King Syndrome: Further Clinical Variability andReview of the Literature

G.E. Graham,1 K. Silver,2 V. Arlet,3 and V.M. Der Kaloustian1*1The F. Clarke Fraser Clinical Genetics Unit, Montreal Children’s Hospital and the Department of Human Genetics,McGill University, Montreal, Quebec, Canada

2Division of Neurology, Montreal Children’s Hospital and Department of Neurology, McGill University,Montreal, Quebec, Canada

3Division of Orthopedics, Montreal Children’s Hospital and Department of Orthopedics, McGill University,Montreal, Quebec, Canada

The King syndrome is characterized by aNoonan-like phenotype, the presence of anonspecific myopathy and a predispositionto malignant hyperthermia. In some fami-lies, mild physical manifestations of thephenotype and/or elevated serum creatinephosphokinase (CPK) in relatives suggestthe presence of an autosomal dominant my-opathy with variable expressivity. We sum-marize the cases of 14 previously reportedpatients and describe a new patient, a 7-year-old girl, with the King syndrome andthe unique findings of diaphragmatic even-tration, tethered spinal cord, and severepaucity of type 2 skeletal muscle fibers. Ithas been proposed that the King syndromerepresents a common phenotype that mayresult from several different slowly progres-sive congenital myopathies. This hypoth-esis, and the phenotypic overlap betweenthe King and Noonan syndromes are dis-cussed in light of the findings in this newpatient. Am. J. Med. Genet. 78:254–259, 1998.© 1998 Wiley-Liss, Inc.

KEY WORDS: King syndrome; Noonan syn-drome; malignant hyperther-mia; myopathy; review

INTRODUCTIONThe association of dominantly inherited myopathy

with susceptibility to malignant hyperthermia first re-ported by King et al. [1972] has been described in 14patients, of whom 12 are male. We report a new femalepatient in which the unique findings of diaphragmatic

eventration, tethered spinal cord, and severe paucity oftype 2 skeletal muscle fibers expand the clinical spec-trum of this condition and support the proposal thatthe King ‘‘syndrome’’ is actually a phenotype resultingfrom a heterogeneous collection of congenital myopa-thies [Chitayat et al., 1992].

CLINICAL HISTORYG.L. is a 7-year-old girl of normal intellect born at

term after an uneventful pregnancy to a healthy 38-year-old G1 French Canadian woman and her noncon-sanguineous 40-year-old French husband. She was de-livered by cesarean section for fetal distress. Birthweight was 2.5 kg (5th–10th centile) with a length of 45cm (<10th centile) and a head circumference (OFC) of34 cm (50th centile). Apgar scores were 3, 9, and 9 at 1,5, and 10 min, respectively. At birth she had bilateralblepharoptosis and a sacral dimple. Radiographs dem-onstrated two distinct spinal blocks resulting from theposterior fusion of L1–L2 and L3–L4–L5 vertebral bod-ies. A mild degree of lumbar lordosis was detectableradiographically but was not clinically evident at thistime. Bilateral grade 2 vesicoureteral reflux requiredprophylactic antibiotics but resolved spontaneously inthe first year of life. She did not have recurrent urinarytract infections nor any signs or symptoms of spinalcord impairment.

Gross motor development was delayed (she walkedat 23 months) with otherwise normal cognitive devel-opment. Her lumbar lordosis became clinically evidentat the age of 3 years and gradually increased in sever-ity over the next 3 years, resulting in a pelvic tilt. Shedeveloped a concomitant thoracic scoliosis that alsoworsened gradually. Although her vertebral fusion wasfelt to be an important contributing factor, it was notconsidered sufficient to cause her skeletal deformities.At the age of 6 years, a magnetic resonance image(MRI) of the spine showed a dextroconvex thoracolum-bar scoliosis with the previously noted vertebralanomalies and a low-lying conus medullaris. A teth-ered spinal cord was diagnosed and the patient wasadmitted to the Montreal Children’s Hospital for sur-gical release.

