Congenital Central Hypoventilation Syndrome Cases Research Articles

Congenital central hypoventilation syndrome in korea: 20years of clinical observation and evaluation of the ventilation strategy in a single center.

Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder characterized by hypoventilation due to impaired breathing control by the central nervous system and other symptoms of autonomic dysfunction. Mutations in paired-like homeobox 2 B (PHOX2B) are responsible for most cases of CCHS. Patients with CCHS have various phenotypes and severities, making the diagnosis difficult. This study aimed to present a comprehensive single-center experience of patients with CCHS, including key clinical features, treatment strategies, and outcomes.A retrospective chart review was performed for patients diagnosed with CCHS between January 2001 and July 2023 at Seoul National University Children's Hospital. Finally, we selected 24 patients and collected their demographic data, genotypes, ventilation methods, and clinical features related to autonomic dysfunction. The relationship between the clinical manifestations and genotypes was also examined.All patients used home ventilators, and tracheostomy was performed in 87.5% of patients. Fifteen (62.5%) patients had constipation and nine (37.5%) were diagnosed with Hirschsprung disease. Arrhythmia, endocrine dysfunction, and subclinical hypothyroidism were present in nine (37.5%), six patients (25.0%), and two patients (16.7%), respectively. A significant number of patients exhibited neurodevelopmental delays (19 patients, 79.2%). There was a correlation between the phenotype and genotype of PHOX2B in patients with CCHS. (r = 0.71, p < 0.001). Conclusion: There was a positive correlation between paired-like homeobox 2 B mutations (especially the number of GCN repeats in the polyalanine repeat mutations sequence) and clinical manifestations. This study also demonstrated how initial treatment for hypoventilation affects neurodevelopmental outcomes in patients with CCHS. What is Known: • Congenital central hypoventilation syndrome is a rare genetic disorder characterized by hypoventilation and dysfunction of autonomic nervous system. • The disease-defining gene of CCHS is PHOX2B gene - most of the cases have heterozygous PARMs and the number of GCN triplets varies among the patients(20/24 - 20/33). What is New: • We have noted in the Korean patients with CCHS that there is a correlation between genotype (number of GCN repeats) and severity of phenotype. • National support for rare diseases allowed for a prompter diagnosis of patients with CCHS in Korean population.

Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions

Abnormal trinucleotide repeat expansions alter protein conformation causing malfunction and contribute to a significant number of incurable human diseases. Scarce structural insights available on disease-related homorepeat expansions hinder the design of effective therapeutics. Here, we present the dynamic structure of human PHOX2B C-terminal fragment, which contains the longest polyalanine segment known in mammals. The major α-helical conformation of the polyalanine tract is solely extended by polyalanine expansions in PHOX2B, which are responsible for most congenital central hypoventilation syndrome cases. However, polyalanine expansions in PHOX2B additionally promote nascent homorepeat conformations that trigger length-dependent phase transitions into solid condensates that capture wild-type PHOX2B. Remarkably, HSP70 and HSP90 chaperones specifically seize PHOX2B alternative conformations preventing phase transitions. The precise observation of emerging polymorphs in expanded PHOX2B postulates unbalanced phase transitions as distinct pathophysiological mechanisms in homorepeat expansion diseases, paving the way towards the search of therapeutics modulating biomolecular condensates in central hypoventilation syndrome.

Congenital central hypoventilation syndrome in Chinese population: Analysis of three new cases and review of the literature.

