Unexpected death due to refractory metabolic acidosis and massive hemolysis in a young infant with Prader–Willi syndrome

We read with interest the two research articles recently appeared in this Journal, about the causes of death in subjects with Prader–Willi syndrome (PWS) [Schrander-Stumpel et al., 2004; Stevenson et al., 2004]. PWS is a genetic disorder, which may be difficult to diagnose at birth given the paucity of dysmorphic features. Beyond the well-known phenotype and the neurodevelopmental features, the recently described hypothalamic dysfunction appears to have a crucial role in the prognosis of infants with this syndrome. In particular, temperature dysregulation, adrenal insufficiency, and impaired ventilation control might be involved in unexpected death cases observed in the first few months of age. We describe the clinical course of a 6-month-old female infant affected by PWS, who eventually died after a short history of acute febrile enteritis followed by generalized seizures, refractory metabolic acidosis, and massive hemolysis. Parents originate from India and are not consanguineous. The mother is a 27-year-old at her first pregnancy no miscarriages were reported (G1 P0 A0). Pregnancy was entirely followed-up in Italy. Intrauterine asymmetric fetal growth restriction was detected by routine ultrasound examinations. Prophylaxis for lung maturity with steroids was administered. The patient was born at 34 weeks of gestational age by caesarian section because of fetal bradycardia. Birth weight was 1,710 g (5–10th centile), length 43 cm (10th centile), and head circumference 31 cm (50th centile). Mild intrapartum asphyxia was recorded. Apgar score was 7, 8, and 9 at the 1st, 5th, and 10th minute, respectively. Free-flow oxygen supplementation was necessary during the first 12 hr of life. Soon after birth she was noted to be limp, poorly reactive, and responsive to tactile stimuli. Cry was very weak. No major physical anomalies were recorded. In the third day of life transient apnea episodes were recorded, with no evidence of infections. In the first well-child visits at the newborn nursery she was noted to be hypotonic (particularly central and upper limbs) and primary neonatal reflexes were not elicitable. During her stay in the nursery, feeding and growth were poor, while persistent mild compensated respiratory acidosis was documented. Basic metabolic studies were normal. Due to her abnormal neurological pattern, further investigations were performed, and a methylation study led to the diagnosis of PWS (a-exon, Prader–Willi–Angelman region; SNRPN 15q11/q13 and absence of paternally derived gene). Her feeding pattern gradually improved and the failure to thrive subsided. The patient was discharged home and no other relevant illnesses were reported in her past medical history. At 6 months of age she was referred to the pediatric emergency department of a district hospital for a few-hours history of non-productive cough and mild upper respiratory tract infections. Body weight was 5.5 kg (3rd centile); with a presumed weight loss of about 5%. She was subsequently admitted to the Pediatric ward and diagnosed with pneumonia. Topical bronchodilator therapy and parenteral broad-spectrum antibiotic therapy were commenced. Respiratory symptoms gradually subsided. After 24 hr since admission she developed watery diarrhea and high fever (398C). The patient was hyponatremic and moderately dehydrated and intravenous fluids were then commenced. Physical examination was otherwise unremarkable. Stool culture revealed a Rotavirus infection. Gastroenteritis symptoms persisted for the subsequent 48 hr. At the sixth day of admission she presented a sudden episode of cardiorespiratory arrest. Cardiopulmonary support was immediately instituted, and return of spontaneous circulation was obtained after 12 min, soon followed by generalized seizures activity. The patient was treated with intravenous diazepam and subsequently referred to our PICU. Upon admission the clinical conditions were critical, with ongoing seizure activity, high fever (408C), tachycardia (heart rate> 200 bpm) and hypotension. Central venous pressure was 4–6 cm H2O. Venous blood gas analysis revealed severe metabolic acidosis (pH1⁄4 6.99, pCO21⁄4 42 mmHg, pO21⁄4 35 mmHg, HCO31⁄4 7, BE1⁄4 25). No evidence of mucocutaneous petechiae or purpura was present. High ventilatory parameters as well as high oxygen concentration were required (Oxygenation Index ranged between 35 and 60). A chest radiograph showed right-sided patchy infiltrates consistent with aspiration. Despite aggressive fluid resuscitation and bicarbonate infusion the acid–base status remained compromised (best pH value1⁄4 7.00), and the patient became oliguric. An echocardiographic evaluation documented a normal biventricular function. Poor peripheral perfusion prompted inotropic support with dopamine and epinephrine, which had to be raised to maximal level in the next few hours, with scarce response. Continuous electroencephalographic recording showed persistent and diffuse seizure activity, which subsided only after repeated boluses of phenobarbital and phenytoin. Blood chemistry showed elevated creatinine and urea nitrogen. Potassium was 5.3 mM/L. *Correspondence to: F. Zaglia, M.D., Pediatric Intensive Care Unit, Major City Hospital, Piazzale A. Stefani, 1, I 37126 Verona, Italy. E-mail: federico.zaglia@azosp.vr.it