Annals of the Child Neurology Society最新文献

We describe a 13-year-old male diagnosed with two rare neurogenetic disorders, transducin (beta)-like X-linked receptor 1 (TBL1XR1)-related disorder and Bainbridge–Ropers syndrome (BRPS), caused by pathogenic variants in additional sex combs-like 3 (ASXL3). Each variant was inherited from an affected parent, although the parents each exhibited much milder phenotypes than the child. TBL1XR1, a widely expressed transcriptional regulator,¹ has been implicated in a range of neurodevelopmental disorders.² TBL1XR1-related disorder includes both Pierpont syndrome, a disorder associated with characteristic dysmorphism, including short stature, along with developmental delay, epilepsy, and feeding difficulties,^{3, 4} and non-Pierpont presentations, including autism spectrum disorder (ASD), intellectual disability (ID), attention deficit hyperactivity disorder (ADHD), epilepsy, and schizophrenia.² Heterozygous pathogenic variants in the ASXL3 transcriptional regulator cause BRPS, characterized by developmental delay with significant language impairment, ID, ASD, feeding difficulties, epilepsy, and dysmorphism.⁵ Nonspecific clinical features that overlap with other genetic syndromes make TBL1XR1-related disorder and BRPS difficult to recognize and diagnose. Further, both disorders typically arise from de novo variants, with few cases of either disorder previously reported to be inherited.

The patient is a 13-year-old Hispanic male found to have a maternally inherited pathogenic ASXL3 variant [c.4678C > T, p.(R1560*) in exon 12] and paternally inherited pathogenic TBL1XR1 variant [c.1291C > T, p.(R431*) in exon 14]. Genetic testing was done by GeneDx using their autism/ID expanded panel with DNA analyzed via next-generation sequencing with copy-number variant calling. Both variants were classified as pathogenic by GeneDx using the 2015 guidelines published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.⁶

His mother has mild ID, ASD traits, ADHD, febrile seizures, and anxiety. His father has been diagnosed with Asperger syndrome, bipolar disorder, fetal alcohol syndrome, ID, ADHD, substance use disorder, anxiety, depression, and psychosis. There are no siblings. The patient was born full term at 6 pounds by Cesarean section due to maternal fever and an amniotic fluid leak. He spent one night in the neonatal intensive care unit for presumed infection. Perinatal difficulties included latching issues, tongue tie, extension contracture of the left hand that corrected over time, reflux, and poor/irritable sleep.

His initial development was normal; however, regression began after a fever at 18 months. Nearly all verbal and communication skills were lost. He made repetitive sounds, stopped pl

The ZNF292 gene encodes a zinc-finger protein that is strongly expressed in the brain during prenatal development.^{1, 2} ZNF292-related neurodevelopmental disorder (NDD) was delineated in a cohort of 28 individuals with 24 different variants in ZNF292.² Our patient displays several prominent features of NDD including intellectual disability (ID), speech/language delays, and autism spectrum disorder (ASD). She also has more significant motor delay and difficulties with coordination associated with hypotonia and chewing/swallowing difficulties from an early age associated with velopharyngeal insufficiency (VPI), oral motor apraxia (OMA), and childhood apraxia of speech (CAS).

This 16-year-old Caucasian female was evaluated for a long-standing history of speech delay with gross and fine motor delay and dyscoordination and hypotonia. She had a history of dysphagia and nasal regurgitation of liquids, characterized as OMA and VPI by otolaryngology and speech pathology. Multiple speech pathology assessments were performed from early childhood until the time of her evaluation due to expressive language delay with poor intelligibility associated with motor planning difficulties, consistent with childhood apraxia of speech. Her math and reading skills were at a grade 7 level. There was no history of seizures or cardiac conditions.

In her late teens, she was formally diagnosed with ASD. Neuropsychological testing showed overall ID from borderline to average ranges with a full-scale IQ of 86. Attention/executive function testing was average.

