Costello Syndrome: Report and Review

Agnies M. van Eeghen,1 Ietje van Gelderen,2 and Raoul C.M. Hennekam1,3*1Emma Kinderziekenhuis AMC, Department of Pediatrics, University of Amsterdam, the Netherlands2Institute for the Mentally Disabled ‘‘Eemeroord,’’ Baarn, the Netherlands3Institute for Human Genetics, Academic Medical Center, University of Amsterdam, the Netherlands

We describe a 34-year-old woman with men-tal retardation, short stature, macro-cephaly, a ‘‘coarse’’ face, hoarse voice, andredundant skin with deep palmar and plan-tar creases who had evident Costello syn-drome. Lacking papillomata, she had wart-like lesions of the skin. The previously re-ported patients with Costello syndrome arereviewed. Costello syndrome is probably anautosomal dominant disorder, either causedby a mutation in a single gene or by micro-deletion. Am. J. Med. Genet. 82:187–193,1999. © 1999 Wiley-Liss, Inc.

KEY WORDS: Costello syndrome; mentalretardation; coarse face; ab-normal skin; autosomal dom-inant; cardiofaciocutaneoussyndrome

INTRODUCTION

In 1971, and again in 1977, Costello described twochildren with psychomotor retardation, postnatalgrowth failure, macrocephaly, ‘‘coarse’’ face, short neck,sparse and curly hair, dark skin colour, and nasal pap-illomata [Costello, 1971, 1977]. Der Kaloustian et al.[1991] described a similar case and proposed the nameCostello syndrome. Thirty-eight other cases have beenreported since [Berberich et al., 1991; Martin andJones, 1991; Borochowitz et al., 1992; Say et al., 1993;Teebi and Shaabani, 1993; Philip and Mancini, 1993;Zampino et al., 1993; Di Rocco et al., 1993; Patton andBaraitser, 1993; Izumikawa et al., 1993; Kondo et al.,1993; Yoshida et al., 1993; Davies and Hughes, 1994;Fryns et al., 1994; Okamoto et al., 1994; Wulfsberg etal., 1994; Lurie, 1994; Vila Torres et al., 1994; Czeizeland Tımar, 1995; Torrelo et al., 1995; Umans et al.,1995; Costello, 1996; Mori et al., 1996; Popa et al.,1996; Fryns et al., 1996; Fukao et al., 1996; Pratesi et

al., 1998; Siwik et al., 1998]. Costello syndrome hasemerged as a distinct entity that should be consideredin the evaluation of patients with coarseness of faceand developmental delay. Here, we present a patientwith similar findings and review the manifestations ofthe condition, with special emphasis on the differentia-tion from the cardiofaciocutaneous (CFC) syndrome.

CLINICAL REPORTThe proposita was born at term to a 39-year-old

mother and a 43-year-old father after an uncompli-cated pregnancy (38.5 weeks) and delivery. The par-ents were nonconsanguineous and of Dutch extraction.Family history was noncontributory. An older sisterwas healthy. Birth weight was 3750 g. Neonatally, shehad mild respiratory problems. During the first 4months of life she was hospitalized because of feedingproblems and failure to thrive. Shortly after birth, shewas noted to have a large tongue and a short neck, aswell as facial manifestations resembling Hurler syn-drome (Fig. 1), but metabolic studies failed to confirmthis diagnosis. Growth was poor during her first 4years of life. A small, symptomless atrial septal defectwas diagnosed. This was no longer present at reinves-tigation at the age of 24 years. At 8 years bone age wasretarded, corresponding to one of 5 years. Independentwalking and speech started around 9 years of age.Breast development started at 26 years of age; mensesnever occurred. Otherwise she has always beenhealthy.

At last examination at 33 years of age, she was short(1.47 m), macrocephalic (OFC 60 cm), and had a re-markably ‘‘coarse’’ facial appearance (Fig. 2). Her voicewas hoarse with a nasal pitch. Hair was short, soft, andcurly. She had telecanthus; mild unilateral ptosis; de-pressed nasal bridge; heavy cheekbones; large mouthwith large, widely spaced teeth; and abnormallyshaped helices. Additionally, she showed some wart-like lesions on her face. She had short hands withbroad fingers and redundant palmar skin. Her kneesand feet were in valgus position. She had almost noaxillary or pubic hair. She mutilated herself and suf-fered from anxiety attacks, but reacted adversely topsychopharmaca. Blood uric acid was normal. Shecould not read and write, but her long-term memorywas good. Psychological testing resulted in an IQ of 50.She was hyperactive.

