De novo mutation in KMT2C and SETD1A manifesting as Kleefstra syndrome 2: case report and literature review

*Correspondence: [e-mail].

Abstract

Case Presentation: We report a case of a White male child born in 2005, in São Paulo - Brazil. He was seen as an outpatient for the first time in 2020 due to recurrent seizures, self-injurious behavior and agitation. He is the first child of an uneventful pregnancy of healthy parents. Born at 9 months with Apgar score of 10. After birth, he had bouts of cyanosis and cow's milk protein allergy. At 1 year and 4 months old, he acquired a pulmonary infection and developed hives due to an allergic reaction to amoxicillin. He was hospitalized due to anaphylactic shock, bronchoaspiration and severe septicemia. He had been in a coma for 48 hours and when he woke-up he already had a squint and stopped talking. Diagnosis of hypoxic-ischemic encephalopathy was questioned. At age 3, he underwent inguinal hernia surgery. At the age of 11, generalized tonic-clonic seizures began, triggered every 2 or 3 months, with a frequency of 3 crises per month. Seizures were controlled with levetiracetam and valproic acid. At the same time, he developed self-injurious behavior, agitation, headache and insomnia. Behavioral symptoms were partially controlled with levomepromazine and did not respond to olanzapine, quetiapine, risperidone, aripiprazole or clonazepam. He had a past medical history of stomach ulcer, intestinal ulcerative colitis and inguinal hernia surgery. Family history was negative for neurologic disease, he has a healthy younger sister. An MRI of the head showed discrete signs of incomplete inversion, left hippocampal malrotation. CSF and lab tests were unremarkable. An exoma was performed that showed de novo mutations in the genes SETD1A and KMT2C, responsible for developmental delay, epilepsy and Kleefstra sydrome-2.

Discussion: Kleefstra syndrome (SF) is an autosomal dominant disease caused by EHMT1 haploinsufficiency, characterized by delay in neuropsychomotor development, intellectual disability and dysmorphic features. Although cases of KLEFS1 have been reported, the number of cases of KLEFS2 are rare in the literature. This study reports a case of KLEFS2, providing a narrative of clinical features, genetic test results, pharmacologic treatment, and long-term follow-up. Kleefstra 2 syndrome is a rare condition, and its diagnosis is difficult mainly due to the high clinical phenotypic heterogeneity.

Final Comments: We report a rare case of a young child with developmental delay, seizures and self-injurious behavior that was diagnosed with mutations in genes SETD1A and KMT2C genes compatible with Kleefstra 2 syndrome.

 

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Publication History

Article published online:
12 May 2025