History

Mellins and colleagues ( Fig. 8.2 ) first reported CCHS as a case of congenital alveolar hypoventilation in 1970 providing a comprehensive summary of the evaluation and management of a patient with the disorder. Initially, CCHS was attributed to an injury to the medullary chemoreceptors. It was not until the early 1990s that larger cohorts were published. The American Thoracic Society (ATS) released its first statement in 1999, and at that time, there were about 160 to 180 children estimated to have CCHS. This led to a better understanding of the clinical presentation, associated conditions related to autonomic nervous system dysfunction, complications, and various treatment strategies applied in children with CCHS; however, an etiology was still unknown. In 2003, Amiel et al. discovered frameshift mutations and polyalanine repeats in the PHOX-2B gene in children with CCHS. They also demonstrated that PHOX-2B was expressed in the central and peripheral autonomic nervous system in human embryonic development. This was an essential milestone in the history of children with CCHS as it led to an opportunity for early diagnosis and optimization of ventilation and phenotyping of patients based on their mutations. In 2009, the ATS released its second statement providing a comprehensive summary of the role of PHOX-2B , diagnosis, and management strategies for individuals with CCHS. Based on the report, about 1000 patients with CCHS were diagnosed worldwide by then. In 2013, the first international CCHS Research database was created.

History of CCHS.

Genetics

PHOX-2B , located on chromosome 4p12, is identified as the CCHS disease-causing gene. Amiel and colleagues described that the PHOX-2B gene encodes a highly conserved homeobox transcription factor of 314 amino acids with two short and stable polyalanine repeats of 9 and 20 residues, respectively. They also demonstrated the expression of PHOX-2B in the central and peripheral autonomic nervous systems in human embryonic development, which further supports the presence of various clinical manifestations ( Fig. 8.3 ) of dysfunction of the autonomic nervous system. Inheritance is typically autosomal dominant with variable penetrance; however, some mutations are de novo . Once a patient is diagnosed with CCHS, the parents should undergo genetic counseling and testing, as this would inform their health risks if they carry mosaicism in their PHOX-2B gene and plan future pregnancies.

Clinical manifestations of CCHS.

Typically, healthy individuals have a repeat sequence of 20 alanines in exon 3 (normal genotype 20/20). The majority (∼90%) of individuals with CCHS are heterozygous for a polyalanine repeat expansion mutations (PARM) mutation, and this can range from an additional 4 to 13 alanines added to the typical sequence of 20 alanine repeats. Hence, 20/24 to 20/33 are the genotypes produced by the PARMs mutation. Other patients with CCHS (∼9%–10%) are heterozygous for a nonpolyalanine repeat mutation (NPARM), including nonsense, frameshift, missense splice-site, or stop codon mutations. Genotypes 20/25, 20/26, and 20/27 are the most common.

Genotype-phenotype relationships have been described and published in the literature. For example, individuals with higher polyalanine repeats (genotypes 20/26, 20/27) and NPARMs are more likely to require day and night ventilation. In comparison, those with fewer polyalanine repeats (genotypes 20/24, 20/25) may only need nocturnal support. Also, patients with NPARMs mutation are at a higher risk of developing tumors of neural crest origin and severe intestinal aganglionosis. Sinus pauses (longest R-R interval ≥3 seconds) are more common in individuals with the 20/27 genotype, with some requiring a cardiac pacemaker. Identifying a specific genotype is crucial as it has implications on evaluation and management of CCHS.

Despite the relationships noted between the genotype and phenotype of CCHS, individuals with NPARMs mutation present with differing severity due to variable penetrance and expressivity. This has been described in a three-generational family of four with NPARM (c.245C > T) genotype. The affected family members had a milder phenotype of CCHS; two of them were ventilator-dependent at night and did not have neural crest tumors or Hirschsprung disease, while the remaining two were asymptomatic. One of the asymptomatic individuals eventually developed systemic hypertension as an adult.

There have also been reports of non- PHOX-2B mutations, such as MYO1H and LBX1 , in patients with CCHS born with consanguineous families, suggesting an autosomal recessive inheritance. ^,

Hence, further research is required to define further the relationships between the rare genotypes with variable penetrance and expressivity.

Neurocristopathy

Neurocristopathies, a spectrum of diseases related to abnormal migration of the neural crest cells, can be seen in children with CCHS. Common neurocristopathies seen in children with CCHS include Hirschsprung disease (partial or complete aganglionosis of the distal intestinal tract) and neural crest tumors, both of which have been observed in those with the NPARMs mutation. A subset of patients has less severe presentations, such as chronic constipation or esophageal dysmotility. The neural crest tumors, including ganglioneuroblastomas, neuroblastomas, and ganglioneuromas, have been described in CCHS. Neuroblastomas tend to present during infancy, and ganglioneuroblastoma and ganglioneuroma are often incidental findings. Death from neural crest tumors is rare.

