Speech, language and communication in Kleefstra syndrome: what an international study of 103 individuals showed

Speech delay is one of the features most frequently reported in Kleefstra syndrome. For many years, however, scientific descriptions were limited to general statements such as «severe speech delay,» «limited speech,» or «non-verbal communication.» This left important questions unanswered for families and therapists: Is the difficulty primarily in language or in the production of sounds itself? Do children understand more than they can say? How common is speech apraxia? When should Augmentative and Alternative Communication be introduced? And does the use of an AAC system hinder a child from developing spoken language?;

A large international study published in 2024 in Journal of Medical Genetics try to answer these questions systematically. The work of Lottie D. Morison, Angela T. Morgan, Tjitske Kleefstra and colleagues assess speech, language, non-verbal communication, and cognitive function 103 individuals with molecularly confirmed Kleefstra syndrome.

And one of its most important conclusions can be summarized in a single sentence:

A person having difficulty speaking does not necessarily mean they do not understand or that they do not have things to communicate.

An international team of 103 people with Kleefstra

The study involved 103 people from 26 countries, aged from about 19 months to 43.5 years, with a median age of 9.5 years. 40 were male. From a genetic perspective, 52 had a deletion of the 9q34.3 region, 50 had an intragenic pathogenic variant of EHMT1 and one person had a balanced chromosomal translocation that disrupted the EHMT1.

This is important because the researchers did not study just one very specific genetic subtype. They included individuals with different molecular mechanisms and with very different ages and levels of functionality.

Standardized tools for language, cognitive and adaptive function, social communication, and speech production were used for the assessment, while information on the use of Augmentative and Alternative Communication was also collected — Augmentative and Alternative Communication, AAC.

The cognitive picture is much more diverse than previously thought

Of the 79 individuals for whom cognitive assessment was available, 67 had some degree of intellectual disability. However, the severity varied significantly: 16 individuals had mild, 38 moderate, and 12 severe intellectual disability, while in one individual the degree had not been determined.

The striking finding was that 12 of the 79 individuals, or approximately 15%, had cognitive function in the average range, although five of them reported borderline cognitive function. One of the study participants had even completed postgraduate university studies, while another was attending a general school at the expected level for his age.

This finding reinforces what more recent genetic studies also show: the KLEFS1 spectrum is much broader than the older picture of a syndrome associated almost exclusively with moderate or severe intellectual disability.

However, an even more interesting element appears here.

Speech and language are not the same thing

In everyday life, we often use the words «speech,» «language,» and «tongue» as if they mean the same thing. Clinically, however, they are not the same.

Η language it concerns, among other things, whether a person understands words and sentences and can form and convey meanings.

Η speech it concerns the physical production of these words: the planning and coordination of movements of the mouth, tongue, jaw, and breathing, the articulation of sounds, voice, rhythm, and prosody.

And the study by Morison and colleagues showed that this distinction is particularly important in Kleefstra.

Of the individuals who could be evaluated for speech and used oral communication, 48 out of 49 — 98% — had a speech disorder. Even more interesting is that such impairments were also present in certain individuals whose language and cognitive function were at a much better level.

In other words, a person can he knows what he wants to say and understands much more than his spoken speech allows him to express.

This is perhaps one of the most important messages of the study for parents, educators, and therapists.

Dysarthria and childhood apraxia of speech were very common

The researchers didn't just limit themselves to recording that «speech was delayed.» They tried to determine what kind of speech disorder was there.

Among the 49 verbal items evaluated in detail:

34 of the 49 (69%) exhibited dysarthria, while
29 of the 49 (59%) had childhood apraxia of speech (CAS).

In 16 people, meaning about one-third of this specific group, dysarthria and apraxia coexisted. Articulatory disorders and phonological difficulties were also recorded.

Η dysarthria it concerns difficulties in the neuromuscular control of speech. Voice volume, rate, articulation, breathing, or prosody may be affected.

Η childhood apraxia of speech, on the contrary, it is primarily a disorder of speech motor planning and programming: the child may know the word they want to say, but the brain has difficulty accurately planning and organizing the sequence of movements required to produce it.

The fact that both speech motor disorders appeared so frequently led the authors to argue that the Motor speech disorders are a core part of the Kleefstra communication phenotype.

This also has practical significance: a general assessment that «the child has a speech delay» is not always enough. It is necessary, when possible, specialized evaluation of speech production itself, so that the intervention is adapted to the actual mechanism of the difficulty.

How understandable was the speech?;

The study also showed something that many families likely recognize from their daily lives.

Individuals with Kleefstra syndrome typically became much easier to understand by the people who knew them well. Parents and primary caregivers reported that they usually understood their speech. However, intelligibility decreased when the interlocutor was a member of the extended family or a friend, and decreased even further when it was an acquaintance or a stranger. Only five participants were characterized as «always» intelligible.

This shows why functional communication should not be assessed only within the home or in a therapeutic environment where everyone already knows the child.

A child can communicate effectively with their mother or father and at the same time experience great difficulty when trying to make themselves understood at school, in the community, or from a stranger.

