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Disease Profile

Kleefstra 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.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

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)

9q34.3 microdeletion syndrome; Chromosome 9q deletion syndrome; Chromosome 9q34.3 deletion syndrome;

Categories

Chromosome Disorders

Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 261494

Definition
Kleefstra syndrome (KS) is a genetic disorder characterized by intellectual disability, childhood hypotonia, severe expressive speech delay and a distinctive facial appearance with a spectrum of additional clinical features.

Epidemiology
The prevalence is unknown. To date, 114 cases have been described.

Clinical description
Patients with KS have a distinctive facial appearance comprised of brachymicrocephaly, midface hypoplasia, unusual eyebrow shape, synophyrs, cupid bow upper lip, full everted lower lip, protruding tongue and prognathism. With age, facial features become coarser and dental anomalies, like retention of primary dentition, are seen. Birth weight is normal but half of children go on to suffer from obesity. Childhood hypotonia causes motor delay but most children walk independently by age 2 or 3. Most patients have moderate to severe intellectual disability with expressive speech delay and little speech development (nonverbal communication is possible). Additional features include congenital heart malformations (interauricular communication, ventricular septal defects, bicuspid aortic valve, pulmonary valve stenosis (see these terms)), genital defects in males (hypospadias, cryptorchidism, micropenis), renal defects (hydronephrosis, chronic renal insufficiency, renal cysts, vesico-ureteral reflux), epilepsy, recurrent infections, severe constipation and hearing problems. In adolescence/adulthood behavioral problems (aggressive/emotional outbursts, attention deficit problems, self-mutilation and severe sleep disturbances) can begin. Autistic-like behavior can be noted earlier in some children. Recurrent pulmonary infections, overweight and behavioral problems seem to be reported more often in those with KS due to a point mutation, whereas microcephaly, short stature, respiratory complications and tracheomalacia are more frequently seen in those with KS due to a 9q34 microdeletion.

Etiology
KS is caused by either a point mutation in the euchromatic histone-lysine N-methyltransferase 1 (EHMT1) gene (rarely) or by a microdeletion in the chromosome region 9q34.3 (seen in >85% of cases), leading to the loss of the entire gene. This gene encodes an enzyme that modifies histone function and is essential for normal development. Larger deletions (>1mb) are associated with more severe symptoms.

Diagnostic methods
Diagnosis of KS is determined by the presence of the characteristic clinical features and molecular genetic testing. A microarray detects any duplications/deletions. Fluorescent in situ hybridization (FISH) or multiplex ligation-dependent probe amplification (MLPA) can then be used to detect the specific 9q34.3 deletion seen in KS. Sequencing of the entire coding region of the EHMT1 gene can detect sequence variants.

Differential diagnosis
Differential diagnoses include Down, Pitt-Hopkins, Smith-Magenis, Rett and 2q23.1 microdeletion syndromes (see these terms).

Antenatal diagnosis
Antenatal diagnosis is offered to unaffected parents of a child with KS as they have a higher risk of having another child with this disorder.

Genetic counseling
Most reported cases have been de novo but familial recurrence has been seen. KS has a theoretical autosomal dominant transmission, but the majority of patients do not reproduce.

Management and treatment
Treatment requires a multidisciplinary team, specializing in patients with intellectual deficiencies. Special education and vocational training along with speech therapy, physical and occupational therapy and sensory integration therapy are recommended from an early age. Standard treatment is necessary for those with renal, cardiac and urologic issues and for hearing loss. Psychiatric care along with behavioral intervention therapy may be needed. Cardiac screening (for the presence of arrhythmias) as well as intestinal and renal/urologic monitoring is recommended. Medical follow-up is life-long.

Prognosis
The prognosis of KS is variable but in most cases it is not a life-threatening disease.

Visit the Orphanet disease page for more resources.

