The modern story of CCHS began in 1970 with the first description by Mellins et al., came most vi... more The modern story of CCHS began in 1970 with the first description by Mellins et al., came most visibly to the public eye with the ATS Statement in 1999, and continues with increasingly fast paced advances in genetics. Affected individuals have diffuse autonomic nervous system dysregulation (ANSD). The paired-like homeobox gene PHOX2B is the disease-defining gene for CCHS; a mutation in the PHOX2B gene is requisite to the diagnosis of CCHS. Approximately 90% of individuals with the CCHS phenotype will be heterozygous for a polyalanine repeat expansion mutation (PARM); the normal allele will have 20 alanines and the affected allele will have 24-33 alanines (genotypes 20/24-20/33). The remaining approximately 10% of individuals with CCHS will have a non-PARM (NPARM), in the PHOX2B gene; these will be missense, nonsense, or frameshift. CCHS and PHOX2B are inherited in an autosomal dominant manner with a stable mutation. Approximately 8% of parents of a CCHS proband will be mosaic for the PHOX2B mutation. A growing number of cases of CCHS are identified after the newborn period, with presentation from infancy into adulthood. An improved understanding of the molecular basis of the PHOX2B mutations and of the PHOX2B genotype/CCHS phenotype relationship will allow physicians to anticipate the clinical phenotype for each affected individual. To best convey the remarkable history of CCHS, and to describe the value of recognizing CCHS as a model for translational and transitional autonomic medicine, we present this review article in the format of a chronological story, from 1970 to the present day.
Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (... more Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare disorder of respiratory control, the endocrine system, and the autonomic nervous system. Affected children typically present between 1.5 and 10 years of age with rapid and significant weight gain. Subsequently, they develop alveolar hypoventilation, autonomic nervous system dysfunction, and, if untreated, cardiorespiratory arrest. Early recognition and conservative management are essential to optimize outcome. With the epidemic of childhood obesity and related sleep-disordered breathing, it is essential that physicians are attuned to children who develop endogenous/pathological obesity and who therefore may be at risk for cardiorespiratory arrest.
Diseases that affect peripheral vasculature or neurological function can manifest with peripheral... more Diseases that affect peripheral vasculature or neurological function can manifest with peripheral skin temperature abnormalities. This pilot study investigates the accuracy of current physical examination techniques and determines whether a handheld infrared device can be used to estimate peripheral skin temperature and detect temperature disparities. Comparison between traditional physical examination of hands/feet by 30 health care professionals and a handheld infrared device was made in 12 individuals (ages 4-25 years; 5 with disorders affecting peripheral skin temperature). Thermal camera measurements served as the reference temperature for comparison. 231 extremity examinations by health care professionals were analyzed. Health care professionals correctly identified subjects with colder or warmer than normal peripheral temperature. Handheld device measurements were significantly different than reference measurements, with the size of the temperature difference diverging significantly between hands (1.20°C) and feet (0.78°C). When analyzing temperature disparities, health care professionals identified fewer clinically significant disparities (≥3.0°C) than the handheld device (76% vs. 99%). Although different from reference temperatures, the handheld infrared device provided a more accurate and objective method than traditional physical exam in identifying peripheral skin temperature asymmetries that may be related to chronic pediatric illness. This article is protected by copyright. All rights reserved.
Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (... more Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare pediatric disease of unknown cause. Here, in response to a recent case report describing a ROHHAD patient who suffered from secondary narcolepsy confirmed by an absence of hypocretin-1 in the cerebrospinal fluid, we consider whether the ROHHAD phenotype is owing to one or more mutations in genes specific to hypocretin protein signalling. DNA samples from 16 ROHHAD patients were analyzed using a combination of next-generation and Sanger sequencing to identify exonic sequence variations in three genes: HCRT, HCRTR1, and HCRTR2. No rare or novel mutations were identified in the exons of HCRT, HCRTR1, or HCRTR2 genes in a set of 16 ROHHAD patients. ROHHAD is highly unlikely to be caused by mutations in the exons of the genes for hypocretin and its two receptors.
Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by se... more Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by severe hypoventilation and autonomic dysregulation, with typical presentation in the neonatal period, and deficient cognitive skills in school-age patients. We hypothesized that younger (preschool) children with CCHS would also show neurocognitive delay, and that CCHS-related physiologic factors would impact neurocognitive test results. We studied developmental (Bayley) test results collected during routine clinical care in 31 children (mean age 25.0±8.5 months, range: 6-40 months) with PHOX2B mutation-confirmed CCHS by comparing them to the normative reference mean from the Bayley standardization sample, and examined associations between Bayley scores and CCHS disease-related factors. Preschool CCHS patients fell significantly below the normative mean of 100 on Bayley indices of mental (mean 83.35 ± 24.75) and motor (mean 73.33 ± 20.48) development (P < 0.001 for both). Significantly l...
Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy, which includes a c... more Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy, which includes a control of breathing deficit and features of autonomic nervous system (ANS) dysregulation. In recognition of the fundamental role of the ANS in temperature regulation and rhythm and the lack of any prior characterization of circadian temperature rhythms in CCHS, we sought to explore peripheral and core temperatures and circadian patterning. We hypothesized that CCHS patients would exhibit lower peripheral skin temperatures (PST), variability, and circadian rhythmicity (vs. controls), as well as a disrupted relationship between core body temperature (CBT) and PST. PST was sampled every 3 min over four 24-hr periods in CCHS cases and similarly aged controls. CBT was sampled in a subset of these recordings. PST was recorded from 25 CCHS cases (110,664 measures/230 days) and 39 controls (78,772 measures/164 days). Simultaneous CBT measurements were made from 23 CCHS patients. In CCHS, mean PS...
Stillbirth remains a devastating health issue with 26,000 stillbirths occurring annually in the U... more Stillbirth remains a devastating health issue with 26,000 stillbirths occurring annually in the United States. Formalin-fixed, paraffin-embedded (FFPE) umbilical cord samples are available for many stillbirths. Our aim was to validate the use of these samples in identifying genetic variations in stillbirth through microarray analysis. This is a retrospective case-control study from a single institution of stillbirths ≥23 weeks gestational age and control liveborn infants. Fetal genomic DNA was extracted from FFPE umbilical cord samples of stillborn and control placentas, and genotyping was performed using the Illumina HumanOmniExpresss-12v1 Beadchip. Array results were verified with qPCR. 31 case-specific CNVs (17 deletions and 14 amplifications) with an average size of 294 kb for amplifications and 74 kb for deletions were identified among 94 FFPE samples (86 cases; 8 controls). In total 38 (44%) of the stillbirth samples had a CNV detected. Validation of a subset of microarray findings with qPCR confirmed deletions on 1p (2 cases), 11q (4 cases) and amplifications on 18 (1 case). Placental underperfusion changes were seen in stillborns with deletions on 1p, a region containing complement regulatory genes which have been shown to play a role in preeclampsia. This study validated the use of archived FFPE umbilical cord samples for genome-wide copy number profiling in stillbirths, and demonstrates specific CNV deletions and amplifications. Microarray analysis in an expanded cohort of stillbirth FFPE samples has the potential to identify biomarkers involved in stillbirth pathogenesis.
/ Thematic Poster Session / Monday, May 16/8:15 AM-4:30 PM / Area C, Hall B (Upper Level), Colora... more / Thematic Poster Session / Monday, May 16/8:15 AM-4:30 PM / Area C, Hall B (Upper Level), Colorado B73 PEDIATRIC SLEEP ... Clinical Phox2b Testing In Congenital Central Hypoventilation Syndrome (cchs): Genotype/phenotype Correlation ... , MS Carroll , EM Berry-Kravis , L. ...
The modern story of CCHS began in 1970 with the first description by Mellins et al., came most vi... more The modern story of CCHS began in 1970 with the first description by Mellins et al., came most visibly to the public eye with the ATS Statement in 1999, and continues with increasingly fast paced advances in genetics. Affected individuals have diffuse autonomic nervous system dysregulation (ANSD). The paired-like homeobox gene PHOX2B is the disease-defining gene for CCHS; a mutation in the PHOX2B gene is requisite to the diagnosis of CCHS. Approximately 90% of individuals with the CCHS phenotype will be heterozygous for a polyalanine repeat expansion mutation (PARM); the normal allele will have 20 alanines and the affected allele will have 24-33 alanines (genotypes 20/24-20/33). The remaining approximately 10% of individuals with CCHS will have a non-PARM (NPARM), in the PHOX2B gene; these will be missense, nonsense, or frameshift. CCHS and PHOX2B are inherited in an autosomal dominant manner with a stable mutation. Approximately 8% of parents of a CCHS proband will be mosaic for the PHOX2B mutation. A growing number of cases of CCHS are identified after the newborn period, with presentation from infancy into adulthood. An improved understanding of the molecular basis of the PHOX2B mutations and of the PHOX2B genotype/CCHS phenotype relationship will allow physicians to anticipate the clinical phenotype for each affected individual. To best convey the remarkable history of CCHS, and to describe the value of recognizing CCHS as a model for translational and transitional autonomic medicine, we present this review article in the format of a chronological story, from 1970 to the present day.
