42047MJed Genet 1998;35:420-424

49,XXXXY: a distinct phenotype. Three new

cases and review J Med Genet: first published as 10.1136/jmg.35.5.420 on 1 May 1998. Downloaded from

Jennifer Peet, David D Weaver, Gail H Vance

Abstract timing of genes expressed on the X chromo- Over 100 cases of 49,XXXXY syndrome some is altered. have been published to date. Classic find- The classic clinical findings reported in per- ings include radioulnar synostosis, hy- sons with a 49,XXXXY have pogonadism, and mental retardation. The included radioulnar synostosis, mental defi- majority ofreported cases have not distin- ciency, and hypogonadism.9-" Because these guished the 49,XXXXY syndrome from findings are not distinctive from the clinical (47,XXY), and these findings in Klinefelter syndrome, subjects with patients are frequently labelled as having 49,XXXXY syndrome are often labelled as Klinefelter syndrome or as being a having Klinefelter syndrome (47,XXY) or as "KIinefelter variant." Because of dist- being a "Klinefelter variant". There are a few inct clinical features, we delineate the reports, however, which do make a point ofdif- 49,XXXXY syndrome as separate from ferentiating this Klinefelter syndrome, and emphasise the from Klinefelter syndrome.'2 " After reviewing prevalence ofcongenital heart defects. We published reports on 49,XXXXY and examin- also report three new cases of 49,XXXXY ing the three subjects reported in this paper, we syndrome and briefly discuss patient have concluded that the 49,XXXXY syndrome management. should be classified separately from Klinefelter (7Med Genet 1998;35:420-424) syndrome. People with 49,XXXXY syndrome have characteristic facial features, particular Keywords: sex chromosome; Klinefelter syndrome; habitus, multiple skeletal anomalies, cardiac aneuploidy defects, genital abnormalities, variable degree of mental impairment, and speech problems apart from those classically seen in Klinefelter The was first in 49,XXXXY syndrome reported syndrome. 1960 by Fraccaro et al' and represents a rare sex chromosome aneuploidy syndrome with an

approximate incidence of 1 in 85 000 male Case reports http://jmg.bmj.com/ births.2 A 49,XXXXY karyotype is thought to CASE 1 arise from maternal non-disjunction during Case 1 (Fam No 87398), now a 31/2 year old both I and meiosis 1I.36 Such successive white male, was referred to the medical genet- non-disjunction theoretically produces an egg ics service as a neonate following postnatal with four X chromosomes, which, when ferti- identification of a 49,XXXXY karyotype. He lised by a Y bearing sperm, results in an embryo was born by caesarean section to a non- with 49,XXXXY syndrome."4 Interestingly, the consanguineous, 23 year old, G(2)P(l)Ab(l) on September 27, 2021 by guest. Protected copyright. occurrence of this syndrome does not appear to mother and a 26 year old father. The be related to maternal age. Several suggestions pregnancy reportedly was complicated by have been made to account for the phenotype oligohydramnios and intrauterine growth re- associated with a 49,XXXXY genotype, as well tardation. Apgar scores were 7 at one minute as for other . Two and 8 at five minutes. Length and weight were prevalent theories for the abnormal phenotype <5th centile and OFC was greater than 2 SD include (1) increased dosage of active genes in below the mean (table 1). On examination after regions which escape X inactivation, and (2) birth there were upward slanting palpebral fis- asynchronous replication of the extra X sures, telecanthus, prominent maxilla, bilateral Department of chromosomes.7 In either case, the amount/ of the 5th fingers with converging Medical and Molecular Genetics, Indiana University School of Table 1 Measurements ofthe three patients reported here Medicine, 975 W Walnut Street, Case 1 Case 2 Case 3 Room IB-264, Indianapolis, Birth Birth Birth IN 46202-5251, USA Wt 1880 g (<5%) Wt 3450 g (50%) Wt 2380 g (<5%) J Peet Ht 43.18 cm (<5%) Ht 48.26 cm (3-10%) Ht 47cm (<5%) D D Weaver OFC 30.48 cm (<-2SD) OFC N/A OFC 31 cm (<-2SD) G H Vance 3mth ly 1'/2y Wt 4.06 kg (<5%) Wt 9.37 kg (10-25%) Wt 7.2 kg (<3%) Ht 56 cm (3-10%) Ht 73.5 m (10-25%) Ht 73 cm (<3%) Correspondence to: OFC 37 cm (<-2SD) OFC 45 cm (<-2SD) OFC 45 cm (<-2SD) Dr Vance. 21/2 y 141/2 y Wt 9.9 kg (3%) Wt 48.4 kg (25-50%) Received 24 June 1997 Ht 86 cm (25-50%) Ht 158.7 cm (25-50%) Revised version accepted for OFC 44.6 cm (<2-SD) OFC 54 cm (<-2SD) publication 3 November 1997 Wt=weight, Ht=height, OFC=occipitofrontal circumference. 49,XXXXY: a distinct phenotype 421

