GeneReview Sotos Sydrome

7/27/2019 GeneReview Sotos Sydrome

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Sotos Syndrome

Synonym: Cerebral Gigantism

Katrina Tatton-Brown, BM BCh, MD, Trevor RP Cole, MB ChB, and Nazneen Rahman, BM BCh, PhD.

Author Information

Initial Posting: December 17, 2004; Last Update: March 8, 2012.

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Summary

Disease characteristics. Sotos syndrome is characterized by the cardinal features of typical facial

appearance, overgrowth (height and/or head circumference 2 SD above the mean), and learning

disability ranging from mild (children attend mainstream schools and are likely to be independent as

adults) to severe (lifelong care and support will likely be required). Sotos syndrome is associated with themajor features of behavioral problems,congenitalcardiac anomalies, neonatal jaundice, renalanomalies, scoliosis, and seizures.

Diagnosis/testing. The diagnosis of Sotos syndrome is established by a combination of clinical findings

andmolecular genetic testing.NSD1is the onlygenein which mutations are known to cause Sotossyndrome. About 80%-90% of individuals with Sotos syndrome have a

demonstrable NSD1abnormality..

Genetic counseling. Sotos syndrome is inherited in anautosomal dominantmanner.

More than 95% ofindividuals have a de nov omutation.

(If neither parent of aprobandhas Sotos syndrome, the risk to sibs of the proband is low (


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Ultrasound examination. Prenatal diagnosis cannot be accurately accomplished by ultrasound

examination: the features of Sotos syndrome likely to be detected by ultrasound examination, such as

macrocephaly and increased length, are nonspecific.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal

menstrual period or by ultrasound measurements.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview:

tables may contain more recent information. ED.

Table A. Sotos Syndrome: Genes and Databases

Gene

Symbol

Chromosomal

Locus

Protein Name Locus Specific HGMD

NSD1 5q35.2-q35.3 Histone-lysine N-methyltransferase, H3 lysine-36

and H4 lysine-20 specific

Nuclear receptor bindingSET Domain protein 1

(NSD1) @ LOVD

NSD1

A recurrent 1.9-Mb 5q35 microdeletion encompassing NSD1has been reported in mostJapanese and some non-Japanese individuals with Sotos syndrome[Kurotaki et al 2003,Tatton-Brown

et al 2005a,Tatton-Brown et al 2005b,Visser et al 2005]. The majority are generated bynonallelic homologousrecombinationbetween flanking low-copyrepeats [Kurotaki et al 2003,Tatton-Brown et al 2005a,Visser et al 2005]. Many of these recurrent

deletions have the same breakpoints, and a specific chromatin structure may increase recurrent crossoverevents and predispose to recombination hot spots at 5q35 [Visser et al 2005].

Normalgene product. Only limited data exist regarding the functions of histone-lysine N-methyltransferase, H3 lysine-36 and H4 lysine-20 specific (NSD1), a protein of 2696 amino acids. It isexpressed in the brain, kidney, skeletal muscle, spleen, thymus, and lung. NSD1 contains at least 12

functional domains including two nuclear receptor interaction domains (NID -L and NID+L), two proline-

tryptophan-tryptophan-proline (PWWP) domains, five plant homeo domains (PHD), and a SET (su(var)3-9,

enhancer of zeste, trithorax) domain. The most distinctive of these domains are the SET and associated

SAC (SET-associated Cys-rich) domains, which are found in histone methyltransferases that regulate

chromatin states. The SET domain of NSD1 has unique histonespecificity, methylating K36 on H3 and K20

on H4 [Rayasam et al 2003]. PHDs are also typically found in proteins that act at the chromatin level, and

PWWP domains are implicated in protein-protein interactions and are often found in methyltransferases. Thenuclear receptors of NSD1, NID-L, and NID+L are typical of those found in corepressors and coactivators

[Huang et al 1998]. The presence of these distinctive domains suggests that NSD1 is a histone

methyltransferase that acts as a transcriptional intermediary factor capable of both negatively and positively

influencingtranscription, depending on the cellular context [Kurotaki et al 2001].