Autonomic nervous system (ANS) dysregulation

Cardiac abnormalities like sinus pauses and bradycardia, transient asystole, decreased heart rate variability, and blood pressure are seen. Some patients may require cardiac pacemakers. Ophthalmologic manifestations such as anisocoria, altered response to light, strabismus, and convergent gaze may also be seen. Other signs of ANS dysregulation are temperature dysregulation (hypothermia), sporadic profuse sweating, poor pain perception, and anxiety. Endocrinopathies have been described, such as hypoglycemia, hyperglycemia, and hyperinsulinism, suggesting possible hypothalamic dysfunction; however, the pathophysiology for this is not entirely understood.

Neurocognitive abnormalities

Reported neurological and neurocognitive deficits have been attributed to the possible direct result of a primary neurological problem, suboptimal ventilatory support, or dysfunction of cerebral autoregulation. For example, a study by Zelko and colleagues demonstrated that parents reported that 30% of children with CCHS had a formal diagnosis of learning disabilities, and about half the children with CCHS had additional educational needs or were in supported classrooms. ^, Charnay and colleagues demonstrated significantly lower Bayley mental and motor scores in children with CCHS who had severe cyanotic breath-holding spells, required continuous ventilatory support, and had a history of prolonged sinus pauses. They also demonstrated that Bayley motor scores alone were significantly lower for children with seizures. The degree of cognitive impairment may correlate with disease severity; however, this needs to be further explored.

Diagnostic evaluation

A diagnosis of CCHS should be considered in a child with evidence of sleep-related hypoventilation without any known cardiopulmonary, neuromuscular, metabolic, or brainstem dysfunction. According to the ICSD-3, a diagnosis of CCHS is made based on the presence of sleep-related hypoventilation and an identified mutation in the PHOX-2B gene.

A PHOX-2B screening test is initially recommended in patients with suspected CCHS to identify known PARM (genotypes 20/24 to 20/33), frameshift NPARM, and somatic mosaicism. The fragment analysis involves the polymerase chain reaction amplification of the 20 repeat polyalanine expansion region of exon three and determines the polyalanine repeat length, identifying 95% of patients with CCHS. If no mutations have been detected, with an ongoing strong suspicion for CCHS, a PHOX-2B sequencing test is recommended as this additionally identifies missense and nonsense mutations. As a final step, a PHOX-2B deletion/duplication analysis by multiplex ligation-dependent probe amplification (MLPA) test can also be performed. This would identify the whole gene or exon deletions and duplications and would be needed to identify asymptomatic or mildly symptomatic individuals with CCHS.

Management of central hypoventilation syndromes

Follow-up

Close follow-up with a multidisciplinary team with expertise in CCHS is recommended, including parents/family members, pediatricians, pulmonologists, sleep medicine physicians, cardiologists, endocrinologists, gastroenterologists, ophthalmologists, neonatal and pediatric intensivists, psychologists, nursing support, respiratory therapists, speech therapists, occupational therapists, and social workers.

As patients with CCHS may not perceive dyspnea or manifest other signs of respiratory distress, careful monitoring of their respiratory status and gas exchange at home is required. Families should be informed about avoiding high-risk activities such as breath-holding, unsupervised swimming, and use of CNS depressants, alcohol, or other recreational drugs. Additionally, close cardiorespiratory monitoring during and after anesthesia with adequate respiratory support is vital to prevent acute respiratory failure.

Families should be provided with resources to help with home management, including home nursing, parent support groups, durable medical companies to provide adequate supplies, and a sick plan. In addition, in case of natural disasters, it is helpful for the local emergency services, such as the fire department and police department, to be aware of the patient’s medical needs.

Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation

ROHHAD is a rare disorder of central hypoventilation that was first described as a case report in 1965 by Fishman and colleagues from Southern California. Based on the onset of hypoventilation during childhood and the association with hypothalamic endocrinopathies, it was initially referred to as “late-onset central hypoventilation syndrome with hypothalamic dysfunction” and later renamed in 2007 as ROHHAD. Late-onset CCHS has been considered an important differential for ROHHAD but is now clinically distinguished based on the absence of the PHOX-2B gene.

