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).
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.
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.