Diagnosis

Clinical Diagnosis

The clinical diagnosis of Sotos syndrome can be made if an individual has a characteristic facial gestalt,

a learning disability, and overgrowth[Rio et al 2003,Turkmen et al 2003,Cecconi et al 2005,Faravelli

2005,Tatton-Brown et al 2005b,Waggoner et al 2005]. Based on the analysis of more than 500 individuals
http://www.ncbi.nlm.nih.gov/gene/64324http://www.ncbi.nlm.nih.gov/gene/64324http://www.ncbi.nlm.nih.gov/projects/mapview/maps.cgi?taxid=9606&chr=5&query=NSD1&qstr=NSD1&maps=snp,genes-r,pheno&zoom=2http://www.ncbi.nlm.nih.gov/projects/mapview/maps.cgi?taxid=9606&chr=5&query=NSD1&qstr=NSD1&maps=snp,genes-r,pheno&zoom=2http://www.uniprot.org/uniprot/Q96L73http://www.uniprot.org/uniprot/Q96L73http://www.uniprot.org/uniprot/Q96L73https://grenada.lumc.nl/LOVD2/shared1/home.php?select_db=NSD1https://grenada.lumc.nl/LOVD2/shared1/home.php?select_db=NSD1https://grenada.lumc.nl/LOVD2/shared1/home.php?select_db=NSD1https://grenada.lumc.nl/LOVD2/shared1/home.php?select_db=NSD1http://www.hgmd.cf.ac.uk/ac/gene.php?gene=NSD1http://www.hgmd.cf.ac.uk/ac/gene.php?gene=NSD1http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2003.378http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2003.378http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2003.378http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005a.307http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005a.307http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005a.307http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005a.307http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.visser.2005.e66http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.visser.2005.e66http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.visser.2005.e66http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/recombination/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/recombination/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/recombination/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2003.378http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2003.378http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2003.378http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005a.307http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005a.307http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005a.307http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.visser.2005.e66http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.visser.2005.e66http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.visser.2005.e66http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.visser.2005.e66http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.visser.2005.e66http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.visser.2005.e66http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene-product/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene-product/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene-product/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/specificity/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/specificity/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/specificity/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.rayasam.2003.3153http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.rayasam.2003.3153http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.rayasam.2003.3153http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.huang.1998.3398http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.huang.1998.3398http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.huang.1998.3398http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/transcription/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/transcription/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/transcription/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2001.197http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2001.197http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2001.197http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.rio.2003.436http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.rio.2003.436http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.rio.2003.436http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.turkmen.2003.858http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.turkmen.2003.858http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.turkmen.2003.858http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cecconi.2005.247http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cecconi.2005.247http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cecconi.2005.247http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.faravelli.2005.24http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.faravelli.2005.24http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.faravelli.2005.24http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.faravelli.2005.24http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.waggoner.2005.524http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.waggoner.2005.524http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.waggoner.2005.524http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.waggoner.2005.524http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.faravelli.2005.24http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.faravelli.2005.24http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cecconi.2005.247http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.turkmen.2003.858http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.rio.2003.436http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2001.197http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/transcription/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.huang.1998.3398http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.rayasam.2003.3153http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/specificity/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene-product/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.visser.2005.e66http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.visser.2005.e66http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005a.307http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2003.378http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/recombination/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.visser.2005.e66http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005a.307http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005a.307http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2003.378http://www.hgmd.cf.ac.uk/ac/gene.php?gene=NSD1https://grenada.lumc.nl/LOVD2/shared1/home.php?select_db=NSD1https://grenada.lumc.nl/LOVD2/shared1/home.php?select_db=NSD1https://grenada.lumc.nl/LOVD2/shared1/home.php?select_db=NSD1http://www.uniprot.org/uniprot/Q96L73http://www.uniprot.org/uniprot/Q96L73http://www.uniprot.org/uniprot/Q96L73http://www.ncbi.nlm.nih.gov/projects/mapview/maps.cgi?taxid=9606&chr=5&query=NSD1&qstr=NSD1&maps=snp,genes-r,pheno&zoom=2http://www.ncbi.nlm.nih.gov/gene/64324


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with an NSD1 abnormality, these three cardinal features were shown to occur in at least 90%

ofaffectedindividuals [Tatton-Brown et al 2005b]. Where an individual does not fulfill all three clinical

criteria, the clinical suspicion of Sotos syndrome can be confirmed with genetic testing (seeMolecular

Genetic Testing).

Characteristic facial appearance. The facial gestalt is the most specific diagnostic criterion for

Sotos syndrome and also the feature most open to observer error and inexperience. The gestalt is

most easily recognizable between ages 1-6 aa. In older children and adults, the facial features,although still typical, can be more subtle [Allanson & Cole 1996,Tatton-Brown et al 2005b].

