CME
AADMD
American Academy of Developmental Medicine and Dentistry
Developmental Medicine
and Dentistry Reviews & Reports
Editorial Commentary:
In this issue of the “Reviews and Reports”, Virginia Isaacs
reports on the tortuous path taken by her as a parent of an
individual with Klinefelter Syndrome. She also provides some
basic information on this syndrome that will be of value to
any parent of a child with Klinefelter Syndrome or any professional working with such a person. While basic endocrine
treatment has become the standard of care, there remains
much for research to elucidate about timing, doses and extent
of benefit and side effects of endocrine treatment.
Psychosocial supports as well as early diagnosis are also
extremely important in helping ensure the successful treatment of the child with Klinefelter Syndrome.
Steven G. Zelenski, D.O., Ph.D.
Our Journey with Klinefelter Syndrome
VIRGINIA ISAACS, MSW, MBA, DEVELOPMENT OFFICER
FOR
AUTISM
AND
D ISABILITIES
ur journey with Klinefelter Syndrome began nineteen
years ago in the fifth month of a much-desired pregnancy
with a second child. Because I was 38 years old, I had had
amniocentesis to determine if the fetus had chromosomal
abnormalities such as Down Syndrome, or even less wellknown and more severe disorders. During genetic counseling,
we had been told that the test could also detect milder disorders
associated with extra sex chromosomes, but I paid little attention. Several weeks after the test, I received a phone call from
my obstetrician informing me that I was carrying a boy and that
his genetic signature indicated a disorder called Klinefelter
Syndrome, or 47,XXY. She had arranged for us to see the
geneticist that afternoon in order to determine if we wanted to
carry this pregnancy to term.
Klinefelter Syndrome, also known as 47,XXY, is estimated to
occur in 1 out of 600 males, making it the most common male
chromosomal disorder. Rather than the usual male pattern of
46 chromosomes, with one X chromosome and one Y chromosome, there is an additional X chromosome, resulting in a
genetic signature of 47,XXY. The exact cause is unknown. The
extra chromosome can come from either parent; there is little
relation to either maternal or paternal age. An extra chromosome in a pair (ie the X and Y chromosomes) is called a trisomy.
Klinefelter Syndrome, unlike most trisomy conditions, is highly survivable for the fetus and causes symptoms that vary greatly from one person to another. An extra or missing sex chromosome yields a syndrome called sex chromosome aneu-
O
56 October 2006 • EP MAGAZINE/www.eparent.com
AT
FOR THE
CODY CENTER
STONY B ROOK U NIVERSITY
ploidy. In females, Polysomy X, 47,XXX, or Turner Syndrome,
45,X, may occur. Variations of the condition can include
mosaicism where the child has two cell lines (ie 46,XY/47,XXY)
and conditions involving 48 chromosomes (XXYY, XXXY) or 49
chromosomes (XXXXY). XY/XXY males may have fewer symptoms while those with 48 or 49 chromosome variations may
have more pronounced disabilities. (1)
Babies with Klinefelter Syndrome rarely have any physical
differences that are detectable, which is the reason that so few
children are diagnosed soon after birth. However, a baby may
have very low muscle tone (hypotonia) or (rarely) an extremely
small penis (micropenis) that may cause a pediatrician to suspect a genetic problem. A condition known as torticolis, in
which the baby’s head and neck are slightly twisted to one side,
may be present.
Speech delay is one of the most common symptoms in
young children. They may be shy and hesitant about any new
experiences, such as pre-school or new foods. Children with
Klinefelter Syndrome can seem immature by comparison with
other children their age, and their limited verbal skills may contribute to difficulty in play situations. XXY boys may have poor
impulse control and attention deficits, which may be diagnosed
as attention deficit hyperactivity disorder (ADHD). The majority
of XXY boys have learning disabilities, although mental retardation is rare except in the 48 and 49 chromosome variations
of the disorder.