The language also exhibited tremendous variability

Language proficiency was not the same for everyone.

In the 90 individuals for whom relevant data were available, overall communicative performance ranged from severe difficulty to the average range. Ten individuals had communication scores in the average range.

Another interesting finding was that the researchers did not find a significant difference between receptive and expressive language at the group level. That is, a simple generalization of the type «in Kleefstra comprehension is always much better than expression» was not confirmed.

This does not mean that for a specific child, comprehension cannot be clearly better than their expression. It means that when the entire group was examined, there was no single standard that applied to everyone.

And this is yet another reminder that in Kleefstra, individual assessment has greater value than general predictions.

The 59% used Augmentative and Alternative Communication

One of the most important findings of the study concerns Augmentative and Alternative Communication (AAC).

Overall, 61 of the 103 individuals — 59% — had used some form of AAC.

AAC does not just mean electronic devices. In the study, it included gestures and signs, boards or other low-tech systems, as well as speech-generating devices and other technological systems.

More than half of the participants, 53/103, they had used signs. 37/103 they had used an aided AAC system, either low or high tech. One individual was even in the process of learning an eye-gaze controlled system.

And here is a very important element:

AAC was not only used by non-verbal individuals.

Of the participants who used sign language or some aided AAC system, several were also able to speak — and 22 of the 103 people were even able to use spoken sentences.

So AAC should not be treated exclusively as a «speech replacement.».

It might work alongside the speech, offering a second, more reliable way of communication when oral expression is not sufficiently understandable or when the person has difficulty expressing more complex messages.

«If we give him AAC, won't he try to speak?»

The study also recorded a concern that exists in many families.

Out of the 94 caregivers who answered the relevant question, 19 — approximately 20% — believed that the use of AAC could hinder the development of natural speech.

The authors address this perception with particular clarity. They point out that AAC should not be considered an obstacle to speech development and that it can instead support essential communication skills, such as turn-taking, symbolic communication, and the ability to express one's needs and choices.

Therefore, one of the central conclusions of the paper is the need for early access to media communication, without waiting first for it to be proven that oral speech «will not come.» The authors believe that early access to AAC can support communication and quality of life.

This point is particularly important for Kleefstra, precisely because an individual may have greater linguistic or cognitive ability than is apparent from his speech.

Communication is not just about «asking for something»

In a subgroup of 41 participants, the Communication Matrix, a tool that examines different functions of communication.

The greatest relative capabilities were identified in communication for denial of one thing and for the acquisition or the request of something. On the contrary, communication for social reasons and especially for the exchange of information was more difficult.

This has practical value for the design of the intervention.

The goal of a communication system should not only be to enable a child to say «I want water», «I want food» or «no».

Communication also means:

to narrate something that happened, to ask a question, to share a thought, to comment, to express an emotion, to participate in a conversation and to build social relationships.

The study therefore supports the need to address communication much broader than the simple expression of basic needs.

What did the study find regarding the loss of previously acquired skills?;

The paper also examined the issue of developmental and functional regression.

Out of the 80 people for whom the relevant questionnaire was completed, 11 — 14% — had experienced a loss of previously acquired skills. The loss most frequently involved language (9/11), but was also recorded in social, fine motor, and gross motor skills.

The age of onset varied significantly. In six individuals, remission began between 12 and 28 years of age, while in five it had appeared before 4 years of age. In several individuals it occurred later partial skills recoveryseven of the nine individuals who had lost language skills regained at least some of them.

Parents reported illness, epileptic seizures, or significant life changes as potentially temporally associated events. However, these were retrospective family reports and do not prove a causal relationship. The authors themselves emphasize that the mechanism of functional regression in Kleefstra remains unknown and that prospective natural history studies are required.

Another interesting finding was that four individuals started using AAC again when the loss of skills affected their speech and language.

This highlights yet another reason why AAC can be lifelong communication tool and not just an intervention for early childhood.

Can we predict speech from genetic variation?;

Generally speaking, no.

Despite the wide variety of genetic alterations included in the study, the researchers they did not identify a clear new genotype-phenotype relationship which could explain the wide variation in speech and language among individuals. Nor could age explain to a significant degree the variability in communicative ability.

However, the earlier observation that the larger deletions over 1 Mb tend to be associated with a more severe overall phenotype. For the smaller deletions and the various intragenic variants of EHMT1, however, the picture was much more variable.

Again, this means that the result of a genetic test it cannot tell us with certainty today how a specific child's communication will develop.

The need for early as well as lifelong support

The authors of the study do not propose a specific therapeutic protocol for all individuals with Kleefstra. Instead, they emphasize that the range of difficulties is so vast that the intervention must be personalized.

A child with childhood apraxia of speech may need a different therapeutic approach than a child with a predominantly dysarthric pattern. An individual with minimal verbal speech may need a comprehensive AAC system, whereas a verbal child may also benefit from AAC as a supplementary mode of communication when they are not understood.

And the needs do not stop when the child grows up.

Researchers emphasize the need for lifelong access to personalized speech, language, and communication services, especially as needs change during school age, during the transition to adulthood, or in the event of a loss of already acquired skills.