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
there is no congenital
heart disease, mental retardation, or webbed
neck. Serum creatinine kinase (CK) might be elevated.
King Syndrome; Malignant Hyperthermia Susceptibility,
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 ...