9/26/2014
Genetic Counseling for
SCAs
Challenges and Strategies
Susan Howell, MS, CGC, MBA
University of Colorado Denver, Dept. Pediatrics
Children’s Hospital Colorado, Child Development Unit
September 2014
Conflict of Interest Disclosures
In relation to this presentation, I declare that there are no conflicts of interest.
Genetic Counseling for SCAs
Challenges and Strategies
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Background: Incidence, Ascertainment and Parent of Origin
Genetic Counseling - Prenatal
Genetic Counseling - Pediatric
Genetic Counseling -Adult
Recurrence Risks
Counseling for endocrinology care in XXY
Diagnosis Disclosure
Resources
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Incidence of SCAs
Most common chromosomal aneuploidy conditions (~1/400)
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47,XXY = Klinefelter syndrome
47,XYY = Jacob’s syndrome
48,XXYY
48,XYYY
48,XXXY
49,XXXXY
47,XXX = TriploX, Trisomy X syndrome
48,XXXX = Tetra X
49,XXXXX = Penta X
45,X and others = Turner syndrome
1:650 males
1:1000 males
1:18,000 males
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1:250,000
1:1000 females
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1:2500
Ascertainment of SCAs
SCAs are underdiagnosed (10-25%)
• XXY
– Prenatal
– Age 0-4
7%
3%
(developmental delays, hypotonia)
– Age 5-12
0.5%
(learning disabilities, behavior)
– Small testicles, hypogonadism and/or gynecomastia
10%
• 20% Age 11-20
• 80% Age 20+
– Infertility in adulthood
– Other
– Undiagnosed
15%
1.5%
68%
• XXX and XYY ~10% ascertained in lifetime
Abramsky & Chapple, Prenatal Diagnosis, 17:4: 363-368 (1997)
Bojesen et al, Jrnl Clinical Endo & Metab, 88(2): 622-626 (2003)
Why such low rates of
ascertainment?
To the PCP, most children with SCAs do not look very different or dysmorphic.
2014 publication: Even with parental concern about development, avg 4.8 yrs
before XXY is diagnosed.
Visootsak et al Timing of Diagnosis of 47,XXY and 48,XXYY: A Survey of Parent Experiences, Am J Med Genet A, Feb 2014
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Parent of Origin in SCAs
47,XXY
Maternal
Overall
Meiosis I
Meiosis II
Postzygotic
mitotic
Paternal
~50%
34%
~50%
90+%
(AMA)
(NO APA)
9%
0%
3-10%
47,XYY
Maternal
Paternal
Overall
0%
100%
Jacobs and Hassold, 1995; MacDonald et al., 1994; May et al., 1990
47,XXX
Maternal
Overall
90%
Meiosis I
58-63%
Paternal
10%
0%
(AMA)
Meiosis II
Postzygotic
mitotic
16-17.4%
18-19.6%
100%
Meiosis I
0%
Meiosis
II
Postzygotic
mitotic
16/19
3/19
Current Opinion in Genetics & Development (0959-437X), 16 (3)
**Risk for XO/XXX**
Jacobs and Hassold et al, Ann Hum Genet. 1988 May;52(Pt 2):93-109
Genetic Counseling- Prenatal
• Include SCAs in pre-test genetic counseling (most common
aneuploidies)
– Many families unprepared for SCA results
• Broad spectrum of variability, imprecise prognosis
– Developmental, psychological, medical
– Appropriate pathology (not over nor under)
• Prognosis in context of family history and support
– Linden 2002 demonstrated that outcomes from prenatal diagnosis were better in
development and education and more typical peer relationships
– Influence of background genes and family history
• Common prenatal concerns: ID, dysmorphic features, infertility (XXY)
• IQ in context of family
• Pictures of children with the condition (not from a textbook!)
• Discussion of ICSI possibility and success rates
• Access to published information, other families, and support groups.
– AXYS (formerly known as KS&A) is national support group (www.genetic.org)
Prenatal Follow-up
Important to encourage follow-up counseling (or
referral) if pregnancy is continued.
• Postnatal recommendations:
– Confirmatory testing (karyotype and/or FISH-mosiaicism)
– Planning for developmental, medical and academic assessments
• Benefit of prenatal diagnosis is ability to be proactive (no “wait and
see”)
• Access local resources
– Many specialists have significant waitlists
• Timeliness for screening
• Preventing “delayed grief” and parental crisis
– Planning for Diagnosis Disclosure
• Child, doctors, school, family members, friends/neighbors
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Genetic Counseling- Pediatric
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Context: Indication for diagnosis and parental concerns (broad variability)
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Incidence of condition, benefits of ascertainment
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Sensitivity to infertility, as this aspect is often unexpected
Avoid emphasis of genetics and etiology
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Helping family understand how issues relate to SCA diagnosis
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Navigating to appropriate evaluations and referrals based on age and
presenting concerns (developmental, medical, psychological, emotional,
academic, supports)
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contextualize the “alphabet soup” of other diagnoses
Consideration of language weaknesses in regard to counseling and behavior issues
• Guidance and Advocacy for IEP and/or services
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Don’t wear the diagnosis, don’t qualify or continue to qualify
Connection to other families/children, when appropriate
Access to support groups – helping to find local resources and educational
opportunities
Diagnosis Disclosure to child, doctors, school, family members, etc
Genetic Counseling- Adults
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Understanding indication for diagnosis and presenting concerns (broad
variability, possible long history, when they were told)
Counseling in context of cognitive and emotional status
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Incidence of condition
Medical issues
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Reproductive issues
– Recurrence risks for XXX, XXY, and XYY in their children
– Resources for prenatal testing or ART
Vocational issues and resources
Social / emotional issues and resources
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Disability SSI and access to community services and supports
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Language weaknesses, literal translation
– Endocrinology for XXY
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Sensitivity to infertility, as this aspect may be unexpected
– Relationships
– Consideration of language weaknesses in regard to counseling
– Daily living skills / IQ
Common Mistakes Counseling SCAs
• Overemphasis on genetics and chromosomes
– “girls have two Xs and boys have an X & Y”…
So what is XX+Y?