Our family had excellent genetic counseling. I subsequently
found that this is not the norm for sex chromosome aneuploidy. The majority of families that learn their babies will have
this condition are given limited information emphasizing special needs and possible intellectual disability, and choose to terminate the pregnancy. Our geneticist provided copies of a number of recent Klinefelter Syndrome articles, although there was
relatively little research for what we learned was a not-uncommon chromosomal condition. A pediatric endocrinologist gave
us a realistic portrayal of possible developmental problems that
our son might encounter, but characterized XXY as a mild to
moderate developmental disorder amenable to high quality
education and the security of caring and supportive parenting.
No one, however, could provide another parent to speak with us
for support or additional information. These were the preInternet days before web sites and listservs were available to
parents of children with special needs.
Our baby, Jonathan, was beautiful and had a charming personality. As we had been told might be the case, his speech and
motor skills were delayed. By fifteen months, he began receiving
early intervention services which allowed him to nearly catch up
by the time he entered a special education kindergarten program.
He was almost eight, however, before we had any contact with
other families with XXY children.
Despite the frequency with which Klinefelter Syndrome and
other sex chromosome aneuploidies occur, accurate diagnosis
is made in less than 35 percent of all cases in children and
adults (2). Unless a child is diagnosed prenatally, as are about
10 percent of cases, physicians are far less likely to consider
possible sex chromosome aneuploidy than they are to diagnose
ADHD, learning disabilities, pervasive developmental disability
or other similar conditions.
An astute pediatrician, developmental pediatrician or geneticist may recognize the subtle physical signs of Klinefelter
Syndrome in a child leading to genetic testing and a more complete diagnosis. Small testes, a smaller-than-average penis,
hypospadius (urethra located on the shaft of the penis) or
chryptorchidism (undescended testicle) are included in these
physical signs. Other signs include an arm span greater than
the boy’s height and a significant acceleration in height per-
centile around the age of 6 or 7 years. Another body disproportion that may be present is leg length (foot to waist) that
exceeds head to seat measurement. Some boys may have clinodactyly (slightly curved fifth finger), pectus excavatum (a
depression in the chest over the sternum), radio-ulnar synostosis (inability to completely straighten the elbow joint) or taurodontism (relatively thin enamel on the tooth with a large,
pulpy root area). For boys ages 13 or over, failure to begin
puberty or to progress through puberty completely may alert
the pediatrician to consider and test for Klinefelter Syndrome.
These physical signs are frequently accompanied by speech
delay, behavioral difficulties, learning disabilities, or attention
deficits. There is anecdotal evidence that because XXY boys
often have social skill deficits, poor verbal abilities, shyness to
the point of avoiding eye contact, and rigidity and inflexibility
in their play and socialization patterns (ie insisting on lining up
all car and truck toys and becoming upset when the toys are
disturbed), an initial diagnosis of an autism spectrum disorder,
such as Asperger Syndrome or Pervasive Developmental
Disorder, is made. (3) Klinefelter Syndrome is not an autism
spectrum disorder, even though there appears to be significant
overlap of symptoms in some children. Related sex chromosome aneuploidies, including XYY in males and XXX in girls,
may also produce similar behavioral and learning difficulties
that are incompletely diagnosed.
For children with Klinefelter Syndrome, early intervention is
the key to promoting speech and strengthening motor skills,
allowing children to reach developmental milestones at the
appropriate age. Children with Klinefelter Syndrome or any of
the other sex chromosome aneuploidies are eligible for early
intervention and for special education services to address verbal deficits, as well as any other learning disabilities that may
be present. For those with social skill deficits and low self
esteem, counseling, social skills training, cognitive behavior
therapy, and other interventions can help the child to develop
friendships and appropriate peer relationships. (4,5) Despite
the learning and behavioral challenges, most children with sex
chromosome aneuploidy graduate from high school, establish
continued on page 58
INSTRUCTIONS
For CME Credit read the editorial above and the article
below and complete the Content Test and CME Evaluation
Form at the end. Please read “Information and Instructions”
following the article.
Specific learning objectives for this CME activity (please
refer to general objectives).
