Wolcott–Rallison syndrome (WRS) is a rare autosomal recessive disease caused by endoplasmic reticulum (ER) dysfunction.1 It was first reported in 1972 and fewer than 60 cases of WRS have been reported so far in the literature.2 It is characterised by neonatal/early-onset nonautoimmune insulin-dependent diabetes associated with skeletal dysplasia. Liver dysfunction is the third most common and the most life-threating complication. Other manifestations include hypothyroidism, renal dysfunction, neutropenia, recurrent infections, mental retardation, exocrine pancreas insufficiency, mitral valve dysplasia, laryngeal stenosis, pulmonary hypoplasia and arrhinencephaly. Death can occur in a situation of multiple organ failure with predominant liver and renal dysfunction, sometimes associated with encephalopathy.
After obtaining parental consent to both the intervention and to publish this case report, we present the perioperative management of a patient with WRS, undergoing elective orthopedic surgery. A 12-year-old girl (height 1.45 m; weight 32 kg) was scheduled for distal femoral varusosteotomy and total hip replacement. Medical history revealed atlas hypoplasia, magnum foramen stenosis, type 4 renal tubular acidosis and insulin-requiring diabetes. She had previously suffered from paracetamol-induced acute liver failure, caused by treatment with normal doses (15 mg kg–1), and also developed acute kidney failure that required haemodialysis after appendectomy. She was treated with oral sodium bicarbonate and a combination of intermediate-acting insulin and short-acting insulin. The patient was followed up by her paediatrician once a year and presented neither cardiovascular nor other disease manifestations. Preanaesthesia evaluation included admission 24 h before surgery. Continuous intravenous insulin infusion with glucose 5% was started 2 h before surgery. Blood glucose was monitored hourly before and during surgery. Glycaemic target levels were set between 5 and 11 mmol l–1 (90 to 200 mg dl–1).3 Anaesthesia chosen was total intravenous anaesthesia with propofol and fentanyl in combination with epidural anaesthesia. Intubation with a size 6 endotracheal tube was performed with in-line head and neck position without difficulty. No muscle relaxant was used. The epidural puncture was performed at L3-L4 with an 18G Tuohy needle; the response to a test dose with lidocaine and adrenaline 1 : 100 000 was negative. After a 6-ml bupivacaine 0.33% bolus, continuous epidural infusion of bupivacaine 0.33% (3 ml h–1) was started. Anaesthesia was maintained by propofol infusion so that bispectral index was 40 to 60; the dose never exceeded 4 mg kg–1 h–1. Surgery lasted nearly 10 h. About 3100 ml of Plasmalyte and 150 ml of red blood cells were administered. Blood gas and lactic acid analysis were performed every hour in order to detect any metabolic problems – for example, the start of a propofol infusion syndrome – as soon as possible. The maximum level of lactic acid was 1.8 mmol l–1. Arterial pH was always within the range 7.30 to 7.45. Extubation took place in the operating room. She was admitted to the ICU for a 24-h period, where she made an uneventful recovery.
WRS is caused by mutations in the gene encoding eukaryotic translation initiation factor 2α-kinase (EIF2AK3), an ER transmembrane protein, which plays a key role in translation control during the unfolded protein response. Molecular genetic testing confirms the diagnosis.
Typically, diabetes occurs before 6 months of age and it is the first cause of paediatric diabetes in consanguineous parents.4 Close therapeutic monitoring is recommended because of the tendency for frequent acute episodes of both hypoglycaemia and ketoacidosis. Treatment with insulin should not target a very tight control of blood glucose, in order to avoid hypoglycaemia, which may trigger episodes of acute aggravation of the disease. All patients with WRS must be admitted to hospital for general anaesthesia and need insulin, even if fasting, to avoid ketoacidosis. In the context of major surgery, treatment using an insulin pump is recommended. They should receive a glucose infusion when fasting for more than 2 h before an anaesthetic to prevent hypoglycaemia. Procedures are preferably scheduled first on the operating list.
Skeletal dysplasia is diagnosed within the first year or two of life; it affects the long bones, pelvis and vertebrae. Bone mineralisation is affected. Multiple fractures can be observed. Regarding vertebrae, changes are especially marked at the dorsolumbar level with a consequent appearance of thoracic kyphosis and/or lumbar lordosis. Difficulty in walking is frequent. The extreme skeletal condition may manifest with severe cervical spine instability, which may result in spinal cord compression and motor neuropathy in arms and legs.5 Radiography is the mainstay in scoliosis imaging to both confirm the diagnosis and rule out any underlying conditions. Patients presenting with scoliosis have to be evaluated carefully, because this can make neuraxial blockade extremely difficult. MRI is useful for diagnosing associated spinal and neurological lesions.6 Preoperative chest and abdominal radiographs revealed no signs of scoliosis in our patient, so we placed our epidural catheter with no further examination.
Liver disease may manifest as elevated liver enzymes or hepatomegaly and it may lead to liver failure,7 sometimes accompanied by acute multiple organ failure (encephalopathy, renal and bone marrow failure). As ER dysfunction is central to the disease processes and although clinical experience does not substantiate concerns over the potential hepatotoxicity and nephrotoxicity of the sevoflurane byproducts (plasma fluoride ions and pentafluoroisopropenylfluoromethyl ether, also known as ‘Compound A’), the activation of free radical metabolising enzymes and the increased cytosolic free calcium, we chose to perform total intravenous anaesthesia.8,9
As WRS involves a major risk, an interdisciplinary team approach is the cornerstone for a well tolerated management throughout the perioperative period. It is very important to inform the patient's relatives of the risk of developing acute multiple organ failure during any intercurrent illness, in order that they can recognise these episodes very early and arrange for appropriate symptomatic treatment to be instituted. Interventions under general anaesthesia increase the risk of acute aggravation. Regional techniques are an excellent option in these patients. They are at a high risk for metabolic, liver and kidney failure and should be managed accordingly.
Acknowledgements relating to this article
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