Smith-Kingsmore Syndrome and MTOR Gain-of-Function Disorders

Spectrum of disorders caused by activating variants in the MTOR gene: constitutional form (Smith-Kingsmore syndrome), widespread mosaicism with pigmentary mosaicism, asymmetric megalencephaly or hemimegalencephaly, and brain-restricted mosaicism with focal cortical dysplasia type II.

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

Related entities

The disorders of the phosphoinositide 3-kinase (PI3K), protein kinase B (AKT) and mechanistic target of rapamycin (mTOR) pathway are covered here only in what distinguishes them from the MTOR spectrum: tuberous sclerosis complex (TSC), PIK3CA-related overgrowth spectrum (PROS), PTEN hamartoma tumour syndrome, overgrowth syndromes in the diagnostic approach, malformations of cortical development, including FCD, HME and the GATOR1 complex epilepsies, and genetic epilepsies.

1. Introduction

1.1. Historical overview

The first pathogenic variant described in the MTOR gene in a human developmental disorder was not germline. In 2012, Lee and colleagues sequenced the exomes of paired brain and blood DNA from 20 patients with hemimegalencephaly (HME) who underwent hemispherotomy and found somatic de novo variants in PIK3CA, AKT3 or MTOR in 30% of cases, present in 8% to 40% of alleles in several brain regions and associated with increased neuronal phosphorylation of ribosomal protein S6, a marker of activation of mTOR complex 1 (mTORC1) [22]. The MTOR variant in that study, p.(Cys1483Tyr), was present in the affected tissue and absent from the unaffected brain and blood mononuclear cells, and the patient became symptom-free after lateral hemispherotomy [22, 23].

In 2013, Smith and colleagues, in an exome sequencing study coordinated by S. F. Kingsmore, described a girl with megalencephaly and intractable seizures carrying the de novo germline variant p.(Cys1483Phe), at the same residue as the 2012 somatic variant [1, 24]. The pregnancy had been complicated by maternal hypothyroidism and pre-eclampsia; the child was born at 35 weeks, by caesarean section, with macrocephaly, feeding difficulties, hypoglycaemia, thrombocytopenia and hypotonia, developed seizures with apnoea at 2 months, refractory to antiseizure medications, and had dysgenesis of the corpus callosum, a large anterior fontanelle, frontal bossing, midface hypoplasia, small chin, hypertelorism with downslanting palpebral fissures, depressed nasal root, smooth philtrum, thin upper lip, narrow chest, umbilical hernia and rhizomelic shortening; she died of pneumonia at 19 months [1]. The eponym joins the surnames of the first author (L. D. Smith) and the senior author (S. F. Kingsmore) of that report [1, 24].

In 2015 there were four milestones. Baynam and colleagues described three Aboriginal Australian siblings, with different fathers, with intellectual disability (ID), dysmorphism, macrocephaly, seizures, umbilical hernia, café-au-lait spots and a small thorax, carrying p.(Glu1799Lys) absent from maternal blood, which pointed to maternal gonadal mosaicism; this was the first family with a germline MTOR variant, and the phenotype gave rise to the Orphanet name MINDS [1, 2, 25]. Lim and colleagues showed that activating somatic brain variants of MTOR cause FCD type II, in 12 of 77 patients, and that rapamycin suppresses seizures and cytomegalic neurons in a mouse model [13]. Mroske and colleagues identified the same p.(Glu1799Lys) in two siblings with megalencephaly and autism spectrum disorder (ASD), with parents negative in blood, and confirmed gonadal mosaicism as the mechanism of recurrence [23]. Nakashima and colleagues found somatic MTOR variants in 6 of 13 FCD IIb (46%), with allele fractions of 1.11% to 9.31% [5].

In 2016, Mirzaa and colleagues showed that the same gene produces a continuum of malformations, from FCD type IIa to diffuse megalencephaly, distinguished by the variant and the level of mosaicism, and for the first time associated MTOR mosaicism with cutaneous pigmentary mosaicism [3]. In the same year, Møller and colleagues extended the germline spectrum to focal epilepsies without cortical malformation and with normal cognition, including a mother-to-daughter transmission [14]. Gordo and colleagues reviewed in 2018 the 23 patients then published, with four new cases [26], and Poole and colleagues added in 2021 16 patients with p.(Glu1799Lys) to the 14 already described and proposed clinical criteria [27]. In 2021, Carmignac and colleagues delineated MTOR-related hypomelanosis of Ito as a distinct neurocutaneous phenotype [4].

The Cincinnati natural history cohort, published in 2024, added 28 patients to 73 published ones (101 in total) and described circadian rhythm and sleep disturbances as a core component of the disorder, with the first systematic data on the use of sirolimus [10]. GeneReviews published the first dedicated text on 20 November 2025 [8], and Raski and Prada updated their review of the syndrome in the same month, with developmental milestones for 14 patients [28].

1.2. Current nomenclature and classifications

OMIM records the constitutional form as Smith-Kingsmore syndrome (SKS, #616638), with the alternative titles macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, MINDS syndrome and macrocephaly, seizures, intellectual disability, umbilical hernia and facial dysmorphism syndrome, and the somatic brain form as FCD type II (FCORD2, #607341), also called Taylor cortical dysplasia, with MTOR, TSC1 and TSC2 as somatic genes [1, 5]. Orphanet uses the name MINDS (ORPHA:457485) for the syndrome and classifies HME (ORPHA:99802) and isolated FCD (ORPHA:65683, with histopathological subtypes IIa and IIb) as distinct entities [2, 6, 11]. The International Classification of Diseases, 11th revision (ICD-11), codes SKS as LA05.51 [12].

The International League Against Epilepsy (ILAE) consensus classification of FCD, updated in 2022, maintains the histopathological distinction between type IIa (dysmorphic neurons without balloon cells) and type IIb (with balloon cells), recognises the mTOR pathway as the molecular basis of type II and proposes an integrated diagnosis combining histopathology, genetics and imaging [29]. GeneReviews and the recent literature group the constitutional and mosaic forms under the term mTORopathies, neurodevelopmental disorders caused by variants in genes of the mTOR pathway [10, 30].

1.3. Definitions of the entities in scope

SKS is the autosomal dominant disorder caused by a heterozygous activating MTOR variant, constitutional or early post-zygotic, present in several tissues, which combines overgrowth of variable degree, macrocephaly or megalencephaly, global developmental delay and ID usually moderate to severe, neurodevelopmental disorders (autistic traits, attention deficit hyperactivity disorder, ADHD) and congenital anomalies [8]. Widespread MTOR mosaicism corresponds to post-zygotic variants detectable in skin and sometimes in blood, with Blaschko-linear pigmentary mosaicism, asymmetric megalencephaly or HME and epilepsy; GeneReviews includes it in the diagnosis of SKS when the variant is early post-zygotic (20% to 25% of patients), and the literature also describes it as a distinct phenotype [4, 8]. Brain-restricted mosaicism produces apparently isolated FCD type II or HME, with drug-resistant focal epilepsy and no systemic manifestations [3, 8]. Somatic MTOR variants in sporadic tumours (colon, fallopian tube, glioblastoma, melanoma, renal cell carcinoma) do not confer hereditary predisposition and fall outside the clinical scope of this article [8].

