Multiorgan Dysfunction in a 7-Month-Old Boy With Developmental Delay and Poor Growth

A 7-month-old male infant presents to a community emergency department with increased work of breathing and several days of vomiting and fevers. He is tachycardic with a heart rate of 180, febrile to 38.9°C, hypotensive with blood pressure of 60/40, and hypoxemic with an oxygen saturation below 80% on room air. He appears toxic with sluggishly reactive pupils, poor perfusion, and an agonal breathing pattern. He is intubated for his depressed mental status and acute hypoxemic respiratory failure. He receives 40 mL/kg of normal saline, is started on an epinephrine infusion for continued hypotension, and is given ceftriaxone for possible septic shock. His laboratory workup is significant for leukocytosis with a white blood cell count of 15.5 × 109/L and acute kidney injury with a blood urea nitrogen of 38 mg/dL and creatinine of 1.24 mg/dL. A chest radiograph shows a normal cardiac silhouette, clear lung fields, and no fractures. Urinalysis is normal with no signs of infection. Due to his altered mental status, a urine drug screen is sent and is positive for methamphetamine. Computed tomography of the head (CT Head) is performed, demonstrating expansion of the subarachnoid space, most likely due to global atrophy with areas of remote infarction involving the basal ganglia and frontal lobe corona radiata without evidence of acute fracture, hemorrhage, or edema. During transfer to the pediatric intensive care unit (PICU) at the children’s hospital, he has an episode of upward gaze deviation with rhythmic bilateral upper extremity jerking concerning for seizure activity that resolves with midazolam.On arrival to the PICU, he is persistently febrile to 38.4 °C and, tachycardic with a heart rate of 172, and now has oxygen saturations in the low 90s on 60% fraction of inspired oxygen. He is hypertensive with systolic blood pressures in the 200s, so the epinephrine infusion is weaned. His examination reveals an intubated infant with a cervical collar in place. He has spontaneous eye opening but does not blink to threat. His pupils are small but reactive bilaterally. Overlapping sutures with plagiocephaly are noted with sparse hair. He has poor peripheral perfusion with a capillary refill of 3 seconds. His lung examination reveals equal air movement bilaterally with spontaneous respirations above the ventilator. He has increased appendicular tone, with spontaneous asynchronous, nonrhythmic, nonpurposeful movements of his extremities. Admission laboratory results demonstrate lactic acidosis with a venous pH of 7.22 and lactate of 3.9 mmol/L (reference range: 0.7 to 2.0 mmol/L). Complete blood count reveals thrombocytopenia with a platelet count of 28 × 109/L, a normal hemoglobin of 10.5 g/dL, and normal white blood cell count of 9.9 × 109/L with a lymphocytic predominance with 44% lymphocytes, 31% neutrophils, and 1.7% bands. Thyroid-stimulating hormone is normal. Evaluation for infections includes a rapid viral panel, which is positive for coronavirus NL63, and blood cultures. Due to his thrombocytopenia, no lumbar puncture is performed. His mother reveals he was in his usual state of health until 5 days prior to presentation when he developed nonbloody and nonbilious emesis and diarrhea with associated decreased oral intake. His brother had symptoms of an upper respiratory tract infection recently, but otherwise, there are no other known sick contacts. Past medical history includes birth at 35 and 6/7 weeks unexpectedly at home. He was admitted to the neonatal intensive care unit for 10 days for respiratory distress and temperature instability requiring noninvasive ventilation. He was appropriate for gestational age, with a birth weight at the 46th percentile (2.65 kg), length at the 21st percentile (45 cm), with head circumference at the 62nd percentile (33 cm). Due to the COVID-19 pandemic, he has had poor follow-up and is incompletely immunized with only documented immunizations at age 4 months. The mother describes severe global developmental delay with general hypotonia, inability to control his head, positional plagiocephaly, no babbling, and inability to transfer objects. Admission measurements reveal he has poor growth with weight at the seventh percentile (7.0 kg), height less than first percentile (63cm), and head circumference less than the third percentile (41.7 cm). Additional medical history reported by his mother includes an accidental mild head trauma at age 3 months where the mother reports she witnessed his then 1-year-old brother attempting to lift him from the floor and dropping him from standing height. He was immediately brought via emergency medical services (EMS) to a local emergency department. A CT Head revealed no acute fracture, hemorrhage, or edema; however, there were symmetric hypodensities in the basal ganglia that could represent old infarcts and encephalomalacia. EMS reported concerns of drugs and alcohol in the home, but a urine drug screen was negative, and he was discharged home. He lives with his parents, 2-year-old brother, and maternal grandparents. Family history is significant for 2 maternal uncles who died at a young age. On the evening of admission, the mother mentioned that the patient had coarse curly hair at birth, which became sparse over time.Osseous survey