OVERVIEW: What every practitioner needs to know

Are you sure your patient has congenital central hypoventilation syndrome? What are the typical findings for this disease?

Congenital central hypoventilation syndrome (CCHS) is a rare disorder of respiratory control with autonomic nervous system dysregulation (ANSD). Impaired breathing regulation (respiratory control) is the hallmark of CCHS. Individuals with CCHS typically present in the newborn period with shallow breathing (alveolar hypoventilation) during sleep and, in more severely affected individuals, during wakefulness and sleep. Breathing complications occur despite the lungs and airways being normal.

A growing number of individuals are now being identified who present in later infancy, childhood, or even adulthood and are referred to as Later-Onset Congenital Central Hypoventilation Syndrome (LO-CCHS).

The symptoms and severity of CCHS vary from one individual to another. This variation is becoming clearer when studied by PHOX2B genotype/mutation, such that repeat length and PARM versus NPARM are related to disease severity. A rapidly expanding understanding of the risks specific to the PHOX2B mutation is allowing physicians and parents to anticipate risks for continuous ventilation, pauses in the heart rhythm, and potentially factors that will influence neurocognitive outcome in individuals with CCHS.

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The classic description of an infant with CCHS is cyanosis and hypercarbia, resulting from very shallow breathing during sleep (nap and night), but alertness and adequate breathing during wakefulness. If on a ventilator, the infant would be described as breathing synchronously with the ventilator when asleep but adding extra breaths during wakefulness. Also, these infants will do exceedingly well with minimal ventilator support and have repeated failed extubations. These individuals will not increase breathing or awaken in response to abnormal oxygen and carbon dioxide levels. This same lack of responsivity to low oxygen and elevated carbon dioxide occurs during wakefulness as well, even when awake breathing is adequate.

Individuals with CCHS may also have a characteristic facies, heart rhythm abnormalities such as prolonged asystoles (up to 3 seconds) necessitating a cardiac pacemaker, altered gut motility even in the absence of Hirschsprung disease often presenting as constipation, altered temperature regulation such that they have low body temperatures and decreased pain perception, decreased anxiety and eye abnormalities that include strabismus, convergence insufficiency, and decreased pupil response to light.

Late Onset Congenital Central Hypoventilation Syndrome

Individuals with LO-CCHS, indicating presentation after the newborn period, might present with centrally mediated alveolar hypoventilation/hypercarbia or with seizures after 1)recurrent pneumonia, 2)sedation or anesthesia, or 3)diagnosis of obstructive sleep apnea unresponsive to traditional management. With a heightened clinical suspicion for the later onset form of CCHS, and prompt testing to confirm presence of a PHOX2Bmutation (typically with genotype 20/25 or 20/24), the physician can avert potentially life-threatening decompensation as well as risk for neurocognitive compromise.

Evaluation of later presentation cases requires a careful history with attention to past exposure to anesthesia or sedation, delayed “recovery” from a severe respiratory illness, and unexplained seizures or neurocognitive impairment.

Review of digital AP and lateral photographs (to evaluate for facies consistent with CCHS; adult males often have a moustache to conceal the “lip trait”), any ECG documentation of prolonged sinus pauses (ideally via 72 hour Holter monitoring), any physiologic evaluations documenting ventilation both while awake and asleep (for hypercarbia and/or hypoxemia), a hematocrit and reticulocyte count (for polycythemia and response to hypoxemia), a bicarbonate level (for signs of compensated respiratory acidosis), or chest x-ray, echocardiogram, or electrocardiogram (for signs of right chamber enlargement or pulmonary hypertension) should be completed.

In cases of constipation a barium enema or manometry may be considered to exclude short segment HSCR.

What other disease/condition shares some of these symptoms?

Congenital myopathy is a term for any muscle disorder present at birth, potentially including any of several hundred distinct neuromuscular syndromes and disorders. In general, congenital myopathies cause loss of muscle tone and muscle weakness in infancy and delayed motor milestones, such as walking, later in childhood. Three distinct disorders are definitively classified as congenital myopathies: central core disease, nemaline rod myopathy, and centronuclear (myotubular) myopathy.

Congenital myasthenia usually occurs in infants but may become evident in adulthood. Associated features may vary in severity from case to case. Such abnormalities may include feeding difficulties, periods with absence of spontaneous breathing (apnea), failure to grow and gain weight at the expected rate, muscle weakness and fatigue, weakness or paralysis of eye muscles (ophthalmoplegia), and/or other abnormalities.