Typical facial features include

malar flushing,

sparse frontotemporal hair,

high bossed forehead,

downslanting palpebral fissures,

a long narrow face, and

prominent narrow jaw; the head is said to resemble an inverted pear. The facial shape is retained

into adulthood, but with time the chin becomes squarer in shape and more prominent.

Learning disability. Delay of early developmental milestones is very common and motor skills

may appear particularly delayed because of the large size, hypotonia, and poor coordination.

Language delay is also usually apparent [Ball et al 2005]. The great majority ofaffectedindividuals

have some degree of intellectual impairment. However, the extent is highly variable, ranging from

mild (in which children attend mainstream schools and are likely to be independent in

adulthood) to severe (in which lifelong care and support are required) [Tatton-Brown et al 2005b].

Overgrowth. Approximately 90% of children have a height and/or head circumference two or

more SD above the mean [Tatton-Brown et al 2005b]. Height may normalize in adulthood, but

macrocephaly is usually present at all ages [Agwu et al 1999; Cole, personal communication].

Testing

Cytogenetic testing. Mostaffectedindividuals do not have a cytogenetic abnormality. Rarely, a cytogenetic

abnormality such as atranslocationinvolving 5q35 results in Sotos syndrome[Kurotaki et al 2002].

Molecular Genetic Testing

Gene.NSD1 is the onlygenein which mutations are currently known to cause Sotos syndrome.
http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.Molecular_Genetic_Testinghttp://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.Molecular_Genetic_Testinghttp://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.Molecular_Genetic_Testinghttp://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.Molecular_Genetic_Testinghttp://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.allanson.1996.13http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.allanson.1996.13http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.allanson.1996.13http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.ball.2005.363http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.ball.2005.363http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.ball.2005.363http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.agwu.1999.339http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.agwu.1999.339http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.agwu.1999.339http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/translocation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/translocation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/translocation/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2002.365http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2002.365http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2002.365http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2002.365http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/translocation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.agwu.1999.339http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.ball.2005.363http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.allanson.1996.13http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.Molecular_Genetic_Testinghttp://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.Molecular_Genetic_Testinghttp://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/


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Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Sotos Syndrome

Gene

Symbo

l

Test Method Mutations Detected

Mutation Detection

Frequency by Test

Method 1 Test

Availabilit

y

JapaneseNon-

Japanese

NSD1

Sequence analysis/mutation

scanning2

Sequence variants 3 ~12% 427%-

93% 5

ClinicalDeletion

/duplicationanalysi

s 6

5q35 microdeletion

encompassing NSD1 andNSD1 part

ial-genedeletions

~50% 7, 8,9

~15% 8, 9

FISH5q35 microdeletionencompassing NSD1

~50% 4, 8,10

~10% 5, 8,10

1. The ability of the test method used to detect amutationthat is present in the indicatedgene

2. Sequence analysis andmutation scanningof the entiregenecan have similar mutation detection frequencies;

however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the

specific protocol used.

3. Examples of mutations detected bysequence analysismay include small intragenic deletions/insertions and

missense, nonsense, and splice site mutations.

4. Limitedmutationscreeninghas been undertaken in Japanese individuals [Kurotaki et al 2003,Miyake et al

2003,Tei et al 2006].

5. The variability in detection rate reflects different eligibility criteria forscreening[Douglas et al 2003,Rio et al

2003,Cecconi et al 2005,Faravelli 2005,Melchior et al 2005,Waggoner et al 2005,Saugier-Veber et al 2007].

An NSD1 detection rate of at least 90% was achieved when the clinical diagnosis of Sotos syndrome had been made

by clinicians with expertise in the condition [Turkmen et al 2003,Tatton-Brown et al 2005b].

6. Testing that identifies deletions/duplications not readily detectable by sequence analysisof the coding and flanking

intronic regions of genomicDNA; a variety of methods includingquantitative PCR, long-range PCR, multiplex ligation-

dependentprobeamplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH

analysis that detects deletions/duplications across thegenomemay also include this gene/segment.
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7. The contribution of partial-genedeletions to Sotos syndrome in Japanese individuals is currently unknown [Douglas

et al 2005,Tatton-Brown et al 2005b].

8. The microdeletions can be detected with equalsensitivitybyFISHor otherdeletion/duplicationanalytic methods

(e.g., multiplex ligation-dependentprobeamplification [MLPA]) [Douglas et al 2003,Kurotaki et al 2003,Rio et al

2003,Turkmen et al 2003,Cecconi et al 2005,Tatton-Brown et al 2005a,Visser et al 2005,Waggoner et al 2005].

