Clinical manifestations

Presentation and course

Sotos syndrome is characterized by the following:

Craniofacial features. Sotos patients with NSD1 variants typically present with macrodolichocephaly, a characteristic facial gestalt of high and prominent forehead, and a small, pointed chin, giving the appearance of an inverted pear. Further, they have a receding anterior hairline, hypertelorism, malar flushing, downslanting palpebral fissures, anteverted nostrils, relatively large ears, and highly arched palate (Allanson and Cole 1996; 47; 48). Nevertheless, these characteristic facial features change with time; in youth, the face is round with disproportionate prominence of the forehead, whereas in adolescence the face lengthens, with less prominence of the square or pointed chin, and macrocephaly is no longer pronounced but the downslanting palpebral fissures and the high hairline remain distinctive (09; 35; 14). It is noteworthy to mention that mild facial features with normal head circumference were reported in Sotos-like patients (06). In comparison, Sotos 2 patients with NFIX variants display long or triangular face, prominent forehead, depressed nasal bridge, deeply set eyes, down-slanting palpebral fissures, short nose with anteverted nares and upturned tip, long philtrum, small mouth that is often held open with a thin upper vermillion in a cupid bow shape, an everted lower lip, and a prominent chin. These facial features became more prominent among adults with Sotos 2 showing more elongated face, prominent chin, deeper skin folds, and more open mouth (37).

Overgrowth. It is present in 90% of individuals and usually starts prenatally and increases rapidly in infancy, but settles down above the 97th centile in early childhood, and tends to follow this during childhood; but, the adult height remains close to normal, especially in females (48). This is quite expected, as advanced bone age results in earlier closure of epiphyses. However, 20% of patients were described to have normal growth and bone age (25; 06).

Developmental delay and learning disability. Sotos patients typically present with neonatal hypotonia that improves with age. Therefore, walking is usually delayed. In general, the majority of patients with Sotos syndrome have some degree of learning disability, which may vary from mild to profound learning difficulties requiring lifelong care (15). Although 18% of patients harboring NSD1 variants (Sotos 1) are reported to have normal learning, patients harboring NFIX variants (Sotos 2) usually display severe to profound disability (37). Males with Sotos syndrome may be more likely to have a greater degree of intellectual disability than females with Sotos syndrome.

Behavioral disturbances with aggressiveness. Although no characteristic behavioral profile has been specified among patients with Sotos 1 and Sotos 2 syndrome, they usually have social contact problems, and 38% had ADHD and anxious behavior. Aggression and self-injurious behavior were also noted. Patients with Sotos syndrome usually display considerable delay in expressive language when compared to receptive language (24). Furthermore, speech articulation difficulties including delayed or no speech development were observed.

The Sotos syndrome cognitive profile is characterized by relative strength in verbal ability and visuospatial memory but relative weakness in nonverbal reasoning ability and quantitative reasoning (24).

Patients with missense mutations had milder phenotype than those with truncating mutations (39). Severe cognitive impairment was observed in patients harboring large NSD1 deletions (52; 45; 33), whereas those with NSD1 point mutations show fewer behavior problems, an easier temperament, and fewer internalizing behaviors (11).

Neuroradiologic anomalies. In general, disturbed development of the midline structures of the brain such as ventricular dilatation, hypoplastic corpus callosum, heterotopias, periventricular leukomalacia, macrocerebellum, open operculum, and cavum septum pellucidum are the main neuroradiologic anomalies described with Sotos 1 and 2 (40). In comparison, Chiari malformation type I, nodular heterotopias, and cortical dysplasia were reported in few patients with NFIX variants or Sotos 2 (42; 37). In one study, hypoperfusion of the frontal lobe was noticed in two of the three patients with Sotos syndrome, suggesting some associations with the abnormal behavior noticed in Sotos syndrome (17).

