What are the other Names for this Condition? (Also known as/Synonyms)

• NOCARH Syndrome (Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome)

What is Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome? (Definition/Background Information)

• Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome (NOCARH Syndrome) is a rare genetic disorder that presents at birth or early infancy. It is characterized by fever, rashes, chronic inflammation, cytopenias (low blood cell counts), failure to thrive, hepatosplenomegaly, and increased activity of the immune cells called histiocytes.
• Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome is caused by a mutation in the CDC42 gene that may be inherited; the inheritance pattern is presently unknown. This gene provides signals controlling many cellular processes, including cellular adhesion, migration, orientation, and proliferation. The inflammatory processes are also affected
• The specific abnormalities triggered by this variation of the abnormal CDC42 gene results in the signs and symptoms of Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome. These include recurrent fever, rashes on the skin, anemia, low white blood cell and platelet count, enlarged liver and spleen, and gastrointestinal issues
• The diagnosis of Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome is made by a combination of clinical findings, laboratory tests, and genetic testing for the presence CDC42 gene mutation. The treatment typically includes the use of anti-inflammatory and immunosuppressive medications to control the inflammation and prevent damage to the skin
• The prognosis of Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome varies depending on the severity of the disorder and how early it is diagnosed and managed. However, without early diagnosis and treatment, NOCARH Syndrome can lead to severe disability and even death

Who gets Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome? (Age and Sex Distribution)

• Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome is an extremely rare disorder with congenital manifestation. The term neonatal indicates that it begins in the first days and weeks of life
• It can affect both males and females
• As of 2020, only 5 cases have been reported (four cases were first reported in 2019, another case was reported in 2020

What are the Risk Factors for Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome? (Predisposing Factors)

• Currently, the only known risk factor for Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome may be having a family history of the disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome? (Etiology)

The cause of development of Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome (NOCARH Syndrome) is a mutation in the CDC42 gene.

• This gene provides instructions for many complex fundamental cell functions, some of which play a role in the immune system
• When this gene is mutated, it leads to the overproduction of inflammatory biochemicals, and other aberrant cell functions, resulting in the symptoms of NOCARH Syndrome
• The syndrome may be inherited (may run in families), although presently the manner of inheritance is unknown

There are other syndromes with mutations in the CDC42 gene that has hemophagocytic lymphohistiocytosis (HLH) and cytopenia as findings, as well as significant neurologic effects. However, NOCARH Syndrome does not routinely have severe uniform neurologic effects.

What are the Signs and Symptoms of Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome?

The signs and symptoms of Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome (NOCARH Syndrome) include:

• Recurrent fever
• Rashes 
• Gastrointestinal symptoms such as diarrhea
• Swollen lymph nodes (lymphadenopathy)
• Low red blood cell count or anemia
• Low white blood cell count (leukopenia)
• Low platelet count (thrombocytopenia)
• Hepatosplenomegaly (enlarged liver and spleen)
• Hemophagocytic lymphohistiocytosis (HLH): The overactive histiocytes aberrantly ingest and destroy red and white blood cells, which is termed HLH

HLH is seen in other syndromes besides NOCARH Syndrome. Untreated HLH in children and adults is fatal in not treated.

How is Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome Diagnosed?

• Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome is diagnosed by a combination of clinical findings and laboratory tests
• A blood test can help detect elevated levels of inflammatory markers and low blood cell counts
• Genetic testing can confirm the presence of a mutation in the CDC42 gene

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome?

Complications of Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome can include:

• Frequent infections
• Failure to thrive
• Developmental delays
• Bleeding disorder

Without intensive care and possibly bone marrow transplantation, the disorder may result in fatalities.

How is Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome Treated?

Treatment for Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome typically includes the use of anti-inflammatory and immunosuppressive medications to control systemic inflammation.

• Corticosteroids control the inflammation, but does not address bone marrow arrest/failure
• Interleukin-1 inhibitors (anakinra, rilonacept, and canakinumab) can help with symptoms, such as fever and rash, but does not affect the cytopenias (low blood cell counts)
• Emapalumab-Lzsg, an interferon gamma blocking antibody, is known to help control hemophagocytic lymphohistiocytosis
• Bone marrow transplantation was successful in stabilizing the disorder

How can Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome be Prevented?

Presently, it is not possible to prevent Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome as the cause is due to genetic factors.

• Genetic counseling and testing may be recommended for individuals with a family history of the disorder and couples planning to have children
• However, early diagnosis and appropriate treatment can help manage the symptoms and prevent complications

What is the Prognosis of Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome? (Outcomes/Resolutions)

The prognosis for Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome (NOCARH Syndrome) is generally unfavorable without early diagnosis and intensive care provided by a multispecialty team with advanced medical support.

• Without treatment, NOCARH Syndrome can lead to severe disability and death
• Of the four patients in the initial report of NOCARH, three died before age 1.5 years. The other survived after treatment with Emapalumab followed by bone marrow transplantation

Additional and Relevant Useful Information for Neonatal-Onset Cytopenia, Autoinflammation, Rash, and Hemophagocytosis Syndrome:

The following link is a useful resource for information on other rare conditions on DoveMed:

https://www.dovemed.com/diseases-conditions/rare-disorders/