Upon completion of reading of this article the learner will
be able to:
1. Describe the chromosomal abnormality associated with
Klinefelter Syndrome.
2. Describe the typical physical and behavioral phenotype.
3. Discuss treatment options for the individual with
Klinefelter Syndrome.
Upon receipt and acceptance of the completed evaluation
form/post-test, the AADMD CME Program will maintain on
file a record for 6 years designating your credits earned. If
you should need a written verification contact Philip May MD
at 908 510-3062.
www.eparent.com/EP MAGAZINE • October 2006 57
continued from page 57
careers, and have successful adult relationships. Many also
graduate from college.
Proper diagnosis is particularly important before the XXY
boy reaches puberty, so that supplemental testosterone can be
initiated. Most XXY males do not produce adequate testosterone, which can result in minimal facial and body hair, a more
feminine fat distribution, muscle weakness, fatigue and depression. In addition, incomplete mineralization of the bones
places XXY males at risk of early development of osteoporosis.
Testosterone, however, cannot prevent or reverse the infertility
caused by Klinefelter Syndrome.
One of several organizations devoted to education around the
issues associated with Klinefelter’s Syndrome is Klinefelter
Syndrome and Associates. Known as KS&A, the organization
was started by Melissa Aylstock, the mother of a boy with substantial learning and behavior difficulties who went undiagnosed until age eight. Once diagnosed, his family struggled to
access appropriate education and medical treatment for their
son. Melissa’s commitment to providing information and support to other families was expressed in building KS&A into a
national organization. www.genetic.org
Another support site was developed by Stefan Schwarz, a
software engineer. To see another story of frustration and
accomplishment as well as a site that provides information see:
www.klinefeltersyndrome.org
A third site that readers should find interesting is that of the
American Association for Klinefelter Information and Support
(http://www.aaksis.org/)
Testosterone treatment is recommended for the majority of
XXY adolescents and adults, although some men produce adequate levels on their own. Once given only by injection, there
are now patches and topical gels and creams that make administration painless. The hormone does not “cure” Klinefelter
Syndrome but it can reduce the fatigue and depression that
many XXY men experience, and increase their levels of confidence and feelings of well-being. There is considerable debate
about the appropriate age for initiating therapy, although it is
usually done between the ages of 11 and 14. There are currently several research studies taking place concerning the
impact of testosterone on brain development, and the optimal
time for administration. (6,7)
47,XXY nearly always leads to male infertility. Many men only
discover that they have the extra chromosome when they consult a physician because they and their partner have been
unsuccessful at achieving infertility. Infertility is painful emotionally and remains one of the more challenging problems to
address for this population. Couples where the man has XXY
have always turned to adoption or donor sperm to build families.
In the last ten years, however, infertility specialists have been
able to help some these couples achieve pregnancies using an in
vitro technique called intracytoplasmic sperm injection (ICSI).
References
Klinefelter Syndrome and Its Variants: An
Update and Review for the Primary
Pediatrician Jeannie Visootsak, Melissa
Aylstock, and John M. Graham, Jr
Clinical Pediatrics, Dec 2001;
40: 639 - 651.
X Chromosomal effects on social cognitive processing and emotion regulation: A
study with Klinefelter men (47,XXY).van
Rijn S, Swaab H, Aleman A, Kahn RS.
Schizophr Res. 2006 June;
84(2-3):194-203. Epub 2006 Apr 17
Diagnosis and management of the adolescent boy with Klinefelter syndrome
Melanie Manning and H. Eugene Hoyme
Adolescent Medicine, June 2002, 13[2]
367
The psychosocial impact of Klinefelter
syndrome—a 10 year review.
Simm PJ, Zacharin MR. J Pediatr
Endocrinol Metab. 2006 Apri1
9(4):499-505.
Pubertal androgen therapy in boys. Rogol
AD. Pediatr Endocrinol Rev. 2005
Mar;2(3):383-90.
58 October 2006 • EP MAGAZINE/www.eparent.com
Behavioral Phenotypes of Males with Sex
Chromosome Aneuploidy.
