How We Fail Children With Developmental Language Disorder

Developmental language disorder (DLD) is a neurodevelopmental condition that emerges in early childhood and frequently persists into adulthood. People with DLD have significant difficulty learning, understanding, and using spoken language. Under U.S. Public Law 101-476 (Individuals with Disabilities Education Act [IDEA], 2004; first issued in 1990 and reissued in 2004), children may be eligible for school-based services, typically under the category “speech-language impairment,” if their DLD affects educational performance and requires specially designed support. DLD is one of the most common neurodevelopmental disorders. With an estimated prevalence of 7.58% it is nearly 7 times more common than autism spectrum disorder (ASD; prevalence = 1.1%; and 46 times more common than permanent childhood hearing impairment (prevalence = 0.165%; ).

As a population, people with DLD face significant risks. Compared to other students, those with DLD are 6 times more likely to have reading disabilities, 6 times more likely to have significant spelling problems, 4 times more likely to struggle with math, and 12 times more likely to face all three of these difficulties combined . People who have DLD are 6 times more likely than others to experience clinical levels of anxiety and 3 times more likely to have clinical depression. Girls with DLD are 3 times more likely to experience sexual abuse. Boys with DLD are 4 times more likely to engage in delinquent behaviour. Adults with DLD are twice more likely to go over a year without employment than other adults.

Without a doubt, DLD is a common condition that limits the health, happiness, and success of many who live with it. Nevertheless, people with DLD are underserved, and the condition itself is under-researched. The reasons are complicated, but the consequences of continued failure are dire. This clinical focus article is a call to action. It will provide evidence to demonstrate the ways that we are failing children with DLD; explore the reasons for these failures; and encourage change. The institutions and policies that dictate, support, or constrain clinical services and research efforts vary widely from country to country. This review is admittedly United States–centric, with some attention paid to the United Kingdom as well, but it is our hope that some of the points raised here are universally relevant.

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Recognition of Genital Differences Among Some 47XXY Infants

Klinefelter syndrome (KS) is a sex chromosome variation caused by the presence of one or more supernumerary X chromosomes. Common clinical phenotypes of KS are comprised of tall stature with a feminine body type, gynecomastia, small testes and infertility. Cases of KS with genital differences as the main evaluation in childhood are rarely disclosed. We report four children presented to our clinic for assessment of ambiguous genitalia who were ultimately diagnosed with KS. The first patient was a 4 months male baby who presented with phenoscrotal hypospadias, bifid scrotal and small testes.

Endocrine studies suggested a normal hypothalamic-pituitary-gonadal axis. The second patient was a 3 weeks baby born with the concern for ambiguous genitalia. He was evaluated at birth for bifid scrotum, small testes and glanular hypospadias. The third and fourth patients were three and seven years old boys with severe hypospadias, bifid scrotal and small testes. Hormonal analysis showed a low level of testosterone with normal level of FSH and LH. The chromosome analysis was 47, XXY for all of the patients confirming the diagnosis of KS. Individuals with KS have a highly varied phenotype comprising a range of physical features, however, genital differences are rarely reported as characteristics feature of the syndrome in childhood. Clinicians need to be aware of the phenotypic variability of KS and recognize KS as one of the causes of abnormal genitalia at birth. This finding, along with appropriate genetic counselling, suggest that early detection of KS is important in monitoring potential development problems; such as hypogonadism, gynecomastia and gender dysphoria in the future.


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Exogenous Testosterone is not a requirement of 47XXY’s at Mini and Pre‑Puberty

The hypothalamus–pituitary–gonadal axis (HPG) during mini-puberty in boys with KS has been evaluated by several investigative groups and “all” possible results recorded: above normal, below normal or indistinguishable from normal (Aksglaede, Petersen, Main, Skakkebæk, & Juul, 2007; Lahlou, Fennoy, Ross, Bouvatier, & Roger, 2011; Ross et al., 2005). None of these studies has enough boys evaluated at various times over the course of mini-puberty and very few studied longitudinally. That has led to variable prescription of T for infant boys with KS. Davis et al. have noted that T secretion during mini-puberty leads to sexually dimorphic changes in linear growth, genital growth, and anabolic changes in body composition. Her group has further studied those with KS by administering 3 monthly doses of T, 25 mg each. The results compared to boys with KS who did not receive T indicate lesser increase in fat mass and greater increase in fat free mass and linear growth (Davis, Reynolds, Dabelea, Zeitler, & Tartaglia, 2019). One cannot determine from these data whether one is replacing subnormal amounts of T or using T as a pharmacological agent

