SKS
MCID: SMT020
MIFTS: 36

Smith-Kingsmore Syndrome (SKS)

Categories: Fetal diseases, Genetic diseases, Mental diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Smith-Kingsmore Syndrome

MalaCards integrated aliases for Smith-Kingsmore Syndrome:

Name: Smith-Kingsmore Syndrome 57 20 43 58 73 36 29 6
Macrocephaly-Intellectual Disability-Neurodevelopmental Disorder-Small Thorax Syndrome 57 20 43 58 73 17
Minds Syndrome 57 20 43 58 73
Sks 57 43 73
Macrocephaly, Seizures, Intellectual Disability, Umbilical Hernia, and Facial Dysmorphism 20 43
Macrocephaly, Seizures, Mental Retardation, Umbilical Hernia, and Facial Dysmorphism 57 73
Syndrome, Smith-Kingsmore 39

Characteristics:

Orphanet epidemiological data:

58
macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome
Inheritance: Autosomal dominant; Prevalence: <1/1000000 (Worldwide); Age of onset: Infancy,Neonatal; Age of death: early childhood;

OMIM®:

57 (Updated 05-Mar-2021)
Inheritance:
autosomal dominant

Miscellaneous:
variable features present


HPO:

31
smith-kingsmore syndrome:
Inheritance autosomal dominant inheritance


Classifications:

Orphanet: 58  
Rare neurological diseases
Developmental anomalies during embryogenesis


Summaries for Smith-Kingsmore Syndrome

MedlinePlus Genetics : 43 Smith-Kingsmore syndrome is a neurological disorder characterized by a head that is larger than normal (macrocephaly), intellectual disability, and seizures. In some people with this condition, the ability to speak is delayed or never develops. Some children with Smith-Kingsmore syndrome have features of a behavioral condition called attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder, which is characterized by impaired communication and social interaction. Structural brain abnormalities may also be present in affected individuals. For example, one or both sides of the brain may be enlarged (hemimegalencephaly or megalencephaly) or have too many ridges on the surface (polymicrogyria), or the fluid-filled spaces near the center of the brain (ventricles) may be bigger than normal (ventriculomegaly).Many people with Smith-Kingsmore syndrome have unusual facial features, such as a triangular face with a pointed chin, a protruding forehead (frontal bossing), widely spaced eyes (hypertelorism) with outside corners that point downward (downslanting palpebral fissures), a flat nasal bridge, or a long space between the nose and upper lip (long philtrum). However, not everyone with Smith-Kingsmore syndrome has distinctive facial features.

MalaCards based summary : Smith-Kingsmore Syndrome, also known as macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, is related to alacrima, achalasia, and mental retardation syndrome and overgrowth syndrome. An important gene associated with Smith-Kingsmore Syndrome is MTOR (Mechanistic Target Of Rapamycin Kinase), and among its related pathways/superpathways is mTOR signaling pathway. Affiliated tissues include brain and pons, and related phenotypes are macrocephaly and intellectual disability

OMIM® : 57 Smith-Kingsmore syndrome is a rare autosomal dominant syndromic intellectual disability syndrome characterized by macrocephaly, seizures, umbilical hernia, and facial dysmorphic features including frontal bossing, midface hypoplasia, small chin, hypertelorism with downslanting palpebral fissures, depressed nasal bridge, smooth philtrum, and thin upper lip (Smith et al., 2013; Baynam et al., 2015). (616638) (Updated 05-Mar-2021)

KEGG : 36 Smith-Kingsmore syndrome (SKS), also known as macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (MINDS syndrome), is a rare autosomal dominant disorder. Heterozygous mutations in MTOR gene have been shown to underlie SKS. The most consistent findings in SKS are intellectual disability (ID), developmental delay, megalencephaly, and seizures. There is moderate clinical variability, ranging from patients with macrocephaly, mild ID, and no convulsions, to severe forms in patients with intractable epilepsy, megalencephaly, severe ID, and autistic spectrum disorder.

UniProtKB/Swiss-Prot : 73 Smith-Kingsmore syndrome: An autosomal dominant syndrome characterized by intellectual disability, macrocephaly, seizures, umbilical hernia, and facial dysmorphic features.

