Inspired by a recent patient encounter
Kleefstra T, Nillesen WM, Yntema HG. Kleefstra Syndrome. 2010 Oct 5 [updated
2015 May 7]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH,
Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews®
[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
Excerpt
CLINICAL CHARACTERISTICS:
Kleefstra syndrome is characterized by intellectual disability, childhood hypotonia, and distinctive facial features. The majority of individuals function in the moderate to severe spectrum of intellectual disability although a few individuals have mild delay and total IQ around 70. Although most have severe expressive speech delay with little speech development, general language development is usually at a higher level, making nonverbal communication possible. A complex pattern of other findings can also be observed including heart defects, renal/urologic defects, genital defects in males, severe respiratory infections, epilepsy/febrile seizures, autistic-like features in childhood, and extreme apathy or catatonic-like features after puberty.
DIAGNOSIS/TESTING:
About 75% of Kleefstra syndrome is caused by a heterozygous microdeletion at chromosome 9q34.3 that includes at least part of EHMT1, and about 25% by a heterozygous intragenic EHMT1 pathogenic variant.
MANAGEMENT:
Treatment of manifestations: Ongoing routine care by a multidisciplinary team specializing in the care of children or adults with intellectual disability. Referral to age-appropriate early-childhood intervention programs, special education programs, or vocational training; speech/language therapy, physical and occupational therapy, and sensory integration therapy; specialized care for those with extreme behavior problems, movement disorders, sleep disorders, and/or epilepsy; standard treatment for cardiac, renal, urologic, hearing loss, and other medical issues. Surveillance: Monitoring as needed of cardiac and renal/urologic abnormalities.
GENETIC COUNSELING:
Kleefstra syndrome, caused by a microdeletion at 9q34.3 or pathogenic variants in EHMT1, is inherited in an autosomal dominant manner. Almost all cases reported to date have been de novo; rarely, recurrence in a family has been reported when a parent has a balanced translocation involving the 9q34.3 region or somatic mosaicism for an interstitial 9q34.3 microdeletion. Except for individuals with somatic mosaicism for a 9q34.3 microdeletion, no individuals with Kleefstra syndrome have been known to reproduce. Prenatal testing may be offered to unaffected parents of a child with a 9q34.3 microdeletion or an EHMT1 pathogenic variant because of the increased risk of recurrence associated with the possibility of germline mosaicism, somatic mosaicism including the germline, or a balanced chromosome translocation.
Segar DJ, Chodakiewitz YG, Torabi R, Cosgrove GR. Deep brain stimulation for
the obsessive-compulsive and Tourette-like symptoms of Kleefstra syndrome.
Neurosurg Focus. 2015 Jun;38(6):E12.
Abstract
Deep brain stimulation (DBS) has been reported to have beneficial effects in severe, treatment-refractory cases of obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). In this report, the authors present the first case in which DBS was used to treat the neuropsychiatric symptoms of Kleefstra syndrome, a rare genetic disorder characterized by childhood hypotonia, intellectual disability, distinctive facial features, and myriad psychiatric and behavioral disturbances. A 24-year-old female patient with childhood hypotonia, developmental delay, and diagnoses of autism spectrum disorder, OCD, and TS refractory to medical management underwent the placement of bilateral ventral capsule/ventral striatum (VC/VS) DBS leads, with clinical improvement. Medical providers and family observed gradual and progressive improvement in the patient's compulsive behaviors, coprolalia, speech, and social interaction. Symptoms recurred when both DBS electrodes failed because of lead fracture and dislodgement, although the clinical benefits were restored by lead replacement. The symptomatic and functional improvements observed in this case of VC/VS DBS for Kleefstra syndrome suggest a novel indication for DBS worthy of further investigation.
Willemsen MH, Vulto-van Silfhout AT, Nillesen WM, Wissink-Lindhout WM, van Bokhoven H, Philip N, Berry-Kravis EM, Kini U, van Ravenswaaij-Arts CM, Delle Chiaie B, Innes AM, Houge G, Kosonen T, Cremer K, Fannemel M, Stray-Pedersen A, Reardon W, Ignatius J, Lachlan K, Mircher C, Helderman van den Enden PT, Mastebroek M, Cohn-Hokke PE, Yntema HG, Drunat S, Kleefstra T. Update on Kleefstra Syndrome. Mol Syndromol. 2012 Apr;2(3-5):202-212.
ReplyDeleteAbstract
Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual disability, (childhood) hypotonia and distinct facial features. The syndrome can be either caused by a microdeletion in chromosomal region 9q34.3 or by a mutation in the euchromatin histone methyltransferase 1 (EHMT1) gene. Since the early 1990s, 85 patients have been described, of which the majority had a 9q34.3 microdeletion (>85%). So far, no clear genotype-phenotype correlation could be observed by studying the clinical and molecular features of both 9q34.3 microdeletion patients and patients with an intragenic EHMT1 mutation. Thus, to further expand the genotypic and phenotypic knowledge about the syndrome, we here report 29 newly diagnosed patients, including 16 patients with a 9q34.3 microdeletion and 13 patients with an EHMT1 mutation, and review previous literature. The present findings are comparable to previous reports. In addition to our former findings and recommendations, we suggest cardiac screening during follow-up, because of the possible occurrence of cardiac arrhythmias. In addition, clinicians and caretakers should be aware of the regressive behavioral phenotype that might develop at adolescent/adult age and seems to have no clear neurological substrate, but is rather a so far unexplained neuropsychiatric feature.
Courtesy of a colleague
Verhoeven WM, Egger JI, Vermeulen K, van de Warrenburg BP, Kleefstra T. Kleefstra syndrome in three adult patients: further delineation of the behavioral and neurological phenotype shows aspects of a neurodegenerative course. Am J Med Genet A. 2011 Oct;155A(10):2409-15.
ReplyDeleteAbstract
Kleefstra syndrome (KS), previously known as the 9q subtelomeric deletion syndrome (9qSTDS) is caused by haploinsufficiency of the EHMT1 gene. Both a single mutation and 9q34 microdeletions encompassing the entire gene can be responsible for this syndrome which is characterized by intellectual disability, hypotonia, and typical dysmorphisms, and may be associated with congenital heart and/or renal defects and epilepsy. Its behavioral phenotype has recently been described and comprises particular sleep disturbances and apathy. In this report, the evolution of the behavioral profile of KS is outlined by the description of three female patients aged 19, 33, and 43 years, respectively. In two patients, the syndrome was caused by an intragenic mutation and in the third by a 9q34 microdeletion encompassing the EHMT1 gene. MRI scanning of the brain in the two eldest patients demonstrated multifocal subcortical signal abnormalities. In general, the severity of the behavioral and motor deficiencies increased over time and became apparent after adolescence. It is concluded that the "regressive" phenotype of KS seems to be associated with the EHMT1 gene in particular. In addition, the utility of uncritical use of a classificatory diagnostic approach is discussed in the context of the motor and motivational disturbances that are prominent in this syndrome.
Courtesy of a colleague.