Search for a command to run...
Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive immunodeficiency characterized by the triad of eczema, recurrent infections, and thrombocytopenia. Neonatal presentation of WAS can be nonspecific and overlap with common neonatal conditions, posing diagnostic challenges. We report a term male neonate who presented at day of life 46 with persistent feeding intolerance (FI), recurrent infections, and thrombocytopenia. Despite initial treatment of suspected sepsis and necrotizing enterocolitis (NEC), the infant showed minimal clinical improvement. Extensive investigations ruled out common infectious, metabolic, and hematologic causes. Immunological workup revealed low immunoglobulin M (IgM) and markedly elevated IgE levels, raising suspicion of an underlying immunodeficiency. Whole-exome sequencing (WES) identified a hemizygous pathogenic variant in the WAS gene (NM_000377:c.91G>A; p.Glu31Lys), confirming the diagnosis of WAS. Despite supportive care, including parenteral nutrition, antimicrobial therapy, and intravenous immunoglobulin, the infant succumbed to overwhelming sepsis at day of life 93. This case underscores the importance of considering congenital immunodeficiency, including WAS, in neonates with persistent thrombocytopenia and recurrent infections, especially when gastrointestinal symptoms such as FI are present. Coexistence of NEC in this case may have been exacerbated by immune dysregulation. Early recognition and genetic confirmation of WAS is essential for timely initiation of definitive therapy, such as hematopoietic stem cell transplantation. WAS, although rare, should be considered a differential diagnosis of neonatal thrombocytopenia and sepsis-like illness.A term male infant (2900 g) was born via cesarean section to nonconsanguineous parents and was well until day of life 4, when he developed FI, vomiting, and bloody stools. After admission at the referring hospital, investigations revealed a platelet count of 25 000/mm3. After keeping nil per oral for 2 days, feeds were initiated, but the infant did not tolerate, and symptoms of FI, ie, blood-stained vomiting and abdominal distension, persisted. Supportive treatment included blood components and broad-spectrum antibiotics. However, there was no clinical improvement, and the infant continued to have blood in the stool along with persistent thrombocytopenia. Owing to the persistence of symptoms and lack of response to treatment, the infant was referred to the current health facility for further evaluation and management at day of life 45. There was no history of fever, rash, breathing difficulty, or seizures.At the time of admission, the infant was extremely emaciated and icteric with normal vitals on room air. The abdomen was distended without any significant hepatosplenomegaly. At the time of admission, all of the anthropometric parameters, ie, weight (2800 g), length (52 cm), and head circumference (35 cm), were at less than the third percentile.Maternal age was 30 years with uneventful antenatal course. The infant had a 4-year old male sibling without any significant illness. The extended family history was not significant for any recurrent infection, thrombocytopenia, or death in early age.In view of abdominal distension and altered aspirates from the orogastric tube, the infant was kept nil per oral. The detailed investigations were performed for persistent FI. Abdominal radiograph (Figure 1) and ultrasonography showed dilated bowel loops without signs of malrotation. The gastrointestinal contrast study suggested delayed transit of contrast with dilated loops, raising suspicion of intestinal obstruction. An exploratory laparotomy was performed, which showed a segment of dilated small bowel, mainly jejunum, with a patchy area of necrosis and adhered omentum (Figure 2). Gentle bowel decompression and peritoneal lavage was performed, and a peritoneal drain was inserted. Once the abdomen was soft with minimal drain and no gastric aspirate, expressed breast milk feeds were restarted on sixth postoperative day. However, vomiting and bloody stools still persisted.Repeated abdominal sonography findings were normal. A trial of a lactose-free diet was given, which showed no improvement. The platelet count at admission was markedly low at 10 000/mm3 with normal total leucocyte count. The C-reactive protein was elevated at 9.8 mg/dL. Despite multiple transfusions with random donor platelets and single donor platelets, the thrombocytopenia persisted, with platelet counts