Authors: Pedro Solorzano, MD and Destiny F. Chau, MD - Arkansas Children’s Hospital/University of Arkansas for Medical Sciences, Little Rock, AR
A 4-year-old child with Kleefstra syndrome and obstructive sleep apnea presents for tonsillectomy and adenoidectomy. Which of the following cardiac defect is MOST commonly associated with Kleefstra syndrome?
EXPLANATION
Kleefstra Syndrome, previously “9q subtelomere deletion syndrome”, is a rare disorder linked to microdeletions or mutations on 9q34.3, which is related to the Euchromatin Histone Methyl Transferase 1 (EHMT1) gene. This gene encodes a histone methyltransferase enzyme involved in chromatin remodeling. Although most reported cases to date involve de novo mutations, autosomal dominant familial inheritance occurs in cases of balanced translocations or somatic mosaicism.
The phenotype for Kleefstra syndrome includes microcephaly, arched eyebrows, synophrism (unibrow), hypertelorism, anteverted nares, mid-face hypoplasia, macroglossia, and prognathism. Typical facial features of a patient with Kleefstra syndrome are illustrated in the picture below.
Figure: Phenotypical features of Kleefstra syndrome. Karlak et al. Creative Commons License
Major associated defects include congenital heart disease (40%), urogenital disease (50%), recurrent infections (60%), intellectual disability (100%), behavioral problems (75%), obesity (40%), hearing deficits (25%), and seizures (25%). The behavioral/ psychiatric issues have been observed to worsen after puberty. An increasing number of EHMT1 mutations have been detected in patients with the Kleefstra syndrome phenotype in recent years.
Analysis of the two largest known Kleefstra syndrome registries has demonstrated a 40% prevalence of cardiovascular abnormalities including atrial septal defects (14%), ventricular septal defects (12%), Tetralogy of Fallot with pulmonary valve stenosis (8%), cardiomyopathy (1%) and vascular malformations (9%). It also revealed a prevalence (8%) of early-onset arrhythmias including atrial fibrillation, supraventricular tachycardia, and ventricular tachycardia, in the absence of structural heart disease. Pulmonary hypertension (PH) in patients with repaired congenital heart disease with severity out of proportion to the preoperative pathophysiology has been observed in patients with Kleefstra syndrome. Concurrent sleep apnea likely contributes to the severity of PH in some patients with this syndrome.
Patients with Kleefstra syndrome present for a range of procedures necessitating anesthetic care. A thorough multisystem preoperative evaluation is essential for delineating anesthetic considerations and comprehensive perioperative planning. In addition to congenital heart disease, cardiovascular assessment should include screening for pulmonary hypertension and malignant arrhythmias, even in the absence of structural heart disease. Phenotypical facial features may cause difficulty with airway management. Associated congenital cardiac lesions warrant anesthetic management tailored to the specific cardiac defect.
Of the three choices listed, this patient is most likely to have had an atrial septal defect (ASD). ASDs and ventricular septal defects are the most prevalent congenital cardiac lesions associated with Kleefstra syndrome. At present, left sided heart defects such as coarctation of the aorta and hypoplastic left heart syndrome are rarely reported in patients with Kleefstra syndrome.
REFERENCES
Kleefstra Syndrome UK. Accessed November 14, 2023. https://www.kleefstrasyndrome.org/
Karlak V, Jankowski J, Kolasińska J, Nijakowski K. Kleefstra Syndrome—Dental Manifestations and Needs: A Case Report with a Literature Review. Case Rep Dent. 2023;2023:2478465. doi: 10.1155/2023/2478465
Willemsen MH, Vulto-van Silfhout AT, Nillesen WM et al. Update on Kleefstra Syndrome. Mol Syndromol. 2012;2(3-5):202-212. doi: 10.1159/000335648
Volkan Okur, Nees SN, Chung WK, Krishnan U. Pulmonary hypertension in patients with 9q34.3 microdeletion-associated Kleefstra syndrome. Am J Med Genet A. 2018;176(8):1773-1777. doi: 10.1002/ajmg.a.38852
Vasireddi SK, Draksler TZ, Bouman A et al. PO-04- 124 arrhythmias including atrial fibrillation in KLEEFSTRA syndrome: A possible epigenetic link. Heart Rhythm. 2023;20(5): S597-S598. doi:10.1016/j.hrthm.2023.03.1263
Campbell CL, Collins RT, Zarate YA. Severe neonatal presentation of Kleefstra syndrome in a patient with hypoplastic left heart syndrome and 9q34.3 microdeletion. Birth Defects Res A Clin Mol Teratol. 2014;100(12):985-990. doi:10.1002/bdra.23324
