Rare Gastroenterology News

Disease Profile

49, XXXXY syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Childhood

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ICD-10

Q98.1

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

XXXXY syndrome; 49,XXXXY

Categories

Congenital and Genetic Diseases; Endocrine Diseases; Kidney and Urinary Diseases;

Summary

49,XXXXY syndrome is a type of chromosome abnormality characterized by the presence of 3 extra X chromosomes in males. It is sometimes referred to as a variant of Klinefelter syndrome, but differs from Klinefelter syndrome in many ways and is more severe.[1] Signs and symptoms of 49,XXXXY syndrome can vary but may include learning difficulties or intellectual disability; low muscle tone; hypogonadism; infertility; delayed growth; distinctive facial features; and a variety of birth defects that may affect the heart, bones, brain and/or kidneys.[1][2] It is usually not inherited and caused by a random error in cell division. Treatment depends on the features in each person and is often managed by a multidisciplinary team.[1]

Symptoms

49,XXXXY syndrome can affect many parts of the body. Affected people typically have delayed growth (often seen in utero, before birth).[1] Some have short stature and a deficit of growth hormones.[1] There may be varying degrees of learning difficulty and intellectual disability which can be severe; some report that this worsens with age.[1][3][4] Behavioral problems can also arise.[1]

There is usually severe hypogonadism with an abnormally small penis (micropenis), small testes, and/or undescended testes (cryptorchidism).[1] Most have distinctive facial features which may include a large, flat nose with an up-turned tip; wide-set eyes (hypertelorism); epicanthal folds; protrusion of the lower jaw (prognathism); folded ears; and/or a short neck.[1][3] Other abnormalities may include:[1][3]

  • skeletal abnormalities and joint laxity
  • congenital heart defects
  • other endocrine disorders (affecting the hormones)
  • abnormalities in the brain (cerebral defects) such as underdevelopment of the corpus callosum (the pathway connecting the 2 hemispheres of the brain)
  • renal defects such as renal hypoplasia (small kidneys)
  • eye problems such as strabismus and severe nearsightedness (myopia)

Although people with 49,XXXXY syndrome are sometimes referred to as having a variant of Klinefelter syndrome, the features of these are generally distinct and 49,XXXXY syndrome is more severe.[3]

You can read more about the features of 49,XXXXY syndrome in a fact sheet provided by Unique. The information in this fact sheet comes from both the medical literature and reports of some members of Unique who took part in a survey in 2004.

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormality of dental enamel
Abnormal tooth enamel
Enamel abnormalities
Enamel abnormality

[ more ]

0000682
Azoospermia
Absent sperm in semen
0000027
Carious teeth
Dental cavities
Tooth cavities
Tooth decay

[ more ]

0000670
Decreased testicular size
Small testes
Small testis

[ more ]

0008734
Global developmental delay
0001263
Hypogonadism
Decreased activity of gonads
0000135
Hypoplasia of penis
Underdeveloped penis
0008736
Infertility
0000789
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Language impairment
0002463
Muscular hypotonia
Low or weak muscle tone
0001252
Open bite
Absence of overlap of upper and lower teeth
Open bite between upper and lower teeth

[ more ]

0010807
30%-79% of people have these symptoms
Abnormality of epiphysis morphology
Abnormal shape of end part of bone
0005930
Asthma
0002099
Attention deficit hyperactivity disorder
Attention deficit
Attention deficit disorder
Attention deficit-hyperactivity disorder
Attention deficits
Childhood attention deficit/hyperactivity disorder

[ more ]

0007018
Autism
0000717
Blepharophimosis
Narrow opening between the eyelids
0000581
Chronic otitis media
Chronic infections of the middle ear
0000389
Clinodactyly of the 5th finger
Permanent curving of the pinkie finger
0004209
Constipation
0002019
Coxa valga
0002673
Cryptorchidism
Undescended testes
Undescended testis

[ more ]

0000028
Delayed eruption of teeth
Delayed eruption
Delayed teeth eruption
Delayed tooth eruption
Eruption, delayed
Late eruption of teeth
Late tooth eruption

[ more ]

0000684
Down-sloping shoulders
Rounded shoulders
Rounded, sloping shoulders
Sloping shoulders

[ more ]

0200021
Elbow dislocation
Dislocations of the elbows
Elbow dislocations

[ more ]

