Our report describes the phenotype in a family with a previously undescribed KMT2B variant and highlights failure to thrive, an overlooked manifestation. Thus far, 80 additional patients have been described (Additional Table) [5, 6, 10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28]. A recent report identified KMT2B mutations in 21.5% of patients with previously undiagnosed childhood-onset dystonia suggesting KMT2B mutations may be a relatively common cause of dystonia in children . The natural course of KMT2B dystonia involves focal onset lower limb dystonia with progression to generalization. Of reported cases, 23 noted dysphagia, 6 required gastrostomy tube but failure to thrive was rarely mentioned (Additional Table) [5, 6, 10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28]. In our series, the proband and two cousins had dysphagia. Poor weight gain despite normal swallowing study in one cousin and refractory weight gain after gastrostomy tube placement in the proband, suggest factors other than mechanical impairments to swallowing may underlie FTT in this condition.
Progressive dystonia with prominent oromandibular involvement, mild cognitive dysfunction and imaging findings in the proband are consistent with features previously described in KMT2B mutation carriers . Other previously described neurologic features noted in the proband include dysfluency, bulbar dysfunction, dysphagia, intellectual disability, and developmental delay [5, 6]., Additional reported features not present include eye movement abnormalities, skin changes, psychiatric co-morbidities (anxiety, depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder), myoclonus, seizures, spasticity, sensorineural hearing loss, microcephaly, and parkinsonism [5, 6, 10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28].
Interestingly, the proband’s mother did not manifest poor weight gain and reported no motor symptoms until age 29. Similarly, maternal uncles report only adult-onset neurologic symptoms. Reduced penetrance, variable expressivity, and adult onset up to 43 years of age have been reported [14, 26]. As neither maternal grandfather, nor either maternal uncle was examined, we cannot confirm whether dystonia is present. Similarly, it is unclear if mother’s signs and symptoms are due to genetic dystonia, unrecognized cerebrovascular accident, or a combination of both given imaging evidence for remote infarct. Vascular insults have not been reported in KMT2B mutation carriers though most reported cases are children without long-term follow-up. Further study will be necessary to determine whether KMT2B mutation is a risk factor for stroke.
Since molecular diagnosis, the proband has trialed levodopa/carbidopa and trihexyphenidyl without benefit. Deep brain stimulation of globus pallidus (DBS) is reported to improve dystonia in select patients, suggesting another possible avenue for efficacious treatment for affected members of this family [5, 6, 26].
Our case series underscores the importance of careful history and thorough examination when determining etiologies for failure to thrive. In the presence of an abnormal neurologic exam or history of developmental delays, clinicians should strongly consider genetic testing. Unbiased genetic testing in this setting, including whole exome and genome sequencing, has enabled identification of rare disorders, especially those presenting with non-typical phenotypes. This case series highlights the non-neurologic aspects of KMT2B mutation and demonstrates the advantages of molecular genetic testing for defining the precise and potentially treatable etiologies of FTT. It also reinforces the importance of cascade screening of family members to bring clarity of unrecognized diagnoses more broadly beyond the presenting family member.