Imprinting Syndrome

CLINICAL CHARACTERISTICS

imprinting syndrome is characterized by congenital central hypotonia (manifest as decreased movement, lethargy, and weak cry), severe feeding difficulties (resulting from facial weakness and poor suck), delayed development/intellectual disability, and dysmorphic manifestations. Poor feeding can cause failure to thrive during infancy unless managed appropriately. Significant dysphagia of solid foods typically persists until puberty. Intellectual disability can be severe. To date 19 individuals with a molecularly confirmed diagnosis have been reported.

DIAGNOSIS/TESTING: The diagnosis of the imprinting syndrome is established in a proband with suggestive clinical findings and detection of the heterozygous pathogenic variant p.Gly236Arg on the maternal allele.

MANAGEMENT

A multidisciplinary team of specialists in clinical genetics, plastic surgery, ophthalmology, pulmonology, gastroenterology, feeding, endocrinology, and neurology is recommended (depending on the individual’s needs). Standard treatment for lacrimal duct obstruction, obstructive sleep apnea, scoliosis, and seizures. Feeding problems typically require use of special nipples and/or bottles and/or nasogastric/gastrostomy tube feedings. Cleft palate and velopharyngeal insufficiency are managed as per standard practice as are developmental delay/intellectual disability. Transient neonatal hypoglycemia responds to diazoxide treatment. Monitoring of serum glucose levels for hypoglycemia in the neonatal period. At least annual ophthalmology evaluation, monitoring for the development of scoliosis, and monitoring of nutritional status, growth, and feeding.

GENETIC COUNSELING

imprinting syndrome is inherited in an autosomal dominant maternally imprinted manner (i.e., a heterozygous pathogenic variant on the maternally derived allele results in disease; a pathogenic variant on the paternally derived allele does not result in disease because normally the paternally derived allele is silenced). The pathogenic variant can either be inherited from the mother (80%) or arise on the maternally derived allele (20%). The risk to the sibs of the proband depends on the genetic status of their mother: if she is heterozygous for the pathogenic variant, the risk to the sibs is 50%; if the pathogenic variant cannot be detected in her leukocyte DNA, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of maternal germline mosaicism. To date, no individual with imprinting syndrome has been known to reproduce. Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for imprinting syndrome (i.e., one in which the mother is heterozygous for a pathogenic variant) and preimplantation genetic testing are possible.