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XYY Syndrome

Double Y

XYY syndrome is a genetic condition where an extra copy of a Y chromosome is present in each of the cell of human male, resulting in 47 chromosomes instead of 46.


Presentation

Tall stature, macrocephaly, macroorchidism, hypotonia, hypertelorism, and tremor are the common features of the XYY phenotype. There is no gross difference of physical phenotypic features whether the syndrome is diagnosed prenatally or postnatally. However, prenatal diagnosis of this syndrome is associated with the development of higher cognitive function.

Features of XYY syndrome include:

  • Taller stature
  • Comparatively low body weight relative to stature
  • Larger craniofacial dimensions
  • Development of severe acne in adolescence
  • Behavioral problems
  • Learning disabilities
  • Slightly lower IQ than their normal counterpart
  • There have been reports that suggest that there is increased tooth-size in 47, XYY males and it is due to a direct genetic effect. The boys present with multiple over-retained deciduous, unerupted permanent teeth and increased incidence of carious lesions which can also be attributed to decreased oral hygiene.
Asymptomatic
  • It is often asymptomatic and identified incidentally following genetic analysis for other conditions. The syndrome can be associated with an increased risk of learning difficulties and delayed language skills.[ncbi.nlm.nih.gov]
Liver Dysfunction
  • High-dose quetiapine, along with possible baseline liver dysfunction secondary to XYY syndrome, may have contributed to the development of NMS in this patient, which resolved after the discontinuation of quetiapine.[ncbi.nlm.nih.gov]
Macrocephaly
  • Rare diseases Search Search for a rare disease 47,XYY syndrome Disease definition 47, XYY syndrome is a sex chromosome aneuploidy where males receive an additional Y chromosome, and is characterized clinically by tall stature evident from childhood, macrocephaly[orpha.net]
  • Macrocephaly along with few other typical facial features (mild hypertelorism, low set ears and a mildly flat malar region), delay in speech development are common to this disorder.[symptoma.com]
  • Physical features related to 47,XYY syndrome can include increased belly fat, a large head ( macrocephaly ), unusually large teeth ( macrodontia ), flat feet ( pes planus ), fifth fingers that curve inward ( clinodactyly ), widely spaced eyes ( ocular[ghr.nlm.nih.gov]
Large Hand
  • Several other physical characteristics, including large hands and feet, have been associated (although not definitively) with XYY syndrome.[symptoms101.com]
Low Set Ears
  • set ears, a mildly flat malar region), speech delay and an increased risk for social and emotional difficulties, attention deficit hyperactive disorder and autistic spectrum disorder.[orpha.net]
  • For others, signs and symptoms may include learning disabilities, speech delay, low muscle tone ( hypotonia ), and being taller than expected. 0000750 Low-set ears Low set ears Lowset ears The Y chromosome is one of the sex chromosomes, and the other[rarediseases.info.nih.gov]
  • Macrocephaly along with few other typical facial features (mild hypertelorism, low set ears and a mildly flat malar region), delay in speech development are common to this disorder.[symptoma.com]
Aggressive Behavior
  • We want to present the case of young man with 47 XYY karyotype who was admitted into our ward due to aggressive behaviors endangering self and others.[priory.com]
  • XYY in a ten year old child with aggressive behavior. Annales de Génétique , 1969, 12 , 202–203. Google Scholar Zeuthen, E., Hansen, M., Christensen, A.-L., & Nielsen, J. XYY males found in a general male population.[link.springer.com]
  • I of course googled it and saw some things about aggressive behavior but was told that those studies were very old and rebunked more recently and that i should ignore those studies.[community.babycenter.com]
  • Role of multidisciplinary counseling for parental guidance and prevention of aggressive behavior. Ital J Pediatr. 2012 Oct 3;38:52. doi: 10.1186/1824-7288-38-52. Robinson DO, Jacobs PA.[ghr.nlm.nih.gov]
  • The effects of MPA in the treatment of 11 temporal lobe epileptics and 5 other patients with severe angry-aggressive behavior disorder are reported. Most temporal lobe epileptics responded well to MPA.[doi.org]
Withdrawn
  • On the Child Behavior Checklist, mean problem behaviors t scores were higher in the XYY versus KS groups for the Problem Behavior, Externalizing, Withdrawn, Thought Problems, and Attention Problems subscales.[ncbi.nlm.nih.gov]
Somnolence
  • He had been experiencing episodes of severe confusion, somnolence, and extreme agitation. He was also ataxic and unbalanced on his feet.[ncbi.nlm.nih.gov]