The clinical presentation of ROHHAD is usually during early childhood, between 2 and 4 years of age, and most children are typically healthy until the onset of disease. The clinical syndrome is characterized by rapid onset of excessive weight gain, other hypothalamic endocrinopathies (diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, hyperprolactinemia, hypothyroidism, growth hormone deficiency, hypogonadism, or precocious puberty), followed by autonomic dysregulation, and alveolar hypoventilation. Manifestations of autonomic dysfunction include ophthalmologic findings (pupillary dysfunction and strabismus), cardiac arrhythmias, gastrointestinal dysmotility, and temperature dysregulation. Sleep-related hypoventilation is variable in presentation and can occur at any point of the disease spectrum. Hypoventilation can also occur during wakefulness. Patients may have a blunted hypoxic-hypercapnic ventilatory response suggesting central chemoreceptor dysfunction. Given their obesity, these patients are also at risk for obstructive sleep apnea. In addition, a subset of patients with ROHHAD may present with neuroendocrine tumors, in which case their condition is referred to as ROHHAD-NET. Behavioral issues may be seen and can be quite debilitating, with presentations varying from irritability and aggression to psychosis. Other associated conditions such as autism, self-injurious behavior, oppositional-defiant disorder, major depressive disorder, anxiety, and hyperactivity have been reported.

The diagnosis of ROHHAD is based on the clinical findings and a negative PHOX-2B genetic test. Despite evaluating several candidate genes, the genetic etiology for ROHHAD remains undetermined. Current theories include an unknown epigenetic etiology and/or an autoimmune process. There have been case reports of improvement in neuropsychological comorbidities following treatment with immunosuppressants such as cyclophosphamide. While pharmacotherapies are being investigated as potential forms of treatment, management of each comorbidity is essential to reduce morbidity and mortality.

Since central control of breathing in children with ROHHAD may progressively worsen, the outcome can be deleterious, including respiratory failure, pulmonary hypertension, and cardiac arrest. Therefore, prompt diagnosis and treatment, including aggressive ventilatory support, are needed.

Prader-Willi syndrome

PWS is a rare genetic disorder that presents with hypotonia and failure to thrive in early infancy. It is due to the absence of paternal expression of imprinted genes on chromosome 15 (15q11.2-q13). Later in childhood, hyperphagia, obesity, and behavioral issues may present. In addition, children with PWS are at risk for various sleep-disordered breathing, including central sleep apnea earlier in infancy, as well as OSA and hypoventilation. These are due to a combination of craniofacial factors, hypotonia, obesity hypothalamic dysfunction. CSA is frequently seen in infants and children with PWS less than 2 years old, while OSA is more common in those older than 2 years.

While ventilation may be normal during wakefulness, patients with PWS have demonstrated hypoxic, hypercapnic, and hyperoxic response abnormalities, suggesting a dysfunction in the central and peripheral chemoreceptors. Gozal and colleagues demonstrated a paradoxical response to hyperoxia with an increase in minute ventilation compared to controls, suggestive of a peripheral chemoreceptor dysfunction and/or abnormalities in the afferent pathways to the central control of breathing. Arens and colleagues observed a blunted hypercapnic ventilatory response in obese children with PWS compared to obese controls. They also demonstrated a higher threshold of PCO ₂ for appropriate hypercapnic ventilatory response in obese PWS subjects, suggesting a central cause for hypoventilation. Hypoxic ventilatory response was also evaluated, and most patients with PWS either had an absent or a decreased response, suggesting additional peripheral chemoreceptor dysfunction.

Infants and young children with PWS may be at risk of developing severe respiratory failure during acute respiratory illness and initiation of growth hormone. As a result, a screening polysomnogram should be obtained to evaluate for sleep-disordered breathing before starting growth hormone therapy and periodically afterward. Identifying sleep-disordered breathing in children with PWS and implementing prompt treatment may improve a variety of outcomes and reduce the likelihood of acute respiratory failure. Respiratory support depends on the primary etiology of sleep-disordered breathing and can include surgical intervention with adenotonsillectomy, supplemental oxygen, and noninvasive ventilation.

Chiar II malformation

Chiari malformation type 2 (CM-2), often associated with myelomeningocele, is characterized by herniation of the cerebellum, fourth ventricle, and caudal brainstem through the foramen magnum into the cervical spinal cord. This herniation can obstruct the cerebrospinal fluid with resultant hydrocephalus. Variable degrees of central apnea and hypoventilation can occur due to the involvement of the respiratory centers in the brainstem as a result of dysgenesis or damage of the neural tissues from traction and herniation into the spinal cord. Ventilatory challenge testing in this population has shown blunted hypercapnic responses, suggesting impaired central chemoreceptor function.

