47, XXY

47,XXY, also commonly referred to as Klinefelter syndrome, is estimated to occur in 1 out of 600 males, making it the most common chromosomal disorder.  Rather than the usual 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.  This happens when paired chromosomes fail to separate at the first or second stage of meiosis.  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.  47,XXY, 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 aneuploidy.  A syndrome is a collection of symptoms and physical signs.  In some individuals, the manifestations of 47,XXY are mild and barely noticeable while in others, there is more severe symptomatology.

From the NIH Genetic and Rare Diseases Information Center: 47, XXY refers to the presence of an additional X chromosome in a person’s body cells. Some individuals with a 47, XXY chromosome finding do not appear different from other individuals, and they may have mild symptoms or no apparent symptoms. During the first few years of life, most 47, XXY individuals do not show any obvious differences from typical male infants and young boys. Children may have slightly weaker muscles, delayed development of motor skills, and learning and/or language problems. In later adolescence and adulthood, 47, XXY individuals can have features of Klinefelter syndrome, which can include primary hypogonadism (decreased testosterone production), small testes, enlarged breast tissue (gynecomastia), tall stature, and/or other features. Although the vast majority of individuals with 47, XXY identify as males, some develop atypical gender identities. There have been reports of individuals with 47, XXY having a female physical appearance, but in most cases this was attributed to changes in specific genes related to sexual development. Most 47, XXY males are infertile, but many produce sperm and may be able to conceive with assisted reproduction. Treatment varies among individuals and may include testosterone therapy; however, this therapy may not be appropriate for all individuals.

http://rarediseases.info.nih.gov/gard/11920/47-xxy/resources/1

See question below for more on this matter.

AXYS celebrates the diversity of the human family; including sex and gender, skin color, ethnicity, religion, sexual orientation, gender identity, age, socioeconomic status, physical characteristics, and mental abilities.  While the majority of 47,XXY individuals we serve identify as male, a minority identifies as “intersex” or another gender. Many also consider themselves as “being XXY” rather than “having XXY.”  Out of respect for these individuals, we have attempted to minimize gender references, and, where practical, we have called individuals XXYs and stated that they “are XXY.”

It should be emphasized that most XXYs have some, but not all, of the symptoms of the condition, and that symptoms vary greatly from one individual to another. Klinefelter syndrome is a term to describe a bundle of symptoms often associated with 47,XXY. Not all XXYs have Klinefelter syndrome, and Klinefelter syndrome is sometimes used to describe the symptoms associated with other conditions.  They are not interchangeable terms despite the fact they are often used interchangeably. One of the most fundamental and prevalent symptoms of 47,XXY is hypogonadism. In XXYs, hypogonadism manifests as small, firm testes, near infertility and inadequate levels of testosterone. Hypogonadism can also lead to delayed or incomplete puberty, sparse facial and body hair, female pattern body-fat distribution, gynecomastia (breast development, long limbs and poor coordination. A small number of individuals may have a micro-penis, which can be partially corrected with testosterone therapy at “mini-puberty” as a toddler. Untreated, hypogonadism can also contribute to problems with concentration, mood swings and other emotional and behavioral difficulties. It can also lead to a number of other conditions, such as osteoporosis, that can be prevented with testosterone hormone replacement therapy (HRT).

Numerous other symptoms can be associated with 47, XXY and its related variations. Many individuals exhibit several of these, but each person is different.  Other symptoms may include:

 

Pre Puberty Post Puberty
Speech/Language Difficulties Low muscle tone (hypotonia) Gender identity issues
Autism Spectrum Disorders or Asperger’s Syndrome Pervasive Developmental Disorders Low testosterone levels
ADD/ADHD Sensory Integration Problems Stalled Puberty
Learning Disabilities Impulse Control Difficulties Higher risk for autoimmune disorders
Obsessive Compulsive Disorder Poor Social Skills and Delayed Social Development Near infertility that advances with age and HRT (see section below)
Anxiety Low Self Esteem Osteoporosis
Depression Immaturity Ineffective coping strategies
Shyness Taurodontism Depression
Clinodactyly Pectus excavatum Greater risk for developing diabetes
Radio-Ulnar Synostosis Hypospadias Difficulty with interpreting or reacting to social cues
Micro-Penis (Rare) Torticolis Difficulty with expressing emotions
Cryptorchidism Low energy Challenges with employment

Because the condition is characterized by an extra chromosome, cells must be obtained, prepared and observed to count the extra chromosome. Generally, a specialized blood test, called karyotyping (a karyotype), a new buccal swab test called XCAT, or in some cases, FISH (fluorescence in situ hybridization), or microarray analysis is performed to look for chromosomal abnormalities. Any physicians, including family physicians and geneticists, can order genetic testing when a chromosomal or genetic condition is suspected or needs to be ruled out. Some pregnant women who have specific risk factors or have other concerns regarding possible genetic conditions have invasive prenatal testing during pregnancy. The two invasive prenatal tests available are amniocentesis or chorionic villus sampling. These tests provide cells from the fetus that can be studied to detect extra chromosomes. A new, noninvasive prenatal test is also available. Because most pregnant women do not have invasive prenatal testing during pregnancy, only about 10 percent of cases of 47,XXY are detected prenatally.