She was a slender young lady with minor dysmorphic features including relatively small ears, a bulbous nasal tip, relatively large lips and mouth with thin upper lip, and long slender fingers. She was able to respond to questions although her speech was hypernasal and difficult to understand. She had difficulties with tongue protrusion and imitating tongue movements, and she was not able to puff her cheeks, consistent with her history of oromotor apraxia. Her neurological examination was significant for hypotonia with normal resistive strength and normal deep tendon reflexes.

Magnetic resonance imaging of the brain showed a normal myelination pattern without cortical malformation. A GeneDx ID/ASD expanded panel at age 16 years was negative. Reanalysis of the GeneDx panel, at age 22, revealed a de novo pathogenic variant in the ZNF292 gene [c.3432_3436del; p.(N1114Kfs*5)]. Both parents did not carry the variant. This specific variant has not been reported in the literature.

This patient expands upon the previously described phenotypes associated with ZNF292-related NDD (Table 1).² The phenotypic expression is variable except for almost universal presentations of ID (96%) and speech delays (93%) as well as autistic features (61%). Our patient had speech delays and autistic features with

Moral distress, moral injury, and burnout are terms used to encapsulate the difficulties that arise when the relationship that individuals have with their work goes awry.^{1, 2} Burnout, in particular, exquisitely captures the feeling of having had fizzled out. What started as a purposeful and fulfilling profession ends in a disappointing way. Among clinicians, the incidence of moral distress, moral injury, and burnout exceeds 50%.^{3, 4} Moral distress, moral injury, and burnout—collectively termed moral suffering^{5, 6}—stem from a self-evident reality: grief. Clinicians suffer, and as a consequence, so do patients. Among clinicians, the angst is moral—it is the distress that arises in response to an adversity that challenges our integrity.⁶

Moral distress is the emotion experienced by an individual when the appropriate course of action is evident, but a series of obstacles such as scarcity of time, limited resources, lack of seniority, an organization's power structure, institutional policies, red tape, or legal considerations make it difficult to pursue the right course of action.^7-9 Moral distress tends to be situational, and as such it can be a collective emotion. In healthcare, moral distress arises from having to remain silent in the face of rude behavior, from witnessing wasteful use of medical resources, when doing things to the patient and not for the patient, and from lack of autonomy.⁴

Moral injury goes a critical step further. It is the enduring psychological, spiritual, behavioral, social, and emotional harm inflicted on an individual's conscience when that person perpetrates, fails to prevent, or witnesses acts that conflict with their values or beliefs.^{4, 10} Because moral injury stems from an affront to an individual's integrity, it can leave those who endure it feeling victimized, betrayed, wounded, guilty, and ashamed.^{6, 11} If moral distress is situational and possibly collective, moral injury is individual and transcendent.⁴

While we might speak of them in the same breath, moral distress, moral injury, and burnout are not the same. The latter can be a consequence of either one of the former two. Burnout is a syndrome caused by intellectual, physical, and emotional exhaustion in the face of unrelenting stressors in the workplace.⁴ The burnout syndrome's signs and symptoms include malaise, frustration, cynicism, low self-esteem, hopelessness, isolation, sleeplessness, emotional exhaustion, despondency, broken relationships, alcohol and substance abuse disorder, suicidal ideation, and completed suicide.^{12, 13} Burnout thwarts our ability to adapt to the present, and it gives us the impression that our fut

Writing the counterpoint article to Pedro Weisleder's commentary on moral injury among medical practitioners has been challenging, largely because I tend to agree with much of what my friend has to say.¹ I am also at a considerable disadvantage because, unlike Dr. Weisleder, I am not a trained ethicist. Thus, I have few options in this debate but to provide a smattering of personal observations in an effort to ensure a balanced perspective.

There is considerable research on burnout among physicians, but moral injury is not as well studied. Physicians are often reluctant to acknowledge concerns about moral injury lest they appear inadequate or weak. Their hesitancy to speak may also be related to a denial of personal vulnerability or to the long-standing stigma surrounding mental health disorders among physicians, a broader problem for another day's discussion.

