Rhombencephalosynapsis (RES) is a midline brain malformation involving partial or complete agenesis of the cerebellar vermis, fusion of the cerebellar hemispheres, merging of the dentate nuclei, and rarely fusion of the superior cerebellar peduncles [1]. RES can be isolated or occur in association with other congenital anomalies, such as in Gómez-López-Hernández syndrome (GLHS) [2, 3]. GLHS is a rare congenital neurocutaneous syndrome characterized by RES, partial bilateral hair loss (alopecia), distinct craniofacial features (e.g., abnormal head shape and posterior angulated ears), and, in a subgroup of patients, trigeminal anaesthesia [4, 5]. The aetiology of RES is still largely unknown. In addition to a wide range of motor symptoms, which may include developmental delays, ataxia, swallowing difficulties, muscular hypotonia, abnormal eye movements, and “figure of eight” head-nodding stereotypy [6], cognitive and emotional disturbances occur in varying degrees of severity [6, 7]. The collection of cognitive and emotional disturbances associated with cerebellar pathology is known as the cerebellar cognitive affective syndrome (CCAS) or Schmahmann’s syndrome [8,9,10]. CCAS is characterized by deficits in one or more of the following four domains: (i) executive functions, (ii) visuospatial cognition, (iii) linguistic processing and (iv) affect regulation.

Longitudinal studies on psychological functioning and wellbeing from childhood to early adulthood in RES remain scarce. Here, we describe a 22-year-old white woman with RES and bilateral parietal alopecia who underwent neuropsychological evaluations and brain imaging on several occasions during her life.

She was delivered at 39-weeks gestational age by caesarean section following an uncomplicated pregnancy, born to non-consanguineous parents. There was no family history of developmental delay, intellectual disability, autism, hydrocephalus, cerebral palsy, seizures, other birth defects, or neurological conditions in general. Maternal grandmother developed post-traumatic epilepsy in her 30s after a neck injury. Medical records documented the presence of psychiatric symptoms, including anxiety, depression, attention deficits, and hyperactivity on the maternal side of the family.

Prenatal ultrasound in the ninth month of pregnancy revealed a dilated left lateral ventricle. Additional ultrasound scans during the first 6 months postpartum confirmed the unilateral ventriculomegaly. No other significant neurological findings were observed during this period.

At 5 months, she developed a sensorimotor anomaly of the binocular vision system in which the foveal line of alignment of one eye occasionally deviated inward and failed to intersect the object of fixation (i.e., alternating esotropia). After patching and wearing glasses, strabismus surgery was performed at 16 months. Her development was characterized by hypotonia with delayed attainment of motor milestones for which she received occupational and physical therapy. She also received speech therapy for low tone in her mouth and jaw. She drooled all the time. Postural instability, perceptual difficulties, and poor gross and fine motor skills were noted. At approximately 7 years of age, she had an episode of repeated tongue chewing to the point that she developed an ulcer. In addition, she developed an oral allergy syndrome and her tongue began to itch extremely and relentlessly. She was put on divalproex sodium, which effectively eliminated the tongue chewing. Magnetic resonance imaging of the brain at 8 years of age showed left ventriculomegaly, especially of the left temporal and occipital horns (Fig. 1A) and identified RES (Fig. 1B).

T1-weighted axial 3T MRI scan at the age of 8 years showing left ventriculomegaly (A) and fusion of the cerebellar hemispheres (B)

Concomitant 99mTc-HMPAO single photon emission computed tomography (SPECT) showed moderately elevated relative perfusion of the bilateral orbitofrontal cortex. A marked elevation of relative perfusion was seen in the right insular cortex, as well as in the anterior and posterior cingulate cortex, adjacent precuneus area, right caudate head, and to a lesser extent the bilateral putamen. A focal area of marked elevated relative perfusion was also observed in the superior aspect of the left cerebellar hemisphere. By contrast, marked relative underperfusion was found in the left mesial temporal lobe.

Neuropsychological evaluation performed at age 7 showed that the patient fell in the high-average psychometric range of intelligence with a WISC-4 full scale IQ of 112. There were initially no indications of verbal or reading deficits, and also no signs of deficits in factual learning and declarative memory. However, the presence of inattentiveness, distractibility, impulsive behaviour, and emotion dysregulation fulfilled the Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV) characteristics of attention-deficit (hyperactivity) disorder (ADHD). Notably, she did not meet diagnostic criteria for autism. At 12 years of age, she underwent a renewed evaluation of psychological and social-emotional functioning. Results of the examination revealed that according to the DSM-IV criteria along with the results of the prior assessment, she met diagnostic criteria for ADHD, depressive disorder, generalized anxiety disorder, and developmental coordination disorder. In addition to experiencing a considerable number of problematic thoughts, ideas, and feelings, her emotional reactions were strong and at the same time variable and unpredictable. Difficulties in emotion regulation were considered the underlying cause of the intensity, unpredictability, changeability, and inconsistency of her behaviour. Moreover, she exhibited an external locus of control as she believed that events beyond her control drove her actions and outcomes. This constellation of signs and symptoms is reminiscent of CCAS [8, 11].