Workup

Two tests may be used to diagnose XYY Syndrome:

  • Hormonal assay. A lowered testosterone level in an adult male sometimes points towards the possibility of any chromosomal aberration. An estimation of sex Hormone-Binding Globulin (SHBG) can reflect the testosterone level in a male. A serum total testosterone assay may sometimes be needed to assess the testosterone level. By analyzing the blood or urine samples for testosterone assay, if it has been found low, a presumption of chromosomal anomalies can be aroused. A low testosterone level warrants other specific additional tests to determine the underlying basic pathology.
  • Chromosomal analysis. A chromosomal analysis can readily clinch the diagnosis of this disease if morphological features and symptoms in a male are suggestive of 47, XYY syndrome.

Several brain malformations in the form of posterior fossa anomalies, such as cerebellar dysplasia or hypoplasia, cerebellar cysts, vermis dysgenesis or hypoplasia, mega cistern magna were previously thought to be associated with sex chromosome anomalies. It was suggested that presence of an extra copy of sex chromosome may affect prenatal brain development. XYY syndrome, with an extra copy of the Y chromosome, thus may have a chance to develop those anomalies. Brain radiological imaging of males with XYY syndrome could be utilized to determine whether the existence of such brain abnormalities is an incidental or part of the spectrum of XYY syndrome. A deeper understanding is needed through further research for correlating the effect of an extra chromosome with the pathophysiology of the development of behavioral and physical disorders in affected individuals.

Treatment

Treatment options are mainly supportive as it is not possible to alter the basic pathology of 47, XYY syndrome:

Medications

  • Testosterone replacement therapy. Testosterone therapy in adolescent 47, XYY boys can help to achieve normal puberty as they have deficient blood-testosterone level. Older persons also can be benefited by achieving their sexual drive and improving their muscle mass and bony strength by testosterone replacement therapy. Testosterone is administered in the form of an injection or occasionally as a rub-on gel. 
  • Fertility treatment. Men with XYY Syndrome may have fertility problem as they suffer from various forms of semen-disorders ranging from low sperm count to abnormal sperm with chromosomal anomaly. Thus, they face a difficulty to father a child. Testosterone replacement therapy does not help as it further reduces the existing sperm count. Fertility specialists can advice regarding assisted reproductive technique in the form of intracytoplasmic sperm injections (ICSI). ICSI is a procedure where the sperms are retrieved directly from the testicles, checked for its fertility potential, and then injected directly into an ovum. Following fertilization, it is placed inside the fallopian tube for further maturation.

Surgical option

Low testosterone level often result in men with 47 XXY syndrome having gynecomastia. They may need plastic surgery to remove the excess tissue.

Alternative therapies

  1. Speech therapy. Young boys with 47 XYY may need speech therapy as they are prone to develop speech disorders as well as motor skill disabilities. A professional approach is needed to counsel and support them at an earliest age. 
  2. Physical or occupational therapy. Physiotherapy and occupational therapy is needed for boys who are suffering from delayed motor skill development and weak muscle strength.
  3. Educational therapy. Learning disabilities are common in children with XYY Syndrome. A composite workout comprising of the involvement of teacher, principal and educational coordinators is needed to work out the best schedule that is best suited for the child's need. Apart from this, outside help from other tutors or educational instructions are often needed.

XYY syndrome is occasionally diagnosed in boys of 11 and 12 years of age, referred actually for attention deficit hyperactivity disorder (ADHD). Abnormally high stature (patients were above 97.5% height for age), typical muscle consistency and persistence of tremor among the boys points towards a need for chromosomal analysis. A team consisting of a neuropsychologist, a physiotherapist along with a physician is needed to monitor and treat them. Psychological tests results also did not suitably fully fit with the ADHD diagnosis. It was felt following evaluating the boys that stimulant medication might benefit them. Administration of methylphenidate led to improved motor and cognitive functions as well as social adaptation of these boys. Treatment with methylphenidate thus might be considered in 47, XYY syndrome patients with similar clinical presentation.

Prognosis

Men with XYY syndrome or Klinefelter syndrome have been found to have an increased overall risk of conviction (excluding traffic offenses). However, when compared after adjusting for socioeconomic parameters, this rise appeared statistically insignificant. The conviction rate of 47, XYY males for sexual abuse, burglary, arson, and 'others' were found significantly increased. An association between the poor socioeconomic condition and the chromosomal aberrations can explain partly or fully the increased risk of convictions of 47, XYY males.

