Introduction
Smith-Magenis syndrome (SMS) is a complex genetic disorder caused by deletion or mutation of the retinoic acid-induced 1 (RAI1) gene located primarily on chromosome 17p11.2. The incidence of SMS is estimated to be between 1 in 15,000 and 1 in 25,000 births, making it a rare condition [1]. The clinical presentation of SMS is multifaceted and encompasses a range of physical, neurodevelopmental, and behavioral abnormalities, including intellectual disability, distinctive craniofacial features, and sleep disorders [2].
Studies on the immunological features of SMS suggest the role of frequent recurrent infections as part of the overall clinical presentation of the syndrome. Perkins et al. [3] reported that 74 of 76 patients with SMS experienced a high frequency of infections, including otitis media, sinusitis, and pneumonia. The study highlighted that many of these patients require more aggressive interventions, including intravenous antibiotics [3]. Additionally, it was noted that these patients exhibited a deficiency in isotype-switched memory B cells, suggesting an impairment in adaptive immune responses [3]. These findings highlight the need to monitor for infections in individuals with SMS and possibly treat them proactively.
Interestingly, the immunologic features associated with SMS are not seen in all patients, suggesting variability in immunologic profiles that may be influenced by other genetic or environmental factors [3]. This variability highlights the complexity of SMS as a genetic condition with multifaceted clinical implications and necessitates personalized approaches to treatment and care.
Here, we report a 4-year-old male patient who presented to the pediatric immunology-allergy clinic with the complaint of frequent illnesses with the diagnosis of SMS.
Case report
A 4-year-old male patient diagnosed with SMS presented to the outpatient clinic with the complaint of frequent lower respiratory tract infections. When the patient’s anamnesis was examined, it was learned that the patient was born on time, stayed in the neonatal intensive care unit for 7 days due to respiratory distress for 1 week, and upon detection of a murmur during hospitalization, ventricular septal defect and pulmonary stenosis were detected in the examinations performed by the pediatric cardiology department and therefore he was operated on later. It was learned that the patient, who had neuromotor developmental delay, syndromic face and cardiovascular system disease, was diagnosed with SMS with the genetic examination planned by the pediatric neurology department when he applied when he was 6 months old. Complete blood count, serum immunoglobulin levels, IgG subclasses, anti-HBs, anti-Rubella IgG, anti-A/B isohemagglutinins and flow cytometry examinations were done for the patient. Serum IgG2 and IgG4 levels were detected as low in the patient’s laboratory results (Table 1). The patient’s anti-HBs value was negative even though he was immunized and other antibody titers were evaluated as normal (Table 2). In the patient’s flow cytometry, a decrease in the ratio of recent thymic emigrant (RTE) cells and naive CD4+-T cells and an inversion in the CD4/CD8 ratio were detected (Table 3). In the repeated examinations, the same results were detected and it was decided to start intravenous immunoglobulin (IVIG) replacement therapy with the diagnosis of IgG subclass deficiency. The patient, who has not had lower respiratory tract infections for the last 6 months, showed a good clinical response to the IVIG treatment that was started. (Informed consent was obtained from the patient’s relatives for this presentation.)
Table 1
Serum immunoglobulin isotype and IgG subclass levels
* Reference [8].
Table 2
Specific antibody levels against vaccinations and isohemagglutinin
| Anti-HBs [IU/ml] | Anti-Rubella IgG [IU/ml] | Blood group | Anti-B titer (isohemagglutinins) |
|---|---|---|---|
| 4.02 (Negative) | 41.9 (Positive) | A Rh + | 1/256 + |
Table 3
Flow cytometric analysis of B- and T cell subtypes shown in our patient
[i] Ucsm B – unclass/non-class-switched memory B cells, Csm – class-switched memory B cells, DNT – double negative T cells, RTE – recent thymic emigrants, CM – central memory T cells, EM – effector memory T cells, EX – terminally differentiated T cells. **Reference [9].
Discussion
Smith-Magenis syndrome (SMS) is a complex genetic disease characterized by interstitial deletions of chromosome 17p11.2 (90%), which includes a multitude of phenotypic features and health problems. However, recent studies have shown that individuals with SMS may experience frequent recurrent infections, which raises the need to question the association of the syndrome with immune deficiency.
Studies have shown that certain abnormalities in the B cells of individuals with SMS affect the functionality of their immune system. A comprehensive review by Perkins et al. [3] emphasized that most patients with SMS have antibody deficiencies but do not exhibit other immune pathologies. Antibody deficiencies imply that T-cell functions are largely preserved, reflecting an immune system status that is consistent with the profile of infections encountered by SMS patients [3, 4]. In our case, there were low RTE and naive CD4+-T cells and a reversal in the CD4/CD8 ratio. In addition, there was an IgG subclass deficiency.
The behavioral and neurological disorders seen with SMS further complicate the clinical picture of the syndrome. Social and psychological symptoms such as insomnia and compulsive behaviors can significantly affect the quality of life of individuals, and when this is combined with its effects on the immune system, it creates a difficult picture to manage [5, 6]. It has been suggested that imbalances in the melatonin hormone may affect the immune responses of patients, and therefore may be related to the dysregulation of the immune system [6]. Our patient was receiving melatonin treatment due to sleep disturbances and risperidone treatment due to behavioral disorders. The genetic mechanisms behind the immune deficiency seen in SMS require further information on the role and interactions of the related genes. Considering the role of the RAI1 gene in particular, as well as the effects of other genes related to the immune system, it is critical to understand the effects of this genetic structure on patients. Not only the loss of the RAI1 gene, but also a wider genetic core, and various genes acting together, may affect immune responses and other syndromic features that coexist [3, 7–9].
Conclusions
SMS presents a unique intersection of genetic, developmental, and immunologic challenges. Evidence suggests that individuals with SMS are at higher risk for immune deficiencies that can lead to recurrent infections and complicate overall health management. Future research should focus on elucidating the mechanisms behind these immune challenges and developing targeted interventions to improve health outcomes for those affected by SMS.