Tartaglia N, Reynolds A, Visootsak J,
Gronli S, Hansen R, Hagerman R.
Journal of Developmental & Behavioral
Pediatrics. 26(6):464-465, December
2005.
New facets of androgen replacement
therapy during childhood and adolescence.
Rogol AD. Expert Opin Pharmacother.
2005 Jul;6(8):1319-36.
CME
AADMD
Continuing Medical Education Offered by
The American Academy of Developmental Medicine & Dentistry
Continuing Medical Education Program
INFORMATION AND INSTRUCTIONS
1. Overall program goal: The goal of the AADMD Continuing
Medical Education Program (CMEP) is to improve the overall
health of adults with neurodevelopmental disorders (mental
retardation and other developmental disabilities) by enhancing
the ability of primary care physicians and specialists to effectively evaluate and manage those complex health conditions
that frequently occur in this patient population.
2. Target audience: Our educational activities are designed
for primary care physicians and specialists whose practice consists of significant numbers of adults with neurodevelopmental
disorders, such as those physicians who practice in State
Developmental Centers, State Mental Health facilities, public or
private Intermediate Care Facilities for the Mentally Retarded,
Family Practice Clinics, and General Internal Medicine Clinics.
3. General learning objectives of the AADMD
Northeastern Regional CME Program: Our educational
/training programs are designed so that trainees will be
better able to:
a. Apply the concepts of the “Developmental Medicine
Paradigm”;
b. Setermine an accurate neurodevelopmental diagnosis.
c. Evaluate and manage cognitive dysfunction in adults
with neurodevelopmental disorders;
d. Evaluate and manage motor dysfunction in adults with
neurodevelopmental disorders;
e. Evaluate and manage seizure disorders in adults with
neurodevelopmental disorders;
f. Evaluate and manage behavior disorders of adults with
neurodevelopmental disorders;
g. Evaluate and manage syndrome-related conditions in
adults with neurodevelopmental disorders;
h. Evaluate and manage secondary health consequences
of complications in adults with neurodevelopmental
disorders;
i. Effectively practice “care-coordination”;
j. Effectively work with families and other caregivers;
k. Apply a data-driven medical decision-making process to
clinical practice, known as Longitudinal Graphic
Analysis (LGA).
4. Full Disclosure Policy Affecting CME Activities: As a sponsor of CME which is accredited by the Medical Society of NJ
(MSNJ), it is the policy of the AADMD CME Program to require
the full disclosure of the existence of any financial interest or
other relationship an author, speaker or co-sponsor has with
the manufacturer (s) of any commercial product(s) or service(s)
discussed in an educational activity. The author of this article
(Ms. Isaacs) reports no financial or advisory relationships with
corporate organizations related to this activity. Costs of publication of this article, including graphic design, promotion and
distribution of this CME activity have been contributed in-kind
by EP Global Communications.
5. Accreditation Statement: This activity was planned and
implemented in accordance with the Essential Areas and Their
Elements of the MSNJ-CME Accreditation Program. The AADMD
CME Program is accredited by the MSNJ to
sponsor continuing medical education for
physicians.
6. Credit Designation Statement: The AADMD CME
Program designates this activity for a maximum of 1.0 AMA
PRA Category 1 Credit(s) ™. Physicians should only claim credits commensurate with the extent of their participation in the
activity. The estimated maximum time to complete this activity: 1 hour.
7. Disclaimer Statement: The opinions and recommendations expressed by authors/contributors are their own. This
journal article is produced for educational purposes only. Use
of the AADMD CME Program name implies review of educational format design and approach. The AAMDD is not itself
responsible for statements made by any contributor.
