Shining a TORCH on a Case of Blueberry Muffin Rash in a Newborn Infant

A female infant born at 37 weeks gestation to a G2P1 (gravidity 2 para 1) woman via cesarean section presents with hepatosplenomegaly and diffuse rash consisting of the following: petechiae; macules of variable size on legs, back, arms, and head; and violaceous firm, smooth nodules throughout the back, abdomen, and extremities, with the largest on the left posterior elbow and left knee (Figure 1A–C) resembling a “blueberry muffin” rash. This term is usually used to describe numerous, scattered, nonblanching, popular, or nodular blue to purple purpura in a neonate.1 The infant was admitted to the neonatal intensive care unit for advanced management and care.Pregnancy was significant for severe polyhydramnios (amniotic fluid index was 42 cm) and maternal “flu-like” illness a couple of weeks prior to delivery. The mode of delivery was secondary to a former cesarean section and worsening polyhydramnios of unknown etiology. Prenatal laboratory evaluation was reassuring with a rubella immune status and negative testing for HIV, syphilis, group B streptococcus, hepatitis B, chlamydia, and gonorrhea. The parents declined noninvasive prenatal testing.Laboratory evaluation on admission (Table 1) was significant for pancytopenia with an absolute neutrophil count of 0, coagulopathy, unconjugated hyperbilirubinemia, and elevated aspartate aminotransferase, ferritin, uric acid, and lactate dehydrogenase. Infectious testing was obtained and included cultures, serologies for HIV, toxoplasmosis, syphilis, and rubella, and polymerase chain reaction (PCR) testing for cytomegalovirus (CMV), parvovirus, human herpesvirus 6, herpes simplex virus 1 and 2 (HSV 1 and 2), HIV, enterovirus, and adenovirus. A head ultrasound was obtained given concerns for congenital infections and demonstrated lenticulostriate vasculopathy.2,3 Given the clinical presentation, the infant started treatment with antibiotic (ampicillin and gentamicin) and antiviral (ganciclovir) therapy while awaiting the results of the diagnostic workup. Initial consults were placed to infectious diseases and hematology followed by oncology and dermatology.The differential diagnosis for blueberry muffin type rash is broad1 and includes infection, blood dyscrasias, and malignancies because these observed skin lesions can be caused by dermal erythropoiesis, vasculopathy or vascular malformations, or neoplastic dermal infiltration. TORCH (toxoplasmosis, rubella, cytomegalovirus, HSV, syphilis) infections are commonly implicated, and timely treatment is crucial to prevent associated complications. In this case, TORCH infections, such as congenital CMV, were a strong possibility given the maternal history of flu-like illness during the third trimester of pregnancy and the infant’s presentation with hepatosplenomegaly, pancytopenia, and findings on head ultrasound.2,3 Upon initial suspicion of congenital CMV, empirical treatment with valganciclovir was started pending testing results due to devastating complications of uncontrolled disease.4,5 Similarly, other TORCH infections can usually be diagnosed by serology or PCR testing and occasionally treated with antiviral therapies.More rarely, hematologic disorders can result in such a rash including oncologic entities resulting in neoplastic infiltration. Biopsy of the lesion is crucial to differentiate and confirm these diagnoses to determine appropriate therapeutic interventions in a timely fashion.6 In our case, a biopsy of the lesion was performed on the second day of life.Our patient’s infectious testing returned negative, and antibiotic treatment was transitioned to cefepime monotherapy due to the patient’s persistent neutropenia. Given persistent neutropenia, the infant was also started on antifungal (micafungin and pentamidine) prophylaxis. Urine studies for neuroblastoma including homovanillic acid and vanillylmandelic acid were also negative.Biopsy results from a skin nodule revealed KMT2A (lysine-specific methyltransferase 2A) rearrangement consistent with neonatal acute myeloid leukemia (AML) with subcutaneous myeloid cell lineage infiltration.7 The infant’s fluorescence in situ hybridization (FISH) returned negative for trisomy 21.Neonatal leukemia is defined as occurring within the first 28 days of life, and nearly all cases are