Costello syndrome was first described 30 years ago [Costello, 1971, 1977]. Since then this multiple congenital anomaly syndrome has been increasingly recognized [for review see Johnson et al., 1998; Van Eeghen et al., 1999]. Characteristic findings include polyhydramnios, overgrowth at birth with subsequent severe failure to thrive and feeding problems, relative macrocephaly, loose soft skin with deep palmar and plantar creases, laxity of small joints, tight Achilles tendons, hypertrophic cardiomyopathy and arrhythmia, coarse facial features, the development of benign papillomata and developmental delay or mental retardation. A calcified epithelioma in a patient with Costello syndrome was described [Martin and Jones, 1991], followed by reports on neuroblastoma [Zampino et al., 1993; Flores-Nava et al., 2000; Moroni et al., 2000], rhabdomysarcoma (RMS) [Kerr et al., 1998; Feingold, 1999], vestibular schwannoma [Suri and Garrett, 1998], and bladder carcinoma [Franceschini et al., 1999; Gripp et al., 2000]. We now report five additional patients with RMS in Costello syndrome. On three patients detailed information and photographs are available, the other patients are described in Table I.
Table I. Clinical and Histological Findings in Patients With Costello Syndrome and Rhabdomyosarcoma*
This Caucasian male was born by C/section at 38 weeks gestational age after a pregnancy complicated by polyhydramnios. His 36 year-old mother and 35 year-old father were non-consanguineous and subsequently had a second healthy child. The birth weight of 3.8 kg was above the 90th centile. Severe feeding problems necessitated G-tube placement at age 1 month. Multifocal atrial tachycardia and hypertrophic cardiomyopathy were diagnosed at age 5 months. Subaortic resection of the ventricular septum was performed at age 3 years. Additional surgeries included bilateral cryptorchidism and inguinal hernia repair, and bilateral pelvic tenotomies for hip contractures. Ulnar deviation of both hands was present. The patient had generalized developmental delays. Costello syndrome was diagnosed at age 13 months, based on his medical history and the characteristic facial features (Fig. 1).
At 5½ years the patient developed intermittent intestinal obstruction due to a pelvic mass. A biopsy showed this mass to be an embryonal RMS, and pulmonary metastases were present. The tumor was surgically removed after the first chemotherapy. Cytogenetic analysis of the tumor showed a normal 46,XY karyotype in the majority of cells. Clonal chromosomal abnormalities with a 60,XY,+2,+3,+5,+7,+8,+8,t(9;16)(p24;q12.1),+11,+13,+13, +18,+19,+20,+21,+mar karyotype were seen in 5 cells, and 61,XY,+der(2)t(1;2)(q21;q33),+3,+5,+7,+8,+8,+11,+13,+13,+18,+18,+19,+20,+21,+mar were seen in 3 cells.
Due to recurrent airway problems postoperatively, a tracheostomy was placed. The patient is continuing chemotherapy.
This Caucasian female was the product of a pregnancy complicated by polyhydramnios, gestational diabetes, and fetal tachycardia first noted at around 24 weeks gestational age. She was born to a 36 year-old mother and a 38 year-old non-consanguineous father. Delivery was by Cesarean section for premature rupture of membranes at 33 weeks gestational age. Birth weight of 2.8 kg was above the 90th centile, 50th centile for 37 weeks gestational age. Postnatally her tachycardia was described as an ectopic atrial tachycardia and required medication. When medication was withdrawn she had recurrent tachycardia which persisted throughout her life. She had severe feeding difficulties leading to prolonged hospitalization and G-tube placement. Ulnar deviation of both hands was treated with splints, and release of bilateral Achilles tendon contractures was performed at age 20 months. Mild scoliosis did not require treatment. The patient had hypotonia, and motor development was delayed with sitting at around age one year, and walking independently at age 3 years. Language development was delayed, but she reportedly spoke in sentences at age 3½ years. Chromosome analysis showed a 46,XX karyotype.
At age 3½ years the patient appeared to have abdominal discomfort and increasingly frequent episodes of emesis, leading to discovery of an unresectable abdominal mass encasing the superior mesenteric and celiac arteries. Biopsy was consistent with a pleomorphic RMS. On a CT scan a single pulmonary nodule was noted. The tumor did not respond to chemotherapy and she died shortly after her 4th birthday.
Costello syndrome was diagnosed posthumously after a review of the medical history, the notes describing physical findings and the photographic documentation of her physical and facial features (Fig. 2).
