ROHHAD Syndrome

ROHHAD syndrome is an extremely rare and life-threatening disorder that causes previously healthy children to suddenly gain dramatic amounts of weight, develop serious breathing problems, and experience multiple body system failures. With fewer than 200 documented cases worldwide, this mysterious condition poses unique challenges for families and doctors alike.

Table of contents

• What is ROHHAD syndrome?
• Symptoms and hallmark features
• What causes ROHHAD syndrome?
• Complications and associated conditions
• How is ROHHAD syndrome diagnosed?
• Treatment and management
• Outlook and prognosis

What is ROHHAD syndrome?

ROHHAD syndrome is an extremely rare and life-threatening disorder that affects multiple body systems in children. The name ROHHAD is an acronym that describes the main features of the condition: Rapid-onset Obesity, Hypothalamic dysregulation, Hypoventilation, and Autonomic Dysregulation^[1].

This condition affects a child’s endocrine system (which controls hormones), autonomic nervous system (which controls automatic body functions like breathing and heart rate), and breathing. Before symptoms begin, children with ROHHAD syndrome usually have completely normal health with typical growth and development^[1].

ROHHAD syndrome was first described in 1965 and remains a fairly new condition in medical literature. To date, there are fewer than 200 documented cases of ROHHAD syndrome worldwide, making it one of the rarest medical conditions^[1][3]. Because of its extreme rarity, ROHHAD is classified as an “orphan disease,” which typically means it affects fewer than 1 in 2,000 people^[3].

Symptoms and hallmark features

Children may develop ROHHAD syndrome up to age 9, but most children start showing signs between ages 2 and 4. The first symptom usually appears between ages 1.5 and 7 years^[1][4].

Rapid-onset obesity

The rapid-onset obesity aspect of ROHHAD is usually the first diagnostic indicator of the disease. This refers to dramatic and rapid weight gain with an associated increase in appetite. Children typically gain 20 to 30 pounds over a period of just 6 to 12 months. One real patient’s weight jumped from the 25th percentile to the 99th percentile in just six months^[1][4][5].

ROHHAD affects the child’s metabolism, making it extremely difficult to lose weight. Children must carefully watch everything they eat and exercise regularly just to maintain an overweight status^[17].

Hypothalamic dysregulation

The hypothalamus is a part of the brain that controls the pituitary gland and regulates several important body functions including growth, weight, appetite, puberty, emotions, and behavior^[1].

When hypothalamic dysregulation occurs, children may develop a variety of symptoms including obesity, short stature, seizures, developmental delay, too much or too little urination, and early or late puberty. They can also develop hypothyroidism (low thyroid hormone) and diabetes^[1].

Other signs include abnormal sodium balance in the blood (either too high or too low), high prolactin levels (a hormone), low cortisol levels, irregular temperature regulation, and diabetes insipidus (a condition causing excessive urination and dilute urine)^[4][14].

Sodium imbalance within the body can have severe symptoms and be potentially life-threatening if not controlled. Low sodium levels can cause nausea, headache, seizures, or even coma. High sodium levels can cause nausea, muscle weakness, altered mental status, or coma^[4].

Hypoventilation

Hypoventilation is abnormally slow or shallow breathing that does not adequately meet the body’s needs. Children with ROHHAD cannot properly regulate their breathing. Their body does not automatically take deeper or faster breaths when oxygen levels are low and carbon dioxide levels are high^[1].

This breathing problem is present during sleep in all children with ROHHAD, and in more severe cases, it occurs while awake as well. ROHHAD essentially shuts off the part of the brain that controls automatic breathing. In children with ROHHAD, this can often first appear as respiratory failure from a mild respiratory illness such as a cold or following anesthesia^[1][4].

Autonomic dysregulation

The autonomic nervous system controls basic body functions that happen automatically, like breathing, digestion, heart rate, and body temperature. When this system malfunctions, children can develop various symptoms^[1].

Common signs of autonomic dysregulation include:

• Bradycardia (abnormally slow heart rate)
• Decreased body temperature and cold hands and feet
• Reduced sensitivity to pain
• Abnormal sweating (either too much or too little)
• Abnormal blood pressure regulation
• Decreased or increased stomach motility leading to chronic constipation or diarrhea^[2][4]

What causes ROHHAD syndrome?