There is some debate about the prevalence of 47,XXY.  Studies have demonstrated between 1 in 500 and 1 in 800. A large-scale genetic screening of over 40,000 newborns in Denver demonstrated a rate of approximately 1 per 600 male births.  Longitudinal population studies in the Netherlands have confirmed these estimates. 47,XXY is more common than Down Syndrome. It is estimated that only 35 percent of all individuals with XXY are ever diagnosed, due in part to the subtle and varying physical and psychological symptoms, and in part to a lack of training in medical schools about sex chromosome aneuploidies and their diagnosis and treatment.

Approximately 80 percent of those born with 47,XXY have the 47,XXY genetic signature.  In the other 20 percent, there may be more X and Y chromosomes, with genetic signatures of 48,XXXY, 48,XXYY, and 49,XXXXY. Or, individuals may have a mix of cells within the body, some XY and others XXY, which is called mosaicism. Some individuals have a genetic signature of 46,XX, but have a tiny piece of the Y chromosome appended to one of the X chromosomes, giving them male genitalia and secondary sex characteristics, such as facial hair and male muscle development.47,XYY is incorrectly associated as a variant of 47,XXY, but it is actually a distinctly different sex chromosome aneuploidy. The most obvious difference is that 47, XYY males have none of the medical and infertility issues that individuals with 47,XXY may have, although there can be behavioral difficulties and learning disabilities associated with XYY.

In general, yes, but with notable exceptions:

  • Individuals with XXY/XY mosaicism may produce enough viable sperm to be biological fathers without requiring infertility treatment.
  • In the last decade, with the use of reproductive technology advances, a number of males with XXY have achieved biological fatherhood.  However, this can be an expensive process, ranging upwards from $20,000 per attempt.  Typically three techniques are required:

a.      TESE:  Testicular sperm extraction, which typically involves harvesting sperm directly from the testes;

b.      ICSI:  Intracytoplasmic sperm injection, an in vitro technique in which individual sperm are injected into ova in a Petri dish to create embryos;

c.       IVF:  In vitro fertilization, which then implants the fertilized egg into the womb.

Time is of the essence for those with XXY who are considering reproductive therapies. Hormone replacement therapy must be managed very carefully to avoid total suppression of sperm production, and the availability of viable sperm declines rapidly with age. Parents of adolescents are advised to explore fertility questions with a qualified fertility clinic soon after puberty.

It’s also important to note that most people with XXY are capable of having a normal, satisfying sex life despite their infertility. Many become parents via adoption, donor sperm and other techniques commonly employed by other families who face fertility challenges.

Babies born with 47,XXY rarely have any obvious physical differences, 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. In children with 48 and 49 chromosome variations, there may be more pronounced physical signs including facial abnormalities or ambiguous genitalia that indicate a possible chromosomal or genetic condition.

Children with 47,XXY may be language-delayed and have poor muscle tone, leading to poor fine and gross motor skills. They may be shy and very hesitant about any new experiences, such as pre-school or trying new foods. They can seem immature by comparison with other children their age, and their limited verbal skills may contribute to difficulty in play situations.

Many children with XXY have poor impulse control and attention deficits, which may be diagnosed as attention deficit disorder or attention deficit hyperactivity disorder (ADD or ADHD). Children with XXY can be misdiagnosed with Asperger syndrome or pervasive developmental disorder. This is because many exhibit social skill deficits, poor verbal abilities, shyness to the point of avoiding eye contact, and rigidity and inflexibility in their play patterns (i.e. insisting on lining up all car and truck toys, and becoming upset when the toys are disturbed). They may have difficulty in interactions with other children and adults. 47,XXY is not an autism spectrum disorder, even though there appears to be significant overlap of symptoms.

Children who have XXY may need special supports in school, including the protections of an IEP or 504 Plan. They may also benefit from a teacher’s aide, protection from bullying and special accommodations such as  “self-imposed time outs.” A developmental pediatrician or geneticist will often recognize the subtle physical signs of 47,XXY in a child initially diagnosed with learning disabilities, ADHD, and/or an autism spectrum disorder, 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 measure that is greater than the child’s height, and a significant acceleration in height percentile 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. They 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 adolescents ages 13 or over, failure to begin puberty or to progress through puberty completely may alert the pediatrician to consider and test for 47,XXY.

Early intervention appears to be very effective in reducing delays in development of both motor skills and language. Children who are diagnosed prenatally or in infancy may begin receiving services within the first year if they show early delays in motor skill acquisition. For children who have not been diagnosed, families may be wrongly reassured that “He will catch up—boys are slower.” Children who are not meeting speech, motor and social developmental milestones on pediatric screening instruments need to be evaluated further by a developmental pediatrician or at a child development center. Parents are encouraged to insist on evaluation where development is progressing slowly because these children rarely “catch up” without intervention services.