Results of standard chromosome analysis (600 band

*Correspondence to: Dr. R.C.M. Hennekam, Institute for Hu-man Genetics, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. E-mail: r.c.hennekam@amc.uva.nl

Received 24 March 1998; Accepted 24 July 1998

American Journal of Medical Genetics 82:187–193 (1999)

© 1999 Wiley-Liss, Inc.

level) were normal. Ophthalmologic investigations didnot show any anomalies, except myopia. Standard uri-nary metabolic investigation, including mucopolysac-charides, sialic acid, oligosaccharides, amino acids, im-idazols, fenolic acids, purine- and pyrimidinemetabo-lites, and organic acids showed only an elevatedhydroxyproline concentration. Radiographs of thespine, skull, pelvis, and the long bones showed a thickskull, mild irregularities of the vertebral endplates, anopen arch of the fifth lumbar vertebra, bilateral dys-plastic hip joints, and moderate generalized osteoporo-sis. Neurological investigations showed normal re-flexes, muscle tonus, and sensory system. The electro-encephalogram showed no asymmetry or epileptiformactivity. Visual evoked potentials and electromyogramwere normal. Brain magnetic resonance imaging (MRI)showed dilatation of the first and second ventricles,especially of the anterior horns. Furthermore, therewas some atrophy of the frontal and occipital corticalgyri, a small corpus callosum, and slight atrophy of thecerebellum.

DISCUSSION

Our patient is compared with the 39 previously re-ported patients with Costello syndrome in Table I. Inthe table a comparison with CFC syndrome is also pro-vided. The following is a review of the literature on theCostello syndrome.

Pregnancy and Delivery

In most cases the pregnancy was complicated bypolyhydramnios. Some pregnancies were complicatedby fetal distress [Zampino et al., 1993; Yoshida et al.,1993; Mori et al., 1996], poor fetal movements [Cos-tello, 1977; Davies and Hughes, 1994], bleeding in thefirst trimester of pregnancy [Borochowitz et al., 1992;Izumikawa et al., 1993], diabetes mellitus [Fryns et al.,1994], low maternal serum a-fetoprotein [Borochowitzet al., 1992], and mild hypertension, combined in twocases with premature cervical dilatation [Davies andHughes, 1994; Umans et al., 1995; Fryns et al., 1996].One mother took barbiturates and carbamazepine dur-ing pregnancy [Di Rocco et al., 1993]. Of 28 pregnanciesin which the presentation at delivery was specified,there was breech position in four [Borochowitz et al.,1992; Fryns et al., 1994; Czeizel and Tımar, 1995], ver-tex position in one, and a normal vertex presentation inall other cases. Three deliveries were induced [Yoshidaet al., 1993; Umans et al., 1995; Fryns et al., 1996], 10were by caesarian section [Borochowitz et al., 1992;Zampino et al., 1993; Izumikawa et al., 1993; Fryns etal., 1994; Vila Torres et al., 1994; Pratesi et al., 1998],and two by forceps extraction [Costello, 1977; Fryns etal., 1994]. Immediately after birth, seven patients suf-fered respiratory distress [Borochowitz et al., 1992; Sayet al., 1993; Yoshida et al., 1993; Torello et al., 1995;Fryns et al., 1996; Fukao et al., 1996; Pratesi et al.,1998]. One infant developed massive aspiration syn-drome and had to be ventilated artificially [Mori et al.,1996].

Neonatal Period

At birth all reported (at term) patients had a normalor relatively high weight (mean 3770 g, range 2770–4700 g), normal length (mean 48.7 cm, range 44–54cm), and large OFC (mean 35.5 cm, range 32–38.1 cm).Severe early postnatal growth retardation was com-

Fig. 2. The proposita at 33 years. Note ‘‘coarse’’ face, large head, shortnose with broad base, long philtrum, and large mouth. Dermatologic in-vestigations showed the facial skin lesions to be wart-like.

