Mowat-Wilson Syndrome Presenting With Purpura Fulminans

Purpura fulminans is a rapidly progressive syndrome of intravascular thrombosis and hemorrhagic infarction of the skin. It is a hematologic emergency characterized by ecchymotic skin lesions associated with vascular collapse and disseminated intravascular coagulation and can rapidly progress to multiorgan dysfunction. Purpura fulminans may be the presenting sign of severe heritable deficiency of protein C or protein S; however, it is most commonly a complication of Neisseria meningitidis sepsis, and less commonly, it has been documented to occur as a complication of other infections, including Streptococcus pneumoniae.^1,2 In children who are otherwise healthy, splenic dysfunction in the form of functional or anatomic asplenia is the most common predisposing factor for invasive pneumococcal infection.³ 

A 10-month-old girl with a past medical history of gross motor developmental delay was transferred from an outside hospital for further management. Before presentation to the outside emergency department, she had 1 day of mild, clear rhinorrhea and tactile fever, developing drowsiness and poor feeding on the morning of admission. On initial examination in the outside emergency department, she was hypotensive and tachycardic; she had a generalized tonic-clonic seizure lasting 15 seconds and was found to have a petechial rash that quickly progressed to purpura. A lumbar puncture was performed but was contaminated with blood, and computed tomography of the head was unremarkable. She was empirically treated with ceftriaxone and vancomycin for bacterial meningitis. She was volume resuscitated with normal saline and fresh-frozen plasma and started on continuous infusions of norepinephrine, epinephrine, dopamine, milrinone, and 25% albumin, as well as given intravenous hydrocortisone. Levetiracetam was started for seizure prevention.

Extensive purpuric lesions were present on her bilateral hands, feet, and face with areas of skin necrosis. Her international normalized ratio was 2.3, partial thromboplastin time was 62 seconds, fibrinogen was 72 mg/dL, C-reactive protein was 63.29 mg/L (normal is <8 mg/L), and lactate was 21.90 mg/dL. Over the next 48 hours, the patient’s cerebrospinal fluid culture grew S pneumoniae with pan sensitivity.

The infant was transferred to our regional Pediatric Trauma and Burn Center for management of extensive tissue ischemia and necrosis (Fig 1). On presentation, she was noted to be in worsening shock and required additional fluid resuscitation with the escalation of vasoactive infusions. Bilateral escharotomies of her upper and lower extremities and hands were performed in the PICU to relieve her severely compromised tissue compartments, and she was taken to the operating room for emergent tracheotomy. Once stabilized, she had an abdominal ultrasound that revealed asplenia and right-sided hydronephrosis; she subsequently underwent an abdominal MRI, which confirmed asplenia. An MRI of the brain and an echocardiogram were unremarkable for structural abnormalities.

The patient had a history significant for developmental delay, hypotonia, and head circumference at the third percentile, noted since 6 months of age. At the age of 10 months, she was unable to sit with support and was only intermittently rolling over. She had been evaluated by early intervention but had not begun therapy at the time of admission. She was born at full term via repeat cesarean delivery and had no previous hospitalizations or surgeries. She had 1 previous episode of pneumonia at 6 months of age, which was treated with outpatient antibiotic therapy. A review of medical records revealed that she was up to date on all recommended immunizations, including 3 doses of the pneumococcal conjugate vaccine. She had no sick contacts or travel history. There was no family history of genetic disease, and her parents denied consanguinity.

Full immunologic investigation revealed normal immunoglobulin levels for her age. S pneumoniae titers were robust for the 13 serotypes of the pneumococcal conjugate vaccine. T-cell receptor excision circles analysis was normal at birth, ruling out severe combined immunodeficiency. In addition, she had a history of tolerance to live viral vaccines and had normal lymphocyte counts. Therefore, severe B- or T-cell immunodeficiency was deemed unlikely.

Once anasarca resolved, she was noted to have microcephaly with a high forehead (Fig 2). Her eyes were deep set and hyperteloric with bilateral epicanthal folds. She had anteverted alae nasi with a prominent, rounded nasal tip and a low-lying columella. Her ears were posteriorly rotated with thick, uplifted lobes with a central depression. On the basis of her unique facial gestalt, genetic analysis of the ZEB2 gene was performed, revealing a pathogenic variant c.1426dup consistent with the diagnosis of Mowat-Wilson syndrome (MWS); her parents opted not to undergo genetic testing.

