Years published: 2023
NORD gratefully acknowledges Meena Balasubramanian, MBBS, DCH, FRCPCH, MD, Sheffield Children’s NHS Foundation Trust, University of Sheffield, Sheffield, UK, for the preparation of this report.
ASXL3-related disorder, also known as Bainbridge-Ropers syndrome, is a neurodevelopmental disorder that was first described by Bainbridge et al. in 2013. It is associated with changes (pathogenic variants or mutations) in the ASXL3 gene.
The initial description of this syndrome by Bainbridge et al. was based on four individuals with developmental delay, feeding difficulties, neurological abnormalities and difficulty gaining weight (failure to thrive). With the identification and publication of more patients, the spectrum of characteristics has expanded to include low muscle tone (hypotonia) (88%), characteristic facial features (92%), palate abnormalities (61%), musculoskeletal features (67%), behavioral issues (92%), crossed eyes (strabismus) (56%), sleep disturbance (50%) and autistic features (65%). Intellectual disability (or its precursor, global developmental delay) was noted in 95% of affected children.
Developmental delay and intellectual disability
All patients described in the published literature, with sufficient clinical information to ascertain the level of delay in various developmental areas, had a speech and language delay. Some patients have been described with language regression as a child, and some patients have been described to communicate by alternate methods, such as Makaton signing. Developmental delay and intellectual disability ranged from mild to very severe.
Autism spectrum disorder (ASD) and other behavioral concerns
Autism diagnosis or autistic behaviors were described in 65% of individuals in the literature. Autistic traits included obsessions, inflexibility and incapacity for change, hand-flapping and rocking, and difficulties with sensory processing. Other behavioral difficulties described included self-injurious behaviors and aggression towards caregivers, emotional dysregulation with outbursts of either laughter, screaming, aggression and teeth grinding (bruxism).
Feeding difficulties were described in 74% of individuals in the literature. Several presented with failure to thrive in infancy. Feeding difficulties included poor neonatal suck or latch, vomiting, gastroesophageal reflux, food refusal behaviors and requirement for assistance-feeding. Some babies required nasogastric tube insertion. There were reports of ongoing requirement for tube feeding in childhood. Some feeding difficulties in infancy were reported to improve with time.
Musculoskeletal features were seen in 67% of individuals reported in the literature. Many individuals had hypotonia (88%), which could have explained the accounts of wide range of movement (hypermobility). Other musculoskeletal features were accounted for by spine and thoracic wall abnormalities (scoliosis, kyphosis, pectus excavatum), digit and joint abnormalities (contractures, arachnodactyly, ulnar deviation, camptodactyly, overlapping digits) and foot abnormalities (pes planus, narrow feet, varus deformity).
A severe multi-joint condition of arthrogryposis multiplex congenita has been described in patients with pathogenic ASXL3 variants. There were reports of long slender hands and digits, and a long, thin body with long arms, legs, fingers and toes (Marfanoid body habitus).
Palate abnormalities were described in 61% of individuals in the literature; these were most often a high and narrow palate, but there was also a description of a submucous cleft . Despite the Marfanoid habitus, there have been no reports of children with a dilated aorta, as is associated with Marfan syndrome and other connective tissue disorders. One child with ASXL3-related disorder was found to have a subclavian artery aneurysm.
Non-specific abnormal facial features have been described in most affected children (92%). There are no specific or defining facial features, but typical features included abnormal head shape, prominent forehead, highly arched eyebrows, eyebrows that meet in the center of the face (synophrys), widely spaced and deep-set eyes, down-slanting palpebral fissures, long and tubular nose, low-hanging columella, prominent nasal bridge, wide mouth, high arched palate, everted vermilion of the lower lip, small lower jaw (micrognathia), and crowded teeth, but these may not be recognized until after diagnosis. Additional dental abnormalities have also been reported, including large teeth, missing teeth and lack of enamel development (enamel hypoplasia).
Sleep disturbance was described in 50% of patients in the literature. This included reports of obstructive sleep apnea, poor sleep and easy waking. A report of rapid, deep breathing and slow, writhing movements (hyperventilation athetosis) was reportedly associated with the sleep-wake cycle, immediately prior to falling asleep.
Structural brain abnormalities
Structural brain abnormalities have been described, but are not as easily quantified, as MRI brain imaging is not routinely carried out unless there is a clinical indication. This may mean an under-reporting of brain abnormalities in the literature. Normal brain imaging was reported in most individuals, however there were some non-specific abnormalities such as white matter loss. One individual was reported to have normal early MRI scans but saw a clinical decline in correlation with subsequent cerebral and cerebellar atrophic changes. Cerebellar vermis hypoplasia has been described in some individuals.
Seizures or epilepsy have been described in 32% of individuals. A variety of seizure types have been reported in the literature, including generalized (tonic-clonic and absence), focal and complex focal seizures.
Variations of focal seizures have been described including atonic seizures (associated with other behaviors such as head-bobbing or spontaneous outbursts of laughter), myotonic seizures (with partial-body stiffness or shaking) and subclinical seizures.
A typical epilepsy was described, consisting of generalised epilepsy that starts in childhood, with absence seizures and tonic-clonic seizures. However, there have been reports of later-onset epilepsy starting during adulthood. Seizure frequency has been variably reported, with some individuals having sporadic and self-limiting epilepsy, some that resolved with treatment, and some individuals having up to 140 seizures a day despite treatment.
ASXL3-related disorder is caused by pathogenic or likely pathogenic variants in the ASXL3 gene. The majority of variants are new mutations that result in a shortened protein product that does not function properly.
ASXL3-related disorder follows an autosomal dominant pattern of inheritance. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
ASXL3-related disorder has been described all over the world and is not population specific.
ASXL-related disorder may be suspected based on the signs and symptoms associated with the disorder. The diagnosis is confirmed with genomic testing that shows a pathogenic variant in the ASXL3 gene.
Multidisciplinary care is recommended and includes management of multiple subspecialty appointments, equipment, medications and supplies. Ongoing assessment for palliative care involvement and/or home nursing is needed.
Developmental delay and intellectual disability should be managed by a developmental pediatrician. Speech and language delay should be managed by appropriate healthcare professionals.
Epilepsy should be treated with antiepileptic drugs (AEDs) by an experienced neurologist. Many different AEDs may be effective; no one AED has been demonstrated effective specifically for this disorder.
Poor weight gain and failure to thrive may require feeding therapy and gastrostomy tube placement for persistent feeding issues.
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