Related Diseases for Smith-Kingsmore Syndrome

Diseases related to Smith-Kingsmore Syndrome via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 17)
# Related Disease Score Top Affiliating Genes
1 alacrima, achalasia, and mental retardation syndrome 10.3
2 overgrowth syndrome 10.3
3 autoimmune disease 10.1
4 tuberous sclerosis 1 10.1
5 macrocephaly/megalencephaly syndrome, autosomal recessive 10.1
6 hypomelanosis of ito 10.1
7 tuberous sclerosis 10.1
8 antiphospholipid syndrome 10.1
9 hemimegalencephaly 10.1
10 pik3ca-related overgrowth spectrum 10.1
11 hypotonia 10.1
12 megalencephaly 10.1
13 systemic autoimmune disease 10.1
14 pik3ca-related overgrowth syndrome 10.1
15 polydactyly 9.9
16 small cell carcinoma 9.9
17 cervix small cell carcinoma 9.9

Graphical network of the top 20 diseases related to Smith-Kingsmore Syndrome:



Diseases related to Smith-Kingsmore Syndrome

Symptoms & Phenotypes for Smith-Kingsmore Syndrome

Human phenotypes related to Smith-Kingsmore Syndrome:

58 31 (show top 50) (show all 66)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 macrocephaly 58 31 hallmark (90%) Very frequent (99-80%) HP:0000256
2 intellectual disability 58 31 hallmark (90%) Very frequent (99-80%) HP:0001249
3 megalencephaly 58 31 hallmark (90%) Very frequent (99-80%) HP:0001355
4 frontal bossing 58 31 frequent (33%) Frequent (79-30%) HP:0002007
5 neurological speech impairment 58 31 frequent (33%) Frequent (79-30%) HP:0002167
6 global developmental delay 58 31 frequent (33%) Frequent (79-30%) HP:0001263
7 abnormal facial shape 58 31 frequent (33%) Frequent (79-30%) HP:0001999
8 specific learning disability 58 31 frequent (33%) Frequent (79-30%) HP:0001328
9 ventriculomegaly 58 31 frequent (33%) Frequent (79-30%) HP:0002119
10 large for gestational age 58 31 frequent (33%) Frequent (79-30%) HP:0001520
11 generalized-onset seizure 58 31 frequent (33%) Frequent (79-30%) HP:0002197
12 curly hair 58 31 frequent (33%) Frequent (79-30%) HP:0002212
13 focal-onset seizure 31 frequent (33%) HP:0007359
14 gait disturbance 58 31 occasional (7.5%) Occasional (29-5%) HP:0001288
15 hypertelorism 58 31 occasional (7.5%) Occasional (29-5%) HP:0000316
16 pes planus 58 31 occasional (7.5%) Occasional (29-5%) HP:0001763
17 prominent forehead 58 31 occasional (7.5%) Occasional (29-5%) HP:0011220
18 strabismus 58 31 occasional (7.5%) Occasional (29-5%) HP:0000486
19 cryptorchidism 58 31 occasional (7.5%) Occasional (29-5%) HP:0000028
20 wide mouth 58 31 occasional (7.5%) Occasional (29-5%) HP:0000154
21 open mouth 58 31 occasional (7.5%) Occasional (29-5%) HP:0000194
22 long philtrum 58 31 occasional (7.5%) Occasional (29-5%) HP:0000343
23 hypopigmented skin patches 58 31 occasional (7.5%) Occasional (29-5%) HP:0001053
24 asthma 58 31 occasional (7.5%) Occasional (29-5%) HP:0002099
25 hemangioma 58 31 occasional (7.5%) Occasional (29-5%) HP:0001028
26 polymicrogyria 58 31 occasional (7.5%) Occasional (29-5%) HP:0002126
27 diastasis recti 58 31 occasional (7.5%) Occasional (29-5%) HP:0001540
28 autistic behavior 58 31 occasional (7.5%) Occasional (29-5%) HP:0000729
29 cafe-au-lait spot 58 31 occasional (7.5%) Occasional (29-5%) HP:0000957
30 thoracic hypoplasia 58 31 occasional (7.5%) Occasional (29-5%) HP:0005257
31 hyperactivity 58 31 occasional (7.5%) Occasional (29-5%) HP:0000752
32 protuberant abdomen 58 31 occasional (7.5%) Occasional (29-5%) HP:0001538
33 abnormal corpus callosum morphology 58 31 occasional (7.5%) Occasional (29-5%) HP:0001273
34 capillary malformation 58 31 occasional (7.5%) Occasional (29-5%) HP:0025104
35 lactose intolerance 58 31 occasional (7.5%) Occasional (29-5%) HP:0004789
36 hypotonia 31 occasional (7.5%) HP:0001252
37 depressed nasal bridge 58 31 very rare (1%) Very rare (<4-1%) HP:0005280
38 downslanted palpebral fissures 58 31 very rare (1%) Very rare (<4-1%) HP:0000494
39 hypospadias 58 31 very rare (1%) Very rare (<4-1%) HP:0000047
40 neonatal hypoglycemia 58 31 very rare (1%) Very rare (<4-1%) HP:0001998
41 decreased circulating iga level 58 31 very rare (1%) Very rare (<4-1%) HP:0002720
42 short chin 58 31 very rare (1%) Very rare (<4-1%) HP:0000331
43 intestinal polyp 58 31 very rare (1%) Very rare (<4-1%) HP:0005266
44 allergy 58 31 very rare (1%) Very rare (<4-1%) HP:0012393
45 seizures 58 Frequent (79-30%)
46 muscular hypotonia 58 Occasional (29-5%)
47 umbilical hernia 31 HP:0001537
48 short nose 31 HP:0003196
49 smooth philtrum 31 HP:0000319
50 hypoglycemia 31 HP:0001943