This Caucasian female was the product of non-consanguineous parents' second pregnancy. Two siblings are in good health. Her mother was 28, her father was 30 years old at the time of conception. The pregnancy was complicated by polyhydramnios at 24 weeks gestational age and treated with indomethacin. At 34 weeks paroxysmal fetal tachycardia occurred. Persistent tachycardia with a heart rate of 240 bpm was noted at 36 ½ weeks gestational age and led to delivery by Cesarean section. Birth weight was 3.5 kg (> 90th centile). Atrial fibrilliation required digitalization until age 8 months. There was concern about cardiomyopathy on echo cardiography and mild subpulmonic hypertrophy has continued to her present age 7 years. Hyperbilirubinemia was treated with phototherapy. The patient was hypotonic and had a tendency to arch her back. Severe feeding problems and failure to thrive led to G-tube placement at age 3 months. Excessive diaphoresis was described on numerous occasions. She had tight Achilles tendons. Development was delayed with sitting at 9 months and walking independently at 5 years. Expressive language was delayed 18–24 months.
At age 2½ years an abdominal mass was detected and led to the identification of an embryonal RMS, apparently originating from the bladder. There were no metastases. Treatment was a combination of surgery, chemo- and radiotherapy, continued until age 3½ years. She remained tumor free at her current age of 7 years (Fig. 3). Growth hormone injections were initiated at age 6 10/12 years in order to improve strength and growth velocity.
A brain MRI scan performed at age one year showed abnormally prominent lateral and 3rd ventricles, an increased T2 signal intensity in the dorsal brain stem, and a prominent cerebellum with tonsillar ectopia. Multiple laboratory studies, including chromosome analysis on lymphocytes and fibroblasts, plasma amino acids, urine organic acids, plasma carnitine, CPK, ammonia, very long-chain fatty acids, phytanic acid, plasmalogens, thyroid function studies, DNA molecular analysis for myotonic dystrophy, and muscle histology, did not identify a diagnostic abnormality. Costello syndrome was diagnosed at age 7 years.
Rhabdomyosarcoma is, after neuroblastoma and Wilms tumor, the third most common extracranial malignant tumor in childhood [for review see Wexler and Helman, 1997]. Its annual incidence is 4–7 cases per million children under the age of 16 years, with the majority of cases occurring under age 6 years. Rhabdomyosarcoma is thought to arise from mesenchymal cells with some skeletal muscle differentiation, but can originate from locations where striated muscle is not usually found. The most common histologic type seen in > 50% is embryonal, followed by alveolar seen in 20–30%. Pleomorphic RMS is rare (1%) and has a poor prognosis. In alveolar RMS a characteristic t(2;13)(q35;q14) has been shown to result in a fusion protein involving the PAX3 and FKHR genes, a variant t(1;13)(p36;q14) results in a fusion of PAX7 and FKHR. The PAX3/FKHR chimeric gene has transforming properties through activation of a myogenic transcription program [Khan et al., 1999]. In embryonal RMS loss of heterozygosity for 11p15, the location of IGF2, has been noted in some cases. While the majority of RMSs occur as sporadic cases, this tumor has been reported in Beckwith-Wiedemann syndrome (BWS) and neurofibromatosis type 1. It is more common in patients with Li-Fraumeni syndrome, a tumor predisposition most often due to a mutation in the p53 tumor suppressor gene.
Previously Kerr et al.  described embryonal RMS in two patients with Costello syndrome. The first patient has since relapsed, but was successfully treated and is tumor free at her current age of 7 years. The second reported patient relapsed and died [Bronwyn Kerr, personal communication]. Feingold  described alveolar RMS in a boy with Costello syndrome. Bisogno et al.  reported a RMS in a patient thought to have cardio-facio-cutaneous syndrome, but a more appropriate diagnosis of Costello syndrome was suggested by Innes and Chudley . Sigaudy et al.  described a series of Costello patients, one of whom had an embryonal RMS. The 5 new cases increase the total of RMS in Costello syndrome to 10 (Table I). The age at diagnosis ranged from 6 months to 6 years, and is comparable to that seen in the general population. The embryonal subtype was identified in 7 tumors, there was one each with alveolar and pleomorphic histology, and in one the histology is not known. This is comparable to what is seen in the general population, in which the embryonal type represents over half. Of interest is the tumor location. In the Costello patients, 8 of 10 tumors originated from the abdomen, pelvis or urogenital area. Only one occurred in the head and neck, while in the general population about 35% of RMS originate from the head and neck.
