multiple congenital anomalies-hypotonia-seizures syndrome 3

Multiple congenital anomalies-hypotonia-seizures syndrome 3 is a very rare congenital disorder of glycosylation that primarily affects infants. It is caused by pathogenic variants in the PIGT gene and is inherited in an autosomal recessive pattern. Affected infants present with neonatal hypotonia, global developmental delay, and seizures, with many also exhibiting distinctive facial and skeletal features. The condition is extremely rare, affecting fewer than 1 in 1,000,000 people.

Affected children typically present in infancy with marked hypotonia, impaired vision including hypermetropia, cerebral visual impairment, strabismus, and nystagmus, all of which are universally observed. They also experience severe to profound intellectual disability and a range of seizures, initially associated with febrile episodes and later occurring unprovoked. After a period of apparently typical early development, affected children experience a phase of developmental regression marked by loss of previously acquired skills, followed by a course that may stabilize, although variability in progression is common. Additional features include dysmorphic facial characteristics such as a high narrow forehead, frontal bossing, short nose, and wide open mouth, as well as skeletal abnormalities like delayed bone age, scoliosis, pectus excavatum, and inverted nipples. Not all individuals experience all features, and severity varies considerably.

This condition is caused by pathogenic variants in the PIGT gene, which plays a critical role in glycosylphosphatidylinositol (GPI) biosynthesis, a process important for anchoring proteins to the cell surface. Disruption of PIGT function affects multiple organ systems, leading to the congenital and progressive features observed. The disorder is inherited in an autosomal recessive pattern, meaning that an affected child has received one altered copy of the gene from each parent. Families, especially those with a shared genetic background, may benefit from genetic counseling to better understand recurrence risks and options for family planning.

Currently, management focuses on supportive care and symptom management, as there are no foundational therapies or FDA-approved treatments specifically linked to this condition. Treatment is tailored to the individual and typically involves a multidisciplinary care team that may include neurologists, developmental specialists, ophthalmologists, and orthopedic experts. Regular surveillance is an essential part of long-term care, helping to identify complications—such as cardiac, skeletal, or visual issues—before they become serious. Patients and families are encouraged to discuss treatment options with their healthcare team and to consider genetic counseling for further guidance.

The prognosis for individuals with multiple congenital anomalies-hypotonia-seizures syndrome 3 is variable and largely depends on the severity of symptoms, age at diagnosis, and access to specialized care. The lifelong neurodevelopmental condition is characterized by an initial phase of regression, followed by a period of relative stabilization, although some individuals may experience later motor decline. With current standards of care, many individuals benefit from supportive therapies and ongoing surveillance, and outcomes continue to improve as clinical practices evolve. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialists familiar with this condition and to engage with genetic counseling services for personalized management strategies.