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.

Suggestive Findings

Shashi-Pena syndrome should be considered in individuals with the following clinical findings and family history.

Clinical findings

• Distinctive facial features (most recognizable in infancy and becoming less discernible in older individuals) (see Figure 1):
  • Nevus simplex in the glabellar region of the forehead
  • Widely spaced and prominent/proptotic eyes with epicanthal folds
  • Ptosis
  • Arched eyebrows
  • Broad nasal tip
  • Low-set/posteriorly rotated ears
• Macrosomia, defined as weight and length/height >2 standard deviations (SD) above the mean for age and sex.
• Macrocephaly, defined as a head circumference that is >2 SD above the mean for age and sex
• Generalized hypotonia of infancy
• Mild-to-severe developmental delay or intellectual disability
• Seizures, which may be febrile and/or non-febrile; among the non-febrile seizures, focal, generalized tonic-clonic, and absence have been described.
• Dental findings, including early tooth eruption, premature loss of primary dentition, and small teeth
• Congenital heart defects
• Hypoglycemia that typically starts in the neonatal period and can be persistent into older ages
• Deep palmar/plantar creases
• Skeletal manifestations, including scoliosis/kyphosis or frequent fractures

Figure 1.

Photographs of six affected individuals at different ages. Distinctive facial features include epicanthal folds, widely spaced eyes, a wide nasal bridge, broad nasal tip, and a glabellar nevus simplex. Reproduced with permission from Shashi et al [2016] (more...)

Family history. Because Shashi-Pena syndrome is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Potentially, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations), although all known affected individuals to date have had a de novo genetic change.

Establishing the Diagnosis

The diagnosis of Shashi-Pena syndrome is established in a proband with suggestive clinical findings and a heterozygous pathogenic (or likely pathogenic) variant in ASXL2 identified by molecular genetic testing (see Table 1 and Molecular Genetics).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous ASXL2 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Shashi-Pena syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Shashi-Pena syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Shashi-Pena syndrome is characterized by distinctive facial features accompanied by variable further clinical findings, which may include macrocephaly, dental anomalies, congenital heart defects, seizures, hypoglycemia, hypotonia, developmental delays / intellectual disabilities, skeletal abnormalities, and global volume loss on brain MRI.

To date, at least 23 individuals have been identified with pathogenic truncating variants in ASXL2, including published and non-published individuals [Shashi et al 2016; Alqaisi & Hassona 2022; Murphy et al 2022; Ho et al 2023; Yuan et al 2023; Zheng et al 2023; JM Porter, LDM Pena, RC Spillmann, A Johnson, & V Shashi, unpublished data]. The following description of the phenotypic features associated with this condition is based on these individuals.

Skin. Glabellar nevus simplex has been seen in all individuals diagnosed with Shashi-Pena syndrome but may fade with age. Other dermatologic findings include deep palmar creases, hypertrichosis, and capillary malformations.

Craniofacial features. Individuals with Shashi-Pena syndrome demonstrate a distinct facial gestalt summarized in Suggestive Findings (see Figure 1). Notably, these features tend to be more evident at younger ages and may not be as readily recognizable in older individuals.

Dental. Teeth often erupt early and are small with weak enamel [Alqaisi & Hassona 2022]. Likewise, primary teeth are often lost early with early eruption of secondary (permanent) teeth. Additional dental features include:

• Gingival overgrowth
• Microdontia
• Sialorrhea
• Increased alveolar bone density

Developmental delay (DD) and/or intellectual disability (ID). To date, almost all identified individuals with Shashi-Pena syndrome have demonstrated some degree of developmental delay and/or intellectual disability ranging from mild to severe.

• Gross motor delays have manifested as delayed walking (range: age 18 months to after age 4 years).
• Verbal communication may be achieved as early as age two years, although some affected individuals continued to be nonverbal at age four years.
• The range of intellectual abilities extends from low-average IQ (reported in one such person) to severe ID.

Other neurologic features

• Hypotonia is observed in almost all infants with Shashi-Pena syndrome and tends to improve as affected individuals enter childhood to adolescence.
• Temperature dysregulation. Several affected individuals reported overheating easily and higher basal body temperatures.
• Seizures have been reported in about two thirds of individuals with Shashi-Pena syndrome.
  • Of these, about one third have febrile seizures only, one third have non-febrile seizures only, and one third have both febrile and non-febrile seizures.
  • Among non-febrile seizures, generalized tonic-clonic, focal, and absence seizures have been described.
  • There is no specific pattern of EEG changes noted in people with Shashi-Pena syndrome, but EEG findings tend to be consistent with the reported seizure type.
  • Seizures are typically well controlled with standard anti-seizure medications when needed (see Management).

Neurobehavioral/psychiatric manifestations. Anger outbursts and aggression are common and can be difficult to manage. No specific treatment has been found to be superior for behavioral challenges. Anxiety, attention-deficit/hyperactivity disorder, and autism spectrum disorder, either as single diagnoses or in combination, have been observed in a few affected individuals, but there is not enough data to determine if these are consistent findings in individuals with Shashi-Pena syndrome.

Growth. At least two thirds of individuals with Shashi-Pena syndrome have macrosomia, which may be associated with advanced bone age. Macrocephaly is present in about three quarters of affected individuals. Macrocephaly and macrosomia may be present at birth or develop over time.

Gastrointestinal problems. The majority of affected individuals demonstrate feeding difficulties from infancy, most likely due to low tone. Typically this is transient and may be accompanied by poor uncoordinated suck/latch, which can translate into oral apraxia in childhood. Dysphagia and aspiration are not common findings in this condition, and affected individuals are typically able to eat by mouth as children and into adulthood. However, some affected individuals experience sensory issues / food texture aversions.