2. Molecular Genetics and Pathophysiology

2.1. The gene and the protein

MTOR is located at 1p36.22 and encodes the serine/threonine kinase mTOR, also known as FRAP1 or RAFT1, a protein of about 300 kDa expressed in all tissues and at high levels in the brain [7, 12, 23]. The N-terminal half contains up to 20 HEAT repeats (huntingtin, elongation factor 3, protein phosphatase 2A, TOR1), each with two alpha helices of about 40 amino acids, involved in protein interactions; the C-terminal half contains the FAT domain (FRAP, ATM, TRRAP), which interacts with other components of the complex and wraps around the kinase domain, the FRB domain that binds the FKBP12–rapamycin complex, the catalytic domain, the small negative regulatory FIT domain (found in TOR, also called PRD) and the FATC domain, required for the active conformation [7, 10]. Rapamycin, a macrolide isolated in the 1970s from a soil sample from Easter Island (Rapa Nui), binds FKBP12 and the complex inhibits mTOR through the FRB domain [7].

mTOR is the catalytic core of two complexes. mTORC1 (mTOR, RAPTOR and mLST8) stimulates protein, lipid and nucleotide synthesis and inhibits autophagy; its core substrates are the kinase S6K1, which phosphorylates ribosomal protein S6, and the factor 4E-BP1 [10, 31]. mTORC2 regulates the actin cytoskeleton and cell survival [12]. The TSC2 protein of the tuberous sclerosis complex, a GTPase activator, integrates glucose and growth factor signals and controls the small GTPase RHEB, which directly stimulates the mTOR kinase; amino acids activate the RAG GTPases, and RHEB and RAG coordinate mTORC1 activation at the lysosomal surface [10]. The TSC complex is the central regulator of mTORC1 and also receives signals from AMP-activated kinase (AMPK) [31]. The GATOR1 complex (DEPDC5, NPRL2, NPRL3) represses mTORC1 in the amino acid-sensing branch; loss of function of DEPDC5 causes autosomal dominant focal epilepsies [14, 32].

In the central nervous system, mTOR takes part in neurodevelopment, synaptic plasticity and regulation of the circadian rhythm [8]. Activation of mTOR shortens the circadian period, and continuous inhibition lengthens the period and reduces amplitude; heterozygous deletion of Mtor in the mouse lengthens the period of locomotor rhythms [10]. Homozygous absence of Mtor is embryonic lethal shortly after implantation, and heterozygotes are normal and fertile [7].

2.2. Disease mechanism: gain of function

All causal variants described in MTOR are activating missense variants (or small in-frame deletions) in the coding region, clustered mainly in the FAT and kinase domains; no intragenic deletions or duplications have been described, and loss of function is not a known mechanism of the Mendelian phenotype [8, 12]. In the ExAC database, MTOR had 438 observed missense variants against 930 expected (z = 7.89) and a residual variation intolerance score (RVIS) of 0.34%, among the most constrained human genes [14]. Hyperactivation of mTORC1 would explain the megalencephaly, epilepsy, neurodevelopmental abnormalities and sleep disturbances [8].

Functional studies confirm gain of function of variable intensity. In rat cortical neurons, all MTOR variants identified by Mirzaa and colleagues caused constitutive mTORC1 activation under nutrient deprivation and increased neuronal size, reversed by 7 days of everolimus (RAD001); the variants found in megalencephaly and HME with a wide distribution of mutant cells (p.Glu1799Lys, p.Thr1977Ile, p.Cys1483Tyr) produced activation intermediate between wild type and the FCD variants (p.Ser2215Phe, p.Ser2215Tyr, p.Leu1460Pro) [3]. The authors proposed that the strongest variants are only compatible with life when restricted to a small territory, and that small lesions with intense activation are epileptogenic [3]. In brain tissue, samples with PIK3CA, PTEN and AKT3 variants had increased p-AKT (threonine 308), unlike those with MTOR or DEPDC5 variants, whereas p-S6 was increased in all — a pattern consistent with the position of each gene in the cascade [3].

In U2OS cells in which endogenous MTOR was silenced and replaced by lentiviral expression at a near-physiological level, the five mutants tested had basal activity higher than wild type under glucose, serum or amino acid deprivation; the in-frame deletion Δ(R1480-C1483) and p.Cys1483Phe were three to four times more active, and p.Gly2464Val only slightly [10]. All mutants remained activatable by nutrients and inhibitable by rapamycin, but Δ(R1480-C1483), p.Ser2215Tyr and p.Val2406Met were more resistant to rapamycin over one hour, and all were at basal level with 5 to 10 nM after two hours [10]. The mutants reduced the amplitude of the cellular circadian rhythm, and low-dose rapamycin (1.25 to 5 nM) increased it; in a line with the deletion introduced by CRISPR editing at the endogenous locus, activity depended on gene dosage (homozygous > heterozygous > wild type), and low amino acid content revealed the reduction in circadian amplitude, corrected by rapamycin at 2.5 nM [10]. Biochemical activity tracked clinical severity: the patient with Δ(R1480-C1483) had the most severe picture, and the carriers of p.Val2406Met had milder sleep disturbances [10]. These results are preclinical.

The p.(Glu1799Lys) variant lies in the FAT domain, which negatively regulates the kinase; structural modelling suggests that its alteration destabilises this regulation and shifts the protein towards a more active state [7, 23]. In HEK293 cells, the variant selectively increases activity towards AKT and 4E-BP1, with minimal effect on S6K, according to the authors who characterised it [23]. In the blood cells of one of the Aboriginal siblings, the mTOR response to stimulation was increased and was inhibited by rapamycin [7].

2.3. Mosaicism: timing of the variant and extent of the phenotype

The phenotype depends on the timing and the lineage in which the variant arises. Mirzaa and colleagues separated three groups: FCD IIa with low-level mosaicism only in the brain (allele fractions of 0.012 to 0.086), asymmetric megalencephaly with cortical dysplasia and pigmentary mosaicism with intermediate mosaicism for p.(Thr1977Ile) (0.23 to 0.55 in affected skin; 0.07 to 0.20 in blood or saliva), and symmetric megalencephaly with ID and autism due to constitutional de novo p.(Glu1799Lys) (fraction close to 50% in saliva or blood) [3, 7]. In one patient with FCD IIa and ten brain samples, the allele fraction ranged from 0 to 0.086, with an epicentre in the posterior temporal lobe, the most epileptogenic zone, and was undetectable in six of seven samples from the anterior margin, although all had FCD IIa histology: fractions below the detection threshold of next-generation sequencing are enough to produce the lesion [3].

In the combined cohort of 81 patients with SKS and known origin, the variant was germline de novo in 53%, post-zygotic (somatic mosaicism) in 33%, inherited through gonadal mosaicism in 11% and inherited from an affected parent in 3%; the sum of the first two categories corresponds to the approximately 86% de novo in GeneReviews [8, 10]. In MTOR-related hypomelanosis of Ito, the allele fraction in hypopigmented skin ranged from 10% to 40% (median 21%), and in blood from 0% to 30% (median 0%), with the variant absent from blood in half of cases [4]. In a boy with HME, hypomelanosis of Ito and lateralised overgrowth, p.(Cys1483Tyr) was in 32% of reads in skin, 3% in saliva and 0.46% in blood [16]. Szczałuba and colleagues described an SKS phenotype with recurrent hypoglycaemia caused by low-level brain-restricted mosaicism [33], and Karaca and colleagues a monozygotic twin with subtle hypomelanosis of Ito and FCD whose complex variant was only detected by RNA sequencing of paraffin-embedded tissue, with the co-twin healthy [18].

The hypopigmentation has a demonstrated cellular basis: in the hypopigmented skin of patients with an MTOR variant, the number of melanocytes per field was 5.2 against 15.8 in controls (p = 2.6 × 10⁻⁹), and mature stage IV melanosomes were reduced, which suggests a defect in melanogenesis due to mTORC1 activation, analogous to that of the hypomelanotic macules of TSC [4].

2.4. Variant spectrum and normalised nomenclature

The c.5395G>A p.(Glu1799Lys) variant accounts for almost half of patients with SKS; in 2021 it was 14 of 30 published patients (47%), and in 2024 the combined cohort had 35 unique alleles [8, 10, 27]. The distribution by domain in the combined cohort of 101 patients was: FAT 75%, kinase 15%, FIT 6%, HEAT 2%, FRB 1% and FATC 1% [10]. Residue Glu1799 is also a somatic hotspot in several cancers, including colon cancer, and four of five MTOR variants in the Mirzaa study were recorded in the COSMIC catalogue of somatic mutations in cancer [3, 34]. The literature often uses the abbreviated one-letter notation (E1799K, T1977I, C1483F, S2215F), which corresponds to protein HGVS without the prefix [10].