Fig. 1. The proposita at age 6 months. Note ‘‘coarse’’ face, depressednasal bridge, bulbous and upturned nose; low-set ears; and large, pouting,lower lip.

188 Van Eeghen et al.

mon. All children fed poorly in the neonatal period, andin some swallowing difficulties [Costello, 1977; DiRocco et al., 1993; Patton and Baraitser, 1993; Izumi-kawa et al., 1993; Okamoto et al., 1994; Umans et al.,1995; Popa et al., 1996; Fryns et al., 1996; Pratesi et al.,1998] and gastroesophagal reflux [Costello, 1977; DiRocco et al., 1993; Patton and Baraitser, 1993; Costello,1996] were reported. The presence of polyhydramniosin many of these patients suggests that swallowing dif-ficulties were present prenatally as well. Zampino et al.[1993] identified oral motor apraxia in their two pa-tients. As a high caloric intake was artificially assuredin most cases, it is less probable that poor feeding con-tributed to the failure to thrive. The above period hasbeen called the marasmic phase [Zampino et al., 1993].Patients with Costello syndrome generally go throughtwo clinical phases: first the marasmic phase, and thenthe so-called pseudothesaurismotic phase, which showsa storage-disease-like picture [Zampino et al., 1993].The pseudothesaurismotic phase is characterized bymacrocephaly, full cheeks, large mouth with thick lips,large tongue, and gingival hyperplasia. In this respectit is worth mentioning that in the present patient thediagnosis of Hurler syndrome had been suspected dur-ing childhood.

Growth and Development

The age of the reported patients ranges from 4months to 33 years. So far, the proposita is the oldestreported patient. Including her, the mean adult heightis 1.38 m, ranging from 1.18 to 1.48 m. OFC averages57.3 cm with a range from 55.5 to 60 cm. Psychomotorretardation is consistent, with IQs ranging from 47 to85 with a mean of 60. Walking generally started be-tween the ages of 1 and 9 years with a mean age of 4years. The gait is generally unsteady. Speech develop-ment is delayed, with the first sentences being formedbetween the ages of 4 and 9 years old (mean 5 years).Most patients with Costello syndrome are described ashaving a warm, sociable personality.

Six patients died at a very young age: one died of anunspecified cause at the age of 4 months [Borochowitzet al., 1992] and another at 17 months due to pneumo-nia [Zampino et al., 1993]. Mori’s patient died of rhab-domyolysis due to viral infection at the age of 6 months[Mori et al., 1996]. Three died at 20 months, 2 years,and 7 years of age, respectively, due to failure to thriveand cardiac problems [Berberich et al., 1991; Pattonand Baraitser, 1994; Fukao et al., 1996].

Facial Characteristics

At birth, absolute or relative macrocephaly was ob-served in all cases (mean OFC of 35.5 cm, range from32–38.1 cm). In some, the head circumference laternormalized [Der Kaloustian et al., 1991; Costello,1996]. Hydrocephaly was observed in three patients[Borochowitz et al., 1992; Say et al., 1993; Pratesi et al.,1998]. An abnormally shaped neurocranium, i.e., tur-ricephaly [Der Kaloustian et al., 1991], dolichocephaly[Fryns et al., 1994; Fryns et al., 1996; Patresi et al.,1998], or a square head [Borochowitz et al., 1992] havealso been described. A large and persistent anterior

TABLE I. Signs in the Present Patient Compared WithPertinent Data in Costello Syndrome and CFC Syndrome

Costellosyndromea

(%)Presentpatient

CFCsyndromeb

(%)

PregnancyPolyhydramnios 53 − 22

Growth and developmentMental retardation 100 + 93Characteristic clinical coursec 97 + −Postnatal growth retardation 97 + 67d

