Failure to thrive - an overlooked manifestation of KMT2B-related dystonia: a case presentation

Background KMT2B-related dystonia is a recently described form of childhood onset dystonia that may improve with deep brain stimulation. Prior reports have focused on neurologic features including prominent bulbar involvement without detailing general health consequences that may result from orolingual dysfunction. We describe a family with novel KMT2B mutation with several members with failure to thrive to highlight this non-neurologic, but consequential impact of mutation in this gene. Case presentation We present a case of a 15-year old female who was admitted and evaluated for failure to thrive. On exam, she had severe speech dysfluency, limited ability to protrude the tongue, and generalized dystonia involving the oromandibular region, right upper and left lower extremity with left foot inversion contracture. The proband and her parents underwent whole genome sequencing. A previously undescribed variant, c.4960 T > C (p.Cys1654Arg), was identified in the KMT2B gene in the proband and mother, and this variant was subsequently confirmed in two maternal cousins, one with failure to thrive. Literature review identified frequent reports of prominent bulbar involvement but failure to thrive is rarely mentioned. Conclusion Failure to thrive is a common pediatric clinical condition that has consequences for growth and development. In the presence of an abnormal neurologic exam, a search for a specific underlying genetic etiology should be pursued. With this case series, we highlight an unusual potentially treatable cause of failure to thrive, reinforce the importance of precise molecular diagnosis for patients with failure to thrive and an abnormal neurologic exam, and underscore the importance of cascade screening of family members.


Background
Failure to thrive (FTT), a common clinical condition warrants hospitalization to ensure adequate nutrition and thorough investigation of etiology. FTT is defined as weight less than 0.4-5th percentile, weight less than 80% normal weight for age, or weight decline across more than 2 major percentiles [1]. The causes include poor nutrition, inadequate absorption, and increased energy expenditure. Careful attention to history and comprehensive physical exam can yield clues to etiology.
Dystonia is a movement disorder characterized by involuntary hyperkinetic movements involving sustained or intermittent contractions of agonist and antagonist muscles that frequently lead to abnormal posturing or movements [2]. Dystonia is classified based on clinical characteristics (age of onset, regional distribution, temporal pattern, coexistence of other movement disorders, and other neurological manifestations) and etiology (genetic, acquired, or idiopathic) [3]. Orolingual dystonia can cause eating dysfunction leading to weight loss [4].
Lysine Methyltransferase-2B (KMT2B) dystonia is a recently described autosomal dominant disorder [5,6]. The KMT2B gene encodes a lysine methyltransferase involved in H3K4 methylation, an epigenetic modifier active in development [7]. This condition is characterized by childhood lower-limb onset dystonia that progressively generalizes with prominent cranial, cervical, and laryngeal involvement [5,6]. Though dysphagia has been described, reports have focused on neurologic rather than gastrointestinal symptomatology and presentation. We report the first case series where failure to thrive was the presenting feature prompting diagnosis. Our report identifies a novel KMT2B pathogenic variant, c.4960 T > C (p.Cys1654Arg), and expands both the spectrum of phenotypic presentation for KMT2B mutation and genetic causes for FTT.