Congenital central hypoventilation syndrome (CCHS) is a rare autosomal dominant disease that is mainly caused by PHOX2B mutations. The purpose of this study is to analyze and summarize the clinical and genetic characteristics of CCHS patients in the Chinese population from our study and previous literature. The potential pathogenic gene mutations of CCHS were identified and verified by next generation sequencing combined with Sanger sequencing, fluorescent probe PCR and capillary electrophoresis. The clinical characteristics and gene mutations of CCHS cases in Chinese population were summarized from our study and previous literature to explore the genotype-phenotype correlations. We identified 48 CCHS cases including three new cases from our report in China. Overall, 77.1% of the patients had PHOX2B polyalanine repeat expansion mutations (PARMs), and the remaining 22.9% had 10 distinct PHOX2B non-polyalanine repeat expansion mutations (NPARMs). Compared to those with PARMs, patients with NPARMs were more likely to have premature birth (54.5% vs. 2.8%, p < 0.001) and lower birth weight (33.3% vs. 3.2%, p = 0.030), with statistical significance. The patients with PARMs were more likely to have cardiovascular defects (64.9% vs. 27.3%, p = 0.063), cerebral hemorrhage (29.7% vs. 9.1%, p = 0.322) and seizures (37.8% vs. 9.1%, p = 0.151) than those with NPARMs, with no statistical significance. CCHS patients with PHOX2B NPARMs were more likely to have premature birth and low birth weight, while PHOX2B PARMs tended to be positively associated with the risk of cardiovascular defects, cerebral hemorrhage and seizures in Chinese population.

Congenital Central Hypoventilation Syndrome (Ondine’s Curse): Clinical Case

Background. Congenital central hypoventilation syndrome (CCHS), or Ondine’s Curse, is rare, incurable and life-threatening disease characterized by autonomic nervous system disorders, it manifests with disability to maintain ventilation function during sleep. Sensitivity to hypoxia and hypercapnia is reduced in case of CCHS, thus, it leads to recurrent episodes of deep apnea. The world literature describes just over 1000 cases of this disease. Clinical case description. An infant born at 37th week of gestation, weight of 3330 g, had episodes of apnea and hypercapnia from the first day of life. CCHS was suspected by the 28th day of life after excluding other causes of respiratory disorders, and it was genetically confirmed by the 43rd day of life — pathogenic variant of PHOX2B gene was revealed. Mechanical ventilation has been initiated by the age of 1 month after disease worsening. Analysis of CCHS cases published in Russian-language medical literature was performed. Typical symptoms and timing of their manifestation, as well as the time before correct diagnosis were mentioned. Conclusion. Symptoms that can be suggestive of CCHS presence early after birth and can urge to perform all the necessary genetic testing that are crucial for timely treatment onset and for minimizing the negative effect of hypoxemia and hypercapnia on the child are described.

Congenital Central Hypoventilation Syndrome in Israel-Novel Findings from a New National Center.

Congenital central hypoventilation syndrome (CCHS) is a rare autosomal-dominant disorder of the autonomic nervous system that results from mutations in the PHOX2B gene. A national CCHS center was founded in Israel in 2018. Unique new findings were observed. All 27 CCHS patients in Israel were contacted and followed. Novel findings were observed. The prevalence of new CCHS cases was almost twice higher compared to other countries. The most common mutations in our cohort were polyalanine repeat mutations (PARM) 20/25, 20/26, 20/27 (combined = 85% of cases). Two patients showed unique recessive inheritance while their heterozygotes family members were asymptomatic. A right-sided cardio-neuromodulation was performed on an eight-year-old boy for recurrent asystoles by ablating the parasympathetic ganglionated plexi using radiofrequency (RF) energy. Over 36 months' follow-up with an implantable loop-recorder, no bradycardias/pauses events were observed. A cardiac pacemaker was avoided. A significant benefit and new information arise from a nationwide expert CCHS center for both clinical and basic purposes. The incidence of CCHS in some populations may be increased. Asymptomatic NPARM mutations may be much more common in the general population, leading to an autosomal recessive presentation of CCHS. RF cardio-neuromodulation offers a novel approach to children avoiding the need for permanent pacemaker implantation.

