Handbook of Genetic Counseling/Sotos Syndrome

Introduction edit

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)

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

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

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

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

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

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

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

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

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)

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

(thought to be rare)

(rare, but may occur in approximately 2-4% of individuals with Sotos syndrome)

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

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

http://www.well.com/user/sssa/ -- website is very updated and contains good accurate information

Three Danada Square East, #235

Wheaton, IL 60187

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.

Named after Dr Juan F. Sotos who described it in 1964.

The information in this outline was last updated in 2003.