Case presentation
A 15-year-old girl (III-1) was admitted to the hospital for FTT: 36 kg(0.18%ile), 151 cm (4%ile). She had not seen a physician for 2 years due to socioeconomic issues. History revealed mild cognitive impairment, gait abnormality (left foot inversion) onset age 3, speech dysfluency onset age 9, and slowness with eating onset age 13 with dysphagia to solids and liquids onset age 14. Previous evaluation for gait abnormality resulted in unsuccessful trials of muscle relaxants and orthotics. Family history was initially negative for neurologic conditions. On exam, there was severe speech dysfluency, limited ability to protrude the tongue, and generalized dystonia involving the oromandibular region, the right upper and the left lower extremity with left foot inversion contracture (Additional files 1, 2, 3).
Initially, neglect was considered a possible etiology given the delay in seeking medical evaluation. However, abnormal neurologic exam prompted further testing. Labs were normal except for mild thrombocytopenia likely due to malnutrition (Table 1). Brain magnetic resonance imaging (MRI) showed bilateral hypointensity in globi pallidi on susceptibility-weighted imaging supporting an organic etiology (Fig. 1). Radiofilm revealed left foot 5th metatarsal fracture. Muscle biopsy showed myopathic fiber size variation and mild vasculopathic changes. Video-swallow fluoroscopy showed dysphagia to liquids and solids. Gastrostomy tube was placed with significant weight gain but persistence of weight below the second percentile despite appropriate caloric intake. Levodopa/carbidopa and trihexyphenidyl After identification of the KMT2B variant in the proband and mother, additional history was obtained. A three-generation pedigree was constructed (Fig. 2). Cascade testing of maternal cousins (III-6 and III-7) revealed that they carried the same KMT2B c.4960 T > C (p.Cys1654Arg) variant. The father (II-4) of maternal cousins (III-6 and III-7) is an obligate carrier.
Mother, age 34(II-2), relayed history of painful right arm posturing, worsening handwriting, intermittent numbness, and gait disturbance onset age 29. She denied speech changes or dysphagia. She recalled history of encephalitis at age three. She was in special education classes and was unable to complete high school. She had anxiety onset age 19. Examination revealed normal speech, right > left hand dystonia, right foot eversion while ambulating, 4/5 weakness in finger extensors and finger intrinsic muscles on the right, and 2 beats of clonus in the right ankle (Additional files 4, 5, 6). MRI brain showed T2 hyperintensity without enhancement in the deep and subcortical white matter of the left frontal lobe suggesting remote infarct in the left middle cerebral territory (Fig. 3).
Maternal male cousin, age 4(III-7), had delayed milestones, attention deficit hyperactivity disorder, anxiety, and behavioral concerns. There was history of frequent choking; however, video-fluroscopy was normal. Height was consistently less than the 10th percentile and weight less than the 3rd percentile. Examination revealed hypernasal speech and preferential toe walking, although he was able to walk heel toe when prompted.
Maternal female cousin, age 6(III-6), initially presented for evaluation of hypernasal speech. A submucous cleft palate was identified and she underwent a Furlow palatoplasty without improvement. She had difficulties swallowing as an infant, requiring feed thickener.  Dysphagia resolved over time. Growth was consistently below the 10th percentile for height and weight. Early toe walking improved with therapy. She has learning delays and receives therapies and support in school. Vision abnormalities include left-sided strabismic amblyopia, hyperopia, accommodative esotropia, and astigmatism. Neurological evaluation revealed hypernasal, but fluent speech, normal resting tone with normal deep tendon reflexes, and gait with external rotation of the left leg with weight distribution on the lateral aspect of the foot, suggesting mild dystonia.
Signs and symptoms in maternal grandfather and maternal uncles are reported by other relatives; none have been examined by a neurologist. Maternal grandfather I-1 had mild short stature and was aesthenic. Maternal uncle, age 41(II-3), recently lost use of his left arm; he has not had testing for the familial variant. Maternal uncle, age 40(II-4), an obligate carrier of the variant, is intellectually impaired and has short stature. He reported tingling and numbness in the neck that progressed to painful paresthesias in all four limbs onset age 20.

Methods
Sequencing WGS was performed as previously described [8,9]. Variants were prioritized by allele frequency, conservation, and predicted effect on protein function and confirmed by Sanger sequencing. Phenotypic terms included the following: dysarthria, gait disturbance, failure to thrive, and dysphagia. Given MRI findings, the sequence was re-queried to specifically exclude other variants in genes associated with brain iron accumulation. Subsequent family studies were performed by targeted Sanger sequencing.

Literature review
We reviewed 80 cases obtained by PubMed Search using term KMT2B as well as cases in the reference list for these manuscripts or otherwise known to the author, that were not identified by PubMed search. (Additional Table).
Interestingly, the proband's mother did not manifest poor weight gain and reported no motor symptoms until age 29. Similarly, maternal uncles report only adultonset 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.