Exon skip-inducing variants in FLNA in an attenuated form of frontometaphyseal dysplasia.

Pathogenic variation in the X-linked gene FLNA causes a wide range of human developmental phenotypes. Loss-of-function is usually male embryonic-lethal, and most commonly results in a neuronal migration disorder in affected females. Gain-of-function variants cause a spectrum of skeletal dysplasias that present with variable additional, often distinctive, soft-tissue anomalies in males and females. Here we present two, unrelated, male individuals with novel, intronic variants in FLNA that are predicted to be pathogenic. Their phenotypes are reminiscent of the gain-of-function spectrum without the skeletal manifestations. Most strikingly, they manifest urethral anomalies, cardiac malformations, and keloid scarring, all commonly encountered features of frontometaphyseal dysplasia. Both variants prevent inclusion of exon 40 into the FLNA transcript, predicting the in-frame deletion of 42 amino acids, however the abundance of FLNA protein was equivalent to that observed in healthy individuals. Loss of these 42 amino acids removes sites that mediate key FLNA functions, including binding of some ligands and phosphorylation. This phenotype further expands the spectrum of the FLNA filaminopathies.

X-linked frontometaphyseal dysplasia with severe scoliosis and spinal cord compromise in an Indian boy.

Frontometaphyseal dysplasia (FMD) is a rare genetic disorder with morphological abnormalities of the skeletal and extra skeletal tissues. It belongs to the group of otopalatodigital spectrum disorders. Here we report a 12-year-old boy from India with features of frontometaphyseal dysplasia who had severe scoliosis with neurological complications due to spinal cord compromise. Clinical examination of his mother also revealed mild features of FMD. The manuscript highlights the clinical presentation of the disorder and discusses the clinical heterogeneity of the otopalatodigital spectrum disorders.

Investigation of the Impact of Infrared Sensors on Core Body Temperature Monitoring by Comparing Measurement Sites.

Many types of thermometers have been developed to measure body temperature. Infrared thermometers (IRT) are fast, convenient and ease to use. Two types of infrared thermometers are uses to measure body temperature: tympanic and forehead. With the spread of COVID-19 coronavirus, forehead temperature measurement is used widely to screen people for the illness. The performance of this type of device and the criteria for screening are worth studying. This study evaluated the performance of two types of tympanic infrared thermometers and an industrial infrared thermometer. The results showed that these infrared thermometers provide good precision. A fixed offset between tympanic and forehead temperature were found. The measurement values for wrist temperature show significant offsets with the tympanic temperature and cannot be used to screen fevers. The standard operating procedure (SOP) for the measurement of body temperature using an infrared thermometer was proposed. The suggestion threshold for the forehead temperature is 36 °C for screening of fever. The body temperature of a person who is possibly ill is then measured using a tympanic infrared thermometer for the purpose of a double check.

[A pulsatile mass on the forehead after a fall]. / Een bult op de slaap na een val.

A 84-year-old man presented with a pulsatile mass on the forehead 2 weeks after blunt head injury. Doppler ultrasonography showed a yin-yang sign. The man was diagnosed with a pseudoaneurysm of the left superficial temporal artery.

Whole genome sequencing and 6-year follow-up of a mother and daughter with frontometaphyseal dysplasia associated with keratitis, xerosis, poikiloderma, and acro-osteolysis: A case report.

RATIONALE: Frontometaphyseal dysplasia (FMD) is a dominant X-linked rare disease caused by mutations of FLNA. The distinctive features of FMD include skeletal dysplasia, facial dysmorphism, extremities anomalies, deafness, cleft palate and eye anterior segment anomalies, yet none of the complications, such as acro-osteolysis, keratitis, xerosis or poikiloderma, have been reported in FMD. PATIENT CONCERNS: A 29-year-old mother and her 7-year-old daughter, both presented with congenital glaucoma, craniofacial dysmorphism, xerosis and poikiloderma, were admitted to our hospital in 2011. Additionally, the mother also suffered from acro-osteolysis, keratitis, camptodactyly of hands and metastatic cutaneous squamous cell carcinoma (SCC) which turned out to be fatal 5 years later. In 2017, keratitis and acro-osteolysis were noticed in the daughter as well. Radiography showed bowed long bones with thickening cortex, and distal phalangeal osteolysis. DIAGNOSES: Whole genome sequencing (WGS) was conducted in 2016, resulting in 71491 single-nucleotide polymorphisms and 7616 indels shared by patients while the father was taken as control. A FLNA variant was classified likely pathogenic, supporting the diagnoses of FMD. In addition, though our patients' symptoms were highly consistent with xeroderma pigmentosum variant, a mild subtype of xeroderma pigmentosum (XP) with merely accumulated UV-induced lesions like xerosis and poikiloderma limited to sun-exposure sites, higher risks of cutaneous neoplasms and absence of classical XP features, WGS didn't find supportive genetical evidence, but 2 HERC2 variants were assigned highest suspicion in both XP and SCC by bioinformatical analyses. INTERVENTIONS: Anti-inflammatory treatment, sunscreens and moisturizers were administered. OUTCOMES: The daughter's cutaneous lesions developed slowly during the 6-year follow-up, but the keratitis seriously weakened her sight. LESSONS: To our knowledge, it's the first report of cases carrying FMD, keratitis, xerosis, poikiloderma and acro-osteolysis simultaneously, and 3 likely pathogenic variants were identified. Whole genome/exon sequencing is recommended as a common test for patients with rare phenotypes.