Moebius syndrome is a rare developmental disorder with varied causes. Characterized by facial paralysis present at birth, facial nerve development is absent or diminished causing abnormalities of the facial muscles and jaw. Additional symptoms may include numerous abnormalities of the mouth and face, limb malformation, and (in 10% of cases) mental retardation.

When CCHS occurs in adults it may be confused with other more common respiratory diseases such as obstructive sleep apnea unresponsive to traditional management. Notably individuals with CCHS will not have dyspnea as they do not perceive low oxygen or elevated carbon dioxide.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a related but separate disorder. Children with ROHHAD typically present between the ages of 1.5 and 9 years of age with a rapid weight gain of 20 or more pounds over a 6 month period. They are then noted to have symptoms of hypothalamic dysfunction such as growth insufficiency, hypothyroidism and water imbalance. A subset of the cases will experience a respiratory arrest subsequent to an intercurrent illness, and a subset will initially be noted to have some element of obstructive sleep apnea.

Once the obstructive sleep apnea is treated the children will be noted to have alveolar hypoventilation, even among those who did not endure a cardiorespiratory arrest. Soon thereafter the children will be noted to have other symptoms of autonomic nervous system dysregulation including dramatically low body temperatures and very slow heart rates. A subset of the children will have tumors of neural crest origin (ganglioneuromas and ganglioneuroblastomas).

Children with ROHHAD do not have CCHS-related mutations in the PHOX2B gene, though a definitive gene/mutation has not yet been identified.

The following disorders may be associated with CCHS as secondary characteristics. Though not necessary to confirm a diagnosis of CCHS, when documented in an infant/child with cyanotic spells during sleep, these disorders will heighten the suspicion of the physician that an individual has CCHS:

1. Hirschsprung disease is a rare gastrointestinal disorder characterized by aganglionosis of the distal hindgut. Peristalsis may be impaired or absent and the distal bowel is typically abnormally dilated (megacolon). Symptoms of Hirschsprung disease appear soon after birth and may include constipation, abdominal distention and vomiting. Older infants may have anorexia, failure to thrive and severe constipation. Hirschsprung disease may be diagnosed in older children and adults, with short segment Hirschsprung disease.

2. Epilepsy is a group of disorders of the central nervous system characterized by repeated convulsive electrical disturbances in the brain. In CCHS, the cause of seizures is most often due to suboptimal ventilatory management, resulting in hypoxemia and/or hypercarbia. The major symptoms may include loss of consciousness, convulsions and spasms. The symptoms of a grand mal seizure may include loss of consciousness, violent muscle spasms, gnashing of teeth, loss of bladder and/or bowel control, confusion, and/or drowsiness.

What caused this disease to develop at this time?

The majority of CCHS cases are caused by a de novo mutation in the
PHOX2B gene, though 5-10% (and more recent publications indicate this number could be as high as 25%) can be inherited in an autosomal dominant manner from a parent who is mosaic for PHOX2B mutation. The cases may also be inherited from a fully affected parent (parent with CCHS).

The vast majority of individuals (90-92%) with CCHS are heterozygous for a polyalanine repeat expansion mutation (PARM) in exon 3 of the PHOX2B gene: the normal allele will have the normal 20 alanine repeats and the expanded allele will have anywhere from 24-33 repeats. So the PHOX2B genotype range for an individual with a PARM will be 20/24-20/33.

The majority of the remaining individuals with CCHS have a non-polyalanine repeat expansion mutation (NPARM) typically between the end of exon 2 and into exon 3 of the
PHOX2B gene. The altered DNA sequences resulting in the PARMs and NPARMs cause the protein resulting from the PHOX2B gene to function improperly. A very small number of individuals with CCHS or CCHS-like symptoms will have whole gene or exon deletions of
PHOX2B.These cases have only been recently identified, are rare, and are phenotypically variable.

The PHOX2B mutation results in altered development and regulation of the autonomic nervous system, primarily by abnormal development of early embryonic cells that form the neural crest. Individuals with the NPARMs will typically be more severely affected than individuals with the PARMs, and individuals with the greater number of alanines repeats will typically be more severely affected than those with the fewer number of repeats. The small number of identified cases with whole-gene or exon deletions makes prediction of phenotype difficult in these cases, but thus far disease seems to be less severe in these cases.

