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Disease Profile

Koolen de Vries 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

Infancy

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ICD-10

Q87.8

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.

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)

17q21.31 deletion syndrome; Monosomy 17q21.31; Microdeletion 17q21.31 syndrome;

Categories

Chromosome Disorders; Congenital and Genetic Diseases

Summary

Koolen de Vries syndrome is a disorder characterized by developmental delay, mild to moderate intellectual disability, congenital malformations, and behavioral features.[1][2] Developmental delay is noted from an early age. Other problems include weak muscle tone (hypotonia) in childhood, recurrent seizures (epilepsy), and distinctive facial features. Males with Koolen de Vries syndrome often have undescended testes (cryptorchidism). Other symptoms may include defects in the walls between the chambers of the heart (septal defects) or other heart defects, kidney problems, and skeletal anomalies such as foot deformities.[1] It is caused by mutations in the KANSL1 gene, or by the loss of a small amount of genetic material in chromosome 17 that includes the KANSL1 gene (chromosome 17 q21.31 microdeletion).[2][3] Inheritance is autosomal dominant. Treatment may include physiotherapy, speech therapy, and educational programs, as well as medication for epilepsy and surgical treatment for malformations needing to be corrected.[2]

Symptoms

The most frequent symptoms (present in more than 75% of the cases) may include:[2][1]

  • Distinctive facial features (including a high, broad forehead; droopy eyelids (ptosis); a narrowing of the eye openings (blepharophimosis); outer corners of the eyes that point upward (upward-slanting palpebral fissures); skin folds covering the inner corner of the eyes (epicanthal folds); a bulbous nose; and prominent ears)
  • Developmental delay/ intellectual disability
  • Low muscle tone (hypotonia) in childhood
  • Friendly and cheerful attitude

In about 50% to 75% of the cases the following symptoms may be present:[2]

  • Epilepsy
  • Skin and hair problems
  • Nasal speech
  • Narrow/high palate
  • Dental anomalies
  • Slender/long fingers
  • Joints that are too flexible (hypermobility) and/or joint dislocation or deformation
  • Brain anomalies
  • Kidney and genital anomalies

Less frequent symptoms (25%-50%) are:[2] 

  • Far-sightedness (hypermetropia)
  • Crossed eyes (strabismus)
  • Narrow hands
  • Small hands
  • Heart defects
  • Hip dislocation/dysplasia
  • Persistence of fingertip pads
  • Slender lower limbs
  • Positional deformity of the feet
  • Abnormal curvature of the spine (scoliosis/kyphosis)

In some cases (10% to 25% of the cases) the following symptoms may be present:[2]

  • Hearing loss due to chronic infection of the ears (otitis media)
  • Low birth weight
  • Short stature
  • Abnormal head shape
  • Sunken chest (pectus excavatum)

Uncommon symptoms (in less than 10% of the cases) include:[2]

  • Cleft lip/palate
  • Very small head (microcephaly)
  • Clouding of the lens in the eye (cataract)
  • Narrowing of the muscular opening at the lower end of the stomach that connects to the intestines (pyloric stenosis)
  • Vertebras that are joined together (fused vertebrae)
  • A condition in which a bone (vertebra) in the spine moves forward out of the proper position onto the bone below it (spondylolisthesis)
  • Hypothyroidism

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
Blepharophimosis
Narrow opening between the eyelids
0000581
Broad forehead
Increased width of the forehead
Wide forehead

[ more ]

0000337
Bulbous nose
0000414
Coarse facial features
Coarse facial appearance
0000280
Epicanthus
Eye folds
Prominent eye folds

[ more ]

0000286
Everted lower lip vermilion
Drooping lower lip
Outward turned lower lip

[ more ]

0000232
Global developmental delay
0001263
High forehead
0000348
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Long face
Elongation of face
Increased height of face
Increased length of face
Vertical elongation of face
Vertical enlargement of face
Vertical overgrowth of face

[ more ]

0000276
Muscular hypotonia
Low or weak muscle tone
0001252
Overfolded helix
Overfolded ears
0000396
Overfriendliness
0100025
Prominent nasal bridge
Elevated nasal bridge
High nasal bridge
Prominent bridge of nose
Prominent nasal root
Protruding bridge of nose
Protruding nasal bridge

[ more ]

0000426
Protruding ear
Prominent ear
Prominent ears

[ more ]

0000411
Ptosis
Drooping upper eyelid
0000508
Thick nasal alae
0009928
Underdeveloped nasal alae
Underdeveloped tissue around nostril
0000430
Upslanted palpebral fissure
Upward slanting of the opening between the eyelids
0000582
Wide nasal bridge
Broad nasal bridge
Broad nasal root
Broadened nasal bridge
Increased breadth of bridge of nose
Increased breadth of nasal bridge
Increased width of bridge of nose
Increased width of nasal bridge
Nasal bridge broad
Wide bridge of nose
Widened nasal bridge

[ more ]

0000431
30%-79% of people have these symptoms
Abnormal cardiac septum morphology
0001671
Abnormality of hair texture
0010719
Aplasia/Hypoplasia of the corpus callosum
0007370
Arachnodactyly
Long slender fingers
Spider fingers

[ more ]

0001166
Cryptorchidism
Undescended testes
Undescended testis

[ more ]