Face cooling reveals a relative inability to increase cardiac parasympathetic activation during passive heat stress.

NEW FINDINGS: What is the central question of this study? Does passive heat stress attenuate the increase in cardiac parasympathetic stimulation, vascular resistance and blood pressure evoked by face cooling? What is the main finding and its importance? Passive heat stress attenuates the capacity to increase cardiac parasympathetic activation and impairs the ability to increase vascular resistance during sympathoexcitation, which ultimately results in a relative inability to increase blood pressure. These findings cast doubt on the efficacy of face cooling at augmenting blood pressure during orthostasis while heat stressed. ABSTRACT: We tested the hypothesis that passive heat stress attenuates the increase in cardiac parasympathetic stimulation, vascular resistance and blood pressure evoked by face cooling. During normothermia and when intestinal temperature was elevated by 1.0 ± 0.2°C, 10 healthy young adults underwent 3 min of face cooling. Face cooling was accomplished by placing a 2.5 litre bag of ice water (0 ± 0°C) over the cheeks, eyes and forehead. Primary variables included forehead skin temperature, mean arterial pressure and systemic, forearm and cutaneous vascular resistances. Indices of heart rate variability in the time domain provided an index of cardiac parasympathetic activity. The magnitude of reduction in forehead skin temperature during face cooling was slightly greater during normothermia (-17.6 ± 1.9 versus -16.3 ± 3.0°C, P = 0.03). Increases in heart rate variability evoked by face cooling were attenuated during heat stress. Changes in systemic, forearm and cutaneous vascular resistances during face cooling were virtually abolished during heat stress (P < 0.01). However, when forearm and vascular data were reported as conductance, differences between normothermia and heat stress were not apparent (P ≥ 0.62). Nevertheless, the increase in mean arterial pressure was attenuated during heat stress with face cooling (at 3 min: 2 ± 7 mmHg) compared with normothermia (at 3 min: 19 ± 7 mmHg, P < 0.01). These data indicate that passive heat stress attenuates face cooling-evoked increases in cardiac parasympathetic activation, vascular resistance and blood pressure. However, they also indicate that changes in indices of vascular resistance do not always reflect equivalent changes in conductance.

Profiling subjective symptoms and autonomic changes associated with cybersickness.

Our aim was to expand knowledge of cybersickness - a subtype of motion sickness provoked by immersion into a moving computer-generated virtual reality. Fourteen healthy subjects experienced a 15-min rollercoaster ride presented via a head-mounted display (Oculus Rift), for 3 consecutive days. Heart rate, respiration, finger and forehead skin conductance were measured during the experiment; this was complemented by a subjective nausea rating during the ride and by Motion Sickness Assessment Questionnaire before, immediately after and then 1, 2 and 3h post-ride. Physiological measurements were analysed in three dimensions: ride time, association with subjective nausea rating and experimental day. Forehead, and to a lesser extent finger phasic skin conductance activity showed a correlation with the reported nausea ratings, while alteration in other measured parameters were mostly related to autonomic arousal during the virtual ride onset. A significant habituation was observed in subjective symptom scores and in the duration of tolerated provocation. The latter increased from 7.0±1.3min on the first day to 12.0±2.5min on the third day (p<0.05); this was associated with a reduced slope of nausea rise from 1.3±0.3units/min on the first to 0.7±0.1units/min on the third day (p<0.01). Furthermore, habituation with repetitive exposure was also determined in the total symptom score post-ride: it fell from 1.6±0.1 on the first day to 1.2±0.1 on the third (p<0.001). We conclude that phasic changes of skin conductance on the forehead could be used to objectively quantify nausea; and that repetitive exposure to provocative VR content results in habituation.

Activity and topographic changes in the somatosensory system in embouchure dystonia.

