• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
  • Programs & Resources
  • Complete Report

Kleefstra Syndrome

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Last updated: 8/25/2023
Years published: 2023


Acknowledgment

NORD gratefully acknowledges Taylor Jacobs, MS, Cheng-Wei Jan, MS, Astrid Torres Zapata, MS, Jennefer Kohler, MS, and Dena Matalon, MD, FACMG, FAAP, Stanford University, for the preparation of this report.


Disease Overview

 

Summary

Kleefstra syndrome is a rare genetic condition that affects multiple organ systems and has specific developmental and behavioral symptoms. Children with Kleefstra syndrome may have specific facial features including a small head size (microcephaly), a broad forehead, widely spaced eyes (hypertelorism), distinctive eyebrows and large tongue (macroglossia). Low muscle tone (hypotonia) along with a large birth weight and childhood obesity are also common. Additionally, heart (cardiac), kidney (renal), genital and brain abnormalities may be seen. Most people with Kleefstra syndrome will have some form of intellectual disability which may occur with autistic-like features, speech delay and the development of extreme apathy and/or lack of movement and communication (catatonia) after puberty. Additional symptoms that can occur include epilepsy (seizures) and/or febrile seizures (seizures in the setting of a fever), hearing loss, stomach (gastrointestinal) issues, respiratory infections and farsightedness (hyperopia). Fewer than 1,000 people have been diagnosed with Kleefstra syndrome in the U.S.

 

Introduction

Kleefstra syndrome was initially known as “9q subtelomeric deletion syndrome” because it is caused by changes in a specific region of chromosome 9, known as 9q34.3. It was renamed in honor of Dr. Tjitske Kleefstra, a clinical geneticist who was one of the first to describe the syndrome in scientific publications. This renaming occurred in the early 2000s.

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Synonyms

  • 9q-syndrome
  • 9q34.3 deletion syndrome
  • chromosome 9q deletion syndrome
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Signs & Symptoms

Kleefstra syndrome has a wide range of symptoms that include physical, developmental and behavioral characteristics. While some physical features are apparent from birth (congenital), other symptoms, particularly behavioral, often develop during early childhood.

People with Kleefstra syndrome have distinctive facial features including a small head size (microcephaly), flattening of the back of the skull (brachycephaly), broad forehead, arched or connected eyebrows (synophrys), widely spaced (hypertelorism) and up-slanting eyes, nostrils that open to the front instead of downwards (anteverted nares), a flatter appearance of the midface (midface hypoplasia), large tongue (macroglossia), full bottom lip (everted lower vermilion), protruding jaw (prognathism) and thickened outer-ear (thickened helix). As children get older, their facial characteristics become more defined and noticeable.

Low muscle tone (hypotonia) is a common symptom. About half of babies with Kleefstra syndrome are born with a large birth weight and may develop childhood obesity.

Other physical symptoms include heart (cardiac) defects such as a hole in the wall between the heart’s chambers (atrial septal defect and/or ventral septal defect), narrowing of the heart vessels (aortic coarctation and/or pulmonic stenosis) and a malformed heart valve (bicuspid aortic valve). These symptoms have been seen in about half (50%) of people diagnosed with Kleefstra syndrome.

Kidney (renal) issues, including abnormal flow of urine (vesicoureteral reflux), stretching and swelling of the kidney (hydronephrosis), development of fluid-filled pouches (renal cysts) and chronic renal failure (insufficiency) are found in approximately 10%-30% of people with Kleefstra syndrome.

Genital differences, including the failure of the testicles to descend into the scrotum (cryptorchidism), the opening of the urethra not being located at the tip of the penis (hypospadias) and small penis, are reported in 30% of affected males.

Brain abnormalities can include underdevelopment (hypoplasia) of the connection between the left and right side of the brain (corpus callosum) and outer layer of brain (cortex).

Most people with Kleefstra syndrome will have some form of intellectual disability which is typically moderate to severe. Autism spectrum disorder along with expressive speech delay is also common. People with Kleefstra syndrome may develop a lack of interest/difficulty in communicating or moving (catatonia) and extreme apathy after puberty. Psychiatric and sleep problems are also associated with the condition.

Other symptoms include epilepsy (seizures) and/or febrile seizures (seizures in the setting of a fever), hearing loss, stomach (gastrointestinal) issues, respiratory infection and farsightedness (hyperopia).

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Causes

Kleefstra syndrome is a genetic condition caused by changes in a specific region of chromosome 9, known as 9q34.3. The genetic changes that lead to Kleefstra syndrome can take different forms, including deletions (missing pieces) of the chromosome or pathogenic variants (previously known as mutations) within a specific gene called EHMT1.

The EHMT1 gene provides the instructions for making an enzyme called euchromatin histone methyl transferase 1, which is involved in a cellular process called histone methylation. This enzyme plays an essential role in controlling how genes work by stopping specific genes from being active, which is crucial for proper growth and body functions. Genetic changes (deletions or pathogenic variants) within the EHMT1 gene result in a loss of function of this enzyme, which can disrupt the normal regulation of other genes and lead to the symptoms of Kleefstra syndrome.

