Congenital Central Hypoventilation Syndrome - A Case of Breathing Inadequacy

Introduction

Congenital central hypoventilation syndrome (CCHS), also known as Ondine’s curse, is a rare neurological disorder characterized by inadequate breathing when asleep and, in severe cases, even in waking hours. Individuals with CCHS possess an impaired nervous system. The malfunction is seen in the system that controls the involuntary nervous system and is also associated with abnormal embryonic development of the spinal cord. The term “Ondine curse” is derived from German folklore involving a curse by the nymph king on mortals such that they forget automatic bodily functions, like breathing.

Who Is Susceptible to Congenital Central Hypoventilation Syndrome?

CCHS is considered a rare disorder affecting about one in 200,000 live births in the US, with around 1000 children diagnosed worldwide as of date. The prevalence is believed to be higher after the introduction of screening measures for PHOX2B gene mutations. The condition shows no apparent racial predilection nor any gender predominance. As with its nomenclature, it is evident that the condition is present at birth, but the diagnosis may be delayed. Later onset of CCHS is seen in school-going children to adults as an abnormal ventilatory response to severe systemic infections, administration of anesthesia, or CNS (central nervous system) depressant during surgery.

What Is the Cause of Congenital Central Hypoventilation Syndrome?

CCHS is caused due to poly-alanine repeat expansion mutations in the PHOX2B gene, which encodes instructions for proteins responsible for the formation of neurons. These proteins are active in the neural crest during the early embryonic stage, give rise to various tissues and organs, and also regulate the differentiation of the neurons into specific functions. The protein migrates along with the neural crest cells to form the ANS (autonomic nervous system), parts of the face, skull, and other tissues and cells.

The mutation interferes with the protein’s role in neuron formation and differential, especially in the formation of ANS. This interference ultimately results in the dysfunction of various involuntary bodily functions, including breathing regulation, heart rate, blood pressure, and temperature. Some children have been diagnosed with CCHS with non-poly-alanine repeat expansion mutations of the PHOX2B gene. Both types of mutations are etiologic to CCHS.

What Is the Pathophysiology of Congenital Central Hypoventilation Syndrome?

The PHOX2B gene is composed of 20 repeated regions of alanine coding. The mutation is caused due to poly-alanine repeat expansion (PARM) or non-poly-alanine repeat expansion mutations (NPARM). Heterozygous PARM mutations increase the number of alanine repeats from 20 to a range of 24 to 33, most commonly 25, 26, and 27 repetitions. This is true for 90 percent of the CCHS cases. The rest ten percent of the cases are due to NPARMs, which can be of missense, nonsense, or frameshift mutations.

Studies have shown associations between the number of repetitions and the phenotype of the disease. 25-PARM cases usually do not require round-the-clock ventilation. 26- PARM require ventilatory support events during waking hours. Whereas 27 to 33 PARMS require all-time ventilatory support. Mild and late-onset CCHS have been associated with 24 and 25 repetitions. NPARM presents a more severe phenotype and requires all-time ventilation. These patients are also at high risk of having Hirschsprung disease and neural crest tumors. Frameshift mutations are the most common type of NPARMs, and the degree of shifts determines the type of CCHS; a two-step frame shift gives classical or isolated CCHS, whereas a single-step shift shows syndromic presentation like in combination with Hirschsprung disease and neural crest tumors. This syndrome is known as Haddad syndrome.

A transcriptional factor responsible for the development of the ANS is also encoded by the PHOX2B gene, a depletion of which leads to deficiency in the expression of genes like dopamine-β-hydroxylase (DBH), PHOX2A, and TLX-2. Mutated PHOX2B also interferes with the normal activity of other chromosomes.

What Are the Clinical Features of Congenital Central Hypoventilation Syndrome?

Since a heavy load of bodily functions is carried by the autonomic nervous system. CCHS can cause dysfunction of the various systems, including pulmonary, cardiac, and digestive.

Neonatal Onset CCHS Shows:

• Shallow breathing.

• Hypoventilation while awake or asleep.

• Abnormal ventilatory drive.

• Apnea.

• Central hypoventilation.

• Hypoxemia.

• Hypercarbia.

• Cyanosis.

• Seizure.

• Lack of physiologic responsiveness.

• Anxiety.

• Esophageal dysmotility.

• Constipation.

• Profuse sweating.

• Reduced body temperature.

• Diminished pupillary light response.

• Asphyxia.

• Hypotonia.