The conversions between c., p. and g. levels were obtained in VariantValidator with the MANE Select transcript NM_004958.4, and the classifications in ClinVar [9, 35]. Some studies used the previous version NM_004958.3 [14, 36]. The 2025 review in the Orphanet Journal of Rare Diseases writes "p.(Gly1799Lys)" for c.5395G>A; the correct form is p.(Glu1799Lys) [9, 30].

2.5. Genotype–phenotype correlations, penetrance and expressivity

Kinase domain variants were associated with more hearing problems and FAT domain variants with more autistic behaviour (p ≤ 0.05 for both), and facial dysmorphism is more consistent with variants in these two domains [8, 10]. Carriers of p.(Glu1799Lys) have a more uniform neurodevelopmental picture, with global delay, ID and autistic behaviour; megalencephaly and ID were present in all 30 patients with this variant gathered by Poole and colleagues [8, 27]. One patient with a FIT domain variant was alive at 70 years [8].

Germline expressivity is variable. In the Møller series, eight patients with germline variants (including monozygotic twins and a mother–daughter dyad) had focal (six) or generalised (one) epilepsy, with onset between 8 months and 10 years, about half with delay or ID, five with macrocephaly, none with a cortical malformation visible on magnetic resonance imaging (MRI) and at least three with near-normal cognitive development [1, 14]. The mother–daughter dyad with p.(Ile2501Val) had non-lesional nocturnal frontal lobe epilepsy, compatible with autosomal dominant nocturnal frontal lobe epilepsy, and normal intellectual development [14]. In a Danish diagnostic cohort of 245 children with epilepsy, germline MTOR variants accounted for about 1% [14]. The penetrance of the classic SKS variants has not been quantified, because almost all cases are de novo.

2.6. Allelic disorders and entities of the class

Apart from SKS, no phenotypes associated with germline MTOR variants are known; post-zygotic variants cause apparently isolated FCD type II and HME, and somatic tumour variants are not hereditary [8]. In FCD type II, the initial series gave detection rates of 15.6% (12 of 77, Korea; fractions of about 1% to 12%, absent from blood), 46% (6 of 13 FCD IIb, Japan) and 37% (6 of 16 FCD II, France; fractions of 1.1% to 6.3% in the brain) [5, 13, 14]. With sequencing depth above 2000 reads, the variants were also detected in blood, at about half the brain fraction (0.1% to 3%) [14]. In Mirzaa's pooled analysis, the pathway genes explained 19 of 53 HME (36%) and 23 of 116 FCD II (20%), with PIK3CA as the most frequent gene in HME (17%) and MTOR in FCD II (19%) [3]. MTOR is the most frequent causal gene of FCD IIa and IIb and the second most frequent of HME [15].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and limits

The clinical description rests on small and heterogeneous series: the case reports and series published before 2024, the series of 16 patients with p.(Glu1799Lys) by Poole and colleagues, and the Cincinnati natural history cohort, with 28 patients (23 new and 5 already published) recruited through the Smith-Kingsmore Syndrome Foundation and collaborating clinicians, which together with those published make up 101 individuals [10, 27]. In the Cincinnati cohort, the median age at last assessment was 7 years (1.5 to 31), the median age at diagnosis 3 years (3 months to 30 years), and 61% were male; in the published patients, the median age at diagnosis was 7 years (1.5 to 70) [10]. Denominators vary between manifestations, because many reports do not describe all systems, and data on adolescents and adults are scarce [8]. Most data describe natural history; patients treated with sirolimus are identified in section 7.

Source: Liu et al. 2024, Table 1, reproduced in GeneReviews [8, 10].

3.2. Growth and skull

Macrocephaly (head circumference, HC, at or above +2 standard deviations, SD) is the most constant sign, present in 90% of patients, and corresponds to true megalencephaly [8]. HC growth may be progressive and run parallel to very high values: in the siblings described by Mroske, HC tracked +6 SD from 2 to 3 years of age, and the older brother reached 65 cm as an adult; in the German family described by Moosa, progressive macrocephaly reached +6 SD [1, 23]. Generalised overgrowth, at birth or in the first months, occurs in 47% and lessens with age; stature may normalise in adulthood, although data on final height are scarce [8]. Many patients are born large for gestational age (weight and/or length above +2 SD), and fetal macrocephaly was detected in at least one pregnancy [8]. The Cincinnati cohort also recorded growth delay in 16% and precocious puberty in 13% [10].

3.3. Development and cognition

Developmental delay is usually the first sign, before 2 years, and affects the gross motor, fine motor and language domains; some patients have predominant language delay [8]. Independent walking appears on average at 2.5 years (from about 18 months to 5 years), and about one third never walk unaided; practically all have speech delay, and about 50% achieve verbal communication [8]. ID is usually in the moderate to severe range [8]. In a series of 14 patients, 8 of 12 crawled (67%; mean 23 months), 9 of 14 walked (64%; mean 32 months), 5 of 9 acquired a pincer grasp (56%; 23 months), 8 of 12 used utensils (67%; 3.4 years), 10 of 13 babbled (77%; 20 months), 8 of 14 said their first word (57%; 34 months) and 4 of 14 used short sentences (29%; 4.6 years) [28]. Developmental regression occurs in about 18%, almost always in patients with autism and, in some, with epilepsy [8]. The lack of longitudinal follow-up prevents knowledge of the cognitive trajectory in adulthood [8].

3.4. Neuromuscular system, epilepsy and electroencephalogram

Neuromuscular problems affect 79% of patients; congenital hypotonia is present in 46%, is mild to moderate and does not progress, and hypertonia is less common [8]. About 60% of patients have epilepsy, with onset in childhood in many, generalised or focal seizures, and status epilepticus apparently more frequent in patients with brain malformations [8]. In the Cincinnati cohort, six patients treated for epilepsy needed several antiseizure medications [10]. The electroencephalogram (EEG) may show rhythmic midline waves combined with asynchronous spike-and-wave discharges and anterior fast activity in wakefulness and sleep, a pattern proposed as a possible marker of the syndrome in a small series [8]. Catatonia-like episodes were recorded in 4 of 25 patients (16%) [10].

3.5. Neuroimaging

About 80% of patients studied have abnormalities on MRI: megalencephaly, agenesis or hypogenesis of the corpus callosum, cortical malformations (polymicrogyria, FCD, HME), generalised white matter loss with ex vacuo ventriculomegaly, white matter abnormalities and atrophy [8]. In one of the Aboriginal siblings, MRI at 2 years and 6 months showed megalencephaly, perisylvian polymicrogyria, hypogenesis of the corpus callosum, three small frontal heterotopias and an arachnoid cyst; in another, peritrigonal white matter loss and a small brainstem [1]. In constitutional megalencephaly due to p.(Glu1799Lys), polymicrogyria is limited or absent, and three of four patients in the Mirzaa series had only focal areas of cortical dysplasia [3].

3.6. Behaviour and mental health

ASD or autistic behaviours occur in 46%; on the SRS-2 (Social Responsiveness Scale, 2nd edition), applied to 18 children, most scored in the moderate (T above 66) to severe (above 76) ranges, with a mean of 77 [8, 10]. ADHD or hyperactivity and impulsivity occur in 22%, more than half with concomitant ASD; self-injury or aggression towards others in 27%; and anxiety in about 15%, sometimes from early childhood [8].