The mortality rate of these affected males is also found significantly higher if compared to the age and gender-matched controls from the background population. Furthermore, the causes of death are scattered uniformly throughout the all informative chapters according to the ICD-10. The identifiable causes of death of 47, XYY individuals are in a significantly higher proportion due to cancer, neurological disorders, pulmonary diseases, and trauma are due to some unspecified diseases. It is felt that there are many undiscovered facts about this syndrome that need to be explored. Further scientific researches are needed to explore the facts behind the clinical problems inherent with this disease which are responsible for higher incidences of mortality.

Etiology

Each cell of a normal person possesses 46 chromosomes. Two chromosomes among of them, termed as X and Y, and are designated as sex chromosomes as they possess the capacity to determine whether a person will ultimately develop a male or female phenotypic characteristics. A normal female thus typically has one pair of X chromosomes (46, XX) and a normal male has one X and one Y as sex chromosome (46, XY).

XYY syndrome occurs due to the addition of an extra copy of the Y chromosome to that of a male's normal chromosomal pattern. With this addition, each cell now contains total 47 chromosomes instead of 46. This rearrangement of chromosomal number relates to the development of few abnormal phenotypically and behavioral characteristics like tall stature, macrocephaly, or learning disabilities. But it is unclear how the presence of an extra Y chromosome is linked with the development of these above-mentioned characteristics.

Inheritance is least likely related as a cause to the majority of 47, XYY syndrome. Actually this is a development defect of the sperm cells during their formation. There are random chromosomal changes while formation and maturation of sperm cells which could result in any form of aberration. This may lead to an accidental production of sperm cells with an extra copy of Y chromosome. This error in cell division called nondisjunction. If any of these atypical sperms with an extra Y chromosome fertilizes the ovum and thus subsequently contributes to the genetic makeup of a child; the boy will carry an extra Y chromosome in his body’s entire cell and thus develop XYY syndrome.

Epidemiology

Following the incidence of Klinefelter syndrome, XYY sex chromosome aberration appears to be the second most common sex chromosome anomaly [1] [2] [3]. Its incidence appears to be approximately 1 out of 1000 live male births [4] [5]. These boys have an increased puberty growth spurt and usually appear taller than the other normal boys with the same matched genetic growth potential. On an average, usually they have been found to have a 10- to 15-point IQ reduction compared to the other family members. Boys with this genetic makeup are usually prone to develop few physical disabilities along with minor behavioral disorders. Hyperactivity, attention-deficit disorder, and learning disorders are more commonly found in them in contrast to the general population.

An average prevalence of 14.1 per 100,000 of 47, XYY persons have been identified by a first nationwide study conducted to find its prevalence. However, this incidence appeared much lower than the expected incidence of 98 per 100 000 population. The average age of diagnosis of this syndrome is relatively late with a median of 17.1 years.

Sex distribution
Age distribution

Pathophysiology

A 47, XYY karyotype is produced as a result of parental non-disjunction at the step of meiosis II and subsequent addition of an extra Y chromosome in the affected offspring [6] [7] [8]. In another way, 46, XY/47, XYY mosaics from parental nondisjunction during cell division after postzygotic mitosis can also result an addition of an extra Y chromosome in early embryonic development [6].

Studies have shown an increased association between 47, XYY and sub-fertility. Men with XYY syndrome can have variable sperm counts, ranging from normal to azoospermia [3] [4] [5] [6] [7] [8] [14] [15] [16] [17]. Routine examination of the semen of men with XXY syndrome show increased incidences of spermatozoa with chromosomally anomaly [3] [8] [9] [10] [11] [12] [13] [14] [15]. Due to the greater prevalence of hyperhaploid sperm in their semen; there is also an increased risk of passing this extra Y chromosome to the offspring of 47, XYY male [14].

Prevention

Considering the frequency of 47, XYY karyotype in the general population (one out of 1,000 newborn males), it is not often detected unless there is detection by prenatal testing. The clinicians must remain alert about the existence of this pathology and search for the new opportunities to find out appropriate educational interventions that target the specific learning challenges of XYY boys. Obviously, an early diagnosis carries a better prognosis of XYY and this message has to be forwarded to those involved in prenatal counseling and pediatric surveillance.

