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Last updated: 3/4/2025
Years published: 2021, 2025
NORD gratefully acknowledges Loren Pena, MD, PhD1, Vandana Shashi, MD2 and Kelly Schoch, MS2, 1Previously at the Division 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.
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Summary
Shashi-Pena syndrome is a rare multiple malformation syndrome that presents at birth. Characteristics include facial differences, enlarged head circumference and other characteristic findings such as a birthmark above the bridge of the nose (glabellar nevus simplex), 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 (variants) in the ASXL2 gene that have occurred as new variants (de novo) in affected individuals. The condition is thought to follow an autosomal dominant pattern of inheritance. Treatment is targeted to individual symptoms and consists of supportive care for developmental therapies and cardiology follow up for congenital heart disease.
Introduction
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 simplex), low set and posteriorly rotated ears, a small mouth 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 delays in gross motor skills that manifest as delayed walking. Affected children may also have a delay in speech and behavioral problems that can include aggressive behavior, attention deficit and autistic features. Some people have capillary malformations in addition to the glabellar nevus simplex, skeletal abnormalities such as an advanced bone age, curvature of the spine (scoliosis and kyphosis), overgrowth, contractures of certain joints, deep palmar and plantar creases and congenital heart defects such as atrial septal defects. Some people may have seizures while having a fever and epilepsy may sometimes develop. Several people have had brain abnormalities consisting of enlarged ventricles and loss of cerebral white matter.
Shashi-Pena syndrome is caused by changes (variants) in the ASXL2 gene. The function of the ASXL2 gene is not known but may have a role in regulating gene expression during embryological development.
The ASXL2 gene variants are new (de novo) in all the individuals described in the medical literature to date. This means that neither parent has the gene variant.
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 disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant 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. As of 2023, there have been 23 identified cases.
The condition is diagnosed by DNA-based testing to look for variants in the ASXL2 gene.
Treatment
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 and feeding evaluation if feeding difficulties and low blood sugar (hypoglycemia) are present. There are currently no FDA-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.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
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Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Ho SKL, Cheng SSW, Cheng THT, et al. Extending the phenotype of Shashi-Pena syndrome: a case report and review of literature. Clin Dysmorphol. 2023;32(3):139-146. doi:10.1097/MCD.0000000000000462
Cuddapah VA, Dubbs HA, Adang L, et al. Understanding the phenotypic spectrum of ASXL-related disease: Ten cases and a review of the literature. Am J Med Genet A. 2021;185(6):1700-1711. doi:10.1002/ajmg.a.62156
Shashi V, Pena LD, Kim K, et al. De Novo Truncating variants in ASXL2 are associated with a unique and recognizable clinical phenotype [published correction appears in Am J Hum Genet. 2017 Jan 5;100(1):179. doi: 10.1016/j.ajhg.2016.12.004.]. Am J Hum Genet. 2016;99(4):991-999. doi:10.1016/j.ajhg.2016.08.017
INTERNET
Porter JM, Pena LDM, Spillmann RC, et al. Shashi-Pena Syndrome. 2024 Nov 7. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK609017/ Accessed Feb 13, 2025.
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