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Sotos Syndrome

, BM BCh, MD, , MB ChB, and , BM BCh, PhD.

Author Information

Initial Posting: ; Last Update: November 19, 2015.


Clinical characteristics.

Sotos syndrome is characterized by a distinctive facial appearance (broad and prominent forehead, sparse frontotemporal hair, downslanting palpebral fissures, malar flushing, long and narrow face, long chin); learning disability (early developmental delay, mild to severe intellectual impairment); and overgrowth (height and/or head circumference ≥2 SD above the mean). These three clinical features are considered the cardinal features of Sotos syndrome. Major features of Sotos syndrome include behavioral problems, advanced bone age, cardiac anomalies, cranial MRI/CT abnormalities, joint hyperlaxity / pes planus, maternal preeclampsia, neonatal jaundice, neonatal hypotonia, renal anomalies, scoliosis, and seizures.


The diagnosis of Sotos syndrome is established in a proband by identification of a heterozygous NSD1 pathogenic variant on molecular genetic testing.


Treatment of manifestations: Referral to appropriate specialists for management of learning disability/speech delays, behavior problems, cardiac abnormalities, renal anomalies, scoliosis, seizures; intervention is not recommended if the brain MRI shows ventricular dilatation without raised intracranial pressure.

Surveillance: Regular review by a general pediatrician for younger children, individuals with many medical complications, and families requiring more support than average; less frequent review of older children/teenagers and those individuals without many medical complications.

Other: Education of affected individuals and their families regarding natural history, treatment, mode of inheritance, genetic risks to other family members, and consumer-oriented resources; genetic counseling of young adults regarding risk to offspring.

Genetic counseling.

Sotos syndrome is inherited in an autosomal dominant manner. More than 95% of individuals have a de novo pathogenic variant. If neither parent of a proband has Sotos syndrome, the risk to sibs of the proband is low (<1%). The risk to offspring of affected individuals is 50%. Prenatal testing is possible for pregnancies at risk if the NSD1 pathogenic variant has been identified in an affected family member.


Suggestive Findings

No formal clinical diagnostic criteria are published for Sotos syndrome; the clinical diagnosis should be suspected in individuals with the following features:

Characteristic facial appearance – easily recognizable between ages one and six years

  • Broad, prominent forehead with a dolichocephalic head shape
  • Sparse frontotemporal hair
  • Downslanting palpebral fissures
  • Malar flushing
  • Long narrow face (particularly bitemporal narrowing)
  • Long chin
    Note: Facial shape is retained into adulthood; with time the chin becomes broader (squarer in shape).

Learning disability

  • Early developmental delay
  • Mild to severe intellectual impairment


  • Height and/or head circumference is two or more SD above the mean (which approximates to the 98th centile).
  • Height may normalize in adulthood.
  • Macrocephaly is usually present at all ages.

Note: Based on the analysis of more than 230 individuals with an NSD1 pathogenic variant, these three cardinal features were shown to occur in at least 90% of affected individuals [Tatton-Brown et al 2005b].

Establishing the Diagnosis

The diagnosis of Sotos syndrome is established in a proband by identification of a heterozygous pathogenic variant in NSD1 on molecular genetic testing (see Table 1). No clinically based diagnostic criteria have been widely accepted.

Molecular testing approaches can include single-gene testing and the use of a multigene panel:

  • Single-gene testing. Sequence analysis of NSD1 is performed first, in individuals of non-Japanese ancestry, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. In individuals of Japanese ancestry, gene-targeted deletion/duplication analysis or FISH analysis may be considered first.
  • A multigene panel that includes NSD1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Sotos Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
NSD1Sequence analysis 3~12% 427%-93% 5
Gene-targeted deletion/duplication analysis 6~50% 7, 8~15% 8
Unknown 9NA

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Limited sequence analysis has been undertaken in Japanese individuals [Kurotaki et al 2003, Miyake et al 2003, Tei et al 2006].


The variability in detection rate reflects different eligibility criteria for screening [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 [Türkmen et al 2003, Tatton-Brown et al 2005b].


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


The contribution of partial-gene deletions to Sotos syndrome in Japanese individuals is currently unknown [Douglas et al 2005, Tatton-Brown et al 2005b].