3.7. Sleep and circadian rhythm

Sleep-wake disturbances affect about 75% of patients and include sleep-onset and, above all, sleep-maintenance insomnia, obstructive sleep apnoea syndrome (OSAS) and circadian rhythm disorders [8]. In the Cincinnati cohort, 11 patients had insomnia and 10 a history of OSAS; some were described by their parents as a morning chronotype, and the patient with Δ(R1480-C1483) had an advanced sleep phase, falling asleep at 7 or 8 p.m., with difficulty falling and staying asleep [10]. The carriers of p.(Val2406Met) had mild symptoms, without difficulty falling asleep or an advanced phase [10].

3.8. Face, skin and hair

Facial dysmorphism includes macrocephaly, a broad and high forehead with frontal bossing, widely spaced eyes, downslanting palpebral fissures, long philtrum, thin upper vermilion, wide mouth and open mouth; it is more evident in early childhood, more subtle in adults and not sufficient for diagnosis without molecular testing [8, 10]. The hair may be wavy or curly, the skin dry, and hyperpigmented naevi and pigmentary mosaicism are frequent in patients with a mosaic variant [8]. The Orphanet definition includes umbilical hernia and café-au-lait spots [2].

3.9. Eyes and hearing

Ophthalmological abnormalities occur in 71%: cortical visual impairment, strabismus, refractive errors, optic atrophy, enlarged retinal vessels, iris coloboma and drusen-like pigmentation [8]. Iris colobomas were present in both of Mroske's siblings [23]. Sensorineural hearing loss is uncommon according to GeneReviews, but the Cincinnati cohort recorded hearing problems in 21%, more frequent with kinase domain variants [8, 10].

3.10. Cardiovascular and neurovascular system

About 40% of patients who had cardiac imaging have abnormalities: mitral dysplasia and stenosis, septal defects, bicuspid or bicommissural aortic valve and stable aortic root dilatation [8, 10]. In 2026, two patients with neurovascular complications and stroke were described; the content of the report was not accessible beyond the title [37]. A Spanish patient with SKS due to p.(Asp2412Val) had antiphospholipid syndrome, a unique association [36].

3.11. Digestive system, nutrition and endocrinology

Hyperphagia, with onset in early childhood, was described in 41%, and obesity in one adult woman [8]. There are reports of dysphagia in two patients and gastrostomy in one patient, of constipation, and of hernias in 38% [8, 10]. One adult had multiple polyps in the ileum, caecum and colon, and his sister renal cysts with a paternal history of polycystic kidney disease due to PKD1; the relationship of the polyps to SKS is not established [1, 34]. Infantile hypoglycaemia has been described in some patients and usually resolves after early childhood; one of Mroske's siblings had hyperinsulinaemia treated with frequent meals and diazoxide [8, 23].

3.12. Skeleton, genitourinary system and other

Skeletal anomalies (64%) include abnormal gait, flat feet and scoliosis; the narrow or small thorax, which gave its name to the MINDS designation, and short distal phalanges were described in the initial families [1, 8]. In boys, cryptorchidism and hypospadias are the most common genitourinary anomalies [8].

3.13. Widespread mosaic forms

In the French series of 15 patients with MTOR-related hypomelanosis of Ito (10 female, aged 1 to 30 years, median 6 years), 14 had linear hypopigmentation along the lines of Blaschko, in S, V or whorled patterns, mainly on the trunk and lower limbs, more visible with a Wood's lamp, and one had a flag-like patch on the shoulder, a hypopigmented lock of hair and heterochromia of the iris [4]. Twelve had psychomotor delay, from walking at 20 months to sitting only at 6 years, all later with ID; four had ASD; eight had macrocephaly (HC at or above +3 SD), four of them with body hemihypertrophy; and ten had seizures, two without ID [4]. Among the six patients with seizures and MRI, all had HME, with increased white matter volume and, in some, cortical thickening, narrowing of the frontal horns and ipsilateral enlargement of the thalamus, caudate or cerebellar hemisphere; none had angiomyolipomas or renal cysts [4]. Mirzaa described three children with p.(Thr1977Ile) with asymmetric megalencephaly, polymicrogyria and hypo- and hyperpigmented streaks, termed Blaschko-linear cutis tricolor, and Handoko a fourth, aged 3 years, with obstructive hydrocephalus due to aqueductal stenosis, asymmetric polymicrogyria and dysgenesis of the corpus callosum [3, 38]. Lateralised overgrowth was added to the spectrum by Carli and colleagues [16].

3.14. FCD type II and HME due to somatic brain variants

FCD type II presents with refractory seizures, usually with onset in early childhood, and may be accompanied by persistent ID; most patients need surgical resection [5]. There are also adult-onset forms: in a series of 21 adults who underwent surgery, seizures usually began in the third decade (18 to 55 years), and 76% became seizure-free after surgery [5]. In the Japanese sirolimus trial, a patient with MTOR p.(Cys1483Tyr) at 4% in tissue had her first seizure at 53 years [15]. FCD is the most frequent known cause of intractable focal epilepsy in children, found in almost half of children referred for epilepsy surgery [3]. Isolated HME presents in early childhood with progressive hemiparesis, severe psychomotor delay and intractable seizures [6].

4. Clinical Recognition and Red Flags

4.1. Prenatal period and newborn

Prenatal suspicion is rare and rests on fetal macrocephaly, described at least once, and on a fetus large for gestational age [8]. In the newborn, the combination of macrocephaly with weight or length above +2 SD, hypotonia, feeding difficulties and hypoglycaemia should lead to consideration of SKS alongside the other overgrowth syndromes [1, 8]. The Oxford Desk Reference recommends excluding causes of falsely increased HC (hairstyle, craniosynostosis, abnormal skull shape), measuring the parents' HC and plotting it against height, and notes that macrocephaly with delay increases the risk of seizures (odds ratio of 7.7 in an Israeli community study of more than 4000 children with neurodevelopmental disorder) [39].

4.2. Infant and child

In a child, SKS should be considered in the presence of macrocephaly (HC at or above +2 SD) with global delay or moderate to severe ID, especially if associated with ASD or ADHD, generalised or focal epilepsy, sleep-wake disturbances, hyperphagia, hypotonia, ophthalmological abnormalities (strabismus, refractive errors, optic atrophy) and facial dysmorphism, and on MRI with polymicrogyria, FCD, HME, an atypical corpus callosum or ventriculomegaly [8]. The family history is usually that of a simplex case; affected siblings with healthy parents suggest gonadal mosaicism, and affected individuals in successive generations suggest dominant transmission [8]. Early-onset hyperphagia with macrocephaly distinguishes SKS from Prader-Willi syndrome, in which there is no macrocephaly [8].

4.3. Signs pointing to mosaicism

Streaks of hypo- or hyperpigmentation along the lines of Blaschko, sometimes only visible with a Wood's lamp or oblique lighting, asymmetric megalencephaly, HME, body hemihypertrophy and discordance between monozygotic twins indicate post-zygotic mosaicism and the need to study affected skin [4, 16, 18]. Hypomelanosis of Ito is absent in patients with a heterozygous constitutional variant [4].

4.4. Drug-resistant focal epilepsy

A focal epilepsy that resists two antiseizure medications, with FCD type II on MRI, usually leads to surgical resection [5]; examination of the skin (hypomelanotic macules, shagreen patch) and of the MRI (other foci, subependymal nodules) separates TSC from the somatic MTOR forms, and the resected tissue is the sample that allows the molecular diagnosis of the latter [3, 13].

