Thermal dysregulation in Prader-Willi syndrome: a potentially fatal complication in adolescence, not just in infancy

Abstract

A 13-year-old boy with a background of Prader-Willi syndrome (PWS) was admitted to the regional paediatric intensive care unit, with community-acquired pneumonia. Despite a week of intravenous antibiotics, resolution of inflammatory markers and resolving consolidation on radiograph, he remained feverish. Fever of unknown origin investigations were negative and he was diagnosed with central thermal dysregulation secondary to hypothalamic dysfunction in PWS. Following a hyperpyrexia period, secondary rhabdomyolysis and renal failure developed. This was successfully managed with active cooling, ventilation and haemofiltration. After weaning from haemofiltration, the patient was successfully extubated to non-invasive respiratory support.

Background

Thermal dysregulation is a recognised complication of Prader-Willi syndrome (PWS).¹ It is usually a benign situation but can, in extremes, result in hyperpyrexia.² Hyperpyrexia can result in multiorgan failure and death if not treated correctly. Previous cases of hyperpyrexia in PWS have been reported during infancy.^{1 2} This case illustrates that it can also occur in adolescence.

Case presentation

A 13-year-old boy with a background of PWS was admitted to the paediatric intensive care unit (PICU) following intubation for severe respiratory distress and acute on chronic type 2 respiratory failure. His presenting symptoms included a 2-day history of shortness of breath, left upper quadrant pain, fever and wheeze. He was initially managed with nebulised and intravenous bronchodilators. Despite treatment, his acute on chronic type 2 respiratory failure worsened, necessitating intubation.

His comorbidities included obesity, obstructive sleep apnoea, asthma, hypertension, fatty liver disease, type 2 diabetes mellitus, hypercholesterolaemia and hypospadias. This was his first acute paediatric admission. His regular medications on admission to PICU were Enalapril, Metformin, Montelukast and Loperamide. Enalapril was discontinued 2 days following admission as his mean arterial blood pressure was initially noted to be low.

Chest radiograph following intubation confirmed left lower lobe consolidation (figure 1) and he was treated with intravenous piperacillin/tazobactam and oral clarithromycin. White cell count was 14.5×10⁹/L with neutrophils 11.5×10⁹/L and a maximum C reactive protein of 88 mg/L. Blood culture, blind bronchoalveolar lavage (BAL) and respiratory virology were negative. The patient's inflammatory markers normalised and consolidation on chest radiograph improved significantly with antibiotic therapy. However, despite this, he remained feverish with baseline temperature between 38°C and 39°C. He did not display clinical features in keeping with Kawasaki disease.

Figure 1.

Chest radiograph on admission to paediatric intensive care unit, 2 days following onset of symptoms, showing left lower lobe consolidation.

Two attempts at extubation were unsuccessful on day 7 and day 11 in PICU. On day 9 in PICU, antibiotic therapy was discontinued and a full septic screen was repeated. This included central and peripheral blood culture, urine, blind BAL and lumbar puncture. Chest X-ray appearances continued to improve, although residual changes remained present at the left lower lobe. All cultures remained negative.

Following the negative septic screen, further investigations directed towards the underlying aetiology of ongoing fever of unknown origin were undertaken. Inflammatory markers remained normal, while viral serology and an autoimmune screen were negative. Hormone assays showed a sick euthyroid pattern on thyroid function tests and normal cortisol levels. Follicle-stimulating hormone, luteinising hormone and testosterone level were low, in keeping with hypogonadotropic hypogonadism. Abdominal CT and ultrasound revealed no intra-abdominal source. CT of the head and sinuses showed paranasal sinus congestion secondary to nasal intubation. Ear, nose and throat department review felt this was unlikely to be the cause of persistent fever and would clear with extubation. Transoesophageal echocardiogram showed no evidence of bacterial endocarditis. A diagnosis of thermal dysregulation secondary to PWS was made.

The patient's parents were unsurprised by their son's high temperatures and reported that from a young age he would subjectively have felt hot at home. As he was always systemically well and asymptomatic, they had never formally measured his temperature during these periods. No previous investigation work up had been performed and fever had never necessitated hospital admission prior to this episode.