In addition to RMSs, other malignant tumors have been reported in Costello syndrome (Table II). Three patients age 2 months to 4 years with neuroblastoma have been reported [Zampino et al., 1993; Flores-Nava et al., 2000; Moroni et al., 2000]. While the thoracic neuroblastoma in the two month old [Flores-Nava et al., 2000] was an incidental autopsy finding, the mediastinal ganglioneuroblastoma in the 4 year-old [Moroni et al., 2000] caused spastic paraparesis. Of note is an adrenal ganglioneuroblastoma identified on a CT study in a 17-month-old, which did not lead to an increased excretion of urinary catecholamines [Zampino et al., 1993].
Table II. Malignant Tumors in Costello Syndrome, Other Than Rhabdomyosarcoma
The age at diagnosis in these cases of neuroblastoma was similar to that in the general population, where about 1/3 of all cases occur before age one year, 80% by 4 years and 97% by 10 years. About 2/3 of all cases arise from the abdomen, but thoracic tumors are more common in infants. Most cases are diagnosed as disseminated disease, and, with the exception of the 4S stage, have a poor prognosis. More than 90% of neuroblastomas produce the catecholamine metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA), which can be measured in urine. Several studies evaluated mass screening for neuroblastoma in infants by measuring urinary HVA and VMA excretion. One of these studies showed a detection rate for preclinical neuroblastoma of 10.3/100,000 in patients age 10–18 months [Schilling et al., 2000], which is significantly higher than the expected 8/1,000,000 cases. This discrepancy is likely due to the complex biology including spontaneous differentiation in many unrecognized cases. A nationwide screening program for 6-month-old infants has been in place for 15 years in Japan. Based on their experience comparing preoperatively obtained data with histological and molecular studies from the tumor specimens, a Japanese group began to follow patients considered low risk clinically, without tumor removal. While some tumors were subsequently surgically removed for a variety of reasons, others became undetectable. In none of the cases an upgrading of the tumor stage or unfavorable biologic factors were noted [Nishihira et al., 2000]. Thus, the value of a screening protocol for neuroblastoma in the general population remains controversial.
Two transitional cell carcinomas of the bladder have been reported in patients with Costello syndrome [Franceschini et al., 1999; Gripp et al., 2000]. The first case presented in an 11-year-old male with macroscopic hematuria. After removal of the primary lesion, recurrences were noted [Franceschini et al., 1999]. The second case was identified in a 16-year-old female with microscopic hematuria. Six papillary tumors were visualized cystoscopically and removed without complications. The patient remains tumor free at her current age of 20 years. Bladder carcinoma is extremely rare in adolescents, therefore the occurrence of two cases in young patients with Costello syndrome is unlikely to be coincidental.
Suri and Garrett  reported a 33 year-old patient with Costello syndrome who died from cerebellar herniation due to a vestibular schwannoma. Martin and Jones  described a 12 year-old female with a large calcified epithelioma of the neck, removed surgically. It is not clear if this epithelioma should be considered a malignancy. If the epithelioma is included, the total number of malignant tumors in patients with Costello syndrome is 17 (Tables I and II). These tumors occurred in almost 100 patients with a known diagnosis of Costello syndrome [Lin et al., 2001]. While there may be ascertainment bias due to the incomplete identification of all Costello syndrome patients, the frequency of malignant tumors in Costello syndrome could be as high as 17%. This frequency is comparable to the 7–21% reported in BWS [Schneid et al., 1997; DeBaun and Tucker, 1998]. The high frequency of malignancies in Costello syndrome may warrant tumor screening.
We propose a screening protocol (Table III) for the most common tumors, based on the tumor location and the age at diagnosis. Ultrasound examination of the abdomen and pelvis may identify RMS and abdominal neuroblastoma. Anticipated problems with tumor screening may be due to RMSs occurring at variable locations, as opposed to the localized occurrence of Wilms tumor or hepatoblastoma in BWS. However, eight of the 10 RMS in Costello syndrome (Table I), may have been seen on such ultrasound examinations, as they originated from the abdomen, pelvis or urogenital area. The oldest Costello syndrome patient to be diagnosed with RMS was 6 years old (Table I). In the general population, almost two thirds of RMS are diagnosed by 10 years of age [Wexler and Helman, 1997]. Due to the small number of cases we do not know if the age distribution in Costello syndrome is similar to that in the general population, but it appears reasonable to discontinue ultrasound screening by age 10 years. No information is available on the ideal time interval between ultrasound examinations to screen an at-risk population for RMS. In patients with BWS ultrasound examinations for Wilms tumor performed in intervals of four months or less, but not in larger intervals, have a significant impact on tumor stage at diagnosis [Choyke et al., 1999]. Realizing that tumor screening in Costello syndrome differs from tumor screening in BWS, the screening frequency cannot simply be copied, but the experience with Wilms tumor screening may support a screening interval of three to six months. Further studies in patients with Costello syndrome are needed to refine and validate this suggestion.