4.5. Red flags and emergencies

Status epilepticus is more frequent in patients with brain malformations, and GeneReviews recommends teaching caregivers to recognise seizure presentations [8]. Developmental regression, new seizures, hypoglycaemia in early childhood, dysphagia with risk of aspiration and nocturnal desaturation due to OSAS are reasons for targeted assessment [8]. Acute focal neurological symptoms warrant vascular investigation, in light of the two cases of neurovascular complications and stroke described in 2026 [37]. There is no newborn screening for SKS.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

GeneReviews states that no consensus clinical criteria have been published; the diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic or likely pathogenic activating variant in MTOR, constitutional or early post-zygotic [8]. Poole and colleagues proposed that the combination of megalencephaly with HC at or above +3 SD, ID and a de novo missense MTOR variant absent from population databases be considered diagnostic in the absence of functional studies [27]. The two approaches differ in the HC threshold (+2 SD as a suggestive finding in GeneReviews, +3 SD in the proposed criterion) and in the role of ID, which is not obligatory for GeneReviews and is absent in some patients with mild germline variants [8, 14, 27]. A variant of uncertain significance (VUS) in MTOR neither establishes nor excludes the diagnosis [8].

5.2. Molecular tests and their order

When the phenotype and MRI suggest SKS, a multigene panel including MTOR and the genes of the differential diagnosis identifies the cause while limiting incidental findings; when the phenotype is indistinguishable from other disorders with macrocephaly, delay and epilepsy, the exome or genome is preferable [8]. The American College of Medical Genetics and Genomics (ACMG) and the American Academy of Pediatrics (AAP) recommend the exome or genome as a first- or second-tier test in children with global developmental delay, ID or multiple congenital anomalies [40, 41]. As all known variants are coding missense variants, sequencing detects about 100% of pathogenic variants, and targeted deletion and duplication analysis has no described yield [8].

Source: GeneReviews, Table 1 and laboratory considerations [8].

5.3. Mosaicism: choice of tissue and depth

As 20% to 25% of patients with SKS have a post-zygotic variant, more than one tissue may need to be studied, preferably DNA from a freshly collected dermal biopsy [8]. In MTOR-related hypomelanosis of Ito, targeted deep sequencing on hypopigmented skin found variants in 35% of 40 selected patients, with blood negative in half [4]. The tissue gradient can be steep: 32% in skin, 3% in saliva and 0.46% in blood in one patient [16]. In Handoko's case, trio exome on blood and a panel on skin fibroblasts were negative, and only exome sequencing of fibroblasts from hyperpigmented skin detected p.(Thr1977Ile) at 32% [38]. The Oxford Desk Reference suggests very high-depth sequencing (more than 1000 reads) on germline or affected-tissue DNA when there is strong suspicion of a PIK3CA/AKT pathway disorder [39].

In FCD and HME, the tissue of choice is resected brain: allele fractions are about 1% to 12%, and the variant may be absent from fragments with typical histology, because of the intralesional gradient [3, 5, 13]. With sequencing of more than 2000 reads, the variant was detected in the blood of patients with FCD at about half the brain fraction (0.1% to 3%), but not in the blood of patients without a brain variant [14]. When DNA from paraffin-embedded tissue is of poor quality, RNA sequencing can reveal complex variants that DNA methods do not detect [18]. The 2022 ILAE classification proposes an integrated diagnosis, with histopathology, immunohistochemistry, imaging and tissue genetics [29].

5.4. Limits of the tests

A negative result does not exclude the disease. Standard-depth exome or genome on blood misses low-level variants; brain-restricted variants are not detectable in peripheral tissues with the usual sensitivity; and standard sequencing may not detect complex structural variation or deep intronic variants [8, 30]. The proportion of variants detected by sequencing (about 100%) describes the known mutational spectrum and is not equivalent to clinical sensitivity in an individual patient, which depends on the tissue, the depth and the allele fraction [8]. An MTOR variant inherited from an asymptomatic parent, such as p.(Asp1376Glu) in a non-lesional focal epilepsy, was classified as a VUS [14].

5.5. Interpretation and report content

The report should state the gene, the transcript with version (NM_004958.4), the HGVS c. and p. nomenclature, the zygosity or allele fraction and the tissue studied, and the class according to the ACMG/AMP (Association for Molecular Pathology) standards, in which pathogenic and likely pathogenic are clinically equivalent [8, 9]. For new variants, the pathogenicity elements used in the literature include confirmed de novo occurrence, absence from population databases, conservation, location in the FAT or kinase domains and functional demonstration of gain of function (phosphorylation of S6, S6K or 4E-BP1 under nutrient deprivation) [10, 14, 36]. Liu and colleagues and GeneReviews suggest assessing the biochemical and functional impact of the variant before starting an mTOR inhibitor, in order to adjust the dose and timing [8, 10].

5.6. Complementary non-molecular assessment

Brain MRI identifies malformations; EEG documents epileptiform activity; echocardiogram, ophthalmological and audiological assessment, polysomnography, blood glucose monitoring in early childhood, measurement of growth and HC and clinical and radiological assessment of scoliosis complete the work-up [8, 12]. There are no confirmatory biochemical or non-molecular tests [12].

5.7. Algorithm

1. Clinical suspicion (macrocephaly with delay or ID, plus one of the suggestive findings) → targeted clinical assessment (skin with Wood's lamp, body asymmetry, parental HC) and brain MRI [8, 39].
2. Test on blood: panel including MTOR or exome/genome [8, 40].
3. Negative with strong suspicion, or signs of mosaicism → deep sequencing on a biopsy of affected skin; consider saliva [4, 8].
4. Focal epilepsy with operated FCD type II or HME → deep sequencing of the resected tissue, on DNA or RNA depending on sample quality [13, 18].
5. Variant identified → ACMG/AMP classification, parental testing when constitutional, genetic counselling [8].

5.8. Prenatal and preimplantation diagnosis

When the familial variant is known, prenatal diagnosis and preimplantation genetic diagnosis are possible [8].

6. Differential Diagnosis

6.1. Comparative table

Sources: GeneReviews, Table 3 and text; Oxford Desk Reference; Smith's Recognizable Patterns [3, 8, 14, 39, 42].

6.2. Overgrowth syndromes with macrocephaly

The main distinction is from the overgrowth syndromes with ID, which include the epigenetic regulators (Sotos, Weaver, Tatton-Brown-Rahman) and the genes of the PI3K/AKT/mTOR pathway, a group that the Oxford Desk Reference organises into two families and in which it includes PPP2R5D, MTOR, AKT3 and PIK3R2 among the autosomal dominant phenotypes of the pathway [43]. In Sotos syndrome, dolichocephaly, prognathism and advanced bone age guide the diagnosis [8].

6.3. Disorders of the PI3K–AKT–mTOR pathway

Megalencephaly–capillary malformation–polymicrogyria (MCAP) due to post-zygotic PIK3CA shares megalencephaly, polymicrogyria and HME, but combines overgrowth of prenatal onset, progressive macrocephaly without hydrocephalus, midline naevus flammeus (nose and philtrum), cutis marmorata, capillary malformations that fade with age, postaxial polydactyly, syndactyly, asymmetry, progressive tonsillar herniation and Chiari I; the variant is not found in blood and requires affected tissue [39, 42]. Megalencephaly–polymicrogyria–polydactyly–hydrocephalus (MPPH) has no vascular malformation or syndactyly [39]. PHTS combines often extreme macrocephaly with mucocutaneous lesions and cancer risk, and TSC adds skin lesions, tubers, subependymal nodules and renal, cardiac and pulmonary tumours [8]. The absence of angiomyolipomas and renal cysts in patients with MTOR mosaicism and the Blaschko-linear nature of the dyspigmentation, instead of ash-leaf macules, help to separate them from TSC [4]. In brain tissue, increased p-AKT points to PIK3CA, PTEN or AKT3, and its absence with increased p-S6 to MTOR or DEPDC5 [3].

6.4. Pigmentary mosaicism

Hypomelanosis of Ito is a cutaneous marker of mosaicism with multiple causes. In the French cohort of 31 patients with Blaschko-linear or segmental hypopigmentation and extracutaneous manifestations studied by exome on skin and blood, only one had an MTOR variant; seven had mosaic chromosomal anomalies, one a germline X-linked variant in TFE3, two post-zygotic RHOA variants, four other candidates and 16 remained undiagnosed [4]. Mendelian pigmentation disorders (Waardenburg, piebaldism) and inflammatory hypochromic bands (lichen striatus, inflammatory linear verrucous epidermal naevus) were exclusion criteria in the French study [4].