*Correspondence to: Dr. Vazken M. Der Kaloustian, Division ofMedical Genetics, Room A-608, Montreal Children’s Hospital,2300 Tupper St., Montreal, Quebec, Canada H3H 1P3. E-mail:MDDK@MUSICA.McGill.CA

Received 25 November 1997; Accepted 24 April 1998

American Journal of Medical Genetics 78:254–259 (1998)

© 1998 Wiley-Liss, Inc.

Within minutes of the administration of halothane,isoflurane, pancuronium, and propofal she experienceda generalized increase in muscle tone that progressedto marked stiffening of the limbs, a rapid rise in bodytemperature to 39.1°C, hypercapnea (PCO2 >80 mmHg), and a mixed metabolic and respiratory acidosis(lowest measured pH, 7.15). Malignant hyperthermiawas suspected, anesthesia was discontinued, and dan-trolene sodium was administered with intravenous flu-ids and furosemide. An immediate decrease in muscletone was accompanied by marked facilitation of venti-lation and a lowering of body temperature. A coolingblanket was applied and the patient was transferred tothe intensive care unit for monitoring. Serum creatinekinase (CK) peaked at 13,300 U/L approximately 22 hrafter anesthetic induction and fell to 1,196 U/L 4 dayslater (normal, 75–230 U/L). Urine output remained sat-isfactory throughout the ICU stay with a mild degree ofrhabdomyolysis and no evidence of renal impairment.The patient recovered completely.

Two months later, with nontriggering anestheticagents (vecuronium, sufentanil, and propofal) she un-derwent successful excision of a fixed lipomatous filumterminale. It was not thought to be related pathoge-netically to the vertebral fusion. Chest radiographsdemonstrated a soft tissue density with smooth up-ward concave margins along the lower right cardiacborder that obliterated the cardiophrenic angle. It wassuggestive of a diaphragmatic eventration and furtherinvestigation was not undertaken. At 7 1/2 years of ageshe was 113 cm tall (<5th centile) and had an OFC of 51cm (50th centile). She had bilateral blepharoptosiswith horizontal palpebral fissures, malar hypoplasia,mild micrognathia, and mild pterygium colli (Fig. 1).The cranial nerves and muscles were normal, with nofasciculations. There was a prominent lumbar lordosisand a dextroconvex thoracic scoliosis with scapularwinging. She was noted to have a generalized reductionin muscle mass with proximal limb weakness, anequivocal Gower sign, diminished deep tendon reflexesand an awkward, waddling gait. No fasciculations werenoted. Elbows and thumbs were hyperextensible.There were no joint contractures. The remainder of herphysical findings were normal. The clinical impressionwas that of an underlying myopathy.

Family History

The patient was an only child and the only memberof her family with craniofacial or musculoskeletalanomalies. Her parents were in good health and deniedany history of gross motor delay, poor exercise toler-ance, muscle cramping, weakness, or adverse reactionto anesthesia. Her mother was of slender build withnormal muscle mass and a normal resting serum CK.She had had a tonsillectomy as a child and a hemor-rhoidectomy as an adult, both under general anesthe-sia. Her father was of average build and had severalsurgical procedures under general anesthesia for acci-dental injuries. He did not consent to a blood test forresting serum CK. The maternal grandparents and twoof the four maternal sibs had experienced at least oneuneventful operation under general anesthesia. The

only paternal sib had one exposure to a general anes-thetic and the paternal grandmother had two. Therewere no reported adverse reactions to anesthesiaamong any of these relatives.

Investigations

Complete blood count, RBC and serum folate, vita-min B12, ammonia, lactate, venous blood gas, plasmaamino acids, and urine organic acids were all normal inthe proposita. Her bone age was consistent with herchronologic age. The karyotype was 46,XX. Her eyefindings, including fundi, were unremarkable. Restingserum CK values at 2 and 10 months after the malig-nant hyperthermia reaction were 304 and 336 U/L, re-spectively, with a normal range of 60–365 U/L.

