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Sotos Syndrome European Journal of Human Genetics (2007) 15, 264–271 & 2007 Nature Publishing Group All rights reserved 1018-4813/07 $30.00 www.nature.com/ejhg PRACTICAL GENETICS In association with Sotos syndrome Sotos syndrome is an autosomal dominant condition characterised by a distinctive facial appearance, learning disability and overgrowth resulting in tall stature and macrocephaly. In 2002, Sotos syndrome was shown to be caused by mutations and deletions of NSD1, which encodes a histone methyltransferase implicated in chromatin regulation. More recently, the NSD1 mutational spectrum has been defined, the phenotype of Sotos syndrome clarified and diagnostic and management guidelines developed. Introduction In brief Sotos syndrome was first described in 1964 by Juan Sotos Sotos syndrome is characterised by a distinctive facial and the major diagnostic criteria of a distinctive facial appearance, learning disability and childhood over- appearance, childhood overgrowth and learning disability growth. were established in 1994 by Cole and Hughes.1,2 In 2002, Sotos syndrome is associated with cardiac anomalies, cloning of the breakpoints of a de novo t(5;8)(q35;q24.1) renal anomalies, seizures and/or scoliosis in B25% of translocation in a child with Sotos syndrome led to the cases and a broad variety of additional features occur discovery that Sotos syndrome is caused by haploinsuffi- less frequently. ciency of the Nuclear receptor Set Domain containing NSD1 abnormalities, such as truncating mutations, protein 1 gene, NSD1.3 Subsequently, extensive analyses of missense mutations in functional domains, partial overgrowth cases have shown that intragenic NSD1 muta- gene deletions and 5q35 microdeletions encompass- tions and 5q35 microdeletions encompassing NSD1 cause ing NSD1, are identifiable in the majority (490%) of 490% of Sotos syndrome cases.4–10 In addition, NSD1 Sotos syndrome cases. abnormalities are only very rarely identified in other The phenotype is largely independent of the under- overgrowth phenotypes.10 Thus, identification of an lying NSD1 defect, although cases with 5q35 micro- NSD1 abnormality is essentially diagnostic of Sotos syn- deletions tend to have more severe learning disability drome and provides an objective method of identifying a and less pronounced overgrowth. condition that can be challenging to confidently diagnose NSD1 is a histone methyltransferase that acts at H4 clinically. Over the last few years, large-scale analyses of K20 and H3 K36. such molecularly confirmed cases of Sotos syndrome has NSD1 has multiple functional domains and may have clarified the clinical and molecular spectrum of the complex roles in transcriptional regulation. condition and provided the basis for diagnostic and management protocols (Figure 1). Clinical overview Cardinal features of Sotos syndrome Three features have been designated the cardinal features of Sotos syndrome, a characteristic facial appearance, Katrina Tatton-Brown1 and Nazneen Rahman*,1 learning disability and overgrowth resulting in tall stature 1Section of Cancer Genetics, Institute of Cancer Research, 15, Cotswold and macrocephaly which is evident from birth. These Road, Sutton, Surrey, SM2 5NG, UK features are each present in over 90% of individuals with European Journal of Human Genetics (2007) 15, 264–271. doi:10.1038/ Sotos syndrome (Table 1).10 sj.ejhg.5201686; published online 13 September 2006 The facial appearance is most distinctive between 1 and 6 Keywords: Sotos; NSD1; overgrowth syndrome; histone methyltransfer- years and consists of a high, broad forehead (the head is ase said to resemble an inverted pear), fronto-temporal hair *Correspondence: Dr N Rahman, Section of Cancer Genetics, Institute of sparsity, malar flushing, down-slanting palpebral fissures Cancer Research, 15, Cotswold Road, Sutton, Surrey, SM2 5NG, UK. and a pointed chin (Figure 2a). In some children, there may Fax: þ 44 208 722 4359; E-mail: [email protected] be atypical features such as up-slanting palpebral fissures or Received 14 February 2006; revised 12 April 2006; accepted 21 April 2006 a normal hairline. In adulthood, the appearance remains Sotos syndrome K Tatton-Brown and N Rahman 265 Sotos syndrome clinically suspected Yes No NSD1 mutation analysis NSD1 abnormality detected NSD1 abnormality not detected Sotos syndrome facial appearance Learning disability Overgrowth Sotos syndrome Sotos syndrome is unlikely Manage as Sotos syndrome Consider other diagnoses Figure 1 Diagnostic strategy for individuals in which a diagnosis of Sotos syndrome is suspected. Table 1 Cardinal and associated features of Sotos syndrome Cardinal features – present Major features – present in X15% of in X90% of cases cases Characteristic facial Advanced bone age appearance