Adults and adolescents who have reached the age of puberty often require supplemental testosterone because their bodies make insufficient hormone to help them develop male secondary sex characteristics such as facial hair, a deep voice, and male pattern muscle and fat distribution. Those who identify as another gender are encouraged to seek the guidance of an endocrinologist to mitigate the risks of low testosterone. Testosterone, however, does not correct infertility.

Testosterone may also be needed to help increase and maintain bone density at normal levels, to create sexual desire and capacity for erections, and to build muscle mass. Individuals whose testosterone levels are low may feel fatigued, anxious and depressed. Testosterone treatment is a very individualized therapy and should be overseen by an endocrinologist who can use blood levels and the patient’s reports of well-being to adjust the dosage properly.

Children who are reaching adolescence should be evaluated by a pediatric endocrinologist who can determine when hormone therapy should begin. This is generally between the ages of 9 and 13, depending on bone development and blood tests. Testosterone can be injected from every 10 days to every 3 weeks. It is also available as a gel applied daily to the shoulders or abdomen, or as an adhesive patch worn daily.

Oral testosterone tablets are not recommended because they can cause liver problems. There are ongoing clinical trials of a buccal dissolving tablet, placed between the gum and cheek.  Implanted pellets that slowly deliver testosterone over several months are also approved for use in the U.S.

Another option is Axiron in a cup applicator with a testosterone gel pumped into it that is applied to each underarm after showering.

In infancy, the only treatments that may be indicated are several injections of testosterone within the first 3 to 4 months, especially if the child has a very small penis. In infants with 46,XYY there is an initial spike of testosterone production, called mini puberty, that infants with 47,XXY may not experience. After this spike in testosterone production, virtually no testosterone is produced again until the start of puberty at the age of 9 to 11.

The symptoms of 47,XXY can be treated and managed in childhood with occupational, physical and speech therapy as well as counseling and social skills training. Special education accommodations and teaching methods can help achieve academic success despite learning disabilities. An increasing number of colleges and vocational schools have instituted programs to help those with learning disabilities to obtain degrees and credentials necessary for careers. Parents are encouraged to explore the benefits and protections afforded by an IEP or 504 plan, covered elsewhere in AXYS’s library.

There is current research that indicates some individuals with 47,XXY may experience delayed maturation relative to brain development associated with executive decision-making. This may be more prevalent with individuals who are not diagnosed at an early age and do not receive testosterone hormone replacement therapy. Anecdotal reports indicate there may be a 5+ year delay between chronological age and maturational age for many of these individuals, which can be very difficult to diagnose or measure objectively. It is a well-known fact that teenagers in general can demonstrate very poor decision-making with respect to risk-taking behavior, suggesting that those with XXYs may benefit from strong guidance and careful parenting for longer periods (i.e., into their late teens and 20s) to prevent serious legal and social problems. For those with tall stature, society may be slow to recognize this immaturity and fail to make needed accommodations.

Hypogonadism associated with 47,XXY can lead to a host of comorbid conditions. None appear at alarmingly high rates, but some are three to five times more prevalent among XXYs that among XY men. Among the more common medical complications are osteoporosis, a thinning of the bones making fractures more likely, and autoimmune disorders such as rheumatoid arthritis, lupus, and Type 1 diabetes. Particularly those who have not had testosterone supplementation may suffer from venous ulcers. Thyroid disorders are also more common than usual. Those with XXY are more likely to suffer from seizures.  There is some suggestion they are also more likely to suffer from mood disorders, including depression and bipolar disorder, than the population as a whole, although this has not yet been studied rigorously enough to quantify. Studies are underway to determine the impact of testosterone therapy on reducing the risks of these complications. AXYS is developing a comprehensive summary of comorbid conditions associated with all X and Y chromosome variations.

Gynecomastia is the development of breast tissue. In those with XXY, this is related to hypogonadism. Most males with XXY develop some gynecomastia in adolescence that resolves in the mid-teens. In some, the breast development is pronounced and becomes both embarrassing and uncomfortable. Approximately one-third continue to suffer from significant gynecomastia after adolescence. Many opt for surgery to remove the excess breast tissue and create a normal male chest profile. Gynecomastia slightly increases the risk of breast cancer from less than 1 % for the male population overall to 3.7%.  All those with XXY should perform regular breast exams to detect any nodules. Mammograms are not medically indicated for individuals with XXY unless a physician orders one to check an unusual finding in a breast exam.

There are no current systematic studies of unusual talents and skills in those with XXY. Anecdotal information from conferences and websites suggests they enjoy math, computers, chess, music and art, and that many excel in these areas professionally. Various magnetic resonance imaging (MRI) studies support this point. A large multi-year study of over 40 children at the National Institutes of Health showed that the volume of gray matter on the right side of the brain (the part controlling spatial abilities and computational skills), was larger for children with XXY than for control subjects. Those with XXY may use this strength to compensate for the slightly smaller than average volumes of the left half of their brains, which control language functions and social skills, and which may explain deficits in these areas.