The electromyogram was suggestive of a myopathy.There was a variable increase in insertional activity insome areas and silence in others. The recruitment pat-tern was increased with somewhat small-amplitudebrief-duration polyphasic units. There were no dener-vation potentials. Motor and sensory nerve conductionstudies were normal. Light microscopic analysis of anopen deltoid muscle biopsy specimen (Fig. 2) demon-strated generally small type 1 fibers, a few of whichwere clearly atrophic. However, the most striking ab-normality was severe paucity of type 2A and, to a lesserextent, type 2B fibers.

Fig. 1. Frontal view of patient. Note bilateral blepharoptosis, mild web-bing of the neck, and prominent lumbar lordosis.

King Syndrome: Clinical Heterogeneity 255

DISCUSSION

Malignant hyperthermia (MH) is a wel l -characterized, usually dominantly inherited, hyper-metabolic reaction to commonly used volatile anesthet-ics and depolarizing muscle relaxants [Kalow, 1987].The condition is heterogeneous with at least six dis-tinct susceptibility loci (RYR1 at 19q13.1, MHS 2 at17q11.2–q24, MHS 3 at 7q21–q22, MHS 4 at 3q13.1,MHS 5 at 1q32, and MHS 6 at 5p). In most patientsthere are no physical characteristics that suggest thepresence of MH susceptibility and several exposures tothe triggering agents (halothane and/or succinylcho-line) may be required before the phenotype is mani-fested. White in vitro contracture tests on biopsiedskeletal muscle are considered more definitive, manysusceptible individuals from MH families have beenidentified on the basis of elevated serum CK measure-ments alone. However, this test may miss a proportionof susceptible individuals and falsely identify others assusceptible.

The King syndrome comprises Noonan syndrome–like craniofacial and skeletal anomalies, myopathy,and predisposition to MH. Most patients are the onlyindividuals in their families with clinical or biochemi-cal evidence of myopathy, though it is not always clearas to what extent relatives have been examined andinvestigated. In the remaining families, first-degreerelatives with mild physical manifestations of the phe-notype, such as blepharoptosis or elevations in restingserum CK, suggest the possibility of an autosomal dom-inant myopathy with variable expressivity. However, amonogenic hypothesis for the King syndrome has notbeen tested and some authors have proposed that itrepresents an heterogeneous phenotype [Chitayat etal., 1992].

We reviewed the phenotype of 15 King syndrome pa-tients reported since 1973 (Table I). This review differsfrom that of Chitayat et al. [1992] by the inclusion ofour patient, the patient of Pippin et al. [1988], and thatof Isaacs and Badenhorst [1992]. We excluded the pa-tients of Kousseff and Nichols [1985], who may argu-ably be distinguished by their unique neonatal presen-tation and the presence of multiple severe contrac-

tures, skin dimpling, axillary webbing, and hypoplasticnipples. One died as a neonate with a respiratory ill-ness after oligohydramnios necessitated delivery at 35weeks. Both sibs had a biopsy-proven myopathy andthe survivor, who grew into the King syndrome pheno-type, experienced at least one episode of malignant hy-perthermia. Because the parents had normal restingserum CK values, these sibs were reported as a newautosomal recessive syndrome. The authors distin-guished them from King syndrome patients on the ba-sis of their contractures and their suspected recessivemode of inheritance, although gonadal mosaicism for anew dominant mutation would be an alternate expla-nation.

Despite the presence of a clinically recognizable phe-notype, all but one of the 15 patients was ascertainedfollowing a life-threatening MH reaction. MH has beenobserved in several myopathies, central core diseasebeing the commonest [Brownell, 1988] There may be acorrelation between the severity of the myopathy andthe likelihood for MH to occur. Such a bias of ascer-tainment would identify those King syndrome patientswith a clinically significant myopathy and the reportedcases may therefore represent the most severe end ofthe spectrum.

