Sotos syndrome (OMIM 117550)

Cerebral Gigantism syndrome

Sotos syndrome is a childhood overgrowth condition, first described in 1964 by Sotos et al 1, though the first patient described may have been reported in 1931 2. The four major diagnostic criteria were established in 1994 by Cole and Hughes 3, based on the systematic assessment of 41 typical cases: overgrowth with advanced bone age, macrocephaly, characteristic facial appearance, and learning difficulties. These clinical criteria remained the cornerstone for the diagnosis of Sotos until 2002. The recent identification of NSD1 mutations and deletions 4 has allowed re-evaluation of the features of this condition 56789. In 2005, Tatton-Brown and the Childhood Overgrowth Collaboration Consortium reviewed the clinical features of 239 Sotos cases with NSD1 abnormalities. They confirmed that overgrowth (including height and occipito-frontal circumference), dysmorphism and learning disability were present in 90% of these NSD1-positive individuals, with a wide spectrum of associated features including macrocephaly, advanced bone age, neonatal jaundice and hypotonia, seizures, scoliosis, cardiac defects and genitourinary anomalies 10.

Sotos syndrome is probably one of the most common overgrowth conditions, after the Beckwith-Wiedemann syndrome. The exact birth prevalence remains unknown. Hundreds of cases are reported. The literature on Sotos syndrome, before the identification of the NSD1 gene responsibility, has to be read carefully since it is mixed with publications that evidently do not deal with the Sotos syndrome.

For forty years, the diagnosis of Sotos syndrome has been based on the subjective evaluation of clinical features. However, although the combination of craniofacial features may be distinctive, the other components are non-specific. This lack of specific clinical features was often the center of nosologic discussion 311. Recently, Tatton-Brown and Rahman analyzed helpfully the clinical features of a large series of more that two hundred Sotos syndrome cases with proven abnormalities in NSD1 1012.

Generally, pregnancy is described as normal; however, toxemia or pre-eclampsia is mentioned in several cases 11. Mean gestational age is normal (39 weeks) but the infants are large for their gestational age. According to Cole and Hughes 3, birth length, weight, and occipito-frontal circumference (OFC) are respectively 3.2, 1.0, and 1.8 standard deviations above the mean. Length is likely more increased than weight. Indeed, the birth weight of 76% of the 107 Sotos cases reported by Tatton-Brown was less than the 98^th centile and the mean birth weight centile was 75^th-91^st 12. In the neonatal period, many infants experience early feeding difficulties (40% required tube feeding 3), variable degree of congenital hypotonia, jaundice by hyperbilirubinemia or hypoglycemia. Throughout childhood, the advance growth is particularly pronounced in the first year of life, after which it stabilizes with a height consistently above the 97^th centile between age 2 and 6 years. This childhood overgrowth may be absent (90% of the affected individuals have height and/or head circumference >2SD above the mean in Tatton-Brown series 10). Growth in height and weight tends to normalize at puberty, probably because of the epiphysal fusion. Final height is, in the majority of cases, within the high normal range 13, particularly in females, in whom the growth pattern correlates well with the presence of advanced bone age and early puberty. Macrocephaly and large hands and feet are also consistent features 1. Craniostenosis by premature fusion of lambdoid, sagittal and coronal sutures has been reported 11. The reported incidence of advanced bone age in Sotos cases varies from 74% to 100% of cases, and this variability is probably related to the frequency, timing and method of assessment. This feature is present in 76% of the NSD1-positive individuals 10. Bone age is often described as dysharmonic with the phalangeal age being in advance in comparison with the carpal age. X-rays of the hand are also useful for metacarpophalangeal profiles, which have been reported to produce patterns that evokes Sotos syndrome 14.

The overall craniofacial features are distinctive, especially between one and six years of age. In infancy, the face is round with disproportionate prominence of forehead and become longer in adolescence, with prominence of the pointed chin. Macrodolichocephaly, receding hairline, apparent hypertelorism with down slanting palpebral fissures, prominent jaw, malar flushing, anteverted nostrils, mild micrognathia, high arched palate and large ears are commonly identified. OFC is between the 98^th and 99.6^th centile in infancy, childhood and adulthood, and is below the 91^st centile in only 7% of the series of Tatton-Brown 10, 60% having an OFC greater than the 99.6^th percentile.

Most patients have a non progressive neurological dysfunction manifested by clumsiness and poor coordination. Cole and Hughes 3 reported a mean developmental/intelligence quotient (DQ/IQ) of 78 Sotos cases with a range 40–129 (n = 23) and, recently, de Boer et al 15 found that the mean IQ, in 21 individuals with NSD1 gene alterations was 76 (range 47–105). Delay in expressive language and motor development during the infancy is particularly common. The degree of learning disability appears extremely variable. Among the 239 NSD1-positive individuals in Tatton-Brown series 10, 97% presented learning difficulties. Delay in walking until after 15 months of age and speech delay until after 2.5 years are usual. Recently was reported a family with segregation of a NSD1 mutation with significant overgrowth but without mental deficiency 16. Seizures are found in about 50% of patients, but in half the cases, they are febrile. Attention deficit and placid behavior may also be a component 1718. Psychiatric manifestations including social inhibition or psychosis have been also noticed 1920. Dilatation of the cerebral ventricles is common. Other non-specific neurological abnormalities include absent corpus callosum, prominent cortical sulci, cavum septum pellucidum and cavum velum interpositi 17. Minor neuroimaging anomalies are frequently found in Sotos syndrome: prominence of the trigone in 90% of cases, prominence of the occipital horns in 75% and ventriculomegaly in 63% of cases 2122. Brisk deep tendon reflexes (sometimes even with a few beats of clonus) are often observed.

Variable degrees of scoliosis are present in 30% of the NSD1-positive cases 10. Genu valga or vara, congenitally dislocated hips, propensity to fracturing with minimal trauma are often reported; one case of cervical instability has been reported 1123. Finger nails are usually deep and brittle. The incidence of congenital heart defects in Sotos syndrome is approximately 8% in the series of Cole and Hughes 3, but 21% in the series of Tatton-Brown 10. The most common defects are septal defects and patent arterial duct. One patient is reported with Wolff-Parkinson-White pattern 24. Recurrent upper respiratory infections and otitis media are frequent, leading to some degree of conductive hearing loss. Constipation is common and may request investigation. Genitourinary anomalies including renal anatomical anomalies (bifid, duplex or absent kidneys, vesico-ureteric reflux, pelvo-ureteric junction obstruction), cystic kidneys and genital anomalies such as hypospadius and cryptorchidism 25, are present in 15% of children with NSD1 abnormalities 10.

Overgrowth syndromes are often associated with neoplasms (Beckwith-Wiedemann syndrome with over-expression of IGF-2 and Simpson-Golabi-Behmel with GPC3 mutations 26). Initial reports suggested a neoplasm frequency of 7% in Sotos patients 27. In a survey of 224 patients with Sotos syndrome, however, the malignancy risk was found lower than 2.2% 28. Cohen reviewed the reported neoplasias critically and suggested a tumor frequency in patients with Sotos syndrome of about 3.9% (more than in the general population) 29. Sotos cases with NSD1 anomalies have been reported with small cell lung cancer 12, ganglioglioma, neuroblastoma in two cases 730, and acute myelocytic leukemia 31. In the large series of Tatton-Brown, three saccrococcygeal teratomas, one presacral ganglioneuroma one neuroblastoma and one acute lymphocytic leukemia occurred in children with confirmed NSD1 mutation 12. Thus, the risk of tumors in childhood appears low but the relative risk of sacrocoggygeal teratomas and neuroblastoma may be increased 1032.

Although most cases are sporadic, autosomal dominant inheritance has been reported in several cases 3536.

The report of a child with Sotos syndrome and a t(5;8)(q35;q24.1) translocation 37, has led to identification of the NSD1 gene, which was disrupted by the 5q35 breakpoint (Nuclear receptor SET domain containing protein) 4. NSD1 intragenic mutations cause 60% to 80% of Sotos syndromes cases in Europe and USA, whereas 5q35 microdeletions encompassing NSD1 cause ~ 10% of cases 5678938. In contrast, NSD1 microdeletions are the primary cause of Sotos syndrome in Japan, accounting for over 50% of cases 394041. Recently, partial NSD1 deletions were detected in Sotos cases without NSD1 mutation or 5q35 microdeletion 42. The systematic NSD1 gene screening in a large series of provisional diagnosis of Sotos and "Sotos-like" syndrome allows to indicate that NSD1 is mostly found in Sotos patients. NSD1 abnormalities rarely occur in other childhood overgrowth phenotypes 5674344. It is so far unknown whether NSD1 anomalies are involved in other entities. Current studies are focused on the identification of hotspots for NSD1 mutations or micro deletions and to establish a genotype-phenotype correlation. Truncating NSD1 mutations occured throughout the gene, but pathogenic missense mutations occurred only in functional domains 1045. To date, no hypermethylation or sequence abnormalities in the promotor region have been detected in Sotos patients 46.