With children who are diagnosed prenatally or as young children, it is best to begin short, simple explanations at about age 5 or 6. You can explain that every cell in the body has “messages” to tell the body how to grow, and that the extra X sends some extra messages that are difficult for the body to understand. This may also help  explain the need for extra help in the resource room at school, or for medication to help with attention. Later, during visits to an endocrinologist, you can provide more detailed explanations about the need to take testosterone supplementation.

47,XXY should never be kept a secret. Your child may well sense when you are withholding. When it’s time to learn about sexuality and reproduction, you can introduce the issue of lowered fertility and the need for infertility treatment, donated sperm or adoption to create a family later in life. Reassure your child that the condition is common and that learning disabilities do not make him “disabled.”

47,XYY

47,XYY is estimated to occur in 1 out of 1000 males. Rather than the usual male pattern of 46 chromosomes, with one X chromosome (from the egg) and one Y chromosome (from the sperm) there is an additional Y chromosome, resulting in a genetic signature of 47,XYY.  This happens when paired chromosomes fail to separate during meiosis in creating a sperm with an extra Y chromosome, or after fertilization during mitosis, when the cells divide in the embryo.  The exact cause is unknown.  An extra chromosome in a pair (i.e. the X and Y chromosomes) is called a trisomy. 47,XYY and the other trisomy sex chromosome aneuploid conditions (47,XXY and Trisomy X), unlike most trisomy conditions such as Down syndrome, are highly survivable for the fetus, rarely cause severe disability, and can have symptoms that vary greatly from one person to another. An extra or missing sex chromosome yields a syndrome called sex chromosome aneuploidy. A syndrome is a collection of symptoms and physical signs.  In some males, the manifestations of 47,XYY are mild and barely noticeable while in others there are much more severe symptoms.
Because the condition is characterized by an extra chromosome, cells must be obtained, prepared and observed to count the extra chromosome.  Generally, a specialized blood test, called karyotyping (a karyotype), a new buccal swab test called XCAT, or in some cases,FISH (fluorescence in situ hybridization), or microarray analysis is performed to look for chromosomal abnormalities.  Any physicians, including family physicians and geneticists, can order genetic testing when a chromosomal or genetic condition is suspected or needs to be ruled out.Some pregnant women who have specific risk factors or have other concerns regarding possible genetic conditions have invasive prenatal testing during pregnancy.  The two invasive prenatal tests available are amniocentesis or chorionic villus sampling.  These tests provide cells from the fetus that can be studied to detect extra chromosomes.  A new, noninvasive prenatal test is also available.  Because most pregnant women do not have invasive prenatal testing during pregnancy, only about 10 percent of cases of 47,XYY are detected prenatally.

Large-scale genetic screening studies of newborns have been used to estimate a rate of approximately 1 per 1000 male births..  However, it is estimated that only 12 percent of all males with 47,XYY are ever diagnosed, due in part to the subtle and varying physical and psychological symptoms of affected males, and in part to a lack of training in medical schools and other graduate programs about sex chromosome aneuploidies and their symptoms, diagnosis and treatment.  If a boy with 47,XYY is not diagnosed prenatally, there are few other opportunities for diagnostic inquiry of a possible genetic disorder.  Men with 47,XYY rarely have infertility problems, unlike girls with Trisomy X and most men with Klinefelter syndrome (which can lead to significantly more diagnoses resulting from efforts to discover the cause of the infertility).  Pediatricians do not yet request genetic testing often enough when there are speech delays, learning disabilities or other developmental problems because they still associate sex chromosome aneuploidy with intellectual disability only, and not the more subtle symptoms of motor delay and learning and speech problems.

Variant karyotypes of 47,XYY, are probably not survivable in most cases.  There have been a few case reports of karyotypes such as 48,XYYY, or 49,XXYYY.  These individuals have had quite severe disability.

It should be emphasized that most boys and men with 47,XYY have some, but not all, of the symptoms and that both symptoms and severity vary greatly from one individual to another.  Many men with 47,XYY are completely unaware of the extra chromosome.  On the other hand, up to 30% of boys with 47,XYY will be diagnosed with an autism spectrum disorder, although it will be of the milder variety.  They may also suffer from delayed speech as children and have continuing difficulties with verbal expression as adults.  Hypotonia, or low muscle tone, and delay in achieving motor skill milestones such as walking independently or holding a crayon to color, may occur.  While most males with 47,XYY will have intelligence in the normal range, many have language-based and other learning disabilities. A small number will have mild intellectual disability.  Other possible problems include social skill disabilities, immaturity, low self-esteem, ADHD, impulsivity, and anxiety or mood disorders.  Boys and men with 47,XYY, tend to be very tall, but this is not always the case.  In adolescents, severe acne may be a problem.  There are also some cases of testicular failure in adolescents or later in adult life, necessitating the use of testosterone.

A mosaic cell line means that a man has one cell line with 46 chromosomes, for instance, including one X and one Y chromosome, as well as a second cell line with one X and two Y chromosomes.  This genetic signature would be written as 46,XY/47,XYY.  The term “mosaic” is used because the cells with different numbers of chromosomes “nest” together in a mosaic pattern, much like tiles on a floor or wall.