Of the 15 King syndrome patients identified to date,12 are male. This sex ratio is unlikely to be due to therelatively small number of reported patients, because amale preponderance has also been observed in autoso-mal dominant MH in the absence of an overtly myo-pathic phenotype. Hormonal influences in muscle de-velopment may play a role [Rubinstein et al., 1988].Despite the small cohort, the syndrome was reported inthree racial groups (caucasian, hispanic, and black).The age of ascertainment of these patients, rangingfrom 30 months to 14 years, is younger than that forMH in the general population, which peaks betweenthe teens and early thirties. This may be due to earlysurgical correction of cryptorchidism and skeletal de-formities in King syndrome patients, possibly com-bined with an increased likelihood for MH to occur withthe first or second general anesthetic exposure.

All patients were the products of unremarkable preg-nancies without teratogenic exposures. Normal intelli-gence was reported in 8 of the 10 individuals for whichthis information was provided, though most patientswould not have had formal cognitive testing. One of thetwo remaining patients was a twin delivered at 34weeks, in whom a subarachnoid hemorrhage, persis-tent hypocalcemia, and hyperbilirubinemia were docu-mented neonatally [Steenson and Torkelson, 1987].The second patient had visual-motor and perceptualdifficulties with a full-scale IQ of 51 [Kaplan et al.,1977]. These cognitive difficulties may be unrelated tothe syndrome; alternatively, as in Noonan syndrome,only a few King syndrome patients may have intellec-tual impairment.

All but one patient [Kaplan et al., 1977] had eitherkyphosis, scoliosis, or lumbar lordosis at the time ofascertainment. All patients except that of Chitayat etal. [1992] also had short stature. We examined birthlength in an attempt to determine whether short stat-ure was a constitutional part of this syndrome, a re-

Fig. 2. Light microscopy of deltoid muscle biopsy. Note small type 2fibers with evidence of atrophy.

256 Graham et al.

flection of the presence of spinal deformities, or both.Birth length was available on the patients of Saul et al.[1984] and Steenson et al. [1987] and was within thenormal range in both cases. Our patient had a birthlength of less than the 10th centile for gestational age.However, she also had radiographic evidence of verte-bral fusion and lumbar lordosis shortly after birth. Thepatient of Chitayat et al. had thoracolumbar kyphosco-liosis at the age of 8 years and a height at the 95thcentile one year later. His tall stature is unusual andmay be a familial trait. While his overall phenotype isconsistent with the King syndrome, he is atypical be-cause of the presence of cardiac anomalies (dilated ven-tricles, aorta, and pulmonary artery) and the absenceof delayed motor development, elevated serum CK,electromyographic abnormalities, convincing biopsyevidence of myopathy, and adverse reaction to anesthe-sia, despite two exposures to known triggering agents.

The similarity of the Noonan and King syndromephenotypes, as first observed by Pinsky [1972], is strik-ing. In both there is delayed motor development, shortstature, skeletal anomalies (scoliosis, pectus carina-

tum/excavatum), and cryptorchidism. All of the cranio-facial anomalies of the King syndrome (blepharoptosis,down-slanting palpebral fissures, malar hypoplasia,high-arched palate, dental crowding/malocclusion, mi-crognathia, low-set ears, and webbed neck) are alsoseen in the Noonan syndrome. However, no King syn-drome patient has been reported with the Noonan com-bination of hypertelorism, epicanthic folds, lymph-edema, bleeding diathesis, or characteristic heart de-fects. A patient that bridges the gap between these twosyndromes was reported by Hunter and Pinsky [1975],who measured serum CK in a series of 27 patients withNoonan syndrome and their first-degree relatives.They identified an 11-year-old male with repeatedlyelevated serum CK levels and a myopathy on biopsy.He was considered to have classical Noonan syndrome,including an eccentric left ventricular hypertrophiccardiomyopathy that had been described in previousNoonan patients [Ehlers et al., 1972; Phornphutkul etal., 1973] and is now recognized to be present in ap-proximately 20% [Noonan, 1994]. His cardiomyopathy,the absence of scoliosis or lordosis, and the fact that he

