3/29/2016
1
Turner Syndrome: Seeing the Whole Girl, Not Just the X
Ellen Lancon Connor, MD
Professor of Pediatric Endocrinology
University of Wisconsin ‐‐Madison
• Dr. Connor has no conflicts of interest to di ldisclose.
3/29/2016
2
Learning Objectives
• TLW describe the care, including surveillance, for a child with Turner syndrome.Turner syndrome.
• TLW will describe the care, including surveillance, for an adolescent with Turner syndrome.
• TLW will describe the methods available to initiate and support pubertal development in the girl and adolescent with Turner syndrome.
The ABC’s of Turner Syndrome• Audiology
• Autoimmunity
• Cardiac defects
D l i if i• Dermatologic manifestations
• Failure to grow
• Gastrointestinal disease
• Genetics
• Metabolic disorders
• Orthopedic complications
• Psychosocial manifestations
• Renal abnormalities
• Reproductive and pubertal disorders
• X‐linked disorders
3/29/2016
3
Disclosures
• Dr. Connor has nothing to disclose.
Turner SyndromeTime of diagnosis:
• 20‐30% dx in neonatal periods
• 35% as children short stature
• 30% as adolescents/adult women with primary amenorrhea, delayed pubertyamenorrhea, delayed puberty
3/29/2016
4
The X Factor
• The X chromosome: contains near 1000 genes; 5% of total DNA in cells.DNA in cells.
• In 46 XX individuals, one of the X chromosomes is randomly inactivated.
http://ghr.nlm.nih.gov/chromosome/X
The X Chromosome
Short arm=p Genes on p arm= SHOX gene
Long arm= q Genes on q arm= gonadal function
3/29/2016
5
Genetics of Turner Syndrome
• Absence of or structural abnormality of one copy of the X chromosome, often due to nondisjunction.chromosome, often due to nondisjunction.
• Sporadic condition, not related to advanced maternal age. More often (70%) “missing” paternal sex chromosome.
Turner SyndromeAbsence of or structural abnormality of one copy of the X chromosome
• Haploinsufficiency‐a condition that arises when the normal phenotype requires the protein product of both alleles, and reduction of 50% of gene function results in an abnormal phenotype.
• i.e. SHOX gene‐present on both X and Y g pchromosome, when missing part of SHOX gene (i.e. Turner Syndrome), leads to short stature.
3/29/2016
6
Postnatal Outcomes
• Half are pure monosomy 45 X karyotype
H lf i• Half are mosaic—
– Degree of mosaicism does not correlate with phenotype
– 46XX/45 X;
– 46 X, del (Xp)—short arm missing
P
q
Normal X Isochrome X q Del Xp Del Xq
3/29/2016
7
What about the Y?
• 46 XY/45 X: found in 6‐11%
• Variable presentation: clitoromegaly vsambiguous genitalia vs descended testes.
• Need to assess for gonadoblastoma. 12% risk, even at a young age.
• One study: prevalence of germ cell tumors y p g18/119 (15%) (Cools et al, Endo Rev 2006)
Postnatal Diagnosis
• Peripheral leukocytes karyotype with minimum of 30 cell count. Identifies 10% mosaicism by 95% confidence.
• If blood tests normal, but strong clinical suspicion—tissue sample.
• Test for Y with the use of FISH/PCR for the patient with am biguity; or if a marker chromosome is present (sex chromosome fragment of unknown origin).
• Routine testing for SRY or Y in 45 X without masculinization is not clinically warranted. (Turner Guidelines‐2007)
Zhong and Layman, Fertility and Sterility 2012
3/29/2016
8
TS and Stature
• Short stature: average of 20 cm shorter than peerspeers
• IUGR
• Slowed childhood growth
• Mild skeletal dysplasia—Upper to Lower ratio
• Lack of pubertal growth spurt
3/29/2016
9
3/29/2016
10
Growth Hormoneand Turner Syndrome
• GH FDA approved for Turner Syndrome in 1996.
• Standard of care to consider growth hormone as soon as evidence of decreased linear growth velocity.
• Best outcomes with younger age of initiation, higher dosing, longer duration of therapy.
