Arq Neuropsiquiatr 2002;60(3-B):739-741
Report of two Brazilian cases
Umbertina Conti Reed 
 , Maria Bernardete Dutra Resende
 Lúcio Gobbo Ferreira
 ,Mary Souza Carvalho
 , Aron Diament 
 , Milberto Scaff 
 , Suely Kazue Nagahashi Marie
ABSTRACT - We report on two boys aged 2 and 6 years-old respectively with dysmorphic face, ptosis, down-slanting palpebral fissures, hypertelorism, epicanthic folds, low-set ears, malar hypoplasia, micrognathia,high-arched palate, clinodactyly, palmar simian line, pectus excavatum, winging of the scapulae, lumbarlordosis and mild thoracic scoliosis who present congenital hypotonia, slightly delayed motor development,diffuse joint hyperextensibility and mild proximal weakness. The muscle biopsy revealed minimal but identifiablechanges represented by size fiber variability, type I fiber predominance and atrophy, perimysial fibrous infiltrationand some disarray of the intermyofibrillary network. These cases correspond to the first Brazilian reports ofthe King-Denborough syndrome and our objective is increasing the awareness of this disorder as these patientsare predisposed to developing malignant hyperthermia.KEY WORDS: King-Denborough syndrome, congenital myopathy, malignant hyperthermia.
Síndrome de King-Denborough: relato de dois casos
RESUMO - Relatamos dois meninos de 2 e 6 anos de idade que apresentam aspectos dismórficos caracterizadospor facies alongada, ptose e fenda palpebral anti-mongólica, hipertelorismo, epicanto bilateral, orelhas deimplantação baixa, hipoplasia malar, micrognatia, pálato ogival, clinodactilia, prega palmar única, “pectusexcavatum”, escápulas aladas, lordose lombar e escoliose torácica. Apresentam hipotonia congênita,hiperextensibilidade articular, fraqueza muscular e retardo do desenvolvimento motor. A biópsia muscularrevelou em ambos alterações mínimas: variabilidade do tamanho das fibras, predomínio e atrofia de fibrastipo I, discreta infiltração perimisial e desarranjo intermiofibrilar. Os aspectos dismórficos associados à miopatiacongênita configuram a síndrome de King-Denborough, da qual acreditamos serem estes os primeiros casosdescritos no Brasil. Como a síndrome se acompanha de alto risco de desenvolver hipertermia maligna naindução anestésica, o objetivo deste relato é chamar a atenção para a necessidade do diagnóstico pré-operatório,a fim de evitar esta gravíssima intercorrência.PALAVRAS-CHAVE: síndrome de King-Denborough, miopatia congênita, hipertermia maligna.
Department of Neurology, Clínicas Hospital, School of Medicine, University of São Paulo, São Paulo SP, Brazil:
Associate Professor;
PostGraduate Student;
Assistant Professor;
Full Professor and Chairman.Received 4 October 2001, received in final form 12 April 2002. Accepted 22 April 2002.
Dr. Umbertina Conti Reed - Departamento de Neurologia, Faculdade de Medicina (USP) - Avenida Dr. Arnaldo 455/4110 - 01246-903 SãoPaulo SP - Brasil. FAX 55 11 3061-4036, 55 11 3742-2340. E-mail address: 
The King-Denborough syndrome (KDS) is a conge-nital myopathy associated with susceptibility to ma-lignant hyperthermia (MH), skeletal abnormalities and dys-morphic features with characteristic facial appearance
.We present the first report in Brazil concerning twoKDS patients and as these children are predisposed todeveloping MH, our objective is increasing the aware-ness of this disorder. Considering the severity and thehigh rate of lethality of a MH reaction, as children withKDS are likely to undergo surgery with general anes-thesia for cryptorchidism and skeletal deformities, apreoperative diagnosis should be recognized.
Case 1
. A one-year-old boy was born at term followingan uneventful pregnancy from non consanguineous pa-rents and presented from birth congenital hypotonia, pto-sis and dysmorphic face. Motor development was modera-tely delayed and the child acquired independent walkingat 19 months of age. Language and mental developmentwere normal. Our first examination at 12 months of agerevealed marked ptosis, down-slanting palpebral fissures,hypertelorism, epicanthic folds, malar hypoplasia, micro-gnathia, high-arched palate, clinodactyly, pectus excavatum,lumbar lordosis and cryptorchidism (Fig 1). At neurologicalexamination we observed normal mental develpment, nor-
740Arq Neuropsiquiatr 2002;60(3-B)
mal muscular strength, diffuse muscular hypotonia and joint hyperextensibility, as well as hypoactive deep tendonreflexes. Ocular motility was normal. Serum creatine kinaselevels were normal and electromyography revealed abnor-mal myopathic pattern of muscle discharges. The musclebiopsy revealed minimal changes represented by size fibervariability, perimysial fibrous infiltration and some roundfibers There was no disarray of the intermyofibrillary net-work. After a follow-up of 15 months the course is stableand the child shows minimal motor disability.
Case 2.
 A 6-year-old male was born at term followingan uneventful pregnancy from non consanguineous pa-rents and presented from birth congenital hypotonia andweakness, ptosis, dysmorphic face, and scoliosis. The neo-natal period was complicated by poor sucking and failure-to-thrive. Motor development was moderately delayed butlanguage and mental development were normal. Cryp-torchidopexy was performed at 3 years of age out of ourinstitution without complications but it was not possibleto confirm which anesthetics were utilized. Our first exa-mination at 6 years of age revealed elongated face withmarked ptosis, down-slanting palpebral fissures, hyperte-lorism, epicanthic folds, low-set ears, malar hypoplasia,micrognathia, high-arched palate, clinodactyly, palmar si-mian line, pectus excavatum, winging of the scapulae, lum-bar lordosis and mild thoracic scoliosis. Neurological exa-mination showed normal intelligence. Weakness was mildshowing proximal predominance in the upper extremitiesand diffuse distribution in the lower extremities. Muscularhypotonia and joint hyperextensibility were diffuse and mo-derate, and deep tendon reflexes were hypoactive. A mildbilateral facial weakness was noted and ocular motility wasnormal. Serum creatine kinase levels and electromyogra-phy were normal. The muscle biopsy revealed minimal butidentifiable changes represented by size fiber variability, typeI fiber predominance and atrophy, perimysial fibrous infil-tration and some disarray of the intermyofibrillary network.Cardiac evaluation was normal. After a follow-up of 27 mon-ths the course can be considered stable and the child isattending a normal school with minimal disability. A testfor MH susceptibility will be scheduled as soon as patient’sage allows and possibly in their family members who live2000 Km faraway from our institution.
King et al.
 described 4 unrelated children fromAustralia and New Zeland with a slowly progressivemyopathy, as well as ptosis, short stature, low-setears, malar hypoplasia, skeletal deformities, and cryp-tochirdism
. All patients were boys and had beendiagnosed after episodes of malignant hypertermia,in which three died. The presence of a myopathyassociated with a predisposition to malignant hyper-thermia suggests an autosomal dominant patternof inheritance with variable expression. Our patientshad most of the characteristic phenotypical aspects,although unlike other reported cases, they had nor-mal height and did not manifest dental crowding / malocclusion. As there is some phenotypic overlapbetween the King and Noonan syndromes, the lattera multiple congenital anomaly syndrome inheritedin an autosomal dominant pattern, a genetic reIa-tionship between the two syndromes has been sup-posed
. However, Noonan syndrome, that was alre-ady reported in Brazilian children
, is not associated
Fig 1. Patient 1 at 21 months. Note the dysmorphic changes: ptosis, down-slanting palpebral fissures, hypertelorism, malar hypoplasia and micrognathia. (Photo authorized by the legal responsible).
Arq Neuropsiquiatr 2002;60(3-B)741
with myopathic changes and presents characteristicheart defect in 65% of the patients. The definitionthat King and Noonan syndromes may represent alle-lic autosomal dominant entities or be independentand linked to separate loci, depends on further mo-lecular studies
. It has also been proposed that theKing syndrome represents a common phenotype thatmay result from several different slowly progressivecongenital myopathies
. It is our opinion that despi-te the clinical phenotype of an underlying myopathy,the rarity of the syndrome among children with con-genital myopathies of different types and the typi-cal dysmorphic changes point to a specific geneticdefect not yet detected. Apparently there is no link-age to any of the already identified MH locus, soindicating the genetic heterogeneity of MH.We recommend to evaluate all patients with cli-nical signs consistent with KDS and their relativesprior to anesthesia. It would be also useful to inves-tigate the possibility of a subclinical myopathy inpatients diagnosed as Noonan syndrome not onlyfor emphasizing the risk, although minimal of MH,but also as a contribution for defining or not theindividuality of the two syndromes.
1.King JO, Denborough MA, Zapf PW. Inheritance of malignant hyper-pyrexia. Lancet 1972;1:365-370.2.McPherson EW, Taylor CA Jr. The King syndrome: malignant hyperther-mia, myopathy, and multiple anomalies. Am J Med Genet 1981;8:159-165.3.Heiman-Patterson TD, Rosenberg HR, Binning CP, Tahmoush AJ. King-Denborough syndrome: contracture testing and literature review.Pediatr Neurol 1986;2:175-177.4.Isaacs H, Badenhorst ME. Dominantly inherited malignant hy-perthermia (MH) in the King-Denborough syndrome. Muscle Nerve1992;15:740-742.5.Graham GE, Silver K, Arlet V, Der Kaloustian VM. King syndrome:further clinical variability and review of the literature. Am J Med Genet1998;78:254-259.6.Chitayat D, Hodgkinson KA, Ginsburg O, Dimmick J, Watters GV.King syndrome: a genetically heterogenous phenotype due to conge-nital myopathies. Am J Med Genet 1992;43:954-956.7.Bertola DR, Sugayama SM, Albano LM, Kim CA, Gonzalez CH.Noonan syndrome: a clinical and genetic study of 31 patients. Rev HospClin Fac Med Sao Paulo 1999;54:147-150.8.Bertola DR, Kim CA, Sugayama SM, et al. Cardiac findings in 31 patientswith Noonan’s syndrome. Arq Bras Cardiol 2000; 75: 409-412.9.Bertola DR, Kim CA, Pereira AC, et al. Are Noonan syndrome andNoonan-like/multiple giant cell lesion syndrome distinct entities? Am J Med Genet 2001;98:230-234.
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