6JMed Genet 1998;35:1036-1039

Costello syndrome: two cases with embryonalrhabdomyosarcoma

B Kerr, 0 B Eden, R Dandamudi, N Shannon, 0 Quarrell, A Emmerson, E Ladusans,M Gerrard, D Donnai

AbstractCostello syndrome is a well delineatedmental retardation syndrome of unknownaetiology in which the occurrence ofbenign tumours, especially papillomata, isrecognised. We report two children inwhom the diagnosis of Costello syndromewas made in the first months of life, whoboth developed a retroperitoneal embryo-nal rhabdomyosarcoma. Although notpreviously reported, the occurrence ofthis relatively uncommon childhoodtumour in two girls with Costello syn-

drome suggests that an increased risk ofmalignancy may be part of this condition.The genetic basis of this susceptibilityrequires further clarification.( Med Genet 1998;35:1036-1039)

Keywords: Costello syndrome; rhabdomyosarcoma

North West RegionalGenetic Service, StMary's Hospital,Manchester M13 OJH,UKB KerrD Donnai

Department ofOncology, RoyalManchester Children'sHospital, Manchester,UKO B EdenR Dandamudi

North Trent ClinicalGenetics Service,Sheffield, UKN ShannonO Quarrell

Department ofPaediatrics, St Mary'sHospital, Manchester,UKA Emmerson

Department ofCardiology, RoyalManchester Children'sHospital, Manchester,UKE Ladusans

Sheffield Children'sHospital, Sheffield, UKM Gerrard

Correspondence to:Dr Kerr.

Received 4 March 1998Revised version accepted forpublication 12 May 1998

In 1971 and 1977, Costello' described two

unrelated children with features of poor

postnatal growth, mental retardation, curlyhair, loose skin of the hands and feet,distinctive facies, and nasal papillomata. Al-though no further reports appeared until1991,2 by 1996 16 cases in English publicationswhere the authors used the designation Cos-tello syndrome were able to be reviewed by DrCostello3 in an update on his original patients.

Borochwitz et ar reported five patients with a

previously unrecognised syndrome and pro-

posed naming it the facio-cutaneous-skeletalsyndrome. It has been suggested that thesepatients and three reported by Berberich et aralso have the Costello syndrome.6 Severalother reports8-'2 bring the total number of pub-lished cases to 31.Although the similarities between Costello

syndrome, Noonan syndrome, and the cardio-facio-cutaneous (CFC) syndrome have longbeen recognised,2 a number of characteristicfindings in Costello syndrome are infrequent or

absent in Noonan and CFC syndromes.2 Inparticular, the natural history of Costellosyndrome is very striking'3 with two distinctdisease phases, the first characterised by a

severe failure to thrive following normal or

increased birth weight and often polyhydram-nios, and the second by a clinical picture whichresembles a storage disorder.

Children with Costello syndrome tend to

develop benign primitive ectodermal tumours.

Papillomas may occur at various ages in nasal,perioral, and anal areas and a calcified epithe-lioma has occurred."' Zampino et al'3 reporteda child with Costello syndrome who was diag-

nosed to have ganglioneuroblastoma, a tumourof neuroectodermal origin, at the age of 17months. An adult with Costello syndrome,unilateral cataract, and a unilateral acousticneuroma has been reported.'5We describe here two children with Costello

syndrome, both of whom have developed inearly life a pelvic embryonal rhabdomysosar-coma, a tumour of mesenchymal origin.

Case reportsCASE 1A 3 year old girl, the only child of unrelatedparents of Anglo-Saxon origin, first came tomedical attention prenatally when an ultra-sound scan at 16 weeks' gestation showednuchal thickening with a normal female karyo-type on amniocentesis. On subsequent scans,increased liquor volume and an abnormal handposture with flexion and ulnar deviation at thewrists was noted. She was born at 38 weeks'gestation by elective caesarean section.At birth her weight was 3470 g (90th centile)

and her head circumference was 37 cm (abovethe 97th centile). She fed poorly from thebeginning and was admitted to neonatal inten-sive care with transient hypoglycaemia. Shedeveloped a supraventricular tachycardia withectopics on day 10. She responded to, andremained well, on oral digoxin and flecainide.Echocardiogram showed a patent foramenovale and mild pulmonary valve stenosis. Shewas eventually discharged home at 1 month ofage.

In the newborn period, she was noted tohave a flat nasal bridge with epicanthus andhypertelorism, downward slanting palpebralfissures, and large, upturned ear lobes. Herhands were tightly clenched and her wrist pos-ture was abnormal with persisting ulnar devia-tion. Hyperextensibility of the small joints ofthe hands was noted with deep set nails anddeep vertical foot creases.Her feeding difficulty persisted with vomit-

ing despite medical management of gastro-oesophageal reflux. By 3 months, she had madelittle developmental progress and, although herhead circumference remained above the 90thcentile, her weight was on the 1 0th centile. Thediagnosis of Costello syndrome was made atthis time on the basis of her facial features,clinical course, and striking excess palmar skin(fig 1).