Rogol, A. D. (2020). Human sex chromosome aneuploidies: The hypothalamic–pituitary–gonadal axis. American Journal of Medical Genetics Part C: Seminars in Medical Genetics

Klinefelter syndrome (XXY), first described by Harry Klinefelter in 1942, is the most common sex-chromosomal variation, with a prevalence of 1:660 in the general population. It is caused by the presence of an extra X chromosome (80% karyotype 47, XXY; 20% 46, XY/47, XXY mosaicism or structural X chromosome variations). It is also one of the most frequent causes of infertility, affecting 11% of azoospermic and 3.1% of all infertile males

The prevalence of diagnosed XXY has risen in recent decades, but its true prevalence is still thought to be underestimated, probably due to the extreme variability of its clinical presentation and a lack of awareness among general practitioners. Abramsky and Chapple showed that up to 64% of KS patients are never diagnosed, with 10% diagnosed prenatally and only 26% in prepuberty or adulthood.

47, XXY males may present with a variety of subtle, age related clinical signs. Hypospadias, small phallus, cryptorchidism, developmental delay, behavioral problems, incomplete pubertal development with eunuchoid body habitus, gynecomastia, and small testes are its most frequent features in infancy and childhood. Adults are often evaluated for infertility and sexual disorders, but metabolic syndrome, osteoporosis, thyroid dysfunctions, humoral immunoreactivity and the presence of specific personality traits and personality disorders are also described. As regards fertility aspects, it has been recently stated that Y chromosome micro-deletions do not represent a further negative genetic factor in KS.

The function of the hypothalamus–pituitary–gonadal (HPG) axis in KS subjects has already been investigated, especially in relation to mini-puberty and puberty. Mini-puberty has been investigated extensively, as it is an important temporal window lasting from the first to about the sixth-to-ninth month of life, in which the first significant HPG axis activation takes place. There is literature evidence of prenatal tubular damage, but these results were not confirmed in childhood biopsies of boys with non-mosaic KS. In 2011, Aksglaede reported that testicular damage begins at the age of 4–9 years with a gradual degeneration of germ cells and reaches its peak from mid-puberty to adulthood, by which time the testes have undergone extensive seminiferous tubule hyalinization and Leydig and Sertoli cell hyperplasia. Literature studies agree that mini-puberty in KS boys is similar to that in healthy boys. However, there is no consensus on the hormonal and clinical profile of young KS patients, nor on when testicular damage occurs.

The aim of this study was therefore to accurately establish the testicular function and the main auxological features over a longer time period, from mini-puberty to the onset of puberty, in order to find any auxological and/or hormonal changes that might be used as an early indicator of KS. This broader clinical and hormonal follow-up might also clarify the specific timing of the onset of puberty, given that while most KS patients present a normal puberty, in some it is delayed and in even more it is precocious

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Fertility Rates Among Non-Mosaic XXY; At Odds With Real Life Experience

Klinefelter syndrome (KS) is the one of the most frequent chromosomal disorder affecting 1/500–600 male newborns in the general population. The vast majority of the cases shows the 47,XXY karyotype, although mosaicism (46,XY/47,XXY) or higher-grade X aneuploidies can be rarely detected. Despite its high incidence, KS frequently remains undiagnosed and it is suspected later in adulthood after a diagnostic workup for hypogonadism, couple’s infertility, and/or sexual dysfunction.

