Weight, growth and metabolism in Kleefstra syndrome: New study of 62 individuals

Kleefstra syndrome is known primarily as a neurodevelopmental disorder. Hypotonia, developmental delay, communication difficulties, and intellectual disability are usually at the center of both clinical monitoring and discussion with families. However, as the number of individuals systematically monitored in specialized centers grows, it is becoming increasingly clear that Kleefstra is not only about the brain and development.

An important study by Arianne Bouman, Joyce Geelen, Joost Kummeling, Tjitske Kleefstra and colleagues examined for the first time in such a systematic way the development, body composition, bone health, and the endocrinological and metabolic profile of people with Kleefstra syndrome. The work was published in American Journal of Medical Genetics Part A, with electronic first publication on December 29, 2023, and inclusion in the May 2024 issue.

A total of 62 individuals with molecularly confirmed Kleefstra syndrome, aged 2 to 57 years. 38 of them had a pathogenic variant in the EHMT1 and the 24q34.3 deletion. The average age of the participants was approximately 19 years. The data came mainly from the specialized center of Radboud University Medical Center in Nijmegen and combined growth measurements, body composition, imaging, and hematological and biochemical tests.

The main conclusion was clear: People with Kleefstra seem to have an increased predisposition to overweight and obesity, increased body fat, and certain metabolic and endocrine disorders, and several of these changes already begin in childhood.

Weight begins to increase as early as childhood

One of the most striking findings was the frequency of overweight and obesity.

Out of the 47 individuals for whom suitable data were available, 28 — approximately 60% — were overweight or obese. Researchers observed that the increase in BMI was not just a characteristic of adults. It appeared to develop gradually during childhood and adolescence. Even in the 2–12 age group, more than half of the participants who could be evaluated were already overweight or obese.

This is of particular importance, because weight gain in Kleefstra can easily be attributed solely to reduced mobility, hypotonia, dietary habits, or medications. However, the study argues that the picture is likely more complex.

The EHMT1 It participates in epigenetic mechanisms that regulate the function of many other genes. Previous animal experimental models had already shown that the EHMT1/EHMT2 protein family is linked to fat metabolism and energy homeostasis. The new clinical study showed that this metabolic predisposition seems to have a corresponding imprint in humans with Kleefstra as well. This of course it does not mean that increased weight is inevitable, nor that every person with Kleefstra will develop obesity. It means that weight is worth monitoring actively and early, rather than being considered a secondary issue to be addressed only when there is a significant increase.

It's not just the weight that matters, but also where the fat is located

Researchers did not limit themselves to the body mass index. They also measured the waist and hip circumference, arm circumference and, in a smaller subgroup, body composition by bioelectrical impedance or DEXA.

The waist circumference was disproportionately increased compared to the hip circumference, an element indicating a greater concentration of fat in the abdominal area. The mean waist-to-height ratio was also increased.

In seven women who underwent a more detailed body composition analysis, all of them had a higher body fat percentage than expected. Of particular interest is that even three women with a normal BMI had an increased fat percentage.

This shows a major limitation of the BMI: a number on the scale or a «normal» body mass index it does not always accurately describe body composition.

For Kleefstra, then, clinical monitoring may need to look not only at weight, but also waist circumference, physical activity, muscle mass, and, where indicated, the broader metabolic profile.

Shorter stature in a significant percentage

The study also confirmed that short stature It is a common feature of the syndrome.

Approximately The 33% group of participants was of short stature. In most of those for whom data on parental height were available, the final or last recorded height was lower than what would have been expected based on familial growth potential.

The growth curves showed that height tends to gradually deviate from the average during childhood and adolescence. The authors believe that a likely contributing factor is advanced skeletal maturation, which may limit the time period during which growth continues.

This does not mean that all children with Kleefstra will have short stature. As with most features of the syndrome, there is a wide variation. However, it supports the importance of systematically recording height and weight over time rather than just a single measurement.

A finding that requires attention: bone health

The study also brought to light a lesser-known issue: the bone mineralization.

In 14 individuals who had hand radiographs available for evaluation, 8 of the 14 — 57% — showed reduced bone mineralization. In addition, 10 out of the 14 had negative ulnar variance, meaning the ulna was relatively shorter in length compared to the radius.

These numbers require careful interpretation because they come from very small subgroup and do not mean that all 57% individuals with Kleefstra have low bone density.

The authors, however, believe that the findings are significant enough to warrant greater vigilance regarding bone health, particularly during adolescence or when multiple or unusual fractures are present.

The thyroid also needs monitoring

Researchers performed an endocrinological and metabolic screening on part of the team.

Out of the 41 individuals examined for thyroid function, 9 — 22% — exhibited some form of disorder. The percentage was higher than that expected in the general population.