• Medical text photos shown to patients
• Under or over-pathology
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“If I had to pick a genetic condition, I’d pick this one.”
“I don’t usually counsel for this condition.”
“Criminal” or “monster” with XYY
Emphasis on gynecomastia in XXY
• Only follow-up “endocrinologist when he’s 10 for help with
puberty”
• Word choice
– “sex” “abnormality”
• Fertility terminology
– Infertility = no sperm in semen, but normal sexual function
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Recurrence risks
• Parents of affected child: <1% or AMA risk
• Affected individuals:
– XXY: Although considered infertile, possible gonadal mosaicism,
~ 2-3% increased risk for SCA
– XXX: Risk for POF, ~2-3% increased risk for SCA (or AMA risk)
– XYY: Normal spermatogenesis in majority of XYY males, ~5%
increased risk for SCA
Endocrinology Counseling for XXY
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Planning first visit before therapy is likely indicated
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Guidance for the initial discussion with endocrinologist
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He should start puberty on his own
Initially ~10 years of age, FU every 6-12m depending on exam
Discussion about diagnosis with child before appointment
Initial visit is less overwhelming for both patient and parents if prior to tx
indicated
When to initiate testosterone therapy (varies by MD)
Understanding benefits (short term and long term) of testosterone
How to administer: Gel vs. shots (MD preferences, adaptive skills)
Comfort level with MD going forward (long term relationship)
Setting expectations for first visit
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May not draw blood or start testo during first visit (based on physical exam)
Timing in early puberty is typically not urgent/crisis (waitlist to be seen)
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Talking with child about blood draws and testo tx prior to appointment
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Gynecomastia may precipitate Tx
Preferably not at same time of diagnosis disclosure
Supports for blood draws if anxiety is present
Concerns about aggression
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May need to address psychological concerns prior to starting therapy
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Compliance for life long therapy
Diagnosis Disclosure- Child
Study aimed to explore the
experiences of parents
disclosing the SCA diagnosis to
their affected child and
individuals with an SCA
learning about their diagnosis
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139 parents and 67 affected
individuals answered survey
questions regarding topics
discussed, parent preparedness,
resources accessed for
preparation, parental concerns, and
recommendations for disclosure
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Disclosure Recommendations
Parents
Individuals
How to tell them
How to tell them
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Gradually, over time
Be honest
Inform yourself first
Be positive
Be honest
Do not lie, omit, or mislead
Be supportive & open
Gradually, over time
When to tell them
When to tell them
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Early
Based upon child’s maturity
Child asks questions
Before puberty
Early
Before puberty
Child asks questions
When treatment/HRT is needed
What to tell them
What to tell them
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Everyone has challenges
You will help your child
Identify child’s strengths
Privacy issues
It is not a disability, disease, or weird
Encourage questions & feelings
Treatments (HRT)
Advancements/future possibilities
Diagnosis Disclosure- Handouts
“Talking with your child about his/(her) diagnosis” handouts created
from Dennis research for XXY, XXX, XYY are available through the
eXtraordinarY Kids Clinic (Denver, Colorado) and at the AXYS Booth
during the conference
Diagnosis Disclosure- Resources
Series of children’s books created by genetic counselor, Arlie Colvin, as a
masters project. Books available at Amazon.com and samples are
available at the AXYS booth during conference.
