Atypical case of Rett syndrome with concurrent MECP2 gene mutation and del(15)(q22qter) karyotype: A case report and review of literature

Abstract

BACKGROUND

Rett syndrome is a monogenic X-linked dominant condition that affects 1/(10000-15000) girls due to de novo mutations in the methyl-CpG binding protein 2 (MECP2) gene mapped to chromosome Xq28. The disease-causing gene was identified as a mutation in the MECP2 gene, which is found in approximately 80% of patients diagnosed with Rett syndrome. Although chromosomal changes resulting in del(15)(q11q13) are usually associated with Angelman and Prader-Willi syndrome, very few cases, if any, of Rett syndrome with terminal 15q22-qter deletion have been published in English literature.

CASE SUMMARY

In this study, we report an unusual and rare clinical presentation of Rett syndrome in a 12-year-old Sudanese girl. The patient was brought in by her parents, complaining of gradual onset of abnormal walking, abnormal hand movement, loss of speech, and mental retardation for ten years. There was no reported history of convulsions or loss of consciousness. Clinical examination revealed microcephaly with no other apparent dysmorphic features, intact cranial nerves, and abnormal gait. She showed repetitive and stereotyped behaviors, including hand flapping, stimming, and chest pounding, which were concomitant with autism spectrum disorder. Magnetic resonance imaging and electroencephalography investigations were normal, and cytogenetic analysis showed 46,XX, del(15)(q22qter). Further molecular analysis using whole sequencing of MECP2 revealed an alteration cytosine > thymine at nucleotide 401, leading to phenylalanine replacing a serine at amino acid position 134.

CONCLUSION

This case, the first reported instance of Rett syndrome in Sudan, is of significant interest. The patient carries both the MECP2 gene mutation and the chromosome 15q22-qter deletion, which may explain the autistic behavior with atypical presentation of Rett syndrome. This report expands the genetic diversity of Rett syndrome, demonstrating how co-occurring 15q22-qter deletions can reshape MECP2-associated phenotypes in Rett syndrome.

Key Words: Rett syndrome; Autism spectrum disorder; Methyl-CpG-binding protein two gene mutation, Chromosome 15 deletion; Atypical presentation; Chromosomal analysis; Case report

Core Tip: This report presents a rare atypical case of Rett syndrome with a novel concomitant of a pathogenic methyl-CpG binding protein 2 p.S134F mutation and 15q22-qter karyotype from Sudan. The patient displayed atypical Rett syndrome phenotype, including significant growth regression and pronounced autistic behaviors, stereotypic hand-flapping and chest-pounding, and absence seizures. The terminal 15q22-qter deletion may disrupt critical neurodevelopmental loci (such as ubiquitin-protein ligase E3A and insulin-like growth factor 1 receptor), which could exacerbate autism and growth failure while potentially reducing susceptibility to seizures. This case expands the phenotypic and genotypic heterogeneity of Rett syndrome, enhances our understanding of how synchronous genomic alterations modulate methyl-CpG binding protein 2-related phenotypes, and underscores the imperative for equitable genetic diagnostics in underrepresented populations.

INTRODUCTION

Rett syndrome is a rare neurogenetic disorder that predominantly affects girls. It is characterized by a period of normal development followed by a significant progressive decline in motor skills, communication abilities, and purposeful hand movements[1]. The syndrome has an estimated prevalence of approximately 1 in 10000 to 15000 female births[2]. The disorder is primarily caused by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene on chromosome Xq28. Mutations in the MECP2 gene disrupt neuronal function, leading to hallmark features of Rett syndrome, including seizures, motor deficits, neurogenic apneas, and speech delay[3,4]. While neurologic symptoms indeed constitute the most apparent aspects of Rett syndrome, these patients may also exhibit significant non-neurologic pathologies such as osteopenia, scoliosis, gastrointestinal dysfunction, and a general growth deficit[5].

Recent studies have highlighted the importance of global representation in understanding the phenotypic and genetic heterogeneity of Rett syndrome[2]. This highlights the need for enhanced documentation from underrepresented populations, particularly those from Africa and the Middle East. This will increase our ability to fully appreciate how environmental, ethnic, and genetic factors influence disease expression and outcomes. Previous studies observed maternal duplications of 15q11-q13 inherited in 1%-3% of children with autism spectrum disorder (ASD), suggesting that an abnormal dosage of the gene within this region, such as ubiquitin-protein ligase E3A (UBE3A) and gamma-aminobutyric acid type A receptor beta3, might cause susceptibility to ASD and other neurodevelopmental disorders resulting from synaptic dysfunction[6]. On the other hand, chromosome 15q11-q13 is a well-established genomic imprinting region linked to Angelman syndrome when maternally inherited or Prader-Willi syndrome when paternally inherited[7]. Furthermore, terminal deletions of 15q11-qter are classically linked to Angelman syndrome and Prader-Willi syndrome, depending on the parental origin of the deletion[8]. However, there have been some reports of patients with Rett syndrome who also exhibit chromosome 15 rearrangements[9]. Such cases often present with atypical or overlapping phenotypes, including autistic features, intellectual disability, and developmental delay, making diagnosis challenging. The co-occurrence of MECP2 mutations and chromosomal deletions suggests that these genetic factors may interact to modify the clinical presentation, diagnosis, and management strategies of Rett syndrome[10,11].