The modern story of CCHS began in 1970 with the first description by Mellins et al., came most vi... more The modern story of CCHS began in 1970 with the first description by Mellins et al., came most visibly to the public eye with the ATS Statement in 1999, and continues with increasingly fast paced advances in genetics. Affected individuals have diffuse autonomic nervous system dysregulation (ANSD). The paired-like homeobox gene PHOX2B is the disease-defining gene for CCHS; a mutation in the PHOX2B gene is requisite to the diagnosis of CCHS. Approximately 90% of individuals with the CCHS phenotype will be heterozygous for a polyalanine repeat expansion mutation (PARM); the normal allele will have 20 alanines and the affected allele will have 24-33 alanines (genotypes 20/24-20/33). The remaining approximately 10% of individuals with CCHS will have a non-PARM (NPARM), in the PHOX2B gene; these will be missense, nonsense, or frameshift. CCHS and PHOX2B are inherited in an autosomal dominant manner with a stable mutation. Approximately 8% of parents of a CCHS proband will be mosaic for the PHOX2B mutation. A growing number of cases of CCHS are identified after the newborn period, with presentation from infancy into adulthood. An improved understanding of the molecular basis of the PHOX2B mutations and of the PHOX2B genotype/CCHS phenotype relationship will allow physicians to anticipate the clinical phenotype for each affected individual. To best convey the remarkable history of CCHS, and to describe the value of recognizing CCHS as a model for translational and transitional autonomic medicine, we present this review article in the format of a chronological story, from 1970 to the present day.
Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (... more Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare disorder of respiratory control, the endocrine system, and the autonomic nervous system. Affected children typically present between 1.5 and 10 years of age with rapid and significant weight gain. Subsequently, they develop alveolar hypoventilation, autonomic nervous system dysfunction, and, if untreated, cardiorespiratory arrest. Early recognition and conservative management are essential to optimize outcome. With the epidemic of childhood obesity and related sleep-disordered breathing, it is essential that physicians are attuned to children who develop endogenous/pathological obesity and who therefore may be at risk for cardiorespiratory arrest.
Diseases that affect peripheral vasculature or neurological function can manifest with peripheral... more Diseases that affect peripheral vasculature or neurological function can manifest with peripheral skin temperature abnormalities. This pilot study investigates the accuracy of current physical examination techniques and determines whether a handheld infrared device can be used to estimate peripheral skin temperature and detect temperature disparities. Comparison between traditional physical examination of hands/feet by 30 health care professionals and a handheld infrared device was made in 12 individuals (ages 4-25 years; 5 with disorders affecting peripheral skin temperature). Thermal camera measurements served as the reference temperature for comparison. 231 extremity examinations by health care professionals were analyzed. Health care professionals correctly identified subjects with colder or warmer than normal peripheral temperature. Handheld device measurements were significantly different than reference measurements, with the size of the temperature difference diverging significantly between hands (1.20°C) and feet (0.78°C). When analyzing temperature disparities, health care professionals identified fewer clinically significant disparities (≥3.0°C) than the handheld device (76% vs. 99%). Although different from reference temperatures, the handheld infrared device provided a more accurate and objective method than traditional physical exam in identifying peripheral skin temperature asymmetries that may be related to chronic pediatric illness. This article is protected by copyright. All rights reserved.
Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (... more Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare pediatric disease of unknown cause. Here, in response to a recent case report describing a ROHHAD patient who suffered from secondary narcolepsy confirmed by an absence of hypocretin-1 in the cerebrospinal fluid, we consider whether the ROHHAD phenotype is owing to one or more mutations in genes specific to hypocretin protein signalling. DNA samples from 16 ROHHAD patients were analyzed using a combination of next-generation and Sanger sequencing to identify exonic sequence variations in three genes: HCRT, HCRTR1, and HCRTR2. No rare or novel mutations were identified in the exons of HCRT, HCRTR1, or HCRTR2 genes in a set of 16 ROHHAD patients. ROHHAD is highly unlikely to be caused by mutations in the exons of the genes for hypocretin and its two receptors.
Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by se... more Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by severe hypoventilation and autonomic dysregulation, with typical presentation in the neonatal period, and deficient cognitive skills in school-age patients. We hypothesized that younger (preschool) children with CCHS would also show neurocognitive delay, and that CCHS-related physiologic factors would impact neurocognitive test results. We studied developmental (Bayley) test results collected during routine clinical care in 31 children (mean age 25.0±8.5 months, range: 6-40 months) with PHOX2B mutation-confirmed CCHS by comparing them to the normative reference mean from the Bayley standardization sample, and examined associations between Bayley scores and CCHS disease-related factors. Preschool CCHS patients fell significantly below the normative mean of 100 on Bayley indices of mental (mean 83.35 ± 24.75) and motor (mean 73.33 ± 20.48) development (P < 0.001 for both). Significantly l...
Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy, which includes a c... more Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy, which includes a control of breathing deficit and features of autonomic nervous system (ANS) dysregulation. In recognition of the fundamental role of the ANS in temperature regulation and rhythm and the lack of any prior characterization of circadian temperature rhythms in CCHS, we sought to explore peripheral and core temperatures and circadian patterning. We hypothesized that CCHS patients would exhibit lower peripheral skin temperatures (PST), variability, and circadian rhythmicity (vs. controls), as well as a disrupted relationship between core body temperature (CBT) and PST. PST was sampled every 3 min over four 24-hr periods in CCHS cases and similarly aged controls. CBT was sampled in a subset of these recordings. PST was recorded from 25 CCHS cases (110,664 measures/230 days) and 39 controls (78,772 measures/164 days). Simultaneous CBT measurements were made from 23 CCHS patients. In CCHS, mean PS...
Stillbirth remains a devastating health issue with 26,000 stillbirths occurring annually in the U... more Stillbirth remains a devastating health issue with 26,000 stillbirths occurring annually in the United States. Formalin-fixed, paraffin-embedded (FFPE) umbilical cord samples are available for many stillbirths. Our aim was to validate the use of these samples in identifying genetic variations in stillbirth through microarray analysis. This is a retrospective case-control study from a single institution of stillbirths ≥23 weeks gestational age and control liveborn infants. Fetal genomic DNA was extracted from FFPE umbilical cord samples of stillborn and control placentas, and genotyping was performed using the Illumina HumanOmniExpresss-12v1 Beadchip. Array results were verified with qPCR. 31 case-specific CNVs (17 deletions and 14 amplifications) with an average size of 294 kb for amplifications and 74 kb for deletions were identified among 94 FFPE samples (86 cases; 8 controls). In total 38 (44%) of the stillbirth samples had a CNV detected. Validation of a subset of microarray findings with qPCR confirmed deletions on 1p (2 cases), 11q (4 cases) and amplifications on 18 (1 case). Placental underperfusion changes were seen in stillborns with deletions on 1p, a region containing complement regulatory genes which have been shown to play a role in preeclampsia. This study validated the use of archived FFPE umbilical cord samples for genome-wide copy number profiling in stillbirths, and demonstrates specific CNV deletions and amplifications. Microarray analysis in an expanded cohort of stillbirth FFPE samples has the potential to identify biomarkers involved in stillbirth pathogenesis.
/ Thematic Poster Session / Monday, May 16/8:15 AM-4:30 PM / Area C, Hall B (Upper Level), Colora... more / Thematic Poster Session / Monday, May 16/8:15 AM-4:30 PM / Area C, Hall B (Upper Level), Colorado B73 PEDIATRIC SLEEP ... Clinical Phox2b Testing In Congenital Central Hypoventilation Syndrome (cchs): Genotype/phenotype Correlation ... , MS Carroll , EM Berry-Kravis , L. ...
The modern story of CCHS began in 1970 with the first description by Mellins et al., came most vi... more The modern story of CCHS began in 1970 with the first description by Mellins et al., came most visibly to the public eye with the ATS Statement in 1999, and continues with increasingly fast paced advances in genetics. Affected individuals have diffuse autonomic nervous system dysregulation (ANSD). The paired-like homeobox gene PHOX2B is the disease-defining gene for CCHS; a mutation in the PHOX2B gene is requisite to the diagnosis of CCHS. Approximately 90% of individuals with the CCHS phenotype will be heterozygous for a polyalanine repeat expansion mutation (PARM); the normal allele will have 20 alanines and the affected allele will have 24-33 alanines (genotypes 20/24-20/33). The remaining approximately 10% of individuals with CCHS will have a non-PARM (NPARM), in the PHOX2B gene; these will be missense, nonsense, or frameshift. CCHS and PHOX2B are inherited in an autosomal dominant manner with a stable mutation. Approximately 8% of parents of a CCHS proband will be mosaic for the PHOX2B mutation. A growing number of cases of CCHS are identified after the newborn period, with presentation from infancy into adulthood. An improved understanding of the molecular basis of the PHOX2B mutations and of the PHOX2B genotype/CCHS phenotype relationship will allow physicians to anticipate the clinical phenotype for each affected individual. To best convey the remarkable history of CCHS, and to describe the value of recognizing CCHS as a model for translational and transitional autonomic medicine, we present this review article in the format of a chronological story, from 1970 to the present day.
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