Anaesthesia for children with DNA repair disorders

DNA repair disorders are caused by genes involved in DNA mutation detection and repair mechanisms. These disorders have diverse phenotypes which manifest at birth or early childhood. Although uncommon, these conditions can have significant implications in the perioperative management of patients affected.¹ In this article we discuss the perioperative management of the more common disorders: ataxia telangiectasia (AT), Cockayne syndrome and Fanconi anaemia.

Ataxia telangiectasia

Ataxia telangiectasia is an autosomal recessive condition with a prevalence of 1:100,000 live births, and a reduced life expectancy (25 yrs).² It is caused by mutations in the ataxia telangiectasia mutated (ATM) gene which leads to neurodegenerative changes, immunodeficiency and a predisposition to cancer.³

Clinical presentation

Ataxia telangiectasia usually presents in preschool age children with unsteady gait progressing to ataxia. Children can also present with difficulties in reading and writing as a result of oculomotor apraxia and fine motor incoordination, and involuntary movements such as chorea.^2,3 Oculomotor apraxia and choreoathetosis distinguish AT from other disorders. Children can exhibit foot abnormalities and scoliosis that may require surgical correction.⁴ Skin manifestations include telangiectasias on sun-exposed areas.³ As decline in neurological function progresses, they can develop dysphagia, which contributes to reduced growth, weight loss and an increased risk of aspiration. The aspiration combined with inherent immunodeficiency leads to sinopulmonary infections.⁵ Patients with AT are prone to developing particular cancers, namely childhood lymphomas, leukaemias and solid organ tumours in early adulthood.⁴ The risk of malignancy further increases with exposure to ionising radiation, making treatment problematic.³

Perioperative care

Preoperative

Children with AT should be managed in specialist centres where possible, because of their complex multisystem medical concerns.^2,6 A neurological examination to assess neuromotor function should be performed if regional or neuraxial anaesthesia is planned. The risk of aspiration should be assessed, based on the presence of swallowing difficulties, recurrent respiratory infections, choking episodes and poor nutritional status. Lung function tests may be helpful in assessing underlying chronic lung disease and decline in lung function, and those with significant respiratory dysfunction may require postoperative intermediate or intensive care. Radiological imaging should be minimised because the risk of developing cancers from ionising radiation is increased.³ As these patients may develop immunodeficiencies including reduced immunoglobulin concentrations, lymphopenia and failure to generate antibodies in response to immunisations or infections, they should be carefully screened for infection and may require immunoglobulin replacement before surgery.⁷ Nutrition may need to be optimised and supplemented before surgery with input from a specialist dietician.³ Adolescents are at a higher risk of developing insulin-resistant diabetes as impaired function of the ATM gene can disrupt insulin signalling, affect adipocyte differentiation and influence insulin-mediated glucose uptake. Patients should be screened for this condition.⁵

Intraoperative

Inhalational induction has been used without reports of significant complications despite the risk of aspiration.^6,7 However, i.v. induction, antisialogogues and using a cuffed tracheal tube should be considered because of hypersalivation and difficulty managing secretions. It is preferable to use non-depolarising neuromuscular blocking drugs as children with AT can exhibit muscle atrophy and weakness, predisposing them to the risk of hyperkalaemia with depolarising neuromuscular blocking drugs.⁷ Temperature should be monitored throughout the perioperative period as children with AT are prone to hypothermia.⁶

Postoperative

Care must be taken to ensure that neuromuscular block is antagonised and the child is fully awake before extubation. Patients with AT may be sensitive to opioids and prone to developing respiratory depression. Hence, doses of opioids may need to be reduced and a multimodal approach to analgesia should be used. After surgery, most children can be managed in the general ward, but some require intermediate or critical care. Chest physiotherapy should be considered to reduce respiratory complications for children with a high volume of pulmonary secretions. Signs of infection should be actively sought, particularly involving surgical sites and the respiratory tract.³

Cockayne syndrome

Cockayne syndrome is a rare autosomal recessive condition caused by mutations in the ERCC genes involved in transcription-coupled DNA repair, with an estimated incidence of 1 in 100,000 live births.⁸ Three phenotypes exist and overlap with the rare genetic disorder xeroderma pigmentosa, a condition associated with extreme photosensitivity and increased risk of skin cancers. Some xeroderma pigmentosa subtypes can exhibit the developmental and neurological features characteristic of Cockayne syndrome. Cockayne syndrome type I, the commonest form, presents in infancy or early childhood with an average life expectancy to early adolescence. Cockayne syndrome type II, the most severe phenotype, manifests at birth and sufferers typically die within the first decade of life. Cockayne syndrome type III is a milder form presenting later in childhood or early teens and with patients surviving into early adulthood.⁹ Cockayne syndrome is characterised by distinctive orofacial abnormalities that predispose to difficult airway management.^10,11