(greater than 2 SD above the mean). Addition- ally, plagiocephaly, a depressed nasal bridge, asymmetrical chest, and clinodactyly of the 2nd toes were noted (fig 1). At the age of 2 J Med Genet: first published as 10.1136/jmg.35.5.420 on 1 May 1998. Downloaded from years 2 months, both his inner and outer canthal distances were above the 97th centile. Further examination showed an open metopic suture, facial asymmetry, underdeveloped or- bital bones, intermittent strabismus, narrow but normally positioned ears, , hyperextensible elbows, dermal hyperkeratosis, and generalised (fig 2). Chest radiographs showed stable cardiome- galy, levoscoliosis of the lower thoracic and upper lumbar spine, and a right cervical rib. The scoliosis, thought in part to be secondary to neuromuscular hypotonia, has gradually improved with time, decreasing from 200 at the age of 1 year to 6° at the age of 3. Case 1 received physical, occupational, and speech therapy from the age of 6 months. Both hearing and vision have been tested and are within normal limits. Developmental assess- ment at several stages of his life indicated global developmental delay. At 6 months, the Bayley Scales of Infant Development rated the mental development index as <50 (age equiva- lent of 3 months). The behavioural age was assessed at 2.2 months using the Wisconsin Behavior Rating Scale, and between 0-3 months on the Rossetti Infant-Toddler Lan- guage Scale. At the age of 1 year, case 1 was evaluated to have gross motor skills at a 4 month level and fine motor skills at a 9 month level. Behavioural age was estimated at 7 months by the Wisconsin Behavior Rating Scale. At a chronological age of 36 months, the

Peabody Developmental Motor Scales-Fine http://jmg.bmj.com/ Motor Scale estimated an age equivalence of F' 15 months. Case 1 sat unassisted at 1 year and scooted and stood with help at 2 years of age. 6,A At 3 years, his only words were "Mama" and "Dada."

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CASE 2 on September 27, 2021 by guest. Protected copyright. Case 2 (Fam No 54754) was last evaluated by us at the age of 15 '/2 years. He is a white male who was born at term to a non-consan- guineous, 22 year old, G(1)P(l) mother and a 24 year old father. The pregnancy was uncom- plicated. Birth weight was 3450 g (50th centile) and length was 48 cm (3rd-i Oth centile) (table Figure 2 Case 1 aged 21 years. 1). Postnatally, he was found to have tetralogy creases, and prominent plantar creases running of Fallot and subsequently underwent ven- between the first and second toes bilaterally. tricular septal defect repair. There was no limitation to extension or Case 2 was ascertained at 1 year of age by rotation of the elbows. Genital abnormalities karyotype analysis for dysmorphic features and included a hypoplastic foreskin, scrotalisation developmental delay. On examination at 1 year, of the penis, small testes, and bilateral hydroce- his height and weight were at the 20th to 25th les. Bilateral inguinal hernias and atrial and centile range for age and head circumference ventricular septal defects were detected at birth was greater than 2 SD below the mean (table and subsequently repaired successfully. The 1). Physical features included plagiocephaly, family history included hyperthyroidism in the low anterior hairline, right preauricular pit, father resulting in thyroidectomy, and pectus short neck, abnormal palmar creases with carinatum in the mother and several of her bilateral fifth finger clinodactyly, small penis uncles. and testes, and delayed bone age. He was lost At the age of 3 months, inner and outer can- to follow up until the age of 14 years 2 months, thal distances (3 cm and 6 cm, respectively) during which time he was reported to have had were both between the 3rd and 25th centile frequent upper respiratory tract infections with and palpebral fissure lengths were both 1.5 cm multiple episodes of pneumonia. On physical 422 Peet, Weaver, Vance