TABLE I. Manifestations of King Syndrome Patients*

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Total

DemographicsSex M M M M M M M F F M M M M M FAge (yrs) 13 11 10 10 14 6 7 12 6 9 13 2 9 14 7Race (black, caucasian, hispanic) C C C C C C H C C H C B C C C

StatureBirth weight <5th centile − − − − − − − − 0/8Birth length <5th centile − − 0/2Height <5th centile for age + + + + + + + + + + + − + + 13/14

DevelopmentDelayed motor development + + + + + + + + + − + 10/11Normal cognitive development + + + + − + + − + + 8/10

Craniofacial findingsPtosis or blepharophimosis − + − + + − + − + + + + + 9/13Down-slanting palpebral fissures + + − + − + + + + + + − 9/12Malar hypoplasia + + + + − + + + + 8/9Cleft (CP) or high-arched palate − CP CP + + 4/5Dental crowding/malocclusion + + − + + + + − 6/8Micrognathia + + + + + + + + + + + + 12/12Apparently low-set ears + + + + − + + + + − + − 9/12Webbed neck + + – + 3/4

TrunkPectus carinatum/excavatum + + + + + + + + − + + + 11/12Scoliosis or kyphoscoliosis + + + + + + + + + + + + + + 14/14Lumbar hyperlordosis + + + + + + + + + + 10/10Vertebral fusion + + 2/2Scapular winging + + + + + + 6/6Cryptorchidism + + + + + + F F + − + − + F 9/11

LimbsWeakness + + + + + + − + + 8/9Diminished DTRs + + + − + + 5/6Contractures + + + − 3/4Hyperextensible joints + + 2/2

MyopathyElevated resting CK + + + − + + + − − + − 7/11Abnormal electromyogram + + + + + − + 6/7Abnormal muscle biopsy + + + + + + − + + 8/9Malignant hyperthermia + + + + + + + + + + + + − + + 14/15

Family HistoryIncreased CK − − − − + − + + − − + 4/11MH reaction − − − + − − − − − + − 2/11

*Patients are as follows: 1–4, King et al. [1972]; King and Denborough [1973]; 5, Isaacs and Barlow [1973]; 6, Lenard and Kettler [1975]; 7, Kaplan [1977];8, McPherson and Taylor [1981]; 9, Saul et al. [1984]; 10, Qazi et al. [1985]; 11, Steenson and Torkelson [1987]; 12, Pippin et al. [1988]; 13, Chitayat etal. [1992]; 14, Isaacs and Badenhorst [1992]; 15, our patient.

King Syndrome: Clinical Heterogeneity 257

did not experience an MH reaction during four opera-tions (with prolonged exposure to halothane and lim-ited exposure to succinylcholine) differentiated himfrom the King syndrome patients.

Two different hypotheses can be proposed to definethe genetic relationship between the King and Noonansyndromes. First, they may represent allelic autosomaldominant entities with variable expressivity in whichsome patients are the products of new mutations. Inthis scenario, King syndrome patients have a more se-vere myopathy manifested by elevations in resting se-rum CK, electromyogram (EMG) abnormalities, andabnormal muscle biopsies, while Noonan syndrome pa-tients have a mild and subclinical myopathy in whichCK is usually normal and there is minimal risk of MH.Since Noonan patients are usually not subjected toelectromyogram or muscle biopsy, there is no evidenceagainst the presence of a mild myopathy in this group.The higher proportion of kyphoscoliosis in the Kingsyndrome (100% in this review) versus the Noonansyndrome (13%) [Sharland et al., 1992] could be attrib-utable to the presence of a more severe myopathy in theformer group. However, congenital heart defects, re-fractive errors, and coagulation abnormalities are pres-ent, respectively, in 62, 67, and 60 percent of Noonansyndrome patients [Patton, 1994]. Their absence in theKing syndrome is unlikely to be explained by a failureto look specifically for these manifestations or thesmall number of reported patients. These significantphenotypic differences argue strongly against this hy-pothesis.

