Blueberry Muffin Baby with Cytomegalovirus Hepatitis.

Sir,

The term blueberry muffin baby came from the superficial similarity of cutaneous manifestations to a blueberry muffin and was used to describe the cutaneous manifestations of congenital rubella in newborns during the American epidemic of the 1960s. It is characterized by widespread reddish-blue to magenta-colored maculopapular lesions. The differential diagnosis of blueberry muffin baby includes conditions associated with TORCH (toxoplasmosis, others, rubella, cytomegalovirus, herpes virus) infections, dermal extramedullary hematopoiesis, infiltrative neoplastic lesions of the skin, and cutaneous vascular anomalies.[12] We present a case of a 9-month-old male infant who was referred to our outpatient department with multiple asymptomatic reddish to bluish raised lesions over the body since 1 month.

A 9-month-old male child with uneventful obstetric history presented with multiple asymptomatic reddish to bluish raised lesions over the body since 1 month. The pregnancy was full term and without infectious complications, with prenatal diagnosis of intrauterine growth restriction. Maternal serology (human immunodeficiency virus, hepatitis B antigen, and TORCH) was negative. Immunization history (bacilli Calmette-Guérin; hepatitis B; diphtheria, pertussis, tetanus; oral polio vaccine; injectable polio vaccine; and measles vaccine) of the infant was adequate till date. Cutaneous examination revealed multiple dusky blue non-blanchable dome-shaped papules and nodules over forehead, trunk, and right cubital fossa [Figure 1]. Ophthalmological examination including fundoscopy was within normal limit except for icterus [Figure 2]. Per-abdominal examination and ultrasound of the abdomen revealed hepatosplenomegaly. Hematological examination showed anemia (9.3 g/dL), thrombocytopenia (95,000/mm3), direct hyperbilirubinemia (2.8 mg/dL), and elevated liver enzymes (alkaline phosphatase 384 IU/L and aspartate transaminase 94 IU/L). Cytomegalovirus (CMV) IgM titer was 2.22 U/mL and CMV IgG titer was 28 U/mL. Workup for other TORCH infections (antibodies for toxoplasmosis, rubella, and herpes simplex virus) was negative. Skin biopsy showed foci of dermal erythropoiesis along with aggregates of nucleated and non-nucleated erythrocyte precursors [Figures 3 and 4]. Based on clinical, biochemical, and histopathological findings, a diagnosis of blueberry muffin baby with CMV hepatitis was made and the patient was started on intravenous ganciclovir 100 mg once daily for 6 weeks. The mother's serology was negative and the baby's IgG CMV was positive, but IgM was negative could point out that the infection was acquired perinatal/postnatal. Polymerase chain reaction/viral culture to confirm the diagnosis could not be performed due to resource and economic constraints.

Figure 1

Multiple dusky blue, non-blanchable, dome-shaped papules over forehead, trunk, and right cubital fossa

Figure 2

Icterus seen in bilateral sclera

Figure 3

Dilated dermal vessels (4×, H and E)

Figure 4

Aggregates of nucleated and non-nucleated erythrocyte precursors (10×, H and E)

Blueberry muffin syndrome, a rare neonatal skin disorder, is characterized by widespread non blanchable, maculopapular lesions of reddish-blue or magenta color seen due to persistent dermal erythropoiesis.[1] The various causes for blueberry muffin syndrome are mentioned in Table 1.[1345] The exact cause of prolonged dermal erythropoiesis in blueberry muffin syndrome is unknown, but it is hypothesized that during normal embryologic development, extramedullary hematopoiesis occurs in a number of organs, including the dermis and this activity persists until the fifth month of gestation.[1] The presence of blueberry muffin lesions at birth represents postnatal expression of this normal fetal extramedullary hematopoiesis.[1] Although most commonly these lesions present in neonatal life, presentation in infantile period has also been noted.[6]

Table 1

Causes of Blueberry muffin baby[2456]

1. Congenital infections	4. Neoplastic disorders
Toxoplasmosis,	Congenital monoblastic leukaemia,
Rubella,	Neuroblastoma,
Cytomegalo virus,	Congenital alveolar rhabdomyosarcoma and Leukemia cutis
Herpes simplex,
Coxsackie virus,
Chicken pox,
Chlamydia,
HIV,
Human T-lymphotropic virus,
Parvovirus,
Epstein-barr virus and
Syphilis
2. Hematologic disorders	5. Congenital vascular lesions
Spherocytosis,	Multiple hemangiomas of infancy
Alloimmuniszation,	Multifocal lymphangioendotheliomatosis,
Twin to twin transfusion syndrome and Fetomaternal transfusion	Blue rubber bleb nevus syndrome and Multiple glomangiomas
3. Metabolic disorders	6. Others
Non-ketotic hyperglycinemia (Glycine encephalopathy)	Langerhans cell histiocytosis and
Mevalonic aciduria	Neonatal lupus erythematosus

Evaluation of blueberry muffin baby begins with careful review of the pregnancy history and prenatal laboratory studies with a special focus on infectious serologies of mother and baby.[1] Histopathology shows foci of dermal erythropoiesis along with aggregates of nucleated and non-nucleated erythrocyte precursors, but generally no cells of myeloid/megakaryocytic type.[4] A stepwise approach in a suspected case of blueberry muffin baby has been highlighted in Table 2.[1] Most cases usually manifest by birth, and a few cases may be reported few months later as was in our case.[1] In most cases, the illness regresses without complications within 4–8 weeks.

Table 2

Approach to investigate a suspected case of blueberry muffin baby[2]

Step 1: History of presenting complaints of baby

Step 2: Pregnancy history of mother to rule out infections such as TORCH and other complications such as hydraminos

Step 3: Maternal serology to rule out TORCH and other congenital infections (antibodies for toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, syphilis, parvovirus B19)

Step 4: Baby’s serology to rule out congenital infections

Step 5: Hematological investigations – hemoglobin with complete blood count and peripheral smear, liver function tests, renal function tests, urine routine microscopy

Step 6: Myelogram to rule out neoplasms

Step 7: Radiological investigations to rule out systemic involvement (chest X-ray, ultrasonography of abdomen and pelvis, CT brain, X-ray of extremities)

Step 8: Skin biopsy to look for extramedullary erythropoiesis

CMV infection is the most common congenital TORCH infection (0.3%–2.2%) with cutaneous involvement seen in less than 5% of cases.[2] The cutaneous involvement may be associated with serious systemic implications, which implies a prompt diagnosis. The incidence of primary CMV infection acquired during pregnancy is 1%–4%, and association with congenital infection is 40%.[2] The diagnosis of congenital CMV infection is established by detecting the virus in the blood, urine, or other tissues obtained within the first 3 weeks of life and detection of antibodies (CMV IgM and IgG) thereafter.[2] Newborns with symptomatic congenital CMV infection and involvement of the central nervous system are treated with ganciclovir for 6 weeks.[2] In our case, the indication for the use of ganciclovir was the diagnosis of congenital CMV infection associated with hematological alterations, hepatosplenomegaly, and hepatitis.

Although CMV-induced blueberry muffin syndrome is well known, it is rare and there is always a confusion and doubt about further investigations and management of such cases. It is our sincere attempt to simplify the approach to a case of blueberry muffin syndrome. As this rash is usually subtle, it may go unnoticed and hence should be investigated thoroughly for early initiation of therapy and prevention of comorbidities.

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Conflicts of interest

There are no conflicts of interest.