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Shashi-Pena Syndrome (ASXL2)

Shashi-Pena Syndrome (ASXL2) is a rare neurodevelopmental disorder caused by a change (mutation) in the ASXL2 gene. Individuals with this condition often experience developmental delays, low muscle tone (hypotonia), feeding challenges, and distinctive facial features. While the medical and developmental needs can vary widely, many individuals require lifelong support. The ARRE Foundation is committed to supporting families, advancing research, and building a more hopeful future for our community.

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What is Shashi-Pena Syndrome (ASXL2)?

Overview

Shashi-Pena Syndrome is an extremely rare neurodevelopmental disorder that is typically caused by a de novo (new) change in the ASXL2 gene. In some rare cases, the variant may be inherited from parents. It has the smallest patient population of the three ASXL-related disorders.

Shashi-Pena Syndrome, which is sometimes abbreviated as SPS or SHAPNS, is named after Vandana Shashi and Loren Peña, two of the doctors who wrote the research paper in 2016 that linked a change in the ASXL2 gene to a unique neurodevelopmental condition identified in six individuals through the Undiagnosed Diseases Network (Shashi 2016).

How the ARRE Foundation is helping

Our understanding of Shashi-Pena Syndrome and the ASXL2 gene has advanced quickly in recent years, thanks in large part to the ARRE Foundation’s support of family-centered research, including the recent publication of a GeneReviews article, the first medical reference guide for Shashi-Pena Syndrome (Porter 2024).

Still, many questions remain about how best to care for individuals with Shashi-Pena Syndrome, what the future looks like, and what treatments may help. Because the ASXL2 community is so small, research participation is especially critical. Several studies have included individuals with Shashi-Pena Syndrome but have not collected enough data from the few participating families to generate meaningful insights. Family participation in research is how we will work toward generating standards of care and finding treatments.

Diagnosis of Shashi-Pena Syndrome and other ASXL2 variants

Gene sequencing, a type of broad genetic testing, is typically used to identify a change or variant in the ASXL2 gene. Shashi-Pena Syndrome is a specific diagnosis usually linked to a specific type of genetic variant in the ASXL2 gene that causes a set of recognizable clinical features. The specific genetic variants associated with Shashi-Pena Syndrome are typically (but not always):

De novo, meaning they are a new variant or mutation and is not inherited from a parent
Pathogenic or likely pathogenic, meaning they are known or suspected to cause disease based on evidence analyzed by the testing laboratory
Truncating variants, like a nonsense or frameshift mutation, that results in the production of a shortened protein than is produced by a typical gene
Occur in the last two sections (exons) of the ASXL2 gene

Other types of variants in the ASXL2 gene, such as inherited or missense variants, may not lead to a Shashi-Pena Syndrome diagnosis. We’re still learning how these other variants affect people and how their symptoms may differ. See below for information about uncertain diagnoses, including a variant of uncertain significance (VUS).

Unless otherwise noted, the information on this page focuses on Shashi-Pena Syndrome, since most research so far has involved people with this specific diagnosis. However, if your loved one has a different ASXL variant, you may still find this information and the community resources helpful. The ARRE Foundation is here to support everyone affected by changes in any of the ASXL genes, as we continue to learn more about these rare and complex conditions.

Uncertain diagnoses: If your loved one has a variant of uncertain significance (VUS) or otherwise does not have a definitive Shashi-Pena Syndrome diagnosis, please reference our Uncertain Genetic Diagnosis resources for more information.

Uncertain Genetic Diagnosis

Prevalence of Shashi-Pena Syndrome

We don’t know how many people have an accurate diagnosis. We estimate that there are approximately 50-60 people diagnosed with Shashi-Pena Syndrome in the world. We also believe there are many people living undiagnosed who have not had genetic testing.

Get your loved one counted! Help us develop a more accurate estimate of the number of people who have Shashi-Pena Syndrome and other ASXL variants by completing the ASXL Census.

Join the ASXL Census

Symptoms and features of Shashi-Pena Syndrome

There is significant variability in the symptoms and clinical features in Shashi-Pena Syndrome, including a wide spectrum of severity. We don’t yet know why changes in the ASXL2 gene cause this wide spectrum of symptoms and features (known as genotype-phenotype correlation).

Some of the most common characteristics of Shashi-Pena Syndrome include:

Distinct features of the face and head, including a heart-shaped birthmark on the forehead (glabellar nevus flammeus) and widely spaced eyes (hypertolerism)
Dental abnormalities, including early tooth loss and small, fragile teeth
Low muscle tone (hypotonia) that may improve with age
Feeding difficulties, particularly in infancy
Bone and skeletal concerns, including bones that fracture easily, scoliosis, and kyphosis
Congenital heart defects
Large body size (macrosomia) and head size (macrocephaly)
Vision concerns, including eye misalignment (strabismus) and “lazy eye” (amblyopia)
Behavioral concerns, including aggression and inattention
Issues controlling blood sugar, including hypoglycemia and hyperinsulinemia
Seizures, including fever-induced seizures (febrile seizures) and non-febrile seizures
Hearing loss
Obstructive and/or central sleep apnea
Constipation and motility issues
Gross motor delay of varying severity
Intellectual disability of varying severity

This list includes features documented in the medical literature noted below and symptoms observed in the ASXL2 family community.

