# Handbook of Genetic Counseling/Sotos Syndrome

Sotos Syndrome

## Introduction

* Overgrowth syndrome
* etiology still uncertain although researchers in Japan found a gene that may be the cause of Sotos syndrome in a large number of individuals with classical Sotos syndrome (published paper in 2002)
* usually sporadic
* <2% show autosomal dominant inheritance (4 of 200 families, but facial gestalt is different)

## Incidence

* Unknown slightly less common than Beckwith-Wiedemann with prevalence of 1 in 13,700 births

## Diagnosis

* Diagnosis is clinical
* 4 core features (must have at least 3 of the 4 to really make a diagnosis)
* First 3 features are relative to general population so setting a cutoff is not always clear
** rapid early growth pre and postnatal
** advanced bone age
** developmental delay
** characteristic facial appearance specific to Sotos syndrome
*** alters in childhood and adolescence
*** in newborn period (macrocephaly, high bossed forehead, dolichocephaly, high palate, appearance suggestive of hypertelorism)
*** face lengthens, jaw becomes more prominent, dolichocephaly (tall narrow skull) and frontal bossing (prominent forehead) become more obvious
*** delay in growth of hair which is often thin "appearance of receding hairline"
*** midchildhood downslant to palpebral fissures, wear and discoloration of teeth, tendency for a rosy coloration of cheeks, chin, and nasal tip.
* All 4 core features are present in at least 75% of true cases of Sotos syndrome and <20% of other specific and nonspecific overgrowth patterns

## At birth

* Often the presence of a high arched palate, poor suck, and low muscle tone which often produce feeding problems
* Jaundice occurs frequently.

## Molecular Genetics and Genetic Testing

* Gene mutation found in a number of Japanese patients with Sotos syndrome
* Located at 5q35 gene named NSD-1
* Lab in Chicago and Germany are doing clinical testing
* Details found at http://www.genes.uchicago.edu/clinic/SotosTest.html
* FISH analysis for NSD1 deletion detection. Mutation analysis is currently being validated for clinical use; please check back on availability.
* No lab listed on GeneClinics doing research testing presently, but lab in UK may be doing research testing
* FISH - 12 days and cost is $325
* NSD1 encodes 2,696 amino acids and may interact with nuclear receptors (NRs)
* expressed in the fetal and adult brain, kidney, skeletal muscle, spleen, and the thymus, and faintly in the lung.
* Among 42 SS patients examined, we detected 4 (10 %) de novo point mutations in NSD1
* In addition, FISH analysis using BAC clones flanking the 5q35 breakpoint revealed submicroscopic deletions involving the entire NSD1 gene in 20 (67%) of 30 patients whose chromosomes were available (Nat Genet 30:365-366, 2002)
* http://caroll.vjf.cnrs.fr/cancergene/CG1830.html discusses the NSD1 protein

## Neuroradiological findings

* Ventricular abnormalities (prominence of trigone, prominent occipital horns, ventriculomegaly)
* Midline defects and absence or hypoplasia of corpus collosum

## Growth and Feeding

* Feeding problems common in neonatal period
* Most LGA (most evident in length and in head circumference)
* Height and head circumference most significantly larger and run parallel to growth curve but sig. above 97th centile
* Excess growth mostly in limbs rather than trunk
* Girls in UK population were an average of 6.2 cm above calculated target height based on parental heights, but were within usual height range
* Boys height less predictable and greater tendency for increased adult stature

## Development, learning, behavior

* Almost all have developmental delay and cognitive impairment (may be selection bias because this is used as diagnostic criteria)
* Behavioral problems common
* Poor concentration and ADHD common
* Difficulty with social interactions results in tendency to associate with younger children and social isolation later in life
* Reliance on routines common in many children
* May have impetuous behavior
* Poor sleep patterns common
* Unusual anxiety and subsequent phobias commonly reported

## Neurological

* Hypotonia usually present from birth but improves during childhood
* Poor coordination and delayed motor skills primarily gross motor (swimming is sport many succeed in)
* Febrile convulsions in almost 50%
* Almost half with febrile seizure will go on to have nonfebrile seizures
* Seizures managed same as in other children/adults

## Immune system

* Infections very common in early childhood
* Recurrent OM and potential conductive hearing loss
* Urinary tract infections in up to 20% (caused by structural abnormalities and reflux usually)

## Eye problems

* poorly documented
* Refractive errors and strabismus (less common, glaucoma and syntagmas reported)
* Regular evaluations

## Dental abnormalities (common)

* Early teeth eruption (54%)
* Excessive wear and discoloration
* Teeth may be crooked due to changes in craniofacial structure and many require orthodontic work

## Heart problems

(thought to be rare)
* Overt congenital heart disease is thought to be rare may be up to 10%
* Most common are ASD, VSD, PDA
* Routine echo not necessary

## Malignant tumors

(rare, but may occur in approximately 2-4% of individuals with Sotos syndrome)
* Embryonal tumors
* Neuroblastoma
* Mephroblastoma
* Hepatoblastoma
* Age of onset is wide and no clear benefit from surveillance

## Musculoskeletal

* Hypotonia, large size, joint laxity can cause complications
* Foot deformities (~50%)
* Flat feet common
* Kyphoscoliosis

## GI

* Tendency for severe constipation in over 10%

## Main Psychosocial Considerations

* Intellectual, social, and emotional maturity may evolve on widely different timetables
* How is school going? (confirm that she is in 4th grade and ask specifically about math and language skills)
* Does she have a new IEP since last visit?
* Is she getting the help you would like her to?
* Math tutoring and speech therapy?
* How is attention and behavior?
* Assess social relationships (is she being teased or socially isolated)
* Any changes in the family?
* Confirm number of siblings

## Differential Diagnosis

* Number of other generalized overgrowth syndromes
* Sotos syndrome is distinguished from others by presence of developmental delay and characteristic facial features.
* Other overgrowth syndromes have other commonly associated characteristics that also aid in distinction

## Patient resources

* Soto Syndrome Support Association
    http://www.well.com/user/sssa/ -- website is very updated and contains good accurate information
    Three Danada Square East, #235
    Wheaton, IL 60187

## References

* Genetests and info from Chicago about NSD1 testing
* Soto Syndrome Support Association
* Sotos Syndrome: A Handbook for Families by Rebecca Rae Anderson, M.S., J.D. and Bruce A. Buehler, M.D.
* Kurotaki et al., Haploinsufficiency of NSD1 causes Sotos syndrome (2002) Nature Genetics, 30: 365-366
* Management of Genetic Syndromes. Edited by S.B. Cassidy and J.E. Chapter ___ Sotos syndrome.

## Notes

Named after Dr Juan F. Sotos who described it in 1964.
The information in this outline was last updated in 2003.