• Height “gain”: 7‐18 centimeters. (Canadian Growth Hormone
Advisory Committee, JCEM 2005, Davenport, JCEM 2010)
3/29/2016
11
Safety of GHin Turner Syndrome
• Intracranial hypertension
Sli d i l f l i h i• Slipped capital femoral epiphysis
• Scoliosis—worsening of underlying risk
• Recommend following IGF‐1, glucose and glucose levels (increased risk of insulin resistance)
• No evidence of adverse effects on cardiac factors (i.e. increased aortic diameter)
Adjunct therapyOxandralone
• Nonaromatizable (does not get converted to estrogen) anabolic steroidestrogen) anabolic steroid.
• Promotes growth independent of GH.
• Studies show increase in growth velocity and increase in final adult height of 2‐4 cm.
• Side effects: virilization, cliteromegaly, deepening i hi h i d d d ( 0 03 /k 0 06voice which is dose dependent ( 0.03 mg/kg vs 0.06
mg/kg).
3/29/2016
12
TS and the Heart
Most Serious and Life Threatening Complications
3/29/2016
13
Bicuspid Aortic Valve(BAV)
• Affects 30% of those with TS (vs 1 2%)• Affects 30% of those with TS (vs 1‐2%)
• Risk of morbidity increases with age.
• Risk of premature valvular stenosis—accelerated by calcification. 26‐48% of adults with TS with BAV.
Biscuspid Aortic Valve(BAV)
• Risk of valvular regurgitation—42‐50% of adults with TS and BAV. Promotes aortic dilatation.
• Risk of aortic wall abnormalities‐dilation, aneurysm, dissection.
• Risk of endocarditis.
3/29/2016
14
Coarctation of the Aorta
• 12‐17% of those with TS (vs 0.04%)
A i t d ith BAV• Associated with BAV.
• Abnormal aortic phenotype.
• Surgical repair—patch angioplasty, balloon or stent repair.
Other less common congenital defects:
ASD VSD P l l i• ASD, VSD, Pulmonary valve stenosis
• Cardiac lesions seen in both monosomy and mosaicism.
3/29/2016
15
Cardiac‐electrocardiographic conduction abnormalities
• Sinus Tachycardia‐increased conduction through h d d l d d k fthe atria and AV node‐leads to increased risk of atrial tachycardia.
• Prolonged QT: 36% of children, 21% of adults. (Bondy et al, Pediatrics 2006)
• Be aware before prescribing certain medications: CNS Stimulants some antibioticsmedications: CNS Stimulants, some antibiotics, antidepressants
Aortic Dissection
• 1‐2% TS. 100‐fold increased risk.
• Peak incidence in third to fifth decadePeak incidence in third to fifth decade.
• 22% die before getting to hospital.
• Accounts for 8% of all deaths in those with TS.
• Descending aorta better prognosis than ascending.
3/29/2016
16
Risk Factors for Dissection
• Congenital Heart Lesion: 87‐95% of those with dissection have history of BAV or Coarc.history of BAV or Coarc.
• Hypertension‐effects 25% of adolescents with TS, and up to 50% of adult women; loss of diurnal drop in BP.
Risk Factor for Dissection
• Aortic Dilatation: affects 19% of children and adolescents with TS and can start from 6 years of agewith TS and can start from 6 years of age
• Measurement:
– young children: echocardiography
– Older adolescents: MRI normalized to BSA to give the aortic size index (ASI)
Treatment: Address modifiable factors more frequentTreatment: Address modifiable factors, more frequent monitoring, counsel on signs of dissection, surgical consult.
3/29/2016
17
Hypertension Therapy
• Lifestyle changes, discuss smoke exposure;
• RX: angiotensin receptor blocker (ARB) at the lowest available dose. g p ( )
• ARBS‐SE: dizziness, headache, cough, Class C/D for pregnancy.
Risk Factors for Dissection
• Pregnancy‐risk for dissection 2 in 100 pregnancies with TS
• In 7 cases of aortic dissection reported after assisted reproductive technologies (ART), 6 patients died (TurtleEJ,et al,Arch Dis Child 2015)
P ti C itt f ASRM “T d i• Practice Committee of ASRM “Turner syndrome is a relative contraindication for pregnancy, and patients should be encouraged to consider alternatives”
3/29/2016
18
Other Acquired Vascular Disease
• Strokes‐increased from the second decade of life. Risk factors: HTN, insulin resistance, visceral obesity; atrial fibrillation.