9. Exonic/multiexonic deletions (i.e.,deletionof one or more exons) are responsible for an estimated 5% of Sotos

syndrome [Douglas et al 2005,Tatton-Brown et al 2005b]. Deletion/duplicationanalytic methods (see footnote 6) are

required; typically,FISHcannot detect exonic/multiexonicgenedeletions. Deletions encompassing exons 1 and 2 are

most common, likely reflecting the high density of Alu repeats in the flanking sequences [Douglas et al 2005].

10. Typically,FISHcannot detect exonic/multiexonicgenedeletions.

Interpretation of test results. All frameshift and nonsense mutations,splicingvariants at consensus

residues, partial-genedeletions, and microdeletions encompassing NSD1 are predicted to be pathogenic.

Missense variants require more careful interpretation.

De novo variants in asimplex caseof Sotos syndrome are highly likely to be pathogenic.

Pathogenic missense mutations typically occur at conserved, functionally relevantresidues within protein domains [Tatton-Brown et al 2005b]. Missense variants outsideconserved domains should be assumed to be normal variants in the absence of additional data

in favor of pathogenicity (e.g., demonstration that the variant is de novo, results of a functional

assay).

For issues to consider in interpretation ofsequence analysisresults, clickhere.

Testing Strategy

To confirm/establish the diagnosis in aproband

If a diagnosis of Sotos syndrome is suspected, NSD1molecular genetic testingshould be

considered to confirm the clinical diagnosis and to provide information about risk of recurrence.

o For individuals ofnon-Japanese ancestry,

o 1) sequencing analysisis the first line of testing, followed by

o 2)deletion/duplication

o 3) orFISHanalysis if the sequencing is does not identify amutation.

o In individuals of Japanese ancestry,deletion/duplicationorFISHanalysis may be

considered first.

Note: If a molecular diagnosis of Sotos syndrome has been made, x-rays for bone age and

MRI scan of the brain are not required to confirm the diagnosis .

If the clinical diagnosis of Sotos syndrome is uncertain or if molecular testing is negative,

routinekaryotype,

array CGH, and

molecular genetic testingforfragile X syndromeshould be undertaken.
http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2005.e56http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2005.e56http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2005.e56http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2005.e56http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sensitivity/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sensitivity/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sensitivity/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/fish/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/fish/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/fish/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/probe/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/probe/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/probe/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2003.132http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2003.132http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2003.132http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2003.378http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2003.378http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2003.378http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.rio.2003.436http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.rio.2003.436http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.rio.2003.436http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.rio.2003.436http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.turkmen.2003.858http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.turkmen.2003.858http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.turkmen.2003.858http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cecconi.2005.247http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cecconi.2005.247http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cecconi.2005.247http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005a.307http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005a.307http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005a.307http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.visser.2005.e66http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.visser.2005.e66http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.visser.2005.e66http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.waggoner.2005.524http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.waggoner.2005.524http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.waggoner.2005.524http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2005.e56http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2005.e56http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2005.e56http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/fish/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/fish/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/fish/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2005.e56http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2005.e56http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2005.e56http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/fish/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/fish/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/fish/http: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ary/def-item/fish/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2005.e56http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/fish/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2005.e56http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.waggoner.2005.524http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.visser.2005.e66http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005a.307http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cecconi.2005.247http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.turkmen.2003.858http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.rio.2003.436http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.rio.2003.436http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.kurotaki.2003.378http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2003.132http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/probe/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/deletion/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/fish/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sensitivity/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2005.e56http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.douglas.2005.e56http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/


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Genetically Related (Allelic) Disorders

NSD1abnormalities have highspecificityandsensitivityfor Sotos syndrome. Molecular genetic testing

failed to identify mutations in NSD1 in more than 500 individuals with clinical diagnoses other than Sotos

syndrome, including Marshall-Smith syndrome,autosomal dominantmacrocephaly, nonspecific overgrowth,

and individuals with macrocephaly in association withautism spectrum disorders[Turkmen et al

2003,Tatton-Brown et al 2005b,Waggoner et al 2005,Buxbaum et al 2007].

In rare cases, other clinical conditions that show overlap with Sotossyndrome and involve NSD1mutations have been reported:

A family with macrocephaly, tall stature, and normal intelligence [van Haelst et al 2005]

An individual with Nevo syndrome [Kanemoto et al 2006] who has many clinical features consistent

with Sotos syndrome. In addition, Nevo syndrome has been shown to be allelic toEhlers-Danlos

syndrome Type VIA. Both conditions are caused by biallelic mutations in PLOD1[Giunta et al 2005].