In most people with Kleefstra syndrome, the genetic change that causes the disorder is not inherited from a parent but occurs spontaneously (de novo) in the individual with Kleefstra syndrome. However, in a small number of patients reported in the medical literature, Kleefstra syndrome was inherited (passed down) from a parent with no symptoms to a child. This type of inheritance is called autosomal dominant. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease.

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Affected populations

Kleefstra Syndrome affects both males and females equally. It occurs in people from all ancestral backgrounds. How often it occurs is not well understood. Many people with Kleefstra syndrome may be undiagnosed, making it challenging to accurately gauge the frequency of the disorder in the general population.

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Diagnosis

Kleefstra Syndrome may first be suspected based on characteristic features of the condition and tests done in a clinical evaluation. Often, a person with Kleefstra syndrome will be the only person with the condition in their family history. Molecular genetic testing that identifies the characteristic deletion in chromosome 9 or identifies a variant in the EHMT1 gene can confirm the diagnosis. Molecular genetic testing for the parents might also be recommended. A genetic counselor can explain what type of testing is most appropriate for the child and family.

 

Clinical Testing and Work-Up

A clinical work up should include a physical examination including evaluation of the height, weight and head circumference, with particular attention to facial features.

An echocardiogram and electrocardiogram (EKG) may be done to look for any potential heart defects and rhythm disturbances. The echocardiogram provides information about the structure of the heart and the EKG uses electrical currents to evaluate the rhythm of the heart.

A neurology evaluation might be suggested, including an electroencephalogram (EEG) and magnetic resonance imaging (MRI) for the brain, in children who have had recorded or suspected seizures. An EEG measures electrical activity in the brain to detect seizures and a brain MRI creates a cross sectional image of the brain. MRIs can also be utilized in children with movement disorders, regression of psychomotor development or extreme catatonia.

The workup might also include a renal ultrasound to evaluate the kidneys, an assessment for sleep disturbances, hearing evaluation for hearing loss, a psychiatric evaluation and a developmental assessment including motor, speech, cognitive and vocational skills.

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Standard Therapies

 

Treatment

An interdisciplinary team should work together to care for these patients under the coordination of a pediatrician or medical geneticist. Members of this team, depending on the specific symptoms unique to the individual, can include a pediatric neurologist (a physician who specializes in the diagnosis and treatment of disorders of the brain, nerves and nervous system in children), an ophthalmologist (a physician who specializes in the diagnosis and treatment of disorders of the eye), an audiologist (a healthcare provider who specializes in the diagnosis and treatment of disorders of the ears), a cardiologist ( a physician who specializes in the diagnosis and treatment of disorders of the heart), a gastroenterologist (a physician who specializes in the diagnosis and treatment of disorders of the gastrointestinal tract), a urologist and/or nephrologist (a physician who specializes in the diagnosis and treatment of disorders of the genitals and/or kidneys), a speech therapist, occupational therapist, physical therapist and a psychiatrist. The addition of a specialist for adults with intellectual disability may be considered in adulthood.

Genetic counseling in encouraged and can be beneficial to both the patient and their family.

A developmental assessment can determine appropriate therapies, such as occupational, speech, physical and feeding therapies to help with the difficulties in motor control. Medical equipment such as wheelchairs and walkers might be considered for some patients. Medications like baclofen, Botox, and anti-parkinsonian prescriptions or orthopedic procedures that can help with symptoms of hypotonia and dystonia should be managed by the appropriate specialist.

To address communication and behavioral concerns, augmentative and alternative communications (AAC) can provide care for those with difficulties in expressive language, and an applied behavior analysis (ABA) can be implemented as treatment for autism spectrum disorder. ABA adapts to the strengths and weaknesses of each child. A developmental pediatrician can provide guidance in behavior management as well as prescriptions when appropriate. Early intervention programs, developmental preschools and individualized education plans (IEPs) are all beneficial for social, cognitive and intellectual development.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact: https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

Kleefstra Syndrome. Boston Children’s Hospital. https://www.childrenshospital.org/conditions/kleefstra-syndrome Accessed August 24, 2023,

Kleefstra T, de Leeuw N. Kleefstra Syndrome. 2010 Oct 5 [Updated 2023 Jan 26]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK47079/ Accessed August 24, 2023.

Kleefstra syndrome. Orphanet. Updated Jan 2021. https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=19881&Disease_Disease_Search_diseaseGroup=Kleefstra-Syndrome&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Kleefstra-syndrome&title=Kleefstra%20syndrome&search=Disease_Search_Simple Accessed August 24, 2023.

Kleefstra syndrome. Genetic and Rare Diseases Information Center (GARD). Last updated Feb 2023. Kleefstra syndrome – About the Disease – Genetic and Rare Diseases Information Center (nih.gov) Accessed August 24, 2023.

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Programs & Resources

RareCare® Assistance Programs

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/

Patient Organizations

No patient organizations found related to this disease state.


National Organization for Rare Disorders