• Thermal lability.

Later-Onset CCHS Shows:

• Unexplained shallow breathing.

• Hypoventilation during sleep.

• Shallow breathing during sleep.

• Nocturnal hypercarbia.

• Nocturnal hypoxemia.

• Delayed recovery from a severe respiratory illness.

• Recurrent severe pulmonic infection.

• Sudden infant death syndrome.

Neurological Manifestation:

• Seizures.

• Neurocognitive delays or impairment.

Ocular Manifestations:

• Abnormal pupils.

• Miotic pupils.

• Anisocoric pupils.

• Abnormal response to light.

• Abnormal irides.

• Strabismus.

• Lack of tears during crying.

Cardiovascular Manifestations:

• Cardiac asystoles.

• Loss of consciousness.

• Altered temperature regulation.

• Altered heart rate variability.

• Altered blood pressure regulation.

• Poor circulation.

Gastrointestinal Manifestation:

• Gastric reflux.

• Poor upper gastrointestinal motility.

Endocrinal Manifestation:

• Growth hormone deficiency.

• Congenital hyperinsulinemia.

Cancers:

• Ganglioneuromas.

• Ganglioneurblastomas.

• Neuroblastomas.

How to Diagnose Congenital Central Hypoventilation Syndrome?

Recognition of clinical features is essential to establish a suspected diagnosis. The gold standard for diagnosing CCHS is to identify the mutations in the PHOX2B gene by molecular genetic analysis.

Other test orders for CCHS diagnosis are:

• Polysomnography to assess sleep-related gas exchange during sleep.

• Brain imaging by MRI (magnetic resonance imaging) to check for gray matter volume and the presence of primary or secondary lesions.

• Echocardiogram to assess baseline structural and functional cardiac activity.

• Comprehensive testing for neuromuscular disorders.

• Hypercoagulability work-up to verify clotting symptoms if imaging indicates the same.

• Complete blood counts to evaluate for polycythemia (secondary to hypoxia).

• Chest radiograph and CT (computed tomography) to evaluate for pulmonary disabilities.

How to Treat Congenital Central Hypoventilation Syndrome?

There is no absolute treatment for CCHS, and the management focuses on providing supportive care for the appeasement of the symptoms and managing the systemic dysfunctions. Based on the type and severity of CCHS, the patient may require ventilatory support for several hours to none. It is advised to follow up with specialists for imaging studies and analyses to look for tumors at least every six months. Periodic ophthalmic evaluation and endocrinal assessments are a must to manage the difficulties. Medications like prokinetic agents and antireflux medications for gastrointestinal problems are prescribed. Surgical gastrointestinal interventions may be required for severe cases, Hirschsprung disease, or distal intestinal obstruction.

Standard pharmaceutical approaches have failed to obtain results in providing respiratory stability and promoting eucapnia in patients. Progesterone and curcumin have shown some positive results. Invasive mechanical and noninvasive ventilator supports are implemented, keeping the patient’s needs in mind. Diaphragm pacing, tracheostomy for ventilatory support, colostomy for Hirschsprung, and gastrostomy tube placement may also be required in a few patients.

What Is the Prognosis of Congenital Central Hypoventilation Syndrome?

Mortality from CCHS is due to complications from long-term mechanical ventilation or from the extent of bowel involvement. Many individuals continue to thrive with artificial ventilation into the third or fourth decade of life.

What Is the Differential Diagnosis of Congenital Central Hypoventilation Syndrome?

• Apnea of prematurity.

• Aspiration syndromes.

• Assisted ventilation of the newborn.

• Childhood sleep apnea.

• Late-onset central hypoventilation syndrome.

• Obesity in children.

• Pediatric botulism.

• Pediatric obesity-hypoventilation syndrome.

• Rapid-onset obesity.

What Are the Complications of Congenital Central Hypoventilation Syndrome?

• Neuroblastoma.

• Ganglioneuromas.

• Ganglioneuroblastomas.

• Sudden infant death syndrome (SIDS).

Conclusion

Congenital central hypoventilation syndrome is a rare disorder with no apparent cure. But the patients can lead a fairly normal life to a certain extent. The management protocol involves a team of various specialists, including pulmonologists, neurologists, cardiologists, gastroenterologists, hematologists, otolaryngologists, social workers, and speech and respiratory therapists. A small number of patient deaths have also been recorded in patients indulging in substance abuse. Although difficult, it is not impossible to live normally.