0994 Neuroblastoma as the Initial Manifestation of Familial PHOX2B NPARM Positive Congenital Central Hypoventilation Syndrome

Abstract Introduction Congenital Central Hypoventilation Syndrome (CCHS) is a genetic disorder of the autonomic nervous system caused by mutations in the PHOX2B gene. Children with CCHS often present as neonates in hypoxemic, hypercarbic respiratory failure. Most causative mutations are de novo Polyalanine Repeat Mutations (PARMs). Non-Polyalanine Repeat Mutations (NPARMs) have been associated with more severe disease, specifically the need for 24-hour ventilatory support, Hirschsprung disease, and neural crest tumors; however, NPARMs may have variable expressivity and incomplete penetrance, resulting in delayed or atypical presentations. We report a toddler with maxillary sinus neuroblastoma, which led to the diagnosis of familial PHOX2B NPARM positive CCHS. Report of case(s) A two-year-old boy presented with right-sided facial swelling. A facial CT uncovered a right maxillary sinus lytic lesion, and biopsy confirmed neuroblastoma. After full recovery from the procedure, he had persistent nocturnal hypoxemia and hypercapnia requiring bilevel positive airway pressure (PAP) during sleep, raising concern for CCHS. Genetic testing revealed a novel PHOX2B NPARM, c.428dup, which likely causes a frameshift and premature protein termination (p.Val144Glyfs*34). His maternal grandfather, mother and brothers tested positive for the same mutation. Family history revealed that his maternal grandfather and maternal great-uncles had frequent childhood apneic spells associated with syncope, his maternal grandfather is currently on nocturnal bilevel PAP, and his mother almost drowned as a younger child while having a breath-holding contest under water. His six-year-old brother underwent polysomnography which showed hypoventilation, now managed with bilevel PAP. His five-year-old brother also underwent polysomnography and does not require nocturnal ventilatory support at this time. Conclusion We report a rare case of familial PHOX2B NPARM positive CCHS which initially presented as maxillary sinus neuroblastoma. Additionally, the child and his family display varying disease severity despite having the same NPARM, highlighting the variable expressivity in this novel NPARM. Support (if any) None

Generation of two hiPSC lines (UMILi027-A and UMILi028-A) from early and late-onset Congenital Central hypoventilation Syndrome (CCHS) patients carrying a polyalanine expansion mutation in the PHOX2B gene

Congenital Central Hypoventilation Syndrome (CCHS) is a rare disorder of the autonomic nervous system (ANS), characterized by inadequate control of autonomic ventilation and global autonomic dysfunction. Heterozygous polyalanine repeat expansion mutations in exon 3 of the transcription factor Paired-like homeobox 2B (PHOX2B) gene occur in 90% of CCHS cases. In this study, we describe the generation and characterization of two human induced pluripotent stem cell (hiPSC) lines from female CCHS patients carrying a heterozygous + 5 alanine expansion mutation. The generated iPSC lines show a normal karyotype, express pluripotency markers and are able to differentiate into the three germ layers.

Cerebral Autoregulation during Orthostatic Challenge in Congenital Central Hypoventilation Syndrome.

Rationale: Congenital central hypoventilation syndrome (CCHS) is a rare autonomic disorder with altered regulation of breathing, heart rate (HR), and blood pressure (BP). Aberrant cerebral oxygenation in response to hypercapnia/hypoxia in CCHS raises the concern that altered cerebral autoregulation may contribute to CCHS-related, variably impaired neurodevelopment. Objectives: To evaluate cerebral autoregulation in response to orthostatic challenge in CCHS cases versus controls. Methods: CCHS and age- and sex-matched control subjects were studied with head-up tilt (HUT) testing to induce orthostatic stress. Fifty CCHS and 100 control HUT recordings were included. HR, BP, and cerebral oxygen saturation (regional oxygen saturation) were continuously monitored. The cerebral oximetry index (COx), a real-time measure of cerebral autoregulation based on these measures, was calculated. Measurements and Main Results: HUT resulted in a greater mean BP decrease from baseline in CCHS versus controls (11% vs. 6%; P < 0.05) and a diminished increase in HR in CCHS versus controls (11% vs. 18%; P < 0.01) in the 5 minutes after tilt-up. Despite a similar COx at baseline, orthostatic provocation within 5 minutes of tilt-up caused a 50% greater increase in COx (P < 0.01) and a 29% increase in minutes of impaired autoregulation (P < 0.02) in CCHS versus controls (4.0 vs. 3.1 min). Conclusions: Cerebral autoregulatory mechanisms appear to be intact in CCHS, but the greater hypotension observed in CCHS consequent to orthostatic provocation is associated with greater values of COx/impaired autoregulation when BP is below the lower limits of autoregulation. Effects of repeated orthostatic challenges in everyday living in CCHS necessitate further study to determine their influence on neurodevelopmental disease burden.