NSD1 partial-gene deletions (i.e., deletion of one or more exons) occur in an estimated 5% of non-Japanese individuals with Sotos syndrome [Douglas et al 2005, Tatton-Brown et al 2005b]. Deletion/duplication analytic methods (see footnote 6) are required; typically, FISH cannot detect exon/multiexon deletions. NSD1 full-gene deletions (detectable by both gene-targeted deletion/duplication analysis and FISH analysis) occur in approximately 10% of non-Japanese individuals with Sotos syndrome.


No other genes/loci have been shown consistently to cause Sotos syndrome. Rather, it is more likely that individuals clinically diagnosed with Sotos syndrome in whom no pathogenic NSD1 variant has been identified have (a) an NSD1 pathogenic variant in a mosaic distribution (and thus not detected on lymphocyte DNA) or (b) a cryptic NSD1 pathogenic variant not detected with the laboratory technique employed.

Clinical Characteristics

Clinical Description

Based on a review of 230 persons with NSD1 abnormalities, the clinical features of Sotos syndrome were classified as cardinal features (occurring in ≥90% of affected individuals), major features (occurring in 15%-89%), and associated features (occurring in ≥2% and <15% of persons) [Tatton-Brown et al 2005b].

It is very likely that additional associated features will be recognized as new cases are identified. For instance, two recent studies have reported patients with a connective tissue-like phenotype: one study described patients with soft, lax skin – and in some cases aortic dilatation; a second, independent study described two individuals with Sotos syndrome and lung cysts [Balasubramanian et al 2014]. It is also possible that some associated features (e.g., constipation) occur with greater frequency than appreciated now and thus could be reclassified as major features in the future.

Cardinal features (present in ≥90% of persons with Sotos syndrome)

  • Characteristic facial appearance
  • Learning disability
  • Overgrowth

Major features (present in 15%-89% of persons with Sotos syndrome)

  • Behavioral problems
  • Advanced bone age
  • 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 is the most specific diagnostic criterion for Sotos syndrome and also the feature most open to observer error and inexperience. The facial gestalt of Sotos syndrome is evident at birth, but becomes most recognizable between ages one and six years. The head is dolichocephalic and the forehead broad and prominent. Often the hair in the frontotemporal region is sparse. The palpebral fissures are usually downslanting. Malar flushing may be present. In childhood the jaw is narrow with a long chin, and in adulthood, the chin broadens [Allanson & Cole 1996, Tatton-Brown & Rahman 2004]. In older children and adults, the facial features, although still typical, can be more subtle [Allanson & Cole 1996, Tatton-Brown et al 2005b].

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. It has been suggested that children with Sotos syndrome have difficulties with speech and language, particularly expressive language and articulation [Ball et al 2005]. The majority of individuals with Sotos syndrome have some degree of intellectual impairment. The spectrum is broad and ranges from a mild learning disability (affected individuals would be expected to live independently and have their own families) to a severe learning disability (affected individuals would be unlikely to live independently as adults). The level of intellectual impairment generally remains stable throughout life [Tatton-Brown et al 2005b; Authors, unpublished data].

Overgrowth. Sotos syndrome is associated with overgrowth of prenatal onset. Delivery is typically at term. The average birth length approximates to the 98th centile and the average birth head circumference is between the 91st and 98th centiles. Average birth weight is within the normal range (50th-91st centile).

Before age ten years, affected children often demonstrate rapid linear growth. They are often described as being considerably taller than their peers. Approximately 90% of children have a height and/or head circumference at least two SD above the mean [Tatton-Brown et al 2005b]. However, growth is also influenced by parental heights and some individuals do not have growth parameters above the 98th centile [Cole & Hughes 1994, 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]. Data on final adult height are scarce; however, in both men and women, the range of final adult height is broad [Agwu et al 1999; Tatton-Brown & Rahman, unpublished data].

The de Boer et al [2005] study of auxologic data supports that of Agwu et al [1999] and shows that individuals with an NSD1 pathogenic variant have an increased arm span/height ratio, decreased sitting/standing height ratio, and increased hand length. These data suggest that the increased height in Sotos syndrome is predominantly the result of an increase in limb length [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]. Often difficulty with peer group relationships is precipitated by large size, naiveté, and lack of awareness of social cues [Finegan et al 1994]. These observations were confirmed in a study of individuals with a clinical diagnosis of Sotos syndrome (some with and some without an NSD1 pathogenic variant); it was additionally noted that attention-deficit hyperactivity disorder (ADHD) is not common among individuals with Sotos syndrome [de Boer et al 2006].