Typically, dysfunction of PHOX2B during development is enough to cause manifestation of disease from the neonatal period or beyond, however the less severe mutations may be “unmasked” with challenges to the respiratory system such as respiratory infection or exposure to sedation, to fully manifest disease symptoms.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The diagnosis of CCHS is based on the clinical presentation, the related clinical features, documented absence of primary pulmonary, cardiac, neuromuscular disease or an identifiable brainstem lesion that can account for the full CCHS phenotype, and confirmation with clinically available PHOX2B testing.

The new American Thoracic Society (ATS) Statement on CCHS (published in 2010) advises that the
PHOX2B Screening Test be the first step in making the genetic diagnosis of CCHS. This test will diagnose all of the polyalanine repeat expansion mutations (PARMs), mosaicism, polyalanine repeat contraction mutations, and the large deletion non-polyalanine expansion mutations (NPARMs). Another name for the PHOX2B Screening Test is fragment analysis.

If the PHOX2B Screening Test is normal and the subject has the clinical presentation of CCHS, then the sequel PHOX2B Sequencing Test should be performed to identify the small subset of patients with small NPARMs. The PHOX2B Sequencing Test will detect the PARMs, the contractions, and the NPARMs, but it will not detect mosaicism, so this test is rarely useful in parents of children with CCHS.

Because the PHOX2B Screening Test is less expensive with a more rapid turnaround time than the PHOX2B Sequencing Test, and it will detect the vast majority of the cases of CCHS, the two-step testing process is least costly, most expeditious, and most efficient for nearly all patients in whom CCHS is considered.

Finally, in cases where both the PHOX2B Screening and Sequencing tests are negative but clinical suspicion remains high, the PHOX2B MLPA test for copy number variations should be performed.

Would imaging studies be helpful? If so, which ones?

Magnetic resonance imaging (MRI) of the head is helpful to rule out a primary brain/brainstem abnormality. In the infants at greatest risk of a tumor of neural crest origin, chest x-ray/abdominal ultrasound in infancy and later chest and abdomen MRI or computerized tomography is of value. A MIBG (iodine meta-iodobenzylguanidine) scan, used to find tumors of neural crest specific origin, might be performed in the patients at highest risk for neuroblastoma.

Thus far, tumors of neural crest origin have been identified in children with NPARM (typically neuroblastoma) and in children with PARMs and the 20/29-20/33 genotype (typically ganglioneuroma and ganglioneuroblastoma, though neuroblastoma remains a possibility). The American Thoracic Society Statement on CCHS suggests screening for tumors of neural crest origin in all NPARM cases and in children with the 20/28-20/33 PHOX2B genotypes.

If you are able to confirm that the patient has congenital central hypoventilation syndrome, what treatment should be initiated?

As recommended in the new ATS Statement on CCHS, evaluation should include annual inpatient comprehensive physiologic assessment during spontaneous breathing awake (in varying levels of concentration, activity, and exercise) and during sleep in a pediatric respiratory physiology laboratory with extensive expertise in CCHS.

Responses to endogenous and exogenous hypercarbia, hypoxemia, and hyperoxia should be assessed, ideally awake and asleep. 72 hour Holter recording should be performed annually (at a minimum) to evaluate for asystoles that might require a cardiac pacemaker (prolonged sinus pause of 3 seconds or longer). A tilt test should be performed annually to better understand the ANS response.

An echocardiogram should be performed annually (at a minimum) to rule out cor pulmonale or right ventricular hypertrophy. Neurocognitive testing should be performed annually to determine the effectiveness of the ventilatory management.

In infants under the age of 3 years, the above-described testing should be performed every 6 months.

Gastrointestinal motility studies and, if indicated, a rectal biopsy should be performed in the event of severe constipation.

All of the above described tests are part of routine standard of care for individuals with CCHS. Efforts are underway to create a comprehensive testing profile for autonomic regulation in children which will also be considered standard of care for children with CCHS, as their autonomic dysregulation necessitates characterization specific to each child.

Most importantly, all individuals with CCHS will require artificial ventilatory support. In infants, the safest way to deliver this is with a mechanical ventilator via a tracheostomy. Individuals with CCHS require a mechanical ventilator at home (with a back-up ventilator, pulse oximeter, end tidal carbon dioxide monitor, generator and preferably ventilator batteries) as well as experienced registered nursing (R.N.) care 24 hours/day.