On day 16 in PICU, while still intubated and ventilated, a marked worsening of the patient's fever developed with a persistent temperature constantly above 39.5°C, contrasting with the previous pattern of a baseline fever between 38°C and 39°C. This period included 6 hours of hyperpyrexia persistently climbing towards 42°C (figure 2). At the peak of the hyperpyrexia, he became hypotensive with systolic blood pressure at 75 mm Hg. Aggressive fluid resuscitation was administered and a norepinephrine infusion was started to maintain a mean arterial pressure between 70 and 80 mm Hg. This target was chosen as it was the patient's 50th centile mean arterial pressure.

Figure 2.

Temperature observations on day 16 in paediatric intensive care unit, showing prolonged hyperpyrexic period.

With the change in fever pattern and deterioration in cardiovascular status, he was recultured before starting meropenem, vancomycin and fluconazole. Despite this, over the course of the day he became oliguric with urine output falling to 0.3 mL/kg/hour.

Investigations

Blood tests taken over the period of deterioration failed to show an inflammatory marker rise, however, creatinine rose from a baseline of 81–231 μmol/L. In addition, creatine kinase (CK) climbed from a baseline of 72 U/L to a peak of 10 339 U/L. Chest radiography showed new right mid-zone changes along with residual changes in the left lower lobe (figure 3). Cultures and virology taken were ultimately negative.

Figure 3.

Chest radiograph on day 16 of paediatric intensive care unit following admission, showing new right middle lobe consolidation and resolving air space opacification in left lower lobe.

Differential diagnosis

1. Hospital-acquired pneumonia leading to hyperpyrexia and rhabdomyolysis culminating in acute kidney injury in the setting of PWS central thermal dysregulation.

2. Hospital-acquired pneumonia causing systemic inflammatory response syndrome, leading to prerenal acute kidney injury and rhabdomyolysis; however:

   1. There was no associated inflammatory marker rise;
   2. No positive cultures with the deterioration and
   3. Mean arterial pressure was quickly maintained with vasopressor support.
3. Malignant hyperthermia or neuroleptic malignant syndrome, however:

   1. There was no positive family history and
   2. No exposure to any known trigger drugs or toxins.

Treatment

The patient was actively cooled with a cooling mattress, cooling blanket and ice packs towards normothermia. He was hyperhydrated with intravenous fluids and cardiovascular support was given via vasoactive drug infusions. He remained intubated and ventilated throughout. Haemofiltration was used to support his kidneys and as a cooling method.

Outcome and follow-up

Following the instigation of active cooling measures, the temperature was quickly controlled below 38°C. The CK level slowly resolved to normal over the following 11 days, while renal function also normalised. The patient was successfully weaned from haemofiltration on day 26 in PICU, at which point his antimicrobial therapy was discontinued. On day 30, he was successfully extubated to continuous non-invasive positive pressure ventilation on the third attempt and then weaned to high flow oxygen therapy.

After 52 days in PICU, he was discharged to the ward on nocturnal non-invasive ventilation for obstructive sleep apnoea. While on the ward, further temperatures between 38°C and 39°C were documented but he remained systemically well and otherwise asymptomatic. He underwent intensive physiotherapy to regain his previous mobility and 78 days postadmission to PICU he was discharged home on nocturnal non-invasive ventilation.

Discussion

PWS is an imprinting genetic disorder caused by loss of expression of paternal chromosome 15q.³ First described in 1956 by Prader et al, PWS is a complex multisystem disorder in which clinical manifestations reflect hypothalamic and autonomic nervous system dysfunction.^3–5 Prevalence has been estimated between 1/15 000 and 1/25 000 live-births.³ While no structural hypothalamic defect has been found in PWS, DiMario and Burleson ⁵ have demonstrated that the primary disturbance in autonomic regulation exists primarily in parasympathetic function.

Typically, infants with PWS demonstrate marked axial hypotonia during the neonatal period, with signs of hypogonadism.^{3 6} These include genital hypoplasia and cryptorchidism. Hypotonia results in difficulty with feeding and delayed motor milestones during infancy.^{3 6} However, as the child ages and enters the preschool years, food obsession and hyperphagia develop, resulting in obesity.^{3 6} In contrast to non-syndromic obese children, those with PWS maintain a short stature due to growth hormone deficiency.

