NORD gratefully acknowledges Loren Pena, MD, PhD1, Vandana Shashi, MD2 and Kelly Schoch, MS2, 1Division of Human Genetics, Cincinnati Children’s Hospital and 2Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, and the ASXL Rare Research Endowment (ARRE) Foundation for the preparation of this report.
Shashi-Pena syndrome is a rare multiple malformation syndrome that presents at birth with characteristic facial features, enlarged head circumference and other characteristic findings such as a birthmark above the bridge of the nose (glabellar nevus flammeus), along with low muscle tone and global developmental delay. Certain features such as epilepsy occur in some affected individuals, but not all. The condition is caused by changes (mutations) in the ASXL2 gene that have occurred as new mutations (de novo) in affected individuals. The condition is thought to follow an autosomal dominant pattern of inheritance. Treatment is targeted to the individual symptoms, and consists of supportive care for the complications, such as cardiology follow up in case of congenital heart disease and developmental therapies.
Shashi-Pena syndrome was initially described in 2016 by Dr. Vandana Shashi and Dr. Loren Pena in a group of six children who had overlapping facial features and clinical findings. The physical findings were most prominent in the first few years of life. The ASXL2 gene had not previously been associated with a disease in humans.
Patients affected with Shashi-Pena syndrome have low muscle tone (hypotonia) and a characteristic facial appearance consisting of wide-set eyes (hypertelorism) that are also prominent, droopy eyelids (ptosis), a red or pink birthmark above the bridge of the nose (glabellar nevus flammeus), low set and posteriorly rotated ears and enlarged head size (macrocephaly). Feeding difficulties early in life are common. Some children have low blood sugar (hypoglycemia) early in life, and rarely this can become a persistent complication. The early hypotonia can evolve into subsequent delays in gross motor skills that manifest as delayed walking. There is also a delay in speech and behavioral problems that can include attention deficit and autistic features. Some patients have capillary malformations in addition to the glabellar nevus flammeus, skeletal abnormalities such as an advanced bone age, curvature of the spine (scoliosis and kyphosis) and congenital heart defects such as atrial septal defects. Some patients may have seizures while having a fever and epilepsy may sometimes develop. Several patients have had brain abnormalities consisting of enlarged ventricles and loss of cerebral white matter.
Shashi-Pena syndrome is caused mutations in the ASXL2 gene. The function of the ASXL2 gene is not known to date, but may have a role in regulating gene expression during embryological development. The specific type of mutation observed in affected individuals is called a premature truncation. This means that the protein produced by the gene is shorter than it would typically be. This abnormal protein may lead to the abnormalities in the body that are seen in this condition.
The ASXL2 gene mutations are new (de novo) in all of the individuals published to date. This means that neither parent has the mutation.
The condition is thought to be inherited in an autosomal dominant manner, although no affected individual is known to have reproduced. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The risk of passing the non-working gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
The disorder has been described in a variety of populations, without preference for a specific race or ethnicity. The prevalence and incidence of Shashi -Pena syndrome are unknown.
Supportive treatment is geared towards the known complications associated with this syndrome. This could include developmental therapies, cardiology surveillance for congenital heart disease, neurology evaluation and management in case of seizures, feeding evaluation if feeding difficulties and low blood sugar (hypoglycemia) are present. There are currently no approved therapies.
Follow up includes a multidisciplinary approach with specialists in these areas: genetics, neurology, cardiology, endocrinology, physical and occupational therapy, feeding and speech therapy.
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Shashi V, Pena LDM, Kim K, Burton B, Hempel M, Schoch K, Walkiewicz M, McLaughlin HM, Cho M, Stong N, Hickey SE, Shuss CM, UDN Members, Freemark MS, Bellet JS, Keels MA, Bonner MJ, El-Dairi M, Butler M, Kranz PG, Stumpel CTRM, Klinkenberg S, Oberndorff K, Alawi M, Santer R, Petrovski S, Kuismin O, Korpi-Heikkilä S, Need AC, Goldstein DB, Kortüm F. De novo truncating variants in ASXL2 are associated with a unique and recognizable clinical phenotype. Am J Hum Genet. 2016;Oct 6;99(4):991-999. doi: 10.1016/j.ajhg.2016.08.017. Epub 2016 Sep 29.
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