The second hypothesis holds that Noonan and Kingsyndrome are similar phenotypes with a dissimilarcause. This is supported by the observation that theindividual craniofacial anomalies common to both syn-dromes are also seen as part of several other pheno-types, suggesting that they are nonspecific and resultfrom dysmorphogenesis of the face as a developmentalfield [Kousseff and Nichols, 1985]. The previouslynoted differences in the phenotype of these two syn-dromes are also compatible with their current classifi-cation as separate entities. To our knowledge, there isno molecular evidence for or against the presence ofseparate loci.

It is also probable that the King syndrome is not asingle entity. Chitayat et al. [1992] have proposed thatthe syndrome is actually a phenotype resulting from aheterogeneous group of myopathies. In support of thishypothesis is the fact that eight of nine King syndromemuscle biopsies demonstrated light microscopic evi-dence of myopathy and none of them were identical.With two exceptions, the biopsies did not suggest adystrophic process. In one of these, a postmortem diag-nosis of ‘‘pseudohypertrophic muscular dystrophy’’ wasassigned [McPherson and Taylor, 1981]. In the second,the presence of giant fibers, occasional necrotic foci,and an increase in fat was thought to be consistentwith ‘‘muscular dystrophy’’ [King and Denborough,1973]. Fiber size variation was often present [King andDenborough, 1973; Isaacs et al., 1973; Kaplan et al.,1977; McPherson and Taylor, 1981; Steenson andTorkelson, 1987; Chitayat et al., 1992; Isaacs andBadenhorst, 1992]. When specified, it was usually re-

lated to pathologic changes in type I fibers, which werefew in number, small, or atrophic [Isaacs et al., 1973;Steenson and Torkelson, 1987; Isaacs and Badenhorst,1992]. Two biopsies demonstrated fiber types whichcould not be distinguished with conventional histo-chemical methods [Qazi et al., 1985; Kaplan et al.,1997] and in the first of these, the pathologic descrip-tion was simply that of a severe and morphologicallynonspecific myopathy.

While it seems likely that these biopsies representdifferent myopathies, the conclusion cannot be drawnwith certainty. The studies were performed over a 25-year period and it is not always clear whether open orneedle biopsies were used. The specimens were takenfrom different sites in different patients. CT visualiza-tion of muscle in one patient suggested the presence offocal, versus generalized, involvement [Qazi et al.,1985], raising the possibility that single biopsies arenot necessarily representative of the myopathy in anyone patient. In addition, the possibility of an evolvinghistologic picture has not been adequately addressedby serial studies.

The current patient is the fourth female to be re-ported with the King syndrome. She is of particularinterest because of the relatively unusual finding ofsevere type 2 fiber atrophy on muscle biopsy and thesimilarity of this finding to the atypical Noonan syn-drome patient of Hunter and Pinsky [1975]. She is alsothe only patient known to have an apparent eventra-tion of the diaphragm and a tethered spinal cord, andone of only two patients to have had congenital verte-bral fusion. Many manifestations in the King syndromecould reasonably be attributed to the presence of my-opathy (delayed motor development, craniofacialanomalies, skeletal deformity, scapular winging, crypt-orchidism, weakness, diminished deep tendon reflexes,contractures, and joint hyperextensibility). However,this does not seem as plausible an explanation for ourpatient’s block vertebrae and tethered spinal cord. In-stead, we feel it is likely that the myopathy, vertebralfusion, and tethered cord in this patient have a com-mon pathogenesis that may date to between the fourthand sixth weeks of gestation.

ACKNOWLEDGMENTS

The authors thank Dr. F. Clarke Fraser for his criti-cal review of the manuscript and Dr. G. Karpati for thepathologic examination of the muscle biopsy.

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