Sotos syndrome is characterised by the presence of excessive growth during childhood, advanced bone age, macrocephaly, characteristic facial appearance and non-progressive learning difficulties [1]. It affects males and females in equal numbers. Its incidence is one in 14,000 live births. It was first described in 1964 by Dr. J.F. Sotos [2].

Until the early 2000s, diagnosis of Sotos syndrome was based upon the presence of characteristic clinical features as listed above [3]. It was subsequently discovered that mutations and deletions of the NSD1 (nuclear receptor-binding SET domain) gene – localised on chromosome 5q35.3, which codes for a histone methyltransferase implicated in transcriptional regulation – is responsible for more than 75 % of cases of Sotos syndrome [4]. In Europe and the USA, NSD1 mutations cause 60–80 % of cases of Sotos syndrome, whereby microdeletions of NSD1 cause approximately 10 % of cases. In contrast: in Japan, NSD1 microdeletions are the primary cause of Sotos syndrome in over 50 % of cases [4].
The function of the NSD1 gene has not yet been fully described. The gene codes for a histone methyltransferase, which acts as a transcriptional intermediary factor capable of both negatively and positively influencing transcription. NSD1 has been described as a “corepressor of genes that promote growth” [5]. While it remains unclear exactly how the malfunction of NSD1 leads to the features of Sotos syndrome, it is thought that mutations and microdeletions involving NSD1 disrupts the activity of genes involved in normal growth and development [4]. While over 95 % of cases are sporadic in aetiology, autosomal dominant inheritance has also been described in several cases [4].
As other genetic abnormalities were identified in patients with Sotos syndrome, patients with abnormalities of the NSD1 gene were later termed ‘Sotos syndrome 1’. Heterozygous mutations in the NFIX (nuclear factor I, X type) on chromosome 19p13.3 were identified in a cohort of children with the Sotos syndrome phenotype. They were labelled ‘Sotos syn-
drome 2’ [6]. Furthermore, in 2015, a loss-of-function, frameshift mutation in the APC2 (adenomatous polyposis coli 2) gene was identified in two siblings with features of Sotos syndrome but without NSD1 mutations [7]. They exhibited intellectual disability, abnormal brain structure and typical facial features but no other features such as bone or heart abnormalities. The APC2 gene is a downstream regulator of the NSD1 gene and its expression is downregulated by abnormalities of the NSD1 gene, potentially explaining the resulting neurological mani¬festations [7]. This genotype-phenotype combination is now known as ‘Sotos syndrome 3’.
In Sotos syndrome, childhood growth is particularly advanced in the first year of life, after which it stabilises, before normalising in puberty. Height measurements are consistently above the 97th percentile in years 2–6, while final height is usually in the high normal range [4].
Craniofacial features are distinctive. The forehead tends to be overly prominent in infancy, while in adolescences an elongated face with a prominent chin is seen. Hypertelorism and down slanting palpebral fissures are common, as are receding hairline, prominent jaw, high arched palate, anteverted nostrils and long ears. Occipitofrontal circumference remains between the 98th and 99.6th percentile throughout life [8].
Most patients have a non-progressive neurological dysfunction, although the degree of learning disability appears to be extremely variable. Delay in motor development and expressive language is common [4].
Other manifestations of Sotos syndrome are variable. Delayed attainment of milestones of development is to be expected. Developmental delay is present in 80–85 % of the patients, for example excessive drooling; central nervous system abnormalities: enlarged ventricles, increased subarachnoid spaces that may require treatment, agenesis or hypoplasia of the corpus callosum, agenesis of the septum pellucidum, hypoplasia and atrophy of the cerebellar vermis, large cisterna magna and abnormalities of the Sylvian fissure. Among musculoskeletal abnormalities, hypotonia is the most frequent (84 %), pectus excavatum or carinatum has also been reported. Ophthalmologic manifestations are frequent: strabismus, nystagmus, retinal and optic nerve anomalies [9]. Hypothyroidism, hyperthyroidism, hypoparathyroidism and thyrotoxicosis has been reported [9,10]. There is an increased incidence of different tumours at a young age [9,11], non-progressive hypotonia [12]. About 14 % of patients present with auditory-related conditions [10] such as hearing loss, EMO, recurrent ear infections, cholesteatoma, and degenerative changes of the eardrum. About
24 % of individuals have congenital malformations or abnormalities of the head and neck [10], including high arched palate, auricular dysplasia, macroglossia, cleft lip and palate, and alveolar cleft. Feeding difficulties have also been reported [10]. It can be due to the hypotonia that may result in weakness in the muscles of swallowing and subsequent feeding difficulties or the associated congenital malformations of the head and neck. About 16 % of individuals were reported to have other conditions, including speech disorder, respiratory difficulties, laryngomalacia, severe OSA, gastroesophageal reflux disease, and parotitis [109].
Scoliosis and kyphoscoliosis are present in approximately 30 % of patients. Early detection of scoliosis is important to facilitate early intervention with back braces and/or surgery [8]. There is no reported or published data on pulmonary function capacity with the subset of patients with scoliosis compared to Sotos syndrome patients without scoliosis. Congenitally dislocated hips, genu vara/valga and propensity to fractures with minimal trauma have been described [8]. Childhood seizures are common in 50 %, frequently febrile in nature [4]. Behaviour abnormalities include social inhibition and attention deficit [13]. An increased occurrence of congenital heart disease is seen, the most common defects being patent ductus arteriosus and septal defects [8]. Renal anomalies (bifid, duplex, cystic or absent kidneys; vesicoureteral reflux; pelviureteric junction obstruction) and genital anomalies (hypospadias; cryptorchidism) are present in 15 % of children with NSD1 abnormalities [14]. Recurrent upper respiration tract infections and otitis media are also common, and constipation also often requires treatment [4].