6.5. Focal epilepsy and FCD

In the presence of FCD type II, the genetic differential includes TSC (germline TSC1 or TSC2 variants, with or without a second hit), the GATOR1 complex epilepsies, which explain part of the familial focal epilepsies and may be associated with FCD, and somatic variants of MTOR, PIK3CA, AKT3, RHEB, TSC1 and TSC2 [3, 5, 14, 32]. FCD types I and III had no MTOR variants in the French series [14]. This differential includes mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE) due to SLC35A2.

7. Treatments and Risk Management Strategies

7.1. Sources of recommendations

There are no published clinical guidelines for SKS; the recommendations of the 2025 GeneReviews chapter are based on the authors' experience and on case series, not on trials [8, 12]. Poole and colleagues proposed in 2021 management guidance based on 30 patients with p.(Glu1799Lys), whose full text was not accessible [27]. For FCD type II and HME, management of epilepsy follows the principles of epilepsy surgery, and mTOR inhibitors were studied in two phase 2 trials with a negative primary outcome [15, 19]. There is no cure and no authorised targeted treatment for any form of MTOR disease [8, 12].

7.2. Evaluation after diagnosis

Source: GeneReviews, Table 4 [8].

7.3. Treatment of manifestations

Source: GeneReviews, Table 5 [8, 44].

Epilepsy is treated with the usual antiseizure medications, chosen according to seizure type; many may be effective, but none has been studied specifically in SKS, and the Cincinnati cohort included patients who needed several medicines [8, 10]. For tone abnormalities (hypertonia, dystonia), specialists may use baclofen, tizanidine, botulinum toxin, antiparkinsonian drugs or orthopaedic surgery [8]. Oromotor dysfunction is assessed at each visit; unsafe swallowing justifies thickening or cooling food and, if severe, a nasogastric tube or gastrostomy [8]. Augmentative and alternative communication, assessed by a speech and language therapist, supports language and does not hinder speech development [8]. Children with ASD may benefit from applied behaviour analysis; ADHD may justify pharmacological treatment guided by a developmental paediatrician, and severe aggression is referred to child psychiatry [8]. GeneReviews describes the American organisation of support (early intervention from 0 to 3 years, developmental preschool from 3 to 5 years, individualised education programme) and notes that recommendations vary from country to country [8].

In a 22-year-old woman with mosaic SKS and severe obesity (body mass index at or above 40 kg/m²), semaglutide, a glucagon-like peptide 1 receptor agonist, produced a weight loss of 9 kg (7.44%) over 12 months without adverse effects [44]. The report does not justify systematic use; the dose follows the label for the obesity indication, and the published abstract does not describe it.

7.4. Epilepsy surgery for focal lesions

In FCD type II and HME, surgical resection is the usual treatment of drug-resistant epilepsy [5, 6]. Data from the MTOR series illustrate the difficulties: in one patient with FCD IIa, relapse led to functional hemispherotomy six months after lobectomy, and genetic mapping showed the variant absent from the anterior margin, which still had dysplastic histology; in another, epilepsy resolved after a second parietal resection guided by intracranial electrodes, in an area with elevated p-S6 [3]. In HME due to somatic p.(Cys1483Tyr), the patient became symptom-free after lateral hemispherotomy [22, 23]. Among the patients in the Korean trial with FCD II, 71% had not been seizure-free for at least one year after surgery [19].

7.5. mTOR inhibitors: rationale and evidence

Gain of function of MTOR makes mTOR inhibitors the plausible targeted treatment. In preclinical models, rapamycin suppressed seizures and cytomegalic neurons induced by mutant MTOR in the mouse, everolimus reversed neuronal hypertrophy in culture, and low-dose rapamycin restored the circadian amplitude of cells with SKS variants [3, 10, 13]. All variants tested remain sensitive to rapamycin, although some require higher concentrations or longer exposure [10]. First-generation (rapamycin and analogues), second-generation (catalytic inhibitors) and third-generation inhibitors have distinct mechanisms and off-target effects [8].

Sources: [10, 15, 17–19, 45].

Data in SKS are limited to uncontrolled, parent-reported observations in seven patients, one negative case and one positive case, without standardised objective outcomes [10, 17, 18]. Liu and colleagues stress that their study is not a clinical trial and that, in the patient with improved sleep, suvorexant (an orexin receptor antagonist) contributed to normalisation [10]. The 2025 British review concludes that there are no published data supporting the widespread use of mTOR inhibitors in SKS, partly because of rarity and the difficulty of measuring cognitive and behavioural response, and Bonniaud and colleagues question the implementation of trials in light of the negative reports [17, 30].

In FCD type II, the two trials did not reach the primary outcome. In FCDS-01, the estimated frequency of focal seizures per 28 days was 32.3 (90% confidence interval, 90% CI, 14.8 to 70.7) at baseline and 19.4 (90% CI 8.8 to 42.5) in weeks 9 to 12; mean trough concentrations were 4.6 to 5.0 ng/mL, lower than expected, with no difference between responders (5.2 ± 1.6 ng/mL) and non-responders (4.9 ± 2.1 ng/mL), and the prospective external control (RES-FCD, 60 patients) had different baseline characteristics [15]. In the Korean trial, the good responders were concentrated among patients with an MTOR variant in the tissue (3 of 5, against none with DEPDC5, TSC1 or TSC2) and in two without a genetic alteration, and in the open-label extension the median daily frequency fell from 1.9 to 1.0 (p = 0.007), significant at 28 and 40 weeks but not at 52 [19]. These are small studies, without direct comparison between medicines, and the response by genotype is an exploratory analysis.

7.6. Sirolimus and everolimus doses: reference and comparison with the labels

Neither medicine is authorised for SKS, FCD or HME; any use is off-label, at the decision of the physician with the patient or caregiver [8]. The reference dose in SKS is that of the Cincinnati series reported in GeneReviews; in FCD, that of the trials cited; the label doses (FDA, EMA, INFARMED) serve for comparison and refer to other indications.

Dose adjustments of both medicines are made by simple proportion (new dose = current dose × target concentration / current concentration), keeping the new dose for at least 7 to 14 days before a further change in the case of sirolimus, because of its long half-life, and measuring the everolimus concentration 1 to 2 weeks after each change, with a maximum increment of 5 mg per titration in the US label and of 1 to 4 mg in the European one [46, 48, 49]. Sirolimus tablets should not be crushed, chewed or split, and Afinitor® and Afinitor Disperz® are not combined to reach the dose [46, 48]. On a stable dose, the Rapamune® SmPC requires concentration monitoring at least every 3 months, and the Votubia® SmPC every 3 to 6 months if body surface area changes or every 6 to 12 months if stable [47, 49].

7.7. Adverse effects and monitoring of mTOR inhibitors

In FCDS-01, all patients had adverse effects; stomatitis was the most frequent, followed by infections, and there was one case of pneumonitis, one of proteinuria and one of anorexia with somnolence that required dose adjustment; the pneumonitis marker KL-6 rose progressively (median from 170.5 to 243 U/mL), and testosterone was monitored in boys older than 9 years because of the risk of male infertility [15]. In the Korean trial, mucositis and skin ulceration were more frequent with everolimus (19 of 21 against 7 of 21; p < 0.001), all resolving without discontinuation [19]. In SKS, the specific toxicity described was disturbance of the sleep-wake cycle when the trough concentration exceeded 3 ng/mL, with sleep fragmentation, awakenings and nocturnal locomotion [10]. Chronic high-dose rapamycin causes insulin resistance [10].