The disorders did not all have the same cause. In one person, it was found central hypothyroidism, meaning a disorder in which the problem does not necessarily lie in the thyroid gland itself, but in its hypothalamic-pituitary regulation. The authors point out that this needs further study and cannot be considered an established feature of the syndrome from a single case.

The practical message is that when checking thyroid function, it is valuable to evaluate both TSH and free T4, especially when there are symptoms or clinical suspicion.

Elevated triglycerides and signs of metabolic risk

In the biochemical tests, another finding that stood out was the increase in triglycerides.

Compared to healthy individuals of the same age and sex, participants with Kleefstra had significantly higher triglyceride levels. In contrast, the researchers found no correspondingly significant differences for total cholesterol, HDL, and LDL.

The overall picture —frequent obesity, increased abdominal fat accumulation, high body fat percentage, and metabolic changes— led the authors to conclude that individuals with Kleefstra may be at increased cardiometabolic risk.

This does not mean that a child with Kleefstra has or will develop diabetes or cardiovascular disease. It means that prevention and monitoring become more important, especially when excess weight, reduced physical activity, or other risk factors coexist.

What did they find regarding glucose and metabolism?;

The study also included tests for glucose, HbA1c, and other metabolic markers. The authors, combining clinical data with body composition results and previous experimental models, believe that there is reason to monitor the insulin sensitivity and glucose metabolism, especially in individuals with obesity.

However, it is important not to translate this observation as «Kleefstra causes diabetes.» This specific study did not show that all or most participants had diabetes mellitus. The message is that there are enough metabolic indications to justify preventive laboratory screening.

Vitamins and other biochemical markers

The researchers also examined vitamin D, vitamin B12, folic acid, and a series of other biochemical parameters.

In the overall evaluation, it was identified vitamin deficiencies in some of the participants, which led the authors to include testing for vitamin D, B12, and folic acid in the recommended metabolic workup, particularly from the onset of puberty onwards.

An unusual finding was also that the levels blood ammonia was lower than those of the control groups. The clinical significance of this finding is not yet clear, and the authors view it more as a potential biological marker worthy of further research rather than something requiring specific treatment.

What do the researchers suggest for monitoring?;

Perhaps the most useful part of the paper for families and health professionals is that the authors did not limit themselves to describing the findings. They formulated specific proposals for clinical monitoring.

They propose lifelong control of weight and waist circumference, along with supporting as healthy a lifestyle as possible. For bone health, they consider it advisable to assess bone mineralization around the onset of puberty and earlier or repeatedly when there are multiple or unusual fractures.

For the thyroid, they recommend screening at the onset of puberty with TSH and fT4, so that potential cases of central hypothyroidism are not missed. At the same time, they recommend screening for glucose metabolism, lipid profile, and levels of vitamin D, B12, and folic acid starting from adolescence.

In children with obesity, the authors suggest starting corresponding metabolic monitoring as early as around the age of 8–10 years old and to be repeated at intervals determined according to the clinical picture.

These proposals come from the specific research team and study data; they should not be treated as a rigid examination schedule that is the same for every person. Follow-up always needs to be personalized by the pediatrician, the clinical geneticist, the endocrinologist, or the team that knows the patient.

Psychiatric treatment and metabolic control

Another point of the work is of particular practical value for Kleefstra.

Some individuals with the syndrome may require psychiatric medication during their lifetime. Some of these medications can affect weight, glucose metabolism, and the lipid profile.

The authors therefore emphasize that before or during the administration of psychiatric treatment, the possibility must also be taken into account physical causes that may worsen behavior or functionality, such as hypothyroidism or certain nutritional deficiencies. At the same time, metabolic monitoring becomes more important when medications with a known effect on weight are used.

This is particularly important in a syndrome in which behavior, sleep, mental health, and physical health may interact.

Why might EHMT1 also affect metabolism?;

The study is of interest not only clinically but also biologically.

The EHMT1 It is an epigenetic regulatory gene. The EHMT1 protein cooperates with EHMT2 and affects gene expression through chromatin modifications. This means that the loss of one functional copy of the EHMT1 can alter the function of many different biological pathways — not just those directly related to neuronal development.

In experimental models, the disruption of the same molecular family has been linked to changes in adipose tissue development, lipid metabolism, and the way the body manages energy reserves. The correspondence of these experimental findings with the high frequency of increased body fat in the study participants leads researchers to believe that the metabolic profile is a real part of the syndrome's biology and not merely a consequence of reduced activity.

Nevertheless, the picture remains multifactorial. Hypotonia, motor disability, dietary preferences, sleep, medications, and the environment can also significantly affect a specific person's weight.