NeoQuest April 2024: Neonate with a Rash

A full-term newborn presents with a rash (Figure 1 Left). Prenatal maternal laboratory tests included a vaginal culture negative for group B Streptococcus, the presence of rubella IgG, and negative HIV and rapid plasma reagin screens. On physical examination, the infant is well-grown and pale, with a murmur, hepatosplenomegaly, and a diffuse maculopapular and nodular rash. A complete blood count with a peripheral blood smear demonstrates leukocytosis with anemia and thrombocytopenia (Figure 2 Right). The head ultrasound shows bilateral grade I intraventricular hemorrhages and lenticulostriate vasculopathy. An echocardiogram demonstrates an atrial septal defect. 

Figure 1: (Left) Diffuse, non-blanching, blue, maculopapular and nodular rash representing leukemia cutis. Image from Gonzales DN, Punia JN, Patil MS. Neonate with a diffuse maculopapular and nodular rash. Neoreviews. 2024;25(4):e232.¹

Figure 2: (Right) Peripheral smear showing increased number of blast cells (orange arrow). Image from Gonzales DN, Punia JN, Patil MS. Neonate with a diffuse maculopapular and nodular rash. Neoreviews. 2024;25(4):e232.¹

Which of the following initial tests should be obtained to confirm the acute diagnosis?

1. Abdominal magnetic resonance imaging
2. Enzyme immunoassay for rubella IgM
3. Flow cytometry
4. Serum rapid plasma reagin
5. Urine polymerase chain reaction assay for cytomegalovirus

Answer: C. Flow cytometry

Explanation:

The newborn described in this vignette has a characteristic “blueberry muffin” rash (Figure 1) accompanied by laboratory findings notable for leukocytosis, anemia, and thrombocytopenia, with a peripheral blood smear demonstrating blast cells (Figure 2). This finding on peripheral smear increases the suspicion for congenital leukemia, which can be confirmed further using flow cytometry (Option C).

Congenital leukemia constitutes less than 1% of childhood leukemias and occurs in 1 in 5 million live births, with acute myeloid leukemia (AML) as the most common subtype.^1–3

Congenital leukemia is defined based on the following features:²

• Presentation in the first 4 weeks of age
• Proliferation of immature myeloid, lymphoid, or erythroid cell lineages
• Infiltration of extra hematopoietic tissues
• Absence of an alternative diagnosis causing a leukemoid reaction, such as congenital viral or bacterial infections and transient myeloproliferative disorder

Neonates with congenital leukemia can present with a wide range of clinical manifestations, including hepatosplenomegaly, pallor, bleeding diathesis, and respiratory distress secondary to leukemic infiltration into the airways and lungs.^1–4 More than 50% of neonates with leukemia present with leukemia cutis, described as a reddish-purple, palpable, and indurated “blueberry muffin” rash (Figures 1 and 3).^1,3,4 Hematologic features consistent with leukemia include hyperleukocytosis, thrombocytopenia, and anemia.^1,3 Diagnosis of congenital leukemia can be made on peripheral smear and bone marrow biopsy, which can show an increased number of immature blasts (Figure 2). Flow cytometry (Figure 4) provides additional information by delineating the specific type of cell population noted in the sample.^1–3,5  However, it is important to note that congenital AML can initially present with isolated leukemia cutis without bone marrow or peripheral blood involvement since skin involvement can precede other signs of leukemia.⁵ In the case of isolated leukemia cutis, performing a tissue biopsy can confirm the diagnosis, which can show leukemic cells that have infiltrated the dermis and subcutaneous tissue.⁵ Fluorescence in-situ hybridization is subsequently performed to detect genetic derangements consistent with congenital leukemia and for risk stratification.^1,3,6 About 50% to 60% of neonates with congenital leukemia have a rearrangement of the KMT2A gene on chromosome 11, which is crucial for the production and differentiation of hematopoietic precursor cells.^1,3 Mutations in KMT2A is associated with overall poor outcomes.^1,6 In this case, the infant’s peripheral smear demonstrated an increased number of blasts suggestive of leukemia. Additionally, flow cytometry confirmed congenital AML, demonstrating predominantly monocytic differentiation-positive markers for CD33, CD11b, CD64, CD14 and cytoplasmic myeloperoxidase (Figure 4).