Two individuals withBeckwith-Wiedemann syndrome(BWS) [Baujat et al 2004] whose findings were

not typical for BWS. Both showed considerable overlap with Sotos syndrome [Tatton-Brown &Rahman 2004].

Six individuals with Weaver syndrome [Douglas et al 2003,Rio et al 2003]. Weaver and Sotos

syndrome show greatest overlap in infancy, and in some of the individuals with Weaver syndrome

and NSD1mutations, the clinicalphenotypeevolved over time to be fairly classic of Sotos

syndrome [Douglas et al 2003,Tatton-Brown et al 2005b]. Weaver syndrome has recently been

shown to be caused by mutations in another histone methyl transferasegene,EZH2, providing

further evidence that Weaver syndrome is a clinical entity distinct from Sotos syndrome [Tatton-

Brown et al 2011,Gibson et al 2012].

Go to:

Clinical Description

Natural History

Based on a review of 230 persons with NSD1 abnormalities, the clinical features of Sotos syndrome were

classified as

cardinal features (occurring in at least 90% ofaffectedindividuals),

major features (occurring in 15%-89%), and

associated features (occurring in 2% and


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Cardiac anomalies

Cranial MRI/CT abnormalities

Joint hyperlaxity/pes planus

Maternal preeclampsia

Neonatal complications

Renal anomalies

Scoliosis

Seizures

Cardinal Features

Characteristic facial appearance. The facial gestalt of Sotos syndrome is evident at birth, but becomes

most recognizable between ages one and six years.

Dolicocefalia Fronte ampia e prominente

Capelli radi in regione frontotemporale

Fissure palpebrali antidown

Flushing malare

Mandibola: piccola alla nascita/ a punta nel bambino/ prominente e squadrata nelladulto

[Allanson & Cole 1996,Tatton-Brown & Rahman 2004].

Learning disability.The majority of individuals with Sotos syndrome have some degree of intellectual

impairment. Da lieve a severo, in particolare ritardo del linguaggio [Ball et al 2005]. Il grado di deficit rimane

stabile durante la vita. [Tatton-Brown et al 2005b; Authors, unpublished data].

Growth. Overgrowth ad esordio prenatale. Parto a temine. Lunghezza alla nascita al 98 e CC tra 91 e

98.Peso alla nascita nella norma (tra 51 e 91)
http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.allanson.1996.13http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.allanson.1996.13http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2004.199http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2004.199http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2004.199http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.ball.2005.363http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.ball.2005.363http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.ball.2005.363http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.ball.2005.363http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2004.199http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.allanson.1996.13


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Prima dei 10 aa rapida crescita lineare. Altezza e CC > 2 DS o oltre. Alcuni non hanno parametri sopra 98

(perch la crescita influenzata dal target genitoriale) [Cole & Hughes 1994,Tatton-Brown et al 2005b].

Il renge di altezza degli adulti riportato ampio, ci sono pochi dati. [Agwu et al 1999; Tatton-Brown &

Rahman, unpublished data].

Span aumentatoAumentata lunghezza mani

Ridotto rapporto altezza seduta/altezza in piedi

E il risultato di aumento degi arti

[Agwu et al 1999,de Boer et al 2005].

Major Features

Behavioral problems. A wide range of behavioral problems are common at all ages:

autistic spectrum disorder,

phobias, and

aggression have been described [Tatton-Brown, personal communication].

Bone age. Bone age often reflects the accelerated growth velocity and is advanced in 75%-80% of

prepubertal children..

Cardiac abnormalities.About 20% of individuals have cardiac anomalies that range in severity fromsingle, often self-limiting anomalies including PDA, ASD, and VSD to more severe, complex cardiac

abnormalities. Recently two unrelated indiv iduals with Sotos syn drome w ere shown to h ave lef t

ventr icular non-compact ion[Martinez et al 2011]. Only a minority of the cardiac abnormalities associated

with Sotos syndrome require surgical intervention.

Joint hyperlaxity/pes planus. Joint laxity is reported in at least 20%of individuals with Sotos syndrome.

Cranial MRI/CT abnormalities are identified in the majority of individuals with Sotos syndrome and

an NSD1mutation.

Ventricular dilatation (particularly in the trigone region) is most frequently identified,

but other

abnormalities include midline changes (hypoplasia or agenesis of the corpus callosum, mega cisterna

magna, cavum septum pellucidum),

cerebral atrophy, and small cerebellar vermis[Waggoner et al 2005].