The patient had a prolonged hospitalization. Extensive tissue damage from progressive necrosis and wet gangrene of her limbs was accompanied by continued hemodynamic instability and ongoing sepsis with multiple organ system failures despite broad-spectrum antimicrobial therapy and daily wound debridement. The difficult decision was made to perform partial limb amputations from all 4 gangrenous limbs, which were judged to be an imminent threat to her survival. Organ failure improved dramatically after the amputations were performed. After 2 months of recovery in the PICU, she was discharged to inpatient rehabilitation.

MWS is a syndrome of congenital anomalies thought to be present in 1:50 000 to 70 000 live births.⁴ Clinical features include microcephaly in infancy and the following characteristic facial features: a square-shaped face with a prominent but narrow triangular chin, hypertelorism, deep-set but large eyes, broad nasal bridge, saddle nose, open-mouthed expression, posteriorly rotated ears, and large uplifted ear lobes with a central depression.^4,–7 Associated findings include Hirschsprung disease (44.2% of patients with MWS), anomalies of the corpus callosum (79.6%), hypotonia (79.1%), seizures (78.5%), and congenital heart disease (58.1%).⁷ Affected individuals have moderate to severe intellectual disability with limited speech development and delayed motor milestones.^5,–8 The behavioral phenotype includes high rates of repetitive and oral behaviors (eg, flipping light switches, tapping or flicking objects, mouthing, bruxism) and a generally happy, social affect.⁸ Authors of several studies have documented a reduced responsiveness to pain.^7,8 In addition to these findings, Mowat et al⁵ described urogenital anomalies such as hypospadias, webbed penis, bifid scrotum, vesicoureteric reflux, and hydronephrosis in a review of the literature published in 2003. Interestingly, Mowat et al⁵ had not identified any female patients with urogenital anomalies, but by 2005, Zweier et al⁶ had documented a small series of female patients.

First described in 1998, MWS is now known to occur secondary to a mutation in gene ZEB2, previously referred to as ZFHX1B, located at chromosome 2q22.⁵ However, the genotype profile leading to MWS is highly variable among the affected population. The majority of genetic defects involve intragenic nonsense mutations or insertions, deletions, or insertion or deletions (indels) that induce a frameshift and transcription of a premature stop codon.⁷ Chromosomal deletions of ZEB2 are another cause of MWS, ranging in size from exon deletions 11-kb long to the 16.7-Mb deletion of an entire allele. Less common defects have involved a deletion within the 3′–untranslated region causing dysregulation of mRNA synthesis and variations in early introns that likely alter splice sites and RNA processing. Almost all cases of MWS have arisen from de novo ZEB2 mutations, although recurrence of MWS has been reported in siblings. Zweier et al⁶ documented 1 affected sibling pair whose healthy father was found to have low-level mosaicism, whereas at least 3 other instances have been reported without parental somatic ZEB2 mutation.^9,–11 Given these findings, familial recurrence of MWS most likely occurs because of parental constitutional or germline mosaicism, with an estimated recurrence risk of 2.3%, and genetic counseling is advised as part of future prenatal care.¹¹ 

The normally encoded protein product, Smad-interacting protein 1, is implicated in transcription modulation and transforming growth factor–β signaling, particularly in early neuroectoderm, neural plate, neural tube, and neural crest development.⁵ ZEB2 expression has been detected in heart, brain, placental, lung, liver, and skeletal muscle as well as fetal brain, kidney, liver, and spleen tissues.⁵ In 2014, Pons et al¹² described 4 cases of spleen hypoplasia or aplasia associated with mutations in the ZEB2 gene. However, a cross-sectional analysis published in 2018 of 87 patients with molecularly confirmed MWS revealed only 1 individual to be affected by asplenia.⁷ 

Although still not well understood, our case supports the association of ZEB2 mutation with asplenia, predisposing to invasive pneumococcal infection. A number of recommendations for initial and follow-up care of patients with MWS have been offered, primarily targeting the acute complications of the syndrome, such as epilepsy and congenital heart disease.⁷ Given the relatively low incidence of this syndrome as reported in the literature, we support the recommendation that all children suspected or confirmed to have MWS be screened for congenital asplenia by abdominal ultrasound. If indicated, antibiotic prophylaxis and proper immunization with pneumococcal polysaccharide vaccine and meningococcal conjugate vaccine should be administered when age appropriate to protect against invasive encapsulated organisms. A high index of suspicion for invasive bacterial disease should be maintained in all patients with MWS presenting with any febrile illness.

• Web site for families affected by MWS: www.mowat-wilson.org/;

• Australian Mowilsi site: www.mowatwilsonsupport.org/;

• French forum for families: smwf.forumactif.org/; and

• Italian support group: www.mowatwilson.it/.

MWS

Mowat-Wilson syndrome