Evaluation of respiratory center function in congenital central hypoventilation syndrome by monitoring electrical activity of the diaphragm.

A definitive diagnosis of congenital central hypoventilation syndrome (CCHS) is made by genetic testing. However, there are only a few examinations that warrant genetic testing. Electrical activity of the diaphragm (Edi) reflects neural respiratory drive from respiratory center to diaphragm. We evaluated the function of the respiratory center in CCHS by Edi monitoring. Monitoring of Edi was performed in six CCHS cases without mechanical ventilation. The monitoring time was 30 consecutive minutes from wakefulness to sleep. The TcPCO2 or EtCO2 and SpO2 were recorded simultaneously. The Edi peak during wakefulness was 14.0 (10.3-21.0) µV and the Edi peak during sleep was 6.7 (3.8-8.0) µV. The Edi peak during sleep was significantly lower than the Edi peak during wakefulness, and patients were in a state of hypoventilation. Although TcPCO2 or EtCO2 increased due to hypoventilation, an increase in the Edi peak that reflects central respiratory drive was not observed. ΔEdi/ΔCO2 was -0.06μV/mmHg. Maximum EtCO2 or TcPco2 was 51mmHg, and the average SpO2 was 91.5% during monitoring. We confirmed that Edi monitoring could evaluate the function of the respiratory center and reproduce the hypoventilation of CCHS. The present study suggested that Edi monitoring is a useful examination in deciding whether to perform genetic testing or not and it may lead to an early diagnosis of CCHS.

Neuropsychological profile and social cognition in congenital central hypoventilation syndrome (CCHS): Correlation with neuroimaging in a clinical case

ABSTRACTIntroduction: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder due to paired-like homeobox gene (PHOX2B) mutations. CCHS patients suffer from dysregulation of the autonomic nervous system characterized by the absence of or extremely reduced response to hypercapnia and hypoxia, with neuropsychological deficits. The aim of this exploratory study is to describe the longitudinal neuropsychological profile and its correlations with magnetic resonance imaging (MRI) of a child with CCHS with a PHOX2B mutation. Method: A comprehensive neuropsychological evaluation was conducted serially at age 7 years 4 months and 10 years 3 months, including assessment of intellectual functioning (IQ), motor functioning, perception, attention, executive functions, language, memory, social cognition, academic skills, and psychopathology. Reliable change index (RCI) scores were used to assess changes between assessments. We collected spin lattice relaxation time (T1)-weighted, fluid-attenuated inversion recovery (FLAIR), and spin spin lattice relaxation time (T2)-weighted images from the child at age 10 years 3 months using a 1.5-tesla MRI scanner. Results: IQ, processing speed index (PSI), social cognition (theory of mind and facial emotion recognition), selective attention, naming, academic skills (reading/comprehension), and manual speed with right hand declined in the second evaluation relative to the initial evaluation, while visuoconstructional praxis, receptive vocabulary, working memory, and arithmetic skill improved. The patient showed a remarkable global deterioration in executive functions (planning, task flexibility, behavioral regulation, and metacognition) as revealed by parental report and clinical evaluation. MRI revealed gliosis from the head to tail of the hippocampus and thinning of parahippocampal gyri. Conclusions: In a clinical case of CCHS, serial evaluation revealed deterioration of executive functions and social cognition over a 3-year interval. These changes corresponded to hippocampal damage as revealed in MRI, which may have affected social cognition through its role in the default mode network. Serial neuropsychological assessment is clinically useful in managing the needs of these patients.