Dental abnormalities.Premature dental eruption and poor dental quality have been reported [Cole &

Hughes 1994,Leventopoulos et al 2009].

Pregnancy. Complications in pregnancy may occur. In particular, maternal preeclampsia occurs in about

15% of pregnanciesof children with Sotos syndrome.

Neonatal complications. Neonates may have

1. poor feeding (~70%)

2. hypotonia (~75%),

3. jaundice (~65%),

These complications tend to resolve spontaneously, but in a small minority intervention isrequired.
http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cole.1994.20http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cole.1994.20http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cole.1994.20http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.agwu.1999.339http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.agwu.1999.339http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.agwu.1999.339http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.agwu.1999.339http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.agwu.1999.339http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.agwu.1999.339http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.deboer.2005.1142http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.deboer.2005.1142http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.deboer.2005.1142http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.martinez.2011.1115http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.martinez.2011.1115http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.martinez.2011.1115http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.waggoner.2005.524http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.waggoner.2005.524http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.waggoner.2005.524http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cole.1994.20http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cole.1994.20http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cole.1994.20http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cole.1994.20http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.leventopoulos.2009.357http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.leventopoulos.2009.357http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.leventopoulos.2009.357http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.leventopoulos.2009.357http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cole.1994.20http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cole.1994.20http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.waggoner.2005.524http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.martinez.2011.1115http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.deboer.2005.1142http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.agwu.1999.339http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.agwu.1999.339http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.cole.1994.20


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Renal abnormalities.About 15% of individuals with an NSD1mutationhave a renal abnormality;

vesicoureteric reflux is the most common. Some individuals may have quiescent vesicouretericreflux and may present in adulthood with renal impairment.

Scoliosis.inel 30%ofaffectedindividuals, scoliosis is only rarely severe enough to require bracing or

surgery.

Seizures. Approximately 25%of individuals with Sotos syndrome develop non-febrile seizures at somepoint in their lives and some require ongoing therapy.

Absence, tonic-clonic, myoclonic, and partial complex seizures have all been reported.

Other

Tumors. Tumors occur in approximately 3% of persons with Sotos syndrome and include

sacrococcygeal teratoma, neuroblastoma, presacral ganglioma, acute lymphoblastic leukemia (ALL)

and small cell lung cancer [Hersh et al 1992,Tatton-Brown & Rahman 2004]. De Boer and colleagues

have characterized and reviewed these problems and compared persons with Sotos syndrome whohave NSD1 mutations to those who do not [de Boer et al 2006].

Various other clinical features

- constipation and hearing problems caused by chronic otitis media,

. The following features are seen in 2%-15% of individuals with Sotos syndrome [Tatton-Brown et al 2005b]:

Conductive hearing loss

Constipation

Astigmatism

Cataract

Cholesteatoma

Contractures

Craniosynostosis

Cryptorchidism

Gastroesophageal reflux

Hemangioma

Hemihypertrophy

Hydrocele

Hypercalcemia

Hypermetropia

Hypodontia

Hypoplastic nails

Hypospadias

Hypothyroidism

Inguinal hernia
http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.hersh.1992.572http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.hersh.1992.572http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.hersh.1992.572http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2004.199http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2004.199http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2004.199http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.deboer.2006.582http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.deboer.2006.582http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.deboer.2006.582http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.deboer.2006.582http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2004.199http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.hersh.1992.572http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/


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Myopia

Neonatal hypoglycemia

Nystagmus

Pectus excavatum

Phimosis

Skin hyperpigmentation

Skin hypopigmentation

Strabismus

Talipes equinovarus

Umbilical hernia

Vertebral anomalies

2/3 toe syndactyly

Genotype-Phenotype Correlations

Through evaluation of 234 individuals with Sotos syndrome with an NSD1 abnormality, it has been shown

that, in general, individuals with a 5q35 microdeletion have less overgrowth and more severe learning

disability than individuals with an intragenicmutation[Tatton-Brown et al 2005b].