Approximately 90% of adult men with homogeneous KS suffer from non-obstructive azoospermia (NOA), while fertility in mosaic KS seems to be less severely affected. Fathering is an important aspect for Klinefelter patients. Maiburg et al. performed a survey on 260 adults with KS and showed that most couples would like to have children and show a positive attitude toward assisted-reproductive techniques (ART). Infertility has been considered an untreatable disease in Klinefelter patients for many years. However, testicular sperm extraction (TESE), associated with ART, were found to be a valuable option for azoospermic men with KS to father a child, due to the presence of residual foci with preserved spermatogenesis

A recent systematic review and meta-analysis evaluated the outcomes of sperm retrieval by conventional TESE (cTESE) and by micro-surgical TESE (mTESE)in 1248 individuals with KS (Corona et al., 2017). Authors reported an average sperm retrieval rate (SRR) of 44% (43% and 45% after cTESE and mTESE, respectively), which is similar to that reported for men without KS. However, these meta-analytic data do not necessarily reflect the rates of SR that physician observe in clinical practice, which is typically lower than 50%. Moreover, results of meta-analysis should be interpreted according to the limitation of the study itself (inclusion of small, single centre studies, effect of un-adjusted confounders).

These meta-analytic data do not necessarily reflect the rates of SR that physician observe in clinical practice, which is typically lower than 50%. Moreover, results of meta-analysis should be interpreted according to the limitation of the study itself (inclusion of small, single centre studies, effect of un-adjusted confounders).

These observations prompted us to conduct a multicenter collaborative study to investigate the rate of and potential predictors of sperm retrieval by TESE in a cohort of azoospermic patients with KS presenting for primary couple’s infertility in the real-life setting.

With the recent improvements of TESE and ICSI procedures infertility has been no longer considered an untreatable disease in Klinefelter patients. In this context, most studies investigating TESE outcomes in patients with KS depicted conflicting results, in spite of having been generally rated of limited quality. A recent review showed that SRR in Klinefelter patients was approximately 50% world wide, thus similar to that of men without genetic abnormalities. However, these results appear to be unrealistic and even far from what physicians typically observe in the clinical practice.

The aim of this cross-sectional, real-life study was to investigate the prevalence of and possible factors associated with a positive SR in a cohort of white-European azoospermic patients with KS undergoing TESE at seven academic Andrology centres.

  • Department of Urology, Foundation IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
  • Division of Experimental Oncology/Unit of Urology; URI; IRCCS Ospedale San Raffaele, Milan, Italy
  • Division of Urology; A.O.U. Città della Salute e della Scienza di Torino – Presidio Molinette; Turin, Italy
  • Andrology Unit, University Hospital S. Orsola, Bologna, Italy
  • Fundació Puigvert, Department of Andrology, Universitat Autonoma de Barcelona, Barcelona, Spain
  • Department of Urology and Andrology, Ospedale di Circolo e Fondazione Macchi, Varese, Italy
  • Department of Urology, AO Papa Giovanni XXIII, Bergamo, Italy

Of clinical relevance, we found that only one out of five KS men had positive SR in the real-life setting. Moreover, we failed to find any clinical, hormonal or procedural factors associated with SRR. These findings confirmed previous studies, where in contrast meta analytic data reported a significant higher SRR.

So far, there is a lack of reliable clinical and biological predictors for sperm retrieval success in NOA patients with KS. Advanced paternal age has been considered a negative predictive factor for SR in Klinefelter men undergoing TESE. Ozer et al, showed that TESE had better outcome before the critical age of 30.5 years, while other Authors suggested that TESE should be performed before 35 years. Recent evidence, however, support the lack of association between age and SR outcome. It has been shown that performing TESE between 15 and 23 years did not increase the SR rate compared to adult KS patients (25–29 years). We also confirm that SRR was not influenced by patient’s age in a real-life study with a large cohort of Klinefelter men.

According to this view it has been postulated that the progressive hyalinization and fibrosis of seminiferous tubules that is accelerated with the onset of puberty in KS is not ubiquitous and it is possible to observe tubules with normal residual activity. The impaired spermatogenesis could also be caused by an intrinsic problem of the germ cells, possibly linked to (epi)- genetics of the X surplus chromosome.

Testicular volume has been considered a possible factor associated with TESE success in Klinefelter patients, for example, showed that testicular volume was significantly higher in men with positive SRR. However, there are several studies reporting that testicular atrophy does not affect the success of SR (Corona et al., 2017; Franik et al., 2016; Garolla et al., 2018; Majzoub et al., 2016; Ozer et al., 2018; Vicdan et al., 2016). Garolla et al. (Garolla et al., 2018), indeed, observed a 23% SRR even in KS patients with testicles <1 mL. Our results support these findings since we failed to find any relationship between testicular volume and SRR in NOA patients with KS.

