King-Denborough Syndrome

Noonan-like features identified in infancy and associated with a significant risk of malignant hyperthermia. Males are affected five times more often than females. However, in contrast to Noonan Syndrome, there is no congenital heart disease, mental retardation, or webbed neck. Serum creatinine kinase (CK) might be elevated.

King Syndrome; Malignant Hyperthermia Susceptibility, Noonan-like Syndrome.

Autosomal dominant, but recessive modes have also been suggested. Genetically heterogeneous. Phenotypic manifestations of King-Denborough syndrome can result from different congenital myopathies. In all cases, there is probably an increased risk of malignant hyperthermia susceptibility. Most common gene locus for malignant hyperthermia is a mutation on the long arm of chromosome 19 at position 13.1 (19q13.1) (malignant hyperthermia susceptibility type 1 or MHS1). This corresponds with an abnormal type 1 ryanodine receptor (RyR1).

The etiology of King-Denborough syndrome is unknown. Multiple different pathophysiologies are possible, depending on the particular myopathy. The physical signs may reflect fetal hypokinesia. Malignant hyperthermia susceptibility is a result of abnormal sarcoplasmic reticulum calcium channel (RyR1). Hyperthermia results from sustained increase in myoplasmic Ca2+, resulting in sustained muscle contraction and a hypermetabolism. Exposure to a triggering agent results in massive and sustained release of calcium, which results in excessive muscle contraction. Twenty percent of all malignant hyperthermic reactions result from mutation in the ryanodine receptor (chromosome 19); in other cohorts, malignant hyperthermia has been linked to mutations in chromosomes 17, 7, 5, 3, and 1.

King-Denborough syndrome phenotype is a clinical diagnosis. Definitive diagnosis of associated MH susceptibility requires a muscle biopsy for halothane-caffeine contracture testing. However, a positive family history of malignant hyperthermia, the presence of muscle wasting, and/or an elevated CK level should make the clinician highly suspicious of malignant hyperthermia susceptibility. If the diagnosis is not determined prior to exposure to triggering agents, onset of malignant hyperthermia may be the event that initiates a diagnosis.

Typical features include an unusual facies often described as “Noonan-oid" with low-set ears, hypertelorism, downslanting palpebral fissures, ptosis, strabismus, a high-arched palate or cleft palate, micrognathia, crowded teeth, and short, webbed neck. Orthopedic findings include short stature, thoracic kyphosis, lumbar hyperlordosis, pectus carinatum, frequent dislocations of shoulders and patellae, and pes cavus. Cryptorchidism and mental delay are other frequent findings. There is one case report about a patient with dilatation of the aorta, pulmonary artery, and the cardiac ventricles. Malignant hyperthermia presents as a hypermetabolic response of the skeletal muscles to triggering agents, namely, inhalational anesthetic agents and succinylcholine. Combined metabolic and respiratory acidosis, tachycardia, hypertension, hypoxia, muscle rigidity, and myoglobinuria occur as a result of sustained muscle contraction. Hyperthermia is often a late sign in the course of malignant hyperthermia. Not all exposures will trigger a malignant hyperthermia response: approximately half of the patients who are susceptible to malignant hyperthermia had uneventful general anesthetics with triggering agents prior to the triggering event (in some patients more than 10 uneventful non-trigger-free anesthetics have been administered).

Careful airway assessment is recommended. Significant kyphoscoliosis may result in restrictive lung disease. Pulmonary function tests such as forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, and diffusing capacity of the lungs for carbon monoxide (DLCO), arterial blood gases, and chest radiography, in addition to history and physical examination, may be done to evaluate pulmonary reserve. Although cardiovascular disease is unusual in this syndrome, a thorough history and physical examination with appropriate investigations (ECG, echocardiogram) should be done. Malignant hyperthermia susceptibility can be evaluated with a family or patient history of malignant hyperthermia reactions, creatine phosphokinase (CPK) levels (for screening), and, if deemed appropriate, muscle biopsy for halothane-caffeine contracture testing. Consultation to an anesthesia or malignant hyperthermia clinic is highly recommended. Dantrolene premedication is no longer indicated prior to anesthesia, but should definitely be available in the room.

Potential for difficult airway because of dysmorphic facies and short neck. Limited pulmonary reserve may indicate the need for postoperative ventilatory support. Use of regional anesthesia may be helpful by limiting use of respiratory depressant analgesics. Considerations for congenital heart disease include knowledge of the anatomy and pathophysiology of the lesion, endocarditis prophylaxis when appropriate, and avoidance of paradoxical air embolus. A malignant hyperthermia “trigger-free” anesthetic should be given unless the patient had a negative halothane-caffeine contracture test. Patients should be monitored at least 6 to 8 hours prior to discharge after an uneventful, trigger-free, day surgery operation.

Inhalational anesthetic agents and succinylcholine are absolutely contraindicated. Judicious use of nondepolarizing muscle relaxants and opioids if significant muscle weakness or respiratory impairment is present. Avoid verapamil and diltiazem because of potential hyperkalemia and ventricular fibrillation if dantrolene has been given.