Table 2 A comparison ofKlinefelter syndrome, 49,XXXXY syndrome, and the three new patients reported in this paper

Klinefelter syndrome * 49,XXXXY syndromet Case 1 Case 2 Case 3

Intelligence Normal/slightly reduced Variable, low normal/MR DD DD DD J Med Genet: first published as 10.1136/jmg.35.5.420 on 1 May 1998. Downloaded from Speech Delay Severe delay, absent Absent Absent Absent Stature Average height ¢ 184 cm Average birth length 48.6 cm 25-50% 25-50% <3% + (90-97%) (25-50%), average adult height 181 cm (75-90%) Skeletal abnormalities Scoliosis, 5th finger Many anomalies, delayed Plagiocephaly, asymmeterical Plagiocephaly, elbow Trigonocephaly, clinodactyly ossification, cartilage chest, levoscoliosis, right contracture, exaggerated hip subluxation degeneration cervical rib, 5th finger lordosis,5th finger clinodactyly, genu valgum clinodactyly, phalangeal hypoplasia, knee enlargement, genu valgum, pes planus Cardiovascular defects Increased incidence of 14-20%t§ ASD,VSD TOF PDA MVP Genital abnormalities Small penis,small testes Small penis,small testes Hypoplastic foreskin, penile Small penis,small testes Normal genitalia scrotalisation, small testes, bilateral hydroceles *Paulsen and Plymate.2' tSijmons et al.23 tKarsh et al.' §Linden et al." ASD=atrial septal defect, DD=developmental delay, MR=mental retardation, MVP=mitral valve prolapse, PDA=patent ductus arteriosis, TOF=tetralogy of Fallot, VSD=ventricular septal defect. examination at 14 years 2 months, his outer He was referred to the canthal distance was 9.25 cm (75th-97th clinic following a peripheral blood karyotype centile) and inner canthal distance was 3.75 cm report of 49,XXXXY. On examination at the (greater than 2 SD above the mean) with a age of 18 months, he was a small, pale, and shy palpebral fissure length of 2.75 cm (greater child with a triangular shaped head. Both his than 2 SD below the mean). Plagiocephaly, height (73 cm) and weight (7.2 kg) were below epicanthic folds, upward slanting palpebral fis- the 3rd centile. Head circumference was sures, prominent nasal bridge, broad and flat greater than 2 SD below the mean (table 1). He nose, left malar flattening, thick superior had a prominent forehead, horizontal palpebral helices, right sided preauricular pit, mandibu- fissures with drooping lower lids, normal inner lar hypoplasia, and micrognathia were noted. and outer canthal measurements, broad nasal Skeletal abnormalities included a raised left bridge, downturned corners of the mouth, an shoulder, exaggerated spinal lordosis, contrac- inverted left nipple, and a sacral dimple. ture ofthe right elbow, bilateral 5th finger clino- Subluxation ofthe right hip and eversion of the dactyly, thin tapering legs with genu valgum, lower legs bilaterally were also noted. He had thin and narrow feet with pes planus, and normal reflexes and truncal hypotonia. He sat