Affected patients can present in the newborn period with apnea, dysphagia, aspiration, stridor, and vocal cord paralysis. During sleep, patients with CM-2 may have OSA, CSA, or hypoventilation. Evaluation for sleep-disordered breathing should include a polysomnogram with CO ₂ monitoring. The presence of these findings may suggest worsening hydrocephalus and should prompt further evaluation for this as a surgical intervention with posterior fossa decompression may be warranted. If the congenital dysgenesis of the neural structures of the brainstem dominates the clinical pathology, then hypoventilation may not resolve and increase the risk for mortality. Patients with CM-2 and sleep-disordered breathing have been treated with oxygen, noninvasive or invasive mechanical ventilation long term.

Neuromuscular disorders of infancy

Diseases affecting the structure and function of the neuromuscular system can result in hypoventilation of varying degrees and are typically less likely a central etiology, depending on the disease process. Neuromuscular disorders frequently cause weakness and hypotonia, which may be generalized or focal. As these disorders may arise from the brain or spinal cord, history, physical examination, and diagnostic testing are essential for a definitive diagnosis. Common neuromuscular disorders present during the newborn period and infancy include spinal muscular atrophy, mitochondrial cytopathies, congenital myasthenic syndromes, and congenital myotonic dystrophy. Depending on the extent of neuromuscular involvement, respiratory manifestations could range from minimal to severe respiratory failure. During infancy, there should be a low threshold for polysomnogram if sleep-related hypoventilation is suspected, as these findings may be subtle. If hypoventilation is present, appropriate mechanical ventilatory support needs to be initiated to optimize gas exchange.

Achondroplasia

Achondroplasia, skeletal dysplasia, is an autosomal dominant condition caused by a fibroblast growth factor receptor type 3 ( FGFR3 ) gene mutation present on chromosome 4p26.3. While inheritance is autosomal dominant, most of the mutations are de novo . FGFR3 is responsible for the formation of bones through endochondral ossification, and a mutation in this gene results in abnormal bone formation through cartilage, affecting longitudinal growth. Most of the bones in the base of the skull and the vertebral bodies are formed through this process and therefore are affected, resulting in foramen magnum and spinal canal stenosis, which can cause compression of the spine and sudden death in infants. Affected infants also have characteristic features, including macrocephaly, mid-face hypoplasia, short limbs, and brachydactyly. These infants are at risk for various sleep-disordered breathing disorders, including hypoventilation in varying degrees. Studies have shown hypoxemia as the most frequent finding noted on polysomnograms, which may be related to a decreased pulmonary reserve from restrictive lung disease. Patients may also have central and obstructive sleep apnea and hypoventilation in varying degrees, some of which have been attributed to compression of the spinal cord or brainstem. There have also been reports of significant respiratory compromise, including apnea and sudden death in infancy. Hence, neuroimaging studies are recommended in affected infants and children with achondroplasia who present with hypoventilation as a timely intervention with mechanical ventilation, and possibly surgical decompression of the spinal canal stenosis can be a life-saving measure.

Familial dysautonomia

Familial dysautonomia (FD) is a rare disorder of the autonomic nervous system due to a mutation in the gene located on chromosome 9q31 encoding for IκB kinase complex-associated protein (IKAP). IKAP is responsible for neuronal development in embryogenesis, and deficiency of IKAP mainly affects the primary sensory afferent neurons. It is predominantly seen in the Ashkenazi Jewish population. Clinical features include hypoventilation, hypoxemia, temperature dysregulation, altered pain perception, dysphagia, and ataxia. Cardiovascular manifestations such as episodic elevated blood pressure resulting in autonomic crises and postural hypotension without reflex tachycardia are more prominent in children and adults with FD. Patients also experience episodes of “autonomic crises” characterized by vomiting, hypertension, tachycardia, and red blotching of skin, typically triggered by stressors. Asystole is typically the cause of sudden death in affected individuals.

Affected children and adults with FD have a blunted ventilatory response to hypoxia and hypercapnia independently. They also lack reflex tachycardia, sympathetic response to hypoxia, and have profound apnea with moderate hypercapnia challenge. Carroll and colleagues demonstrated increased respiratory rate and increased respiratory variability during sleep in children with FD compared to age-, sex- and race-matched controls, indicating a disorder of respiratory control. Hypoventilation has not been consistently demonstrated but is presumably due to profound hypoxemia and blunted ventilatory response to hypercapnia.

Treatment of FD is primarily supportive, and if hypoventilation is present, appropriate mechanical ventilatory support will need to be initiated. This can potentially prevent the morbidity and mortality associated with cardiorespiratory depression from hypoxemia and presumed hypoventilation.