The clinical strength of our study is several-fold. First, we showed a low rate of positive sperm retrieval (up to 21%) in azoospermic men with KS in the real-life setting, thus suggesting that the crude data coming from meta-analytic studies cannot be routinely used in the everyday clinical practice.

There are conflicting results showing the association between serum hormones levels and TESE outcome in Klinefelter patients. Higher serum testosterone levels were found in Klinefelter men with positive SR as compared to those with negative SR . Similarly, the combination of high testosterone levels and low levels of LH was considered as positive predictive marker for SR in in both adolescents and adults with KS. Conversely, recent meta analytic data showed that serum hormones levels did not influence SRR in Klinefelter patients. We also showed that testosterone, FSH and LH levels were not different according to TESE outcome in our cohort of Klinefelter patients; however, additional studies are needed to explore the predictive value of serum hormones levels in KS

Testosterone treatment in KS has been previously considered as a negative factor for sperm recovery. In our population TRT was not associated with worse SRR as compared to that of men who did not received any supplementation. Our findings are in line with previous studies that
did not show any impact of testosterone treatment on spermatogenesis in adolescents and adults Klinefelter men. Therefore, some authors did not recommend postponing androgen treatment in adolescent boys with KS for fear of impairing their TESE results .

Lastly, the superiority of mTESE as compared to cTESE in NOA men has been extensively investigated in the previous literature but with conflicting results. This is particularly true also in the Klinefelter population. Only few reports have shown that mTESE could be associated with better SRR than cTESE. Conversely, our results, in agreement with recent studies showed that TESE technique is not associated with SRR.

Further strength of present study is that we have comprehensively investigated a large homogenous group of patients with a detailed hormonal evaluation, and an accurate assessment of possible confounders for impaired semen parameters, such as recreational habits and health comorbidities. However, none of these parameters were found to be associated with SRR.

The clinical strength of our study is several-fold. First, we showed a low rate of positive sperm retrieval (up to 21%) in azoospermic men with KS in the real-life setting, thus suggesting that the crude data coming from meta-analytic studies cannot be routinely used in the everyday clinical practice. Second, we cross-sectionally showed that clinical, hormonal and procedural factors are unable to predict the SRR in patients with KS. In this context, we believe that Klinefelter patients should be carefully counselled regarding their chance of retrieving spermatozoa after TESE. Further strength of present study is that we have comprehensively investigated a large homogenous group of patients with a detailed hormonal evaluation, and an accurate assessment of possible confounders for impaired semen parameters, such as recreational habits and health comorbidities. However, none of these parameters were found to be associated with Sperm Retrieval Rates.

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What We Would Like Doctors To Know About XXY

If you are a Doctor

And consider yourself an expert in all things XXY, then you will never learn anything about us. Adult XXY’s often have adversarial relationships with physicians. If you have a patient like that, don’t take it personally, it’s probably because the medical community has treated us so badly for the last several decades. When we meet a doctor for the first time, we might be wary. We are assessing you as a potential doctor as you are assessing us as a potential patient.

Don’t assume that by having gone to Medical School you are more educated than those of us who are XXY. When you went to medical school research surrounding XXY was smaller than a paragraph and most all of it was negative.

I need my doctor to keep an open mind. Their main oath is to do no harm thus I expect them to be interested in new studies on XXY and to educate themselves about the latest research both in hard data and testimonials of XXY people. This means if I say testosterone is making me ill or ask for a trial on estrogen, then please explain to me why or why not without judgement and based on my medical tests. Please respect that I know my body better than you and I am in tune with how I feel.

Remember I am a human being first and not a condition, disease, anomaly, freak or abnormality of nature. I am so much more than my chromosomes and my physical body parts. Care for my body, keep it healthy but don’t try to manipulate it or change it with hormones or surgery to how you think it should be without asking me first.

Avoid assumptions. Just because I may also have a phallus, don’t assume that the best solution is to cut off my breasts. Maybe my breasts are an intricate part of maintaining my inner sense of well-being.

I need my doctor to show me how to give a self-breast exam for breast cancer and teach me how often I should do this.

Take the time to explain to me the effects of virilising that testosterone will have on my body and allow me to decide if I want to incorporate body and facial hair, male pattern baldness, and a hyper sex drive into my being. When you are considering any treatment or procedure, be sure to also tell me what will happen if I choose to do nothing.