Seizures. Seizures have been described in 50% of Sotos 1 patients and 18% of Sotos 2 patients (37). Half of those with Sotos 1 had febrile seizures that evolve to tonic/clonic or temporal lobe epilepsy. Temporal lobe epilepsy may include olfactory, gustatory, or auditory hallucinations, automatisms, fear, auras (eg, abdominal aura) with or without behavioral arrest that could be confused with behavioral disorders. Infantile spasms, absence, and myoclonic seizures were also reported. Generally, seizures were easy to control with common antiepileptic drugs (31).

Dental and oral findings. These include premature or ectopic tooth eruption, hypodontia, enamel hypoplasia, excessive tooth wear, maxillary and mandibular recession, talon cusps, fused teeth, expanded pulp cavity of deciduous teeth, and tooth agenesis (found in 69%) involving the premolars (especially the second) are noted (21). High arched palate and dental crowding were reported in few patients with Sotos 2 (37).

Congenital heart defects. Patent ductus arteriosus with or without atrial septal defect are the most frequent, and are reported exclusively among patients with NSD1 gene microdeletions. It ranges from single, self-limiting anomalies to complex anomalies requiring interventional surgery (29; 25). In contrast, one patient with the NFIX variant showed mitral valve prolapse (37).

Urogenital abnormalities. The most common renal abnormality is vesicoureteric reflux, hydronephrosis, and hydroureter, but anatomical abnormalities such as duplex kidney, urethral stenosis, pelviureteric junction obstruction, and absent kidney are also recognized (44). They are commonly associated with NSD1 gene microdeletions (29).

Ocular features. Cataracts, megalophthalmos, exotropia, megalocornea, hyperopia, nystagmus, esotropia, optic disk pallor, and retinal dystrophy were reported in Sotos 1 syndrome (19), whereas strabismus, optic nerve atrophy, or hypoplasia were described in 30% of Sotos 2 patients (12; 37).

Skeletal anomalies. Scoliosis has been reported in about up to 52% of NSD1 variants (13; 14). It develops at an early age and can range from a mild to severe with rapidly progressive curving. In comparison, slender habitus (59%) together with long hands (60%) are frequent in Sotos 2 patients (37).

Tumor risk. The risk of tumors was estimated to be about 2% to 3% (13; 14). Most tumors (45%) developed after the age of five years and were of hematopoietic and neuroectodermal origin (25).

Other features. These include neonatal jaundice, neonatal cutis laxa, feeding problems, hypothyroidism, laryngomalacia, inguinal hernia, craniosynostosis, conductive or sensorineural hearing loss, pneumothorax associated with multiple subpleural blebs, arthrogryposis, hyperpigmentation, hypopigmentation, and hypoplastic nails (09; Allanson and Cole 1996; 48; 04; 30).

Prognosis and complications

Sotos syndrome is not a progressive disorder. Thus, long-term survival is not surprising. Adults with Sotos syndrome who have mild to moderate intellectual disability usually display social isolation, depression, and anxiety. The most common medical problems are scoliosis and/or contractures, visual difficulties (as a result of strabismus, myopia, glaucoma, nuclear cataract, and retinal atrophy), and increased risk of tumorigenesis (13). Less common medical problems are lymphedema, contracture deformities, dilatation of the aortic arch, and tremors (14). The severity of these medical problems could affect the life expectancy (48; 25).

Clinical vignette

Patient 1. A three-year-old boy presented with macrodolichocephaly and developmental delay. He was the fourth child of a healthy nonconsanguineous 39-year-old mother and 45-year-old father. The pregnancy was unremarkable. There was no history of toxemia, preeclampsia, or exposure to any teratogenic agent during the pregnancy. The boy was delivered via normal spontaneous vaginal birth at 38 weeks of gestation. Birth weight, length, and occipitofrontal head circumference measurements were unknown. He had neonatal jaundice, hypotonia, and feeding difficulties, for which he was kept in an incubator for two weeks. Examination showed weight, height, and head circumference of 18.5 kg (+2.5 SD), 101.2 cm (+1.8 SD), and 54 cm (+2.2 SD), respectively. A triangular face, dolichocephaly, hypertelorism with an antimongoloid slant, anteverted nostrils, and a pointed chin were noticed.