During adolescence, complications from obesity develop, resulting in a varied combination of type 2 diabetes, hypertension, hyperlipidaemia and obstructive sleep apnoea.^{3 6} Puberty is often disordered due to hypogonadism. Other associated endocrinopathies include secondary hypothyroidism and central hypoadrenalism.³

Hypothalamic and autonomic dysfunction also predispose to thermal dysregulation.^{3 5} This may present as hyper or hypothermia even without an identifiable cause. Hyperthermia can occur during minor illnesses.³ Conversely, fever may be absent despite severe infection.³ This propensity for thermal dysfunction has been implicated in critical illness in infants with PWS.^{1 2} In this patient, it would appear that hyperpyrexia culminated in rhabdomyolysis and consequential renal failure. Although this sequence has been documented in PWS infants, there are no reports in adolescents.

Hyperpyrexia refers to a core body temperature above 40°C and can result from an infection-driven systemic inflammatory response syndrome, a drug-induced hyperthermia or heat stroke. Heat stroke refers to a systemic inflammatory response syndrome triggered by an environmental or exercise-induced elevated body temperature resulting in multiorgan dysfunction.^{7 8} The exact temperature at which cellular damage occurs is not known.⁸ In hyperpyrexia, the initial heat stress results in peripheral vasodilation and hypovolaemia through increased insensible fluid loss resulting in hypotension.⁸ If left unchecked, subsequent renal hypoperfusion, rhabdomyolysis, cerebral oedema, encephalopathy, hepatic failure and disseminated intravascular coagulopathy develop.⁷

Management of hyperpyrexia requires active and aggressive cooling to 39°C followed by a slower cool towards normothermia.^{8 9} General cooling methods available include external cooling with immersion and internal cooling. Immersion cooling is first line and would include the use of cooling blankets and mattresses in combination with ice packs applied to axilla, groin and neck.^8–11 Internal cooling methods are used where external cooling has been ineffective. These methods would include gastric and bladder lavage with cool water along with infusion of cooled intravenous fluid.^8–11 If these techniques fail, additional methods include non-depolarising muscle relaxants to prevent muscle fasciculation and connection to extracorporeal circuits such as that in haemofiltration.^{8 10}

Intubation and ventilation may be required in those who are severely shocked or comatose. Intravenous fluid administration to treat hypovolaemia should be instigated, with the use of vasopressors as required to treat hypotension. Renal function, liver function, coagulation and CK levels should be closely monitored. Should rhabdomyolysis develop, hyperhydration should be initiated with consideration of urine alkinisation.⁸ In the setting of developing renal failure, haemofiltration should be started.

Specific cooling measures are determined by the aetiology of the hyperpyrexia. When driven by infection, the hypothalamic temperature set point is raised. This can be countered by the use of antifebrile agents such as paracetamol and non-steroidal anti-inflammatory drugs (ibuprofen). These medications work by inhibiting the formation of prostaglandins within the hypothalamus, thus normalising the homeostatic set point. Specific treatments for drug-induced hyperthermia would include intravenous dantrolene for malignant hyperthermia and oral bromocriptine for neuroleptic malignant syndrome.⁸ Antifebriles have no role in the management of heat stroke nor in controlling drug-induced hyperthermia, as homeostatic mechanisms have been overwhelmed rather than reset.⁹

Learning points.

• Hypothalamic dysfunction in Prader-Willi syndrome (PWS) predisposes to thermal dysregulation.

• In PWS, hyperthermia can result from minor illnesses while fever may be absent in severe infection.

• Hyperpyrexia can be drug induced or result from a systemic inflammatory response syndrome in the setting of infection or heat stroke.

• Unchecked hyperpyrexia can result in multiorgan failure.

• Management involves active cooling and fluid replacement. Support of organ system function with ventilation, vasoactive drugs and haemofiltration may be required. Specific therapy is guided by the cause of hyperthermia.

• Thermal dysregulation in PWS can result in potentially fatal complications in adolescence, not just in infancy.