0003042
Epicanthus
Eye folds
Prominent eye folds

[ more ]

0000286
Gynecomastia
Enlarged male breast
0000771
Hip dislocation
Dislocated hips
Dislocation of hip

[ more ]

0002827
Hypertelorism
Wide-set eyes
Widely spaced eyes

[ more ]

0000316
Joint hyperflexibility
Joints move beyond expected range of motion
0005692
Myopia
Close sighted
Near sighted
Near sightedness
Nearsightedness

[ more ]

0000545
Pes planus
Flat feet
Flat foot

[ more ]

0001763
Radioulnar synostosis
Fused forearm bones
0002974
Recurrent respiratory infections
Frequent respiratory infections
Multiple respiratory infections
respiratory infections, recurrent
Susceptibility to respiratory infections

[ more ]

0002205
Renal dysplasia
0000110
Scoliosis
0002650
Scrotal hypoplasia
Smaller than typical growth of scrotum
0000046
Seizure
0001250
Strabismus
Cross-eyed
Squint
Squint eyes

[ more ]

0000486
Taurodontia
0000679
Upslanted palpebral fissure
Upward slanting of the opening between the eyelids
0000582
5%-29% of people have these symptoms
Abnormality of cardiovascular system morphology
0030680
Arrhinencephaly
0002139
Brachycephaly
Short and broad skull
0000248
Cleft palate
Cleft roof of mouth
0000175
Depressed nasal bridge
Depressed bridge of nose
Flat bridge of nose
Flat nasal bridge
Flat, nasal bridge
Flattened nasal bridge
Low nasal bridge
Low nasal root

[ more ]

0005280
Depressed nasal ridge
Flat nose
Recessed nasal ridge

[ more ]

0000457
Gastroesophageal reflux
Acid reflux
Acid reflux disease
Heartburn

[ more ]

0002020

Cause

49,XXXXY syndrome occurs by chance due to a random error in cell division (called nondisjunction) in the egg cells of the mother.[1][2] During normal egg formation, chromosomes separate and a single X chromosome ends up in each egg cell. If chromosomes don't separate correctly during cell division, one egg cell ultimately can retain all of the X chromosomes that would normally be placed into 4 separate egg cells during cell division. If an egg cell containing four X chromosomes is fertilized by a normal male sperm (with one Y chromosome), the resulting fertilized egg cell will be affected. 

The underlying reason for random errors in cell division is not known. However, there is nothing a person can do, or not do, before or during pregnancy to cause 49,XXXXY syndrome to occur.

The specific features of 49,XXXXY syndrome are thought result from increased "doses" of genes from the extra X chromosomes.[5]

Treatment

There is no cure for 49,XXXXY syndrome. Treatment depends on the symptoms present in each person and is often managed by a team of various specialists. Specialists involved in the care of an affected person may include heart doctors (cardiologists), orthopedists, physiotherapists, speech therapists, eye doctors (ophthalmologists), neurologists, and endocrinologists. While life expectancy is thought to be normal in the absence of major complications, affected people will need regular medical visits.[1]

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

    Learn more

    These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

    Where to Start

    • Unique is a source of information and support for families and individuals affected by rare chromosome disorders. Click on the link to view information about 49, XXXXY syndrome.

      In-Depth Information

      • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
      • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
      • PubMed is a searchable database of medical literature and lists journal articles that discuss 49, XXXXY syndrome. Click on the link to view a sample search on this topic.

        Selected Full-Text Journal Articles

          References

          1. Carole Corsini and Pierre Sarda. 49,XXXXY syndrome. Orphanet. May, 2011; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=96264.
          2. 49,XXXXY. Unique. 2015; https://www.rarechromo.org/information/Chromosome_X/XXXXY%20syndrome%20FTNW.pdf.
          3. Carlos A Bacino. Sex chromosome abnormalities. UpToDate. Waltham, MA: UpToDate; October, 2014; Accessed 10/20/2014.
          4. 49,XXXXY Syndrome. Unique. 2005; https://www.rarechromo.org/information/Chromosome_X/XXXXY%20FTNW.pdf. Accessed 10/20/2014.
          5. Tartaglia N, Ayari N, Howell S, D'Epagnier C, Zeitler P. 48,XXYY, 48,XXXY and 49,XXXXY syndromes: not just variants of Klinefelter syndrome. Acta Paediatr. June, 2011; 100(6):851-60. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314712/.

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