The US everolimus label describes non-infectious pneumonitis in up to 19% of patients (grade 3 up to 4%, grade 4 up to 0.2%, with deaths), infections, hypersensitivity reactions, angioedema (higher risk with angiotensin-converting enzyme inhibitors), stomatitis (alcohol-free dexamethasone mouthwash from the start), renal failure, impaired wound healing, glucose and lipid abnormalities, myelosuppression, contraindication of live vaccines and embryo-fetal toxicity [48]. The sirolimus label has a boxed warning on immunosuppression, with increased susceptibility to infection and possible development of lymphoma and other malignancies [46]. Before treatment and periodically, the everolimus label requires renal function, blood glucose, lipids and full blood count; grade 2 or 3 pneumonitis requires interruption until grade 0 or 1 and resumption at 50% of the dose, and grade 4 permanent discontinuation [48].

7.8. Regulatory status

7.9. Developments in the last 12 months (November 2025 to October 2026)

In November 2025, GeneReviews published the first text dedicated to SKS, with recommendations on evaluation, treatment and surveillance by author consensus (a review document, not a guideline) [8], and Raski and Prada published the "Syndrome of the Month" review with the developmental milestones of 14 patients (descriptive series) [28]. In June 2026, Karaca and colleagues described the detection by RNA sequencing of a complex somatic variant in a monozygotic twin, with a partial response to sirolimus (case report) [18], and in July 2026 Donnellan and colleagues reported neurovascular complications and stroke in two patients (case report; content not accessed) [37].

In the therapeutic field, trial NCT07287202, sponsored by Sovargen, started on 14 July 2026 in Australia: an open-label phase 1b/2a study, randomised between low-dose and high-dose paxalisib (SVG103, a PI3K and mTOR inhibitor) orally once daily, for 3 months plus 6 months of extension, in 12 adults (18 to 65 years) with FCD type II, TSC or HME and at least 8 seizures per month despite two antiseizure medications; the primary outcome is safety at 12 weeks, and primary completion is expected in February 2027 (trial recruiting, no results) [53]. The Astroscape trial (NCT06392009, GRIN Therapeutics), an open-label phase 1/2 trial of radiprodil in 30 patients aged 6 months to 18 years with TSC or FCD type II, started in July 2024 and was active, not recruiting, with primary completion estimated for June 2026 and no results published in the sources consulted [54]. There are no interventional trials registered on ClinicalTrials.gov for SKS; there are patient registries (CoRDS) and diagnostic studies of mosaicism in FCD (NCT06053671, NCT02890641) [55, 56]. There were no authorisations, opinions or label changes concerning SKS, FCD or HME in the period, according to the regulatory sources consulted [46, 48, 50, 52].

7.10. Special populations, perioperative care and transition

Sirolimus and everolimus can cause fetal harm; sirolimus crosses the placenta and is embryo-fetotoxic in the rat at subtherapeutic doses, and the everolimus label requires effective contraception in people of reproductive potential [46, 48]. The sources consulted do not describe pregnancies in women with SKS. Perioperatively, everolimus should be stopped at least one week before elective surgery and not resumed for at least two weeks after major surgery, until adequate wound healing, which applies to epilepsy surgery in treated patients [48]. Before starting an mTOR inhibitor, the childhood vaccination schedule should be complete, and live vaccines are avoided during treatment [48]. Transition to adult care should be planned from about 10 years of age, with a realistic plan for adult life [8].

7.11. Registry of off-label experience

GeneReviews refers to Rx-Matcher, a free platform of the University of Washington where clinicians and researchers share reports of off-label treatments in genetic disorders, and reminds readers that the absence of trials for the disease should be confirmed on ClinicalTrials.gov and in the EU clinical trials register [8]. The British mTOR Pathway Diseases node proposes basket trials (several diagnoses of the pathway in the same trial) and repurposing of medicines approved for mechanistically related diseases [30].

8. Reproductive Options and Family Counselling

8.1. Mode of transmission and risk to relatives

SKS is autosomal dominant and usually arises de novo: about 86% of patients have a non-inherited constitutional or early post-zygotic variant, about 11% inherited it from an unaffected parent with gonadal mosaicism and about 3% from an affected parent [8, 10]. Recurrences in siblings with parents negative in blood have been documented in several families: the three Aboriginal siblings, with different fathers, with a mother negative in blood; the two American brothers, with parentage confirmed by microsatellite markers; and the German siblings, whose variant was on the paternal chromosome [1, 23, 25, 34].

GeneReviews gives a 50% risk for each child of a person with SKS [8]. The sources consulted do not describe transmission from a patient with a mosaic variant.

8.2. Testing of parents and relatives

In a simplex case with a constitutional variant, parental testing is recommended to assess the recurrence risk; de novo occurrence is only confirmed when neither parent has the variant and biological parentage has been confirmed [8]. Leucocyte DNA does not detect all somatic mosaicism or exclusively gonadal mosaicism, and a parent with somatic and gonadal mosaicism may be mildly or minimally affected [8]. The mother-to-daughter transmission of p.(Ile2501Val) with nocturnal frontal lobe epilepsy and normal cognition shows that a mild expression may go unnoticed in a parent [14]. The risk to other relatives depends on the parents' status [8].

8.3. Family planning, prenatal and preimplantation diagnosis

The ideal time to determine risk and discuss prenatal and preimplantation diagnosis is before pregnancy, and counselling on risks to offspring and reproductive options should be offered to affected young adults [8]. When the familial variant is known, both tests are possible; views on their use differ among professionals and among families, and the decision is personal [8]. In couples with an affected child and parents negative in blood, the recurrence risk is higher than in the population, and the variant identified in the child allows prenatal or preimplantation testing in a subsequent pregnancy [8, 23].

8.4. Follow-up of counselling and twins

GeneReviews includes in the surveillance at each visit the assessment of the need for further genetic counselling when new questions arise, such as family planning [8]. Phenotypic discordance between monozygotic twins indicates post-zygotic mosaicism [18].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what the data measure

The prevalence of SKS is unknown; up to 2025 at least 100 individuals had been identified, and Orphanet assigns it the class below 1 in 1 000 000, which is a rarity category and not a measured estimate [8, 12]. The figures available for the somatic forms are detection rates in selected surgical series: 15.6% of FCD type II in a Korean series, 46% of FCD IIb in a Japanese series, 37% of FCD II in a French series and 19% of FCD II in Mirzaa's pooled analysis; none of these values can be converted into population prevalence [3, 5, 12–14]. In the French pigmentary mosaicism cohort, the MTOR variant was found in 1 of 31 patients by exome and in 14 of 40 selected for targeted sequencing [4]. In a Danish diagnostic cohort of 245 children with epilepsy, germline MTOR variants accounted for about 1% [14]. Adults are probably underdiagnosed, because many adults with disabilities have not had genomic testing [8].

9.2. Geographical distribution and populations

The descriptions come from diverse populations: North American (Cincinnati cohort; family of European and Japanese ancestry), from Seattle, Florence and Hong Kong (Mirzaa series), Aboriginal Australian, German, French (ten centres, including Réunion Island), Spanish, Italian and Danish (epilepsy series), Korean and Japanese (FCD series) [3, 4, 10, 14, 15, 19, 23, 25, 27, 34, 36]. No founder population has been described; the recurrence of p.(Glu1799Lys), p.(Thr1977Ile) and p.(Ser2215Phe/Tyr) in unrelated patients of various origins reflects mutational hotspots and not a founder effect [3, 4, 34]. In the Aboriginal Australian case, the lack of reference genomic data for that population made interpretation of the variant difficult [25]. The sources consulted do not describe patients from Portugal or Brazil, which does not demonstrate that there are none.

9.3. Access to the medicines in Portugal and Brazil

In Portugal, Rapamune® (sirolimus) and Votubia® (everolimus) are authorised by the centralised procedure and available on Infomed, with the European indications [47, 49]. In Brazil, Rapamune® and Afinitor® have active ANVISA registration [51]. In both countries, use in SKS or FCD is off-label.