Cranial CT/MRI abnormalities Learning disability Poor feeding in infancy Childhood overgrowth Neonatal jaundice Neonatal hypotonia Seizures Scoliosis Cardiac anomalies Renal anomalies Maternal pre-eclampsia Joint laxity/pes planus distinctive but the face is often longer and the chin more prominent (Figure 2b). The great majority of individuals with Sotos syndrome have some degree of learning disability. Most individuals have mild–moderate intellectual impairment but the degree Figure 2 The classic Sotos gestalt in (a) childhood and (b) of impairment is extremely broad, ranging from occasional adulthood. individuals with normal development to children with profound learning difficulties requiring life-long care. and head circumference 42SD above the mean. There is Many babies with Sotos syndrome have a birth length often some ‘normalisation’ of height post-puberty so that 42SD above the mean. The birth weight is often not the height of adults with Sotos syndrome may not be proportionately increased and so babies with Sotos syn- significantly above the norm. By contrast significant drome are usually long and thin. Before puberty the macrocephaly is typical in both children and adults with majority of children with Sotos syndrome have height Sotos syndrome. European Journal of Human Genetics Sotos syndrome K Tatton-Brown and N Rahman 266 Major features of Sotos syndrome these or other features occur in 415% of cases and can be Various medical conditions are described in at least 15% of considered major features of the condition. Sotos syndrome cases and are considered major features of For the many clinical features that have been reported in the condition (Table 1).10 only one, or a few, individuals it can be difficult to Advanced bone age occurs in B75% of affected children. determine whether they signify genuine associations of However, it should be noted that bone age is influenced by Sotos syndrome or are coincidental findings (Table 2). It is age at assessment and variability in interpretation.2,10 very likely that further, currently unrecognised, features Many individuals with Sotos syndrome have abnormal- will be reported in individuals with Sotos syndrome in the ities on cranial imaging. These are largely nonspecific and future. no particular abnormality or pattern of abnormalities is specific to Sotos syndrome.11 Ventricular dilatation is the most commonly reported feature.10 Differential diagnosis of Sotos syndrome In the neonatal period, B70% of babies with Sotos Phenotypic overlap exists between Sotos syndrome and syndrome develop jaundice and/or have difficulty with several other clinical conditions (Table 3). In our experi- feeding. The latter is in part because neonatal hypotonia is ence, the four conditions most commonly confused with also very common. These neonatal problems are generally Sotos syndrome are Weaver syndrome, Bannayan–Riley– self-limiting and do not result in long-term problems.10 Ruvalcaba syndrome, Beckwith–Wiedemann syndrome Cardiac and renal anomalies, seizures and scoliosis occur and benign familial macrocephaly. in 15–30% of cases and are very variable in type and The greatest phenotypic overlap is between Sotos and severity. The cardiac anomalies range from single, self- Weaver syndromes. The facial features of these conditions limiting anomalies such as ASD to complex anomalies are similar, particularly in infancy (Table 3). As children get requiring interventional surgery. The most common renal older the conditions are easier to differentiate as classic abnormality is vesico-ureteric reflux, but anatomical Weaver syndrome cases have widely spaced palpebral abnormalities such as duplex kidney, absent kidney, fissures and a rounder face compared to the normally urethral stenosis and pelvi-ureteric junction obstruction spaced eyes and prominent chin characteristic of Sotos are also recognised. Infantile spasms, absence, tonic/clonic syndrome.2,10,13 The two syndromes can also usually be and myoclonic seizures are all described in Sotos syn- differentiated molecularly as, in our experience, no classic drome. Scoliosis is similarly variable in severity ranging case of Weaver syndrome has an NSD1 abnormality and we from mild, requiring no intervention, to severe, where assume that Weaver syndrome is due to a different gene. bracing or surgery is indicated.10,12 Our practise is to undertake NSD1 analysis in all children in whom a diagnosis of Sotos syndrome or Weaver syndrome Other features associated with Sotos syndrome is being considered. If a mutation is identified the child is Many other clinical features have been reported in managed as other NSD1-positive individuals and a diag- individuals with Sotos syndrome. Some of these are quite nosis of Sotos syndrome is given.
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