Beckwith-Wiedemann syndrome due to CDKN1C mutation

Beckwith-Wiedemann syndrome due to CDKN1C mutation (also known as BWS due to CDKN1C mutation) is a specific molecular subtype of Beckwith-Wiedemann syndrome (BWS) caused by loss-of-function mutations in the CDKN1C gene (also known as p57KIP2), located on chromosome 11p15.5. CDKN1C is a maternally expressed imprinted gene that encodes a cyclin-dependent kinase inhibitor involved in cell growth regulation. When the maternal copy carries a pathogenic variant, it leads to the overgrowth phenotype characteristic of BWS. This subtype accounts for approximately 5-10% of sporadic BWS cases and up to 40% of familial cases. The condition affects multiple body systems and is characterized by macrosomia (large body size at birth), macroglossia (enlarged tongue), abdominal wall defects (such as omphalocele, umbilical hernia, or diastasis recti), visceromegaly (enlargement of abdominal organs), neonatal hypoglycemia, ear anomalies (anterior ear lobe creases or posterior helical pits), and hemihyperplasia (asymmetric overgrowth of body regions). Patients with CDKN1C mutations may have a particularly high risk for omphalocele compared to other BWS molecular subtypes. There is also an increased risk of embryonal tumors, although the tumor risk in the CDKN1C subtype appears to be lower than in some other BWS subtypes (such as those with paternal uniparental disomy of 11p15). Management is primarily supportive and based on surveillance. Treatment includes monitoring and correction of neonatal hypoglycemia, surgical repair of abdominal wall defects, speech therapy and potential surgical reduction for macroglossia, and regular tumor screening with abdominal ultrasound (typically every three months until approximately age 7-8 years). Screening for Wilms tumor and hepatoblastoma is recommended. Genetic counseling is important, particularly because CDKN1C mutations carry a significant recurrence risk in families when the mutation is inherited from the mother. With appropriate monitoring and management, many individuals with BWS have a favorable long-term prognosis.

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