Is growth hormone treatment beneficial or harmful in Costello syndrome?

Costello syndrome (CS) was first described by Costello in two unrelated children, in 1971 and 1977. The major manifestations of CS have been summarised as postnatal growth deficiency, developmental delay, relative macrocephaly, coarse face, thick ears, thick lips, depressed nasal bridge with anteverted nares, excess skin, thick palms and soles, short neck, curly hair, nasal papillomata, and sociable personality. Recently, it has become apparent that children with CS have an increased risk of malignancy, particularly rhabdomyosarcoma. Rhabdomyosarcoma, predominantly embryonal, has been reported in 10 children, ganglioneuroblastoma in three, bladder carcinoma in two, epithelioma in one, and acoustic neuroma in one adult. A further three unpublished cases of rhabdomyosarcoma in children with CS are known to us through the International Costello syndrome support group and a fourth case is included in this report (case 2). The frequency of tumours in CS has been estimated to be as high as 17% and a screening protocol has been proposed. These recommendations for surveillance include three to six monthly abdominal and pelvic ultrasound until the of the age of 8–10 years, urinary catecholamine analysis every six to 12 months until the age of 5, and annual urine analysis after the age of 10. Whether or not abdominal ultrasound would enable detection of early stage disease in rhabdomyosarcoma with a benefit for both survival and morbidity is unknown. For neuroblastoma, however, data from the general population suggested that screening had no impact on mortality or morbidity and the use of urine analysis in detection of bladder cancer has not been evaluated. Evaluation of the risks and benefits of the suggested screening regimen in this rare disorder will require in the first instance a network of collaborating geneticists and parents who are willing to allow screening without proven benefits. Cardiac complications are common in CS. Congenital heart disease, predominantly pulmonary stenosis, occurs in about a third of patients with CS. Arrhythmias, usually atrial tachychardias, occur in a third and, of these, a third will have an otherwise normal heart. A further third of patients with CS have cardiomyopathy, predominantly left ventricular hypertrophy, reported in patients ranging from the first year of life until 27 years. Cardiomyopathy was the only cardiac abnormality in a notable number of the patients reported. These two important risks to health, the development of malignancy and cardiac hypertrophy, in children and adults with CS have led to concern about the use of growth hormone (GH) in CS. 5 Postnatal growth retardation with preservation of head circumference, despite high normal birth weights and normal length at birth, is a consistent feature of CS. It seems unrelated to whether or not adequate nutrition can be maintained in the first years of life when oral feeding is often impossible. Reported adult heights range from 135 to 150 cm. The bone age is delayed in most. Menstruation may not occur and when it does, the onset has varied between the ages of 14 and 18. There have been few published reports of the use of GH in CS and the evidence for effectiveness in the long term in CS is limited. Partial GH deficiency was reported in a Japanese patient but treatment with GH using an unspecified dose for several years was reported to have had only limited effect. A good growth response over several years has been reported in two children. 8 Bladder carcinoma has occurred in a patient with CS treated with GH. In this girl, symptomatic hypoglycaemic episodes at the age of 6.5 years were treated with recombinant GH in association with replacement therapy for secondary hypothyroidism. Growth hormone did improve growth rate over the first four years of treatment, but this was not sustained, with her height after seven years of treatment at the age of 14 years 5 months (four months after menarche) being 5 SD below the mean, as it had been when treatment with GH started. She developed multiple papillary transitional bladder carcinomas at the age of 16. We describe here two patients with CS treated with GH who developed a known complication of CS while on treatment.