Shashi-Pena Syndrome

Excerpt

Clinical characteristics: Shashi-Pena syndrome is characterized by distinctive facial features accompanied by variable further clinical findings. Facial features may include glabellar nevus simplex, widely spaced and prominent/proptotic eyes with epicanthal folds and ptosis, arched eyebrows, broad nasal tip, and low-set/posteriorly rotated ears. Dental anomalies may include early eruption and loss of teeth as well as small and fragile teeth. Most affected individuals have infantile hypotonia that frequently resolves over time. Macrosomia and macrocephaly are also common. Affected individuals can have variable developmental delay / intellectual disability, ranging from low-average intellectual abilities to severe intellectual disability. They often demonstrate difficulties with attention and aggressive behavior. Affected individuals may have feeding difficulties that require supportive nasogastric or gastrostomy tube feeding, skin findings (capillary malformations, deep palmar creases, hypertrichosis), skeletal anomalies (scoliosis/kyphosis, hypermobility, frequent fractures), congenital heart defects, seizures, hypoglycemia (most typically in infancy, may be due to hyperinsulinism), vision abnormalities (strabismus, amblyopia), conductive hearing loss, sleep apnea, temperature dysregulation, and global volume loss on brain MRI.

Diagnosis/testing: The diagnosis of Shashi-Pena syndrome is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in ASXL2 identified by molecular genetic testing.

Management: Treatment of manifestations: Feeding therapy for those with feeding difficulties; consideration of nasogastric or gastrostomy tube placement for those with persistent feeding issues. Review of healthy eating habits; surveillance for euglycemia, hyperlipidemia, hypertension, and consideration of referral to nutrition for those who develop obesity. For infants with hypoglycemia, standard treatment with dextrose and avoidance of fasting is reasonable; octreotide has been used in those with hyperinsulinism. Rapid assessment and management of recurrent otitis media. Pressure-equalizing tubes may be indicated for those with conductive hearing loss. Standard treatment for developmental delay / intellectual disability / neurobehavioral issues, dental anomalies, epilepsy, scoliosis/kyphosis, hip dysplasia, congenital heart defects, ptosis, strabismus, refractive error, and sleep apnea.

Surveillance: At each visit, measure growth parameters; evaluate nutritional status and safety of oral intake; monitor for the following: developmental progress and educational needs; difficulties with attention, anger outbursts, and aggression; signs of ADHD, autism, and anxiety; new manifestations, such as seizures and changes in tone; signs/symptoms of temperature dysregulation; signs/symptoms of sleep apnea; signs of feeding difficulties; development of scoliosis/kyphosis; and signs/symptoms of hypoglycemia. As clinically indicated, consider spine radiographs and DXA scan in those with scoliosis/kyphosis and bony fractures, respectively; dental and/or orthodontic evaluation for those with more significant dental issues; ophthalmology evaluation; blood glucose monitoring if there are concerns about hypoglycemia; and audiology evaluation.

Agents/circumstances to avoid: Prolonged fasting should be avoided in those with hypoglycemia.

Genetic counseling: Shashi-Pena syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Therefore, the risk to other family members is presumed to be low. Once the ASXL2 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.