Clinical presentation

Infants may present with microcephaly, retrognathia and congenital cataracts. As they grow, patients develop distinctive facial (prominent ears, beak-like nose, sunken eyes) and dental abnormalities (fused prominent incisors, protruding maxilla) (Fig. 1), and are prone to poor oral hygiene.⁸ There is often failure to thrive, with stunted growth, neurodevelopmental delay and progressive ataxia.¹² Photosensitivity to ultraviolet light is a typical feature. with the risk of severe sunburn after minimal exposure. Cockayne syndrome is considered a progeria as children show signs of accelerated ageing, perhaps a result of the accumulation of DNA damage and impaired repair mechanisms. As such, they are at risk of adult-onset conditions including cardiovascular disease, diabetes and impaired renal function.¹⁰

Fig 1.

Retrognathia in Cockayne syndrome. (A) Demonstrates prominent incisors which along with micrognathia can make intubation challenging. (B) Demonstrates typical sunken eyes appearance, and beak shaped nose that can make mask ventilation challenging. (Images reproduced with permission).

Perioperative care

Preoperative

Cockayne syndrome has been associated with difficult airway management because of the orofacial abnormalities described above. A thorough airway assessment should be performed followed by careful airway planning.^8,12 Patients should be assessed for aspiration risk, and treatment given to those with gastroesophageal reflux disease. Weight and nutritional status may need optimisation as these children can be severely cachectic. Renal and cardiovascular diseases should be screened for (i.e. through checking renal profile, ECG, blood pressure and blood glucose monitoring) and addressed.¹⁰

Intraoperative

Either inhalational or i.v. induction can be used. Although a modified rapid-sequence induction is advisable in those with a high risk of aspiration, this technique may not be feasible in some children and can be hampered by difficult venous access caused by limb contractures.^10,11 It is important to note that face mask ventilation and airway management can be challenging, and it is crucial to have a comprehensive plan for managing the airway. Difficult airway equipment should be available in the anaesthetic room and videolaryngoscopy considered as the first-line technique for tracheal intubation. Some children may have subglottic narrowing, so smaller sizes of cuffed tracheal tubes should be available.^10,12 Hypotension should be actively treated because patients are susceptible to cardiovascular and cerebrovascular events.

Postoperative

Before extubation, neuromuscular block should be adequately antagonised and the child fully awake. Ensure careful pain management to avoid hypertensive surges.¹² After surgery, these children should continue to be monitored for acute ischaemic events.¹⁰

Fanconi anaemia

Fanconi anaemia (FA) is a rare autosomal recessive disease with an incidence of three per 1,000,000.¹³ It is caused by impaired DNA repair of interstrand cellular crosslinks, particularly affecting stem cells, resulting in bone marrow failure, and is characterised by congenital and haematological anomalies.¹⁴ Fanconi anaemia is distinct from Fanconi syndrome, which is a rare disorder of renal function.

Clinical presentation

Two-thirds of children present with congenital defects; the most common are skeletal. Skin changes (altered pigmentation or café au lait spots) are present in the majority of cases.¹⁴ There may be structural renal abnormalities, and less commonly, cardiopulmonary defects with some overlap with VACTERL association (vertebral defects, anorectal anomalies, cardiac defects, tracheoesophageal fistula, renal and limb anomalies).¹⁵ However, the most concerning abnormality is bone marrow failure, which tends to present in childhood. Patients may experience easy bruising from thrombocytopenia, anaemia, require periodic blood transfusions and are susceptible to recurrent infections because of lymphopenia and neutropenia.¹⁶ Bone marrow failure is a major cause of death. The only curative treatment is haemopoietic stem cell transplantation (SCT), which has significantly improved survival.¹⁴ Children with FA have an increased incidence of endocrine disorders including growth hormone deficiency, hypogonadism, hypothyroidism and impaired glucose tolerance. There is a higher risk of developing early onset haematological and solid tumour malignancies, and patients require lifelong oncological surveillance.¹⁴

Perioperative care

Preoperative

A thorough cardiovascular and airway examination should be performed to identify underlying congenital cardiac defects and facial and axial skeletal abnormalities (i.e. microcephaly, micrognathia, choanal atresia, spina bifida, scoliosis and vertebral abnormalities) that can affect airway management.¹⁵ Signs of active infection should be sought, and if present may be an indication to postpone surgery. Medical therapy should be reviewed, particularly for regular blood product transfusions, systemic steroids, chemotherapy or SCT. Blood tests should be taken to evaluate severity of pancytopenia, glycaemic control and thyroid function, with optimisation before surgery if possible. Discussion with a haematologist is imperative. Blood products should be readily available: fully cross-matched, irradiated and leukocyte-depleted, and should not come from relative donors as this can affect future prospects of bone marrow transplantation and developing graft-vs-host disease.¹³