BACKGROUND: Embouchure dystonia is a highly disabling focal task-specific dystonia affecting professional brass players. OBJECTIVE: This study was designed to analyze activity changes along with topographic representations in primary and nonprimary centers for somatosensory processing in patients with embouchure dystonia. METHODS: We used event-related functional magnetic resonance imaging with automized tactile stimulation of dystonic (upper lip) and nondystonic (forehead and dorsal hand) body regions in 15 professional brass players with and without embouchure dystonia. Statistical analyses included whole-brain between-group comparisons of stimulation-induced activation and region-of-interest-based single patient analyses of topographic activation characteristics. RESULTS: Affected musicians revealed increased stimulation-induced activity in contralateral primary and bilateral secondary somatosensory representations of dystonic and nondystonic body regions as well as in the cerebellum ipsilateral to the left dystonic upper lip. Changes of somatotopic organization with altered intracortical distances and between-group differences of the centers of representations were found in the right primary and the bilateral secondary somatosensory cortex and in the left cerebellum. Positional variability of dystonic and nondystonic body regions was reduced with an emphasis on face representations. CONCLUSIONS: The present findings are supportive of the concept of an abnormal processing of somatosensory information in embouchure dystonia affecting multiple domains. The underlying neurophysiological mechanisms (eg, changes in inhibition, maladaptive plasticity, changes in baseline activity) remain unclear. The involvement of nondystonic body areas can be viewed in the context of possible compensation or an endophenotypic predisposition. © 2016 International Parkinson and Movement Disorder Society.

Does upper blepharoplasty affect frontalis tonicity?

BACKGROUND: Frontalis hypertonicity has long been implicated in patients with significant dermatochalasia or blepharoptosis, as evidenced by eyebrow changes that occur after the resection of redundant skin or after blepharoptosis operation. However, whether upper blepharoplasty affects the forehead muscle has not been reported. Thus, this study investigated electrophysiology of the frontalis muscle and eyebrow morphology in a population of patients undergoing double-eyelid blepharoplasty. METHOD: Patients wishing to undergo upper blepharoplasty were recruited for this prospective study between June 2011 and February 2012. The subjects were excluded for complaints of visual obstruction, trauma history, and for any underlying medical condition that would affect eyebrow height or electromyogram (EMG) findings. Eyebrow morphology was ascertained in a standardized photogrammetric evaluation, and the frontalis muscle activity was recorded with needle EMG. These assessments were carried out at preoperation and at 2 weeks, 3 months, and 6 months. Root-mean-square (RMS) indices of various facial expressions were used to normalize the frontalis activity values across individuals. RESULTS: Thirteen patients with a mean age of 55.5 years were recruited. No statistical significance was observed for eyebrow heights at various assessment points. However, EMG recordings have demonstrated a gradual decrease in the proportional RMS index of the frontalis muscle activity. This difference was statistically significant between preoperation and 6 months postoperation (p < 0.05). CONCLUSION: Upper blepharoplasty was associated with gradual decreases in the frontalis muscle activity. A longer follow-up study is needed to evaluate whether this decreased tonicity results in morphologic changes such as decreased forehead wrinkles and depressed eyebrows. This research indicates that upper blepharoplasty has the potential to interfere with those human-computer interaction designs with facial EMG readings as an input.

Point pressure sensitivity in early stage Parkinson's disease.

A number of sensory changes occur in the earliest stages of Parkinson's disease (PD), some of which precede the expression of the classic motor phenotype by years (e.g., olfactory dysfunction). Whether point pressure sensitivity (PPS), a cutaneous measure of light touch mediated by myelinated Aß fibers, is altered in early PD is not clear. Prior studies on this point are contradictory and are based on non-forced-choice threshold tests that confound the sensitivity measure with the response criterion. While α-synuclein pathology, a defining feature of PD, is present in the skin of PD patients, it is restricted to unmyelinated nerve fibers, suggesting PPS may be spared in this disease. We determined PPS thresholds using a state-of-the-art forced-choice staircase threshold test paradigm in 29 early stage PD patients and 29 matched controls at 11 body sites: the center of the forehead and the left and right forearms, index fingers, palms, medial soles of the feet, and plantar halluces. The patients were tested, in counterbalanced sessions, both on and off dopamine-related medications (DRMs). PPS was not influenced by PD and did not correlate with DRM l-DOPA equivalents, scores on the Unified Parkinson's Disease Rating Scale, side of the major motor disturbances, or SPECT imaging of the striatal dopamine transporter, as measured by technetium-99m TRODAT. However, PPS thresholds were lower on the left than on the right side of the body (p=0.008) and on the upper extremities relative to the toes and feet (ps<0.0001). Positive correlations were evident among the thresholds obtained across all body sectors, even though disparate regions of the body differed in terms of absolute sensitivity. This study indicates that PPS is not influenced in early stage PD regardless of whether patients are on or off DRMs.

Optokinetic stimulation increases limb pain and forehead hyperalgesia in complex regional pain syndrome.