Symptoms

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
Anteverted nares
Upturned nostrils
Upturned nose
Upturned nasal tip
Nasal tip, upturned

[ more ]

0000463
Coarse facial features
Coarse facial appearance
0000280
Delayed speech and language development
Deficiency of speech development
Language delayed
Language delay
Impaired speech development
Impaired speech and language development
Delayed speech development
Delayed speech acquisition
Delayed speech
Delayed language development
Speech delay
Speech and language difficulties
Speech and language delay
Poor language development
Late-onset speech development
Language development deficit

[ more ]

0000750
Everted lower lip vermilion
Drooping lower lip
Outward turned lower lip

[ more ]

0000232
Exaggerated cupid's bow
Cupid bow upper lip
Cupid-bow shaped upper lip
Prominent cupid-bow of upper lip

[ more ]

0002263
Global developmental delay
0001263
Hypertelorism
Wide-set eyes
Widely spaced eyes

[ more ]

0000316
Intellectual disability, severe
Early and severe mental retardation
Mental retardation, severe
Severe mental retardation

[ more ]

0010864
Malar flattening
Zygomatic flattening
0000272
Muscular hypotonia
Low or weak muscle tone
0001252
Short nose
Decreased length of nose
Shortened nose

[ more ]

0003196
Tented upper lip vermilion
0010804
30%-79% of people have these symptoms
Abnormality of the pinna
Abnormally shaped ears
Auricular malformation
Deformed ears
Malformed ears

[ more ]

0000377
Aggressive behavior
Aggression
Aggressive behaviour
Aggressiveness

[ more ]

0000718
Arrhythmia
Abnormal heart rate
Heart rhythm disorders
Irregular heart beat
Irregular heartbeat

[ more ]

0011675
Autism
0000717
Autistic behavior
0000729
Bicuspid aortic valve
Aortic valve has two leaflets rather than three
0001647
Brachycephaly
Short and broad skull
0000248
Broad forehead
Increased width of the forehead
Wide forehead

[ more ]

0000337
Chronic otitis media
Chronic infections of the middle ear
0000389
Coarctation of aorta
Narrowing of aorta
Narrowing of the aorta

[ more ]

0001680
Constipation
0002019
Cryptorchidism
Undescended testes
Undescended testis

[ more ]

0000028
Hearing impairment
Deafness
Hearing defect

[ more ]

0000365
Highly arched eyebrow
Arched eyebrows
Broad, arched eyebrows
High, rounded eyebrows
High-arched eyebrows
Thick, flared eyebrows

[ more ]

0002553
Hypospadias
0000047
Macroglossia
Abnormally large tongue
Large tongue
Increased size of tongue

[ more ]

0000158
Mandibular prognathia
Big lower jaw
Increased projection of lower jaw
Increased size of lower jaw
Large lower jaw
Prominent chin
Prominent lower jaw

[ more ]

0000303
Microcephaly
Reduced head circumference
Decreased size of skull
Decreased circumference of cranium
Abnormally small skull
Small head circumference

[ more ]

0000252
Micropenis
Short penis
Small penis

[ more ]

0000054
Obesity
Having too much body fat
0001513
Protruding tongue
Prominent tongue
Tongue sticking out of mouth

[ more ]

0010808
Recurrent respiratory infections
Frequent respiratory infections
Multiple respiratory infections
respiratory infections, recurrent
Susceptibility to respiratory infections

[ more ]

0002205
Self-mutilation
Deliberate self-harm
Self mutilation

[ more ]

0000742
Sleep disturbance
Difficulty sleeping
Trouble sleeping

[ more ]

0002360
Stereotypy
Repetitive movements
Repetitive or self-injurious behavior

[ more ]

0000733
Synophrys
Unibrow
Monobrow

[ more ]

0000664
Thickened helices
0000391
Upslanted palpebral fissure
Upward slanting of the opening between the eyelids
0000582
U-Shaped upper lip vermilion
Carp-like mouth
Carp-shaped mouth
Fish mouth
Large, carp-shaped mouth
Wide, carp-shaped mouth

[ more ]

0010806
Ventricular septal defect
Hole in heart wall separating two lower heart chambers
0001629
5%-29% of people have these symptoms
Advanced eruption of teeth
Early eruption of teeth
0006288
Agenesis of corpus callosum
0001274
Bowel incontinence
Loss of bowel control
0002607
Cerebral cortical atrophy
Decrease in size of the outer layer of the brain due to loss of brain cells
0002120
Delayed eruption of teeth
Delayed eruption
Delayed teeth eruption
Delayed tooth eruption
Eruption, delayed
Late eruption of teeth
Late tooth eruption

[ more ]

0000684
Developmental regression
Loss of developmental milestones
Mental deterioration in childhood

[ more ]

0002376
Downturned corners of mouth
Downturned corners of the mouth
Downturned mouth

[ more ]

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

      • Genetics Home Reference (GHR) contains information on Kleefstra 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 Kleefstra 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 Kleefstra syndrome. Click on the link to view a sample search on this topic.

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