increased sandal gap between toes 1 and 2 independently but did not walk or speak. http://jmg.bmj.com/ bilaterally. Bilateral thenar eminence hypopla- sia, clubbing of the finger and toenails, and small penis and testes were also observed. Der- Discussion matoglyphic examination showed bilateral hy- Reports describing subjects with 49,XXXXY poplasia of the distal flexion creases of the syndrome have emphasised the "classic triad" of thumb and fingers with a bridged simian crease mental retardation, radioulnar synostosis, and We, and a few others before on the right palm. Sexual development was hypogonadism.9" on September 27, 2021 by guest. Protected copyright. Tanner stage II. Both serum LH and FSH were us, suggest that patients with 49,XXXXY markedly raised, indicating primary gonadal syndrome actually have a more distinctive failure. X ray evaluation of the hands showed phenotype consisting of a characteristic facies hypoplasia of the distal phalanx of each finger and habitus, multiple skeletal anomalies, cardiac and a normal bone age. Testosterone therapy defects, genital abnormalities, a variable degree was refused by the parents. of mental impairment, and severe speech Developmental delay of 6-8 months was impairment (table 2). The clinical phenotype assessed at a chronological age of 17 months. changes as the person grows to an adult. There- Case 2 crawled at 2 years and walked at 2'/2 fore, certain features present in children are not years. He has severe speech impairment and necessarily present in adults and vice versa. communicates primarily by sign language. The characteristic facial appearance of a child Hearing and vision are reported as normal. with 49,XXXXY syndrome includes a full, round face, epicanthic folds, upward slanting CASE 3 palpebral fissures, ocular , telecan- Case 3 (Fam No 88585) is a 3'/2 year old, thus, a broad and depressed nasal bridge, and Amish, white male born by spontaneous vaginal micrognathia.'4 6 With age, the fullness of the delivery to a 25 year old, G(6)P(3)Ab(3) mother face gives way to coarsening of features and and a 27 year old father. Consanguinity was becomes apparent.' 17 18 Patients denied and the pregnancy was uncomplicated. may also have microcephaly, cleft palate, and Apgar scores were 8 at one minute and 9 at five abnormally shaped or positioned ears.12 18 19 All minutes. Birth weight and length were at the 5th three of our patients have characteristic facial centile and his OFC measured greater than 2 features and microcephaly (table 3). Cases 1 and SD below the mean (table 1). A patent ductus 2 also have plagiocephaly and facial asymmetry. arteriosus was identified at birth and ligated at To our knowledge, plagiocephaly in association 15 months. He had pneumonia at 17 months. with 49,XXXXY syndrome has not been 49,XXXXY. a distinct phenotype 423

