.org

Ghayda Mirzaa, gro.snerdlihcelttaes@aazrim.adyahg

• Clinical work: brain malformations, gene discovery
• Research interests: genomics, neurogenetic disorders
• Web page: www.seattlechildrens.org

Aaron Besterman, ude.dscu.htlaeh@namretseba

• Clinical work: child and adolescent psychiatric disorders, neurodevelopmental disorders, and rare neurogenetic disorders
• Research interests: precision medicine in psychiatry, genetic diagnostics in rare neurodevelopmental conditions, abd immunopsychiatry
• Web page: psychiatry.ucsd.edu and radygenomics.org

Darcy A Krueger, gro.cmhcc@regeurk.ycrad

• Clinical work: tuberous sclerosis, neurofibromatosis, mTORopathies, and RASopathies
• Research interests: translational research and clinical trials in tuberous sclerosis and related disorders
• Web page: www.cincinnatichildrens.org

Andrew C. Liu, ude.lfu@uil.werdna

• Research interests: molecular, cellular, and physiologic mechanisms of circadian rhythms and sleep-wake behavior in mammals
• Web page: physiology.med.ufl.edu

Acknowledgments

The authors of this chapter would like to thank the leadership of the Smith-Kingsmore Syndrome Foundation as well as the many families with SKS who have shared their families' experiences in clinic, in research, and at family meetings for their selflessness and advocacy, without which the current awareness and understanding of SKS would not be possible. We would also like to acknowledge the time and effort of the research teams who collected much of the currently published data including Lindsey Aschbacher-Smith, MS, CCRP, without whom much of this work would not be possible. This research is supported at least in part by the National Institutes of Health NINDS R01 NS117457 (to ACL).

Revision History

• 20 November 2025 (ma) Review posted live
• 13 February 2025 (cp) Original submission

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