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Anaesthesia and orphan disease

primary autosomal recessive microcephaly-10 caused by a mutation in the ZNF335 gene

Nishida, Takaya; Mihara, Takahiro; Horiki, Toshimi; Ka, Koui

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European Journal of Anaesthesiology: July 2016 - Volume 33 - Issue 7 - p 543-545
doi: 10.1097/EJA.0000000000000358
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Editor,

Primary autosomal recessive microcephaly-10 (MCPH-10) is caused by a homozygous mutation in the ZNF335 gene on chromosome 20q13.1 The ZNF335 gene is essential for neural progenitor self-renewal, neurogenesis and neuronal differentiation. The prevalence of all types of MCPH ranges from 1 in 30 000 to 1 in 250 000.2 The causes of microcephaly are classified as genetic (e.g. MCPH-10), syndromic [e.g. Seckel syndrome (SCKS)] or acquired (e.g. disruptive injuries or infections). To date, only eight patients with MCPH-10 have been reported, and no case reports have described the anaesthetic management of patients with MCPH-10. Because of the dysmorphic features of patients with MCPH-10, micrognathia and risk of choanal atresia, airway management may be difficult. Here, we report the anaesthetic management of a patient with MCPH-10 caused by a mutation in the ZNF335 gene. Written consent to publish this report was obtained from both parents of the child.

The female infant was born at 40 gestational weeks with an Apgar score of 9 out of 10. Her height was 49.5 cm (48th percentile), weight 3030 g (37th percentile) and head circumference 32 cm (13th percentile). She had been admitted to another hospital with vomiting and epilepsy at 3 months of age. Clinical examination revealed microcephaly, micrognathia, bilateral moderate hearing loss, epilepsy, severe mental retardation, rigidity in the upper limbs and spasticity in the lower limbs. In addition, hypoplasia of the striatum and cerebellum were noted on brain MRI. At 25 months, she could not follow with her eyes nor could she roll over, and she required tube feeding because of malnutrition secondary to severe gastro-oesophageal reflux. In an effort to minimise the latter, a laparoscopic Nissen fundoplication and gastrostomy under general anaesthesia were scheduled. Since birth, her growth had been slow, and at the time of the proposed surgery (25 months of age), her height, weight and head circumference deviated significantly from the normal growth curve. Her height was 84 cm (38th percentile), weight 10.2 kg (21st percentile), head circumference 41 cm (0th percentile) and exome analysis revealed a ZNF335 gene mutation. Phenobarbital 45 mg day−1 was administered for epilepsy, and symptoms were well controlled. Levodopa 0.1 g day−1 was prescribed for rigidity in the upper limbs. The last dose of levodopa was given 5 h before surgery.

The patient was brought to the operating room without premedication. Standard noninvasive monitoring (electrocardiogram, blood pressure and pulse oximetry) was commenced and anaesthesia was induced by inhalation of 5% sevoflurane with 4 l min−1 nitrous oxide and 2 l min−1 oxygen via a face mask. After loss of consciousness, nitrous oxide was discontinued, the inspired concentration of sevoflurane was reduced to 3% in 97% oxygen and an intravenous cannula was inserted. Mask ventilation was confirmed, and atropine (0.01 mg kg−1), fentanyl (1 μg kg−1) and rocuronium (0.5 mg kg−1) were administered intravenously. As one of the potential challenges of anaesthetic management for patients with MCPH-10 is difficult intubation due to micrognathia, a video-laryngoscope (Airtraq) was prepared as a backup device. Initially, the laryngoscopic view was Cormack–Lehane grade 3, but this improved to Cormack–Lehane grade 2 with backwards–upwards–rightwards pressure (BURP) on the larynx, and the trachea was intubated orally using an uncuffed endotracheal tube (internal diameter, 5.0 mm). Anaesthesia was maintained with 1 to 1.5% sevoflurane, fentanyl (total dose 5 μg kg−1) and remifentanil (0.2 to 0.5 μg kg−1 min−1). High-dose remifentanil (0.5 μg kg−1 min−1) was required to control her blood pressure. Because the train-of-four count was 0 after the surgery (more than 3 h after rocuronium administration), sugammadex (4 mg kg−1) was used to reverse the neuromuscular blockade. When effective spontaneous breathing had occurred, along with eye opening, the trachea was extubated. Postoperatively, she was cared for in the ICU and, after an uneventful period of observation, she was transferred to the general ward the day after surgery.

