Alternative titles; symbols
SNOMEDCT: 764957003; ORPHA: 99741; DO: 0080990;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.2 | King-Denborough syndrome | 619542 | Autosomal dominant | 3 | RYR1 | 180901 |
A number sign (#) is used with this entry because of evidence that King-Denborough syndrome (KDS) is caused by heterozygous mutation in the RYR1 gene (180901) on chromosome 19q13.
King-Denborough syndrome (KDS) is an autosomal dominant disorder characterized by the triad of congenital myopathy, dysmorphic features, and susceptibility to malignant hyperthermia (summary by Dowling et al., 2011).
King et al. (1972) reported a group of patients with myopathy and malignant hyperpyrexia (MH; 145600) who also had physical abnormalities, including short stature, cryptorchidism, pectus carinatum, lumbar lordosis, thoracic kyphosis, and unusual facies. They noted that this form of MH, termed King syndrome, was likely to come to attention during corrective surgery. King and Denborough (1973) described 4 unrelated boys with a slowly progressive myopathy, as well as ptosis, short stature, low-set ears, malar hypoplasia, skeletal deformities, and cryptorchidism. All had been identified following episodes of malignant hyperthermia in which 3 of the boys died. Intelligence was normal in all 4.
Pinsky (1972) and Kaplan et al. (1977) noted that the dysmorphic features of persons with King syndrome and malignant hyperpyrexia resembled those observed in Noonan syndrome (see 163950).
McPherson and Taylor (1981) reported a case of King syndrome in a girl and noted that all earlier cases had been in males. Saul et al. (1984) reported an affected female. Steenson and Torkelson (1987) reported a patient with King syndrome in whom there was no pectus carinatum or cryptorchidism; the patient had mental retardation.
Isaacs and Badenhorst (1992) described King-Denborough syndrome in a white male teenager who from birth had been noted to have low-set ears, high-arched palate, undescended testes, and bilateral pes cavus. The patient reportedly had unexplained high fever in the immediate postoperative period after surgery for undescended testes and pes cavus. During tonsillectomy at age 14 years, the patient had a hyperthermic crisis. Physical examination at that time showed pectus deformity, kyphoscoliosis, downslanting palpebral fissures, long upper lip, protuberant nose, and decreased IQ. Serum creatine kinase was increased, and muscle biopsy showed a variation in fiber size and some de- and regenerating fibers. Muscle tension studies confirmed increased susceptibility to malignant hyperthermia. The patient's mother also had increased serum creatine kinase, high-arched feet, and a positive muscle tension test.
Chitayat et al. (1992) described an isolated case in a 9-year-old boy who had, in addition to the usual features of King syndrome, dilatation of the cardiac ventricles, aorta, and pulmonary artery. Although he was thought to have a congenital myopathy and had transient increase in creatine kinase levels during anesthesia, malignant hyperthermia did not occur. Chitayat et al. (1992) concluded that the manifestations of the King syndrome can result from different congenital myopathies and that in all cases there is probably an increased risk of malignant hyperthermia.
Graham et al. (1998) reviewed the cases of 14 previously reported patients and described a new patient, a 7-year-old girl, with the King syndrome and the unique findings of diaphragmatic eventration, tethered spinal cord, and severe paucity of type 2 skeletal muscle fibers. They suggested that King syndrome represents a phenotype that is common to several different slowly progressive congenital myopathies. Graham et al. (1998) commented that although there is considerable overlap with the Noonan syndrome, no King syndrome patient had been reported with the Noonan combination of hypertelorism, epicanthic folds, lymphedema, bleeding diathesis, and characteristic heart defects.
D'Arcy et al. (2008) reported a 27-year-old woman with King-Denborough syndrome and susceptibility to malignant hyperthermia. She was born at term after a pregnancy complicated by decreased fetal movements and breech presentation. At birth, she was noted to have hypotonia, ptosis, high-arched palate, prominent philtrum, and scaphocephaly. The father and paternal grandfather had congenital ptosis, but no other signs of neuromuscular disease. She underwent surgery for ptosis at ages 2 and 9 years without complications. Facial and proximal limb weakness became more apparent with age, and she developed kyphoscoliosis, myopathic facies with flat midface, prominent columella, and webbed neck. An EMG was myopathic and serum creatine kinase was increased. At age 15 years, she developed hyperthermia during surgery for scoliosis repair, and subsequent muscle testing confirmed susceptibility to malignant hyperthermia.
Dowling et al. (2011) reported a patient (patient 1) who presented at 5 years of age with unusual gait, frequent falls, exercise intolerance, myalgia after exercise, and delayed walking. On examination at age 6 years, he had mild ptosis, hypertelorism, webbing of the neck, and a round face with full cheeks. He also had mild truncal hypotonia, mild upper and lower proximal weakness, and an abnormal gait with lumbar lordosis. Laboratory testing showed a mild elevation of creatine phosphokinase (CPK), and spinal x-rays demonstrated thoracolumbar scoliosis and lordosis. Dowling et al. (2011) reported another patient (patient 2) who presented at 14 years of age with scoliosis, recurrent patellar dislocations, and mild hip girdle weakness. On examination, he had mild ptosis and a myopathic facial appearance. Muscle biopsy showed increased variability in fiber size and peripheral and central cores. Laboratory testing showed a mild elevation of CPK. His older brother had a history of elevated CPK and an anesthesia reaction suggestive of malignant hyperthermia. His mother also had a history of patellar dislocations, malignant hyperthermia, mild hip girdle weakness, and mild ptosis. Muscle biopsy showed features of a core myopathy, and an in vitro contracture test confirmed malignant hyperthermia susceptibility.