Table 3 Facialfeatures observed in the 49,XXXXY cases we add three new patients. Case 1 was syndrome and the three reported patients born with atrial and ventricular septal defects, case 2 was born with tetralogy of Fallot, and 49,XXXXY Case 1 Case 2 Case 3 J Med Genet: first published as 10.1136/jmg.35.5.420 on 1 May 1998. Downloaded from case 3 with a PDA. Interestingly, Meschede et Microcephaly + + + aP4 reviewed published reports of another sex Full/round face (childhood) + ? Epicanthic folds + + + aneuploidy syndrome, 48,XXYY, and found Upward slanting palpebral fissures + + that 8% of those examined had a congenital Ocular hypertelorism + + + heart defect. Telecanthus + - - Broad, depressed nasal bridge + + + Genital abnormalities are consistently found Micrognathia + + + in males with a 49,XXXXY karyotype. These Abnormally shaped/positioned ears + + anomalies include small penis and testes, unde- scended testes, bifid scrotum, ambiguous geni- talia, and scrotalisation ofthe penis.' 3 18 25 26 Two reported previously, and we found only one of our patients had hypogonadism and case 1 published case describing facial asymmetry.'6 also had scrotalisation of the penis, hypoplastic The general adult habitus of a person with foreskin, and bilateral hydroceles. 49,XXXXY syndrome is eunuchoid. The neck Another feature of 49,XXXXY syndrome is is short, the shoulders and chest are narrow, and cognitive impairment. Most authors of older frequently the nipples are widely spaced.'0 18 publications predicted a bleak prognosis of Patients often have long, thin tapering arms moderate to severe mental retardation in these and legs with bilateral cubitus valgus, genu val- subjects with an estimated mean IQ of 35.2 13 26 gus, and pes planus. As with facial features, the While patients with moderate to severe mental body habitus of a subject with 49,XXXXY retardation and this karyotype do exist and will syndrome changes over his lifetime. Infants continue to be reported, the above prediction with a 49,XXXXY karyotype are generally of IQ range probably is based on biased data. small for gestational age yet may show "catch Many of the patients in the earlier reports were up" growth later in life. For example, the birth institutionalised and did not receive sufficient length of case 1 was below the 5th centile but early intervention or personal interaction measured between the 25th and 50th centiles which might have enabled them to function at at the age of 2 '/2 years. However, the birth a higher level. More recently, several patients length of case 3 was also below the 5th centile have been reported with IQs in the borderline and remained so at 18 months of age. Case 2 to low normal range. Sheridan et at-6 described had a normal birth length and measured a patient with IQs of 76 and 70 when assessed between the 25th and 50th centiles for height at by the Stanford Binet and Weschler Preschool the age of 14'/2 years. A review of heights and and Primary Scale of Intelligence (WPPSI) weights of published cases of 49,XXXXY syn- tests, respectively. Borghgraef et al'3 reported drome (not including our three cases) showed two patients, both of whom had IQs of 72 as http://jmg.bmj.com/ an average birth weight of 2551 g (<1Oth cen- measured by WPPSI scale. Kleczkowsa et at- tile, n=29) and average birth length of 48.6 cm reported two additional patients with border- (25th-50th centile, n=8). The average adult line IQs of 70 and 72. Lomelino and Reiss27 height was 181 cm (75th-90th centile, n=6) reported a child with 49,XXXXY syndrome and average adult weight was 71 kg (75th-90th who was ascertained only as a control to a centile, n=4). research study. This child had an IQ of 78±6 as Multiple skeletal anomalies occur in people measured by the Stanford-Binet test at 4 years with 49,XXXXY syndrome and include radio- 10 months. Of the three cases reported here, on September 27, 2021 by guest. Protected copyright. ulnar synostosis, delayed bone age with lack of formal developmental data were available only closure of bone growth plates into adulthood, from case 1. However, all three were docu- congenital hip dislocation, early degeneration mented to have developmental delay. of articular cartilage (especially at the elbows), Additionally, speech impairment or even and hypertrophy of epiphyses.20 23 The skeletal speech aphasia is uniformly found in persons anomalies of the three cases reported are listed with 49,XXXXY syndrome.'2 15 26-28 Each pa- in table 2. Case 1 had plagiocephaly, a right tient reported here had significant speech cervical rib, asymmetrical chest, scoliosis, and impairment. Neither cases 1 nor 2 attempt bilateral 5th finger clinodactyly. Case 2 had purposeful verbal communication. Case 2 has plagiocephaly, a raised left shoulder, exagger- successfully learned and uses sign language. ated spinal lordosis, contracture of the right Case 3, at 18 months, also had significant elbow, hypoplasia of the phalanges, bilateral speech delay. 5th finger clinodactyly, genu valgum, and pes In conclusion, we believe that 49,XXXXY planus. Case 3 had congenital hip subluxation. syndrome is a distinct clinical entity and should Congenital heart and vascular disease is also not be "lumped" together with Klinefelter syn- observed in subjects with a 49,XXXXY karyo- drome. People with 49,XXXXY syndrome type. In fact, the first case report by Fraccaro et have distinctive facial features, are more all described a child with a patent ductus arte- mentally handicapped, and have greater speech riosus (PDA). Fifteen years later, Karsh et al difficulty than those with Klinefelter syndrome. reviewed published reports and found that 13 In addition, males with 49,XXXXY syndrome of 88 (14%) reported cases of 49,XXXXY are generally shorter, have distinct skeletal syndrome had a cardiovascular defect with the anomalies, and an increased incidence of con- most common defect being a PDA. Several genital heart defects when compared to males reports since 1975 have also described con- with a 47,XXY karyotype. The presence of genital heart defects.4 5 18'9 To these reported congenital heart defects in subjects with 424 Peet, Weaver, Vance