Congenital central hypoventilation syndrome (CCHS): Circadian temperature variation.

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 PST was lower overall (P = 0.03) and at night (P = 0.02), and PST variability (interquartile range) was higher at night (P = 0.05) (vs. controls). PST circadian rhythm remained intact but the phase relationship of PST to CBT rhythm was extremely variable in CCHS. PST alterations in CCHS likely reflect altered autonomic control of peripheral vascular tone. These alterations represent a previously unreported manifestation of CCHS and may provide an opportunity for therapeutic intervention. The relationship between temperature dysregulation and CCHS may also offer insight into basic mechanisms underlying thermoregulation.

Haddad Syndrome with a Germ-Line Mutation in thePHOX2BGene in a Korean Neonate

Congenital central hypoventilation syndrome (CCHS) is a life-threatening disease that primarily manifests as sleep-associated respiratory insufficiency and a markedly impaired ventilatory response to hypercarbia and hypoxemia. Paired-like homeobox 2b (PHOX2B) gene mutations are known to cause CCHS. Almost all patients with CCHS are heterozygous for a poly-alanine expansion in PHOX2B. However, some patients have other germ-line abnormalities, including missense, nonsense and frame shift mutations. CCHS combined with Hirschsprung disease (Haddad syndrome) is extremely rare. Here, we report the case of a 1-day-old male neonate with recurrent apnea and bowel distension. Genetic analysis showed that he was heterozygous for a germ-line mutation in the PHOX2B gene. Only three cases of CCHS including two with Haddad syndrome confirmed by PHOX2B gene mutations have been reported in Korea. All of these cases have been heterozygous for a poly-alanine expansion mutation. This is the first report describing Haddad syndrome with a germ-line mutation in the PHOX2B gene in a Korean neonate.

Congenital central hypoventilation syndrome and intestinal aganglionosis: A case report

Congenital central hypoventilation syndrome (CCHS), also called ‘Ondine’s curse’, is characterised by an abnormal ventilatory response to progressive hypercapnia and sustained hypoxaemia. Neonates with this condition experience hypoventilation or apnoea while asleep. Patients may also have congenital intestinal aganglionosis (CIA), aganglionic megacolon or Hirschsprung’s disease, suggesting an aberrant phenotype arising from a defect of migration or diff erentiation of neural crest cells. Some patients also have tumours of neural crest cell origin, including neuroblastoma, ganglioneuroma and ganglioneuroblastoma. Th e association of CCHS and CIA is called Ondine- Hirschsprung disease (Haddad syndrome). A few cases have been diagnosed in South Africa, but none has been reported. We report a case of CCHS and CIA with a PHOX2B gene mutation.

Congenital Central Hypoventilation Syndrome

Congenital central hypoventilation syndrome (CCHS) is a relatively rare, life-threatening, and lifelong multisystem disorder characterized by autonomic nervous system dysfunction, which mostly manifests as failure to maintain ventilatory homeostasis during sleep. Infants with CCHS have inadequate sensitivity to hypoxia and hypercapnia during sleep and in some cases during wakefulness, leading to persistent apnea. This article reports a case of CCHS in a 38-week-gestation infant who presented on day of life 2 with persistent apnea. Diagnosis of primary pulmonary, cardiac, metabolic, neurologic disease, or injury was excluded before the diagnosis of CCHS was made. The diagnosis was confirmed by a PHOX2B sequence analysis. A tracheotomy was performed and the infant was discharged home on a home ventilator with outpatient follow-up. The clinical presentation of CCHS, as well as diagnosis and treatment strategies, is reviewed.