In select cases, other assistive breathing apparatus and/or techniques may be used such as diaphragm pacing. In older children and adults, non-invasive (mask) ventilation may be considered. This technique is discouraged in infants and young children because of the risk of facial deformation from the mask and inadequate stability of mask ventilation at a time of rapidly progressing neurodevelopment. The goal is to optimize oxygenation and ventilation in order to optimize neurocognitive outcome.

CCHS is a life-long disease and affected individuals will, at a minimum, always require artificial ventilation during sleep. Ventilatory needs will vary with the specific
PHOX2B mutation. For example, individuals with small repeat expansions will typically require ventilator support during sleep only, whereas individuals with large repeat expansions and those with an NPARM will typically require artificial ventilation 24 hours/day. Supplemental oxygen alone is not adequate for treating the child with CCHS.

Some individuals with CCHS develop prolonged sinus pauses (asystoles) which, if 3 seconds or longer, require a cardiac pacemaker to correct the heart rhythm. The risk for asystoles varies with the specific PHOX2B mutation. Among children with the most common PARMs (20/25, 20/26, 20/27), those with the PHOX2B 20/27 genotype are at greatest risk.

Treatment of Hirschsprung disease usually consists of surgery to remove the non-functional segment of bowel and relieve obstruction. First, a temporary bowel opening of the colon in the abdominal wall (colostomy) is usually performed. The second operation consists of removing the diseased parts of the colon and rectum and connecting the normal bowel to the anus. In some centers with extensive expertise in Hirschsprung disease, the above-described procedures can be performed in one surgery.

Neuroblastomas are removed surgically, followed by chemotherapy in some cases. Treatment for other tumors originating from the neural crest depends on the type and location of the tumor. These other neural crest tumors are often detected anecdotally, but per the 2010 ATS Statement on CCHS should be screened for in children with the 20/28-20/33 PARM genotypes and the NPARMs.

Multidisciplinary care from a Center of Excellence with long-term comprehensive experience in the care of children and adults with CCHS is key to the successful management of these patients. This team working with the patient and the family may include pediatricians, med-peds physicians, pulmonologists, cardiologists, intensivists, ENT physicians, surgeons, gastroenterologists, neurologists, ophthalmologists, oncologists, psychologists, psychiatrists, respiratory therapists, nurses, social workers, speech and language therapists, special education teachers, and more.

A high index of suspicion, early detection, and aggressive conservative intervention are critical to optimize neurocognitive outcome and quality of life for individuals with CCHS and LO-CCHS. If inadequately treated, the affected individuals will likely suffer neurocognitive compromise and potentially sudden death. If treated conservatively and followed comprehensively, individuals with CCHS can have a good quality of life and an anticipated normal life span.

What are the adverse effects associated with each treatment option?

Although oxygen administration without artificial ventilation improves the PaO2 and relieves cyanosis, this treatment is inadequate as hypoventilation persists and pulmonary hypertension ensues. Thus, positive pressure ventilators via tracheostomy, non-invasive positive airway pressure, negative pressure ventilators, or diaphragm pacing are more appropriate options for these patients.

Because mask ventilation has been associated with mid-face hypoplasia when introduced from infancy or early childhood, mask ventilation should be used with extreme caution in young children with a malleable midface, which may be more prone to compression and deformation by a tight-fitting face or nasal mask. A Pediatric Plastic Surgeon and Orthodontist/Oral Surgeon should closely follow any child using mask ventilation.

What are the possible outcomes of congenital central hypoventilation syndrome?

With modern techniques for home ventilation, most children with CCHS can have prolonged survival with a good quality of life. The mortality rate and frequency of hospitalizations for CCHS is low in patients who are conservatively managed and followed in CCHS Centers of Excellence, though continuous vigilance is necessary in terms of home physiologic monitoring, equipment maintenance, and battery replacement in diaphragm and cardiac pacemakers.

As children with CCHS are advancing into adulthood, the development of transitional medicine programs in these Centers already caring for children with CCHS is essential.

What causes this disease and how frequent is it?

Congenital central hypoventilation syndrome (CCHS) is a rare disorder that affects females and males in equal numbers. Though the mutation is already present at birth, in milder cases the diagnosis may be missed until later in childhood or adulthood (LO-CCHS). Some affected individuals will not be identified until after receiving sedation, anesthesia, or anti-seizure medications.

