Kleefstra syndrome

What is Kleefstra syndrome?

Kleefstra syndrome is a genetic condition that exhibits a wide range of symptoms that may affect multiple areas and systems of the body.

The more common symptoms include intellectual disability, low muscle tone, seizures and characteristic facial features.

This rare disease was officially identified as Kleefstra syndrome in April 2010, making it a recently identified syndrome.

Syndrome Synonyms:
9q Subtelomeric Deletion Syndrome 9q- Syndrome Chromosome 9q34.3 Deletion Syndrome Kleefstra syndrome Kleefstrasyndrome

What gene changes cause Kleefstra syndrome?

Deletions from the EHMT1 gene on chromosome 9 are responsible for the development of the syndrome.

The disease is not inherited but the result of de novo deletions. In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.

What are the main symptoms of Kleefstra syndrome?

The main symptoms, which may vary in their severity between individuals, include developmental delay and intellectual disability. Delayed or no speech is characteristic of the syndrome.

Individuals are often born with a high birth weight and obesity in childhood. In adolescence the syndrome may trigger apathy and or catatonia.
The syndrome may also cause developmental disorders similar to those associated with Autism, as well as other behavioral issues.

Physical conditions of the syndrome include dental abnormalities, low muscle tone, strabismus or squint in the eyes and hearing loss. The hands of individuals with the syndrome may have a single palm crease, in-curving fingers. Incurving feet are also not uncommon.

Other health conditions associated with the syndrome include kidney issues, and connective tissue disorders. Respiratory infections are common, as are seizures and possible brain abnormalities.

Possible clinical traits/features:
Cryptorchidism, Feeding difficulties in infancy, Autosomal dominant inheritance, Thin vermilion border, Autistic behavior, Patent ductus arteriosus, Intellectual disability, Muscular hypotonia, Cleft palate, Atrial septal defect, Abnormality of the dentition, Microcephaly, Hypermetropia, Short stature, Global developmental delay

How does someone get tested for Kleefstra syndrome?

The initial testing for Kleefstra syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow. 

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.   