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Mar-2021)
Head And Neck Head:
macrocephaly
frontal bossing
large anterior fontanel
tall forehead

Head And Neck Nose:
depressed nasal bridge
short nose

Abdomen External Features:
umbilical hernia
diastasis recti

Laboratory Abnormalities:
hypoglycemia

Hematology:
thrombocytopenia

Skeletal Feet:
deep plantar creases
short distal phalanges

Muscle Soft Tissue:
hypotonia

Neurologic Behavioral Psychiatric Manifestations:
autistic features

Skeletal Hands:
short distal phalanges
deep palmar creases
short proximal phalanges

Abdomen Gastrointestinal:
poor feeding

Genitourinary Kidneys:
renal asymmetry

Growth Weight:
birth length >3 sd

Skin Nails Hair Nails:
small toenails

Neurologic Central Nervous System:
intellectual disability
perisylvian polymicrogyria
seizures (in some patients)
mild prominence of the ventricular system
hypogenesis of the body and the splenium of the corpus callosum
more
Head And Neck Eyes:
hypertelorism
strabismus
downslanting palpebral fissures

Head And Neck Mouth:
smooth philtrum
long philtrum
thin upper lip
macrostomia
open mouth posture

Genitourinary External Genitalia Male:
cryptorchidism

Growth Other:
large for gestational age

Skin Nails Hair Hair:
curly hair
wavy hair

Head And Neck Face:
midface hypoplasia
small chin

Skeletal Limbs:
rhizomelic limb shortening

Chest External Features:
small thorax

Skin Nails Hair Skin:
cafe-au-lait spots

Immunology:
iga deficiency

Cardiovascular Heart:
aortic sinus to right atrial fistula

Clinical features from OMIM®:

616638 (Updated 05-Mar-2021)

Drugs & Therapeutics for Smith-Kingsmore Syndrome

Search Clinical Trials , NIH Clinical Center for Smith-Kingsmore Syndrome

Genetic Tests for Smith-Kingsmore Syndrome

Genetic tests related to Smith-Kingsmore Syndrome:

# Genetic test Affiliating Genes
1 Smith-Kingsmore Syndrome 29 MTOR

Anatomical Context for Smith-Kingsmore Syndrome

MalaCards organs/tissues related to Smith-Kingsmore Syndrome:

40
Brain, Pons

Publications for Smith-Kingsmore Syndrome

Articles related to Smith-Kingsmore Syndrome:

# Title Authors PMID Year
1
Smith-Kingsmore syndrome: A third family with the MTOR mutation c.5395G>A p.(Glu1799Lys) and evidence for paternal gonadal mosaicism. 57 6 61
27753196 2017
2
Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy. 6 57
27830187 2016
3
Germline activating MTOR mutation arising through gonadal mosaicism in two brothers with megalencephaly and neurodevelopmental abnormalities. 57 6
26542245 2015
4
A germline MTOR mutation in Aboriginal Australian siblings with intellectual disability, dysmorphism, macrocephaly, and small thoraces. 57 6
25851998 2015
5
Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism. 6
27159400 2016
6
De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. 57
22729223 2012
7
A new case of Smith-Kingsmore syndrome with somatic MTOR pathogenic variant expands the phenotypic spectrum to lateralized overgrowth. 61
33506498 2021
8
Expanding the phenotype of MTOR-related disorders and the Smith-Kingsmore syndrome. 61
32494756 2020
9
A novel de novo MTOR gain-of-function variant in a patient with Smith-Kingsmore syndrome and Antiphospholipid syndrome. 61
31053780 2019
10
mTOR mutations in Smith-Kingsmore syndrome: Four additional patients and a review. 61
28892148 2018