Growth and developmentMacrocephaly 98 + 91Coarse face 95 + −Bitemporal constriction 3 − 100Decreased eyebrows/eyelashes − − 65Downslanting palp. fissures 100 + 90Epicanthal folds 94 − 86Ptosis 8 +/− 75Strabismus 61 + 49Hypertelorism 8 − 50Hypoplastic supraorbital ridges − − 100Low-set ears 78 + 86Ear malformations 90 + 88Full cheeks 93 + ?Depressed nasal bridge 97 + 95Short, bulbous nose 97 + 88Long philtrum 5 − 54Large mouth 91 + −Large tongue 65 + −Gingival hyperplasia 69 + −Thick lips 92 + ?High arched palate 67 + 94Teeth abnormalities 59 − 67Hoarse voice 88 + −Short neck 93 + 72e

MusculoskeletalIncreased A-P diameter of thorax 77 + 9Limited extension of elbow 70 + ?Hyperextensible fingers 89 + −Broad distal phalanges 100 + ?Tight achilles tendons 72 + −Delayed bone age 78 + 100

Skin and appendagesLoose skin of hands and feet 100 + −g

Papillomata 73 − −Dark skin 96 + −Deep palmar/plantar creases 100 + −Hyperkeratosis 79 − 20Eczema/ichtyosis − − 85Sparse/curly hair 96 + 100Thin/deep-set/dysplastic nails 94 − 39Hemangiomas − − 50

OtherEEG abnormalities 75 − 89Seizures 8 − 86Hypotonia 64 − 86Cardiac defects 75 + 85

a Costello [1971, 1977, 1996], Berberich et al. [1991], Der Kaloustian et al.[1991], Martin and Jones [1991], Borochowitz et al. [1992], Say et al.[1993], Philip and Mancini [1993], Teebi and Shabaani [1993], Zampino etal. [1993], Di Rocco et al. [1993], Patton and Baraitser [1993], Izumikawaet al. [1993], Kondo et al. [1993], Yoshida et al. [1993], Davies and Hughes[1994], Okamoto et al. [1994], Fryns et al. [1994], Wulfsberg et al. [1994],Costa et al. [1994], Czeizel and Tımar [1995], Torrelo et al. [1995], Umanset al. [1995], Mori et al. [1996], Popa et al. [1996], Fryns et al. [1996], Fukaoet al. [1996], Pratesi et al. [1998], Siwik et al. [1998].b Somer et al. [1992], Krajewska-Walasek et al. [1996].c Marasmic and pseudotherausmosic phase [Zampino et al., 1993].d Twenty-seven percent had prenatal growth retardation.e Thirty-three percent had a webbed neck.f Including cases with an increased carrying angle of the elbow.g 3 cases with redundant skin over the dorsum of the hands were reportedand assumed by the authors to be due to late resorption of excessive lymph-edema [Chrzanowska et al., 1989; Neri et al., 1987; Sorge et al., 1989].

Costello Syndrome 189

fontanel was noted in some cases [Say et al., 1993;Zampino et al., 1993; Patton and Baraitser, 1993;Fryns et al., 1994]. Major facial signs such as a promi-nent forehead, curly hair, low-set ears with fleshy ear-lobes and helices, epicanthal folds, downslanting pal-pebral fissures, a depressed nasal bridge, a bulbousnose with anteverted nostrils, full cheeks, a largemouth, and thick lips give the Costello face a charac-teristic ‘‘coarse’’ look. This may be accompanied by ahirsute forehead [Borochowitz et al., 1992; Der Kalous-tian, 1991; Teebi and Shaabani, 1993; Zampino et al.,1993; Izumikawa et al., 1993], high-arched palate,large tongue, gingival hyperplasia, teeth abnormali-ties, and a bifid uvula [Izumikawa et al, 1993; Mori etal, 1996]. Sometimes prominent scalp veins can be seen[Der Kaloustian et al., 1991; Teebi and Shaabani, 1993;Izumikawa et al., 1993; Fryns et al., 1994; Pratesi etal., 1998], as well as a capillary hemangioma over theglabella [Borochowitz et al., 1992; Philip and Mancini,1993], a metopic ridge [Der Kaloustian et al., 1991],occipital whorls [Borochowitz et al., 1992; Say et al.,1993], or a protruding occiput [Borochowitz et al., 1992;Philip and Mancini, 1993]. Facial asymmetry has alsobeen observed [Philip and Mancini, 1993; Davies andHughes, 1994], as was midface hypoplasia [Pratesi etal., 1998]. One patient had a torticollis [Czeizel andTımar, 1995].

