Kniest1 first labeled this syndrome in 1952 as an “atypical chondrodysplasia” present in a 3-year-old girl. Although the majority of cases are caused by sporadic mutation, the disease exhibits autosomal dominant inheritance with variable penetration which affects males and females equally with an incidence of 1:1,000,000.2 On a molecular level, Kniest dysplasia is caused by a mutation in the COL2A1 gene responsible for encoding type II collagen.3
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DESCRIPTION OF CASE
A 6-year-old boy presented with Kniest dysplasia (dwarfism, skeletal deformities, bilateral hearing loss, and cataracts) and a history of mitochondrial disease for an eye examination under anesthesia before cataract surgery. The patient was born at full term via cesarean delivery with reportedly normal APGAR (activity, pulse, grimace, appearance, respiration) scores. Although he exhibited some neurological weakness and feeding difficulty, resulting in a failure to thrive, the patient met early developmental milestones. At 18 months of age, he underwent gastrostomy tube placement. Unfortunately, after the induction of anesthesia, the child suffered a cardiac arrest during attempted placement of the endotracheal tube (ETT) and subglottic stenosis was identified. Although he was resuscitated and the airway was ultimately secured, the child suffered irreparable neurological damage. It is not clear whether hemodynamic instability occurred after the administration of propofol and/or sevoflurane or was essentially caused by a “lost airway.” Over the next 6 months, the patient exhibited multiple episodes of hypoglycemia, spasticity, and seizures. A muscle biopsy subsequently revealed abnormal proliferation of mitochondria and deficiencies in cytochrome c oxidase, confirming a diagnosis of mitochondrial myopathy. At presentation, the child was nonverbal, was wheelchair bound with diffuse contractures, had limited mouth opening, and weighed 12.5 kg. Hematological and electrolyte laboratory studies were normal, and the electrocardiogram revealed no conduction abnormalities.
The child was given Pedialyte (Abbott Healthcare, Lake Bluff, IL) through the gastrostomy tube 2 hours before arrival in the holding area; finger stick revealed a blood glucose level of 92 mg/dL. On arrival at the operating room, the patient was placed supine and all pressure points were checked and padded. After placement of standard American Society of Anesthesiologists monitors, an intravenous (IV) access was established and an infusion of D5 1/2 normal saline was begun at maintenance; the patient’s blood sugar was checked every 30 minutes during the case. Finger sticks remained between 84 and 120 mg/dL throughout. During discussion with ophthalmology, the decision was made to secure the patient’s airway with an ETT in anticipation of a more extensive surgical procedure including potential cataract extraction.
Anesthesia was induced with dexmedetomidine 12 µg (1 µg/kg) and ketamine 25 mg (2 mg/kg), while intubation was facilitated with a video laryngoscope. A secondary provider held manual inline stabilization of the cervical spine due to the patient’s history of Kniest dysplasia, although no radiologic findings of cervical subluxation were present. The patient was easy to mask ventilate, but muscle relaxants were not utilized to secure the airway due to the patient’s history of difficult intubation. Initial attempted placement of a 5.0 uncuffed ETT was met with resistance in the subglottic area. Subsequent attempts with smaller tubes confirmed subglottic narrowing. Eventually, a 3.5 uncuffed ETT was placed without incident. The patient received rocuronium 12 mg and was maintained on dexmedetomidine infusion (0.5–1.2 µg/kg/h). Ultimately, only an eye examination under anesthesia was performed and concluded within 47 minutes. On termination of the case, 4 twitches were recorded and the patient was reversed with 25 mg (2 mg/kg) of sugammadex. After uneventful extubation, the patient was observed overnight with pulse oximetry and discharged home the next day.
Patients with mitochondrial disease present a challenge to anesthesiologists due to potential higher risk for perioperative complications. Primary complications of mitochondrial myopathies include respiratory failure, cardiac depression, conduction defects, and dysphagia. Although patients with mitochondrial myopathies can be anesthetized safely with most anesthetic techniques, the use of sevoflurane was avoided due to its risk of cardiac depression. Ketamine and dexmedetomidine were utilized as induction agents due to their ability to maintain spontaneous ventilation and facilitate an adequate depth of anesthesia before intubation. Even though propofol has been used successfully as a single bolus, patients with mitochondrial myopathies may be at increased risk for propofol infusion syndrome characterized by severe lactic acidosis, rhabdomyolysis, and lipidemia, which can result in cardiovascular collapse and death.4
Hypoglycemia, prolonged fasting, hypothermia, prolonged tourniquet exposure, postoperative nausea and vomiting, acidosis, and hypovolemia should be minimized to avoid further metabolic insult. Glucose should be supplemented at maintenance rates with perioperative serum glucose monitoring in these patients. Perioperatively, lactate-free IV fluids should be utilized during the fasting period to allow maintenance of normoglycemia, because excessive glycolytic oxidation of glucose may lead to elevated plasma lactate level.5
Initial screening tests for mitochondrial disease include levels of lactate, with elevated lactate-to-pyruvate ratios suggesting a respiratory chain disorder. Although muscle biopsy is crucial for a definitive diagnosis in these patients, brain magnetic resonance imaging may reveal lytic lesions in the basal ganglia and thalamus.6 Children with mitochondrial myopathies are at risk for metabolic decompensation during procedures requiring anesthesia primarily due to fasting and surgical stress. Anesthetic management of patients with mitochondrial myopathies should include a thorough medical history and complete physical examination to exclude potential associated comorbidities, including hypotonia, cardiac dysrhythmias, epileptic seizures, strokes, gastrointestinal dysmotility, diabetes mellitus, and lactic acidosis.7 Patients may exhibit increased sensitivity to nondepolarizing neuromuscular blockade and inadequate reversal by anticholinesterases, resulting in delayed recovery or residual effects.6 Tobias et al7 note the utility of sugammadex in patients where reversal of neuromuscular blockade with acetylcholinesterase inhibitors may be contraindicated or less efficacious, namely patients with neuromyopathic disease.