Sinus vein thrombosis as presenting finding in the congenital central hypoventilation syndrome: An insight on the pathophysiology of the association

Congenital central hypoventilation syndrome (CCHS) is an increasingly recognized diagnosis causing central hypoventilation and may be definitively diagnosed by genetic testing. Previous authors reported the association between CCHS and central sinus venous thrombosis (CSVT) and hypothesized that CCHS could be secondary to CSVT. We report a case of CCHS with the typical PHOX2B mutation who also suffered from CSVT. We assume that effects, secondary to CCHS, upon the central venous system may explain the etiological connection between CSVT and CCHS including dysautoregulation, venous stasis or polycythemia. We believe that CCHS should be included in the differential diagnosis of patients with CSVT accompanied by respiratory abnormalities.

Comparison of PHOX2B Testing Methods in the Diagnosis of Congenital Central Hypoventilation Syndrome and Mosaic Carriers

Clinical diagnostic testing for congenital central hypoventilation syndrome (CCHS) usually involves amplification and detection by (1) targeted mutation analysis or (2) sequence analysis. Test method performance differences are more pronounced when studying difficult templates [eg, guanine-cytosine (GC)-rich regions] or samples with abnormal allele ratios (eg, mosaicism). CCHS, an autosomal dominant disorder with identified mosaic carriers, is caused by expansion mutations of the GC-rich polyalanine-coding region of the PHOX2B gene in greater than 90% of patients (and other PHOX2B mutations in remaining patients). The combination of a GC-rich testing region and known mosaicism in CCHS necessitates the determination of the limit of detection for diagnostic tests. This study compared the limit of detection in CCHS-PHOX2B testing for both targeted mutation analysis and sequence analysis. Test samples included 6 differentially sized PHOX2B expansion mutations and 1 PHOX2B deletion mutation, all diluted over a range of concentrations; and 2 mosaic dyads. The limit of detection for PHOX2B expansion mutations was 1% and 20% mutant allele concentration with targeted mutation analysis and sequence analysis, respectively. These results indicate that PHOX2B testing using targeted mutation analysis is more likely to identify even low-level mosaicism for polyalanine expansion and deletion mutations. However, sequencing of PHOX2B is required to detect single base-pair mutations that cause the remaining small subset of CCHS cases. A combination of both the tests may be required in cases in which 1 test fails to identify the disease-causing mutation. These results can help guide clinicians when choosing a CCHS/PHOX2B clinical diagnostic testing method and interpreting results.

An Official ATS Clinical Policy Statement: Congenital Central Hypoventilation Syndrome

Congenital central hypoventilation syndrome (CCHS) is characterized by alveolar hypoventilation and autonomic dysregulation. (1) To demonstrate the importance of PHOX2B testing in diagnosing and treating patients with CCHS, (2) to summarize recent advances in understanding how mutations in the PHOX2B gene lead to the CCHS phenotype, and (3) to provide an update on recommendations for diagnosis and treatment of patients with CCHS. Committee members were invited on the basis of their expertise in CCHS and asked to review the current state of the science by independently completing literature searches. Consensus on recommendations was reached by agreement among members of the Committee. A review of pertinent literature allowed for the development of a document that summarizes recent advances in understanding CCHS and expert interpretation of the evidence for management of affected patients. A PHOX2B mutation is required to confirm the diagnosis of CCHS. Knowledge of the specific PHOX2B mutation aids in anticipating the CCHS phenotype severity. Parents of patients with CCHS should be tested for PHOX2B mutations. Maintaining a high index of suspicion in cases of unexplained alveolar hypoventilation will likely identify a higher incidence of milder cases of CCHS. Recommended management options aimed toward maximizing safety and optimizing neurocognitive outcome include: (1) biannual then annual in-hospital comprehensive evaluation with (i) physiologic studies during awake and asleep states to assess ventilatory needs during varying levels of activity and concentration, in all stages of sleep, with spontaneous breathing, and with artificial ventilation, and to assess ventilatory responsiveness to physiologic challenges while awake and asleep, (ii) 72-hour Holter monitoring, (iii) echocardiogram, (iv) evaluation of ANS dysregulation across all organ systems affected by the ANS, and (v) formal neurocognitive assessment; (2) barium enema or manometry and/or full thickness rectal biopsy for patients with a history of constipation; and (3) imaging for neural crest tumors in individuals at greatest risk based on PHOX2B mutation.