Various eye abnormalities have been reported, ofwhich strabismus is the most common. Keratoconus[Costello, 1977], myopia [Martin and Jones, 1991; Dav-ies and Hughes, 1994], nystagmus [Di Rocco et al.,1993; Davies and Hughes, 1994; Vila Torres et al.,1994], chorioretinal dystrophy [Di Rocco et al., 1993],delayed myelinization of the optic nerves [Okamoto etal., 1994], and permanent tears in the eyes [Fryns etal., 1994] have also been observed. Hypertelorism, aswell as (mild) ptosis, large eyes or (pseudo)exophthal-mus are sometimes evident. The philtrum has beendescribed as being flat [Borochowitz et al., 1992; Czei-zel and Tımar, 1995] as well as short [Der Kaloustianet al., 1991; Borochowitz et al., 1992; Teebi and Shaa-bani, 1993] or long [Borochowitz et al., 1992; Popa etal.; 1996]. One patient had a congenital laryngeal web[Say et al., 1993] and another had crumpled vocal cords[Zampino et al., 1993]. In some an increased amount ofadipose tissue was present under the chin [Der Kalous-tian et al., 1991; Borochowitz et al., 1992; Izumikawa etal., 1993]. Micrognathia or retrognathia with a largeand ptotic tongue and a tracheo-esophageal fistulawere recorded [Yoshida et al., 1993; Popa et al., 1996].

Skeletal Manifestations

Various abnormalities of the thoracic cage have beendescribed: barrel chest, scoliosis [Costello, 1977; Pattonand Baraitser, 1993; Fryns et al., 1994; Pratesi et al.,1998], and pectus excavatum [Costello, 1996; Izumi-kawa et al., 1993; Davies and Hughes, 1991] or carina-tum [Pratesi et al., 1998].

The hands and feet have been described as short[Borochowitz et al., 1992; Fryns et al., 1994] and broad[Davies and Hughes, 1994; Fryns et al., 1994]. The fin-gers are generally hyperextensible and sometimes

show hypoplasia of the distal phalanges [Zampino etal., 1993; Di Rocco et al., 1993; Fryns et al., 1994]. Thin,dysplastic, and deep-set nails have often been observedtoo. Syndactyly was reported twice [Borochowitz et al.,1992; Pratesi et al., 1998]. Tight Achilles tendons arealso an important clinical sign, as are the diminishedmovements of other joints, such as limited extension ofelbows, wrists [Popa et al., 1996], hips [Borochowitz etal., 1992; Izumikawa et al., 1993; Fukao et al., 1996],and knees [Berberich et al., 1991; Patton and Barait-ser, 1993; Zampino et al., 1993; Umans et al., 1995;Fukao et al., 1996]. Almost all patients have foot posi-tional defects, among which pes equinovarus, verticaltalus, and rocker bottom feet occur most often. Elbowand hip (sub)luxation has occurred [Zampino et al.,1993; Di Rocco et al., 1993; Okamoto et al., 1994; VilaTorres et al., 1994]. Many have a delayed bone age andosteoporosis [Patton and Baraitser, 1993; Di Rocco etal, 1993; Fryns et al, 1994; Czeizel and Tımar, 1995].

Genitalia

Genital abnormalities such as undescended testes[Costello, 1977; Der Kaloustian et al., 1991; Fryns etal., 1994; Pratesi et al., 1998], a small penis [Pratesi etal., 1998], a hypoplastic scrotum [Fryns et al., 1994], orlarge external genitalia [Zampino et al., 1993] wereobserved. Several patients had inguinal hernias [Philipand Mancini, 1993; Zampino et al., 1993; Costello,1996; Fryns et al., 1994; Pratesi et al., 1998] and onepatient had bilateral paratubal cysts [Martin andJones, 1991]. No firm data on pubertal developmentare available.