Cerebral CT scan and subsequent MRIshowed only minor prominence of the lateraland third ventricles. Formal ophthalmologicalassessment at 10 weeks was consistent withdelayed visual maturation. Blood and skinchromosomes were both normal.

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1037Costello syndrome

B

Figure 1 (A) Case 1 signing "home" at the age of 3. (B) Case 1 showing excess palmar skin with deep creases andmarked hyperextensibility of the small joints of the hand

She continued to have intense problems withfeeding and slow weight gain. By 5 months herweight and height were below the 3rd centileand have continued to parallel the 3rd centilesince. She initially was tried on intermittentnasogastric tube feeding to supplement calorieintake. This having failed, she went on to haveregular night time tube feeding. At 6 months,she began to fix and follow and smiled. Sherolled and began to vocalise at 8 months. Shewas sitting unaided at 18 months but wasunable to pull to a sitting position on her ownuntil the age of 2.She had problems with constipation and

recurrent chest infections but no furtherepisodes of supraventricular tachychardia.At the age of 2 years 4 months she was

admitted to hospital with a four week history ofprogressive vomiting and constipation. Herparents noted marked abdominal distensionjust before admission. She was clinically unwellwith acute bowel obstruction. Ultrasound andMRI imaging of her abdomen showed a largemass measuring 10 x 9 x 8 cm arising from theleft psoas major muscle. This mass compressedthe left ureter, causing hydronephrosis. Theureteric obstruction was relieved surgically anda biopsy of the mass taken. Histology wasreported as embryonal rhabdomyosarcoma.No metastatic spread was found on staginginvestigations. She received chemotherapy im-mediately, but in view of her clinical condition,standard rhabdomyosarcoma therapy wasmodified to vincristine, actinomycin, andcyclophosphamide. Ten days later she becameacutely unwell with bowel obstruction. Adhe-sions of the bowel were relieved and, at thissecond laparotomy, major tumour debulkingwas performed. She was continued on chemo-therapy using ifosfamide, vincristine, and

actinomycin. After the second course, whenshe developed ifosfamide induced encepha-lopathy, she was changed back to pulses of vin-cristine, actinomycin, and cyclophosphamidegiven every three weeks for nine courses. Sheexpectedly had problems with nutrition andfebrile neutropenic episodes. Despite regularphysiotherapy her Achilles tendon contracturesbecame worse while on chemotherapy, prob-ably exacerbated by vincristine. A tendonreleasing procedure has been performed.She is now almost a year off treatment and

has remained in remission, confirmed by regu-lar scanning. At the age of 3 years 9 months,she is a happy, sociable, and curious little girlwho is able to use many signs and a number ofwords with meaning. Her food remains liquid-ised but she eats a variety of foods in largerquantities and will attempt to feed herself witha spoon. She has been walking with a frame forthe last month and has taken a few steps alone.Formal psychometric assessment has shown ascatter in performance with the highest scoresbeing achieved in the personal-social domainand the lowest in locomotion and eye-handcoordination.

CASE 2A 31/2 year old girl, the third child of unrelated,Anglo-Saxon parents, was born at 38 weeks'gestation after a pregnancy complicated bypolyhydramnios. Her birth weight was 3250 g(50th centile) and head circumference was38.3 cm (97th centile). She was transferred tothe Special Care Unit shortly after birthbecause of respiratory distress. Subsequentlyshe had feeding difficulties and persistent vom-iting which was unresponsive to all forms ofmedical therapy.

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Kerr, Eden, Dandamudi, et al

Figure 2 (A) Case 2 at 15 months. (B) Excess palmar skin.

At 4 months, she was re-referred to apaediatrician for investigation of persistentfailure to thrive and vomiting despite continu-ous nasogastric feeds. Upper gastrointestinalendoscopy showed mild inflammation at thelower end of the oesophagus while a 24 hourpH study, on antireflux therapy, showed noresidual reflux. Following her endoscopy, shehad several self-correcting episodes of su-praventricular tachychardia and bundle branchblock. A contrast swallow showed poor suck-swallow coordination.She was noted at birth to have dysmorphic