Joseph et al. (2017) reported a 2-year-old boy with a history of bilaterally undescended testicles, hypotonia, ptosis, ventricular septal defect, and delayed walking. He had an episode of malignant hyperthermia treated with dantrolene during orchiopexy surgery.
The transmission pattern of KDS in the families reported by Dowling et al. (2011) was consistent with autosomal dominant inheritance.
In a 27-year-old woman with King-Denborough syndrome, D'Arcy et al. (2008) identified a heterozygous missense mutation in the RYR1 gene (K33E; 180901.0038).
By direct RYR1 sequencing, Dowling et al. (2011) identified heterozygous missense mutations in 4 patients with KDS, a 6-year-old boy (T2203M; 180901.0014) and 3 members of 1 family (R2452W; 180901.0042).
In a 2-year-old boy with KDS, Joseph et al. (2017) identified a heterozygous missense mutation in the RYR1 gene (180901.0043). Functional studies were not performed.
Chitayat, D., Hodgkinson, K. A., Ginsburg, O., Dimmick, J., Watters, G. V. King syndrome: a genetically heterogenous phenotype due to congenital myopathies. Am. J. Med. Genet. 43: 954-956, 1992. [PubMed: 1415346] [Full Text: https://doi.org/10.1002/ajmg.1320430610]
D'Arcy, C. E., Bjorksten, A., Yiu, E. M., Bankier, A., Gillies, R., McLean, C. A., Shield, L. K., Ryan, M. M. King-Denborough syndrome caused by a novel mutation in the ryanodine receptor gene. Neurology 71: 776-777, 2008. [PubMed: 18765655] [Full Text: https://doi.org/10.1212/01.wnl.0000324929.33780.2f]
Dowling, J. J., Lillis S., Amburgey, K., Zhou, H., Al-Sarraj, S., Buk, S. J. A., Wraige, E., Chow, G., Abbs, S., Leber, S., Lachlan, K., Baralle, D., Taylor, A., Sewry, C., Muntoni, F., Jungbluth, H. King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromusc. Disord. 21: 420-427, 2011. [PubMed: 21514828] [Full Text: https://doi.org/10.1016/j.nmd.2011.03.006]
Graham, G. E., Silver, K., Arlet, V., Der Kaloustian, V. M. King syndrome: further clinical variability and review of the literature. Am. J. Med. Genet. 78: 254-259, 1998. [PubMed: 9677061] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19980707)78:3<254::aid-ajmg9>3.0.co;2-p]
Isaacs, H., Badenhorst, M. E. Dominantly inherited malignant hyperthermia (MH) in the King-Denborough syndrome. Muscle Nerve 15: 740-742, 1992. [PubMed: 1508238] [Full Text: https://doi.org/10.1002/mus.880150619]
Joseph, M. R., Theroux, M. C., Mooney, J. J., Falitz, S., Brandom, B. W., Byler, D. L. Intraoperative presentation of malignant hyperthermia (confirmed by RYR1 gene mutation, c.7522C-T; p.R2508C) leads to diagnosis of King-Denborough syndrome in a child with hypotonia and dysmorphic features: a case report. A. A. Case Rep. 8: 55-57, 2017. [PubMed: 27918309] [Full Text: https://doi.org/10.1213/XAA.0000000000000421]
Kaplan, A. M., Bergeson, P. S., Gregg, S. A., Cruless, R. G. Malignant hyperthermia associated with myopathy and normal muscle enzymes. J. Pediat. 91: 431-434, 1977. [PubMed: 894412] [Full Text: https://doi.org/10.1016/s0022-3476(77)81314-0]
King, J. O., Denborough, M. A., Zapf, P. W. Inheritance of malignant hyperpyrexia. Lancet 299: 365-370, 1972. Note: Originally Volume I. [PubMed: 4109748] [Full Text: https://doi.org/10.1016/s0140-6736(72)92854-1]
King, J. O., Denborough, M. A. Anesthetic-induced malignant hyperthermia in children. J. Pediat. 83: 37-40, 1973. [PubMed: 4149045] [Full Text: https://doi.org/10.1016/s0022-3476(73)80309-9]
McPherson, E. W., Taylor, C. A., Jr. The King syndrome: malignant hyperthermia, myopathy, and multiple anomalies. Am. J. Med. Genet. 8: 159-165, 1981. [PubMed: 7282770] [Full Text: https://doi.org/10.1002/ajmg.1320080206]
Pinsky, L. The XX-XY Turner phenotype and malignant hyperthermia. (Letter) Lancet 300: 383 only, 1972. Note: Originally Volume II. [PubMed: 4114756] [Full Text: https://doi.org/10.1016/s0140-6736(72)91773-4]
Saul, R. A., Stevenson, R. E., Roberts, T. L. A female with the King syndrome in a family with elevated CPK levels. Proc. Greenwood Genet. Center 3: 7-10, 1984.
Steenson, A. J., Torkelson, R. D. King's syndrome with malignant hyperthermia: potential outpatient risks. Am. J. Dis. Child. 141: 271-273, 1987. [PubMed: 3812408] [Full Text: https://doi.org/10.1001/archpedi.1987.04460030049022]