Diffuse neonatal hemangiomatosis (DNH) is a potentially fatal disorder where multiple benign (non-cancerous) blood vessel tumors (hemangiomas) are present in the skin and other organs. The mortality rate of diffuse neonatal hemangiomatosis is 50-90%. This disease is normally found in female Caucasian infants. The most common site of internal organ damage, or lesions, is the liver, which can redirect blood away from the heart and cause arteriovenous shunting. This can cause high cardiac output, leading to further complications such as congestive heart failure. This condition affecting the liver is also known as infantile hepatic hemangioma (IHH). Other sites of internal organ damage can include the intestines, nervous system, lungs, and sometimes the skeletal system. Early detection and treatment with steroids results in most newborn babies with this disease remaining healthy, with serious problems developing for some individuals during the hemangioma's growth phase.

Diagnosis

Newborn babies with multiple cutaneous hemangiomas or large facial hemangiomas are associated with a greater likelihood of internal organ involvement. These infants should be carefully observed and have abdominal screenings to rule out internal organ involvement, with additional brain ultrasonography and Doppler studies if needed. Liver involvement complications such as high-output heart failure include signs and symptoms such as tachypnea, hepatomegaly, jaundice, diaphoresis, and nasal flares.

Differential Diagnosis In the past, the diagnosis of "diffuse neonatal hemangiomatosis" included both infantile hemangioma (IH) and multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT). With advances in medicine and vascular anomalies, there is now a differentiation between the diagnosis of IH, which is benign, and MLT, which has a high mortality rate. Because of this misdiagnosis of MLT as DNH, it is believed that DNH has lower mortality rate than the report 50-90% that it is currently believed to have.

In a literature review of 73 cases of DNH that have been reported, many of these reports classified diffuse neonatal hemangiomatosis as other multifocal vascular abnormalities such as multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT). It is important to have an accurate diagnosis and reference the correct data in order to administer adequate treatment for individuals.

Mechanism Cutaneous hemangiomas are non-cancerous tumors that are commonly present at infancy, affecting around 4-10% of newborns. Around 80% of these hemangiomas stay as a single lesion, or tumor. However, when the presence of multiple lesions (hemangiomatosis) have involvement in both skin and with other organs of the newborn, this condition is called diffuse neonatal hemangiomatosis. Multiple cutaneous hemangiomas or large facial hemangiomas are associated with a greater possibility of multiple organ involvement, or internal hemangiomatosis. The liver is the most common organ involvement in diffuse neonatal hemangiomatosis, and its involvement can be determined through imaging and presence of hepatomegaly, or enlarged liver. The multiple lesions on the liver cause arteriovenous shunts, causing high-output heart failure and pulmonary hypertension as compensation.

Classifications Hepatic hemangiomas have three different classifications that help improve management and risks. The three types include focal, multifocal, and diffuse.

Focal hepatic hemangiomas are large tumors that are present at birth and not associated with skin lesions. In addition, they remain solitary and do not express the glucose transporter 1 channel (GLUT-1), which is found in hemangiomas on the skin. Focal hemangiomas can resolve without treatment.

Multifocal hepatic hemangiomatosis have GLUT-1 expressed as multiple lesions, often having no symptoms or complications. A percentage of these hemangiomatosis will result in high-output heart failure.

Diffuse hepatic hemangiomatosis is classified as a large replacement of the functional tissue of the liver with hemangiomas. Generally, these newborns will suffer from signs and symptoms of hepatomegaly, as well as respiratory complications. This classification has also been associated with hypothyroidism, which can also contribute to heart failure in the newborn. Diffuse hepatic hemangiomatosis carries a poor prognosis and high risk of mortality.

Epidemiology

The cause of IH is not completely clear and infants often do not show signs of IH when discharged after birth. However, several risk factors may be associated with the development of IH, with the most important risk factor being low birth weight. One study showed that for every 500 gram decrease in normal birth weight, there was a 40% increased risk of having an IH. Other risk factors include the sex, including individuals with female infants, being more likely to develop an IH, multiple gestation pregnancy, antenatal vaginal bleeding, and advanced maternal age. Traditionally, IH was viewed as a sporadic disorder, but continuous research has seen that genetic predisposition may play a role in individuals who develop IH.

Hepatic hemangiomas

Hepatic hemangiomas are the most common site for internal organ damage. Hepatic hemangiomas may be difficult to identify, because it can be inaccurately diagnosed as a hyper-vascular malignancy. These malignancies can live alongside other liver tumors such as hepatic cysts, hepatic angiosarcoma, focal nodular hyperplasia, and a myriad of others. Hepatic hemangiomas are usually small and discovered by chance when looking at the liver with an ultrasound, MRI, or other medical scans. Normally, these hepatic hemangiomas are seen on the right lobe of the liver.