Skin Manifestations

The most striking cutaneous sign of Costello syn-drome is the redundant skin of the hands and feet,which is present from birth. This excessive skin causesdeep palmar and plantar creases and ridges and maycause an unusual soft and velvety feeling of the hands[Teebi and Shaabani, 1993; Patton and Baraitser,1993; Davies and Hughes, 1994]. Another major sign isrepresented by the papillomata that have been re-ported in patients whose ages range from 2 to 15 years(mean of 6 years). They were localized on the face,anus, axillae, elbows, knees, vocal cords, and abdomenand are considered to be the result of friction or pres-sure. Several patients between the ages of 17 monthsand 10 years did not have papillomata at the time theywere reported or followed up [Teebi and Shaabani,1993; Zampino et al., 1993; Yoshida et al., 1993; DiRocco et al., 1993; Czeizel and Tımar, 1995; Mori et al.,1996]. Acanthosis nigricans as well as hyperkeratosisand increased skin pigmentation are often seen. Mul-tiple pigmented nevi are not exceptional [Martin andJones, 1991; Say et al., 1993; Teebi and Shaabani,1993; Davies and Hughes, 1994; Torrelo et al., 1995].Three patients had generalized hypertrichosis [DerKaloustian et al., 1991; Borochowitz et al., 1992]. Somehad short or thin hair [Der Kaloustian et al., 1991;Borochowitz et al., 1992; Teebi and Shabaani, 1993;Zampino et al., 1993; Davies and Hughes, 1994; Frynset al., 1994; Mori et al., 1996]. In one patient a de-

190 Van Eeghen et al.

creased number of hair follicles was noted [Vila Torreset al., 1994], and another had hyperhydrosis [Mori etal., 1996]. Unusual fat deposition, like the increasedadipose tissue under the chin, was also observed else-where in some patients [Berberich et al., 1991; Fryns etal., 1994; Czeizel and Tımar, 1995]. Elastic fiber or col-lagen abnormalities were also reported [Yoshida et al.,1993; Patton and Baraitser, 1993; Vila Torres et al.,1994; Czeizel and Tımar, 1995; Mori et al., 1996]. Cos-tello’s female patient developed a severe mammary fi-broadenosis [Costello, 1996], another patient had a cra-nial dermoid cyst [Di Rocco et al., 1993], and still an-other had calcified epitheliomas [Martin and Jones,1991]. Accessory nipples have been noted [Vila Torreset al., 1994], as well as an omphalocele in two patients[Fryns et al., 1994]. Umbilical abnormalities such ashernias and cutaneous protrusions are common [Boro-chowitz et al., 1992; Say et al., 1993; Patton and Bara-itser, 1993; Izumikawa et al., 1993]. Abnormal derma-toglyphics have been noted [Borochowitz et al., 1992;Zampino et al., 1993; Davies and Hughes, 1994].

Neurology

Through neuroradiologic studies (either sonography,MRI, or computed tomography scan) many brainanomalies have been found: mild brain atrophy[Torello et al., 1995; Fukao et al., 1996; Pratesi et al.,1998], atrophy of the cerebellum [Zampino et al., 1993;Vila Torres et al., 1994; Mori et al., 1996], generalizedventricular dilatation [Zampino et al., 1993; Izumi-kawa et al., 1993, Fryns et al., 1994; Pratesi et al.,1998], dilatation of the inferior and occipital horns[Zampino et al., 1993; Izumikawa et al., 1993], hy-podensity of the white matter [Zampino et al., 1993],mild ventricular asymmetry [Der Kaloustian et al.,1991], mild subcortical atrophy [Fryns et al., 1994],cerebellar anomalies [Di Rocco et al., 1993], frontal lobehypoplasia [Di Rocco et al., 1993], diffuse cerebralanomalies [Fryns et al., 1994], slight deviation of thecerebellar tonsillae [Okamoto et al., 1994], and type IArnold-Chiari malformation [Say et al., 1993]. Threepatients needed shunting because of dilated ventricles[Say et al., 1993; Zampino et al., 1993; Vila Torres etal., 1994]. Three patients had seizures or spasms [Cos-tello, 1977; Di Rocco et al., 1993; Say et al., 1993]. Hy-pertonia as well as hypotonia have been described.