Statements or opinions expressed in the AADMD Reviews and
Reports reflect the views of the author(s) and not the official
policy of the Academy unless so stated. The Academy does not
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Material printed by the Academy is copyrighted by the
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and EP Global Communications. No part of this publication
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8. Instructions: Physicians who read specific articles designated for CME credit in this issue of the AADMD Developmental
Medicine and Dentistry Reviews & Reports can complete the
CME evaluation form for AMA Physicians Recognition Award
credit. To earn credit you must read the entire article(s) and
then successfully (minimum 70 percent correct answers) complete both the Content Test and the CME Evaluation Form located following the article(s). Mail the documents to:
American Academy of Developmental Medicine and Dentistry
CME Program, PO Box 5220, Clinton, NJ 08809
Disclaimer Statement: The opinions and recommendations expressed by authors/contributors are their own. This journal article is produced for
educational purposes only. Use of the AADMD Northeastern Regional CME Program name implies review of educational format design and approach.
www.eparent.com/EP MAGAZINE • October 2006 59
CME
AADMD
AADMD Developmental Medicine and Dentistry Reviews & Reports,
Content questions (Release Date: October 1, 2006
Expiration Date: October 30, 2007)
Our Journey with Klinefelter Syndrome
Specific learning objectives for this CME activity
(please refer to general objectives).
Upon completion of reading of this article the learner will be able to:
1. List the major variants of sex chromosome aneuploidy
3) Treatment of Klinefelter Syndrome may
include:
a) Endocrine replacement therapy
b) Adequate psychosocial support
c) Speech therapy
d) All of the above
2. Describe common expressions of Klinefelter Syndrome in children and adults
3. Identify sources of further information on Klinefelter Syndrome.
CIRCLE THE CORRECT ANSWER
1) The diagnosis of Klinefelter Syndrome in
infants is frequently missed because:
a) Signs and symptoms of the syndrome can
be very subtle early on
b) Most pediatricians have little personal
experience with the condition
c) It is relatively rare, occurring in about 1 out
of 600 babies
d) All of the above
2) Genetic counselling once the diagnosis has
been made is valuable because
a) It would inevitably lead to higher insurance premiums
b) It will help the parents and child understand the genetic underpinnings of the disease and help destigmatize the differences
in behavior that may occur
c) It will help the parents understand the
probably course of development in their
child with Klinefelter Syndrome
d) b and c
e) All the above
CME evaluation form
Specific learning objectives for this CME activity (please refer to general objectives)
Upon completion of this activity, the learner will be able to:
1. List the major variants of sex chromosome aneuploidy
2. Describe common expressions of Klinefelter Syndrome in children and
adults
3. Identify sources of further information on Klinefelter Syndrome.
1. Educational value
I learned something new that was important
I plan to seek more information on this topic
I will share this information with colleagues
This information will likely affect my practice
Strongly Agree
5
4
5
4
5
4
5
4
3
3
3
3
Strongly Disagree
2
1
2
1
2
1
2
1
2. Commitment to change
What changes, if any, do you plan to make in your practice as a result of reading these articles?
Please explain: ____________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
____________________________________________________________________________________
3. Do you agree or disagree with any of the conclusions as presented in these articles?
Please explain: ____________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
__________________________________________________________________________________
General comments:__________________________________________________________________
4) Which of the following web sites provides
reliable
information
on
Klinefelter
Syndrome?
a) WebMD
b) www.genetic.org
c) www.aaksis.org
d) All of the above
5) If a parent suspects Klinefelter Syndrome,
what is the most definitive test for diagnosis?
a) Serum testosterone levels
b) Chromosomal analysis
c) Consultation with a developmental neuropsychiatrist
d) All of the above
Please mail the Content Test and this evaluation form to:
American Academy of
Developmental Medicine and Dentistry
Continuing Medical Education Program
P.O. Box 5220
Clinton, NJ 08809
Upon receipt and acceptance of
the completed evaluation form/
post-test, the AADMD CME
Program will maintain on file a
record for six years designating
your credits earned. If you should
need a written verification, contact
Philip May M.D. at (908) 510-3062.
Please include your name and address
below.
Name: _____________________________
Address ____________________________
___________________________________
___________________________________
E Mail______________________________
PLEASE WRITE LEGIBLY
60 October 2006 • www.eparent.com