49,XXXXY syndrome suggests special atten- 13 Borghgraef M, Fryns JP, Smeets E, Marien J, Van den Berghe H. The 49,XXXXY syndrome: clinical and tion be given to the cardiac evaluation. psychological follow-up data. Clin Genet 1988;33:429-34. Conversely, males with congenital heart defects 14 Hayeka A, Riccardi V, Atkins L, Hendren H. 49,XXXXY chromosomal anomaly in a neonate. .7 Med Genet J Med Genet: first published as 10.1136/jmg.35.5.420 on 1 May 1998. Downloaded from who fit the phenotypic description of 1971;8:220-1. 49,XXXXY syndrome or who have significant 15 Moric-Petrovic S, Laca Z, Markovic S, Markovic V. speech impairment or both are candidates for 49,XXXXY karyotype in a mentally retarded boy. _7 Ment Defic Res 1973;17:73-80. chromosome analysis. 16 Kushnick T, Colondrillo M. 49,XXXXY patient with hemi- facial microsomia. Clin Genet 1975;7:442-8. 17 Cowie VA, Singh RR, Wheater R. 49,XXXXY chromosome anomaly in a mentally retarded man. Br3r Psych 1986;148: 1 Fraccaro M, Kaijser K, Lindsten G. A child with 49 210-12. chromosomes. Lancet 1960;ii:899-902. 18 Linden MG, Bender BG, Robinson A. Sex chromosome 2 Kleczkowska A, Fryns JP, Van den Berghe H. and pentasomy. Pediatrics 1995;96:672-82. X-chromosome in the male. Hum Genet 1988;80: 19 Curfs LMG, Schreppers-Tijdink G, Wiegars A, Borghgraef 16-22. M, Fryns JP. The 49,XXXXY syndrome: clinical and psy- 3 Villamar M, Benitez J, Fernandez E, Ayuso C, Ramos C. chological findings in five patients. _7 Ment Defic Res 1990; Parental origin of chromosomal in a 34:277-82. 49,XXXXY male using recombinant-DNA techniques. 20 Sergovich F, Uilenberg C, Pozsonyi J. The 49,XXXXX Clin Genet 1989;36:152-5. chromosome constitution: similarities to the 49,XXXXY 4 Deng HX, Abe K, Kondo I, et al. Parental origin and mech- anism of formation of polysomy X: an XXXXX case and condition. _7 Pediatrics 1971;78:285-90. four XXXXY cases determined with RFLPs. Hum Genet 21 Schmidt R, Pajewski M, Malka R. Epiphysial dysplasia: a 1991;86:541-4. constant finding in the XXXXY syndrome. .7 Med Genet 5 Huang THM, Greenberg F, Ledbetter DH. Determination 1978;15:282-7. of the origin of nondisjunction in a 49,XXXXY male using 22 Tumba A, Laredo JD, Corvol MT, et al. Evolution of bone hypervariable dinucleotide repeat sequences. Hum Genet anomalies in 49,XXXXY syndrome. Can Assoc Radiolj 1991;86:619-20. 1993j44:107-11. 6 Leal CA, Belmont JW, Nachtman R, Cantu JM, Medina C. 23 Sijmons RH, van Essen AJ, Visser JD, et al. Congenital knee Parental origin of the extra chromosomes in polysomy X. dislocation in a 49,XXXXY boy. J7Med Genet 1995;32:309- Hum Genet 1994;94:423-6. 11. 7 Scheres JMJC, Merkx GFM, Hustin TWJ. Prometaphase 24 Meschede D, Nekarda T, Kececioglu D, et al. Congenital banding of human chromosomes with basic fuchsin. Hum heart disease in the 48,XXYY syndrome. Clin Genet 1995; Genet 1982;61:8-11. 48:100-2. 8 Sarto GE, Otto PG, Kuhn EM, Therman E. What causes 25 Hecht F. Observations on the natural history of 49,XXXXY the abnormal phenotype in a 49,XXXXY male? Hum Genet individuals. Am 7 Med Genet 1982;13:335-6. 1987;76:1-4. 26 Sheridan MK, Radlinski SS, Kennedy MD. Developmental 9 Karsh RB, Knapp RF, Nora JJ, Wolfe RR, Robinson A. outcome in 49,XXXXY Klineflelter syndrome. Dev Med Congenital heart disease in 49,XXXXY syndrome. Pediat- rics 1975;56:462-4. Child Neurol 1990;32:528-46. 10 Tenbrinck MS, Boyd JH, Buchin SY. The chromosome 27 Lomelino CA, Reiss AL. 49,XXXXY syndrome: behav- 49,XXXXY syndrome. Arizona Med 1976;33:546-50. ioural and developmental profiles. _7 Med Genet 1991;28: 11 Singh TH, S Rajkowa. 49,XXXXY chromosome anomaly: 609-12. an unusual variant of Klinefelter's syndrome. Br Psych 28 Pallister PD. 49,XXXXY syndrome. Am _7 Med Genet 1982; 1986;148:209-10. 13:337-9. 12 Zaleski WA, Houston CS, Pozsonyi J, Ying KL. The 29 Paulson CA, Plymate SR. Klinefelter's syndrome. In: King XXXXY chromosome anomaly: report of three new cases RA, Rotter JI, Motulsky AG, eds. The genetic basis of and review of 30 cases from the literature. Can Med Assoc 7 common diseases. NewYork: Oxford University Press, 1992: 1966;94:1143-54. 876-94. http://jmg.bmj.com/ on September 27, 2021 by guest. Protected copyright.