congenital.8,9 Excluding patients with trisomy 21, the incidence of neonatal leukemia is less than 1% of all childhood leukemias.8 AML is the predominant type of neonatal leukemia10,11 and is associated with KMT2A rearrangements (KMT2Ar) in approximately 50% of cases, which leads to a monocytic AML phenotype. In contrast, 75% of infants with acute lymphoblastic leukemia harbor KMT2Ar.8 Hyperleukocytosis (white blood cells [WBC] >100 × 103/mcL) is the most consistent hematologic feature associated with neonatal leukemia and occurs commonly in those with KMT2Ar, often causing respiratory distress, hypoxia, acidosis, and cardiac and renal failure due to hyperviscosity.7,8 Our patient presented with pancytopenia, which is atypical and more suggestive of marrow suppression from possible infection. Extramedullary leukemic involvement including skin, liver, and/or central nervous system (CNS) is common in infants with leukemia and is also associated with KMT2Ar.11,12 Leukemia cutis, the rash visualized in this case, is seen in two-thirds of babies with congenital AML and can occur in the absence of peripheral blood and bone marrow involvement.8 Other clinical features include jaundice, hepatosplenomegaly, ascites, and pleural effusions.11,12 Congenital AML is typically associated with high-risk clinical and cytogenetic features leading to 5-year overall survival rates of around 50%.7,11–15 This is, in part, because infants are at increased risk of infectious and pulmonary toxicities, early death, and treatment-related mortality with therapy.7,16–18A unique and rare feature of congenital AML is that it can undergo spontaneous remission (SR) without cytotoxic therapy, similar to transient abnormal myelopoiesis seen with Down syndrome.8,11,19 This phenomenon is most commonly described in neonates with a specific KAT6A::CREBBP gene fusion ([t(8;16)]) resulting in a monocytic or myelomonocytic AML phenotype, and although some of these patients eventually relapse, there are cases of neonates who have sustained long-term remission without treatment.8,19 SR is very unusual in neonatal AML with KMT2Ar; however, a case series described 5 neonates with KMT2Ar AML who had SR, 3 of whom experienced relapse by 6 months of age and 2 of whom remained in remission at the time the report was published (2 years and 7 months) without chemotherapy.8Prompt consultation with hematology/oncology colleagues is crucial for diagnosing and treating neonatal and infantile acute leukemias. Evaluation of neonatal leukemia typically consists of a bone marrow aspiration and biopsy to confirm diagnosis, establish leukemia immunophenotype and cytomolecular genetic drivers, and better understand risk stratification and treatment. Obtaining bone marrow aspirates and biopsies can be very challenging in this population, and for those for whom marrow samples are inadequate or unable to be obtained, peripheral blood flow cytometry can help to confirm a diagnosis and determine immunophenotype. Biopsy of a leukemia cutis lesion, if present, is also diagnostic and can be sent for genetic studies, including FISH and next-generation sequencing. A lumbar puncture is needed to evaluate for the presence of leukemia in the CNS and to administer intrathecal chemotherapy. In patients with hyperleukocytosis and/or coagulopathy, a lumbar puncture should be delayed until the WBC count has decreased and coagulopathy is corrected, so as not to contaminate the CSF by introducing peripheral leukemic cells. An echocardiogram is needed to establish heart function prior to giving anthracycline therapy. Lastly, baseline laboratories to assess renal and hepatic function and risk of tumor lysis syndrome are also needed prior to chemotherapy initiation.Infants with AML are typically treated with the same intensive anthracycline and cytarabine-based chemotherapy regimens used in older children, often with the addition of gemtuzumab ozogamicin, an anti-CD33 humanized antibody conjugated with a cytotoxic antibiotic recently shown to be safe and effective in this population.16,20 Hematopoietic stem cell transplant (HSCT) is considered for those with high-risk disease based on leukemia genetics such as KMT2Ar and/or suboptimal response to induction chemotherapy.16 Delivering intensive therapy to this population, including HSCT, can be challenging due to differences in drug