Just because I choose to identify as male and take testosterone does not mean I am no longer XXY or that my actual gender identity is any less multifaceted than before. Testosterone does not change my genes. Allow me to talk about how I experience the XXY quality of my being in an open, non-judgemental place of safety.

Allow me to talk about how I experience the XXY quality of my being in an open, non-judgemental place of safety.

XXY’s identify in all genders, inclusive of Male, Female, Non-Binary, to everything in between and beyond. The most important care you can afford an XXY individual is one that’s appropriate for them.

Talk to me, not at me and not just about me with my parents. I can understand things if they are explained to me, and I can make decisions about my own body. Be honest with me. When examining me, first ask for my permission so I know that you recognise it is my body and my choice.

Don’t speak in absolutes or tell me how I am going to turn out

Always remember that my needs come before the needs of my parents, my doctors, or society. If you are unsure about my needs, proceed with caution, especially in areas that cannot be undone, such as with a mastectomy.

Ask to see me without my parents always being in the room.

Allow me or my family to disagree about a particular treatment you wish to try. Be willing to be a part of a respectful negotiation process about any disagreements of treatment.

Celebrate my successes with me. Ask me about my hopes, dreams, and plans.

Don’t try to fix me with hormones or surgical intervention before I am old enough to understand.

Don’t fix my gender without helping me to understand who I am.

Don’t try to fix me with hormones or surgical intervention before I am old enough to understand. Wait until I am old enough to make my own decisions about my body and my identity.

Things I look for in a doctor

  • Curiosity.
  • An ability to actively listen.
  • Provides cooperative healthcare as in co-relationship, not a doctor “doing” something to me, but a doctor working with me to help me achieve my optimum health.



New DNA ‘clock’ could help measure development in young children

Scientists have developed a molecular “clock” that could reshape how paediatricians measure and monitor childhood growth and potentially allow for an earlier diagnosis of life-altering development disorders.

The research, published this week in PNAS, (Full Study) describes how the addition of chemical tags to DNA over time can potentially be used to screen for developmental differences and health problems in children.

The study was led by researchers at BC Children’s Hospital, the University of British Columbia (UBC) and the University of California, Los Angeles. It is the first study to describe a method specifically designed for children, called the Paediatric-Buccal-Epigenetic (PedBE) clock, which measures chemical changes to determine the biological age of a child’s DNA.

Small chemical changes to DNA, known as epigenetic changes, alter how genes are expressed in certain tissues and cells. Some of these changes happen as a person ages and others may be in response to a person’s environment or life experiences.

Steve Horvath presents research on: Universal Epigenetic Aging Clock

In adults, these patterns of epigenetic changes are well established. They can be used to accurately predict a person’s age from a DNA sample or, if a person’s epigenetic age differs from their actual age, it can point differences in health, including age-related diseases and early mortality.

“We have a good idea how these DNA changes occur in adults, but until now we didn’t have a tool that was specific for children,” says Dr. Michael Kobor, senior author of study. “These DNA changes occur at very different rates in kids and so we adapted this technique for younger ages.”

“This powerful and easy-to-use tool could be used by clinicians to identify why some children aren’t meeting early milestones and potentially diagnose children with developmental disorders earlier in life, this would enable doctors and paediatricians to intervene sooner in a child’s life leading to better outcomes for kids.”

Dr. Lisa McEwen, first author on the study

Kobor is an investigator at BC Children’s Hospital and the Centre for Molecular Medicine and Therapeutics, a professor in the Department of Medical Genetics at the University of British Columbia, the Tier 1 Canada Research Chair in Social Epigenetics and the Sunny Hill BC Leadership Chair in Child Development.

The PedBE clock was developed using DNA methylation profiles from 1,032 healthy children whose ages ranged from a few weeks old to 20 years. The researchers found 94 different sites in the genome that, when tested together, could accurately predict a child’s age to within about four months. The team also found that children who spent longer in the womb showed an accelerated rate of DNA change by three months, demonstrating that this tool could be used to indicate an infant’s developmental stage. The analysis can be done cheaply and efficiently on cells collected from a cheek swab.