Advanced bone age. Bone age often reflects the accelerated growth velocity and is advanced in 75%-80% of prepubertal children. However, bone age interpretation is influenced by the "threshold" taken as significant, the method of assessment, subjective interpretative error, and the age at which the assessment is made.

Cardiac anomalies. About 20% of individuals have cardiac anomalies that range in severity from single, often self-limiting anomalies including PDA, ASD, and VSD to more severe, complex cardiac abnormalities. Two unrelated individuals with Sotos syndrome have been shown to have left ventricular non-compaction [Martinez et al 2011]; individuals in another recent study were found to have aortic dilatation.

Cranial MRI/CT abnormalities are identified in the majority of individuals with Sotos syndrome and an NSD1 pathogenic variant. 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].

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

Maternal preeclampsia occurs in about 15% of pregnancies of children with Sotos syndrome.

Neonatal complications. Neonates may have jaundice (~65%), hypotonia (~75%), and poor feeding (~70%). These complications tend to resolve spontaneously, but in a small minority intervention is required.

Renal anomalies. About 15% of individuals with an NSD1 pathogenic variant have a renal anomaly; vesicoureteral reflux is the most common. Some individuals may have quiescent vesicoureteral reflux and may present in adulthood with renal impairment.

Scoliosis. Present in about 30% of affected individuals, scoliosis is rarely severe enough to require bracing or surgery.

Seizures. Approximately 25% of individuals with Sotos syndrome develop non-febrile seizures at some point in their lives and some require ongoing therapy. Absence, tonic-clonic, myoclonic, and partial complex seizures have all been reported.


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 who have NSD1 pathogenic variants to those who do not [de Boer et al 2006].

Various other clinical features have been associated with Sotos syndrome. Some associated features, such as constipation and hearing problems caused by chronic otitis media, are common. If future studies show that some associated features occur in more than 15% of individuals with Sotos syndrome and therefore at higher frequencies than in the general population, these features may be secondary to disruption of NSD1 rather than incidental findings. The following features are seen in 2%-15% of individuals with Sotos syndrome [Tatton-Brown et al 2005b]:

  • Astigmatism
  • Cataract
  • Cholesteatoma
  • Conductive hearing loss
  • Constipation
  • Contractures
  • Craniosynostosis
  • Cryptorchidism
  • Gastroesophageal reflux
  • Hemangioma
  • Hemihypertrophy
  • Hydrocele
  • Hypercalcemia
  • Hypermetropia
  • Hypodontia
  • Hypoplastic nails
  • Hypospadias
  • Hypothyroidism
  • Inguinal hernia
  • 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 the 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 intragenic pathogenic variant [Tatton-Brown et al 2005b].

Genotype-phenotype correlations are not evident between intragenic pathogenic variants and 5q35 microdeletions for other clinical features associated with Sotos syndrome (i.e., cardiac abnormalities, renal anomalies, seizures, scoliosis). In addition, no correlations were observed between type of intragenic pathogenic variant (missense vs truncating) and phenotype or between position of pathogenic variant (5' vs 3') and phenotype [Tatton-Brown et al 2005b].


More than 100 parents of individuals with confirmed Sotos syndrome have been tested [Douglas et al 2003, Rio et al 2003, Türkmen et al 2003, Tatton-Brown et al 2005b]. To date, an NSD1 pathogenic variant has not been identified in an unaffected parent or an unaffected sib. Thus, Sotos syndrome appears to be a fully penetrant condition.

Of note, expressivity is highly variable. Individuals with the same pathogenic variant, even within the same family, can be affected differently [Tatton-Brown et al 2005b].


Sotos syndrome has previously been referred to as cerebral gigantism. This term is now outdated and should no longer be used.


Sotos syndrome is estimated to occur in 1:14,000 live births [Rahman, unpublished data].