features and by 4 months these had becomemore prominent. She had macrocephaly with aprominent occiput and frontal bossing. Shehad a depressed nasal bridge with antevertednares, low set, posteriorly rotated ears, promi-nent epicanthic folds, and a large mouth. Fetalfinger pads were noted along with long fingersand toes and joint laxity. She had loose skin andincreased creases on her palms and soles. It wasevident at 4 months that her development wassignificantly delayed and she was hypotonic. Acerebral CT scan showed poor grey-whitematter differentiation and increased CSFspaces.A diagnosis of Costello syndrome was made

at 10 months based on her evolving phenotypeand striking failure to thrive (fig 2A, B). Shewas readmitted for a repeat 24 hour pH probewhich showed mild reflux and it was decidedthat since she continued to be dependent onnasogastric tube feeds she should have agastrostomy and Nissen's fundoplication.She has continued to grow below the 0.4th

centile despite gastrostomy feeds and trials ofcalorie supplements and has only made slowprogress with oral feeds. She will now take flu-ids by mouth but is not interested in food andusually chokes on it. Her general development

.

(C) Case 2 at 3 years.

has been significantly delayed. She started tobabble at 22 months but has not gained anywords as yet. She now has 12 Makaton signs,can indicate wants by pointing, and shows alevel of understanding above her verbal skillswhile playing (fig 2C). She started to sit aloneat 20 months and at 23 months was bottomshuffling. She was pulling herself up at 3 yearsand is now cruising on furniture, but at 4 yearsis not walking independently and is still unableto roll in either direction.At 3 years 2 months, her mother noted an

abdominal mass. She was otherwise wellthough tolerating slightly less gastrostomy feedthan usual. Examination confirmed a firmmass arising from the pelvis. CT scan showed avascular mass closely apposed to the anteriorabdominal wall and possibly infiltrating it. Nointra-abdominal lymphadenopthy could beseen and the liver looked normal.At operation, the mass appeared to arise

from the urachus and was closely adherent tothe bladder. The upper part of the bladder wasresected en bloc with the encapsulated tumour.Histology showed an embryonal rhabdomyo-sarcoma extending up to the resection margin.Staging investigations showed no evidence ofmetastatic disease.She was treated with chemotherapy, initially

ifosfamide, actinomycin, and vincristine. Afterfour courses, cyclophosphamide was substi-tuted for ifosfamide because of haemhorrhagiccystitis. Treatment was also complicated byrecurrent episodes of moderately severe diar-rhoea and febrile neutropenia requiring re-admission to hospital.CT examination of the abdomen and pelvis

after three courses of chemotherapy showed noresidual tumour. Treatment was completedafter six courses of chemotherapy and, sixmonths off treatment, she remains well.

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Costello syndrome

DiscussionThe clinical features and natural history ofboth of these cases is consistent with the diag-nosis of Costello syndrome. Martin and Jones6suggested that the major manifestations ofCostello syndrome are (1) postnatal growthdeficiency, (2) developmental delay, (3) relativemacrocephaly, (4) coarse face, (5) thick ears,

(6) thick lips, (7) depressed nasal bridge withanteverted nares, (8) excess skin, (9) thickpalms and soles, (10) short neck, (11) curlyhair, (12) nasal papillomata, and (13) sociablepersonality. Equally important in the diagnosisis the combination of these features with thestriking clinical history of early failure to thriveand cardiac and skeletal abnormalities.'3The aetiology of Costello syndrome remains

unknown. Sporadic dominant mutations withgonadal mosaicism or else genetic heterogen-eity as the explanation for the occasional sibrecurrence has been suggested.'6 Sialuria withnormal sialic acid in skin fibroblasts has beendocumented in two patients.'7 Di Rocco et al'7also noted the similarities between the earlystages of Costello sydnrome and leprach-aunism and speculated that the IGF2 receptormay be involved in pathogenesis. Disruption ofelastin fibres has been shown in two patients,one of whom died of rhabdomyolysis at sixmonths.'0 Normal elastin fibres have beenreported in another case.'8 A patient with a denovo apparently balanced translocation hasbeen described with the karyotype46,XX,t(1;22)(q25;ql 1).12

Soft tissue sarcomas (STS) account for4-8% of all childhood tumours in the USA andwestern Europe and have a combined age spe-

cific rate of 5-9 per million.'9 Betweentwo-thirds and three-quarters of all STS are

rhabdomyosarcomas. The occurrence of two

embryonal rhabdomyosarcomas in a rare

syndrome is highly suggestive of a causal link. Itis of interest, given the phenotypic similaritiesbetween Noonan syndrome and Costellosyndrome, that vaginal botryoid rhabdomyo-sarcoma has been reported in Noonansyndrome.20Rhabdomyosarcoma (RMS) is classified

conventionally into botyroid, embryonal, al-veolar, and pleomorphic subtypes. As embryo-nal is the most common, the occurrence of thesame tumour type in these two children may

not be significant. RMS has been reported inassociation with neurofibromatosis type 1 andBeckwith-Wiedemann syndrome. More com-

monly RMS occurs as part of the Li-Fraumenisyndrome owing to mutations in the tumour

suppressor gene TP53. Indeed, 5% ofRMS are

reported to be associated with a TP53mutation.2'

Our identification of two children with Cos-tello syndrome and embryonal rhabdomyosar-coma adds to the previous recognition of anassociation with benign epithelial and neuro-ectodermal tumours. On follow up, any unu-sual symptoms should be investigated for thepossibility of neoplasia. Further investigationsof the mechanisms of tumorigenesis in Costellosyndrome are required.