AXYS (www.genetic.org) is providing free family information kits to booth
visitors, which include:
– Three booklets on XXY, XYY, and XXX, written specifically for children
– Book for parents, "Living with Klinefelter Syndrome, Trisomy X or 47,XYY"
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Disclosure Considerations
• School Disclosure:
– Advocacy for resources
• IEP qualification
– Misperception as lazy
• Self-esteem
• Family / Friends Disclosure:
– Child’s right to privacy
– Child will grow up and others will know already
– Misinformed by internet / perception by others
• Doctor disclosure:
– Providing medical care appropriately
– Absence of parents
• Community and cultural considerations
Resources
• AXYS (formerly known as KS&A and AAKSIS), www.genetic.org
– Association for X and Y chromosome variations
– Families bi-annual conference to be held July 24-26, 2015 at Johns Hopkins in
Baltimore, MD
• Triplo-X group (www.triplo-x.org), Unique (www.rarechromo.org)
• Facebook groups
• Multidisciplinary Clinics:
– Denver: eXtraordinarY Kids Clinic
• Susan Howell, CGC, 720-777-8361, [email protected]
– Emory: eXceptional Kids Clinic and EmorY
• Kimmie Lewis, CGC, 404-778-8484, [email protected]
– Johns Hopkins Klinefelter Clinic
• Hopkins USA Concierge Service: 855-695-4872, http://klinefelter.jhu.edu
Interdisciplinary Team Approach
• Finding local providers as referral sources in your area
– Developmental: Child Psychology, Developmental Pediatrics
– Medical: Endocrinology, Developmental Pediatrics, Genetic Counseling
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Urology / Reproductive Endocrinology, Neurology, Orthopedics
Academic: Neuropsychology
Emotional/Social: Clinical psychology
Speech language: Speech language pathology
Motor / sensory issues: Occupational therapy
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Publications- Professionals
SCAs
• Bishop DVM et al. Autism, Language and communication in children with sex
chromosome trisomies. Arch Dis Child. 2011;96(10):954–959
• Hutaff-Lee C, Cordeiro L, Tartaglia N. Cognitive and medical features of
chromosomal aneuploidy. Handb Clin Neurol. 2013;111:273-9.
• Linden MG, Bender BG, Robinson A. Genetic counseling for sex chromosome
abnormalities. Am J Med Genet. 2002 June 1; 110(1): 3–10.
• Ross JL, Roeltgen DP, Kushner H, Zinn AR, Reiss A, Bardsley MZ, McCauley E,
Tartaglia N. Behavioral and social phenotypes in boys with 47,XYY syndrome or
47,XXY Klinefelter syndrome. Pediatrics. 2012 Apr;129(4):769-78
• Simpson, J. L., Graham, J. M., Samango-sprouse, C. and Swerdloff, R. 2005.
Klinefelter Syndrome. Management of Genetic Syndromes. 28.
• Visootsak J, Graham JM Jr. Klinefelter syndrome and other sex chromosomal
aneuploidies. Orphanet J Rare Dis. 2006 Oct 24;1:42. Review
• Wilson R, Bennett E, Howell S, Tartaglia N. Sex Chromosome Aneuploidies,
Handbook of Pediatric Neuropsychology. 2010; (65):805-819
Publications- Professionals
XXY
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Boada R, Janusz J, Hutaff-Lee C, Tartaglia N. The Cognitive Phenotype in Klinefelter Syndrome:
A Review of the Literature Including Genetic and Hormonal Factors. Dev Disabil Res Rev. 2009;
15(4): 284–294.
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Geschwind, D. H., Boone, K. B., Miller, B. L. and Swerdloff, R. S. (2000), Neurobehavioral
phenotype of Klinefelter syndrome. Ment. Retard. Dev. Disabil. Res. Rev., 6: 107–116
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Tartaglia N, Cordeiro L, Howell S, Wilson R, Janusz J. The spectrum of the behavioral phenotype
in boys and adolescents 47,XXY (Klinefelter syndrome).Pediatr Endocrinol Rev. 2010 Dec;8
Suppl 1:151-9. Review.
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Visootsak J, Aylstock M, Graham JM Jr. Klinefelter syndrome and its variants: an update and
review for the primary pediatrician. Clin Pediatr , 2001 Dec;40(12):639-51. Review
XXX
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Otter M, Schrander-Stumpel CT, Curfs LM. Triple X syndrome: a review of the literature. Eur J
Hum Genet. 2010;18:265-271.
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Tartaglia NR, Howell S, Sutherland A, Wilson R, Wilson L. A review of trisomy X (47,XXX).
Orphanet J Rare Dis. 2010 May 11;5:8.
XYY
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Geerts M et al. The XYY syndrome: a follow-up study on 38 boys. Genet Couns. 2003;14:267–
279.
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Bardsley MZ, Kowal K, Levy C, Gosek A, Ayari N, Tartaglia N, Lahlou N, Winder B, Grimes S,
Ross JL. 47,XYY syndrome: clinical phenotype and timing of ascertainment. J Pediatr. 2013
Oct;163(4):1085-94.
Patient materials
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"Living with Klinefelter Syndrome, 47XYY, and Trisomy X", Virginia Cover (2012)
Brochures available through AXYS, www.genetic.org
Brochures and Study Day reports about XYY and XXX, (www.rarechromo.org)
Visootsak J, Aylstock M, Graham JM Jr. Klinefelter syndrome and its variants:
an update and review for the primary pediatrician. Clin Pediatr , 2001
Dec;40(12):639-51. Review
Children’s books on SCAs, www.amazon.com
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Acknowledgments
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eXtraordinarY Kids and Families
AXYS
NSGC Prenatal SIG
XXYY Project
eXtraordinarY Kids Clinic Team & Genetic Counseling students
eXceptional Kids Clinic and EmorY Team
Johns Hopkins Klinefelter Clinic Team
QUESTIONS?
Susan Howell, MS, CGC, MBA
720-777-8361 or [email protected]
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