Intraoperative

The lower limbs may need to be used for i.v. access and to monitor blood pressure if upper limb defects are present. Difficult airway equipment including a videolaryngoscope and fibreoptic bronchoscope should be available. Given the risk of significant bleeding, nasal intubation should be avoided in children who are thrombocytopenic. Experimental studies have suggested caution when using higher concentrations of inspired oxygen because of the potential risk of cellular damage from free radical production in FA-affected cells.¹⁷ The use of nitrous oxide is contentious, and should be avoided given concerns of inducing bone marrow suppression with prolonged exposure.¹⁵ Neuraxial and deep regional blocks may be precluded in patients with thrombocytopenia. Strict asepsis should be adhered to when performing invasive procedures.¹³ Blood-sparing techniques such as minimally invasive surgery, using haemostatic sealants and cell salvage where possible, may help reduce blood loss and the need for transfusions.

Postoperative considerations

After surgery, patients with FA should be closely monitored for bleeding and infection. Neutropenic sepsis should be identified early and treated promptly. Long-acting opioids and non-steroidal anti-inflammatory medication should be avoided in patients with impaired hepatic or renal function who have hepatorenal impairment.¹⁵

Conclusions

It is important to appreciate the varied phenotypic manifestations of these complex DNA repair disorders, and although rare, their clinical features can have serious implications for perioperative care, including difficulties in airway management, the presence of concurrent malignancy and bone marrow failure (Table 1). It is paramount that these patients should be managed in specialist centres and involve the coordinated efforts of the multidisciplinary team.

Table 1.

Clinical features and perioperative management of children with common DNA repair disorders. GORD, gastro-oesophageal reflux disease; HbA1c, haemoglobin A1c; HDU, high dependency unit; LMA, laryngeal mask airway; NCA, nurse-controlled analgesia; PCA, patient-controlled analgesia; PICU, paediatric intensive care unit; PPI, proton pump inhibitor; RSI, rapid-sequence induction.

Clinical features	Preoperative considerations	Intraoperative considerations	Postoperative considerations
Ataxia telangiectasia
•Ataxia •Oculomotor apraxia •Choreoathetosis •Neurodegenerative changes •Dysphagia •Immunodeficiency •Recurrent sinopulmonary infections •Increased risk and early development of malignancies •Sensitivity to ionising radiation	•Assess aspiration risk •Neurological assessment •Lung function tests •Screen for infections •Avoid unnecessary exposure to ionising radiation	•I.V. induction •Use of non-depolarising neuromuscular blocking drugs •Consider RSI if possible •Cuffed tracheal tube •Regular temperature monitoring and avoiding hypothermia	•Adequate reversal of neuromuscular block •Awake extubation •May require HDU/PICU after surgery •Early weaning of ventilatory support •Chest physiotherapy •Monitor for infections
Cockayne syndrome
•Facial and dental abnormalities (e.g. micrognathia, prominent incisors) •Failure to thrive •Stunted growth •Progressive ataxia •Neurodevelopmental delay •Mental deterioration •Blindness •Deafness •Accelerated ageing •Early onset of cardiovascular and renal disease •Photosensitivity	•Airway assessment and plan for a difficult airway •Assess for aspiration risk •PPI premedication for GORD •Optimise weight and nutrition •Screen for diabetes, cardiovascular and renal disease	•I.V. induction •Use of non-depolarising neuromuscular blocking drugs •Videolaryngoscopy as first line •Rescue LMA •Smaller cuffed tracheal tubes •Nasogastric tube •Avoid significant fluctuations in BP	•Adequate reversal of neuromuscular block •Awake extubation •Optimise analgesia—may require PCA/NCA •Monitor for acute ischaemic events
Fanconi anaemia
•Skeletal defects •Café au lait spots •VACTERL association •Developmental delay •Anaemia •Thrombocytopenia •Bone marrow failure •Recurrent infections •Hypothyroidism •Hypogonadism •Impaired glucose intolerance •Early onset malignancies	•Airway assessment for difficult airway •Screen for congenital cardiac disease •Screen for endocrine abnormalities (i.e. glucose and HbA1c, thyroid function tests) •Optimise anaemia and thrombocytopenia •Ensure irradiated, leuko-depleted blood products are available	•May require lower limb cannulation •Videolaryngoscopy •Caution with high Fio2 •Avoid nitrous oxide •Caution with/avoid neuraxial and deep blocks •Minimally invasive techniques •Blood-sparing techniques •Avoid hypothermia •Avoid acidosis	•Monitor for bleeding •Monitor for infections •Avoid NSAIDs and long-acting opioids in patients with impaired hepatic or renal function

Declaration of interests

The authors declare that they have no conflicts of interest.

Biographies

Rathai Anandanadesan FRCA is a fellow in anaesthesia at Evelina London Children’s Hospital, UK.

Raksa Tupprasoot FRCA is a consultant in paediatric anaesthesia at Evelina London Children’s Hospital, UK.

Matrix codes: 1CO1, 2AO3, 3DO0