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Dyspraxia is more than just “clumsy child syndrome” – it can cause emotional distress and anxiety throughout life

This could be a typical XXY experience, albeit without an additional diagnosis. Of note, the article is well researched with an abundance of additional resources that we are sure you will find helpful.

DCD is a lifelong disorder that cannot be explained by a general medical condition; there is no definitive answer as to what causes it at present. However, it is known that DCD is not due to brain damage, like some learning difficulties.

Although children presenting with the symptoms of DCD have long been recognised, formal diagnosis has only become prevalent recently – compared to some other conditions such as dyslexia – as awareness of it grows. This may be partly because movement difficulties were not previously recognised in themselves as needing attention.

For a long time it was assumed that children would “grow out of” their movement difficulties. But we now have evidence that in many children the motor difficulties persist into adulthood and are commonly associated with a range of socio-emotional problems later on.

Adults with DCD still bump into objects and continue to struggle with handwriting. They may also have trouble with timekeeping and planning ahead, meaning they may be frequently late to work and social events. Self-care is also a problem, but rather than fastening clothes it turns into struggling to keep a home tidy. Tasks such as preparing a meal from scratch and ironing clothes can also be troublesome. DCD adults can also have issues with learning a new skill that requires speed and accuracy – so it can be difficult for them to learn to drive a car.

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Understanding Conversation – Children With an Extra X or Y Chromosome – Now Recruiting!

The Department of Experimental Psychology (EP) at the University of Oxford would like to invite your child to be part of this study investigating how we understand conversation. The project is looking at how children understand conversations. We know that vocabulary and grammar are important in understanding conversation, but social communication is likely to depend on more than just these two aspects. For example, people need to understand how context is important in understanding why someone is saying something – for instance, if you say ‘dinner is on the table’, you are not so much telling your family where dinner is, as inviting your family to come and eat! Currently, very little is known about how children develop the ability to understand meaning flexibly in conversation, and so we are exploring this.

Some children seem to have particular problems with social communication, as well as language more generally. This includes children with an extra X or Y chromosome. We hope the findings will be useful in understanding more about the problems experienced by children with communication difficulties. We are inviting 50 children with an extra X or Y chromosome to take part in this research. Any child with Klinefelter’s Syndrome (XXY), Triple X or XYY is eligible to take part. All children taking part will need to be aged between 7;0 and 14;11 years and speak English as a first language. The children will also need to have no severe hearing/sight problems and no history of neurological illness, brain injury or any genetic conditions besides the extra chromosome. Your child would need to be aware that they have an extra chromosome.

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Chromosome Variant Factsheet

At the XXY Project we are anti anything that depicts Chromosome Variations of any description as being abnormal because what they’re describing is not the natural variation these differences are but rather something that’s broken and something that needs to be fixed. Medical Science, Clinicians and the like are steadfastly stuck on the notion that anything which deviates from the binary sexes (XX Female & XY Male) is abnormal and so only speak in those terms when describing XXY which then lends itself to additional pathological terms such as Klinefelter’s Syndrome where expectant mothers, those who are aware of the fetuses sex are told the child will have a syndrome which in most instances (87%) would see the fetus aborted. As a community, we owe it to ourselves to change the language used when describing us, doing so would allow for greater overall awareness and the realisation of how being XXY and or Variant is really not as bad as what it is otherwise made out to be.

Chromosome variations can be numerical or structural. A numerical variant means an individual is either missing one of the chromosomes from a pair or has more than two chromosomes instead of a pair. A structural variant means the chromosome’s structure has been altered in one of several ways.

What Are Chromosomes?

Chromosomes are the structures that hold genes. Genes are the individual instructions that tell our bodies how to develop and function; they govern physical and medical characteristics, such as hair colour, blood type and susceptibility to disease.

Many chromosomes have two segments, called “arms,” separated by a pinched region known as the centromere. The shorter arm is called the “p” arm. The longer arm is called the “q” arm.

Where Are Chromosomes Found In The Body?

The body is made up of individual units called cells. Your body has many different kinds of cells, such as skin cells, liver cells and blood cells. In the centre of most cells is a structure called the nucleus. This is where chromosomes are located.

How Many Chromosomes Do Humans Have?

The typical number of chromosomes in a human cell is 46: 23 pairs, holding an estimated total of 20,000 to 25,000 genes. One set of 23 chromosomes is inherited from the biological mother (from the egg), and the other set is inherited from the biological father (from the sperm).