One point that is seldom mentioned in contemporary discussions of physician burnout and moral injury is that medicine is an intrinsically difficult profession. How could it be otherwise when we so often deal with untreatable diseases, death, disability, social and family turmoil, and patient financial ruin? It is wrong to assume that only modern physicians face soul-scarring difficulties. Previous generations of physicians had far fewer effective therapies and so more often had to preside over hopeless situations or resort to worthless medications or mutilating amputations in an often-futile attempt to save someone's life. Additionally, physicians once faced a socially accepted dual standard of care that was far worse than the present gap between individuals with commercial health care insurance and those with limited coverage: it was once considered completely acceptable for physicians to simply ignore sick poor people. Indeed, physicians who provided a free cattle-call clinic for a few hours each month were usually considered noble for doing so. Surely these circumstances would have engendered moral injury to many caring, thoughtful physicians of the time. While the recently articulated concept of moral injury makes it easier to recognize the outsized role that our health care system plays in creating physician distress, it is naïve to blame burnout and moral injury solely on the institutions of medicine. Being a physician has always been challenging, and it is likely to remain so even if we can address some of the systemic issues.

I have often pondered why some physicians seem to fare so much better than others when facing situations that typically lead to moral injury and burnout. Even within the same medical specialty, in the same institution, and with the same workload, some people remain grounded and productive while others falter and decompensate. From my own admittedly anecdotal observations, the diverse responses of physicians to professional adversity may be partly explained by intangible individual qualities such as resilience, perfec

Both fissures and sulci are permanent indentations, grooves, or foldings of the cerebral cortex. They are distinguished in large part by timing: fissures form in the first half of gestation and sulci in the second half. A notable exception is the sulcus limitans, a shallow longitudinal groove in the horizontal axis of the embryonic neural tube that extends throughout the spinal cord and brainstem to the mesencephalon and rostrally into the wall of the third ventricle. It is most evident in the lateral wall of the fetal spinal central canal, cerebral aqueduct, and third ventricle and demarcates alar and basal plates of primordial gray matter to denote the separation of dorsal and ventral horns in the spinal cord and sensory and motor cranial nuclei in the brainstem. Other small embryonic grooves, such as the one that demarcates the lateral from the medial ganglionic eminences, also were called sulci, having been named from antiquity to the late 19th century. All sulci in the embryonic brain are transitory, unlike the permanent sulci of the cerebral cortex or interfolial sulci of the cerebellar cortex.

The earliest true fissure to form is the interhemispheric fissure, secondary to cleavage of the prosencephalon at four to five weeks' gestational age (GA); the last fissure to form is the lateral cerebral (sylvian) fissure because of bending of the telencephalic flexure, the primitive telencephalic hemisphere in which the caudal end of the early telencephalon becomes not the occipital pole but rather the rostral pole of the temporal lobe.¹ Examples of intermediately timed fissures are the hippocampal and calcarine. Another distinction is that fissures result mainly from external mechanical or physical forces, whereas sulci principally form because of intrinsic growth.¹ Convolutions are needed so that the cerebrum at term and the fetal head at birth are not so large as to pose an intrapartum traumatic risk to both fetus and mother, which also would be conducive to survival of the species. Small mammals, such as rodents and lagomorphs, have smooth nonconvoluted brains even at maturity because the number of cortical neurons is not enough to require folding; an interhemispheric fissure forms in mice, rats, squirrels, and rabbits, but a lateral cerebral fissure does not develop.² In humans and other large mammals, the sequence of gyral and sulcal formation follows a time-linked predictable program leading to precise gyral identification at each gestational age of the late second and third trimesters and in the mature brain.³ Cortical sulcation not only enables a larger surface area without a concomitant increase in cerebral volume but also provides for intracerebral connectivity conducive to more complex synaptic circuitry.⁴

The development of fissures and sulci often is altered in many m