As of 2010, approximately 1,000 cases are known worldwide with the vast majority diagnosed in the United States by the Chicago laboratories (PHOX2B Testing Without Walls at Ann and Robert H. Lurie Children’s Hospital/Northwestern University, Feinburg School of Medicine and Rush University Medical Center). The birth prevalence of CCHS is unknown as culturally diverse large population-based studies have not been reported. Because the milder cases of CCHS may go unrecognized or misdiagnosed, it is difficult to estimate the true frequency of CCHS in the general population at this time.

How do these pathogens/genes/exposures cause the disease?

While the exact mechanisms of PHOX2B mutations in causing CCHS are still being investigated, preliminary findings have identified several possible roles for these mutations in cellular dysfunction.

PHOX2B is a transcription factor with expression in early human embryos in both central autonomic neuron circuits and in peripheral neural crest derivatives. Mutations have been shown to cause reduced transactivation potential, protein misfolding and mislocalization, and protein aggregation in cellular models. It is likely that some of these mutations act through dominant negative effects, while others may simply cause disease through haploinsufficiency, thus explaining the variable expressivity of disease phenotype.

Other clinical manifestations that might help with diagnosis and management

Some individuals with CCHS have anatomic/structural malformations including Hirschsprung disease and tumors of neural crest origin. Overall, 16-20% of individuals with CCHS have Hirschsprung disease, but the risk is higher for those who have longer PARMs or who have NPARMs. Likewise, only individuals with large repeat expansion PARMs (specifically genotype 20/29 and 20/33 identified thus far; recall the normal genotype is 20/20 reflecting the number of alanines on each allele) and NPARMs have been identified with tumors of neural crest origin, including ganglioneuromas and ganglioneuroblastomas for the PARMs and neuroblastoma for the NPARMs.

How can congenital central hypoventilation syndrome be prevented?

The authors of the ATS Statement recommend prenatal PHOX2B testing in any fetus whose mother or father has PHOX2B mutation-confirmed CCHS, or who has a parent with mosaicism for the PHOX2B mutation, even if termination of pregnancy is not anticipated – in order to optimally plan for the immediate newborn care of the infant with CCHS. The authors also recommend testing of all parents of children with CCHS (with the
PHOX2B Screening Test, the only clinically available test show to diagnose low-level mosaicism) to ascertain mosaicism and risk of producing additional affected offspring.

What is the evidence?

Evidence for the diagnostic testing methods described here can be found in these articles:

Jennings, LJ, Yu, M, Rand, CM, Kravis, N, Berry-Kravis, EM, Patwari, PP, Weese-Mayer, DE. “Variable human phenotype associated with novel deletions of the gene”. Pediatr Pulmonol. vol. 47. 2012. pp. 153-161. (This study was the first to identify whole-gene and whole-exondeletions of the PHOX2B gene in patients with CCHS and patients with CCHS-like symptoms.)

Bachetti, T, Parodi, S, Di Duca, M, Santamaria, G, Ravazzolo, R, Ceccherini, I. “Low amounts of PHOX2B expanded alleles in asymptomatic parents suggest unsuspected recurrence risk in congenital central hypoventilation syndrome”. J Mol Med (Berl). vol. 89. 2011 May. pp. 505-13. (This study identified low level somatic mosaicism for CCHS-causing PHOX2B mutations in a in a subset of parents of CCHS patients, confirming a higher frequency of inherited mutations than previously reported.)

Jennings, LJ, Yu, M, Zhou, L, Rand, CM, Berry-Kravis, EM, Weese-Mayer, DE. “Comparison of PHOX2B testing methods in the diagnosis of congenital central hypoventilation syndrome and mosaic carriers.”. Diagn Mol Pathol. vol. 19. 2010 Dec. pp. 224-31. (This study compared methods of clinically available CCHS testing in detection of mosaicism in the PHOX2B gene, demonstrating that sequencing of this gene is not adequate for identification of low-level mosaicsm of CCHS-causing PHOX2B mutations.)

Weese-Mayer, DE, Berry-Kravis, EM, Ceccherini, I, Keens, TG, Loghmanee, DA, Trang, H. “American Thoracic Society Statement. Congenital central hypoventilation syndrome: Genetic basis, diagnosis, and management”. Am J Respir Crit Care Med. vol. 181. 2010. pp. 626-644. (This Statement was a collaboration between leading experts in CCHS and delineated current recommendations for diagnosis and treatment in CCHS.)

Ongoing controversies regarding etiology, diagnosis, treatment

To date there are no ongoing controversies regarding etiology, diagnosis, or treatment.