View symptom chart

Overview

There are currently no specific treatments to address the underlying cause of Shashi-Pena Syndrome. The treatment approach for Shashi-Pena Syndrome typically includes the management of complications through a multidisciplinary team of medical specialists and therapists. Interventions may include intensive therapies, surgeries, and medication (such as seizure medications) as needed.

Evaluation and management of symptoms

Individuals with Shashi-Pena Syndrome are typically evaluated and followed by multiple medical specialists. These documents may be helpful references in guiding care, including which medical specialists are recommended to evaluate specific symptoms or concerns:

Coordination of care

Coordinating medical care across many specialties can be extremely challenging. Finding a champion in your clinical team can help. A general pediatrician, developmental pediatrician, clinical geneticist, or neurologist might be well-suited to this role. ASXL families have also shared that engaging a complex care team or palliative care team, whose role is to see the patient wholistically, may be helpful in coordinating care.

Supporting development

Individuals with Shashi-Pena Syndrome benefit significantly from different types of therapy to help build skills. Slow or minimal developmental gains are typical. Trained therapists in these specialties may also help you identify and secure specialized adaptive equipment and tools to use at home, at school, and in the community.

Common types of therapy include:
• Physical therapy
• Occupational therapy
• Speech therapy to aid in communication skills
• Feeding therapy to aid in feeding and swallowing skills

ASXL families have also shared benefits of other types of therapies, including equine therapy (horse therapy), water therapy, music therapy, and therapy intensives (frequent therapy sessions over a short period of time).

Life expectancy for Shashi-Pena Syndrome

As genetic testing becomes more widely accessible, we are learning of more people who have been living undiagnosed with Shashi-Pena Syndrome. The oldest known individuals with Shashi-Pena Syndrome are in their twenties.

We don’t know much yet about what life looks like past childhood for someone with Shashi-Pena Syndrome. Some symptoms seem to change over time, including some that improve (such as feeding difficulties) and some that worsen (such as orthopedic challenges and challenging behaviors). From the family community, we know that individuals with Shashi-Pena Syndrome have a wide range of skills and abilities that will influence their ability to live independently or with varying degrees of assistance. There are individuals with Shashi-Pena Syndrome who drive and have attended trade school, and others who will need lifelong support.

Shashi-Pena Syndrome is not known to be a life-limiting disorder and it is not known to be a neurologically degenerative disorder where cognitive function and ability decreases over time. You can help us learn what life with Shashi-Pena Syndrome looks like over time by enrolling your loved one in the ASXL-Related Disorders Natural History Study.

Enroll your loved one

Clinical research papers about Shashi-Pena Syndrome

The following research papers include comprehensive descriptions of the clinical features of Shashi-Pena Syndrome:

GeneReviews: Shashi-Pena Syndrome (Porter 2024)
- Includes recommendations for care management and evaluation
De novo truncating variants in ASXL2 are associated with a unique and recognizable clinical phenotype (Shashi 2016)
- Summarizes first six identified cases of Shashi-Pena Syndrome including clinical features

Additional research papers about Shashi-Pena Syndrome and the ASXL2 gene, including case reports and basic science discoveries, can be found on the published research page.

View more published research

Community and support for Shashi-Pena Syndrome families

ARRE Foundation connections and resources

Connect with us:

Email: Sign up for our email list, which includes our monthly newsletter, announcements, and research opportunities
Social media: Follow us on Instagram, Facebook, and LinkedIn

Find our best resources for families:

Virtual events and conferences

The ARRE Foundation hosts regular virtual events to support ASXL parents and caregivers, including welcome calls for newly diagnosed families, educational webinars, and other support topics.

The ASXL Family Conference, an in-person opportunity to meet other ASXL families and participate in research, is held every other year. The next ASXL Family Conference will be in 2026.

Parent support group (Facebook)

The Shashi-Pena Syndrome support group on Facebook was founded in 2018 by parents of children with Shashi-Pena Syndrome. This grassroots group has grown from just a handful of members in its early days to over 100 members from around the world.

(This group is not administered or managed by the ARRE Foundation.)

Shashi-Pena Syndrome Awareness Day

Shashi-Pena Syndrome Awareness Day is October 6. Stand with families around the world to honor our loved ones living with Shashi-Pena Syndrome, raise awareness, and drive critical ASXL-related research forward.

Check out our Shashi-Pena Syndrome Awareness Day resources.

Other organizations and resources

Shashi-Pena Syndrome/ASXL2 family chats: The ARRE Foundation hosts regularly virtual online meetings for parents of individuals with an ASXL2 variant. See the Events page for upcoming events.

Family stories: Some families have social media pages and blogs about their experience with Shashi-Pena Syndrome and other ASXL2 variants. Those include: