Congenital central hypoventilation syndrome (CCHS) is caused by mutations in PHOX2B,which is essential for maturation of the neural crest into the autonomic nervous system and is expressed in the dorsal rhombencephalo...Congenital central hypoventilation syndrome (CCHS) is caused by mutations in PHOX2B,which is essential for maturation of the neural crest into the autonomic nervous system and is expressed in the dorsal rhombencephalon,a region that gives rise to facial structures. Digital photographs of 45 individuals with PHOX2B-confirmed CCHS,and 45 matched controls were analyzed for 17 linear and 6 angular measurements,and 9 derived indices. Paired t tests were used to compare group means,correlation was calculated between PHOX2B polyalanine expansion number and facial measures,and stepwise logistic regression was used to predict case-control and genotype status. CCHS cases differed significantly from controls on 13 variables (6 after p value correction:nasolabial angle,upper lip height,lateral lip height,facial index,upper facial index,and presence of inferior inflection of the lateral segment of the upper lip vermillion border). Five variables were able to predict correctly 85.7%of CCHS cases and 82.2%of controls:upper lip height,binocular width,upper facial height,nasal tip protrusion,and inferior inflection of the upper lip vermillion border. A negative relationship between number of repeats and four anthropometric measures was observed:mandible breadth,nasolabial angle,lateral lip height,and mandible-face width index. These results suggest a characteristic facial phenotype in children and young adults with CCHS,due to an expansion mutation in PHOX2B.展开更多
The locus coeruleus(LC) has been implicated in the control of breathing.Congenital central hypoventilation syndrome results from mutation of the paired-like homeobox 2 b(Phox2 b) gene that is expressed in LC neurons.T...The locus coeruleus(LC) has been implicated in the control of breathing.Congenital central hypoventilation syndrome results from mutation of the paired-like homeobox 2 b(Phox2 b) gene that is expressed in LC neurons.The present study was designed to address whether stimulation of Phox2 b-expressing LC(Phox2 b~(LC)) neurons affects breathing and to reveal the putative circuit mechanism.A Cre-dependent viral vector encoding a Gqcoupled human M3 muscarinic receptor(hM3 Dq) was delivered into the LC of Phox2 b-Cre mice.The hM3 Dqtransduced neurons were pharmacologically activated while respiratory function was measured by plethysmography.We demonstrated that selective stimulation of Phox2 b~(LC) neurons significantly increased basal ventilation in conscious mice.Genetic ablation of these neurons markedly impaired hypercapnic ventilatory responses.Moreover,stimulation of Phox2 b~(LC) neurons enhanced the activity of preBotzinger complex neurons.Finally,axons of Phox2 b~(LC) neurons projected to the preBotzinger complex.Collectively,Phox2 b~(LC) neurons contribute to the control of breathing most likely via an LC-preBotzinger complex circuit.展开更多
Congenital central hypoventilation syndrome （CCHS, OMIM #209880） is a rare autosomal dominant disorder of the autonomic nervous system （ANS） characterized by an abnormal autonomic ventilatory response to progress...Congenital central hypoventilation syndrome （CCHS, OMIM #209880） is a rare autosomal dominant disorder of the autonomic nervous system （ANS） characterized by an abnormal autonomic ventilatory response to progressive hypercarbia and sustained hypoxemia. Patients typically present in the newborn period with hypoventilation or apnea asleep, awake, or both, without any associated cardiac, pulmonary, neuromuscular or brainstem lesions. Rarely, some patients may present at a later age and are diagnosed to have late onset central hypoventilation syndrome （LOCHS）.1 Other features of ANS dysfunction such as feeding difficulty due to oesophageal dysmotility, severe constipation in the absence of Hirschsprung disease, poor regulation of basal body temperature, episodes of profuse sweating, pupillary and ocular abnormalities, decreased beat-to-beat variability of heart rate, attenuated response of heart rate to exercise, abnormal fluctuation of blood pressure, decreased perception to pain, and decreased perception to anxiety may be variably present but not essential for diagnosis Furthermore, this central hypoventilation can occur as an isolated feature or in association with a number of neurocristopathies, notably Hirschsprung disease （Haddad syndrome, OMIM #209880） and tumours of the sympathetic nervous system particularly neuroblastoma, ganglioneuro- blastoma, and ganglioneuroma, which were found in 20% and 5%--10% of CCHS patients, respectively.2 Studies of genes pertinent to the early embryologic development of the neural crest cells, specifically the endothelin and the RET-GDNF signaling pathways, have recently led to the identification of PHOX2B as the major disease causing gene for CCHS.2-6 PHOX2B was mapped to chromosome 4p12 and consists of 3 exons. It encodes a highly conserved paired-like homeobox transcription factor of 314 amino acids linked to the RET-GDNF signaling展开更多
先天性中枢性低通气综合征(congenital central hypoventilation syndrome,CCHS)是一类罕见的常染色体显性遗传病,主要表现为因化学感受器对高碳酸血症和低氧血症反应低下而引起的肺泡通气不足[1]。于20世纪70年代首次报道,活产儿发病...先天性中枢性低通气综合征(congenital central hypoventilation syndrome,CCHS)是一类罕见的常染色体显性遗传病,主要表现为因化学感受器对高碳酸血症和低氧血症反应低下而引起的肺泡通气不足[1]。于20世纪70年代首次报道,活产儿发病率约为1/200000[2],表现为非肺、神经系统或代谢性疾病所引起的呼吸暂停以及二氧化碳潴留,常于睡眠状态下出现严重的低通气,严重者于清醒状态下也会出现低通气表现,伴或不伴有自主神经系统失调疾病,如消化系统发育异常(先天性巨结肠)、神经嵴源性肿瘤等。展开更多
文摘Congenital central hypoventilation syndrome (CCHS) is caused by mutations in PHOX2B,which is essential for maturation of the neural crest into the autonomic nervous system and is expressed in the dorsal rhombencephalon,a region that gives rise to facial structures. Digital photographs of 45 individuals with PHOX2B-confirmed CCHS,and 45 matched controls were analyzed for 17 linear and 6 angular measurements,and 9 derived indices. Paired t tests were used to compare group means,correlation was calculated between PHOX2B polyalanine expansion number and facial measures,and stepwise logistic regression was used to predict case-control and genotype status. CCHS cases differed significantly from controls on 13 variables (6 after p value correction:nasolabial angle,upper lip height,lateral lip height,facial index,upper facial index,and presence of inferior inflection of the lateral segment of the upper lip vermillion border). Five variables were able to predict correctly 85.7%of CCHS cases and 82.2%of controls:upper lip height,binocular width,upper facial height,nasal tip protrusion,and inferior inflection of the upper lip vermillion border. A negative relationship between number of repeats and four anthropometric measures was observed:mandible breadth,nasolabial angle,lateral lip height,and mandible-face width index. These results suggest a characteristic facial phenotype in children and young adults with CCHS,due to an expansion mutation in PHOX2B.
基金supported by the National Natural Science Foundation of China(31971058 and 31571174)the Youth Fund for Scientific and Technological Research in Higher Education Institutions of Hebei Province(QN2019019)the Youth Science and Technology Talent Support Program of Natural Science in Hebei Medical University(CYQD201907)。
文摘The locus coeruleus(LC) has been implicated in the control of breathing.Congenital central hypoventilation syndrome results from mutation of the paired-like homeobox 2 b(Phox2 b) gene that is expressed in LC neurons.The present study was designed to address whether stimulation of Phox2 b-expressing LC(Phox2 b~(LC)) neurons affects breathing and to reveal the putative circuit mechanism.A Cre-dependent viral vector encoding a Gqcoupled human M3 muscarinic receptor(hM3 Dq) was delivered into the LC of Phox2 b-Cre mice.The hM3 Dqtransduced neurons were pharmacologically activated while respiratory function was measured by plethysmography.We demonstrated that selective stimulation of Phox2 b~(LC) neurons significantly increased basal ventilation in conscious mice.Genetic ablation of these neurons markedly impaired hypercapnic ventilatory responses.Moreover,stimulation of Phox2 b~(LC) neurons enhanced the activity of preBotzinger complex neurons.Finally,axons of Phox2 b~(LC) neurons projected to the preBotzinger complex.Collectively,Phox2 b~(LC) neurons contribute to the control of breathing most likely via an LC-preBotzinger complex circuit.
文摘Congenital central hypoventilation syndrome （CCHS, OMIM #209880） is a rare autosomal dominant disorder of the autonomic nervous system （ANS） characterized by an abnormal autonomic ventilatory response to progressive hypercarbia and sustained hypoxemia. Patients typically present in the newborn period with hypoventilation or apnea asleep, awake, or both, without any associated cardiac, pulmonary, neuromuscular or brainstem lesions. Rarely, some patients may present at a later age and are diagnosed to have late onset central hypoventilation syndrome （LOCHS）.1 Other features of ANS dysfunction such as feeding difficulty due to oesophageal dysmotility, severe constipation in the absence of Hirschsprung disease, poor regulation of basal body temperature, episodes of profuse sweating, pupillary and ocular abnormalities, decreased beat-to-beat variability of heart rate, attenuated response of heart rate to exercise, abnormal fluctuation of blood pressure, decreased perception to pain, and decreased perception to anxiety may be variably present but not essential for diagnosis Furthermore, this central hypoventilation can occur as an isolated feature or in association with a number of neurocristopathies, notably Hirschsprung disease （Haddad syndrome, OMIM #209880） and tumours of the sympathetic nervous system particularly neuroblastoma, ganglioneuro- blastoma, and ganglioneuroma, which were found in 20% and 5%--10% of CCHS patients, respectively.2 Studies of genes pertinent to the early embryologic development of the neural crest cells, specifically the endothelin and the RET-GDNF signaling pathways, have recently led to the identification of PHOX2B as the major disease causing gene for CCHS.2-6 PHOX2B was mapped to chromosome 4p12 and consists of 3 exons. It encodes a highly conserved paired-like homeobox transcription factor of 314 amino acids linked to the RET-GDNF signaling
文摘先天性中枢性低通气综合征(congenital central hypoventilation syndrome,CCHS)是一类罕见的常染色体显性遗传病,主要表现为因化学感受器对高碳酸血症和低氧血症反应低下而引起的肺泡通气不足[1]。于20世纪70年代首次报道,活产儿发病率约为1/200000[2],表现为非肺、神经系统或代谢性疾病所引起的呼吸暂停以及二氧化碳潴留,常于睡眠状态下出现严重的低通气,严重者于清醒状态下也会出现低通气表现,伴或不伴有自主神经系统失调疾病,如消化系统发育异常(先天性巨结肠)、神经嵴源性肿瘤等。