Experts do not know what causes ROHHAD syndrome. The condition remains one of the great medical mysteries. However, there are three main theories being investigated^[1]:

Genetics: Many researchers believe a genetic mutation causes ROHHAD syndrome. However, so far they have not identified a specific gene responsible. Research continues to look for genetic causes, but it remains very limited^[1][3].

Epigenetics: Some researchers believe that genes which manage certain body functions can turn on and off. A research study on identical twins, where one developed ROHHAD syndrome and one did not, supports this theory^[1].

Autoimmunity: Some research studies link autoimmune diseases to ROHHAD syndrome. One study found special proteins called immunoglobulins in the cerebrospinal fluid (the fluid surrounding the brain and spinal cord) of two children with ROHHAD. Researchers used this information to identify inflammation in the central nervous system (brain and spinal cord)^[1].

The exact cause of ROHHAD syndrome is still unclear, but experts believe that it may be a type of autoimmune condition called a paraneoplastic disease. The theory is that the immune system attacks a patient’s own organs, particularly the brain and adrenal glands^[2].

It is likely that ROHHAD syndrome is not one single condition, but a collection of similar conditions with different causes, which would explain the wide range of symptoms and severity seen in different children^[3].

Complications and associated conditions

In addition to the hallmark symptoms, children with ROHHAD syndrome may develop several serious complications^[1][2]:

Behavioral and cognitive issues

Many children experience mood and behavioral conditions that cause symptoms like irritability, emotional outbursts, cursing, spitting, and other challenging behaviors. Some children may also have cognitive challenges and developmental concerns. However, some children with ROHHAD have normal cognitive development and intelligence^[1][2][4].

Some children develop flat affect personality disorder and selective mutism^[14].

Eye abnormalities

Abnormal eye movement or pupil size can occur. Common problems include strabismus (lazy eye) and astigmatism^[2][14].

Seizures

Some children with ROHHAD syndrome experience seizures^[2].

Neuroblastic tumors

About half of children with ROHHAD syndrome develop tumors called neuroblastic tumors. These tend to be relatively benign (not cancerous) and treatable. The most common types are ganglioneuromas or ganglioneuroblastomas, which are tumors with neural crest origin. These tumors are rare and can be found in the chest or abdomen, or anywhere along the sympathetic nervous system chain, and can develop at any age^[2][4][10].

When tumors are associated with ROHHAD, the condition is sometimes called ROHHADNET, with “NET” standing for neuroendocrine tumor^[7].

Cardiorespiratory arrest

The most serious complication is cardiorespiratory arrest (when the heart and breathing stop), which may be fatal. This risk makes ROHHAD an extremely dangerous condition. ROHHAD is fatal in 50 to 60 percent of cases when undiagnosed and untreated, due to cardiopulmonary arrest secondary to untreated hypoventilation^[2][4][10].

How is ROHHAD syndrome diagnosed?

Because ROHHAD syndrome is so rare, it can be very challenging to diagnose. There is no specific test or genetic marker for ROHHAD. Diagnosis is based on clinical signs and symptoms, which can be challenging and may be delayed or unrecognized. Probably 95 percent of doctors and healthcare providers will never hear about ROHHAD^[1][10][14].

To be diagnosed with ROHHAD syndrome, a child must have symptoms such as rapid-onset obesity, hypoventilation during sleep and sometimes while awake, and signs of hypothalamic dysfunction, such as hypothyroidism or early or late puberty^[2].

Your child’s doctor will perform a physical exam and ask about their medical history and symptoms. The doctor may also recommend testing to rule out other genetic syndromes, including a condition called congenital central hypoventilation syndrome (CCHS), which has some similar symptoms. Clear distinction from CCHS is provided on a genetic basis, as CCHS involves a mutation of a gene called PHOX2B, which is not present in patients with ROHHAD^[2][7].