0000028
Delayed speech and language development
Deficiency of speech development
Delayed language development
Delayed speech
Delayed speech acquisition
Delayed speech development
Impaired speech and language development
Impaired speech development
Language delay
Language delayed
Language development deficit
Late-onset speech development
Poor language development
Speech and language delay
Speech and language difficulties
Speech delay

[ more ]

0000750
Feeding difficulties in infancy
0008872
High hypermetropia
Severe farsightedness
Severe long-sightedness

[ more ]

0008499
High, narrow palate
Narrow, high-arched roof of mouth
Narrow, highly arched roof of mouth

[ more ]

0002705
Hip dislocation
Dislocated hips
Dislocation of hip

[ more ]

0002827
Hip dysplasia
0001385
Hypopigmentation of hair
Loss of hair color
0005599
Hypospadias
0000047
Joint hyperflexibility
Joints move beyond expected range of motion
0005692
Joint hypermobility
Double-Jointed
Flexible joints
Increased mobility of joints

[ more ]

0001382
Microdontia
Decreased width of tooth
0000691
Nasal speech
Nasal voice
0001611
Poor speech
0002465
Positional foot deformity
0005656
Prominent fingertip pads
Prominent finger pads
0001212
Seizure
0001250
Strabismus
Cross-eyed
Squint
Squint eyes

[ more ]

0000486
Ventriculomegaly
0002119
5%-29% of people have these symptoms
Abnormality of dental enamel
Abnormal tooth enamel
Enamel abnormalities
Enamel abnormality

[ more ]

0000682
Anxiety
Excessive, persistent worry and fear
0000739
Bicuspid aortic valve
Aortic valve has two leaflets rather than three
0001647
Cataract
Cloudy lens
Clouding of the lens of the eye

[

Cause

Koolen de Vries syndrome is caused by either:

  • Mutations in the KANSL1 gene, resulting in the loss of function of this gene.
  • Loss (deletions) of a small amount of genetic material (microdeletion) from chromosome 17, that includes the KANSL1 gene.

Most of the cases are due to the microdeletion. The microdeletion occurs on the long (q) arm of chromosome 17 at a location q21.31. While the exact size of the deletion varies among individuals, most are missing several genes. However, because people with KANSL1 gene mutations have the same signs and symptoms as those with the microdeletion, researchers have concluded that the loss of this gene accounts for the features of this disorder.[1]

The KANSL1 gene provides instructions for making a protein that helps regulate gene activity (expression) by modifying chromatin. Chromatin is the complex of DNA and protein that packages DNA into chromosomes. The protein produced from the KANSL1 gene is involved in controlling the activity of other genes, and in the development and function of many parts of the body.[1] The relationship of KANSL1 gene loss to the specific signs and symptoms of Koolen de Vries syndrome is unclear.[1][2]

Diagnosis

The symptoms are very variable. Besides developmental delay and intellectual disability, no single clinical feature is required to establish the diagnosis, although childhood low muscle tone (hypotonia) is a common feature, reported in almost all affected people.

To establish the diagnosis of the syndrome one of the following is needed:[2]

  • A 17q21.31 microdeletion involving at least KANSL1
  • A mutation in the KANSL1 gene (through an exam known as sequence analysis)

Testing Resources

  • Orphanet lists international laboratories offering diagnostic testing for this condition.

    Treatment

    Treatment depends on the symptoms and may include:[2] 

    • Early intervention with physiotherapy for feeding problems and motor delay
    • Physical therapy aimed at strengthening the muscles
    • Therapy to improve development of the child's fine and gross motor skills
    • Speech therapy, sign language, pictures and computer touch screens aiming to improve communication skills
    • Educational programming directed to the specific disabilities identified
    • Routine antiepileptic drugs
    • Orthopedic care for scoliosis, hip dislocation, and positional deformities of the feet
    • Standard treatment for cardiac, renal, urologic, and other medical issues
    • Surgery cryptorchidism if indicated.

    Affected people should have routine examinations by a primary care physician and pediatrician, cardiologist, nephrologist, and/or urologist. Referrals to other specialists is indicated if neurological or other problems are suspected.[2][5]

    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

      Social Networking Websites

        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

        • MedlinePlus Genetics contains information on Koolen de Vries syndrome. This website is maintained by the National Library of Medicine.
        • Unique is a source of information and support to families and individuals affected by rare chromosome disorders. Click on the link to view information about 17q21.31 microdeletion syndrome.

          In-Depth Information

          • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
          • 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.
          • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
          • 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 Koolen de Vries syndrome. Click on the link to view a sample search on this topic.

            References

            1. Koolen-de Vries syndrome. Genetics Home Reference. 2013; https://ghr.nlm.nih.gov/condition=17q2131microdeletionsyndrome.
            2. Koolen DA & de Vries BBA. KANSL1-Related Intellectual Disability Syndrome. GeneReviews. 2013; https://www.ncbi.nlm.nih.gov/books/NBK24676/.
            3. Koolen DA & cols. Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nat Genet. 2012; 44::639–41.
            4. Bernardo P, Madia F, Santulli L, Del Gaudio L, Caccavale C, Zara F, Traverso M, Cirillo M, Striano S, Coppola A. 17q21.31 microdeletion syndrome: Description of a case further contributing to the delineation of Koolen-de Vries syndrome. Brain Dev. 2016 Aug; 38(7):663-8. https://www.ncbi.nlm.nih.gov/pubmed/26897099.
            5. Koolen-De Vries syndrome. Orphanet. January, 2009; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=96169.

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