In many circumstances, infants with multiple marks on the skin have hepatic hemangiomas. One retrospective review followed 26 infants between 1996–2007 to evaluate the management of hepatic hemangiomas and whether the infants required more complex treatment methods. The infants were classified as having either focal (8), multiple (12), or diffuse (6) lesions, or injuries. All of the infants who had multiple or diffuse injuries were assessed and screened for congestive heart failure and hypothyroidism, in which four patients later developed congestive heart failure. During the review, nine infants required treatment with steroids, and three infants received additional treatment with alpha-interferon after poor response to the steroids. The review concluded that individuals with multiple marks on the skin required screening for hepatic hemangiomas, and individuals with multifocal or diffuse liver hemangiomas required screening for heart failure and hypothyroidism to determine the most effective treatment method. In addition, the condition of an individual's injuries can indicate whether hepatic hemangiomas are present and if extensive treatment is needed.

Another retrospective review followed 25 infants over a span of ten years with a serious case of hemangiomas, which could even be life-threatening. 68% of the infants displayed an injury in the blood vessel to indicate a hemangioma. 23 out of the 25 infants were given corticosteroids to treat their condition with a range of responses from complete failure to rapid improvement. 30% of the infants given corticosteroids failed the treatment while 30% of the infants saw dramatic improvement in their condition. Out of the 25 infants, three of the infants were diagnosed with hepatic hemangiomas and were associated with cardiac failure and a high mortality rate. In the end, the three infants with hepatic hemangiomas died due to the high mortality.

Intracranial hemangiomas

The patient was suspected to have a fetal brain tumor found through a prenatal ultrasonography when the mother was at 39 weeks gestation. Three weeks later, the ultrasonography showed a light mass on the fetus' frontal lobe. This tumor had no blood flow going to it as seen by the color sonography. The mother had a normal medical history and no hereditary condition.

The infant was 3.1 kg and had normal movement. With a CT scan, it was found that there was cranial edema, and a round mass in the frontal lobe. At birth, there was no skin discoloration. However, six days later, the skin discoloration was found on the abdomen and right scrotum. Additionally, at day six, a four-centimeter hepatic mass was found on the left lobe. On days 13 and 17, a hepatic hemorrhage was found on the left lobe, and the right lobe was damaged as well. The CT scan also found damage to the paraspinal muscles. Then, the provider decided to give the infant propranolol 3 mg/kg/day.

The baby was not taken in for a second round of treatment until two months and 22 days later. The tumor noticeably shrank to cysts; however, the biggest cyst was at the frontal lobe. A myriad of lesions were still found on the thalamus, pons, cerebral hemispheres, cerebellum, and choroid plexus. It was then the radiologist diagnosed the patient with diffuse neonatal hemangiomatosis. At nine months, the patient experienced loss of brain tissue due to the shrunken tumor.

Second to the liver, the brain is the most common place for diffuse neonatal hemangiomatosis. With that being said, there have only been only 16 cases of cranial hemangioma. Nine out of the total 16 cases undergo neurological manifestations. With damage to the brain, the skin red discolorations are usually 0.5–1.5 centimeters.

As emphasized before, it is rare to have a fetal brain tumor. With intracranial hemangiomas, hemorrhages are seen frequently. Since shrinkage of organs, otherwise known as involution, is found with cutaneous hemangioma, it can be said that involution can be used to help diagnose diffuse neonatal hemangiomatosis.

Finally, there is no set therapy or treatment for intracranial hemangioma. For now, small damages are only observed due to the expectation of shrinkage. Oral steroids, vinscritine, thalidomide, temozolomide, propranolol, interferon, and bevacizumab can be used to combat intracranial hemangioma. Propranolol is the most common treatment, although it is not established as a standard treatment. It is essential to follow up three months after the diagnosis of intracranial hemangiomas.

Treatments

Oral Corticosteroids Oral corticosteroids are the primary treatment for hemangiomas, especially in those that have accompanying complications such as respiratory and cardiac issues. The initial discovery of the effectiveness of corticosteroids occurred when administered to a child with thrombocytopenia, and, as a result, the size of the hemangiomas decreased. Corticosteroids that are often used include Prednisone or Prednisolone, and the average dosing is 2–3 mg/kg given daily in the morning. However, the dosing can vary based on the severity of the illness present. The exact mechanism of action is not entirely understood, but it has been proposed that the constriction of blood vessels and prevention of new blood vessel formation could be contributing to its efficacy. Some common side effects can be mood changes, elevated blood pressure, swelling of the face, weight gain, and stomach upset. If the corticosteroid treatment is effective, there should be a noticeable stopping of growth or decrease in size of the hemangiomas after two weeks. Although, stopping the growth of the hemangiomas is more commonly seen. The ineffectiveness of treatment or disruptive side effects have led to the pursuit of other secondary treatments.

Cyclophosphamide