Musculoskeletal features. Skeletal abnormalities are common in Shashi-Pena syndrome.

• About two thirds of affected individuals have scoliosis/kyphosis (11/16; 69%) and/or joint hypermobility (9/14; 64%), although without frank joint dislocations.
• Scoliosis/kyphosis may require significant surgical intervention.
• A predisposition to fractures (5/17; 29%) and hip dysplasia have been noted in fewer than one third of affected individuals.

Cardiac abnormalities. Cardiac anomalies have been identified in about 80% of people with Shashi-Pena syndrome. The most common reported findings are atrial septal defects or patent ductus arteriosus. Other rare findings may include the following:

• Ventricular septal defects
• Coarctation of the aorta
• Pulmonary artery valve thickening
• Pulmonary artery stenosis

Ophthalmologic involvement. About three quarters of people with Shashi-Pena syndrome have ophthalmologic findings, most commonly strabismus and amblyopia. Ptosis is one of the distinctive facial features seen in affected individuals but does not typically impact vision.

Endocrinologic. More than half of affected individuals have hypoglycemia at some point in life.

• The exact presentation is variable. Some affected individuals experienced hypoglycemia only in the neonatal period, others had episodic hypoglycemia, and one affected individual had severe hypoglycemia requiring continuous feeds.
• Hyperinsulinism has been documented in at least two affected individuals, and one was successfully treated with octreotide [Yuan et al 2023] (see Management).

Hearing loss has been identified in approximately half of reported individuals. This is typically conductive hearing loss and may normalize after intervention such as pressure-equalizing (PE) tubes. Multiple sets of PE tubes may be needed. One affected individual had sensorineural hearing loss and received cochlear implants.

Respiratory issues. Nearly half of reported individuals have sleep apnea. While this has not been well characterized in people with Shashi-Pena syndrome, obstructive and mixed obstructive/central sleep apnea has been described. Some affected individuals require positive pressure ventilation during sleep.

Other reported findings

• Neuroimaging. Brain MRI findings are common (15/17; 88%) but are nonspecific. Affected individuals have been noted to have white matter volume loss and increased extra-axial cerebral space.
• Hematologic. Granulocytopenia and thrombocytopenia were reported together in one affected individual [Jiao et al 2022] but have not otherwise been identified as a recurring feature of Shashi-Pena syndrome.

Genotype-Phenotype Correlations

Although no genotype-phenotype correlations have been identified, thus far all pathogenic variants associated with the classic findings of Shashi-Pena syndrome have been de novo pathogenic frameshift, nonsense, or damaging splice variants in the last two exons of the gene resulting in premature protein truncation (see Molecular Genetics).

Prevalence

The exact prevalence of Shashi-Pena syndrome is unknown; it likely is an ultra-rare condition [Richter et al 2018].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Shashi-Pena syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for Shashi-Pena syndrome. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

Prolonged fasting should be avoided in those with hypoglycemia.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In general, women with epilepsy or a seizure disorder of any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASMs to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Shashi-Pena syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• To date, all known individuals with Shashi-Pena syndrome have the disorder as the result of a de novo ASXL2 pathogenic variant.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. * Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for an ASXL2 pathogenic variant may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is heterozygous for the ASXL2 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the ASXL2 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].

Offspring of a proband. Each child of an individual with Shashi-Pena syndrome has a 50% chance of inheriting the ASXL2 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the ASXL2 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the ASXL2 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

ASXL2 is one of three Polycomb group protein genes that act as histone methyltransferases and are implicated in embryogenesis, encoding the putative Polycomb group protein ASXL2. In mice, Asxl2 has been reported to regulate skeletal, lipid, and glucose homeostasis and cardiac development [Khan et al 2014, Izawa et al 2015]. The three ASXL genes (ASXL1, ASXL2, and ASXL3) are involved in body patterning and encode proteins that participate in epigenetic regulation. Each one of the ASXL genes is involved in a developmental disorder: in addition to ASXL2 pathogenic variants, loss-of-function pathogenic variants in ASXL1 lead to Bohring-Opitz syndrome, and ASXL3 loss-of-function pathogenic variants lead to Bainbridge-Ropers syndrome (see Differential Diagnosis). Although the three conditions share overlapping features, individuals with Shashi-Pena syndrome are distinguished by findings of overgrowth and a greater variation in intellectual abilities. Another distinction is that the mechanism of disease causation for Shashi-Pena syndrome appears to be through a dominant-negative effect. This is supported by biallelic expression in blood for both wild type and mutated ASXL2 alleles. All variants identified to date map to the final two exons of ASXL2, and the lack of reduction in transcript expression supports escape from nonsense-mediated decay for transcripts from the variant alleles. Additional molecular studies are needed to confirm and elucidate the dominant-negative mechanism.

Mechanism of disease causation. Current evidence indicates that the mechanism of disease is dominant-negative.

ASXL2-specific laboratory technical considerations. In the original clinical publication by Shashi et al [2016], ASXL2 was described to have 12 exons. Since then, the transcript has been updated to include 13 exons. This update does not change the original observation of all pathogenic variants being located in the final two exons.

Acknowledgments

We gratefully acknowledge the families with Shashi-Pena syndrome and the ARRE Foundation for their support in data gathering as we expand our understanding of the disorder.

We would like to acknowledge Wenying Zhang, MD, PhD, MBA, and Yaning Wu, MD, PhD, from Cincinnati Children's Hospital for assistance in interpretation of genomic data.

The authors also wish to acknowledge funding support from the Undiagnosed Diseases Network, which made the 2016 publication of the initial cohort of affected individuals possible.

Revision History

• 7 November 2024 (ma) Review posted live
• 8 March 2024 (lp) Original submission

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