He had hypotonia, but the deep tendon reflexes were slightly brisk. His psychomotor development showed mild delay in terms of head control at the age of seven months, sitting at the age of nine months, and walking alone at 21 months.

The patient’s Portage development test results were abnormal. His most notable deviations were in language and cognitive behavior. His self-help and gross motor skills were mildly delayed at a 3-year level. His EEG showed nonspecific abnormalities. Electromyography and nerve conduction showed axonal neuropathy. An MRI of the brain showed dysplastic corpus callosum, especially in the posterior part, and mild enlargement of the lateral ventricles.

Bone age at chronological age six years was six years. Examination at the age of seven years showed weight, height, and head circumference of 29.5 kg (+2 SD), 125 cm (+1 SD), and 56.3 cm (+3 SD), respectively. Craniotomy was performed at the age of nine years for cosmetic purpose to improve the shape of the skull. Followup cranial MRI did not reveal further changes. Ophthalmologic examination, echocardiogram, abdominal ultrasound, and karyotype of cultured peripheral blood lymphocytes were normal. His mother reported that he was inattentive, hyperactive, and aggressive toward the other children. At the age of 11 years, weight, height, and head circumference were 56 kg (+3.2 SD), 147.3 cm (+1 SD), and 58.4 cm (+3.2 SD), respectively. Dental examination at this age showed high-arched palate and malposed teeth with missing left upper second premolar. Mutation analysis of NSD1 was not done.

Patient 2. This 15-month-old male was the third child born to nonconsanguineous healthy parents. His mother’s age at the time of conception was 34 years, and his father’s age was 45 years. The patient had an older brother with epilepsy and a sister with hydroureter and learning disability. Further, the familial history showed maternal and paternal cousins with learning disability. The patient was born at term by normal vaginal delivery, and the pregnancy had been uneventful. His birth weight was 4.5 kg. His birth length and his head circumference were not recorded. From the 3rd day after birth, he developed physiological jaundice that lasted for 15 days. He raised his head at five months, sat alone at eight months, stood with support at nine months, and walked at 13 months. He presented to us at 15 months of age. Weight, length, and head circumference were 16.5 kg (+4.2 SD), 85.5 cm (+2.5 SD), and 50 cm (+2.2 SD), respectively. His face was long with prominent forehead, antimongoloid slanting, large ears, long philtrum, high-arched palate, and pointed chin. The patient demonstrated slight generalized hypotonia and umbilical hernia.

Electromyography and nerve conduction showed axonal neuropathy. Abdominal ultrasonography revealed dilatation of left renal pelvis at the pelviureteric junction. His EEG showed bilateral focal epileptogenic dysfunction. Routine blood examination, thyroid hormone levels, electrocardiogram, and ophthalmologic examination were within normal ranges. His bone age at chronological age 15 months was 32 months. His developmental quotient test was 73. Brian CT revealed brain atrophy. Unfortunately, mutation analysis of NSD1 for the family was not performed.

Biological basis

Etiology and pathogenesis

Truncating mutations, missense mutations in functional domains, partial gene deletions, or 5q35 microdeletions involving the entire nuclear receptor binding, SETdomain containing protein 1 (NSD1) gene are identifiable in the majority (90%) of Sotos syndrome patients and classified as Sotos 1. Protein truncation mutations are found throughout the NSD1 gene, whereas missense mutations cluster in the latter half of the gene where functional domains are located (45). The mechanism of generation and size of 5q35 microdeletions differ depending on the ethnic origin of the affected individual. Outside Japan, 5q35 microdeletions are variable in size and predominantly arise through interchromosomal rearrangements (45). In contrast, a uniform 1.9Mb microdeletion, arising through intrachromosomal rearrangements, has been identified in the majority of Sotos syndrome cases of Japanese descent (45; 53; 33). Low-copy repeats flanking the Sotos common deletion showed that the deletion arises through nonhomologous recombination utilizing the low-copy repeats (53). An inversion polymorphism that predisposes to the microdeletion is common in Japan and may explain the high 5q35 microdeletion frequency in the Japanese population, although the frequency of this inversion polymorphism outside Japan is currently not known (53). This suggests possible mechanistic differences in the generation of the microdeletion among different populations. Generally, the paternal allele is preferentially deleted in the majority of cases with NSD1 microdeletions. This could be partly attributed to the greatly increased recombination rate in men compared with women at the 5q telomere. Mutational hotspots do not exist (45).