fluctuating between 10 000 and 79 000/mm3.Empirical broad-spectrum antibiotics were initiated for clinical sepsis. The initial blood culture grew methicillin-resistant coagulase-negative staphylococci (MR-CoNS), and cerebrospinal fluid analysis Gram staining showed gram-positive cocci. The infant was continued on an injection of vancomycin. During hospitalization, the blood culture showed positive growth of Klebsiella pneumoniae and Candida pelliculosa, which were treated by antibiotics and antifungal as per antimicrobial sensitivity.The workup for the TORCH (ie, Toxoplasma, Rubella, Cytomegalovirus, and Herpes) group of infection, metabolic disorders, renal function, electrolytes, and dihydrorhodamine assay was unremarkable. Liver function tests showed direct hyperbilirubinemia with normal transaminases. Thyroid function and vitamin B12 levels were within normal limits. The serum ferritin, triglyceride, and fibrinogen levels were 1365.8 ng/mL (range: 50–200 ng/mL), 254 mg/dL (range: <150 mg/dL), and 146 mg/dL (range: 125–300 mg/dL), respectively.Bone marrow aspiration showed cellular marrow with myeloid preponderance and a left shift, suggestive of an infection. Stool testing for Clostridium difficile was negative. The immunoglobulin profile showed normal IgA (120 mg/dL) and IgG (1760 mg/dL) and low IgM (62.7 mg/dL) but elevated IgE levels at 10 300 IU/mL.This term infant presented with FI, recurrent infection, and persistent thrombocytopenia. Based on these clinical findings, the initial differential diagnoses included the following: SepsisNECIntrauterine infectionNeonatal Alloimmune thrombocytopenia (NAIT)Congenital thrombocytopenia syndromeCongenital immunodeficiency syndromeHemophagocytic lymphohistiocytosisIn view of differentials suggesting a strong possibility of an underlying genetic disorder, WES was performed. During the process of WES, exons and their conserved splice sites of all known genes are sequenced, revealing thousands of variants. Variant filtering is performed, taking into account the phenotype, apparent inheritance pattern, and frequency of the variant expected in normal population. The phenotype of recurrent infection and persistent thrombocytopenia matched well with an immunodeficiency syndrome, particularly WAS. The pathogenic hemizygous (an X-linked variant in a male individual) NM_000377 WAS:c.91G>A (p.Glu31Lys) variant in exon 1 of the WAS gene supported the diagnosis of WAS. The variant was classified as pathogenic (PM3, PS3, PS2, PM2, PP3) as per American College of Medical Genetics and Genomics (ACMG) 2015 guidelines for variant classification (Table 1).1During course of hospital stay, the infant was treated with antibiotics and antifungal medications for recurrent and multiple episodes of bacterial and fungal infection. The nutritional management was facilitated by trial of lactose-free formula followed by hydrolyzed formula in view of persistent signs and symptoms of FI. The infant was able to partially tolerate the enteral feeds. Parenteral nutrition was given to support and complete the nutritional requirement. However, the weight gain, including overall growth, remained suboptimal. The infant required blood component therapy in the form of repeated packed cells and platelets for correction of anemia and thrombocytopenia. During the course of the hospital stay at day of life 75, the infant started having breathing difficulty for which respiratory support was initiated. After the confirmation of diagnosis of WAS in WES, intravenous immunoglobulin (IVIG) infusion was started, and weekly infusions were planned. The infant developed septic shock at day of life 90 and was ventilated and started on inotropic support. Despite IVIG, antimicrobial medications, blood component therapy, and all supportive management, the infant succumbed to infection at day of life 93.Thrombocytopenia, defined as a platelet count of less than 150 000/μL, is a common hematological abnormality in critically ill neonates.2 It affects approximately 22% to 35% of neonates admitted to neonatal intensive care units, with higher incidence noted in very-low birth weight and preterm infants.3 Thrombocytopenia in a well-appearing neonate is usually attributed to placental insufficiency or autoimmune or alloimmune etiology, whereas, in a sick infant, it is caused by NEC, severe sepsis, disseminated intravascular coagulation. or genetic syndromes.4FI is defined as difficulty to digest enteral feedings and is accompanied by an increase in gastric residuals, vomiting, abdominal