Of the 23 pairs of chromosomes, the first 22 pairs are called “autosomes.” The final pair is called the “sex chromosomes.” Sex chromosomes determine an individual’s sex: females have two X chromosomes (XX), and males have an X and a Y chromosome (XY). The mother and father each contribute one set of 22 autosomes and one sex chromosome.

How Do Scientists Study Chromosomes?

For a century, scientists studied chromosomes by looking at them under a microscope. In order for chromosomes to be seen this way, they need to be stained. Once stained, the chromosomes look like strings with light and dark “bands,” and their picture can be taken. A picture, or chromosome map, of all 46 chromosomes is called a karyotype. The karyotype can help identify variations in the structure or the number of chromosomes.

To help identify chromosomes, the pairs have been numbered from 1 to 22, with the 23rd pair labelled “X” and “Y.” In addition, the bands that appear after staining are numbered; the higher the number, the farther that area is from the centromere.

In the past decade, newer techniques have been developed that allow scientists and doctors to screen for chromosomal variations without using a microscope. These newer methods compare the patient’s DNA to a normal DNA sample. The comparison can be used to find chromosomal variations where the two samples differ.

One such method is called noninvasive prenatal testing. This is a test to screen a pregnancy to determine whether a baby has an increased chance of having specific chromosome differences. The test examines the baby’s DNA in the mother’s blood.

What Are Chromosome Variations?

There are many types of chromosome variations. However, they can be organised into two basic groups: numerical variations and structural variations.

  • Numerical Variations: When an individual is missing one of the chromosomes from a pair, the condition is called monosomy. When an individual has more than two chromosomes instead of a pair, the condition is called trisomy.

An example of a difference caused by numerical variations is Klinefelter’s Syndrome also known as 47XXY, where sex along with the severity of symptoms varies amongst individuals, typical symptoms include sterility, dysfunctional gonads, learning difficulties and poor muscle tone (hypotonia) in infancy.  An example of monosomy, in which an individual lacks a chromosome, is Turner syndrome. In Turner syndrome, a female is born with only one sex chromosome, an X, and is usually shorter than average and unable to have children, among other difficulties.

  • Structural Variations: A chromosome’s structure can be altered in several ways.
    • Deletions: A portion of the chromosome is missing or deleted.
    • Duplications: A portion of the chromosome is duplicated, resulting in extra genetic material.
    • Translocations: A portion of one chromosome is transferred to another chromosome. There are two main types of translocation. In a reciprocal translocation, segments from two different chromosomes have been exchanged. In a Robertsonian translocation, an entire chromosome has attached to another at the centromere.
    • Inversions: A portion of the chromosome has broken off, turned upside down, and reattached. As a result, the genetic material is inverted.
    • Rings: A portion of a chromosome has broken off and formed a circle or ring. This can happen with or without loss of genetic material.

Most chromosome variations occur as an accident in the egg or sperm. In these cases, the variation is present in every cell of the body. Some variations, however, happen after conception; then some cells have the variant and some do not.

Chromosome variations can be inherited from a parent (such as a translocation) or be “de novo” (new to the individual). This is why, when a child is found to have a variation, chromosome studies are often performed on the parents.

How Do Chromosome Variations Happen?

Chromosome variations usually occur when there is an error in cell division. There are two kinds of cell division, mitosis and meiosis.

  • Mitosis results in two cells that are duplicates of the original cell. One cell with 46 chromosomes divides and becomes two cells with 46 chromosomes each. This kind of cell division occurs throughout the body, except in the reproductive organs. This is the way most of the cells that make up our body are made and replaced.
  • Meiosis results in cells with half the number of chromosomes, 23, instead of the normal 46. This is the type of cell division that occurs in the reproductive organs, resulting in the eggs and sperm.

In both processes, the correct number of chromosomes is supposed to end up in the resulting cells. However, errors in cell division can result in cells with too few or too many copies of a chromosome. Errors can also occur when the chromosomes are being duplicated.