BACKGROUND: Ambiguous visual stimuli increase limb pain in patients with complex regional pain syndrome (CRPS), possibly due to afferent sensory feedback conflicts. Conflicting sensory stimuli can also generate unpleasant sensations in healthy people such as during motion sickness. We wanted to investigate the mechanisms underlying the link between sensory conflicts and pain in CRPS using optokinetic stimulation (OKS) - a method known to induce motion sickness. METHODS: Twenty-one CRPS patients underwent OKS and rated symptoms of motion sickness. Patients also rated limb pain and pain-related distress before, during and after OKS. In addition, pressure-pain and sharpness sensations were investigated on both sides of the forehead and in the affected and contralateral limb before and after OKS. RESULTS: Limb pain and forehead hyperalgesia to pressure increased in parallel in response to OKS. In a subgroup of nauseated patients who withdrew early from OKS, hyperalgesia to pressure in the ipsilateral forehead persisted longer than in the remaining participants. Sharpness sensations remained constant at all sites. CONCLUSIONS: Sensory conflicts may facilitate pain in CRPS by activating the mechanisms of general facilitation of nociception and, during more severe sensory conflicts, also a facilitatory mechanism that operates mainly ipsilateral to the affected limb.

Forehead sympathetic skin responses in determining autonomic involvement in Parkinson's disease.

OBJECTIVE: The purpose of this study was to evaluate forehead sympathetic skin response (SSR) and demonstrate any differences with extremity SSR in determining autonomic nervous system (ANS) involvement in patients with Parkinson's disease (PD). METHODS: Twenty early stage, 20 advanced stage idiopathic PD patients and 20 healthy controls participated in this study. SSR of forehead, hands and feet, heart rate variability (HRV), orthostatic intolerance, QT intervals and dysautonomic symptoms were evaluated. RESULTS: Absent forehead SSR was determined unilaterally in 4, bilaterally in 7 early stage patients, and unilaterally in 4, bilaterally in 8 advanced stage PD patients; there was significant difference between early and advanced stage PD and control groups in terms of the lack of SSR (p=0.000). Absent extremity SSR was determined in at least 1 extremity of 3 advanced stage PD patients, and none of the early stage PD patients. No difference was noted in HRV at rest between early and advanced stage PD and control groups (p=0.218); but HRV at deep breathing was lower in both early and advanced PD patients compared to controls (p=0.014, p=0.002, respectively). CONCLUSION: Forehead SSR is more sensitive in determining ANS dysfunction not only in late but also in early stage of PD. SIGNIFICANCE: With further supportive research, forehead SSR might be used as a simple diagnostic electrophysiological test in the early diagnosis of ANS dysfunction enabling proper treatment and increasing the quality of life of PD patients.

Analgesia to pressure-pain develops in the ipsilateral forehead after high- and low-frequency electrical stimulation of the forearm.

In healthy participants, high-frequency electrical stimulation of the forearm not only evokes local hyperalgesia but also inhibits sensitivity to pressure-pain in the ipsilateral forehead, possibly due to activation of ipsilateral inhibitory pain modulation processes. The aim of this study was to compare the effects of high- and low-frequency electrical stimulation of the forearm on sensitivity to pressure-pain in the ipsilateral forehead, as inhibitory pain modulation may be stronger after low- than high-frequency electrical stimulation. Before and after high- and low-frequency electrical stimulation, sensitivity to heat and to blunt and sharp stimuli was assessed at and adjacent to the electrically conditioned site in the forearm. In addition, sensitivity to blunt pressure was measured bilaterally in the forehead. Pain was more intense after high- than low-frequency electrical stimulation and was followed by primary and secondary hyperalgesia to mechanical stimulation after high- but not low-frequency electrical stimulation. Nevertheless, sensitivity to pressure-pain decreased to the same extent in the ipsilateral forehead after both forms of electrical stimulation. This decrease was associated with heightened sensitivity to pressure-pain at the electrically conditioned forearm site and with diminished sensitivity to heat around this site. These findings suggest that sensitisation of pressure-sensitive nociceptive afferents at the site of electrical stimulation is associated with generation of an ipsilateral pain-inhibitory process. This ipsilateral pain-inhibitory process may decrease sensitivity to pressure-pain in the ipsilateral forehead and suppress secondary hyperalgesia to heat.

Effects of a facial nerve lesion on responses in forehead microvessels to conjunctival irritation and paced breathing.

To investigate parasympathetic influences on the forehead microvasculature, blood flow was monitored bilaterally in seven participants with a unilateral facial nerve lesion during conjunctival irritation with Schirmer's strips and while breathing at 0.15 Hz. Blood flow and slow-wave frequency increased on the intact side of the forehead during Schirmer's test but did not change on the denervated side. However, a 0.15 Hz vascular wave strengthened during paced breathing, particularly on the denervated side. These findings indicate that parasympathetic activity in the facial nerve increases forehead blood flow during minor conjunctival irritation, but may interfere with the 0.15 Hz vascular wave.