AddendumThe anaesthetic management of case 1 has alsobeen reported in an anaesthetic journal.22

We acknowledge the contribution of Dr Ruth Newbury-Ecobwho made the diagnosis of Costello syndrome in case 2.

1 Costello JM. A new syndrome: mental subnormality andnasal papillomata. Aust PaediatrJ 1977;13:114-18.

2 Der Kaloustian VM, Moroz B, McIntosh N, Watters AK,Blaichman S. Costello syndrome. Am Jf Med Genet1991;41:69-73.

3 Costello JM. Costello syndrome: update on the originalcases and commentary. Am J Med Genet 1996;62: 199-201.

4 Borochowitz Z, Pavone L, Mazor G, Rizzo R, Dar H. Newmultiple congenital anomalies: mental retardation syn-drome (MCA/MR) with facio-cutaneous-skeletal involve-ment. Am Jf Med Genet 1992;43:678-85.

5 Berberich MS, Carey JC, Hall BD. Resolution ofthe perina-tal and infantile failure to thrive in a new autosomal reces-sive syndrome with the phenotype of a storage disorder andfurrowing of palmar creases. The 11th D WSmith workshopon malformation and morphogenesis, Lexington, Kentucky,1990:76.

6 Martin RA, Jones KL. Facio-cutaneous-skeletal syndrome isthe Costello syndrome. Am J Med Genet 1993;47:169.

7 Der Kaloustian VM. Not a new MCA/MR syndrome butprobably Costello syndrome? Am J7 Med Genet 1993;47:170-1.

8 Fryns JP, Vogels A, Haegerman J, Eggermont E, Van DenBerghe H. Costello syndrome: a postnatal growth retarda-tion syndrome with distinct phenotype. Genet Couns 1994;5:337-43.

9 Torrelo A, Lopez-Avila A, Mediero IG, Zambrano A.Costello syndrome. JAm Acad Dermatol 1995;32:904-7.

10 Mori M, Yamagata T, Mori Y, et al. Elastic fiberdegeneration in Costello syndrome. AmIMed Genet 1996;61:304-9.

11 Popa M, Ioan DM, Fryns JP. Costello syndrome: report ofan 8-month-old marasmic boy. Genet Couns 1996;7:27-30.

12 Czeizel EC, Timar L. Hungarian case with Costellosyndrome and translocation t(1,22). Am _J Med Genet1995;57:501-3.

13 Zampino G, Mastroiacovo P, Ricci R, et al. Costellosyndrome: further clinical delineation, natural history,genetic definition, and nosology. Am J Med Genet 1993;47:176-83.

14 Martin RA, Jones KL. Delineation of the Costellosyndrome. Am J Med Genet 199 1;41:346-9.

15 Suri M, Garrett C. Costello syndrome with acousticneuroma and cataract. Is the Costello locus linked to neu-rofibromatosis type 2 on 22q? Clin Dysmorphol (in press).

16 Lurie IW. Genetics of the Costello syndrome. Am _J MedGenet 1994;52:358-9.

17 Di Rocco M, Gatti R, Gandullia P, Barabino A, Picco P,Borrone C. Report on two patients with Costello syndromeand sialuria. Am JfMed Genet 1993;47: 1135-40.

18 Davies SJ, Hughes HE. Costello syndrome: natural historyand differential diagnosis of cutis laxa. J7 Med Genet1994;31:486-9.

19 Stiller CA, Parkin DM. International variations in the inci-dence of childhood soft tissue sarcomas. Paediatr PerinatEpidemiol 1994;8: 107-19.

20 Khan S, McDowell H, Upadhyaya M, Fryer A. Vaginalrhabdomyosarcoma in a patient with Noonan syndrome. J7Med Genet 1995;32:743-5.

21 Toguchida J, Yamaguchi T, Dayton SH, et al. Prevalence andspectrum of germline mutations of the p53 gene amongpatients with sarcomas. N Engl_J Med 1992; 326:1301-8.

22 Dearlove 0, Harper N. Costello syndrome. Paediatr Anaes1997;7:476-8.

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