Handbook of Genetic Counseling/Noonan Syndrome

Noonan Syndrome Introduction and contracting What is your primary concern Do you have any questions for us today What are your expectations for your visit today Outline the session We will be taking medical history information Dr. ___ will come in to perform a physical examination We will be discussing if we think there is a diagnosis that can be made at this time If a diagnosis is made we will explain the inheritance and information we know about the cause Medical history (follow form) Overview of Noonan Syndrome Common autosomal dominant, single gene Mistakenly called male Turner syndrome due to similar characteristics Occurs in both males and females equally Characteristics of Noonan Syndrome Short stature Congenital heart defects Broad or webbed neck Unusual chest shape (low set nipples, superior pectus carinatum, inferior pectus excavatum) Developmental delay Cryptorchidism Characteristic physical appearance changes over time Features irrespective of age Low set posteriorly rotated ears with thick helix (90%) Vivid blue or blue-green eyes (lighter than expected for background) thickened or ptotic eyelids hypertelorism Neonate and Infancy (age features are most striking) tall forehead hypertelorism with downslant palpebral fissures (95%) prominent eyes Nose has depressed root, wide base, bulbous tip Deeply grooved philtrum High wide peaks to vermillion border of upper lip Excess nuchal skin and low posterior hairline Children Facial appearance lacks expression (resembles individual with myopathy) Adolescence Facial shape inverted triangle, wide forehead tapered chin Pinched nasal root and thin bridge Neck lengthens accentuates skin webbing or trapezius muscle Eyes less prominent Curly or wooly hair in older child Adult Nasolabial folds prominent Skin appears transparent and wrinkled Genetics of Noonan syndrome missense mutations in gene PTPN11 at 12q24.1 identified in 50% of patients gene identified in 2001 (normal gene encodes protein-tyrosine phosphatase, non-receptor type 11 seems to be essential in several intracellular signal transduction pathways controlling diverse developmental processes absence of this mutation in some families suggests heterogeneity AD single gene 50% chance to pass on if affected if parents not affected chance is low <1% (gene clinics) direct transmission reported 30-75% of time rest are de novo predominantly mothers not fathers transmit gene (3:1 ratio) (likely due to cryptorchidism and reduced fertility in males) Prevalence 1/1000-1/2,500 Diagnostic testing Testing for PTPN11 mutations available on research basis Diagnosis based on clinical findings though High-resolution ultrasound only prenatal test available Differential Diagnosis Turner syndrome in females should be ruled out through karyotype Trisomy 8p, trisomy 22 mosaicism, sex chromosome rearrangement, in utero exposure to alcohol or primidone Williams, Aarskog, Baraitser-Winter, Costello syndromes share some features Multiple lentigines/LEOPARD syndrome can also have pulmonary valve dysplasia, cardiomyopathy, short stature, hypertelorism, pectus deformity, hearing loss, developmental delay Watson syndrome shares pulmonary valve stenosis, short stature, mild intellectual handicap, café-au-lait patches Cardio-facio-cutaneous syndrome lot of overlap and debate about whether same condition, but MR more severe, skin findings hyperkeratosis, ichthyosis, absent eyebrows, sparse hair, gastrointestinal problems more severe, eyes rarely characteristically light blue/ blue-green Cause of characteristics Hypothesized to be consequences of lymphatic obstruction Growth and feeding B.W. usually normal 15% have poor suck, 38% poor suck and vomiting, 24% require tube feeding 2 weeks or more length at birth normal usually then follows 3% ile final height lower end of normal in adults some endocrinologists choose to treat with growth hormone even if deficiency not seen Development and behavior Delayed milestones Mean age sitting 10 mth, walking 21 mth, two-word sentence 31 mth 10-15 % require special ed IQ usually within normal range, but mild MR seen in 1/3 Verbal lower than nonverbal performance Usually good peer, social interactions and self-esteem, but one study suggests that less socially competent and more behavior problems than sibs (not clinically significant) Ears and hearing May cause delayed speech Reported in >1/3 usually secondary to ottitis media Sensorineural loss in 3% Cardiovascular Potential bias in frequency due to requirement for diagnosis by many (50-80%) Stenotic or dysplastic pulmonary valve most common (20-50%) 7% of all children with pulmonary stenosis have Noonan hypertrophic cardiomyopathy (20-30%) found at birth, infancy or childhood ASD (10-20%) VSD (5-15%) Coarctation of aorta (9%) Others ECG abnormality found in 87-90% Eye Problems (occur in up to 95%) Strabismus (48-63%) Refractive errors (60-70%) Amblyopia (33%) Nystagmus (9%) Other problems common Blood/ liver spleen 1/3 have coagulation problems 2/3 give history of abnormal bleeding or mild-severe bruising hepatosplenomegaly occurs reason unknown(clinically evident 25% ultrasound 51%) should avoid aspirin various lymphatic abnormalities described Genitourinary Renal abnormalities (generally mild 11%) Cryptorchidism in 60-80% of males may cause deficient spermatogenesis Fertility is rule in females Skin Follicular keratosis Scalp hair curly, thick and wooly, or sparse with easy breakage Café-au-lait spots and lentigines more frequent than general population Management if suspected Physical and neuro exam Plot growth on NS charts Cardiology eval Ophthalmology Hearing Coagulation screen Renal ultrasound Clinical and x-ray of spine and rib cage Develop eval Genetics consult Psychosocial considerations Diagnosis may not be certain Difficulty and stress of having child with health concerns or learning issues Guilt if passed on the gene Support resources The Noonan Syndrome Support Group PO box 145 Upperco, MD 21155 Phone: 410-374-5345 Email: info@noonansyndrome.org Website:www.noonansyndrome.org MAGIC Foundation for Children's Growth 1327 North Harlem Ave Oak Park, IL 60302 Phone: 708-383-0899 Email: mary@magicfoundation.org www.magicfoundation.org References Management of Genetic Syndromes, Edited by Suzanne b. Cassidy and Judith e. Allanson. 2001. Wiley-Liss Inc. Chapter 15 written by Judith E. Allanson. Gene Clinics: Noonan Syndrome Notes The information in this outline was last updated in 2002.