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Mixed and blended Phenotype of Sotos Syndrome and KBG Syndrome: Clinical Features in a Girl with Both Syndromes 

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
Sotos syndrome and KBG syndrome are autosomal dominant disorders caused by haploinsufficiency of the NSD1 gene and ANKRD11 gene, respectively. Each syndrome is characterized by distinct clinical features, making them identifiable as separate conditions. However, the coexistence of both syndromes in a single individual is rare. Here, we present a case of a 6-year-old girl with pathogenic variants in both NSD1 and ANKRD11, and we discuss the clinical features of her mixed phenotype.

 

Case Presentation
The patient is a 6-year-old girl born at 41 weeks and 3 days via normal vaginal delivery to non-consanguineous parents. Her birth weight was 3,964 g, length 52 cm, and head circumference 52 cm. She required treatment for jaundice in the neonatal period. Motor development milestones were delayed: head control at 9 months, rolling over at 9 months, and independent walking at 1 year and 9 months. By age 2, she had no meaningful speech and exhibited mild to moderate developmental delay with DQ (developmental quotient) of 53.

The patient had no associated cardiac defects, and brain MRI and EEG findings were normal. She exhibited intermittent exotropia and mild psychomotor developmental delay (DQ 53). Physical characteristics did not include the overgrowth typically seen in Sotos syndrome or the short stature associated with KBG syndrome; her height was within the average range. Facial features included down-slanting palpebral fissures, large ears, and almond-shaped eyes. She did not have macrodontia, which is a common feature of KBG syndrome. Behaviorally, she lacked shyness and exhibited hyperactivity, impulsivity, and increased irritability.

 

Diagnostic Workup
Chromosomal analysis using G-banding and microarray did not reveal any abnormalities, and trio-based whole-exome sequencing identified heterozygous truncating variants in both NSD1 and ANKRD11. Both variants were de novo and classified as pathogenic according to the ACMG/AMP guidelines, leading to a diagnosis of both Sotos syndrome and KBG syndrome.

 

Discussion
This case illustrates a rare presentation of a girl with both Sotos syndrome and KBG syndrome, whose primary symptom was psychomotor developmental delay. Although Sotos syndrome and KBG syndrome typically have contrasting growth patterns (overgrowth in Sotos and growth retardation in KBG), this patient exhibited neither extreme and had an average height. Intellectual disability is common in both syndromes, with Sotos syndrome ranging from mild to severe and KBG syndrome ranging from mild to moderate. However, the patient’s DQ of 53 at age 6 did not suggest a more severe intellectual disability due to the combined effects of both syndromes. Hyperactivity, a feature common to both syndromes, was observed. The coexistence of two syndromes with distinct clinical features creates a challenge in predicting how their phenotypes may interact. Continuous follow-up and careful management are essential to address the health and developmental needs of patients with such mixed phenotypes. Monitoring for specific clinical issues related to both syndromes remains a priority.

 

Conclusion
We report a rare case of a 6-year-old girl with both Sotos syndrome and KBG syndrome, characterized by a mixed phenotype that includes developmental delay, intermittent exotropia, and behavioral abnormalities. Her physical features did not align with the typical growth patterns of either syndrome, and her intellectual disability was not worsened by the coexistence of both conditions. This case highlights the importance of continuous monitoring and individualized care for patients with complex genetic diagnoses.

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