About haddad syndrome
What is haddad syndrome?
Congenital central hypoventilation syndrome (CCHS) is a rare disorder of respiratory control with autonomic nervous system dysregulation (ANSD). The autonomic nervous system is the portion of the nervous system that controls or regulates certain involuntary body functions including heart rate, blood pressure, temperature regulation, breathing, bowel and bladder control, and more. Impaired breathing regulation (respiratory control) is the hallmark of CCHS. Individuals with CCHS typically present in the newborn period with inadequate 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 called Late Onset Congenital Central Hypoventilation Syndrome (LO-CCHS).
All individuals with CCHS have a mutation in the PHOX2B gene. The PHOX2B gene plays an important role in the development of the Autonomic Nervous System (ANS). The normal PHOX2B gene has a section with 20 repeats of a code for the amino acid, alanine. For those individuals with CCHS, the majority (~90%) have a mutation causing an increase in the number of these alanine repeats. This is called a polyalanine repeat expansion mutation (PARM). The remaining individuals with CCHS have a different type of abnormality in the PHOX2B gene. These other mutations in the PHOX2B gene are called a non-polyalanine repeat expansion mutation (NPARM).
What are the symptoms for haddad syndrome?
The hallmark of CCHS is reduced or shallow breathing due to dysregulation of the respiratory drive. In general, reduced and shallow breathing is most apparent in non–REM sleep, but breathing is also abnormal during REM sleep and wakefulness, although usually to a milder degree. Individuals with CCHS also cannot sense oxygen or carbon dioxide levels in their body, which results in discoloration of their skin and lips, indicating that oxygen levels in the body are low. Low oxygen levels can cause increased risk for organ damage, especially to the brain. Thus, it is important to optimize oxygenation and ventilation in these patients. Depending on the severity of CCHS, the degree of life-long ventilatory support can vary from sleep only to constant support.
Adequate ventilation is essential to ensure optimal growth and development of CCHS patients. Ventilation can be managed with a mechanical ventilator via tracheostomy or masks, or using phrenic pacemakers. Monitoring both oxygen saturations and CO2 using end-tidal capnography at home helps ensure adequate ventilation in all conditions (sleep, awake, during illness and growth spurts). The support of experienced at-home nursing care will help families continue functioning at home. Ventilatory needs vary greatly across mutations, and sometimes within the same mutation. Appropriate ventilation for each child is essential to ensure optimal developmental outcomes. Because of the CCHS patient’s inability to sense changes in CO2, as well as O2, supplemental oxygen alone is not adequate for treating the individual with CCHS, and can mask elevated CO2 levels when both are not monitored.
Cardiovascular system Cardiac asystoles (heart stops beating) have been noted in several PARM mutations, and should be monitored extensively and actively throughout CCHS patients’ lives. This can include, but not be limited to regular extended Holter monitoring, implantable loop recorders, etc. CCHS patients do not sense cardiac pauses and are often asymptomatic until a life-threatening event occurs (loss of consciousness, sudden death). Within the CCHS community, children across many PARM mutations have demonstrated need for cardiac pacemaker implantation, even at a young age.
Additional cardiovascular symptoms of CCHS include altered temperature regulation, altered heart rate variability, altered blood pressure regulation, and poor circulation that may only be apparent under stressors such as illness or surgery.
Digestive system Both PARM and NPARM CCHS patients can present with alterations in their digestive system. Mild symptoms can be reflux and poor upper GI motility. Other patients can present with Hirschsprung’s disease (HD). HD is more often present in NPARMs or higher PARM expansions. Reflux is often treated via medication, while poor upper GI motility may often be managed with therapy and altered diets. Surgical treatment is required for HD.
Ophthalmology Some children with CCHS have been identified with ophthalmological problems associated with CCHS. These include, strabismus, abnormal pupil dilation, the need to wear corrective lenses, as well as Marcus Gunn jaw-winking syndrome and absent or reduced depth perception. Management can range from corrective lenses, wearing sunglasses when outside to surgical procedures.
Endocrine system The endocrine system can be affected by mutations in the PHOX2B gene. The most commonly noted are growth hormone deficiency and congenital hyperinsulinemia.
Cancer Patients with CCHS can develop tumors of neural crest origin, such as ganglioneuromas, ganglioneurblastomas, and neuroblastomas. Treatment for these tumors involves surgery followed by chemotherapy, if needed.
The 2010 ATS Statement recommends that CCHS children with 20/29-20/33 PARM mutations as well as those with NPARMs should be screened at diagnosis of CCHS and with advancing age for neural crest tumors.
What are the causes for haddad syndrome?
