Rapidly progressive scoliosis after successful treatment for osteopenia in Costello syndrome

Costello syndrome (CS, OMIM 218040) is a rare congenital disorder characterized by a coarse face, sparse curly hair, feeding problems with failure to thrive, short stature, psychomotor retardation, skeletal problems, cardiac anomalies, deep creases of the palms and soles, loose skin with hyperpigmentation, and an increased risk for solid tumors [Johnson et al., 1998; Hennekam, 2003; Gripp, 2005]. There is a phenotypic overlap with both Noonan and Cardio-facio-cutaneous (CFC) syndrome. Recently, germline or somatic mutations in the HRAS protooncogene (locus on 11p15.5) have been found to be the cause of CS [Aoki et al., 2005; Estep et al., 2006; Gripp et al., 2006a,b]. We report on a Taiwanese girl, the second child of nonconsanguineous parents, who had been described briefly with CS during infancy period [Hou and Tunnessen, 2000]. The initial laboratory findings including plasma amino acids, liver and renal function, blood glucose, acid-base, electrolytes, thyroid function test results, and magnetic resonance imaging study (MRI) of brain were all normal except for a perimembranous ventricular septal defect (VSD), and a small atrial septal defect (ASD) with normal ejection fraction (EF 75%). Because of severe failure to thrive by age 1 year, she required a gastrostomy to supplement nutrition. The ASD closed spontaneously and the VSD was repaired at the age of 1.5 and 3.4 years, respectively. Exotropia with trichiasis of both eyes persists. Electroencephalography (EEG) showed diffuse cortical dysfunction with generalized epileptiform discharges. Thepatient hadmarkedly short staturewith episodes of hypoglycemic drowsiness, mild metabolic acidosis (pH7.325,baseexcess 9.1mEq/L), andhyperlaxityof joints, and further metabolic-endocrine investigation was performed at 3.5 years old. Tandem mass study showed mildly low free carnitine level (7.15 mM, normal range 15–36). Plasma free and total carnitine levels were 21 and 30 mM, respectively (30–44/38–54). Gas chromatography/mass spectrometry study of urine revealed generalized organic aciduria (elevated lactic,methylmalonic, 3-methyl-3-hydroxyglutaric, and dicarboxylic acids). Echocardiography showed slight biventricular hypertrophy, impaired systolic function (EF 60%), and left ventricular diastolic dysfunction (abnormal diastolic total period and duration of the early diastolic flow-velocity peak values), with right bundle branch block on electrocardiographic (EEG) recordings. Blood concentrations of C-peptide and cholesterol were normal, but triglyceride levels were elevated (1.25 g/L, 0.33–1.0). The serum insulin-like growth factor-I level was below 1.3 nmol/L. Growth hormone (GH) deficiency was confirmed by both insulin tolerance (GH peak: 4.86 mg/L with nadir sugar: 0.98 mmol/L) and clonidine stimulation (2.36 mg/L) tests. The bone age was 2years andsuggestedosteoporosis. Bonemineral densitometry (BMD) showed osteopenia (Z-Score 3.3 SD, 65% for age-matched girls). Alkaline phosphatase was 279 U/L (28–94). The biomarkers for bone remodeling including osteocalcin, collagen-I telopeptide, and procollagen-I C-terminal peptide all showed marked elevation (Table I). No abnormalities of calcium, parathyroid hormone or vitamin D3 levels were noted. Pamidronate (Aredia) was infused intravenously (15 mg/m) every month to treat osteopenia from the age of 4 till 6.0 years with improvement in BMD and the related biomarkers (Table I). Oral