ZNF335 gene mutation is associated with extreme microcephaly with a severely simplified gyral pattern, decreased brain size, increased extra-axial space, enlarged ventricles, absence of the corpus callosum and delayed myelination.1 Histopathologically, a thinned cerebral cortex, neuronal disorganisation and abnormalities in the cortex have been noted. In addition, there are dysmorphic features, arthrogryposis, joint contractures and increased muscle tone and spasticity. In MCPH-10 caused by ZNF335 gene mutation, disease features occur as a static developmental anomaly without visceral malformation.

Anaesthetic management of MCPH-10 has not been reported; however, some case reports have described anaesthetic management in patients with SCKS, which is related to MCPH in that patients with SCKS also present with microcephaly and absence of visceral malformation.3 In the case reports of patients with SCKS, anaesthesia was maintained safely with volatile agents,4–6 but frequent problems were encounteredal with mask ventilation and intubation because of the morphologic abnormalities, with friable veins and with postoperative apnoeic spells. Prolonged neuromuscular recovery after vecuronium has also been reported.6 In our case, despite the micrognathia, we were able to intubate the trachea with direct laryngoscopy using the BURP manoeuvre. However, an adequate backup device for difficult intubation should be available in such cases, and in our case, we prepared the Airtraq. The Paediatric Difficult Airway Guidelines7 produced by the Difficult Airway Society propose a step-wise algorithm for unanticipated difficult intubation and recommend inserting a supraglottic airway device if initial tracheal intubation fails. Although the Airtraq was not mentioned in these guidelines, we prepared the Airtraq as the backup device because it has been recommended as an initial approach for intubation in paediatric patients with micrognathia.8 Tracheal growth of the patient was not affected and so we could intubate the trachea of this 33-month-old patient with an uncuffed endotracheal tube with an internal diameter of 5.0 mm. However, because the child's nares are small, if nasal intubation is required, a smaller size of cuffed tracheal tube should be foreseen; as the trachea is normal, a smaller uncuffed tube is likely to lead to a significant air leak around the tube.

Interestingly, the effects of rocuronium were prolonged. The mechanisms associated with this prolonged effect of neuromuscular agents in patients with MCPH-10 have not been elucidated. Thus, the level of neuromuscular blockade should be monitored, and sugammadex could be used safely to reverse the neuromuscular blockade, if necessary.

In our case, levodopa had been prescribed for rigidity. Because this drug can cause intraoperative hypotension, intravenous volume expansion, or administration of a vasopressor such as phenylephrine, should be considered.

Although, postoperatively, desaturation did not occur in our patient, there is a potential for postoperative complication such as airway obstruction, desaturation or apnoeic spells.6 Therefore, we would recommend postoperative monitoring in the postanaesthesia care unit or ICU. The anomalies, which may be associated with MCPH-10, and the associated risks and tasks required to minimise these risks during the perioperative period, are summarised in Table 1.

Table 1
Table 1:
Potential anomalies in MCPH-10 caused by ZNF335 mutation

In conclusion, after adequate preparation for difficult airway management, we successfully anaesthetised a patient with MCPH-10 using volatile anaesthesia. The level of neuromuscular blockade should be monitored, and sugammadex can be used safely to reverse neuromuscular blockade.

Acknowledgements relating to this article

Assistance with the letter: none.

Financial support and sponsorship: none.

Conflicts of interest: none.

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