Handbook of Genetic Counseling/Sotos Syndrome

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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)

Incidence[edit]

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

Diagnosis[edit]

  • 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[edit]

  • 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[edit]

  • 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[edit]

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

Growth and Feeding[edit]

  • 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[edit]

  • 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[edit]

  • 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[edit]

  • 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[edit]

  • poorly documented
  • Refractive errors and strabismus (less common, glaucoma and nystagmas reported)
  • Regular evaluations

Dental abnormalities (common)[edit]

  • 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[edit]

(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[edit]

(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[edit]

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

GI[edit]

  • Tendency for severe constipation in over 10%

Main Psychosocial Considerations[edit]

  • 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[edit]

  • 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[edit]

  • 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[edit]

  • 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[edit]

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

The information in this outline was last updated in 2003.