A Late-Preterm Infant with Ichthyosis, Pancytopenia, and Recurrent Sepsis.

A male preterm infant of second-degree consanguineous parents was delivered vaginally at 34 weeks of gestation. Maternal prenatal history was not significant. The infant needed NICU admission for transient tachypnea of the newborn. He required nasal continuous positive airway pressure support for 2 days. Physical examination at birth revealed thick scales covering the whole body, including the eyes. The infant had a long philtrum, small chin, and wide-spaced nipples. He was given intravenous fluids and supportive care for ichthyosis, including proper humidification, adequate hydration, application of emollients, artificial eye drops, and meticulous attention to asepsis. His routine blood tests revealed normal results, except for borderline low leukocyte and platelet counts. The antibiotics that were started at birth for presumed sepsis were discontinued after blood cultures were found negative.The infant responded well, and the ichthyosis resolved 3 to 4 weeks after birth (Fig). However, he required multiple antibiotic therapy courses (ampicillin and gentamicin [n=1], cloxacillin and gentamicin [n=4], and meropenem [n=1]) for recurrent sepsis. The episodes of sepsis manifested as respiratory deterioration, hemodynamic or thermal instability, fever, elevated C-reactive protein, and fluctuations in white blood cell and absolute neutrophil counts. Though none of the blood cultures revealed any growth, these episodes were treated as presumed sepsis. The white blood cell counts (range, 2,400–6,400/μL [2.4–6.4 × 109/L]; normal value, 6,000–8,000/μL [6–18 × 109/L]) and platelet counts (range, 54–114 × 103/μL [54–114 × 109/]L; normal value: 150–450 × 103/μL [150–450 × 109/L]) remained low throughout the hospitalization even when the infant had no sepsis. He required multiple packed cell transfusions for anemia disproportionate to the blood test results and prematurity. The family history included maternal brothers having infants with ichthyosis (3 children of 1 brother and 2 children of another brother), who died in infancy or early childhood. At this point, the parents were offered skin biopsy and genetic testing. However, the parents refused further investigations.Head ultrasonography and magnetic resonance imaging were performed for the recurrent apnea, which was finally attributed to sepsis. Abdominal ultrasonography and echocardiography were performed, keeping in mind the broad differential diagnoses. All the tests revealed normal results. The infant was discharged from the hospital after 3 months of intensive care.This neonate with recurrent sepsis, pancytopenia, and ichthyosis requires a broad differential diagnosis. Premature infants are at increased risk of sepsis, and recurrent episodes of sepsis may result in bone marrow dysfunction. The infant was not very premature to have recurrent sepsis. The ichthyosis was unrelated to prematurity. The next consideration on the differential included immunodeficiency disorders, such as severe combined immunodeficiency, chronic granulomatous disease, hyper-IgM syndrome, and Wiskott-Aldrich syndrome. These disorders were suspected because the infant had recurrent sepsis but no other risk factors (long-standing indwelling catheters, parenteral nutrition, or exposure to invasive procedures). Ichthyosis, per se, was also a possible entity on the differential as the breakage of skin could result in recurrent infections. However, it resolved by 3 to 4 weeks after birth, and the infant continued to have similar episodes of sepsis.Cytopenia and recurrent infections can also result from hyperinflammatory syndromes, such as primary hemophagocytic lymphohistiocytosis (HLH). However, the infant did not have any additional features that suggested HLH. Childhood malignancies were also included in the differential even though they were unlikely, and no striking abnormalities were found on the peripheral smear. Finally, genetic or chromosomal abnormalities were considered because of the history of a similar condition in other family members.Given the clinical presentation and history of childhood deaths with skin disease in other family members, the team decided that advanced genetic testing was a suitable first step in the diagnostic process. Hence, after reapproaching the family and obtaining their consent, whole-exome sequencing (centrosome gold) was performed. The results revealed a homozygous pathogenic variant in the PRF1 gene consistent with the diagnosis of autosomal recessive familial type 2 HLH.Farquhar and Claireaux first described HLH in 1952 as hereditary medullary reticulosis. (1) It is a fatal condition resulting from the excessive and uncontrolled proliferation of activated histiocytes and T lymphocytes from an enormous release of cytokines, with deposition of macrophages and lymphocytes in tissues and organs, ultimately leading to end-organ damage and death. (2) It is divided into 2 subtypes: primary and secondary HLH. (3) Primary HLH, also known as familial hemophagocytic lymphohistiocytosis (FHL), is more common and has an autosomal recessive mode of inheritance. It usually presents early in infancy and occurs from an underlying genetic defect of immunologic cells.Secondary HLH, more commonly referred to as macrophage activation syndrome, occurs in the older age group. It occurs because of an abnormal immune response to an underlying condition such as infection, malignancy, or immune disorder. Primary and secondary HLH are otherwise labeled as genetic and acquired HLH, respectively. (3) Although it is often necessary to distinguish between 2 subtypes of HLH for prognostic and therapeutic decisions, it is not always possible, particularly when it affects the firstborn child or when the family history is not contributory. (2) As per the diagnostic criteria proposed by the Histiocyte Society in 1994 and revised in 2004, the diagnosis of HLH should satisfy 5 of 8 diagnostic criteria or a molecular diagnosis consistent with HLH (Table). (4)(5)The FHL Registry reports that cutaneous manifestations occur in 24% of patients with HLH. (6) Previous studies indicate that skin manifestations occur in as few as 6% to as many as 65% of patients with HLH. In many instances, cutaneous manifestations aid in early suspicion of HLH, though they are nonspecific and do not contribute to the diagnostic criteria. (2)(3)(4) Henter et al, in an observational study, noted that 43% of affected patients had skin manifestations as early presentation, whereas 65% of patients with HLH had a dermatologic manifestation of some form during disease progression. (2)Dermatologic manifestations of HLH include maculopapular rash, extensive macules, generalized papular eruptions, morbilliform rash, generalized erythroderma, blueberry muffin rash, and edema. The current index case did not show any of the cutaneous manifestations described in previous studies. To the best of our knowledge, there has been no previous case report of neonatal HLH presenting with generalized ichthyosis as a dermatologic manifestation. In general, the dermatologic features are nonspecific, variable, or may occur transiently. In addition, skin biopsy of the lesions does not help to diagnose HLH but may help to exclude other systemic diseases. (7) However, the histopathologic findings on biopsy are often inconclusive. (2)(7)Treatment for HLH involves supportive care, including treatment of sepsis, blood cell transfusion, nutritional and developmental support, immunosuppressive drugs, and chemotherapy. Allogeneic stem cell transplantation (SCT) is the only curative treatment for FHL, pro-vided a suitable donor and appropriate resources are available.The infant stayed in the NICU for 3 months, where he received antibiotics for recurrent infections and blood products for pancytopenia. After discharge, he required multiple hospitalizations for episodes of sepsis. He also developed significant hepatosplenomegaly, bilateral cataract, and failure to thrive. After the diagnosis was confirmed, he was referred to a hemato-oncology center for specific treatment, including chemotherapy and hematopoietic SCT.This infant presented with ichthyosis at birth. He had persistent pancytopenia and developed recurrent infections during the NICU stay. HLH was a potential entity on the differential, but lack of additional criteria, as presented in the Table, did not prompt consideration of HLH initially. Although he had hepatosplenomegaly and elevated ferritin as additional criteria for the diagnosis, they were noted later. Also, these features overlap with various other conditions and are not specific to HLH. Thus, our approach was comprehensive, and we thought whole-exome sequencing was an ideal test that eventually led to the final diagnosis.