Penetrance

Completa ma espressivit variabie (anche intrafamiliare )

Prevalence

Sotos syndrome is estimated to occur in 1:14,000 live births [

Differential Diagnosis

Overgrowth conditions that may be confused with Sotos syndrome:

Weaver syndrome (also known as Weaver-Smith syndrome). Weaver syndrome has recently

been shown to be caused by mutations within the histone methyltransferase, EZH2[Tatton-Brown

et al 2011,Gibson et al 2012]. Affected individuals are tall, have a typical, but subtle, facial

appearance, are frequently hypertonic at birth, and often have associated joint problems suchas camptodactyly and contractures. The classic facial appearance overlaps with that of Sotos

syndrome, particularly in infancy. However, the face in Weaver syndrome is round in shape with

ocular hypertelorism. Prognathism is not a feature, but the chin appears "stuck on" and, frequently,

a horizontal crease is present between the chin and lower lip . Because of the clinical overlap

between Weaver syndrome and Sotos syndrome,NSD1 testing should be considered if

an EZH2mutationis not identified.

Beckwith-Wiedemann syndrome(BWS). Individuals with BWS typically have height and weight

at least 2 SD above the mean; macrosomia is a major diagnostic criterion . However, many of

the other findings in BWS, including macroglossia, anterior ear lobe creases/helical pits,

omphalocele, and visceromegaly, are not evident in Sotos syndrome. Molecular genetic testing can

identify epigenetic and genomic alterations ofchromosome11p15 in individuals with BWS:

(1) loss ofmethylationon the maternal chromosome atimprintingcenter 2 (IC2) in 50%

ofaffectedindividuals;
http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2011.1127http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2011.1127http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2011.1127http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2011.1127http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.gibson.2012.110http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.gibson.2012.110http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.gibson.2012.110http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/bws/http://www.ncbi.nlm.nih.gov/books/n/gene/bws/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/imprinting/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/imprinting/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/imprinting/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/imprinting/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/methylation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/bws/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.gibson.2012.110http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2011.1127http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2011.1127http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.tattonbrown.2005b.193http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/


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(2) paternaluniparental disomyfor chromosome 11p15 in 20%; and

(3) gain of methylation on the maternal chromosome at imprinting center 1 (IC1) in 5%.

Sequence analysis ofCDKN1Cidentifies mutations in approximately 40% offamilialcases and 5%-

10% of cases with nofamily historyof BWS.

Of note, althoughBaujat et al [2004]reported NSD1 mutations in two individuals with BWS, the

individuals do not fulfill the diagnostic criteria for BWS and do fulfill the diagnostic criteria for Sotos

syndrome (seeGenetically Related Disorders). BWS should be distinguishable from Sotos syndrome

clinically. Molecular testing for both conditions is indicated in individuals with clinical overlap.

Simpson-Golabi-Behmel syndrome(SGBS).This X-linked condition is also associated with pre-

and postnatal overgrowth in males. However, other features of SGBS not typically found in Sotos

syndrome include polydactyly, supernumerary nipples, diastasis recti, and pectus excavatum.

The facial gestalt also differs between the two disorders. Microdeletions and mutations

ofGPC3encoding the protein glypican 3 are causative.

Bannayan-Riley-Ruvalcaba syndrome. Thisautosomal dominantcondition is characterized by

macrocephaly, vascular malformations, hamartomatous polyps of the distal ileum and colon,

pigmented macules on the shaft of the penis, lipomas, and increased risk of thyroid and

breast cancer. Mutations ofPTENhave been found in about 60% of cases. A somewhat similar

facial gestalt in combination with overgrowth may lead to confusion with Sotos syndrome, but a

detailed clinical examination andmolecular genetic testingshould differentiate the two conditions.

Benignfamilialmacrocephaly. Thisautosomal dominantcondition is characterized by dolico- or

macrocephaly in an individual who is otherwise neurologically normal. It is likely a heterogeneous

condition and is usually a diagnosis of exclusion.

Fragile X syndrome. Similarities may exist between fragile X syndrome and Sotos syndrome.

However, the two conditions are usually distinguishable on clinical grounds; molecular testing

confirms the diagnosis.

Nevoid basal cell carcinoma syndrome(NBCCS, or Gorlin syndrome)ischaracterized by the development of multiple jaw keratocysts, frequently beginning in the

second decade of life, and/or basal cell carcinomas usually from the third decade onwards .

Most individuals have skeletal anomalies such as bifid ribs or wedge-shaped vertebrae. About

60% of individuals have a recognizable appearance with macrocephaly, bossing of the

forehead, and coarse facial features. Head circumference increases above the 98th centile until

age ten to 18 months, but is not usually associated with global developmental delay. NBCCS is

caused bygermlinemutations in PTCH. Inheritance isautosomal dominant.

Chromosomal abnormalities. A Sotos syndrome-likephenotypehas been associated with

4p duplications,

mosaic 20ptrisomy[Faivre et al 2000], and

22q13.3 deletion syndrome. Karyotyping should identify thesechromosomeabnormalities.

