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At a glance

It is a rare medical condition characterized by the presence of a triad of dysmorphic craniofacial and skeletal abnormalities, malignant hyperthermia susceptibility (MHS), and myopathy. The myopathy is associated with Noonan-like features. However, in contrast to Noonan Syndrome, there is no congenital heart disease, mental retardation, or webbed neck (pterygium colli). Serum creatinine kinase (CK) might be elevated. Males are affected five times more often than females.

Synonyms

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

History

It was first described in 1973.

Incidence

The exact incidence remains unknown. It is diagnosed in males and are affected five times more often than females.

Genetic inheritance

It is believed to be an autosomal dominant; however, recessive inheritance pattern traits have also been suggested. Phenotypic manifestations of King-Denborough Syndrome can result from different congenital myopathies. In all cases, there is probably an increased risk of MHS. 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 ryanodine receptor gene (RYR1) is associated to malignant hyperthermia and central core disease.

Pathophysiology

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. MHS 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.

Diagnosis

King-Denborough Syndrome phenotype is a clinical diagnosis. Definitive diagnosis of associated MHS 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 MHS. If the diagnosis is not determined prior to exposure to triggering agents, onset of malignant hyperthermia may be the event that initiates a diagnosis.

Clinical aspects

Typical features include an unusual facies often described as “Noonan-Old features” including 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 ...

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