absorption, distribution, hepatic metabolism, and renal excretion.21 Additionally, neonates experience increased rates of life-threatening infections, organ toxicities, and overall higher rates of treatment-related mortality.7,16–18,22In clinically well-appearing, stable neonates, watchful waiting and serial disease evaluations may be considered due to the possibility of spontaneous regression, especially in patients with KAT6A::CREBBP.19 Spontaneous regression can occur over the span of weeks to months and is characterized by the resolution of leukemia cutis lesions and/or decreasing absolute blast count in the peripheral blood with the eventual absence of marrow involvement. However, it is worth noting that KAT6A::CREBBP can also present with more aggressive disease.23,24 Due to this and the rarity of this phenomenon, there is no guidance as to which children can be monitored without treatment vs immediately treated with intensive therapy. This decision should be made in conjunction with oncology partners, and observation is only appropriate in neonates who are clinically well. Those patients with spontaneous AML remission remain at high risk of relapse and warrant close outpatient monitoring in the following years.Following the diagnosis, the patient’s rash (confirmed as leukemia cutis via histopathology and KMT2A FISH) began to spontaneously regress, and by day of life 6, the skin findings had nearly resolved prior to any chemotherapy (Figure 1D–F). However, there was worsening conjugated hyperbilirubinemia (maximum 9.7 mg/dL) concerning leukemic involvement of the liver. Thus, the patient started low-dose cytarabine treatment (1.5 mg/kg once daily for 7 days), resulting in an improvement in cholestasis. Two weeks later, at age 3 weeks of life, a repeat biopsy of the largest remaining skin lesion (Figure 1F) was negative for leukemia by morphology, immunohistochemical staining, and FISH.Two weeks after cytarabine completion, bone marrow evaluation revealed residual disease. Prior to proceeding with traditional intensive AML induction chemotherapy, the patient developed bloody stools and was found to have extensive neutropenic enterocolitis involving the cecum, ascending colon, and transverse colon. This intraabdominal infection limited the escalation of chemotherapy, so low-dose cytarabine was restarted. Unfortunately, during this treatment, the patient developed rapidly progressive AML with CNS involvement. Chemotherapy was escalated to more intensive high-dose cytarabine, but despite this, the patient ultimately died at 3 months of age due to progressive leukemia.Blueberry muffin rash does not always indicate a TORCH infection. Considering a broad differential diagnosis is important, including malignant conditions such as congenital leukemia. Prompt biopsy of the skin lesions may be required to make a diagnosis.The most common genetic mutation seen in infantile AML is KMT2Ar, which is typically characterized by a monocytic AML phenotype and associated with hyperleukocytosis and extramedullary involvement, especially skin and CNS.Rarely, congenital leukemia can spontaneously regress without treatment. This is most commonly described in neonates whose AML harbors a t(8;16) KAT6A::CREBBP fusion. These patients remain at high risk of disease relapse and need eventual treatment; therefore, close monitoring is required.Infants with AML are treated with the same intensive cytarabine and anthracycline-based chemotherapy regimens as older children with AML and are at increased risk of chemotherapy-related complications and death.Ultimately, the decision to treat neonatal AML with intensive chemotherapy vs “watch-and-wait” for possible spontaneous regression depends on the individual patient, their clinical status and organ involvement, and their AML cytomolecular genetics. This decision should be made in conjunction with oncology colleagues. Watchful waiting could be considered in well-appearing, clinically stable neonates, provided that close short- and long-term monitoring is available. Given the rarity of both neonatal AML and spontaneous regression, this population is unlikely to be studied in prospective clinical trials.American Board of Pediatrics Neonatal–Perinatal Content SpecificationRecognize different types of TORCH infection.Know the signs of congenital leukemia.Know the signs of neonatal leukemia.