In this report, we present the first confirmed case of Rett syndrome in Sudan, as determined through cytogenetic analysis of the patient’s lymphocytes and complete sequencing of the MECP2 gene. The unique phenotypic findings, particularly the autistic features and absence of seizures, suggest a genetic interplay between MECP2 (p.S134F) and the 15q22-qter deletion, which may contribute to the unusual phenotypic spectrum of Rett syndrome observed in this report. Additionally, this case arose incidentally during routine clinical and genetic evaluation of a patient presenting with developmental regression and stereotypical behaviors, contributes uniquely to the understanding of Rett syndrome’s genetic and phenotypic diversity within underrepresented populations, such as Sudan, where genomic research and neurodevelopmental disorder reporting remain sparse, addressing geographical and genetic gaps in the current literature.

CASE PRESENTATION

Chief complaints

A 12-year-old female originally from North Sudan, ethnically from Rofeen (an Arabic origin tribe), was brought by her family complaining of abnormal walking, abnormal hand movement, loss of speech, and mental retardation for ten years.

History of present illness

The history revealed a gradual onset of the disease at the age of 2 years when the patient started to show abnormal walking and hand movement, loss of speech and acquired language, and regression in social communication. She responded well to sound and made good eye-to-eye contact. There were no reports of convulsions or loss of consciousness.

History of past illness

Patient went through normal milestones till the age of 2 years.

Personal and family history

She was the third offspring from a consanguineous marriage, as her parents were second-degree relatives. She was an outcome of an uneventful pregnancy, terminated by vaginal delivery at home. There was no family history of similar conditions, dysmorphic features, or other neurological illnesses.

Physical examination

On examination, she was conscious and attentive to her surroundings, and her vital signs were normal. She had stunted growth with preadolescent Tanner stage 1. Her body weight was 15 kg, and her height was 118 cm, both were below the 3^rd centile. She had proportionated short stature with an upper/Lower segment ratio of 1:1. Although she had microcephaly (head circumference = 46 cm, < -2 SD), no other dysmorphic features were noted (Figure 1; Video 1). There were abnormal repetitive hand movements and stereotyped behaviors, including hand flapping, stimming, and chest pounding. There was an abnormal gait, but cranial nerves were intact. The upper and lower limbs exhibited hyperreflexia and hypertonia, with impaired complex coordination, and clonus was positive.

Figure 1  The shows clinical features of microcephaly, short stature, and abnormal hand movements in a patient with Rett syndrome.

Laboratory examinations

Investigations revealed normal hematological and urine analyses, liver and kidney function tests, and negative metabolic screening tests. Cytogenetic analysis revealed an abnormal female karyotype 46,XX, del(15)(q22qter) (Figure 2). MECP2 gene sequencing revealed a change cytosine > thymine at nucleotide 401, resulting in phenylalanine replacing a serine at amino acid position 134.

Figure 2 The shows an abnormal female karyotype 46,XX, del(15)(q22qter). Orange arrow shows the terminal deletion in chromosome 15.

Imaging examinations

Both magnetic resonance imaging and electroencephalography results were normal (Figure 3).

Figure 3  The shows normal findings of the magnetic resonance imaging of the brain.

FINAL DIAGNOSIS

Accordingly, a diagnosis of Rett syndrome was established.

TREATMENT

After profound counseling, the patient was referred to a pediatric neurologist to supervise her management plan.

OUTCOME AND FOLLOW-UP

Regular visits were arranged to the multidisciplinary team at the tertiary hospital collaboratively to optimize patient care.

DISCUSSION

This case report details a 12-year-old girl diagnosed with Rett syndrome who carries both a pathogenic MECP2 mutation (p.S134F) and a deletion on chromosome 15q22-qter. She presents a combination of classic and atypical features. The patient demonstrated a typical Rett syndrome medical history characterized by normal development during the first 6 months to 18 months, followed by a regression in acquired skills, growth retardation, loss of speech, gait abnormalities, and intellectual disability[12]. While her developmental regression, speech loss, and gait issues correspond with classic months[13]. Her lack of seizures, hypotonia, and dysmorphic signs, along with noticeable autistic behaviors (such as repetitive hand flapping and chest pounding), indicate a potential phenotypic alteration linked to the 15q22-qter deletion.