Differential Diagnosis

Overgrowth conditions that may be confused with Sotos syndrome include:

  • EZH2-related Weaver syndrome (also known as Weaver-Smith syndrome). Affected individuals are tall, have a typical, but subtle, facial appearance, are frequently hypotonic at birth (although they can present with a mixed central hypotonia/peripheral hypertonia), and often have associated joint problems such as camptodactyly and contractures. The classic facial appearance overlaps with that of Sotos syndrome, particularly in infancy. Facial features which differentiate Weaver syndrome from Sotos syndrome include a round shape to the face 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 EZH2 pathogenic variant is not identified. EZH2-related Weaver syndrome is inherited in an autosomal dominant manner; a de novo germline pathogenic variant may be common.
  • 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 of chromosome 11p15 in individuals with BWS: (1) loss of methylation on the maternal chromosome at imprinting center 2 (IC2) in 50% of affected individuals; (2) paternal uniparental disomy for chromosome 11p15 in 20%; and (3) gain of methylation on the maternal chromosome at imprinting center 1 (IC1) in 5%. Sequence analysis of CDKN1C identifies pathogenic variants in approximately 40% of familial cases and 5%-10% of cases with no family history of BWS. Approximately 85% of individuals with BWS have no family history of BWS while approximately 15% have a family history consistent with autosomal dominant transmission of BWS.
    Of note, although Baujat et al [2004] reported NSD1 pathogenic variants in two individuals with BWS, the individuals do not fulfill the diagnostic criteria for BWS and do fulfill the diagnostic criteria for Sotos syndrome (see Genetically 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 Type 1 (SGBS1). 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. Mutation of GPC3 is causative.
  • Bannayan-Riley-Ruvalcaba syndrome. This autosomal dominant condition 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. Pathogenic variants in PTEN have been found in about 65% of cases. A somewhat similar facial gestalt in combination with overgrowth may lead to confusion with Sotos syndrome, but a detailed clinical examination and molecular genetic testing should differentiate the two conditions.
  • Benign familial macrocephaly. This autosomal dominant condition is characterized by dolicho- and/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) is characterized 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 by germline pathogenic variants in PTCH and is inherited in an autosomal dominant manner.
  • Chromosome abnormalities. A Sotos syndrome-like phenotype has been associated with 4p duplications, mosaic 20p trisomy [Faivre et al 2000], and 22q13.3 deletion syndrome.
  • 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.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Sotos syndrome, the following evaluations are recommended [Tatton-Brown & Rahman 2007]:

  • A thorough history to identify known features of Sotos syndrome: learning difficulties, cardiac and renal anomalies, seizures, and scoliosis
  • Physical examination including cardiac auscultation, blood pressure measurement, and back examination for scoliosis
  • Investigations to detect abnormalities before they result in significant morbidity/mortality:
    • In children in whom the diagnosis has just been established, echocardiogram and renal ultrasound examination
    • In adults in whom the diagnosis has just been established, renal ultrasound examination to evaluate for renal damage from quiescent chronic vesicoureteral reflux
    • Referral for audiologic assessment. Conductive hearing loss may occur at an increased frequency in Sotos syndrome; thus, the threshold for referral should be low.
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

When clinical problems (e.g., cardiac anomalies, renal anomalies, scoliosis, seizures) or difficulties with learning/behavior/speech are identified, referral to the appropriate specialist is recommended.

If MRI has been performed and ventricular dilatation demonstrated, shunting should not usually be necessary as the "arrested hydrocephalus" associated with Sotos syndrome is typically non-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.

Some children in North America have been prescribed methylphenidate with varying success; in Europe, behavioral management strategies are more commonly used, again with varying success.

Prevention of Secondary Complications

Antibiotic prophylaxis is indicated in individuals with vesicoureteral reflux.


Regular evaluation by a general pediatrician is recommended for younger children, individuals with many medical complications needing coordination of medical specialists, and families requiring more support than average [Tatton-Brown & Rahman 2007].

The clinician may wish to evaluate older children/teenagers and those individuals without many medical complications less frequently.

The following are appropriate at the clinical evaluation:

  • Thorough history to identify known clinical sequelae of Sotos syndrome
  • Cardiac auscultation
  • Blood pressure measurement
  • Examination for curvature of the spine
  • Urine dipstick to assess for quiescent urine infection
  • Referral to an ophthalmologist if strabismus or other problem with vision is suspected
  • Referral for audiologic assessment if hearing is a concern or if the child has had many upper respiratory tract infections
  • Referral to the appropriate clinical specialist if problems are identified

Note: Cancer screening is not recommended. (1) The absolute risk of sacrococcygeal teratoma and neuroblastoma is low (~1%) [Tatton-Brown et al 2005b, Tatton-Brown & Rahman 2007]. 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].

Evaluation of Relatives at Risk

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

Pregnancy Management

Preeclampsia occurs at a slightly higher frequency in women carrying a fetus with Sotos syndrome, careful monitoring in at-risk pregnancies is recommended.