• Cardiovascular disease—higher with visceral obesity, insulin resistance.
Guidelines for TS and Cardiac
• Initial evaluation by cardiologist
• BP of all 4 extremities• BP of all 4 extremities
• Imaging: ECHO for younger children, MRI for older adolescents and adults.
• ECG
• Follow up: BP, Reevaluation with imaging‐MRI at age able to cooperate and then every 5‐10 years. Manage hypertension.
Care of girls and women with Turner Syndrome: A Guideline of the Turner Syndrome Study Group: JCEM 2007
3/29/2016
19
Puberty and Reproduction
• Age to initiate estrogen
• Estrogen formulations
• Goals of pubertal initiation
• Introduction of progestin
3/29/2016
20
Fertility
• Statistics
• Considerations for conception
• Ethical concerns
3/29/2016
21
Autoimmunity
• Autoimmune thyroiditis
• Rheumatoid Arthritis
• Celiac disease
• Inflammatory Bowel Disease
• Hypophysitis
Metabolic Disorders
• Insulin resistance
• Type 2 diabetes
• Hyperlipidemia
• Hepatic steatosis
3/29/2016
22
Neuropsychiatric Issues
• Anxiety
• Visual Spatial differences
• Mathematics
• Social recognition
TS and Renal Disease
• Congenital anomalies: 30‐40% of patients with TS
– Collecting system malformations‐ 20%– Collecting system malformations‐ 20%
– Horseshoe kidney – 10%
– Other ‐ 5%
• Monitor for urinary tract infections and hypertension
• Guidelines: all should have baseline renal ultrasound
3/29/2016
23
TS and the Ear
• Conductive Hearing loss—frequent due to abnormal anatomy and increased risk of otitis media.and increased risk of otitis media.
– Aggressive management of OM, middle ear effusion, early referral to ENT
• Progressive sensorineural hearing loss as adults
Guidelines: Baseline assessment by audiologist at diagnosis, then every 1 to 3 years based on history of disease.
Gastrointestinal Problems
• Elevated liver enzymes
• Lymphangiectasia
3/29/2016
24
Dermatology
• Nevi ‐‐‐multiple pigmented, halo
• Keloid and hypertrophic scar formation
• Multiple pilomatrixoma
• Pustular psoriasis
• Vitiligo
Orthopedic Diagnoses
• Scoliosis
• Leg length
• Knee
• Feet
3/29/2016
25
Other Diagnoses
• Must keep in mind X‐linked diagnoses, i l di b t t li it d tincluding but not limited to
– Hemophilia
– Duchenne muscular dystrophy
– Color blindness
3/29/2016
26
References
• Bondy et al. J Clin Endocrinology Metab 2007 92;10‐25. ”Care of Girls and Women with Turner Syndrome: A Guideline of the Turner Syndrome StudyGroup”
• Chacko et al. Endocrinol Metabl Clin N Am 2012 41;713‐734. ”Update on Turner and Noonan Syndromes”Turner and Noonan Syndromes”
• Gonzalez and Witchel. Fertil Sterl 2012 October; 98 (4) : 780‐786. ”The Patient with Turner Syndrome: Puberty and Medical Management Concerns”
• Levitsky et al. Curr Opin Endocrinol Diabetes Obes2015 22;65‐72. ”Turner Syndrome: update on biologyand management across the life span”M i k d O’G BBA Cli i l 3 2015 304• Mavinkurve and O’Gorman. BBA Clinical 3. 2015;304‐309. ”Cardiometabolic and vascular risks in young and adolescent girls with Turner syndrome”
• Mortensen et al. Endocrine Reviews 2012, 33 (5) : 67‐714. “Cardiovascular Phenotype in Turner Syndrome‐Integrating Cardiology, Genetics, and Endocrinology”
• Sas et al. Horm Res Paediatr 2014;81: 289‐297. “Safety and Efficacy of Exandrolone in Growth Hormone‐TratedGirls with Turner Syndrome: Evidence from Recent Studies and Recommendations for Use.
• Turtle EJ,et al. Arch Dis Child 2015;100:662‐666. ”Aortic dissection in children and adolescents withAortic dissection in children and adolescents with Turner syndrome: risk factors and management recommendations”
3/29/2016
27
Website Information
• www.turnersyndrome.org
• www.turnersyndromefoundation.org