9.4. European networks and patient associations

The relevant European reference networks are ERN ITHACA, for rare congenital malformations and rare intellectual disability, and ERN EpiCARE, for rare and complex epilepsies, including presurgical evaluation [20, 21]. The patient organisations and registries listed by GeneReviews are the Smith-Kingsmore Syndrome Foundation (smithkingsmore.org), the National Organization for Rare Disorders (NORD), the CoRDS registry for SKS and the Smith-Kingsmore Syndrome Global Patient Registry [8]. The Cincinnati cohort operates as a biorepository in collaboration with the foundation [10], and in the United Kingdom the mTOR Pathway Diseases node coordinates research on the disorders of the pathway [30].

10. Illustrative Clinical Case

Mroske and colleagues described in 2015 two brothers followed in the United States, born to healthy, non-consanguineous parents with normal intelligence, HC and eyes; the father had Norwegian, German and Bohemian ancestry, and the mother European and Japanese; the couple had also had a miscarriage due to trisomy 18 [23]. The proband was seen in the genetics clinic at 3 years for macrocephaly, bilateral iris colobomas and gross motor delay; he had been born at 35 weeks, large for gestational age (2950 g, 97th centile), macrocephaly was noticed at 6 months, with cranial ultrasound showing no hydrocephalus, and from 3 years of age HC tracked +6 SD, with megalencephaly on MRI [23]. In early childhood he had hyperinsulinaemia, treated with frequent meals and diazoxide; he had asthma and persistent food allergies, underwent surgery for cryptorchidism and inguinal hernia, wore glasses for strabismus and never had seizures [23]. Hypotonic, he walked at 18 months; early language was normal, but social delay appeared that was interpreted as mild ASD, and at 7 years overall cognitive ability was mildly reduced; PTEN sequencing and chromosomal microarray had been normal [23].

The older brother, aged 23 at the time of the study, had been born at 36 weeks weighing 3400 g with an HC of 36 cm (both above the 97th centile); HC tracked +6 SD from 2 years and reached 65 cm in adulthood, with isolated megalencephaly on MRI, unilateral iris coloboma, several strabismus operations, operated cryptorchidism, hypotonia, speech and motor delay, mild to moderate ID and autism diagnosed in adolescence; karyotype and fragile X testing had been normal, and he too never had seizures [23]. Trio exome sequencing (proband, mother and brother; leucocyte DNA; mean coverage of about 66 reads) identified the variant NM_004958.4:c.5395G>A p.(Glu1799Lys) in the heterozygous state in both brothers, confirmed by Sanger sequencing and absent from the mononuclear cells of both parents; microsatellite marker analysis confirmed the family relationships, so the recurrence was explained by gonadal mosaicism in one of the parents [9, 23]. Both brothers were also hemizygous for a variant of uncertain significance in OPHN1, inherited from the mother and not considered causal [23]. Figure 2 of the article shows the brothers at various ages and the segregation chromatograms: https://pmc.ncbi.nlm.nih.gov/articles/PMC4635597/figure/Fig2/ [23].

The case brings together the elements that guide practice: progressive disproportionate macrocephaly with normal linear growth, delay with autistic traits, ocular and genitourinary anomalies, absence of epilepsy in some carriers of p.(Glu1799Lys), hyperinsulinaemic hypoglycaemia in early childhood, and recurrence in siblings with parents negative in blood, which means the recurrence risk should not be given as equal to that of the population [8, 23]. The treatment with diazoxide described was the management in this case, and not a general recommendation; GeneReviews refers hypoglycaemia to endocrinology [8, 23].

11. Prognosis and Long-term Follow-up

11.1. Prognosis

Survival into adulthood is common; early deaths have been described, including that of the first patient, at 19 months, from pneumonia, and that of another patient from hypoxaemic respiratory failure in viral pneumonia, and one patient with a FIT domain variant was alive at 70 years [1, 8]. Overgrowth lessens and stature may normalise in adulthood, but macrocephaly persists [8, 23]. Functional prognosis depends mainly on ID, epilepsy and communication: about one third do not achieve independent walking and about half do not reach verbal communication [8]. Life expectancy and quality of life in adulthood have not been studied, and adults are probably underdiagnosed [8].

The 2025 British review found no evidence of increased cancer risk in SKS and states that there are no specific cancer screening programmes, although data are limited and p.(Glu1799Lys) is a somatic driver variant in several cancers [30, 34]. The intestinal polyps in one adult and the neurovascular complications in two patients are isolated observations whose relationship to the syndrome remains to be established [34, 37]. In the somatic brain forms, the prognosis is that of the epilepsy and the surgery.

11.2. Surveillance

The widespread mosaic forms follow the same scheme, with the addition of monitoring of body asymmetry and epilepsy; the published series did not describe angiomyolipomas or renal cysts, and the sources consulted do not propose specific renal surveillance [4].

12. Summary and Final Considerations

Activating MTOR variants form a spectrum in which the timing of the mutation defines the disease: a constitutional or early post-zygotic variant causes Smith-Kingsmore syndrome, with megalencephaly, global delay and moderate to severe ID, ASD, epilepsy, sleep and circadian rhythm disturbance, hyperphagia and ocular, cardiac and genitourinary anomalies; widespread mosaicism adds Blaschko-linear pigmentary mosaicism, asymmetric megalencephaly, HME and lateralised overgrowth; and brain-restricted mosaicism produces FCD type II and HME with drug-resistant focal epilepsy. About half of patients with the syndrome have the p.(Glu1799Lys) variant, all known variants are missense variants or in-frame deletions detectable by sequencing, and one in four or five patients has a mosaic variant that may be absent from blood, which requires skin or brain tissue to be studied when suspicion persists. The recurrence risk for siblings is higher than in the population when the parents are negative in blood, because of the gonadal mosaicism documented in about 11% of patients, and is 50% for the offspring of an affected person.

Management is supportive and multidisciplinary, following the evaluation, treatment and surveillance tables of the 2025 GeneReviews chapter, with attention to sleep, feeding, epilepsy, behaviour, vision, the heart and hypoglycaemia in early childhood. mTOR inhibitors have a mechanistic and preclinical rationale, but the clinical evidence in the syndrome is limited to uncontrolled observations in seven patients and to conflicting cases, with the particular finding that sirolimus trough concentrations above 3 ng/mL disturb sleep; in FCD type II, two phase 2 trials with sirolimus and everolimus did not reach the primary outcome, with an exploratory signal of response in patients with an MTOR variant in the tissue. No medicine is authorised for these indications, and paxalisib has been in an early-phase trial since 2026. Natural history studies in adults, data on pregnancy and vascular risk, and controlled trials with objective outcomes are lacking, which patient registries and the European networks ITHACA and EpiCARE may make possible.

13. References

1. Online Mendelian Inheritance in Man (OMIM). #616638 Smith-Kingsmore syndrome; SKS. Johns Hopkins University. Edited 8 Dec 2022. Available from: https://www.omim.org/entry/616638
2. Orphanet. Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (ORPHA:457485). Available from: https://www.orpha.net/en/disease/detail/457485
3. Mirzaa GM, Campbell CD, Solovieff N, Goold C, Jansen LA, Menon S, et al. Association of MTOR mutations with developmental brain disorders, including megalencephaly, focal cortical dysplasia, and pigmentary mosaicism. JAMA Neurol. 2016;73(7):836-45. doi:10.1001/jamaneurol.2016.0363
4. Carmignac V, Mignot C, Blanchard E, Kuentz P, Aubriot-Lorton MH, Parker VER, et al. Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities. Genet Med. 2021;23(8):1484-91. doi:10.1038/s41436-021-01161-6
5. Online Mendelian Inheritance in Man (OMIM). #607341 Focal cortical dysplasia, type II; FCORD2. Johns Hopkins University. Available from: https://www.omim.org/entry/607341
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