Men with 47,XYY have normal fertility. The chances of passing the extra Y chromosome on to their offspring is remote, because sperm with extra chromosomes tend not to survive and usually are the ones that do not succeed in fertilizing an egg.  There are reports that a father with XYY has passed an extra Y chromosome on to a son, although this is not common. Couples where the male has 47,XYY may wish to speak with a genetic counselor when contemplating pregnancy, but it should not offer a great risk.

Babies with 47,XYY 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) and later in the first year of life the parents or pediatrician may detect that they are slow to meet developmental milestones such as walking or babbling. At that point, delays could become cause for concern and a referral to early intervention.

Again, 47,XYY is characterized by great variation in how symptoms may appear among young children as well as those who are school age or adolescent.  In many cases, boys with 47,XYY will be language delayed, and some will have poor fine and gross motor skills.  Children with 47,XYY can seem immature by comparison with other children their age, and their more limited verbal skills may contribute to difficulty in play situations.  Some boys with 47,XYY  have attention deficits which may be diagnosed as attention deficit disorder or attention deficit hyperactivity disorder (ADD or ADHD).  They can also demonstrate rigidity and inflexibility in their play patterns as well as interactions with other children and adults, or they can have significant anxiety around particular issues, including starting a new school year or using the toilet.  Up to thirty percent may be diagnosed with a milder version of an autism spectrum disorder, usually Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS), but most will develop functional language and will not have the level of continuing behavioral and language disability that characterizes classical autism.  About two-thirds of children with XYY will have language-based learning disabilities that require some special education services.  They are also more likely than their peers to have anxiety or mood disorders.

A developmental pediatrician or geneticist may recognize the subtle physical signs of 47,XYY in a child initially diagnosed with learning disabilities, as well as language and motor skill delays, leading to genetic testing and a more complete diagnosis.   Boys with 47,XYY are often significantly taller than siblings or peers, and may have physical signs such as an arm span measure that is greater than her height, or a significant acceleration in height percentile 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.  If more pediatricians and professionals who provide therapies to children recognized this constellation of symptoms as possible sex chromosome aneuploidy, there would be greater diagnosis of 47,XYY and the other X and Y chromosome variations.

Early intervention appears to be very effective in reducing delays in development of both motor skills and language in boys with 47,XYY.  Children who are diagnosed prenatally or in infancy may begin receiving services within the first year if they show early delays in motor skill acquisition.  For children who meet the criteria for mild autism, applied behavioral analysis (ABA) is an evidence-based methodology for helping them to develop speech and age-appropriate behavior so that they can participate more successfully in school and in social interactions.  Children who are not meeting speech, motor and social developmental milestones on pediatric screening instruments need to be evaluated further by a developmental pediatrician or a child development center.  When the child has a delay, parents and even physicians will often dismiss this with, “He’s a boy.  He will catch up.”  Parents must insist on evaluation where development is progressing slowly because these children rarely “catch-up” without intervention services.  In some boys with 47,XYY the delays are not significant enough to qualify for early intervention services.  A diagnosis of genetic anomaly, however, would often qualify them to have speech, physical or occupational therapy reimbursed by private insurance.

There are no specific treatments for 47,XYY, although if there are symptoms, various interventions are recommended.  Speech and motor skill difficulties respond to therapy.  Anxiety and mood disorders or ADHD can be treated with individual or family therapy, behavioral therapy, work with an occupational therapist, and sometimes, appropriate medication.Special education accommodations and teaching methods can help boys achieve academic success despite learning disabilities.  These boys may have significant anxiety related to school, and a change to a smaller classroom environment or an alternative learning setting, including part-time home schooling, can help.  An increasing number of colleges and vocational schools have instituted programs to help those with learning disabilities to obtain degrees and credentials necessary for careers.

There are few health risks associated with 47,XYY, except for the tendency of very severe acne in adolescence that may cause scarring.  Mood disorders, including depression and bipolar disorder, appear to be much more common among boys and men with 47,XYY than in the population as a whole, although this has not yet been studied rigorously enough to quantify.  Occasionally, an adolescent or an adult with 47,XYY experiences testicular failure, but this is rare.

With boys who are diagnosed prenatally or as young children, it is best to begin short, simple explanations at about age 5 or 6.  You can explain that every cell in his body has “messages” to tell his body how to grow, and that he has some extra messages, which may help to explain his need for speech therapy or resource room.  Later, you can provide more detailed explanations about the extra chromosome.  47,XYY should never be kept a secret even if it causes few symptoms; the child may sense there is something that his parent is withholding from him.  When he begins to learn about sexuality and reproduction, you can introduce the issue of the extra Y chromosome and its impact of fertility, which is usually not an issue, but is something of which he should be aware.  Reassure him that the condition is surprisingly common and that while he may have learning or other disabilities, he does not have a disease.