The underlying cause of CCHS is a change (mutation) in the PHOX2B gene, a key player in the prenatal development of the nervous system. The majority of individuals with CCHS (~90%) have mutations in exon 3 of the PHOX2B gene that normally has a repeat of 20 alanines. These mutations cause an increase in the number of these alanine repeats from the normal 20 alanines to a range of 24 to 33 alanines and are called poly-alanine repeat expansion mutations (PARMs). The remaining individuals with CCHS have different mutations in the PHOX2B gene not related to PARMs including missense, nonsense, frameshift, or stop codon mutations. These are non-poly-alanine repeat expansion mutations (NPARMs). Both PARMs and NPARMs lead to impaired function of the PHOX2B protein, and the variations in these mutations result in the broad range of symptoms and differing degrees of severity encountered among individuals with CCHS.
CCHS is a dominant genetic condition, meaning only one PHOX2B gene needs to contain a mutation to result in the phenotypic presentation of CCHS. Although most genetic diseases are inherited from parents, the majority of CCHS cases are spontaneous in nature. The rate of inheritance of CCHS from a parent who has CCHS is believed to be 50%. Mosaic parents have been identified within the CCHS population, but this is still extremely rare. Parents who wish to have additional children after having a child with CCHS are encouraged to seek genetic counseling. PHOX2B mutations are stable in transmission from one generation to the next, but penetrance and phenotype can still vary significantly.
What are the treatments for haddad syndrome?
A multidisciplinary team approach to the management of CCHS is essential to ensuring proper ventilation and development of children with CCHS. Local children’s hospitals may be sufficient in the management of CCHS. In complex cases, CCHS specialists (listed below) can be found throughout the world and can be consulted, or seen for management of CCHS. Primary team members who play an active role in patient management should include: the primary caregivers (parents or family members), pulmonologists, cardiologists, ENT physicians, gastroenterologists, endocrinologists, neurologists, ophthalmologists, social workers, and speech/language pathologists (SLPs).
Early detection and management of CCHS with adequate ventilation and appropriate therapies have helped CCHS patients live fulfilling lives. Proper management has allowed CCHS patients to seek higher education, enter the work force and have families of their own
Please refer to the Signs and Symptoms section for additional information.
Clinical Testing and Work-Up The 2010 American Thoracic Society (ATS) statement on CCHS recommends that CCHS patients undergo annual assessment of spontaneous breathing awake, as well as during sleep in a pediatric respiratory physiology laboratory. At minimum, a 72-hour Holter study should also be performed annually to evaluate for cardiac pauses, pauses greater than 3.0 seconds should be assessed for cardiac pacemaker implantation by a cardiologist. An echocardiogram, hematocrits, and reticulocyte counts may also be needed to evaluate for signs of heart problems (cor pulmonale) that occur as a consequence of inadequate ventilation. Consultation with a gastroenterologist (and possibly rectal biopsy) may be needed for patients with constipation to evaluate for Hirschsprung’s disease. In patients with PARM mutations 20/29 and higher, and patients with NPARM mutations, routine serial chest and abdominal imaging is crucial for detecting emergence of a neural crest tumor, specifically neuroblastoma (NPARMs) and ganglioneuroblastoma/ganglioneuroma (PARMs). Ophthalmologic testing may also need to be done in some patients to assess for ophthalmologic dysfunction.
What are the risk factors for haddad syndrome?
CCHS is a rare disorder that affects females and males in equal numbers. Though the mutation is already present before birth, in milder cases the diagnosis may be missed until after the newborn period. Some affected individuals will not be identified until after receiving sedation, anesthesia, or anti-seizure medications, making it especially important to educate health care personnel about CCHS and to have a high index of suspicion for considering a diagnosis of CCHS. As of 2013, more than 1,000 cases are known worldwide. The birth prevalence of CCHS has been extrapolated from incidence figures and general birth rates, but the true prevalence 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, though the anticipation is far greater than the current estimate.
Is there a cure/medications for haddad syndrome?
Normal breathing is impaired by Haddad syndrome, a condition. People with this illness frequently hyperventilate while sleeping, which causes a deficiency in oxygen and an accumulation of carbon dioxide in the blood.
The autonomic nervous system, which regulates unconscious bodily functions, would typically respond to such an imbalance by causing the person to wake up or breathe deeply. People with Haddad syndrome have a poor nervous system response. They require assistance from a mechanical ventilator or other equipment that induces a regular breathing pattern (diaphragm pacemaker). Some affected people require this help around-the-clock, while others only require it at night.
There is currently no cure for Haddad syndrome, but there are different treatments available. Using these treatments, symptoms can be managed.
There are some important treatments that are maintained below.
1. One of the most important treatments is using a ventilator or respirator.
2. The main goal of treatment is to sustain breathing frequently by using a ventilator or respirator.
3. Some Haddad syndrome children will require a ventilator 24 hours a day, while others may only require assistance with breathing while dozing.
4. A surgical implant in the diaphragm muscle can, in some people, enable electrical stimulation of the muscle to regulate breathing.
Poor breathing or no spontaneous breathing at all, especially when sleeping,Abnormal pupils,Acid reflux, and poor intestinal motility cause feeding difficulties,Absent or impaired bowel function
Brain tumors,Infections of the central nervous system,Encephalitis,Trauma, and the aftereffects of neurosurgical procedures are a few of the conditions that can result in acquired central hypoventilation