Table III. Proposed Tumor Screening Protocol for Patients With Costello Syndrome
Ultrasound evaluation of the abdomen and pelvis
Every 3–6 months until age 8–10 years
RMS, abdominal neuroblastoma
Urine catecholamine metabolite assay (spot urine)
Every 6–12 months until age 5 years
Urinalysis for hematuria
Annually starting age 10 years
Urine HVA and VMA analysis may detect abdominal and thoracic neuroblastomas. Urinalysis for hematuria may lead to the early identification of bladder carcinomas. The value of neuroblastoma screening in the general population is controversial (see above), and there is no precedent for neuroblastoma screening in an at-risk population. Therefore it is not known if neuroblastoma screening at the suggested interval will be beneficial for patients with Costello syndrome, and this recommendation may need to be revised. It is unclear if tumor screening in patients with Costello syndrome will improve long term outcome. This question may be addressed by a prospective study. The proposed tumor screening protocol will raise the parents' and primary care physician's awareness for the increased malignancy risk in Costello syndrome. This may represent an indirect benefit from the screening protocol, leading to prompt evaluation and diagnosis of any symptomatic malignancies.
A prerequisite for the implementation of any screening protocol is the prior diagnosis of Costello syndrome. In only three of the 10 RMS cases Costello syndrome was diagnosed prior to the RMS, in five Costello syndrome was diagnosed later than the RMS, and in two the order was not reported. Findings almost universally present during infancy that should lead to the consideration of Costello syndrome include: history of polyhydramnios, large birth weight, severe feeding difficulties, severe failure-to-thrive with relative macrocephaly, connective tissue abnormalities including loose, soft skin, deep palmar creases and laxity of small joints, and characteristic, slightly coarse facial findings in a patient with a normal karyotype. Numerous other features have been reported [Johnson et al., 1998; Van Eeghen et al., 1999], cardiac abnormalities being the most significant [Siwik et al., 1998; Lin et al., 2001]. To facilitate a timely diagnosis of Costello syndrome, we would like to draw attention to less common findings noted in our patients. Fetal tachycardia was present in patients 2 and 3, and fetal tachycardia was reported in a patient with Costello syndrome and neuroblastoma [Flores-Nava et al., 2000]. Increased nuchal thickness was reported on ultrasound examination at 16 weeks gestational age in one patient [Kerr et al., 1998], and we follow a patient with Costello syndrome in whom increased nuchal thickness was noted in the second trimester. Thus, fetal tachycardia and increased nuchal thickness may be added to the prenatal presentations of Costello syndrome. Costello syndrome may also be considered in the differential diagnosis of Chiari 1 malformation and syringomyelia. One of our patients (Case 4) had a Chiari 1 malformation with syringomyelia, and another (Case 3) had tonsillar ectopia. Say et al.  reported a Chiari 1 malformation in Costello syndrome. Okamoto et al.  described “a slight downward deviation of the cerebellar tonsills” in another case. Two additional Chiari 1 malformations, one syringomyelia, and one Chiari malformation with syringomyelia occurred in patients known to the Costello support group (personal communication, Colin Stone, Costello syndrome support group, England).
In conclusion, there is a greatly increased risk for malignant tumors in Costello syndrome, most commonly RMS followed by neuroblastoma and transitional cell carcinoma of the bladder. The proposed tumor screening protocol may allow presymptomatic detection, though it must be balanced against cost-effectiveness and feasibility, issues likely to be raised. Like other guidelines established by peer discussion, these are subject to modification, as new information becomes available. The prior diagnosis of Costello syndrome is a prerequisite for the implementation of a tumor screening protocol. A prospective study is needed to assess the effect of the proposed screening protocol.
We thank the patients, their parents, and the Costello syndrome support group who provided information and encouragement. We thank Dr. Carol Clericuzio for her thoughtful suggestions.