Therapies Under Investigation

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

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Sotos syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • About 5% of individuals diagnosed with Sotos syndrome have an affected parent.
  • The remaining approximately 95% of individuals have a de novo pathogenic variant.
  • If a parent of an individual with an identified NSD1 pathogenic variant does not have any clinical features of Sotos syndrome, that parent is very unlikely to have a pathogenic variant in NSD1. This can be confirmed with molecular genetic testing of the parent for the NSD1 pathogenic variant identified in the proband.

Sibs of a proband

  • The risk to the sibs of a proband depends on the genetic status of the proband's parents.
  • If a parent of the proband has an NSD1 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • The risk to the sibs of a proband with clinically unaffected parents is less than 1%. This residual risk is based on the theoretic risk for germline mosaicism and the background risk for a second de novo pathogenic variant occurring in the same family. To date, no recurrences caused by germline mosaicism have been reported.

Offspring of a proband

  • Each child of an individual with Sotos syndrome has a 50% chance of inheriting the NSD1 pathogenic variant.
  • Phenotypic expression can vary from one generation to the next and thus it is not possible to accurately predict how offspring may be affected.

Other family members

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent has the NSD1 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with Sotos syndrome has the NSD1 pathogenic variant or clinical evidence of the disorder, it is extremely likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

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

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the NSD1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for Sotos syndrome are possible. Note that phenotypic expression can vary from one generation to the next; thus, it is not possible to accurately predict phenotype on the basis of prenatal molecular genetic test results.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • My46 Trait Profile
  • Sotos Syndrome Support Association (SSSA)
    PO Box 4626
    Wheaton IL 60189
    Phone: 888-246-7772 (toll-free)
  • Child Growth Foundation
    21 Malvern Drive
    West Midlands B76 1PZ
    United Kingdom
    Phone: 020 8995 0257

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

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Sotos Syndrome (View All in OMIM)


Gene structure. NSD1 comprises 22 coding exons (NM_022455.4). For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Many benign variants have been identified [Douglas et al 2003, Kurotaki et al 2003, Rio et al 2003, Türkmen et al 2003, Tatton-Brown et al 2005b].

Pathogenic variants. More than 100 pathogenic variants have been published. No mutational hot spots have been identified [Douglas et al 2003, Kurotaki et al 2003, Rio et al 2003, Türkmen et al 2003, Faravelli 2005, Tatton-Brown et al 2005b]. See Table A.

A recurrent 1.9-Mb 5q35 microdeletion encompassing NSD1 has been reported in most Japanese 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 of microdeletions are generated by nonallelic homologous recombination between flanking low-copy repeats [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 crossover events and predispose to recombination hot spots at 5q35 [Visser et al 2005].

Normal gene product. Only limited data exist regarding the functions of the 2696-amino acid protein encoded by NSD1: a histone-lysine N-methyltransferase, H3 lysine-36, and H4 lysine-20 specific. It is expressed 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 histone specificity, methylating lysine residue 36 on histone H3, and lysine residue 20 on histone H4 (K36H3 and K20H4) [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. The nuclear 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 influencing transcription, depending on the cellular context [Kurotaki et al 2001].

Abnormal gene product. How functional abrogation of NSD1 results in Sotos syndrome is not currently known.


Literature Cited

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Suggested Reading

  • Cytrynbaum CS, Smith AC, Rubin T, Weksberg R. Advances in overgrowth syndromes: clinical classification to molecular delineation in Sotos syndrome and Beckwith-Wiedemann syndrome. Curr Opin Pediatr. 2005;17:740–6. [PubMed: 16282780]
  • Naohiro K. Sotos syndrome (SOS). Atlas of Genetics and Cytogenetics Oncology and Haematology. Available online. 2004. Accessed 8-2-18.
  • Rahman N. Mechanisms predisposing to childhood overgrowth and cancer. Curr Opin Genet Dev. 2005;15:227–33. [PubMed: 15917196]

Chapter Notes

Revision History

  • 19 November 2015 (me) Comprehensive update posted live
  • 8 March 2012 (me) Comprehensive update posted live
  • 10 December 2009 (me) Comprehensive update posted live
  • 23 March 2007 (me) Comprehensive update posted live
  • 17 December 2004 (me) Review posted live
  • 26 May 2004 (tc) Original submission
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