NSD1 encodes a histone methyltransferase that catalyzes the transfer of methyl groups to lysine residues of histone tails: more specifically, lysine residue 36 of histone H3 (H3K36) and less frequently lysine reside 20 of histone H4 (H4K20) (Rayasam et al 2003). These methylation marks are regulating the epigenome crucial for embryonic development. NSD1 regulates transcription via interactions with H3K36 methylation and RNA polymerase II (08).

The role of NSD1 in the pathogenesis of Sotos syndrome could be mediated through its action as a corepressor of genes that promote growth (22). It is expressed in several tissues including fetal/adult brain, kidney, skeletal muscle, spleen, and thymus, and the NSD1 protein is probably involved in the transcriptional silencing of developmentally regulated genes during embryogenesis. It was proposed that deregulation of the MAPK/ERK pathway in Sotos syndrome results in altered hypertrophic differentiation of NSD1-expressing chondrocytes and may be a determining factor in statural overgrowth and accelerated skeletal maturation in Sotos syndrome (51). Further, haploinsufficiency of NSD1 results in dysregulated insulin expression (16).

Malan syndrome (Sotos 2) is caused by heterozygous variants or deletions of NFIX clustered mostly in exon 2. These variants are predicting premature stop codons mostly in the 5’ part of the mRNA. It is likely that these mutated mRNAs are cleared by nonsense mediated decay (NMD), thereby leading to haploinsufficiency. Functional studies showed the role of NFIX in chondrocyte differentiation and bone formation and its specific involvement in the endochondral ossification process. The overgrowth in patients with dominant NFIX mutations supports a dysregulation of the switch between proliferation and differentiation stages and also suggests that NFIX could act as a negative regulator of the endochondral ossification process (26; 28; 36; 54). There is no genotype-phenotype correlation in Sotos 2 except for an increased risk for epilepsy with 19p13.2 microdeletions (37).

In two Egyptian siblings with Sotos-like features, homozygous mutation of the APC2 gene was identified. Expression of APC2 was revealed to be under the control of NSD1. The knockdown of NSD1 (the main gene responsible for Sotos syndrome) in neuronal cells suppressed the expression of the APC2 gene, which led to developmental defects in the brain. These results strongly indicated that APC2 is a crucial target of NSD1 (03).

Epidemiology

The prevalence of Sotos syndrome is estimated at about 1 per 15,000 (48). Pathogenic variants of NSD1 were described in approximately 90% of patients with classic Sotos 1 syndrome (20). Microdeletions encompassing the NSD1 gene have been reported in approximately 50% of Japanese patients and in less than 10% of non-Japanese patients (23; 45). The differences in NSD1 frequency are due to differences in genomic architecture rather than case ascertainment bias (23). Furthermore, pathogenic variants in NFIX gene were identified in patients with Sotos-like features to harbor and termed as Sotos 2 (26; 36; 54). Pathogenetic variants cluster mostly in exon 2 (37). Only one family with two affected sibs harboring homozygous mutation of the APC2 gene has been published, thus suggesting autosomal recessive pattern of inheritance with 25% recurrence risk.

Prevention

Genetic counseling is crucial and depends on the family history and genetic testing. Affected individuals will have 50% recurrence risk (48).

The diagnosis of Sotos syndrome may be considered in the antenatal period in cases with a normal fetal karyotype where there is increased risk for Down syndrome demonstrated by maternal serum screening, especially in the presence of supportive ultrasound findings such as macrocephaly, polyhydramnios, and decreased fetal movements (50). When Sotos syndrome is suspected prenatally, genetic testing for NSD1, NFIX, or both should be performed, as it provides a simple, safe, sensitive, and confirmatory test in the great majority of cases (48).