Variations for Smith-Kingsmore Syndrome

ClinVar genetic disease variations for Smith-Kingsmore Syndrome:

6 (show all 14)
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 MTOR-AS1 NM_004958.4(MTOR):c.4785G>A (p.Met1595Ile) SNV Pathogenic 224088 rs869312671 1:11204792-11204792 1:11144735-11144735
2 MTOR NM_004958.4(MTOR):c.5395G>A (p.Glu1799Lys) SNV Pathogenic 217823 rs863225264 1:11190804-11190804 1:11130747-11130747
3 MTOR NM_004958.4(MTOR):c.4448G>T (p.Cys1483Phe) SNV Pathogenic 190121 rs786205165 1:11217230-11217230 1:11157173-11157173
4 MTOR NM_004958.4(MTOR):c.5663T>G (p.Phe1888Cys) SNV Pathogenic 224083 rs869312666 1:11189846-11189846 1:11129789-11129789
5 MTOR NM_004958.4(MTOR):c.6981G>A (p.Met2327Ile) SNV Pathogenic 242349 rs878855328 1:11177096-11177096 1:11117039-11117039
6 MTOR NM_004958.4(MTOR):c.7500T>G (p.Ile2500Met) SNV Likely pathogenic 376455 rs1057519915 1:11169375-11169375 1:11109318-11109318
7 MTOR NM_004958.4(MTOR):c.7292T>C (p.Leu2431Pro) SNV Likely pathogenic 391346 rs1057524044 1:11174383-11174383 1:11114326-11114326
8 MTOR NM_004958.4(MTOR):c.505-2A>G SNV Uncertain significance 224150 rs869312706 1:11316251-11316251 1:11256194-11256194
9 MTOR-AS1 NM_004958.4(MTOR):c.4606A>G (p.Ile1536Val) SNV Uncertain significance 268210 rs886041096 1:11206813-11206813 1:11146756-11146756
10 MTOR NM_004958.4(MTOR):c.743C>T (p.Thr248Ile) SNV Uncertain significance 587518 rs377679898 1:11313993-11313993 1:11253936-11253936
11 MTOR NM_004958.4(MTOR):c.5653G>A (p.Val1885Ile) SNV Uncertain significance 408296 rs139043855 1:11189856-11189856 1:11129799-11129799
12 MTOR NM_004958.4(MTOR):c.112G>A (p.Ala38Thr) SNV Likely benign 652978 rs138117203 1:11319355-11319355 1:11259298-11259298
13 MTOR NM_004958.4(MTOR):c.7391G>T (p.Gly2464Val) SNV not provided 972961 1:11169762-11169762 1:11109705-11109705
14 MTOR NM_004958.4(MTOR):c.6674dup (p.Tyr2225Ter) Duplication not provided 918028 1:11182171-11182172 1:11122114-11122115

UniProtKB/Swiss-Prot genetic disease variations for Smith-Kingsmore Syndrome:

73
# Symbol AA change Variation ID SNP ID
1 MTOR p.Glu1799Lys VAR_075072 rs863225264
2 MTOR p.Trp1490Arg VAR_078832
3 MTOR p.Met1595Ile VAR_078833 rs869312671
4 MTOR p.Ala1832Thr VAR_078835 rs369088781
5 MTOR p.Phe1888Cys VAR_078836 rs869312666
6 MTOR p.Met2327Ile VAR_078840 rs878855328

Expression for Smith-Kingsmore Syndrome

Search GEO for disease gene expression data for Smith-Kingsmore Syndrome.

Pathways for Smith-Kingsmore Syndrome

Pathways related to Smith-Kingsmore Syndrome according to KEGG:

36
# Name Kegg Source Accession
1 mTOR signaling pathway hsa04150

GO Terms for Smith-Kingsmore Syndrome

Sources for Smith-Kingsmore Syndrome

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
20 GARD
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 05-Mar-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 TGDB
70 Tocris
71 UMLS
72 UMLS via Orphanet
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