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.