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. 2024 May;194(5):e63472.
doi: 10.1002/ajmg.a.63472. Epub 2023 Dec 29.

Growth, body composition, and endocrine-metabolic profiles of individuals with Kleefstra syndrome provide directions for clinical management and translational studies

Arianne Bouman  1   2 , Joyce M Geelen  3 , Joost Kummeling  1   2 , Annette Schenck  1   2 , Yvonne G van der Zwan  4 , Willemijn M Klein  5 , Tjitske Kleefstra  1   2   6   7
Affiliations

Growth, body composition, and endocrine-metabolic profiles of individuals with Kleefstra syndrome provide directions for clinical management and translational studies

Arianne Bouman et al. Am J Med Genet A. 2024 May.

Abstract

Mendelian neurodevelopmental disorders caused by variants in genes encoding chromatin modification can be categorized as Mendelian disorders of the epigenetic machinery (MDEMs). These disorders have significant overlap in molecular pathways and phenotypes including intellectual disability, short stature, and obesity. Among the MDEMs is Kleefstra syndrome (KLFS), which is caused by haploinsufficiency of EHMT1. Preclinical studies have identified metabolic dysregulation and obesity in KLFS models, but proper clinical translation lacks. In this study, we aim to delineate growth, body composition, and endocrine-metabolic characteristics in a total of 62 individuals with KLFS. Our results revealed a high prevalence of childhood-onset overweight/obesity (60%; 28/47) with disproportionately high body fat percentage, which aligns perfectly with previous preclinical studies. Short stature was common (33%), likely due to advanced skeletal maturation. Endocrine-metabolic investigations showed thyroid dysregulation (22%; 9/41), elevated triglycerides, and decreased blood ammonia levels. Moreover, hand radiographs identified decreased bone mineralization (57%; 8/14) and negative ulnar variance (71%; 10/14). Our findings indicate a high (cardio)metabolic risk in KLFS. Therefore, we recommend monitoring of weight and endocrine-metabolic profile. Supporting a healthy lifestyle and screening of bone mineralization is advised. Our comprehensive results support translational research and contribute to a better understanding of MDEM-associated phenotypes.

Keywords: 9q34.3; EHMT1; Kleefstra syndrome; MDEM; body composition; growth; metabolism.

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Conflict of interest statement

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationship that would be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Growth parameters in 48 Dutch participants with Kleefstra syndrome (KLFS) caused by a EHMT1 pathogenic variant or 9q34.3 deletion <1.3Mb. Graphs A. and B. show decrease in height Z-scores throughout childhood and adolescence. Graphs A. and C. show that the mean head circumference is lower than the population average, but remains stable over time. Graphs A., D., and E. show an increase in weight and BMI throughout childhood and adolescence. Graph F. shows a significant increase in waist circumference (WC) compared to hip circumference (HipC). Graph G. shows a large decrease in height Z-score in individuals who have a short stature above the age of 21 years.
Figure 2
Figure 2
Results of biochemical endocrine-metabolic evaluations and its distribution per age in Kleefstra syndrome (KLFS). The white area in the graphs shows the reference range for sex and age in the healthy population.
See this image and copyright information in PMC

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References

    1. Abramowitz MK, Hall CB, Amodu A, Sharma D, Androga L, Hawkins M. Muscle mass, BMI, and mortality among adults in the United States: A population-based cohort study. PLoS One. 2018;13(4):e0194697. doi: 10.1371/journal.pone.0194697. - DOI - PMC - PubMed
    1. Balemans MC, Ansar M, Oudakker AR, van Caam AP, Bakker B, Vitters EL, van der Kraan PM, de Bruijn DR, Janssen SM, Kuipers AJ, Huibers MM, et al. Reduced euchromatin histone methyltransferase 1 causes developmental delay, hypotonia, and cranial abnormalities associated with increased bone gene expression in Kleefstra syndrome mice. Developmental Biology. 2014;386(2):395–407. - PubMed
    1. Bocca-Tjeertes IF, van Buuren S, Bos AF, Kerstjens JM, Ten Vergert EM, Reijneveld SA. Growth of preterm and full-term children aged 0-4 years: Integrating median growth and variability in growth charts. The Journal of Pediatrics. 2012;161(3):460–465.:E1. - PubMed
    1. BoneXpert. Bone health index. (n.d.) https://bonexpert.com/what-is-bone-age/#bonehealthindex.
    1. Browning LM, Hsieh SD, Ashwell M. A systematic review of waist-to-height ratio as a screening tool for the prediction of cardio-vascular disease and diabetes: 0.5 could be a suitable global boundary value. Nutrition Research Reviews. 2010;23(2):247–269. - PubMed

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