Characterization of Dermatoglyphics inPHOX2B-Confirmed Congenital Central Hypoventilation Syndrome

Individuals with congenital central hypoventilation syndrome have characteristic variants in the PHOX2B gene (primarily polyalanine expansion mutations). The PHOX2B gene acts as a transcriptional activator in the promotion of pan-neuronal differentiation in the autonomic nervous system during early embryologic development, with a primary role in the sympathetic noradrenergic phenotype in vertebrates. Because sympathetic innervation has been hypothesized to affect the development of dermatoglyphic pattern types, we hypothesized that individuals with PHOX2B-confirmed congenital central hypoventilation syndrome would have characteristic dermatoglyphic patterning and that the dermatoglyphic phenotype would be related to the disease-defining PHOX2B genotype. Dermatoglyphic pattern type frequency, left/right symmetry, and genotype/phenotype correlation were assessed for 33 individuals with PHOX2B-confirmed congenital central hypoventilation syndrome and compared with published control data. Dermatoglyphic pattern type frequencies were altered in congenital central hypoventilation syndrome cases versus controls. In particular, there was an increase of arches in females and ulnar loops in males, with the largest differences for the left hand and for individuals with both congenital central hypoventilation syndrome and Hirschsprung disease. Dissimilarity scores between the congenital central hypoventilation syndrome and congenital central hypoventilation syndrome + Hirschsprung disease cases were not significantly different, nor were dissimilarity scores between all of the female and all of the male cases. No significant association was found between the number of polyalanine repeats in the PHOX2B genotypic category and dermatoglyphic pattern frequencies in the congenital central hypoventilation syndrome study groups. These results represent the first report describing specific dermatoglyphic patterning in congenital central hypoventilation syndrome and suggest a relationship between PHOX2B and the expression of dermatoglyphic pattern types. An expanded congenital central hypoventilation syndrome data set to include the full spectrum of PHOX2B mutations is necessary to further delineate the role of PHOX2B in dermatoglyphic patterning.

Congenital central hypoventilation syndrome combined with Hirschsprung disease diagnosed in the neonatal period

Congenital central hypoventilation syndrome (CCHS) or Ondine's curse is a very rare sleep disorder that is the result of a congenital failure of the autonomic control of ventilation caused by insensitivity of the chemoreceptor to hypercapnea during sleep. Gastrointestinal motility disorders, particularly a congenital megacolon (Hirschsprung disease) is often combined with CCHS. This combination can be explained by a defect in the migration of neuronal cells from the neural crest (neurocristopathy) during the intrauterine period. A diagnosis of CCHS is made by confirming the failure of adequate ventilation in response to hypercapnea and hypoxia during sleep and the exclusion of other diseases. Young infants frequently show atypical clinical courses, and their conditions are frequently complicated with the long-term sequela of hypoxemic episodes. Therefore, a high index of suspicion and active treatment with mechanical ventilation are important for reducing recurrent hypoxemic episodes in the neonatal period. This paper reports the follow up of a case of CCHS in a neonate who showed frequent intractable apnea and cyanosis and was given artificial mechanical ventilation during sleep.

Facial Phenotype in Children and Young Adults with PHOX2B–Determined Congenital Central Hypoventilation Syndrome: Quantitative Pattern of Dysmorphology

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, biocular 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.