Summary

XYY syndrome, also referred to as 47, XYY syndrome, is a type of aneuploidy of the sex chromosome in males where they possess an additional Y chromosome. People with 47, XYY are clinically characterized by an increased growth velocity from childhood and a final tall stature. Macrocephaly along with few other typical facial features (mild hypertelorism, low set ears and a mildly flat malar region), delay in speech development are common to this disorder. They carry an increased risk for development of abnormal social and emotional bonding. In contrast to the general population, they are also found to have higher incidences of attention deficit hyperactive disorder and autistic spectrum disorder.

In XYY syndrome, the individual is phenotypically male, as instead of one, there is presence of 2 Y chromosomes, along with one X.

Patient Information

XYY syndrome is a disorder where a male is born with an extra Y chromosome. Frequency of this syndrome in the general population is about 1 in every 1,000 boys. Boys with this typical genotype tend to be taller and experiences difficulties in learning. They have a low intelligence quotient (IQ) when compared with the other family members. Learning disabilities, hyperactivity, attention deficit disorder, and minor behavioral disorders are more common among these boys. There was a previous speculation that XYY syndrome was related to aggressive or violent criminal behavior. But till today, no such proven data could be derived from the available scientific researches.

References

Article

  1. Gekas J, Thepot F, Turleau C, et al. Chromosomal factors of infertility in candidate couples for ICSI: an equal risk of constitutional aberrations in women and men. Hum Reprod. 2001;16:82–90.
  2. Hook EB, Hamerton JL. The frequency of chromosome abnormalities detected in consecutive newborn studies-differences between studies-results by sex and by severity of phenotypic involvement. In: Hook EB, Porter IH, editors. Population Cytogenetics. New York: Academic Press; 1977. pp. 63–79.
  3. Rives N, Milazzo JP, North MO, et al. From spermatocytes to spermatozoa in an infertile XYY male. Int J Androl. 2005;28:304–310.
  4. Jacobs PA, Melville M, Ratcliffe S, et al. A cytogenetic survey of 11,680 newborn infants. Ann Hum Genet. 1974;37:359–376.
  5. Morel F, Roux C, Bresson JL. Sex chromosome aneuploidies in sperm of 47,XYY men. Arch Androl. 1999;43:27–36.
  6. El-Dahtory F, Elsheikha HM. Male infertility related to an aberrant karyotype, 47,XYY: four case reports.Cases J. 2009;2:28.
  7. Wong EC, Ferguson KA, Chow V, Ma S. Sperm aneuploidy and meiotic sex chromosome configurations in an infertile XYY male. Hum Reprod. 2008;23:374–378.
  8. Moretti E, Anichini C, Sartini B, Collodel G. Sperm ultrastructure and meiotic segregation in an infertile 47,XYY man. Andrologia. 2007;39:229–234.
  9. Stochholm K, Juul S, Gravholt CH. Diagnosis and mortality in 47,XYY persons: a registry study. Orphanet. 2010;5:15.
  10. Children and young adults with sex chromosome aneuploidy- follow-up, clinical and molecular studies. Minaki, Ontario, Canada, June 7–10, 1989. Birth Defects Orig Artic Ser. 1990;26:1–304.
  11. Blanco J, Rubio C, Simon C, et al. Increased incidence of disomic sperm nuclei in a 47,XYY male assessed by fluorescent in situ hybridization (FISH) Hum Genet. 1997;99:413–416.
  12. Chevret E, Rousseaux S, Monteil M, et al. Meiotic behaviour of sex chromosomes investigated by threecolour FISH on 35,142 sperm nuclei from two 47,XYY males. Hum Genet. 1997;99:407–412.
  13. Gonzalez-Merino E, Hans C, Abranowicz M, et al. Aneuploidy study in sperm and preimplantation embryos from nonmosaic 47,XYY men. Fertil Steril. 2007;88:600–606. 
  14. Lim AS, Fong Y, Yu SL. Analysis of the sex chromosome constitution of sperm in men with a 47,XYY mosaic karyotype by fluorescence in situ hybridization. Fertil Steril. 1999;72:121–123.
  15. Speed RM, Faed MJ, Batstone PJ, et al. Persistence of two Y chromosomes through meiotic prophase and metaphase I in an XYY man. Hum Genet. 1991;87:416–420. 
  16. Faed M, Robertson J, MacIntosh WG, Grieve J. Spermatogenesis in an infertile XYY man. Hum Genet.1976;33:341–347.
  17. Egozcue S, Blanco J, Vendrell JM, et al. Human male infertility: chromosome anomalies, meiotic disorders, abnormal spermatozoa and recurrent abortion. Hum. 2000;6:93–105.

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Last updated: 2019-07-11 22:19