The doctor may recommend several tests including^[2]:

• Blood tests to check hormone levels, sodium levels, and other markers
• Sleep study to assess breathing during sleep
• MRI (magnetic resonance imaging) to look at the brain
• Spinal tap to examine cerebrospinal fluid
• Heart monitor to track heart rhythm
• Specialized antibody tests
• Imaging tests to look for tumors

Researchers at Boston Children’s Hospital have identified a possible marker of the disease in the blood and spinal fluid of patients with ROHHAD syndrome, which may be helpful in determining the diagnosis in the future^[2].

Treatment and management

There is no specific test or treatment for ROHHAD syndrome. There is no cure. Healthcare providers manage the condition by addressing each individual symptom. Treatment requires a team of specialists who can address the child’s specific symptoms^[1][3].

Treatment plans for ROHHAD vary depending on each patient’s symptoms. Management is largely supportive and focuses on^[10]:

Breathing support

All children with ROHHAD develop hypoventilation that requires treatment. Many children need mechanical ventilation to help them breathe, especially during sleep. Some children require ventilation only at night, while others need support around the clock. A tracheostomy (a surgical opening in the throat to insert a breathing tube) is often necessary, along with a ventilator machine^[4][17].

Children with tracheostomies need regular suctioning at least three times a day to remove mucus and keep the airway clear. This involves inserting a small tube attached to a machine down the hole in the throat to pull out any mucus^[17].

Hormone replacement

Doctors treat specific hormone problems as they develop, which may include thyroid hormone replacement, growth hormone treatment, medications for diabetes insipidus, and other hormone therapies^[7].

Weight management

Managing obesity is extremely challenging in ROHHAD. Children require careful monitoring of diet and exercise, though weight loss is very difficult due to the metabolic effects of the condition^[17].

Autonomic symptom management

Various medications may be used to manage symptoms like abnormal heart rate, blood pressure problems, and gastrointestinal issues. In some cases, a pacemaker may be needed for severe heart rhythm problems^[4].

Tumor treatment

If neuroblastic tumors are found, they may require surgical removal or other cancer treatments^[14].

Experimental treatments

Because an autoimmune origin has been postulated, some children have been treated with immunosuppressive agents like rituximab or high-dose chemotherapy with cyclophosphamide to “reboot” the immune system. These treatments have been used with variable benefit. One patient treated with experimental high-dose chemotherapy in 2013 showed no disease progression five years later, though symptoms present before treatment remained^[10][12][14].

Constant monitoring

Children with ROHHAD require constant supervision and monitoring. They always need to have a parent or nurse nearby in case of problems with their tracheostomy, ventilator, or need for suctioning or medications. They cannot sleep without being monitored. They are not able to go to school or participate in activities alone^[17].

Families must keep detailed charts tracking height, weight, lab results, oxygen levels, and clinical notes. Parents often become the primary medical decision-makers due to the rarity of the condition and lack of established treatment protocols^[14].

Outlook and prognosis

ROHHAD syndrome is associated with high morbidity and mortality. The mortality risk is between 50 and 60 percent, primarily due to cardiopulmonary arrest from untreated hypoventilation^[4][10].

The earlier the disease is diagnosed and treatment starts, the better a child’s prognosis. Early diagnosis is important, as without intervention, ROHHAD is associated with high morbidity and mortality^[1][10].

No survival has been reported from the third decade of life, and until recently, there had been no reports of diagnosis among older adults. However, one case was recently documented describing a mature adult patient with features consistent with ROHHAD diagnostic criteria, representing a possible new variant of the condition^[6].

Because there is no cure, children with ROHHAD face lifelong challenges. They are dependent on electricity for life-saving equipment like ventilators and monitors. Travel is complicated, requiring sufficient battery life for equipment. Activities are limited due to the need for constant monitoring and ventilation support^[17].

Illness and injury are particularly frightening for families. When children get sick, they require increased oxygen and much more suctioning, with the constant fear of pneumonia. Stomach viruses are especially dangerous because vomiting could go directly into the lungs through the tracheostomy, potentially causing death within minutes from asphyxiation. Surgery is terrifying because if the anesthesia dose is too strong, the child may never wake up^[17].

This life-threatening condition needs greater awareness and understanding. With ROHHAD classified as an orphan disease, governments and pharmaceutical companies do not allocate research budgets to finding treatments or a cure. Several charitable organizations have been established to raise funds for research into ROHHAD^[3][11].