Internal Organs

Congenital heart defects are common in Costello syn-drome: Five patients had pulmonary stenosis [Ber-berich et al., 1991, Borochowitz et al., 1992; Pratesi etal., 1998], five had a ventricular septal defect [Teebiand Shabaani, 1993; Di Rocco et al., 1993; Kondo et al.,1993; Siwik et al., 1998], three a thickening of the in-traventricular septum and tips of the mitral valves[Izumikawa et al., 1993; Davies and Hughes, 1994; Si-wik et al., 1998], two an ASD [Say et al., 1993; Pratesiet al., 1998], one persistent ductus arteriosus [Boro-chowitz et al., 1992], one subpulmonic stenosis [Siwiket al., 1998], and one mitral valve prolaps [Martin andJones, 1991]. In most patients a systolic heart murmurwas detected, and heart dysrrhythmias were also noexception. The association of hypertrophic car-

diomyopathy and other cardiac anomalies with theCostello syndrome are outlined by Wulfsberg et al.[1994] and Siwik et al. [1998].

Hepatosplenomegaly [Costello, 1977; Borochowitz etal., 1992; Patton and Baraitser, 1993; Fukao et al.,1996] occurred in some patients. A partial growth hor-mone deficiency was demonstrated [Okamoto et al.,1993]. The first of Zampino’s patients was diagnosedwith a ganglioneuroblastoma in an adrenal gland, thesecond had metachromatic granulations in his lympho-cytes [Zampino et al., 1993]. No other malignancieshave been reported until now.

Genetics

Two pairs of sibs with Costello syndrome have beenidentified [Berberich et al., 1991; Zampino et al., 1993]as well as two patients born to consanguineous parents[Borochowiz et al., 1992], which favors autosomal re-cessive inheritance. However, the latter families camefrom a community where consanguineity is common.Furthermore, only two of minimally 46 sibs of Costellopatients were affected [Lurie, 1994; Czeizel and Tımar,1995; Fukao et al., 1996; Pratesi et al., 1998]. Thisspeaks strongly against autosomal recessive inheri-tance [Lurie, 1994]. The sex distribution of Costellopatients, 18 males and 20 females, and equal severityof clinical picture in males and females, provide no cluefor X-linked inheritance. Only a Hungarian patienthad a chromosome anomaly, i.e., a balanced transloca-tion: 46,XX, t(1,22)(q25,q11) [Czeizel and Tımar, 1995].The mean paternal age was increased: 35.5 years, themean maternal age was 29 years. This suggests auto-somal dominant mutations to be the most likely cause,either as a single gene or as a microdeletion (‘‘contigu-ous genes syndrome’’), occurring de novo. The recur-rence in sibs can be explained by germline mosaicism,although at present it cannot be excluded that Costellosyndrome is a heterogeneous condition with differentmodes of inheritance.

Our patient shares the ‘‘coarse’’ facial manifestationsof all Costello syndrome patients, as well as short stat-ure, macrocephaly, and excessive skin on hands andfeet. However, she lacks some of the common cutane-ous lesions like acanthosis nigricans and hyperkerato-sis. Additionally, she does not seem to have the warm,social personality described in other Costello syndromepatients, which has been proposed as a diagnostic cri-terion [Philip and Sigaudy, 1998]. As our patient is theoldest of all described patients, and only limited infor-mation is available about Costello syndrome in adults,it is unclear if the dissimilarities in skin symptoms inour patient can be ascribed to the natural course of thiscondition. In an update on the original patients, Cos-tello [1996] pointed out that in both of his patients thegeneralized darkness of the skin had disappeared, asdid the depressed nasal bridge, epicanthal folds, andchest deformity. The hyperkeratosis had persisted[Costello, 1996].