47,XXX

Trisomy X, also known as 47,XXX, is estimated to occur in 1 out of 1000 females. Rather than the usual female pattern of 46 chromosomes with two X chromosomes, there is an additional X chromosome, resulting in a genetic signature of 47,XXX. This happens when paired chromosomes fail to separate during meiosis, creating either an egg or a sperm with an extra X chromosome, or after fertilization during mitosis, when the cells divide in the embryo. The exact cause is unknown. The extra chromosome can come from either the egg or the sperm although in Trisomy X, it is more likely to be contributed by the egg. An extra chromosome in a pair (i.e. the X and Y chromosomes) is called a trisomy. There is some relationship to advanced maternal age, although it is not nearly as strong as in Down syndrome, which is also a trisomy condition involving chromosome 21. Unlike most trisomy conditions, Trisomy X and the other trisomy sex chromosome aneuploid conditions (47,XXY and 47,XYY) are highly survivable for the fetus and cause symptoms that vary greatly from one person to another. An extra or missing sex chromosome yields a syndrome called sex chromosome aneuploidy. A syndrome is a collection of symptoms and physical signs. In some females, the manifestations of 47,XXX, are mild and barely noticeable while in others, there are much more severe symptoms.

Because the condition is characterized by an extra chromosome, cells must be obtained, prepared and observed to count the extra chromosome.  Generally, a specialized blood test, called karyotyping (a karyotype), a new buccal swab test called XCAT, or in some cases,FISH (fluorescence in situ hybridization), or microarray analysis is performed to look for chromosomal abnormalities.  Any physicians, including family physicians and geneticists, can order genetic testing when a chromosomal or genetic condition is suspected or needs to be ruled out.Some pregnant women who have specific risk factors or have other concerns regarding possible genetic conditions have invasive prenatal testing during pregnancy.  The two invasive prenatal tests available are amniocentesis or chorionic villus sampling.  These tests provide cells from the fetus that can be studied to detect extra chromosomes.  A new, noninvasive prenatal test is also available.  Because most pregnant women do not have invasive prenatal testing during pregnancy, only about 10 percent of cases of Trisomy X are detected prenatally.

Large-scale genetic screening studies of newborns have been used to estimate a rate of approximately 1 per 1000 female births. However, it is estimated that only 12 percent of all females with Trisomy X are ever diagnosed, due in part to the subtle and varying physical and psychological symptoms of affected females, and in part to a lack of training in medical schools and other graduate programs about sex chromosome aneuploidies and their symptoms, diagnosis and treatment. If a girl is not diagnosed prenatally, there are few other opportunities for diagnostic inquiry of possible genetic disorder. It is becoming more common for doctors to suspect Trisomy X if there are infertility issues or a woman experiences early menopause. Pediatricians do not yet do genetic testing often enough when there are speech delays, learning disabilities or other developmental problems because they still associate sex chromosome aneuploidy with intellectual disability only, and not the more subtle symptoms of motor delay, and learning and speech problems.

In girls and women with extra X chromosomes, about 10 percent will have 48 or 49 chromosomes. The variation with 48 chromosomes is called Tetrasomy X while the variation with 49 is called Pentasomy X. With each additional X chromosome, there is usually a decrease in IQ of about 15 points, as well as additional disability in various areas. Girls and women with Tetrasomy and Pentasomy X often have cardiac anomalies as well as genitourinary malformations or other birth defects. Unlike females with Trisomy X, many are infertile or fail to go through puberty normally and require estrogen treatment. Intellectual disability is not unusual in this population. It is also possible for a female to have only one X chromosome. This is known as Turner syndrome. It occurs at a rate of approximately 1 in 2000 to 2500 live births; only approximately 1% of fetuses with Turner syndrome survive to term. Most miscarry. Turner syndrome has a very different presentation from the trisomy sex chromosome aneuploid conditions. Girls and women with Turner syndrome usually have short stature and are infertile. They can have cardiac and other health problems.

It should be emphasized that most girls and women with 47,XXX, have some, but not all, of the symptoms of Trisomy X, and that symptoms vary greatly from one individual to another. They may also suffer from delayed speech as children and have continuing difficulties with verbal expression as adults. Hypotonia, or low muscle tone, and delay in achieving motor skill milestones, such as walking independently or holding a crayon to color, may occur. While most females with Trisomy X with have intelligence in the normal or low-normal range, many have language-based and other learning disabilities. A small number will have mild intellectual disability. Other possible problems include social skill disabilities, immaturity, low self-esteem, and anxiety or mood disorders. Girls and women with Trisomy X tend to be tall, but this is not always the case. In a minority of women, there may be premature ovarian failure leading to early menopause. Some women suffer lowered fertility. Among the fairly subtle physical signs may be an epicanthal eye fold, or clinodactyly, a curved little finger. Occasionally, females with Trisomy X will also have more severe difficulties such as seizures or genitourinary malformations, including kidney defects. In girls and women with the 48 and 49 chromosome variations, symptoms are often more pronounced and severe.

