A Case of Blueberry Muffin Rash in a Newborn

A boy approximately 12 hours old presented for a previously arranged evaluation after a home birth with the complaint of purple bumps all over his body. The bumps are described as bluish nodular spots ranging in size from 3 mm to 1 cm in diameter. Several dozen are located on the face, trunk, groin, and back, with the highest concentration being on the face (Figure 1). These abnormalities were noticed immediately following delivery and have not changed. The patient has received no medications or vaccinations including hepatitis B vaccination, erythromycin eye prophylaxis, or vitamin K. He is breastfeeding.The patient was born weighing 3820 g (50th percentile). The patient’s length was 20 in (50th percentile) and head circumference was 13.75 in (30th percentile). Apgar scores were 9 and 10 at 1 and 5 minutes, respectively. It is stated that he was stable after delivery. His mother is a 39-year-old G4P3 female. The pregnancy was uncomplicated, as were labor and delivery. Rupture of membranes occurred approximately 5 minutes prior to vaginal delivery. Amniotic fluid was stated to be clear. The mother tested negative for group B streptococcus and is immune to rubella. Her rapid plasma reagin and venereal disease research laboratory tests are negative. Hepatis C and HIV tests are both negative as well. The mother’s blood type is O+. She had no known infections and took no medications during pregnancy, but she did receive a tetanus booster at 32 weeks’ estimated gestational age following a puncture with a fishing hook. Her 3 older children are healthy. Pets at home include a dog, turtle, and fish.At the time of presentation to the office, the baby had a temperature of 37.4 °C and a respiratory rate of 60. He was alert. The anterior fontanelle was open and flat. The ear, nose, and throat examination was normal. His lungs were clear to auscultation. There was intermittent grunting and mild nasal flaring but no chest retractions. Cardiac examination revealed a regular rate and rhythm and no murmurs. The abdomen was soft and nondistended with no palpable mass. Healthy male genitalia were present with testes descended bilaterally. The extremities were well formed with a normal range of motion. The neonate was grossly intact on neurologic examination. There was no palpable lymphadenopathy. Mucous membranes were moist and without lesions.Skin examination revealed several dozen nodular and flat bluish nonblanching lesions. The lesions ranged in size from 3 mm to 1 cm with distribution on the face, trunk, groin, and back. The largest lesion was on the chin. The findings from the skin examination revealed the appearance of a “blueberry muffin” rash.The patient was discussed with the neonatal intensive care unit team at the local pediatric medical center and referred immediately for care and workup. The workup revealed 58 bluish-gray lesions from the head to the extremities. The highest concentration of lesions was present on the scalp, and the largest was a raised lesion of 1.5 cm in diameter on the chin. Several lesions were biopsied. Initial complete blood cell count (CBC) was completed (Table 1). Electrolytes and renal function were normal. Lactate dehydrogenase was 1228 (reference range, 170–580), and urate was 1.5 (reference range, 1.8–5). The neonate’s blood type is O+, and the Coombs test result was negative. The urine cytomegalovirus (CMV) test result was negative ×2.Differential diagnoses for blueberry muffin rash presenting in the newborn include congenital rubella, along with other congenital infections such as CMV, herpes virus, and toxoplasmosis. These congenital infections are typically grouped together and referred to as TORCH infections. Other differentials include neuroblastoma, congenital hemangioma, and congenital leukemia. Petechia and purpura also resemble blueberry muffin rash and can indicate neonatal thrombocytopenia. Furthermore, bruising due to a lack of vitamin K administration following home birth may also be a consideration; however, the lesions in this baby were present immediately following birth and the birth was noncomplicated.Congenital rubella syndrome (CRS) may present in fetuses born to mothers infected with Rubella virus during their pregnancy. Although rare in countries with effective vaccination programs, CRS can cause significant morbidity and mortality. Presentation and outcomes in the neonate depend on when during pregnancy the mother is infected with Rubella virus. If infected during the first trimester, there is an 80% risk of congenital abnormalities in the neonate.1 Risk of transmission to the fetus is slim if the mother contracts the illness during the second or third trimesters due to developing fetal immune system and transfer of maternal antibodies. The most common presentation of CRS in the newborn includes cataracts and a diffuse purpuric rash. The rash is so common and striking that the term “blueberry muffin rash” was first used to describe rubella in the neonate.2 After a few months, infants typically develop diarrhea and pneumonitis, and the long-term sequalae of sensorineural deafness and cardiovascular anomalies become apparent. In some rare and fatal cases, infants may develop panencephalopathy.3 Diagnosis of CRS is dependent on a mother’s not being immune to rubella