Sotos syndrome Genetic overgrowth syndromes Pediatrics, Genetics, Radiology, Craniofacial Abnormalities

1. Adnan Rashid, MD
The Children’s Hospital of Philadelphia (CHOP)
University of Pennsylvania, PA, USA
SOTOS SYNDROME

2. Outline
 Manifestations
 Patho-physiology & Genetics
 Diagnostic parameters
 Management
 General outcome
 Other Genetic overgrowth syndromes

3. Manifestations
 Craniofacial Abnormalities
 GrowthAbnormalities
 Performance & Behavioral Abnormalities
 Neonatal Problems
 Other associations

4. Craniofacial Abnormalities
-Dolichocephaly
-Receding hairline
-Epicanthic Folds
-Flat Nasal bridge
-Flushingof cheeks and nose
-Apparent hypertelorism
(normal measurements)
-“Antimongoloid slant“
(DSPF)
-Prominent pointed chin Rio M et al. J Med Genet 2003;40:436-440
©2003 by BMJ Publishing Group Ltd

5. Typical MRI findings
Ventricular abnormalities:
-Ventriculomegaly
-Prominence of trigone and
occipital horns
Midline Defects: (increased risk of MR)
-Corpus callosum hypoplasia/ agenesis
-persistence of cavum septum and cavum
velum interpositum
No measure needed if normal CSF pressure

6. Growth Abnormalities
(Length>Weight)
 Prenatal onset
 Length remains at or above 97th %tile
throughout childhood and adolescence.
 Advanced osseous maturation in childhood
Final height…………………….. WNL
 Large Hands and feet( >50th %ile even when
plotted for height age)

7. Performance Abnormalities
 MOTOR:
Poor Coordination (Non progressive, gross>fine)
Hyper-reflexia
Hypo-tonia (poor sucking may need NGF)
Delayed Motor function
 Variable Mental Deficiency: (IQ 40-129)
Mean IQ= 78
 Expressive language delay
 Significant behavioral abnormalities (Due to
difficulty in socializing)

8. Neonatal Problems
large head circumference, body length &
weight
 Poor suckling (may need NGT)
 Difficulty Breathing
 Jaundice
 Constipation
 Otitis Media with conductive hearing loss
 Delayed early developmental milestones

9. Other associations:
 EEG abnormalities and Seizures
 Ophthalmologic :
Strabismus, Nystagmus, Cataracts, Iris Hypoplasia,
Glaucoma, Optic disk pallor and retinal atrophy
 Cardiac and Urogenital Defects (>japan)
 Conductive hearing loss
 Cutis laxa(MCTD) Kypho-scoliosis , Joint laxity
 Abnormal Glucose tolerance(14%)
 Malignancy(2.2%) No screening recommended

10. Etiology
Haplo-insufficiency of NSD-1:
(Nuclear Receptor SET-domain-containing protein, 5q35)
NSD1: (Histone-Lysine Methyltransferase family)
Methylates: H4 K20 and H3 K36
influencesTranscription
NSD1 deletions: paternal origin with advanced of paternal age
- Sporadic >AD
Reference article: J Med Genet 2003;40:436-440doi:10.1136/jmg.40.6.436

11. Phenotype
Independent of underlying mutation except:
 Learning disability and Severe Mental
Retardation; are a feature of deletions.
 Moderate speech delay; is more common
with point mutations.

12. Diagnostic Strategy
clinical findings
+
molecular genetic testing

13. Clinical Diagnostic parameters
(by Cole and Hughes)
 Overgrowth(growth >2 SD):
Large body, Hands & Feet
 Delayed development :
motor, cognitive, social and Speech
 Bone age : (Xray- Hand)
Advanced
 Facial gestalt & Macrocephaly(>2 SD):
are mandatory
Reference article: J Med Genet 1994;31:20-32 doi:10.1136/jmg.31.1.20

14. Management
Evaluations Following Initial Diagnosis
 Echocardiogram and renal ultrasound (VUR)
 Glucose tolerance tests in family members
 IGF-1 & Insulin level(raised)
 T3/T4/TSH (Hypo and hyperthyroidism)
 Referral for Audiologic-assessment
 Genetic counseling and consultation
 Prenatal Diagnisis( 12wk-CVS, 15 wk amnio)
 Prevention of Secondary Complications(Antibiotic
prophylaxis if provenVUR)
 Treatment of Manifestations
 Education

15. General outcome
Muscle tone improves steadily along with
better speech.
Sotos syndrome primarily alters developmental
timing
despite early trends, the adult with Sotos
syndrome may be within the normal range of
height and intellect.
Ref: Arch Dis Child 1999;80:339-342 doi:10.1136/adc.80.4.339

16. Genetic overgrowth syndromes
 Fragile X Syndrome
 Weaver Syndrome( NSD1 mutation)
 Marshall-Smith Syndrome
 Beckwith-Wiedemann Syndrome
 Simpson-Golabi-Behmel Syndrome

17. References:
1)Ref: PMID: 20301652 [PubMed]
2) Arch Dis Child 1999;80:339-342 doi:10.1136/adc.80.4.339
3) J Med Genet 2003;40:436-440doi:10.1136/jmg.40.6.436
4) J Med Genet 1994;31:20-32 doi:10.1136/jmg.31.1.20
5) Smith's Recognizable Patterns Of Human Malformation

18. THANKYOU!