A mosaic cell line means that a woman has one cell line with 46 chromosomes, for instance, including two X chromosomes, as well as a second cell line with a different number of X chromosomes, for instance three X chromosomes. This genetic signature would be written as 46,XX/47,XXX. The term “mosaic” is used because the cells with different numbers of chromosomes “nest” together in a mosaic pattern, much like tiles on a floor or wall. If a female has a large proportion of cells with the typical number of chromosomes, 46, her symptoms may be less marked than someone with non-mosaic Trisomy X. It is also possible to have mosaicism involving 48 and 49 chromosomes, as in 46,XX/47,XXX/48,XXXX. One concern in diagnosing Trisomy X is ruling out mosaicism with a Turner cell line, 45,X/47,XXX. If a woman with Trisomy X has mosaicism with a Turner cell line, she may be at risk of the cardiac and gynecologic anomalies that characterize Turner syndrome.

Most women with Trisomy X can become pregnant, although there are a small number who have lowered fertility. Infertility in women is increasingly a reason for genetic testing, and a number of women have been diagnosed during infertility workups. The risk on passing on the extra chromosome to offspring, however, is low: probably less than 5 percent. If, however, the woman has mosaicism with a Turner cell line, her risk of passing on an extra (or missing) X chromosome is increased. Women with Trisomy X who are contemplating pregnancy should consult a knowledgeable genetic counselor if they are concerned about this possibility.

Babies with Trisomy X rarely have any detectable physical differences, which is the reason that so few children are diagnosed soon after birth. However, a baby may have very low muscle tone (hypotonia), or a girl may have an epicanthal eye fold, which along with low muscle tone, may cause a pediatrician to suspect a genetic problem, such as Down syndrome, and order genetic testing. Girls with Trisomy X may be less active than other baby girls, but these signs are rarely noticeable until late in the first year. At that point, delays in motor skills and a perhaps in babbling could become cause for concern. In girls with Tetrasomy X or Pentasomy X, there may be more pronounced physical signs including facial or genitourinary abnormalities as well as significant motor skill delays that lead to earlier diagnosis.

This would not happen unless a male had a tiny piece of the sex-determining Y chromosome appended to an X chromosome. He would then develop as a male. It is possible, and it has probably occurred although this writer has not seen any such case reports. Boys and men are affected by two different sex chromosome aneuploid conditions. The most common is 47,XXY (Klinefelter Syndrome) affecting 1 in 600 males. Less common is 47,XYY, affecting 1 in 1000 males. All sex chromosome aneuploid trisomy conditions share the same group of developmental, language, motor, and learning and emotional symptoms, and can be characterized by a wide range of functioning, from barely affected to more significantly impacted. In addition, most men with Klinefelter syndrome are infertile, and are at risk for a number of medical problems, such as osteoporosis. Women with Trisomy X and men with 47,XYY, do not have these additional medical risks, and they only rarely have problems with infertility.

Again, Trisomy XXX is characterized by great variation in how symptoms may appear among young children as well as those who are school age or adolescent. In many cases, children with Trisomy X may be language delayed, and have poor muscle tone, leading to poor fine and gross motor skills. They may be shy and hesitant about any new experiences, such as pre-school or new foods, and they may be sensitive to loud sounds or clothing textures, and appear to have sensory issues. Children with Trisomy X can seem immature by comparison with other children their age, and their more limited verbal skills may contribute to difficulty in play situations. Some girls with Trisomy X have attention deficits, which may be diagnosed as attention deficit disorder or attention deficit hyperactivity disorder (ADD or ADHD). They can also demonstrate rigidity and inflexibility in their play patterns as well as interactions with other children and adults, or they can have significant anxiety around particular issues, including starting a new school year or using the toilet. Many girls with have chronic stomach pain and constipation which may be caused by anxiety, or by low muscle tone, or both. A developmental pediatrician or geneticist may recognize the subtle physical signs of Trisomy X in a child initially diagnosed with learning disabilities, as well as language and motor skill delays, leading to genetic testing and a more complete diagnosis. Girls with Trisomy X are often somewhat taller than siblings or than peers, and may have physical signs such as an arm span measure that is greater than her height, or a significant acceleration in height percentile 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. If more pediatricians and professionals who provide therapies to children recognized this constellation of symptoms as possible sex chromosome aneuploidy, there would be greater diagnosis of Trisomy X and the other X and Y chromosome variations.

Early intervention appears to be very effective in reducing delays in development of both motor skills and language in girls with Trisomy X. Children who are diagnosed prenatally or in infancy may begin receiving services within the first year if they show early delays in motor skill acquisition. Children who are not meeting speech, motor and social developmental milestones on pediatric screening instruments need to be evaluated further by a developmental pediatrician or a child development center. Parents must insist on evaluation where development is progressing slowly because these children rarely “catch-up” without intervention services. In some girls with Trisomy X, the delays are not significant enough to qualify them for early intervention services. A diagnosis of genetic anomaly, however, would often qualify them to have speech, physical or occupational therapy reimbursed by private insurance.