Figure 3: Patient with congenital leukemia demonstrating the characteristic blueberry muffin rash (black arrow) on the chest and torso (A) and lower extremity (black arrow) (B). Image adapted from Schiff AF, Supples SP, Walsh MJ, Russell TB, Pylipow ME. Case 1: A blueberry muffin rash complicated by cardiomyopathy. Neoreviews. 2019;20(7):e409-e411.²

Figure 4: Flow cytometry plots of the patient in the given vignette, showing two distinct populations of blasts. The major blast population was 82% (red colored) with monocytic differentiation (CD45 dim, CD11b, CD64, CD14 partial, CD33 and cytoplasmic myeloperoxidase), and the minor blast population was 4% (brown colored) with immature B differentiation (CD45 dim, CD19, CD34 and cytoplasmic CD79a). Image from Gonzales DN, Punia JN, Patil MS, Neonate with a diffuse maculopapular and nodular rash. Neoreviews. 2024;25(4):e232.¹

Neuroblastoma is a common malignant tumor found in neonates, with the majority localized to the adrenal glands.^7,8 Symptoms depend on the location of the tumors. Most infants are asymptomatic, but they can present with hepatomegaly due to metastasis and metastatic skin nodules resembling a “blueberry muffin” rash that blanches on palpation.⁸ Neuroblastomas are typically detected on routine prenatal ultrasound. In patients with suspected neuroblastoma, a complete blood count, electrolyte panel, liver panel, and urine tests for catecholamine, vanillylmandelic acid and homovanillic acid should be performed to support the diagnosis and to help with prognostication.⁸ Abdominal imaging such as magnetic resonance imaging (Option A) can help confirm the diagnosis and delineate the extent of the tumor (Figure 5).^7,8 The presence of cell count abnormalities and blasts in the peripheral smear makes the diagnosis of neuroblastoma less likely in the described patient.

Figure 5: A. Magnetic resonance imaging of the abdomen shows an abdominal mass noted on the right kidney with numerous hepatic lesions (blue arrow) concerning for a neuroblastoma. B. Magnetic resonance imaging of the abdomen shows a small neuroblastoma (yellow arrow). Image adapted from Fernández KS. Solid tumors in the neonatal period. Neoreviews. 2014;15(2):e56-68.⁷

Congenital rubella syndrome (CRS) is among the most common infections associated with a “blueberry muffin” rash. CRS can result from rubella infection in the pregnant person occurring in the first trimester.⁴ Infants with CRS can also present with growth restriction, eye abnormalities (cataracts, salt and pepper chorioretinitis, microphthalmia), cardiac defects (patent ductus arteriosus and pulmonary arterial hypoplasia), hepatosplenomegaly, thrombocytopenia, and radiolucent bone disease.⁹ Diagnosis of CRS occurs by detection of rubella specific IgM antibodies using enzyme immunoassay (Option B) within the first six months of age.⁹ Laboratory findings may also include anemia and thrombocytopenia. Additional evaluation includes long bone radiographs, an echocardiography, lumbar puncture to evaluate for evidence of neurosyphilis, serial audiological and ophthalmological evaluations, and long-term surveillance for complications such as diabetes and hypothyroidism.⁹ The patient in the vignette has appropriate growth, and the maternal history reveals immunity to rubella, which makes the diagnosis of CRS less likely.

Infants with congenital syphilis may present small for gestational age with hepatosplenomegaly, lymphadenopathy, copious nasal secretions and various mucocutaneous manifestations.^4,10 The rash in congenital syphilis (Figure 6) is described as a diffuse, papulosquamous eruption of small red spots involving the palms and soles that desquamate over time.^10,11 The initial evaluation for congenital syphilis includes nontreponemal testing such as rapid plasma reagin testing (Option D) or venereal disease research laboratory testing followed by potential cerebrospinal fluid analysis and additional imaging based on risk stratification.¹⁰ Although false-negative rapid plasma reagin screening results can occur in the pregnant person if the infection is acquired late in the pregnancy, the patient in the vignette demonstrates appropriate growth with no history of maternal syphilis. The presence of blasts on the peripheral smear makes the diagnosis of congenital syphilis less likely.

