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