Patients with Costello syndrome tend to develop be-nign tumors of ectodermal origin, especially papillo-mata. Initially, it was thought that the facial lesions inour patient were papillomata, but expert dermatologic

Costello Syndrome 191

inspection made the presence of wart-like lesions morelikely. Unfortunately, in our patient no biopsy was pos-sible, but histopathological investigation of skin erup-tions are recommended in all patients to distinguishbetween papillomata and wart-like lesions. One ofZampino’s patients developed a ganglioneuroblastoma[Zampino et al., 1993], and Martin and Jones [1991]reported on a patient with a progressive benign epithe-lioma. It seems justified to provide a careful follow-upof all Costello patients because of a possibly increasedtumor risk. Okamoto et al. [1994] pointed out that es-pecially any growth stimulation should be performedunder close observation for tumor development. As car-diac disease often occurs with Costello syndrome, echo-cardiography should be considered in all patients sus-pected of having this syndrome [Wulfsberg et al, 1994].

As our patient did not show the characteristic skinlesions associated with the Costello syndrome, the CFCsyndrome was considered as an alternative diagnosis(Table I). Both entities share many manifestationssuch as short stature, developmental delay, macro-cephaly, cardiac defects, skin involvement, and manyof the facial signs, such downward slanted palpebralfissures, depressed nasal bridge, short nose with anupturned tip, and the low-set, posteriorly rotated earswith thick helices. However, in CFC patients the faceshows a high cranial vault, bitemporal constriction,ptosis, and decreased or absent eyebrows that shouldallow differentation from the facial signs associatedwith the Costello syndrome [Somer et al., 1992; Kra-jewska-Walasek et al., 1996]. Additionally, the skinmanifestations in the CFC syndrome are mostly lim-ited to eczema, ichtyosis, and sometimes hyperkerato-sis, as opposed to redundant and dark skin, papillo-mata, hyperkeratosis, deep palmar and plantarcreases, and acanthosis nigricans seen in Costello syn-drome patients. Redundant skin has been observed inCFC patients, but not at the palms or soles [Neri et al.,1987; Sorge et al., 1989; Chrzanowska et al., 1989;Borochowitz et al., 1993; Der Kaloustian, 1993; Teebi,1993].

Noonan syndrome patients also share some charac-teristics with Costello syndrome patients, but theyhave a less coarse face. Other signs are a high anteriorhairline, hypertelorism, webbed neck, cryptorchidism,easy bruising, limited skin involvement (mainly nevi),and much milder developmental delay, occurring onlyin 40% of affected individuals. Furthermore, patientswith Noonan syndrome and mental retardation are of-ten microcephalic [Krajewska-Walasek et al., 1996], incontrast to the macrocephaly in Costello syndrome. Forall patients with cutis laxa, macrocephaly, short stat-ure, delayed psychomotor development a diagnosis ofCostello syndrome should be considered [Sakati et al.,1983; Allanson et al., 1986; Patton et al., 1987]. Lepre-chaunism, progeria, Weaver syndrome, Hurler syn-drome, I-cell disease, and the SCARF association alsoshow an overlap in symptomatology with Costello syn-drome, but the additional findings symptoms in thesedisorders will easily allow differentiation.

In conclusion, Costello syndrome is a distinct mul-tiple congenital malformation syndrome characterizedby postnatal growth retardation, distinctive face, lax

skin, and developmental delay. The cause remains un-certain; although the facial traits bear a remarkableresemblance to a storage disorder, there is no progres-sive coarsening with age. Either an autosomal domi-nant mutation in a single gene or a microdeletionseems the most probable cause.

ACKNOWLEDGMENTS

We thank Drs. Zvi Borochowitz (Haifa, Israel), JohnCarey (Salt Lake City, Utah), Andrew Czeizel (Budap-est, Hungary), Sally Davies (Cardiff, UK), Vazken DerKaloustian (Montreal, Canada), Maja Di Rocco (Genoa,Italy), Jean Paul Fryns (Leuven, Belgium), ToshiyukiFukao (Gifu, Japan), Yoshinori Izumikawa and KenjiNaritomi (Okinawa, Japan), Michael Patton (London,UK), Nicole Philip (Marseille, France), and Burhan Say(Tulsa, Oklahoma) for providing us with additional in-formation on their patients, and Dr. J.H. Sillevis Smittfor his dermatological investigations.

NOTE ADDED IN PROOF

Suri and Garrett [1998] recently described a 33-year-old case with Costello Syndrome who died with vestib-ular schwannoma. They suggested that Costello Syn-drome may be linked to the neurofibromatosis type 2gene on chromosome 22q12.

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