Between 9 and 12 years of age several stimulants were trialed to manage her ADHD symptoms. Methylphenidate (10–20 mg) was started at about 9 years of age and continued for more than 2 years. Despite the positive effect, medication was terminated due to poor weight gain. A dextroamphetamine-amphetamine stimulant caused headache and nausea and was discontinued after 2 days. A methylphenidate transdermal patch did not improve symptoms and was stopped. Another trial of methylphenidate and atomoxetine was without success. Guanfacine, an adrenergic alpha-2 receptor agonist, did not seem to have a positive effect but was nonetheless continued given the positive clinical evidence in children and adolescents with ADHD (e.g., [12]). At 12 years of age the selective serotonin reuptake inhibitor (SSRI) escitalopram (10 mg) was started, which was stopped due to hyperactivity and restlessness. A trial of the SSRI citalopram (30 mg) when she was 13 years old was also deemed unsuccessful.

Due to reading problems and persistent postural instability, oculomotor and vestibular testing were performed. Results revealed abnormal conjugate eye movements and abnormalities in visuo-vestibular interactions, both of which are consistent with involvement of the oculomotor vermis and its target in the posterior portion of the fastigial nucleus [13]. As she progressed into college, an evaluation of her strengths and weaknesses was performed at the age of 18. At that time, she was taking the following drugs on a daily basis: Guanfacine (2 mg) and methylphenidate (15 mg in the morning and 5 mg at midday as needed) for ADHD, divalproex sodium (1000 mg) for tongue chewing, a serotonin-norepinephrine reuptake inhibitor (100 mg) for anxiety, vitamin D to help with anxiety and depressive mood, melatonin (5 mg) for sleeping difficulties, anti-histamines (10 mg) for allergies, probiotics and the food supplements zinc, magnesium, vitamin A, and co-enzyme Q10 (50 mg).

Results of the Behavior Rating Inventory of Executive Functioning that was administered when she was 18 years old showed significant problems in her ability to inhibit impulses, shift to new situations, and maintain emotional control. She frequently experienced intense emotions, which she found difficult to regulate. From the cognitive viewpoint, she had the tendency to get ‘stuck’ in the moment, showing difficulties in implementing subsequent steps toward resolving a conflict or negotiating challenge. Difficulties in executive functioning were seen in solving time-efficiency problems and rapid processing of visual information. By contrast, she demonstrated extraordinary language and strong conversation skills. She was emotionally insightful, articulate, and well-liked by adults and her peers. She made friends easily, but found it hard to maintain relationships as she experienced abnormally heightened levels of anxiety in regard to social interactions. Moreover, she was and still is highly talented in the arts, including acting, dancing, and singing.

Currently, at the age of 22, a repeated, contrast enhanced 3T MRI scan demonstrates a stable RES condition, normal grey-white matter distinction, and no signs of malformations of the cerebral hemispheres. There is no indication of interhemispheric cerebral fusion, no midline fusion of the colliculi in the midbrain, and no abnormalities in the basal ganglia and thalamus. The septum pellucidum is present. In the infratentorial brain, mild flattening of the ventral pons can be observed. The cerebellum shows nearly complete fusion of the cerebellar hemispheres across the midline (Fig. 2A and E). The anterior and posterior vermis are absent, but a distinct nodulus is present (Fig. 2A). The hypointense signal across the midline present in the susceptibility-weighted image indicates that the dentate nuclei are fused (Fig. 2C). The shape of the fourth ventricle is enlarged and square-shaped on the axial view (Fig. 2B). As a result of the ventriculomegaly, a mild upward bowing of the corpus callosum was noted, but without signs of thinning or dysgenesis.

Axial T1-weighted MRI scan at the age of 22 years showing an absent vermis with the nodulus (black arrow) still present (A). T2-weighted axial image showing the fused cerebellar hemispheres, an abnormally square-shaped fourth ventricle, and mild flattening of the ventral pons (B). Axial susceptibility-weighted image depicting an area of hypointense signal crossing the midline dorsal to the fourth ventricle (white arrow) indicating dentate nuclei fusion (C). T2-weighted axial image visualizing the asymmetric enlargement of the left lateral ventricle with dilation especially of the left temporal and occipital horn (D). Coronal multi-echo gradient-recalled echo T2*-weighted image showing dilation of the left occipital horn and fused cerebellar hemispheres (E)

CCAS-related neuropsychiatric symptoms have persisted up to this day and include emotional reactivity, emotion dysregulation, anxiety, attentional problems, impulsivity, and impairments in executive functioning. In fact, with increasing age her tics and emotions appear to have gotten harder to manage. Also, her obsessive thoughts and compulsive behaviours, as well as anxiety, have become worse. To manage her symptoms related to the tics and anxiety she takes the benzodiazepine alprazolam on a regular basis. Furthermore, her mother noticed a growing lack of social awareness as she does not always seem to read social cues well and understand what appropriate conversation is.

Notwithstanding her strengths, continued support remains necessary to maintain her cognitive and socio-emotional functioning in daily life activities. For example, stress management (e.g., deep breathing exercises and mindfulness), cognitive behavioural therapy methods, acceptance and/ or commitment therapy to address anxiety management and for developing effective coping skills focussed on adaptive problem solving. These forms of support may help to decrease her emotional reactivity, improve symptom management of tic behaviours, and acquire skills to help recognize changes in mood or an increase in anxiety.