Rett-Like Phenotype in a Patient with a Novel Pathogenic FBXW7 Variant

Article information

Ann Child Neurol. 2025;33(2):77-79

Publication date (electronic) : 2025 April 1

doi : https://doi.org/10.26815/acn.2024.00724

Jee Min Kim, MD, Byung Chan Lim, MD

Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Korea

Corresponding author: Byung Chan Lim, MD Department of Pediatrics, Seoul National University Children’s Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-2072-2364, Fax: +82-2-743-3455 E-mail: prabbit7@snu.ac.kr

Received 2024 October 15; Revised 2024 December 31; Accepted 2025 February 3.

Protein synthesis and degradation are tightly regulated both spatially and temporally. The ubiquitin–proteasome system plays a crucial role in controlling protein degradation, with F‑box proteins (FBX) being particularly important for substrate recognition [1]. To date, 69 human FBX proteins have been identified [2]. FBXW proteins are characterized by their tryptophan-aspartic acid 40 (WD40) repeat domain. Neurodevelopmental syndromes related to FBXs—such as F-box and leucine rich repeat protein 4 (FBXL4), F-box protein 11 (FBXO11), F-box and WD repeat domain containing 7 (FBXW7), FBXW11, and FBXO28—are associated with neurodevelopmental disabilities and hypotonia [3]. Patients with FBXW11 pathogenic variants may exhibit microcephaly or macrocephaly, brain structure abnormalities, autistic and stereotypical behaviors, as well as ocular, digital, and mandibular anomalies [4]. A report on 35 patients with FBXW7 variants noted variable degrees of neurodevelopmental delay or intellectual disability; however, unlike patients with FBXW11 pathogenic variants, associations with autistic or stereotypical behaviors have rarely been reported [3].

According to Neul et al. [5], patients with Rett syndrome experience regression that includes the loss of purposeful hand skills and acquired spoken language, along with stereotypic hand movements and gait abnormalities. Some patients may also exhibit breathing abnormalities, bruxism, impaired sleep patterns, decreased pain sensitivity, and inappropriate laughing [5].

Here, we present a case of a 31‑month‑old female patient with a novel missense variant in FBXW7. She demonstrated clinical features resembling a Rett‑like phenotype, including hand stereotypies such as mouthing, wringing, and flapping, as well as bruxism, sleep disturbances, and abnormal breathing.

The patient presented to the pediatric neurology clinic with developmental delay and seizures. She was born at 40 weeks of gestation, weighing 3.1 kg, to non‑consanguineous parents following an uneventful delivery. Her development appeared normal until 7 months of age, when a delay in gross motor skills became apparent. She began walking independently at 24 months and remained nonverbal at 31 months. Her family history was unremarkable.

Seven months prior to the visit, at 24 months of age, she experienced a febrile seizure lasting 1 minute during an influenza infection. One month later, she began to exhibit hand‑mouthing stereotypies. At 30 months, she experienced three focal motor seizures involving clonic movement of the right lower extremity each lasting 1 minute. Her parents also reported frequent arousal during sleep.

Physical examination revealed thick eyebrows, hypertelorism, a high forehead, and a depressed nasal bridge. At 31 months, her height was 89 cm (10th–25th percentile), her weight was 14.2 kg (50th–75th percentile), and her head circumference measured 49 cm (75th–90th percentile). Her muscle tone was normal, and no pathological reflexes were observed. During the examination, she exhibited poor eye contact, hand‑wringing and flapping stereotypies, bruxism, and irregular breathing.

Laboratory tests, including a metabolic evaluation and brain magnetic resonance imaging, were within the normal range. Electroencephalography revealed intermittent diffuse delta activity and occasional spikes from the left centro-parietal area.

Chromosomal microarray analysis did not identify any pathogenic copy number variants. Methylation‑specific multiplex ligation‑dependent probe amplification for the 15q11–13 region (relevant to Prader–Willi syndrome and Angelman syndrome) showed a normal methylation pattern. Trio whole exome sequencing identified a de novo FBXW7 variant, c.1168T>C (p.Cys390Arg), which was classified as likely pathogenic based on the American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria. This variant is located in the first WD40 repeat domain. Fig. 1 illustrates the location of the FBXW7 variant in the three‑dimensional protein structure.

Fig. 1.

Three-dimensional (3D) protein structure of F-box and WD repeat domain containing 7 (FBXW7) p.Cys390Arg with substrate cyclin E1. Three-dimensional protein structure of FBXW7 interacting with the ubiquitin-activating enzyme (E1). F-box proteins interact with substrates destined for degradation, and with ubiquitin ligase and conjugating enzymes, facilitating protein ubiquitination. The tryptophan-aspartic acid 40 (WD40) domain forms an eight-bladed -propeller structure. The amino acid change in our patient’s FBXW7 variant, p.Cys390Arg, resides in the first WD repeat domain, but on the opposite side of the propeller-shaped surface that interacts with E1.

Freedom from seizures was achieved with oxcarbazepine and clobazam. At 37 months, the Bayley Scales of Infant and Toddler Development III indicated severe delays across all domains: gross motor (11 months), fine motor (5 months), cognition (4 months), receptive language (3 months), and expressive language (7 months). Her verbal expression was limited to the repetition of single syllables.

We report a novel missense variant in FBXW7 associated with features resembling a Rett‑like phenotype. From the age of 24 months, the patient exhibited hand stereotypies that initially presented as mouthing and evolved into wringing and flapping. Additional symptoms included abnormal breathing patterns and bruxism, which are suggestive of a Rett‑like phenotype. At 37 months, developmental assessment revealed severe delays across all domains, with no regression noted at 41 months. After a febrile seizure at age 2, the patient developed focal tonic seizures, which were well‑controlled with two antiseizure medications.

Genotype‑driven research has identified FBXW7 as a gene associated with neurodevelopmental disorders, with 35 individuals in 32 families reported to date [3]. Notable features of FBXW7 variants include mild to severe intellectual disability or global developmental delay in 86% of cases and seizures in 23%. FBXW11 and FBXW7 variants share several clinical features, such as neurodevelopmental problems, microcephaly or macrocephaly, and delays in speech and language development. Until recently, only eight patients with pathogenic variants in FBXW11 had been reported [4,6]. Interestingly, four of five patients with available clinical data exhibited autistic or stereotypical behaviors. This tendency for patients with FBXW11 pathogenic variants to present with prominent behavioral and psychiatric phenotypes, in addition to global developmental delay or intellectual disability, has been suggested as a distinguishing feature from patients with pathogenic FBXW7 variants [3]. To our knowledge, characteristic wringing and flapping hand stereotypies, poor eye contact, bruxism, as well as breathing and sleep abnormalities—in addition to severe developmental delay—have not previously been reported as part of the FBXW7‑linked neurodevelopmental phenotype. Whether this represents an incidental association or a possible new genotype–phenotype correlation requires further investigation. An interesting aspect of this case is the variant’s location. Whereas most previously reported variants in the WD40 domain are located on the surface of the β‑propeller structure interacting with cyclin E1 [2], the present variant is predicted to be on the opposite side of the surface. In conclusion, we describe a patient with a novel FBXW7 pathogenic variant who exhibits Rett‑like phenotypes and autistic features—including hand stereotypies, bruxism, and abnormal breathing patterns. This case may expand the clinical spectrum of FBXW7‑linked neurodevelopmental syndromes.