Nonspecific overgrowth. Many individuals with overgrowth do not fulfill the diagnostic criteria for

any of the above conditions but nevertheless have other features (e.g., learning difficulties,

distinctive facial features) that suggest an underlying genetic cause. Nonspecific overgrowth is likely

to be a heterogeneous group of conditions with multiple causes.

Management

Evaluations Following Initial Diagnosis
http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/uniparental-disomy/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/uniparental-disomy/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/uniparental-disomy/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/familial/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/familial/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/familial/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.baujat.2004.715http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.baujat.2004.715http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.baujat.2004.715http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.Genetically_Related_Allelic_Disordhttp://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.Genetically_Related_Allelic_Disordhttp://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.Genetically_Related_Allelic_Disordhttp://www.ncbi.nlm.nih.gov/books/n/gene/sgbs/http://www.ncbi.nlm.nih.gov/books/n/gene/sgbs/http://www.ncbi.nlm.nih.gov/books/n/gene/phts/http://www.ncbi.nlm.nih.gov/books/n/gene/phts/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/familial/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/familial/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/familial/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/fragilex/http://www.ncbi.nlm.nih.gov/books/n/gene/fragilex/http://www.ncbi.nlm.nih.gov/books/n/gene/bcns/http://www.ncbi.nlm.nih.gov/books/n/gene/bcns/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/germline/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/germline/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/germline/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trisomy/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trisomy/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trisomy/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.faivre.2000.273http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.faivre.2000.273http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.faivre.2000.273http://www.ncbi.nlm.nih.gov/books/n/gene/gr_22q13_3/http://www.ncbi.nlm.nih.gov/books/n/gene/gr_22q13_3/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/chromosome/http://www.ncbi.nlm.nih.gov/books/n/gene/gr_22q13_3/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.faivre.2000.273http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trisomy/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/germline/http://www.ncbi.nlm.nih.gov/books/n/gene/bcns/http://www.ncbi.nlm.nih.gov/books/n/gene/fragilex/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/familial/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/phts/http://www.ncbi.nlm.nih.gov/books/n/gene/sgbs/http://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.Genetically_Related_Allelic_Disordhttp://www.ncbi.nlm.nih.gov/books/NBK1479/#sotos.REF.baujat.2004.715http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/familial/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/uniparental-disomy/


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To establish the extent of disease in an individual diagnosed with Sotos syndrome, the following evaluations

are recommended [Tatton-Brown & Rahman 2007]:

A thorough history to identify known features/associations of the disorder: learning difficulties,

cardiac and renal anomalies, seizures, and scoliosis

Physical examination including cardiac auscultation, blood pressure measurement, and backexamination for scoliosis

Investigations to detect abnormalities before they result in significant morbidity/mortality:

o In children in whom the diagnosis has just been established, echocardiogram and renal

ultrasound examination

o In adults in whom the diagnosis has just been established, renal ultrasound examination

to evaluate for renal damage from quiescent chronic vesicoureteric reflux

o Referral for audiologic assessment. Conductive hearing loss may occur at an increased

frequency in Sotos syndrome; thus, the threshold for referral should be low.

Medical genetics consultation

Treatment of Manifestations.

If MRI has been performed and ventricular dilatation demonstrated, shunting should notusually be necessary as the "arrested hydrocephalus"associated with Sotos syndrome is typicallynon-obstructive and not associated with raised intracranial pressure . If raised intracranial pressure is

suspected, investigation and management in consultation with neurologists and neurosurgeons would be

appropriate.

Surveillance

The following are appropriate at the clinical review:

Thorough history to identify known clinical sequelae of Sotos syndrome

Examination for curvature of the spine

Cardiac auscultation

Blood pressure measurement

Referral for audiologic assessment if hearing is a concern or if the child has had many upper

respiratory tract infections

Referral to an ophthalmologist if strabismus or other problem with vision is suspected

Urine dipstick to assess for quiescent urine infection

Referral to the appropriate clinical specialist if problems are identified

Note: Cancerscreeningis not recommended. (1) The absolute risk of sacrococcygealteratoma and neuroblastoma is low (~1%) [Tatton-Brown et al 2005b,Tatton-Brown & Rahman2007]. This level of risk does not warrant routine screening, particularly as screening for neuroblastoma

has not been shown to decrease mortality and can lead to false positive results [Schilling et al 2002].

(2) Wilms tumor risk is not significantly increased and routine renal ultrasound examination is not indicated

[Scott et al 2006].
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