followed by isolation of rubella-specific immunoglobulin M in the neonate. CRS was ruled out in our patient because the mother was immune to rubella. Other TORCH infections that may present with blueberry muffin rash include CMV, herpes virus, and toxoplasmosis, all of which were ruled out by laboratory workup on initial hospitalization.Congenital neuroblastoma may also present with skin lesions in the newborn, specifically subcutaneous nodules that appear blue beneath the skin. Lucky et al suggest that blanching cutaneous nodules are a unique finding in congenital neuroblastoma and may be the first sign of disease.4 Furthermore, D’Souza et al describe a case of “multiple shiny, pinkish purple nodules all over the body in addition to the bluish subcutaneous nodules” in a neonate diagnosed with congenital neuroblastoma.5 Congenital neuroblastoma is distinct from infantile neuroblastoma and accounts for only 5% of total yearly diagnoses of neuroblastoma cases.6 Neuroblastoma can have a wide variety of presentations including tumors of the adrenal glands that may cause dysautonomia or tumors in the spinal cord that can cause weakness or paralysis. The prognosis of the disease largely depends on the location of the tumor. The prognosis for tumors limited to subcutaneous tissue is generally good. Congenital neuroblastoma is diagnosed through biopsy. “Microscopically, the tumors are composed of sheets of small cells with hyperchromatic nuclei and scanty cytoplasm. These tumors frequently have a lobular appearance owing to the presence of thin fibrovascular septa between groups of tumor cells.”7 Congenital neuroblastoma was ruled out with his biopsy result.Congenital hemangioma was also considered in the differential diagnosis. Although often solitary, they present as round or oval vascular nodules with overlying telangiectasias or venules. Unlike infantile hemangiomas, congenital hemangiomas are present at birth as their proliferation occurs in utero. They may be rapidly involuting and regress in the first few months of life or may be nonrapidly involuting and persist and grow with the patient.8 The prognosis is normally good; however, large, persistent hemangiomas must be watched closely and periodically imaged to ensure that there is no visceral involvement that may compromise the airway, central nervous system, or other critical structures. Diagnosis is through biopsy with histopathology showing “lobules of congested capillaries with intervening fibrous stroma involving the mid to deep dermis.”9 Congenital hemangioma was ruled out in our patient based on his biopsy results. Additionally, the findings of computed tomography (CT) scans of the head, thorax, abdomen, and pelvis were negative for hemangiomas.The biopsy of the lesions was consistent with congenital leukemia. Additional bone marrow aspirate and biopsy followed by genetic testing confirmed the diagnosis of myelomonocytic leukemia cutis.Congenital leukemia cutis is a rare malignancy that occurs at a rate of 1 per 5 million births and accounts for less than 1% of cases of childhood leukemia.10 The disease presents as a blueberry muffin rash. This rash of congenital leukemia cutis may be an isolated finding, or it may be a dermatologic finding of systemic leukemia. When systemic disease is present, either acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), the cutaneous findings are often accompanied by hepatosplenomegaly, lymphadenopathy, and central nervous system involvement.11 In rare cases when the disease is limited only to the skin, it is called aleukemic leukemia cutis.12 In this rare case of aleukemic leukemia cutis, leukemic cells are located in the skin biopsy alone. Although congenital leukemia cutis is a rare malignancy, the clinical finding of blueberry muffin rash is the presenting sign in about half of the cases of neonatal leukemia, and thus it is important for the clinician to consider this as a differential diagnosis.13Blueberry muffin rash presents as violaceous nodules affecting any area of the skin but often sparing palms and soles. In the case of congenital leukemia cutis, these lesions are caused by an infiltration of the skin by leukemic cells.14 In aleukemic leukemia cutis, skin manifestations may be due to metastatic infiltration of the skin with primary bone marrow involvement that becomes undetectable after birth. It may also involve embryonic hematopoiesis in undifferentiated mesenchyme.15 Erythropoiesis normally occurs in the dermis during the first to fifth months of gestation. During this time, dermal pluripotent mesenchymal cells maintain hematopoietic capabilities.15,16 Causes of congenital leukemia are yet undefined, but increased risk has been demonstrated following maternal radiation exposure, maternal exposure to bioflavonoids in the diet, and maternal alcohol and marijuana use.17 Association with inherited syndromes such as Noonan syndrome and Down syndrome have also been reported.18Diagnosis of congenital leukemia cutis is confirmed by skin biopsy, often followed by bone marrow biopsy. Histopathological analysis of skin lesions of leukemia cutis reveals several different patterns of infiltration. “Most commonly, a dense diffuse dermal infiltrate of pleomorphic leukemic cells is observed in a linearly array between collagen bundles in the reticular