Clinical Reasoning: Importance of clinical phenomenology in the era of genetic testing

SECTION 1

A 13-year-old right-handed girl had abnormal involuntary movements since infancy. She was born full-term by vaginal delivery with birthweight of 8 pounds, 3 ounces, from a mother who smoked cigarettes. The delivery was complicated by meconium aspiration but she did not require intubation or intensive care. Throughout her life, the abnormal movements remained stable. She described these movements as involuntary, nonsuppressible shaking, involving her entire body. The movements were continuous throughout the day, without diurnal variation, resolved only during sleep, were exacerbated by anxiety and excitement, and caused frequent falls. Medication trials with baclofen and levodopa were ineffective. She had history of global developmental delay (GDD), intellectual disability (ID), and adjustment disorder with anxiety, treated with sertraline. She also had intermittent asthmatic exacerbation and insomnia.

The patient’s parents were deceased at the time of assessment. Her paternal grandmother, who had difficulty walking as a child but denied any ongoing neurologic symptoms, provided limited history. Her father reportedly had involuntary movements since early infancy with motor delay, inattentive symptoms, and frequent falls, and carried a presumed diagnosis of cerebral palsy. He died of lung cancer at age 41 years. Her mother had multiple sclerosis and died in early adulthood, reportedly from myocardial infarction. The patient was enrolled in 7th grade under an individualized educational program.

Neuropsychological evaluation revealed low-average to average intelligence, very low to low-average performance in verbal fluency, average working memory, and poor fine motor skills. Neurologic examination (video, http://links.lww.com/WNL/A116) showed random multifocal movements involving the patient’s trunk and limbs. These movements were predominantly nonrhythmic, nonstereotyped, nonsynchronous, and flowing in nature but also with superimposed jerky movements giving rise to an appearance of restlessness. During tongue protrusion, she demonstrated motor impersistence,¹ which is the inability to sustain persistent muscle contractions. These movements were worse during speech and motor tasks. There were no muscle spasms, abnormal posturing, rhythmic movements, dysmetria, or dysdiadochokinesia. Cranial nerves, motor strength, deep tendon reflexes, and sensory examination results were normal. She walked with a narrow base. General physical examination was unremarkable.

SECTION 2

The patient's hyperkinetic movement was consistent with chorea with relatively minor superimposed myoclonus. Chorea, the predominant phenotype, is an involuntary hyperkinetic movement disorder characterized by irregular, nonrhythmic, nonsynchronous, flowing movements that appear restless.¹ Phenomenologically, athetosis, chorea, and ballism exist on a spectrum and are differentiated based on speed, amplitude, and distribution.¹

The differential diagnosis for childhood chorea is broad. Etiology can be primary (hereditary, often insidious onset) or secondary (acquired, acute, or subacute onset). Although Sydenham chorea is the most common form of acquired chorea in children,² early-infancy onset made this condition and other pediatric autoimmune chorea disorders (e.g., systemic lupus erythematosus, antiphospholipid antibody syndrome, anti-NMDAR encephalitis) less likely.²

The persistence of chorea into the teen years ruled out physiologic chorea of infancy, and the continuous symptom ruled out paroxysmal dyskinesia. Furthermore, the medication history ruled out an iatrogenic etiology. A normal noncontrast brain MRI excluded structural abnormalities, such as prenatal or perinatal brain injury or brain malformation.

Family history suggested an autosomal dominant inheritance pattern. Normal caudate size on MRI excluded juvenile-onset Huntington disease, which would have more likely presented with a hypokinetic phenomenology. Given the patient’s nonprogressive course and family history, benign hereditary chorea (BHC) was the most plausible syndromic diagnosis. Mutations in 3 genes have been identified as pathogenic. NKX2-1 mutations are associated with developmental delay, learning difficulties, hypotonia, variable hypothyroidism, pituitary involvement (empty sella syndrome), and history of neonatal respiratory distress.³ ADCY5 gene mutations have been recently recognized as a relatively common etiology of BHC.⁴ Finally, de novo dominant mutations in PDE10A also cause BHC but with bilateral striatal lesions.⁵ Both NKX2-1- and ADCY5-related BHC can also include additional abnormal movements such as dystonia and myoclonus.^3,4

Given these genetic considerations, thyroid function laboratory tests were ordered and revealed elevated thyroid-stimulating hormone ranging from 4.76 to 8.68 (normal range 0.53–4.00 μIU/mL), increasing the likelihood of a pathogenic NKX2-1 mutation. Sanger sequencing analysis of the NKX2-1 gene, however, did not reveal any pathogenic variation.

SECTION 3

Given the patient’s GDD/ID history, high-resolution chromosomal karyotyping was performed, which identified an inversion in chromosome 14 (46,XX,inv[14][q13q21]). The American Academy of Neurology published a practice guideline on the genetic workup of children with GDD/ID.⁶ After detailed history and examination, it recommended obtaining karyotype, microarray, or fluorescence in situ hybridization (FISH) studies, with rates of abnormality in nonsyndromic GDD/ID children of >4%, 7.8%, and 3.5%, respectively.⁶

One of this patient's chromosomal inversion breakpoints was in the 14q13 region, which is in the approximate location of the NKX2-1 gene. Her early-onset nonprogressive generalized chorea associated with thyroid dysfunction strongly argued in favor of NKX2-1-related BHC. Parental testing was not possible to determine if this inversion was de novo or inherited from her symptomatic father. Subsequent Sanger sequencing of NKX2-1 was negative. However, this testing methodology only examines the exons and is not designed to detect chromosomal rearrangements. As a result, this negative test result did not exclude the possibility that the NKX2-1 gene was affected by this inversion. Thus, this test provided a false-negative result. Appropriate interpretation of the separate genetic data was only possible by the proper interpretation of the historical and semiologic data.

Given the lack of disease-specific treatments, the management approach was symptom-based. Functional impairment due to chorea persisted despite occupational and physical therapies. Symptomatic treatment of chorea includes the use of benzodiazepines, agents that reduce dopaminergic transmission (dopamine receptor antagonists [neuroleptics], dopamine depleters), and select antiepileptic medications.^3,7 Although the mechanism is unknown, levodopa has also been reported to be therapeutic in some patients with NKX2-1-related BHC.³ In severe cases, children may be considered for deep brain stimulation of bilateral internal globus pallidi.⁴ Our patient was treated with oral diazepam and fluphenazine after obtaining a baseline ECG. This combination provided satisfactory reduction in her chorea. She was also evaluated by an endocrinologist but was not placed on levothyroxine due to normal free T4 levels.