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.