Costello syndrome with growth hormone deficiency and hypoglycemia: A new report and review of the endocrine associations

Abstract

We describe an 18-month-old boy with Costello syndrome (CS) with proven partial growth hormone (GH) deficiency and hypoglycemic episodes. The hypoglycemia is deemed to be due to cortisol deficiency. This report represents the second published case of cortisol deficiency in the CS. A brief review of the endocrine disturbances in the syndrome is provided. We highlight the need for careful endocrinological evaluation of individuals with CS. ß 2004 Wiley-Liss, Inc.KEY WORDS: Costello syndrome; growth hormone; cortisol deficiency; glucose metabolism; endocrine disturbances INTRODUCTIONPatients with Costello syndrome (CS) typically have mental retardation, prenatal overgrowth with postnatal failure to thrive, a distinctive facial appearance suggestive of a storage disorder, soft skin with deep creases on the palms and soles, hyperextensible digits, and increased skin pigmentation [Costello, 1971]. Affected persons tend to develop papillomata around the nose, mouth, and anus from late childhood [Johnson et al., 1998;Hennekam, 2003]. About 63% of patients with CS have cardiac abnormalities . It has also been noted that patients with CS are at increased risk for the development of tumors [DeBaun, 2002;Gripp et al., 2002]. Further, a few reports describe endocrine abnormalities in some patients with CS, specifically of growth hormone (GH) [Okamoto et al., 1994;Schimke et al., 1996;Yetkin et al., 1998;Legault and Gagnon, 2002;Delrue et al., 2003] and glucose metabolism [Di Rocco et al., 1993;Johnson et al., 1998;Yetkin et al., 1998;Szalai et al., 1999;Gripp et al., 2000]. We describe a patient with CS, with partial GH deficiency and hypoglycemia. The hypoglycemia is thought to be related to abnormal cortisol metabolism. CLINICAL REPORTOur patient (Fig. 2a,b) is the second child of a nonconsanguineous couple. His 7-year-old brother is healthy. His parents were aged 26 and 30 years at the patient's conception. His mother required thyroid replacement in pregnancy, but was documented biochemically as being euthyroid throughout. The patient was born at term by caesarean section, with a birthweight of 2.7 kg (3rd centile), length of 45 cm (<3rd centile), and head circumference of 35 cm (25th centile). He was noted to have unusual facial features. A right orchidopexy and bilateral inguinal hernia repairs were performed at 6 weeks of age. Poor weight gain was noted from shortly after birth. He had sucking difficulties, but he was able to tolerate small volume feeds from a bottle, and by 6 months of age, he was feeding well.At 9 months of age the patient had a prolonged generalized seizure, and was found to be hypoglycemic (blood glucose ¼ 1.2 mmol/L) with an appropriately low insulin level (0.3 iU/L). The cortisol level was not checked during the hypoglycemic episodes, but a subsequent random level was found to be normal. Further endocrine evaluation confirmed a partial GH deficiency after a clonidine stimulation test (basal level ¼ 3.48 mg/L, peak ¼ 8.89 mg/L). Thyroid function was questionable with a low free thyroxine (FT 4 ) o...

Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations

“…46 Hypoglycemic episodes unresponsive to GH therapy responded well to cortisone replacement in another individual. 47 Thus, cortisol deficiency may also be considered. Because of the severe feeding difficulties, most loose joints, particularly the fingers.…”

Prenatal features of Costello syndrome: ultrasonographic findings and atrial tachycardia

“… 1 Costello et al ., 1977 and Costello et al ., 1996; Der Kaloustian et al ., 1991; Martin and Jones, 1991; Borochowitz et al ., 1992; Teebi et al ., 1993; DiRocco et al ., 1993; Izumikawa et al .,1993; Kondo et al .,1993; Patton et al ., 1993; Phillip and Mancini, 1993; Zampino et al ., 1993; Say et al ., 1993; Yoshida et al ., 1993; Davies et al ., 1994; Okamoto et al ., 1994; Fryns et al ., 1994; Torres et al, 1994; Umans et al ., 1994; Torrelo et al, 1995; Mori et al ., 1996; Fukao et al ., 1996; Johnson et al ., 1998; Pratesi et al ., 1998; Tomita et al, 1998; Siwik et al ., 1998; Franceshini et al, 1999; Szalai et al , 1999; van Eeghen et al, 1999; Bisogno et al ., 1999; Innes and Chudley, 2000; Moroni et al ., 2000; Sigaudy et al ., 2000; Hatamochi et al ., 2000; Boente et al, 2001; Gripp et al, 2002; Kaji et al ., 2002; Kamoda et al ., 2002; van den Bosch et al ., 2002; Urakami et al ., 2002; Kawame et al, 2003; Delrue et al, 2003; Mancini et al ., 2003; DiRocco et al ., 2003; Nasca et al, 2003; Cakir et al ., 2004; Waldburg et al ., 2004; Dickson et al, 2004; Gregersen et al ., 2004; Stein et al, 04; Hinek et al, 2005; Alexander et al ., 2005; White et al ., 2005. 2 Lin et al ., 2008 represented the compilation of Gripp et al ., 2006 and Estep et al, 2006; Kerr et al ., 2006; Steens et al, 2006; Zampino et al, 2006; Digilio et al ., 2007; Limongelli et al ., 2007; Denayer et al ., 2007; Lo et al ., 2008; Hou et al ., 2008; Gripp et al, 2008. 3 Case reports in the literature who were later included in extensive reviews were generally reported only in Group II, e.g. patients 1 and 3 in Zampino et al , 1993 were also patients CS-01 and CS-04 in Zampino et al, 2006).…”

Rapidly progressive scoliosis after successful treatment for osteopenia in Costello syndrome

“…GH deficiency, adrenal insufficiency, hyperinsulinemic hypoglycemia, parathyroid adenoma with hyperprolactinemia and hypoglycemia [Johnson et al, 1998;Gregersen and Viljoen, 2004;Stein et al, 2004;Alexander et al, 2005;White et al, 2005] have all been reported in CS patients. The administration of rhGH in CS individuals with GH deficiency has been successful without adverse events till now [Gripp et al, 2000;Gregersen and Viljoen, 2004;Stein et al, 2004;White et al, 2005] despite concerns about the potential impact on cardiomyopathy progression and tumor risk [Kerr et al, 2003]. Osteoporosis, central hypogonadism and delayed puberty are not rare in the young adult [White et al, 2005].…”