Medical information on Kleefstra Syndrome

Common features in patients with Kleefstra syndrome include intellectual disability, hypotonia, brachymicrocephaly, epilepsy, heart defects, and a flat face with hypertelorism, synophrys, anteverted nares, everted lower lip, and macroglossia. This syndrome is typically caused by haploinsufficiency of the EHMT1 gene, located in the subtelomeric region of chromosome 9q.
In the series of Knight et al., (1999) two severely intellectually disabled sisters (six and 11 years old) with a der(9)t(9;13)(q34;p11.1) were reported. Both were severely hypotonic with similar dysmorphism: brachymicrocephaly, coarse facies, long eyebrows with synophrys, large tongue, upturned nose with prominent nares, tented mouth, short philtrum, and low-set posteriorly rotated ears. Both sisters had periventricular white matter changes, epilepsy, joint laxity and sensorineural deafness. The youngest also had a congenital heart abnormality (PDA, PFO and VSD). The mother was the carrier of the balanced t(9;13).
Rossi et al., (2001) reported a de novo 9qter deletion in a moderately intellectually disabled child with facial dysmorphism (not further specified); Anderlid et al., (2002) in a 25-year-old severely intellectually disabled woman with epilepsy, synophrys, hypertelorism and strabismus; and Rio et al., (2002) in a severely intellectually disabled female with obesity, abnormal genitalia and hyperactivity.
Cormier-Daire et al., (2003) suggest that obesity might be characteristic of 9qter deletions.
A further 12 patients from 11 families were reported by Stewart et al., (2004). Five had previously been reported. Facial features (brachycephaly, synophris, anteverted nostrils, thin or tented upper lip, macroglossia) were very similar to those reported by Cormier-Daire et al., (2003), but obesity was not a feature. Looking at the excellent photos published in this report, the lower lip seems prominent and everted.
The patient reported by Quigley et al., (2004) with a submicroscopic deletion of 9q34 and duplication of 19p13 was intellectually disabled, microcephalic and had alopecia universalis.
Five cases were reported by Yatsenko et al., (2005). One looked like trigonocephaly C. Three cases were reported by Neas et al., (2005). These authors show pictures of one of the cases, with coarse facial features.
Kleefstra et al., (2006) showed a case without the classical phenotype. Using a patient with a balanced translocation, Kleefstra et al., (2005) showed haploinsufficiency of EHMT1 (euchromatin histone methyl transferase 1) was responsible for the 9q subtelomeric deletion syndrome. This was confirmed in a larger series of patients by Kleefstra et al., (2006).
Klitten et al., (2009) reported a case with a diaphragmatic hernia.
Verhoeven et al., (2011), reported three female patients. MRIs showed multifocal subcortical signal abnormalities, and there was a suggestion of regression.
In a cohort of individuals without an EHMT1 mutation, mutations were found in MBD5, MLL3, SMARCB1 and NR113 (Kleefstra et al., 2012). All encode epigenetic regulators.
Rump et al., (2013) reported a patient whose normal mother (except for minor facial dysmorphism) was mosaic.
A severe case with a hypoplastic left heart and multiple renal cysts was reported by Campbell et al., (2014). Duplications of EHMT1 can also cause this syndrome (Schwaibold et al., 2014).
Samango-Sprouse et al., (2016) described a girl with Kleefstra syndrome and a low-average intelligence - verbal IQ was 81, performance IQ 79, and global language IQ 89. As a child she had developmental delay, torticollis, hypotonia, swallowing difficulties and apraxia due to oral motor discoordination. Chromosomal microarray showed a de novo intragenic microdeletion of 17.8 kb in the 9q34.3 chromosomal region containing the EHMT1 gene. Vargiami et al., (2016) described a 20-month-old girl with Kleefstra syndrome with multiple coronary artery microfistulas, originating from the left main coronary artery and draining into the left ventricle. Bock et al., (2016) identified a de novo truncating mutation in the EHMT1 gene in an autistic girl with dysmorphic facial features typical of Kleefstra syndrome. Unlike other reported Kleefstra syndrome patients, this individual did not present with intellectual disability, brachycephaly, microcephaly, regressive phenotype, congenital structural heart defects, urogenital defects, epilepsy or overweight.
Blackburn et al., (2017) described two unrelated female patients with clinical characteristics of Kleefstra syndrome and a missense mutation in EHMT1, p.P809L. The mutation affects the conserved TPLX motif within the ankyrin repeat. Both patients showed intellectual disability, hypotonia in childhood, coarse facies, cardiac anomalies (aberrant right subclavian artery and atrial septal defect) and autism spectrum disorder. Additional findings in the first patient included overweight, cerebral ataxia, diastasis recti, hypermobility, sensory processing disorder, monocular elevation palsy, blue sclera, exotropia of the left eye, pointed chin, dysplastic ear helices, tracheomalacia, long tubular epiglottis and chronic lung disease. The second patient had a left kidney upper pole defect, left supernumerary nipple and reduced extension of the elbow. Her brain MRI showed white matter abnormalities in the periventricular and peritrigonal brain regions.
Three individuals with mosaic deletions in the EHMT1 gene were reported by de Boer et. al (2018) in apparently unaffected parents of children with Kleefstra syndrome. Psychological and psychiatric studies demonstrated autism spectrum disorder, major depression and reduced cognitive flexibility.
Three new and five previously reported patients with 9q34.3 deletions and pulmonary hypertension were reviewed by Okur et. al. (2018). Congenital heart anomalies included aortic stenosis, bicuspid aortic valve, coarctation of aorta, mitral stenosis, atrial septal defect, ventricular septal defect, double outlet of right ventricle, patent ductus arteriosus, and patent foramen ovale.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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