demonstrates multiple abnormal skeletal findings: asymmetry of the skull with prominent lucencies (likely wormian bones) without fracture (Figure 1), mild irregularity and lucency of the right lateral fifth and sixth ribs, symmetric cortical thickening of the humerus midshaft, subtle bilateral periosteal thickening of the medial distal humerus, and small distal femoral metaphyseal spurs (Figure 2). No previous imaging is available for comparison. An ophthalmologic examination and echocardiogram are normal. He develops synchronous movements with bilateral flexion and elevation of the upper extremities with subtle neck flexion and is placed on a video electroencephalogram (vEEG), which demonstrates electroclinical seizures consistent with infantile spasms. He is started on vigabatrin and clobazam. Based on his severe presentation, multiorgan dysfunction, bone abnormalities, chronic brain injury, and vEEG findings, there is concern for a possible chronic underlying disorder. Consultation with genetics and neurology results in the initiation of a genetic evaluation that reveals the eventual diagnosis.This patient presented in acute cardiopulmonary failure of unclear etiology associated with fevers and nonbloody and nonbilious emesis. His medical history was significant for global developmental delay, poor growth, and progressive microcephaly. A broad differential was considered with increased suspicion for an acute illness superimposed on an underlying chronic medical condition leading to the severity of presentation.With his initial positive drug screen, additional toxic ingestions (ie, anticholinergics and/or sympathomimetics) were considered. Further urine drug testing included liquid chromatography–tandem mass spectrometry, which is validated to detect more than 50 substances. No additional unprescribed substances were detected and these results were reviewed by the laboratory director to ensure accuracy.Both accidental and nonaccidental trauma (NAT) were strongly considered based on the findings of bony abnormalities and abnormal brain imaging. Accordingly, the Child Abuse Pediatrics team was consulted and the state-mandated investigatory agencies were involved; however, with a skin examination without bruising or injury, normal retinal examination, head imaging without any signs of acute injury or bleeding, and bony abnormalities without any evidence of callus formation or remodeling on repeated imaging, trauma was an unreasonable explanation of his presenting symptoms, chronic poor growth, and developmental delay.Based on the presence of fever, emesis, and cardiorespiratory failure, acute infectious etiologies were strongly considered. It is important to consider sepsis as a cause of his presentation given his fevers, hypotension, leukocytosis, and multiorgan dysfunction. His presentation could be consistent with an acute systemic viral infection secondary to coronavirus NL63 with central nervous system involvement, such as encephalitis or meningitis. Although his acute viral infection likely contributed to his seizure activity, his vEEG was suggestive of an underlying seizure disorder rather than an acute infectious process, furthering the suspicion of an underlying chronic illness.With respect to a possible underlying etiology that linked metabolic acidosis, poor growth, microcephaly, and developmental delay with maternal uncle death in infancy, the team considered inborn errors of metabolism such as disorders of fatty acid oxidation, organic acidemias, pyruvate dehydrogenase deficiency, mitochondrial disorders, and X-linked disorders. Micronutrient and vitamin deficiencies, such as thiamine or zinc deficiency, were also considered.The patient underwent additional neurologic evaluation with magnetic resonance imaging of the brain (MRI Brain), which identified tortuous cervical and intracranial arteries (Figure 3). His metabolic screening was significant for low ceruloplasmin of 6 mg/dL (normal 14–40 mg/dL) and low serum copper of 0.22 μg/mL (normal 0.4–1.7 μg/mL). Copper levels can be low secondary to nutrition during infancy or indicate an inherited disease of copper metabolism. To distinguish between these, rapid whole exome sequencing was performed, which demonstrated a pathogenic X-linked hemizygous nonsense mutation in the ATP7A gene consistent with Menkes disease.In addition to Menkes disease, a child maltreatment diagnosis was indicated because methamphetamine exposure represents harm from an unsafe environment. Unfortunately, the precise nature of his methamphetamine exposure was not able to be determined. Although children living in a drug-endangered environment are at higher risk of physical abuse than children not exposed to such an environment, a comprehensive evaluation by the Child Abuse Pediatrics team and investigation by state-mandated investigatory agencies was unable to identify direct evidence of trauma (accidental or nonaccidental). Aside from the methamphetamine-positive drug screen, all findings were consistent with a diagnosis of Menkes disease. Ultimately, it was determined that he presented with viral septic shock complicated by methamphetamine drug exposure in the setting of undiagnosed and untreated Menkes disease.Menkes disease is an X-linked recessive disorder characterized by generalized copper deficiency with an incidence of 1 in 35 000 live male