Although all anesthetic agents depress mitochondrial function, general anesthesia may be induced and maintained with IV or inhalational agents. A primary advantage of inhalational agents relates to their excretion via respiration with minimal metabolism. When selecting an inhalational agent, the greater degree of cardiac depression associated with sevoflurane should be considered. Of the IV agents, propofol exerts the greatest negative effect on mitochondrial function.8 Propofol affects mitochondria by up to 4 different mechanisms, inhibiting multiple electron transport chain complexes, preventing fatty acid transport into the mitochondrion, obstructing mitochondrial function at the level of complex I and complex IV, and uncoupling oxidative phosphorylation.9
Identification of Kniest dysplasia is difficult in infancy because some characteristic manifestations are age related. In a dysmorphic child with skeletal abnormalities and cleft palate, the diagnosis of Kniest dysplasia should be considered. Life expectancy is normal in these patients.10 One of the primary anesthetic considerations for patients with Kniest dysplasia includes concern for spinal abnormalities, specifically atlantoaxial or occipitoatlantal instability.11 Documentation of cervical spine instability with lateral flexion and extension cervical spine radiographs may be useful. In cases of instability, manual inline stabilization of the cervical spine during direct laryngoscopy and tracheal intubation is recommended with a video laryngoscope or fiberoptic-assisted intubation.11
Until the patient’s airway is secured, neuromuscular blocking drugs should be avoided and spontaneous ventilation maintained. Difficult airway management is due to kyphoscoliosis, tracheomalacia, midface hypoplasia, cleft palate, and the potential for edema during airway instrumentation.12 Postoperative management in a monitored setting with the potential need for mechanical ventilation should be thoroughly assessed. Hasegawa-Moriyama et al12 report that perioperative rapid development of airway edema may be seen in patients with Kniest dysplasia due to connective tissue vulnerability. Segawa et al13 also report a case in a patient with Kniest dysplasia in which increasing difficulty with performing tracheal intubation occurred as the patient aged.
Although Kniest dysplasia patients are of normal intelligence, they are often developmentally delayed. Affected patients exhibit gross motor delays due to short stature, deformed arms and legs, and a “barrel-shaped” chest. The femurs have a characteristic dumbbell shape (Figure), which distinguishes Kniest dysplasia from other connective tissue dysplasias. Fixed flexion of major joints of the upper and lower limbs can make IV access and patient positioning for surgery challenging. Careful positioning is imperative to avoid pressure sores and nerve palsies in this patient population.14
Ocular abnormalities include myopia which can progress to retinal detachment and cataracts.2 Hearing deficits, frequent ear infections, and a higher incidence of umbilical and inguinal hernias have been described.14 Treatment of Kniest dysplasia consists of stabilization of lax joints, repair of retinal detachments and cleft palate, and surgical correction to prevent contractures. Treatment is otherwise supportive and symptomatic.
The combination of Kniest dysplasia and mitochondrial disease presents an array of challenges to the anesthesiologist but can be overcome with careful perioperative planning. Patients with mitochondrial disease face an increased risk of perioperative complications including cardiac arrhythmias, respiratory depression, metabolic disturbances, and the potential for severe neurological injury. Metabolic decompensation can result from anesthetic agents, a fasting state, catabolism, or prolonged pain exposure. Anesthetics should be titrated meticulously to achieve desired effects in these patients. Patients with Kniest dysplasia have an increased risk of a difficult airway, perioperative respiratory distress, positioning challenges due to limited joint mobility, and atlanto-occipital instability. Practitioners must take these various considerations into account when anesthetizing patients with this challenging combination of diseases.
Name: Irim Salik, MD.
Contribution: This author helped prepare and edit the manuscript.
Name: Keshar Kubal, MD.
Contribution: This author helped prepare and edit the manuscript.
Name: Samuel Barst, MD.
Contribution: This author helped prepare and edit the manuscript.
This manuscript was handled by: Kent H. Rehfeldt, MD.
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