Differential diagnosis

Phenotypic overlap with other overgrowth syndromes exists, in particular with the following:

Weaver syndrome. The facial features of Sotos syndrome and Weaver syndrome are similar, particularly in infancy. However, as children get older, patients with Sotos usually have the characteristic prominent chin. Further, advanced dental maturation is remarkably observed in Sotos syndrome but rarely commented on in Weaver syndrome. Moreover, Sotos syndrome may be a cancer syndrome, whereas Weaver syndrome is not. Finally, mutations in the histone methyltransferase EZH2 were shown to cause Weaver syndrome (46).

Marshall-Smith syndrome. It is characterized by increased birth length with subsequent failure to thrive, prominent forehead, prominent eyes, underdeveloped midface and prominent premaxilla micrognathia, anteverted nares, broad proximal and middle phalanges, disharmonic bone maturation, and respiratory compromise secondary to upper airway obstruction, (26; 36; 54).

Variants associated with Marshall-Smith syndrome have exclusively been found in regions outside of those coding for the DNA binding and dimerization domain, especially in exons 6-8 and sometimes in exons 9 and 10. For several Marshall-Smith-associated variants it has been demonstrated that mutant mRNA does not undergo nonsense mediated decay (26; 41), whereas variants associated with Malan syndrome are instead restricted to the 5’ part of the gene encoding for the DNA binding and dimerization domain (37).

Tatton-Brown-Rahman syndrome. Tatton-Brown-Rahman syndrome is a new overgrowth syndrome characterized by a tall stature, large head circumference, ID, and a facial gestalt that is characterized by a round face, heavy, horizontal eyebrows, and narrow palpebral fissures. It is caused by DNMT3A (DNA cytosine 5 methyltransferase 3A) mutations or 2p23 microdeletion (49; 34).

Bannayan-Riley-Ruvalcaba syndrome. Bannayan-Riley-Ruvalcaba syndrome is differentiated by the characteristic lipomatosis and hemangiomatosis and penile freckling in boys, which has not been reported in Sotos syndrome. It is due to PTEN mutations in about 60% of cases.

Beckwith-Wiedemann syndrome. Macroglossia is the hallmark in Beckwith-Wiedemann syndrome but has never been reported in Sotos syndrome. Further, visceromegaly, hemihypertrophy, and embryonal tumors are usually associated with Beckwith-Wiedemann syndrome (Baujat et al 2005). Hypomethylation of KCNQ1OT1 is the most common cause of Beckwith-Wiedemann syndrome, although it was reported in three patients with Sotos-like features (28).

Benign familial macrocephaly. Benign familial macrocephaly lacks the distinctive facial features of Sotos syndrome.

Simpson-Golabi-Behmel syndrome. Coarse facies, vertebral segmentation defects, supernumerary nipples, dental malocclusion, organomegaly, and diaphragmatic hernia make Simpson-Golabi-Behmel syndrome quite distinct from Sotos syndrome. Besides, it has an X-linked mode of inheritance. It is caused by mutations and deletions in GPC3 (Baujat et al 2005).

Diagnostic workup

When suspecting Sotos syndrome, anthropometric measures and scrutinized clinical examination should be taken:

Management

Rehabilitation. No specific treatment is available, but symptomatic treatment for the associated complications depends on the age and severity.

Outcomes

Special considerations

Pregnancy

It was observed that there is unexplained low vertical transmission rate. However, when pregnancy occurs, it is described to have normal prenatal history. Nevertheless, toxemia or preeclampsia is mentioned in several cases (48; 25). After birth, many of Sotos babies may develop neonatal hyperinsulinemic hypoglycemia, neonatal jaundice, and/or feeding difficulty.

Anesthesia

Regional techniques of anesthesia are the reasonable choice. They should be performed after induction as most of the children with Sotos syndrome are uncooperative and possibly aggressive (07). The use of muscle relaxants may not be necessary in patients with marked hypotonia. Further, it can be suggested to avoid opioids, drugs that decrease seizure threshold, and antiepileptic drugs (01).