births.1 Pathogenic variants in the ATP7A gene result in a defect in the copper transport protein causing a spectrum of X-linked disease processes including Menkes disease, occipital horn syndrome, or ATP7A-related distal motor neuropathy.2–7 As copper is a necessary cofactor for multiple enzymes within the human body, the phenotypes present as a range of abnormalities of the musculoskeletal, cardiovascular, and nervous system.4Menkes disease is characterized by progressive neurodegeneration, connective tissue abnormalities, and distinctive “kinky” hair. These patients often appear healthy for the first few months of life. Diagnosis is often suspected in the setting of neurodevelopmental deficits, seizures, growth failure, and characteristic hair growth abnormalities with short, sparse, coarse, twisted, and lightly pigmented hair.3–5,7,8 Decreased activity of the key copper-dependent enzyme that catalyzes elastin and collagen cross-linking (lysyl oxidase) significantly contributes to the connective tissue abnormalities of Menkes disease.7–9 As a result, patients with Menkes disease have fragile bones, which may result in fractures. Abnormal blood vessel structure due to defective elastic fibers causes distinctive vascular tortuosity and increased risk for spontaneous arterial thrombotic and/or hemorrhagic events.6,10 The most commonly reported vascular event is spontaneous intracranial hemorrhage, including subdural hemorrhage. There are also reports of spontaneous subserosal gastrointestinal (GI) hemorrhage leading to bowel obstruction and upper GI bleeding from hyperplastic gastric polyps.10–12 With the increased risk for fractures and spontaneous hemorrhage, findings of Menkes disease can mimic NAT. With multidisciplinary evaluation and thorough physical examination and radiograph/laboratory evaluation, distinguishing between the 2 becomes more distinct.8,10,13–15Early detection and implementation of copper-histidine injections are crucial to increase survival and reduce the progression of this neurologic disease. Unfortunately, current evidence suggests that copper injections only modify disease progression if initiated within days after birth.7,9,10 Without treatment, the neurologic manifestations appear between ages 2 and 3 months, with loss of developmental milestones, hypotonia, and seizures. Disease progression is variable regardless of treatment, but most children die before age 3 years.3 Currently, the use of adeno-associated virus-based gene therapy to target the underlying genetic defect in muscular dystrophy is being investigated as a potential therapeutic approach.2 Genetic counseling is recommended for the parents of affected children with maternal genetic testing and subsequent discussion of recurrence risk. There is currently no standard practice for earlier identification; however, with a known familial mutation, prenatal and neonatal testing is feasible.7 Recent efforts have focused on the development of a primary DNA-based newborn screen to allow for earlier detection and treatment in asymptomatic neonates.16The patient improved with supportive care for his viral illness and was able to be extubated and on room air 12 days after admission. His PICU course was complicated by left common femoral vein and left subclavian vein thromboses, for which he was started on therapeutic enoxaparin. He was transferred to the inpatient floor to further understand his long-term medical needs. Repeat MRI Brain identified the progression of his disease with marked further parenchymal loss. Unfortunately, on hospital day 19, he developed bloody stools associated with acute abdominal distension and hemorrhagic shock prompting transfer back to the PICU. A CT abdomen revealed a large intramural hematoma extending along the rectosigmoid colon. This was not present on the CT abdomen obtained at admission and occurred after weeks of hospitalization, indicating that this was not related to his initial presentation but a complication of his disease and anticoagulation. He underwent emergent bowel resection and sigmoid colostomy.Following his surgical intervention, he remained critically ill with an overall poor prognosis. Due to the late diagnosis and rapid progression of his disease, he was deemed ineligible for copper therapy. The patient’s parents were at the bedside throughout his admission, understanding the terminal nature of his disease. They chose to transition to end-of-life care and he ultimately died 30 days after admission.Menkes disease is an X-linked recessive disorder characterized by generalized copper deficiency resulting in progressive neurodegeneration, connective tissue abnormalities, and distinctive kinky hair.Molecular genetic testing should be performed to confirm the diagnosis as ceruloplasmin, and copper can be low secondary to nutrition during infancy.Menkes disease requires early treatment with copper injections to slow progression of the disease.Menkes disease can mimic signs of nonaccidental trauma.Medically complex children are at higher risk of maltreatment than other children so diagnoses may coexist.Consider an underlying chronic disease when the severity of an illness is out of proportion to the expected course of that illness.In the setting of developmental delay, poor growth, and a family history of early deaths, consider an underlying (genetic) process.