Sotos syndrome, Genetics, Radiology, Craniofacial Abnormalities, Management

Adnan Rashid, MDThe Children’s Hospital of Philadelphia (CHOP)University of Pennsylvania, PA, USA

SOTOS SYNDROME

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

Manifestations

Craniofacial Abnormalities Growth Abnormalities Performance & Behavioral

Abnormalities Neonatal Problems Other associations

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

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 interpositumNo measure needed if normal CSF

pressure

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)

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)

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

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

Etiology

Haplo-insufficiency of NSD-1: (Nuclear Receptor SET-domain-containing protein, 5q35) NSD1: (Histone-Lysine Methyltransferase family) Methylates: H4 K20 and H3 K36 influences Transcription

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

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.

Diagnostic Strategy

clinical findings

+ molecular genetic testing

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

ManagementEvaluations 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 proven VUR) Treatment of Manifestations Education

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

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

References:

1)Ref: PMID: 20301652 [PubMed] 2) Arch Dis Child 1999;80:339-342 doi:10.1136/adc.80.4.3393) 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.31.1.205) Smith's Recognizable Patterns Of Human Malformation

THANK YOU!