There are no specific treatments for Trisomy X, although if there are symptoms, various treatments are recommended. Speech and motor skill difficulties respond to therapy. Anxiety and mood disorders can be treated with individual or family therapy, behavioral therapy, work with an occupational therapist, and sometimes, appropriate medication. For girls who are having stomach pain, a diet rich in fiber, regular exercise, and, if necessary, a mild laxative such as Senacot can help. Special education accommodations and teaching methods can help girls to achieve academic success despite learning disabilities. Girls with Trisomy X will often have significant anxiety related to school, and a change to a smaller classroom environment or an alternative learning setting, including part-time home schooling, can help. An increasing number of colleges and vocational schools have instituted programs to help those with learning disabilities to obtain degrees and credentials necessary for careers.

Health risks are not common, but it appears that some disorders, such as autoimmune problems (lupus or rheumatoid arthritis) may be seen more often. While rare, seizure disorders, cardiac problems, and genitourinary disorders (i.e. kidney malformations) may be slightly more common. Mood disorders, including depression and bipolar disorder, appear to be much more common among girls and women with Trisomy X than in the population as a whole, although this has not yet been studied rigorously enough to quantify. We also know that infertility and premature ovarian failure are more often seen in women with Trisomy X.

This is a complex and personal decision that depends on individual circumstances. With girls who are diagnosed prenatally or as young children, it is generally best to begin short, simple explanations at about age 5 or 6. You can explain that every cell in her body has “messages” to tell her body how to grow, and that she has some extra messages, which may help to explain her need for speech therapy or resource room. Later, you can provide more detailed explanations about the extra chromosome. Trisomy X should never be kept a secret even if it causes few symptoms; the child may sense that there is something that her parent is withholding from her. When she begins to learn about sexuality and reproduction, you can introduce the issue of the extra X chromosome and its impact of fertility, which is usually not an issue, but is something of which she should be aware. Reassure her that the condition is surprisingly common and that while she may have learning disabilities, for instance, she does not have a disease.

All Conditions

Before disclosing a diagnosis to relatives, such as grandparents, determine whether they are likely to be supportive and tolerant of a range of learning disabilities and other possible health and behavior problems. It is reasonable to wait with a prenatal diagnosis until some developmental delay presents, and an explanation to grandparents or to siblings is necessary. A significant factor in disclosure is the need for social benefits and supports.  Most accommodations of any type have their basis in the American’s with Disabilities Act. The XXY individual may not be disabled and yet still qualify for services and accommodations. For example, an XXY may benefit from the protections and supports afforded by an IEP or 504 plan in school. In the case of a child with language, physical, learning or behavioral difficulties, disclosing the chromosomal condition to relatives is often reasonable and reassuring to them. It is important to know as much information as possible so that you can address concerns, particularly where the relative has heard one of the myths about 47,XXY. Some of the myths about 47,XXY are that XXY causes intellectual and developmental disabilities (previously called mental retardation), increased criminal behavior, or that individuals with 47,XXY are actually women.

It is important to emphasize that most XXYs have IQs between 85 and 120 although some individuals with more than two additional chromosomes may have intellectual and developmental disabilities. In addition, XXYs as a group actually have lower than expected rates of criminal convictions, when compared with the general population of males. And, while respecting those XXYs who identify as a different gender, the presence of a Y chromosome almost always determines that a human develops as a male, although there are some syndromes (not related to 47,XXY) where a human with a Y chromosome may develop as a female, rather than as a male. As mentioned previously, a minority of XXYs identify as another gender or intersex.

Disclosure to an employer is rarely necessary unless the employee is seeking employment through a supported work program or is seeking some other special accommodations under the ADA.  Genetic information should remain private because disclosing such information may make obtaining health or life insurance difficult.  Employers or others may make unjustified assumptions that certain myths (cited above) are true for persons with 47,XXY. In some cases, however, it may be necessary in order to obtain Federally-mandated Family and Medical Leave, or some other benefit such as disability coverage or an accommodation under the Americans with Disabilities Act (ADA).

Disclosure to the school is only necessary if there are significant learning or behavior problems that require special education classification, such as an IEP or Section 504 accommodation. Schools will often be unaware of the condition, and staff will need to be educated about XXY, usually by the parent. Bring a selection of website printouts explaining the condition and its impact on learning. Some parents have found that special education services are more likely to be appropriate when the pediatrician provides a diagnosis under the classification of “other health impaired” such as Pervasive Developmental Disorder-NOS (PDD), rather than 47,XXY. Schools understand autistic-like behavioral and language difficulties when they occur in high-functioning children and many schools have programs in place to address these problems. In addition, these programs are mandated in many states for children with autism spectrum disorders of which PDD is one. The schools may not realize that XXY children often have the same deficits and are also eligible for these services.

To access these accommodations, parents are well advised to learn the glossary of key terminology that “pushes all the right buttons” that qualify the student for these supports. It also may be helpful to recruit local disabilities advocates such as the ARC to assist with the qualification process.

Individuals with 47,XXY fall in love just as other human beings do, and the condition, as any other medical condition, should be discussed at the appropriate time, without obligation to divulge all early in a relationship. If and as a relationship becomes “serious,” disclosure that is accompanied by a thorough education about the condition should take place. Support groups and list-serves can introduce couples to others who have been through building a relationship and a family; this is an occasion on which support from others in the same situation can be very helpful.