In addition to neurological symptoms, Rett syndrome is recognized as a multisystem disorder that can present with growth failure characteristics, including short stature and growth stagnation, as observed in this patient. These features may relate to MECP2’s function in regulating mitochondrial activity and bone health. Recent studies emphasize the highly variable clinical pictures among patients carrying MECP2 variants, extending to males and mosaic individuals, further complicating genotype-phenotype correlations[14,15]. The existence of a terminal 15q22-qter deletion may worsen somatic comorbidities due to disrupted imprinting[16,17], where complex interactions between multiple genetic variants can lead to syndromic autism presentations[18].

Approximately 50 cases of 15q22-q24 deletion have been documented globally, sharing several characteristics such as hypotonia, feeding issues, and global developmental delays. These cases also exhibit similar dysmorphic traits, including a flat face, flat nasal bridge, epicanthic fold, micrognathia, microphthalmia, and minor skeletal and urogenital abnormalities[19]. However, our patient shows no dysmorphic traits or hypotonia, which suggests potential regional genotypic variability or the presence of protective modifiers. This observed phenotypic variation aligns with the emerging understanding of how genetic modifiers and background genomics can influence expressivity in neurodevelopmental disorders, where 15q deletions, particularly those at 15q13.3, are increasingly recognized for their diverse phenotypic impact beyond classic syndromes (e.g., 15q13.3 microdeletion syndrome, which also exhibits highly variable penetrance and expressivity). Moreover, recent studies found that patients with Rett syndrome and additional chromosomal anomalies often exhibit atypical presentations, including milder motor involvement or altered seizure profiles[16]. This aligns with our observation of absent seizures despite confirmed MECP2 mutation and neurodevelopmental impairment.

This case represents the first instance of a terminal 15q22-qter deletion and is among the few globally that involve a combination of genetic abnormalities. This may clarify the unusual movement patterns previously overlooked in Rett syndrome. However, some studies have noted cases of Rett syndrome with interstitial deletion or duplication of 15q11q22 that exhibit Prader-Willi-like features[20]. In contrast, our case displays a deletion karyotype of 15q22-qter and does not show this overlap, indicating different gene involvement and the typical dysmorphism and hypotonia associated with Rett syndrome syndrome[21]. The deletion at 15q22-qter may worsen features of Rett syndrome, likely by affecting neurodevelopmental genes (UBE3A, cytoplasmic FMR1 interacting protein 1) linked to ASD[22], which accounts for her ongoing autistic behaviors, differing from the temporary ASD-like traits observed in typical Rett syndrome[4].

The loss of insulin-like growth factor 1 receptor (15q26.3) could also aggravate growth failure by disrupting somatic growth regulation[23]. Furthermore, MECP2 is recognized for its role in regulating chromatin structure, while UBE3A (on 15q) manages synaptic protein degradation; their joint disruption may enhance neurodevelopmental deficits, suggesting potential epigenetic influences[24]. Prior research has highlighted common features between Rett syndrome and Angelman syndrome, especially in instances involving rearrangements of chromosome 15q[25]. The presence of both genetic abnormalities in our patient hints at a possible interaction between MECP2 gene mutations and chromosomal deletions, potentially altering the clinical presentation of Rett syndrome. The continuity of autistic characteristics in our patient, in contrast to the temporary autism-like traits typical of Rett syndrome, may signal disruption of 15q neurodevelopmental genes (e.g., UBE3A, cytoplasmic FMR1 interacting protein 1), which are closely linked to ASD[26]. The MECP2 p.S134F variant is associated with milder Rett syndrome symptoms[27].

Our research highlights the crucial role of comprehensive genetic testing, encompassing chromosomal analysis, for individuals with neurodevelopmental disorders, notably when their clinical presentation deviates from the typical phenotype. It also highlights the need for greater awareness and research on Rett syndrome in underrepresented groups, such as Sudan, where access to advanced diagnostic resources may be restricted. Documenting cases from various populations enriches our understanding of Rett syndrome’s genetic and phenotypic diversity and supports initiatives to enhance global health equity[28]. In summary, this case report contributes to the growing body of research on the genetic diversity of Rett syndrome. It highlights the influence of additional genetic factors on its clinical manifestation. Further studies are needed to elucidate the molecular mechanisms underlying the interaction between MECP2 gene mutations and chromosomal abnormalities, as well as their impact on disease progression and outcomes. In instances involving 15q22-qter, the potential disruption of the UBE3A gene suggests possibilities for tailored therapy through UBE3A-targeted treatments (e.g., antisense oligonucleotides), which could alleviate ASD-related symptoms[29]. While insulin-like growth factor-1 supplementation may help resolve growth issues[30].

CONCLUSION

This case highlights a novel genetic interplay between the MECP2 (p.S134F) mutation and the 15q22-qter deletion, expanding the phenotypic range of Rett syndrome to include atypical autism and absence seizures. This highlights the critical need for comprehensive genetic screening in atypical Rett syndrome cases, particularly in underrepresented populations, to understand their genetic diversity and clinical heterogeneity better. Future studies should explore mechanistic links in induced pluripotent stem cells models and personalized therapies for these complex genotypes.