The functions of the NSD1 gene have not been fully established. The gene contains 23 exons and encodes a protein of 2696 amino acids. The protein is a transcriptional intermediary factor and may act as either a nuclear receptor co-repressor or co-activator by interacting with the holo- or apoforms respectively, of the ligand binding domain of different subsets of nuclear hormone receptors. NSD1 expression in human tissue has been detected in fetal/adult brain, kidney, skeletal, muscle, spleen, lung and thymus 3. The protein contains multiples functional domains, including the SET (Su [VAR]3–9, E [Z], trithorax) domain (initially identified in Drosophila genes as involved in chromatine-mediated regulation during development) and a SET associated Cys-rich (SAC) domain adjacent to the SET domain 47. The combination of SAC and SET domains is present in proteins that function as histone-methyltransferase suggesting that NSD1 may be involved in histone modification and the establishment and maintenance of chromatin states. NSD1 contains also five plant homeodomains (PHD). The PHD domain is a zinc finger-like motif that occurs predominantly in proteins that functions at the chromatin level. NSD1 contains two PWWP (Proline-tryptophane- tryptophane-proline) domains. Their role has not been established but they are presumably involved in protein-protein interactions. Finally, NSD1 contains two distinct nuclear receptor interaction domains 4.

Rare cases of Sotos syndrome have been reported in association with other chromosomal abnormalities: apparently balanced t(3;6) (p21;p21), deletion 15q12, 45, XY, t(15q;15q) robertsonien translocation 4849.

Seven to 35% of Sotos patients of the reported series do not have any NSD1 anomalies. In these patients, the involvement of the NSD2 and NSD3 genes has been already excluded by sequencing 50.

Diagnosis is based on clinical exam and radiographic bone age (cf. clinical description). The clinical diagnosis can be confirmed by FISH analysis or, if available, by MLPA (Multiplex Ligation Dependent Probe Amplification), a simple and reliable technique to detect 5q35 microdeletion and partial NSD1 deletions (both account for approximately 15% of the Sotos cases in West Europe 51); DNA analysis by sequencing will let to look for NSD1 mutations.

In patients without NSD1 anomalies, cytogenetic studies as high resolution karyotyping and comparative genomic hybridization on microarray techniques may be useful.

Sotos syndrome belongs to a group of overgrowth syndromes that have some clinical features in common such as pre- and/or postnatal overgrowth and/or advanced bone age. Many of these syndromes, however, can be easily excluded on the bases of other major clinical features. The entities that should be considered in the general differential diagnosis of Sotos syndrome are: Weaver syndrome; Beckwith-Wiedemann syndrome; Perlman syndrome; Simpson-Golabi-Behmel syndrome; Fragile X syndrome; Bannayan-Zonana syndrome; PTEN mutations; Trisomy 15q26-qter; Nevo syndrome; Neurofibromatosis I; Marshall syndrome; Marfan syndrome; Homocystinuria; Acromegaly.

Sotos syndrome is caused by hemizygous mutations in an autosomal non-imprinted gene. The mental difficulties in Sotos syndrome are usually in the mild-to-moderate range, and are not sufficient to account for the extreme paucity of familial Sotos cases. Fifteen familial cases of Sotos syndrome have been reported with NSD1 mutations 105253. It has been suggested that this lack of family cases is associated with an underlying defect in fertility associated with NSD1 mutations. A three generation family with NSD1 mutation has been reported 16.

Chromosome analysis of both parent needs to be performed when a deletion of NSD1 is detected in the affected child. The recurrence risk for a family with an affected child is very low (<1%). Germline mosaicism has never been reported.

The identification of NSD1 has been a major step in the history of Sotos syndrome and has opened a new area in the elucidation of this condition. The evaluation of the tumor frequency in patients with NSD1 anomalies will be important to further define the tumor risk in patients with Sotos syndrome.

In the neonatal period, phototherapy is often required because of jaundice. Sucking and swallowing difficulties need adjustments of baby food. Alternate methods of feeding may need to be considered such as the use of a nasogastric tube. Another common problem is gastroesophageal reflux which causes heartburn, vomiting, esophageal irritation and respiratory problems. Treatments may include adaptations such as eating upright and elevating the head of the bed, medications and, in rare cases, surgery. Oral-motor treatment plan may be a part of the child's therapy program.

Initial systematic screening include renal, cardiac and orthopedic clinical examination and investigations. Scoliosis and vesico-ureteral reflux have to be detected early.

In infancy and the early years, general and specialized pediatrics follow-up, every one or two year, is still important because of the possible clinical events, including constipation, respiratory infections, seizures and because of the possible increased risk of tumors. Anesthesia may require special precautions 54.

Early in the childhood, programs including infant stimulation, occupational therapy, speech therapy, and adaptive physical education play a significant role in the nurturing of a child with Sotos syndrome. Later, some children participate in regular classrooms with support and some others are enrolled in classes for appropriate education.

As mentioned previously, some Sotos patients develop behavior problems during the school age years. As a result, parents and school staff may have to spend significant amount of time and attention dealing with these problems because they can interfere with learning, social interaction and family functioning. A psychologist may work with parents and teachers to develop appropriate and effective methods.

Final body height is difficult to predict but growth in height tends to normalize after puberty.