XXXXY syndrome, also known as 49,XXXXY syndrome or Fraccaro syndrome, is an extremely rare aneuploidicsex chromosomal abnormality. It occurs in approximately 1 out of 85,000 to 100,000 males. This syndrome is the result of maternal
non-disjunction
Nondisjunction is the failure of homologous chromosomes or sister chromatids to separate properly during cell division (mitosis/meiosis). There are three forms of nondisjunction: failure of a pair of homologous chromosomes to separate in meiosis I ...
during both
meiosis I
Meiosis () is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, the sperm or egg cells. It involves two rounds of division that ultimately result in four cells, each with only one co ...
and II. It was first diagnosed in 1960 and was coined Fraccaro syndrome after the researcher.
Signs and symptoms
The symptoms of 49,XXXXY are slightly similar to those of
Klinefelter syndrome
Klinefelter syndrome (KS), also known as 47,XXY, is a chromosome anomaly where a male has an extra X chromosome. These complications commonly include infertility and small, poorly functioning testicles (if present). These symptoms are often n ...
and 48,XXXY, but they are usually much more severe.
Aneuploidy
Aneuploidy is the presence of an abnormal number of chromosomes in a cell (biology), cell, for example a human somatic (biology), somatic cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more plo ...
is often fatal, but there is "
X-inactivation
X-inactivation (also called Lyonization, after English geneticist Mary Lyon) is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into ...
", where the effect of the additional gene dosage due to the presence of extra X chromosomes is greatly reduced.
Reproductive
Those with 49,XXXXY syndrome tend to exhibit infantile secondary sex characteristics with sterility in adulthood.
*
Hypoplastic
Hypoplasia (; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a Tissue (biology), tissue or Organ (biology), organ.
* Absent or delayed puberty
Physical
Males with 49,XXXXY tend to have numerous skeletal anomalies. These skeletal anomalies include:
*
Genu valgum
Genu valgum, commonly called "knock-knee", is a condition in which the knees angle in and touch each other when the human leg, legs are straightened. Individuals with severe valgus deformity, valgus deformities are typically unable to touch thei ...
clinodactyly
Clinodactyly is a medical term describing the curvature of a digit (a finger or toe) in the plane of the palm, most commonly the fifth finger (the "little finger") towards the adjacent fourth finger (the "ring finger").
It is a fairly common i ...
The effects also include:
49,XXXXY may also be associated with increased rates of
primary immunodeficiency
Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. To be considered a ''primary'' immunodeficiency (PID), the immune deficiency must be inborn, not caused by secondary facto ...
.
Cognitive and developmental
Much like Down syndrome, the mental effects of 49,XXXXY syndrome vary. Impaired speech and maladaptive behavioral problems are typical. One study looked at males that were diagnosed with
48,XXYY
XXYY syndrome is a sex chromosome anomaly in which males have two extra chromosomes, one X and one Y chromosome. Human cells usually contain two sex chromosomes, one from the mother and one from the father. Usually, females have two X chromosomes ...
, 48,XXXY and 49,XXXXY. They found that males with 48,XXXY and 49,XXXXY function at a much lower cognitive level than males their age. These males also tend to exhibit more immature behavior for their chronological age; increased aggressive tendencies were also cited in this study.
A 2020 study found that boys with 49,XXXXY have heightened rates of internalizing behavior and anxiety, beginning as early as preschool. Tests using the
Social Responsiveness Scale
The Social Responsiveness Scale, developed by John Constantino in 2002 and expanded upon by Constantino et al. in 2003, is a quantitative measure of autistic traits in 4–18 year olds. Its correlation with behaviour problems and autism spectrum d ...
-2 (SRS-2) found that while those with the condition generally showed more signs of social impairment, there was minimal effect on their social awareness.
Pathophysiology
As its name indicates, a person with the syndrome has one
Y chromosome
The Y chromosome is one of two sex chromosomes in therian mammals and other organisms. Along with the X chromosome, it is part of the XY sex-determination system, in which the Y is the sex-determining chromosome because the presence of the ...
and four
X chromosome
The X chromosome is one of the two sex chromosomes in many organisms, including mammals, and is found in both males and females. It is a part of the XY sex-determination system and XO sex-determination system. The X chromosome was named for its u ...
s on the 23rd pair, thus having forty-nine chromosomes rather than the normal forty-six. As with most categories of
aneuploidy
Aneuploidy is the presence of an abnormal number of chromosomes in a cell (biology), cell, for example a human somatic (biology), somatic cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more plo ...
disorders, 49,XXXXY syndrome is often accompanied by
intellectual disability
Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
. It can be considered a form or variant of
Klinefelter syndrome
Klinefelter syndrome (KS), also known as 47,XXY, is a chromosome anomaly where a male has an extra X chromosome. These complications commonly include infertility and small, poorly functioning testicles (if present). These symptoms are often n ...
(47,XXY). Individuals with this syndrome are typically
mosaic
A mosaic () is a pattern or image made of small regular or irregular pieces of colored stone, glass or ceramic, held in place by plaster/Mortar (masonry), mortar, and covering a surface. Mosaics are often used as floor and wall decoration, and ...
, being 49,XXXXY/48, XXXX.
It is genetic but not hereditary, meaning that while the genes of the parents cause the syndrome, there is a small chance of more than one child having the syndrome. The probability of inheriting the disease is about one percent.Webspawner.com article on 49,XXXXY syndrome . Retrieved 26 March 2008.
Diagnosis
49,XXXXY can be clinically diagnosed through
karyotyping
A karyotype is the general appearance of the complete set of chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is discerned by de ...
.Facial dysmorphia and other somatic abnormalities may be reason to have the
genetic testing
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
done.
Treatment
While there is no treatment to correct the genetic abnormality of this syndrome, there is the potential to treat the symptoms. As a result of infertility, one man from Iran used artificial reproductive methods. An infant in Iran diagnosed with 49,XXXXY syndrome was born with
patent ductus arteriosus
Patent ductus arteriosus (PDA) is a medical condition in which the ''ductus arteriosus'' fails to close after childbirth, birth: this allows a portion of oxygenated blood from the left heart to flow back to the lungs from the aorta, which has a h ...
, which was corrected with surgery, and other complications that were managed with replacement therapy.
The administration of testosterone therapy has been shown to improve motor skills, speech, and nonverbal IQ in males with 49,XXXXY.
See also
*
Sex chromosome anomalies Sex chromosome anomalies belong to a group of genetic conditions that are caused or affected by the loss, damage or addition of one or both sex chromosomes (also called ''gonosomes'').
In humans this may refer to:
* 45, X, also known as Turner s ...
*
Aneuploidy
Aneuploidy is the presence of an abnormal number of chromosomes in a cell (biology), cell, for example a human somatic (biology), somatic cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more plo ...
*
Turner syndrome
Turner syndrome (TS), commonly known as 45,X, or 45,X0,Also written as 45,XO. is a chromosomal disorder in which cells of females have only one X chromosome instead of two, or are partially missing an X chromosome (sex chromosome monosomy) lea ...
*
Klinefelter syndrome
Klinefelter syndrome (KS), also known as 47,XXY, is a chromosome anomaly where a male has an extra X chromosome. These complications commonly include infertility and small, poorly functioning testicles (if present). These symptoms are often n ...
*
49, XXXXX
Pentasomy X, also known as 49,XXXXX, is a chromosomal disorder in which a female has five, rather than two, copies of the X chromosome. Pentasomy X is associated with short stature, intellectual disability, characteristic facial features, hear ...