distension, and/or bloody stools.5 It is common in preterm infants and is observed in one-third of such infants, resulting in feeding disruptions.6 The episodes of FI can range from minor and self-limiting to serious, life-threatening illnesses. It can also occur in sick full-term neonates with similar symptoms.6 FI along with thrombocytopenia can be present in a large spectrum of diseases ranging from perinatal asphyxia, sepsis, growth restriction with abnormal antenatal Doppler, inborn errors of metabolism, and genetic condition.6In the present case, a term neonate presented with FI and persistent thrombocytopenia, which was finally diagnosed as NEC and WAS, highlighting the complexity and overlapping presentation of immune, hematological, and gastrointestinal pathologies in neonates.WAS is a rare X-linked recessive immunodeficiency characterized by eczema, recurrent infections, and thrombocytopenia.7 It occurs in approximately 1 in 100 000 live births and results from mutations in the WAS gene on the short arm of X-chromosome, ie, the Xp11.22–23 region, which encodes the WAS protein (WASp).8 The index case had persistent thrombocytopenia along with recurrent culture-proven bloodstream and central nervous system infections by bacteria and fungus.Clinical features of WAS are often present at birth, including petechiae, bruising, and bloody diarrhea.9 Most patients (84%) experience bleeding episodes in the form of petechiae, epistaxis, hematemesis, or melena, and approximately 30% develop life-threatening gastrointestinal or intracranial hemorrhage.10 Both T- and B-cell functions are impaired, and lymphocyte counts typically decline over time, causing variable lymphopenia. IgG and IgM levels are usually normal, whereas IgA and IgE levels are elevated.11 The bleeding manifestation in the present case included bloody stools.Colitis has been reported in patients with WAS. Lee and colleagues found ulcerative colitis in 1 of 11 patients, and Dupius-Girod and colleagues reported inflammatory bowel disease (IBD) in 5 of 55 patients with WAS.12,13 Ohya and colleagues observed reduced WASp expression in 3 of 18 children with early-onset IBD.14 Although the exact mechanism is unclear, WASp deficiency is thought to disrupt innate and adaptive immunity in the gastrointestinal tract, predisposing patients to IBD.15The variant mutation NM_000377 WAS:c.91G>A (p.Glu31Lys) detected in our case was found to be pathogenic and thereby considered to be the disease causing the symptoms in this case. Functional studies supported pathogenic effect.16 There was ClinVar submission with the following ClinVar identifiers: https://www.ncbi.nlm.nih.gov/clinvar/variation/528222/The definitive treatment of WAS is hematopoietic stem cell transplantation (HSCT), although supportive therapy remains essential. Supportive care includes prophylactic azithromycin and trimethoprim–sulfamethoxazole, along with IVIG administered every 3 weeks.17 Without transplantation, mortality occurs in 36% of cases by 8 years of age, whereas long-term survival after HSCT reaches approximately 75% at 25 years of age.18,19This case highlights the importance of a high index of suspicion for genetic disorders in neonates with persistent or unexplained hematologic abnormalities, especially in presence of coexistent gastrointestinal symptoms. Although rare, WAS should be considered in the differential diagnosis of neonatal thrombocytopenia, especially in the presence of recurrent or severe infections.The association of NEC with WAS is notable. The underlying immune dysregulation may predispose to mucosal injury, contributing to secondary NEC or worsening its severity. Therefore, a term neonate with NEC without another clear cause should be evaluated for underlying genetic conditions.Early diagnosis is vital because HSCT offers definitive treatment. Given the high morbidity and mortality associated with WAS in infancy, genetic counseling, family screening, and prenatal testing for at-risk couples are essential.The recurrent infection with thrombocytopenia should be evaluated for an immunodeficiency disorder.Initial presentation of WAS may be nonspecific, mimicking neonatal sepsis.Immunoglobulin profiling can provide an early diagnostic clue.Genetic testing in cases of persistent thrombocytopenia facilitates confirmation of WAS and timely initiation of definitive treatment, including HSCT.American Board of Pediatrics Neonatal-Perinatal Content SpecificationRecognize neonatal bacterial infections.Recognize neonatal platelet disorders.