Other factors that can increase the risk of chromosome variations are:

  • Maternal Age: Women are born with all the eggs they will ever have. Some researchers believe that errors can crop up in the eggs’ genetic material as they age. Older women are at higher risk of giving birth to babies with chromosome variations than younger women. Because men produce new sperm throughout their lives, paternal age does not increase the risk of chromosome variations.
  • Environment: Although there is no conclusive evidence that specific environmental factors cause chromosome variations, it is still possible that the environment may play a role in the occurrence of genetic errors.

Source: National Human Genome Research Insitute 


Interview: David Cooke on 47XXY

Had he been practising some forty years ago, pediatric endocrinologist David Cooke’s profile of patients who are 47XXY would have differed sharply from today’s view. Then, late-adolescent boys would have comprised most of Cooke’s patients. Now, with amniocentesis and prenatal karyotyping more routine, however, Cooke, as the pediatric endocrinologist with the Johns Hopkins Klinefelter Syndrome Center, also sees far younger boys—babies, even—whose extra X chromosome signals the variation.

“Before puberty, there’s little that cries out, oh, this is a child with Klinefelter syndrome,” Cooke says. Nothing commonly sets the boys apart. If slightly weaker muscles or cognitive or social delays surface, he adds, they tend toward the low-end-of-normal. In mid-puberty the syndrome’s phenotype gains strength—luteinizing and follicle stimulating hormones rise above normal; plasma testosterone drops. Still, few early-teen boys know they have Klinefelter. The characteristic mildly enlarged breasts, sparse chest hair or tallness can seem unremarkable. Mid-puberty, however, opens a brief and perhaps critical window of opportunity to address adult problems that can follow. What prompts the “perhaps” is research’s lag in nailing down best practices, says Cooke.

Here he comments on current issues in treating and studying Klinefelter syndrome:

Androgen replacement therapy (ART) typically starts when a peri-pubertal XXY boy shows low testosterone, yes? That seems clear-cut.

Not quite. First, you need to know: Is testosterone truly low or is a patient just not yet in puberty? Clearly, puberty’s a moving target: Some start around age 10 with a testosterone level at 100 ng/dl that reaches 500 ng/dl by age 13. Others hover at a level near zero until into their teens. A physical exam helps decide, but it’s more clear if you follow the LH level. If LH exceeds the normal level seen in an adult male, then you know the body expects more testosterone than it’s getting.

And the benefits of ART?

In XXY adults, the benefits of testosterone therapy overwhelmingly relate to sexual health—normal libido, erections. Therapy also increases energy, muscle mass and strength. That’s true as well in XXY adolescent boys. But it can be hard to know what effects to expect in treating them.

Do you mean there are no data to show ART can bring these things about? Or is it that some of these benefits occur, but it’s difficult to predict which ones for a particular patient?

Both. I am not aware of any controlled trials that have studied testosterone treatment in boys with Kleinfelter. We know the effects of testosterone, for example, in boys or men who make no hormone if their testes completely fail from another cause. But adolescents with Kleinfelter make some testosterone. We can’t predict the effect of increasing levels from slightly low to mid-normal for a given patient. In general, no one knows the best approach for sure in testosterone therapy—when, optimally, to begin it, how long to treat, what dosage is best or if better options exist.

Some clinicians talk about low-dose testosterone before puberty.

Without evidence, I don’t know what to make of that.

Until research comes through, what do you offer to boys with Klinefelter during puberty?

Two things. Once LH levels rise above normal, ART should be considered. For some boys, this will be needed for lagging sexual characteristics. For other boys, we discuss what might be expected with ART and decide whether such treatment is appropriate. The other issue we address is fertility preservation. The approach to infertility in individuals with Klinefelter now includes consideration of harvesting sperm for storage at the earliest signs of testicular failure, and before starting testosterone treatment. This approach is felt to lead to greater success.

What is the most appropriate clinical setting for patients with Klinefelter Syndrome?

Because patients with KF vary widely in symptoms and biology, not surprisingly a multidisciplinary clinic offers the best diagnostics and therapeutics for these patients. Here at the Johns Hopkins Klinefelter Syndrome Center, we see both adult men and children with this not-uncommon chromosome anomaly—the only such dual centre in this country. Our staff include experts in pediatric and adult internal medicine and endocrinology, urologists who address infertility, a neuropsychologist skilled in treating cognitive or mood problems, speech therapists, genetic counsellors, and surgeons who specialize in male breast reduction. You really do need this type of centre to provide best practices care for these patients.