Figure 6: Rash seen in congenital syphilis, characterized by: (A) small red spots involving the palm and soles and (B) progression to a desquamating rash. Image adapted from Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH. Syphilis. In: Report of the Committee on Infectious Diseases, Committee on Infectious Diseases. Red Book. 32nd Edition. 2021. American Academy of Pediatrics.¹⁰

Most neonates with congenital cytomegalovirus (CMV) are asymptomatic at birth. However, 10% can present with manifestations such as hepatosplenomegaly, microcephaly, and intracerebral calcifications with laboratory abnormalities, including conjugated hyperbilirubinemia and thrombocytopenia.¹² Dermatologic manifestations include a generalized, maculopapular “blueberry muffin” rash, and on histological examination, showing dermal infiltration of nucleated erythrocytes (Figure 7).^4,12 Isolation of CMV in urine or saliva using polymerase chain reaction can be used to confirm the diagnosis (Option E). CMV is the most common non-genetic cause of sensorineural hearing loss and requires serial audiologic surveillance.¹² This clinical vignette describes the presence of lenticulostriate vasculopathy on head ultrasound, which is a finding associated with congenital CMV infection.¹³ However, the presence of blasts on peripheral smear makes the diagnosis of CMV unlikely.

Figure 7:  Rash associated with congenital cytomegalovirus infection (Panels A-B). Diffuse maculopapular “blueberry muffin” rash is attributed to extramedullary hematopoiesis. Image adapted from Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH. Cytomegalovirus Infection. In: Report of the Committee on Infectious Diseases, Committee on Infectious Diseases. Red Book. 32nd Edition. 2021. American Academy of Pediatrics.¹²

Did you know?

Transient myeloproliferative disorder, which is a self-resolving phenomenon described commonly in patients with trisomy 21, can present with leukocytosis, thrombocytopenia, and hepatosplenomegaly. In contrast to congenital leukemia, patients with this disorder have lower blast counts on peripheral smear, and on flow cytometry, are typically negative for cytoplasmic myeloperoxidase.¹⁴

What are some of the cutaneous findings noted in congenital infections?

For a detailed description of cutaneous findings in congenital infections, please refer to Table 3 in Goodarzi H, Wu TT, Wang J, Teng JM. Neonatal dermatology: the normal, the common, and the serious. Neoreviews. 2021;22(1):e40-e51.⁴

NeoQuest April 2024 Authors:

Srirupa Hari Gopal, MBBS, FAAP, Baylor College of Medicine, Houston, Texas

Faith Kim, MD, Columbia University Medical Center, New York New York

References:

1. Gonzales DN, Punia JN, Patil MS. Neonate with a diffuse maculopapular and nodular rash. Neoreviews. 2024;25(4):e232-e236
2. Schiff AF, Supples SP, Walsh MJ, Russell TB, Pylipow ME. Case 1: A blueberry muffin rash complicated by cardiomyopathy. Neoreviews. 2019;20(7):e409-e411
3. Gupta S, Anwar A, Kirk JJ, Makker K. Case 1: Fever, rash, and hyperleukocytosis in a newborn. Neoreviews. 2017;18(12):e712-714
4. Goodarzi H, Wu TT, Wang J, Teng JM. Neonatal dermatology: the normal, the common, and the serious. Neoreviews. 2021;22(1):e40-e51
5. Solomon T. Index of suspicion in the nursery. Neoreviews. 2008;9(11):e534-538
6. Li Q, Xing S, Zhang H, Mao X, Xiao M, Wang Y. FISH improves risk stratification in acute leukemia by identifying KMT2A abnormal copy number and rearrangements. Sci Rep. 2022;12(1):9585
7. Fernández KS. Solid tumors in the neonatal period. Neoreviews. 2014;15(2):e56-68
8. Minakova E, Lang J. Congenital neuroblastoma. Neoreviews. 2020;21(11):e716-727
9. Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH. Rubella. In: Report of the Committee on Infectious Diseases, Committee on Infectious Diseases. Red Book. 32nd Edition. 2021  American Academy of Pediatrics. 
10. Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH. Syphilis. In: Report of the Committee on Infectious Diseases, Committee on Infectious Diseases. Red Book. 32nd Edition. 2021. American Academy of Pediatrics 
11. Satti KF, Ali SA, Weitkamp JH. Congenital infections, part 2: parvovirus, Listeria, tuberculosis, syphilis, and varicella. Neoreviews. 2010;11(12):e681-695
12. Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH. Cytomegalovirus Infection. In: Report of the Committee on Infectious Diseases, Committee on Infectious Diseases. Red Book. 32nd Edition. 2021. American Academy of Pediatrics
13. Almeida AC, Freitas A, Vieira MJ. A newborn with an incidental finding on cranial ultrasonography. Neoreviews. 2022;23(3):e221-413
14. O’Connell AE, Mulla BM, O’Brien K, Yoon EJ, Carterson A, Brodsky D. Perinatal transient myeloproliferative disorder in trisomy 21. Neoreviews. 2016;17(11):e636-644