dermis. Alternatively, bandlike or compact nodular infiltrates may be seen.”15 Bone marrow findings are variable. In cases of isolated aleukemic leukemia cutis, the bone marrow reveals less than 5% blast content, which is considered normal. In cases of systemic leukemia, blast content is greater than 20%. Following skin and bone marrow biopsies, genetic testing is paramount because chromosomal instability is a hallmark of congenital leukemia. The most common mutation involves the mixed-leukemia lineage (MLL) gene. Specifically, a translocation at 11q23 is involved in the majority of cases.19 Although there is no consensus on prognostic factors, the presence of the 11q23 translocation is often associated with worse outcomes.20 Outcomes range from complete and spontaneous resolution to rapid progression, systemic involvement, and death.When systemic leukemia is diagnosed, chemotherapy is the treatment of choice. Neonatal ALL is more common than neonatal AML; however, AML has a better prognosis.13 Even with chemotherapy, the survival rate for neonatal ALL is reported to be as low as 26% and there is significant morbidity and mortality due to the intensity of drug treatment.15 When there is no blood or bone marrow involvement, as in the case of aleukemic leukemia cutis, patients may be managed conservatively without chemotherapy. Grundy et al advised that chemotherapy be withheld in newborns unless the 11q23 translocation is identified.21 Furthermore, Landers et al advise that patients presenting with suspected leukemia cutis be evaluated with skin biopsy, serologies, laboratory studies, peripheral smear, bone marrow aspirate, and cytogenetics. They concur with Grundy et al that in the absence of clear prognostic indicators, these patients with aleukemic leukemia can be watched for the fading of nodules and monitored for signs of systemic involvement.22 There are several reported cases of spontaneous resolution, with children going on to live normal lives.The mechanism of spontaneous remission is unclear, but there are several hypotheses. It may be that the lesions are not representative of a true leukemia but rather a transient myeloproliferative disorder. This hypothesis has fallen out of favor. Additional hypotheses include the idea that with such a low tumor burden, the immune system can successfully attack the malignancy, or the notion that the abnormal cells observed in the neonatal period have not yet acquired full proliferative capacity and still maintain a high rate of spontaneous apoptosis.23,24 Furthermore, it has been suggested that the maternal-fetal immune interactions be studied in search of an answer.25Biopsy was consistent with congenital leukemia. He was also diagnosed with transient tachypnea of the newborn (TTN). An initial chest x-ray revealed fluid in the fissures. He was monitored on room air for TTN. A bone marrow aspirate and spinal tap were performed looking for blasts. The bone marrow revealed 3.5% presence of myelomonoblasts, which is within normal limits. The findings of thoracic CT were negative for internal hemangiomas and otherwise normal. The findings of the CT scans of his head, abdomen, and pelvis were negative for hemangiomas or abnormal findings. Sepsis was ruled out. He developed slight jaundice that peaked at 12.4 at age 3 days. This was not treated with phototherapy. The baby was discharged at age 5 days with a plan to readmit the baby for further evaluation and discuss starting chemotherapy.Further consultation with a hematologist/oncologist at a different institution was pursued at age 9 days. The diagnosis of myelomonocytic leukemia was confirmed, and further genetic testing was performed. Fluorescence in situ hybridization testing on the bone marrow sample showed MLL to be intact, no trisomy or monosomy, and 7% of cells with a 7q deletion. The bone marrow appeared grossly normal without fibrosis but had a predominance of lymphoid-appearing cells, which were deemed likely hematogones by the oncology consultant. Although similar in morphology to blasts found in ALL, hematogones are normal B-lymphocyte progenitor cells. They are typically found at high levels in the bone marrow of infants and decrease with age.Lesions were fading at age 9 days. Although there was no consensus on prognostic factors, it was thought that should an MLL rearrangement be identified, consideration for prompt chemotherapy would be warranted. Given our patient’s specific genetic findings, it was decided to manage conservatively with surveillance.At age 3 weeks, a plan was formulated for close follow-up and to institute a regimen of the following: Weekly physical examinations to monitor for resolution of the skin lesions and assess for hepatosplenomegalyWeekly CBCs with differential until all skin lesions disappearedRepeat bone marrow aspirate at age 2 monthsThe parents reported that the follow-up bone marrow aspiration at age 2 months was normal, with resolution of the 7q deletion. The skin lesions slowly faded, with the chin lesion being the last to resolve by age 4 months. At this time, monitoring was extended to monthly intervals through the first year of life. The patient received routine well-child checks and immunizations; he continued to demonstrate healthy growth and development. At the time of writing, the patient is a healthy 16-year-old adolescent.