Growth Hormone & IGF Research 24 (2014) 271–275
Contents lists available at ScienceDirect
Growth Hormone & IGF Research journal homepage: www.elsevier.com/locate/ghir
Growth hormone replacement therapy in Costello syndrome Panagiota Triantafyllou, Athanasios Christoforidis, Euthymia Vargiami, Dimitrios I. Zafeiriou ⁎ 1st Department of Pediatrics, Aristotle University, Thessaloniki, Greece
a r t i c l e
i n f o
Article history: Received 17 June 2014 Received in revised form 26 August 2014 Accepted 12 October 2014 Available online 30 October 2014 Keywords: Costello syndrome Growth hormone deficiency Hypothyroidism Endocrine disorders
a b s t r a c t Costello syndrome (CS) is considered an overgrowth disorder given the macrosomia that is present at birth. However, shortly after birth the weight drops dramatically and the patients are usually referred for failure to thrive. Subsequently, affected patients develop the distinctive coarse facial appearance and are at risk for cardiac anomalies and solid tumor malignancies. Various endocrine disorders, although not very often, have been reported in patients with CS, including growth hormone deficiency, hypoglycemia, ACTH deficiency, cryptorchidism and hypothyroidism. We report a case of Costello syndrome with hypothyroidism, cryptorchidism and growth hormone deficiency and we evaluate the long-term safety and efficacy of growth hormone replacement therapy. The index patient is a paradigm of successful and safe treatment with growth hormone for almost 7 years. Since patients with CS are at increased risk for cardiac myopathy and tumor development they deserve close monitoring during treatment. © 2014 Elsevier Ltd. All rights reserved.
1. Introduction Costello syndrome (CS, OMIM 218040) is considered an overgrowth disorder given the macrosomia that is present at birth in 89% of the cases. However, shortly after birth the weight drops dramatically and the patients are usually referred for failure to thrive. Subsequently, affected patients develop the distinctive coarse facial appearance of CS, including relative macrocephaly, hirsute forehead, curly and often sparely implanted hair, thick eyebrows, epicanthal folds, strabismus, downward slanted palpebral fissures, low-set pinnae with large ear lobes, and a depressed nasal bridge. Dermatological manifestations include redundant skin with deep creases on the palms and soles, generalized hyperpigmentation, acanthosis nigricans and papillomata around the mouth, nares and anus [9]. Cardiac involvement is commonly seen, either as congenital heart defects or later presenting valvular defects, dysarhythmias and hypertrophic cardiomyopathy [14]. Central nervous system manifestations include mental retardation, which is one of the main features of the syndrome, and various structural defects as brain atrophy, ventricular dilatation, white matter hypodensity, Arnold–Chiari malformation type I and frontal lobe hypoplasia [10]. Predisposition to tumor development has been associated with CS [7]. Rhabdomyosarcoma bladder carcinoma, acoustic neuromas and neuroblastoma have more commonly been reported and proposals for tumor screening protocols have been suggested [8]. ⁎ Corresponding author at: 1st Department of Pediatrics, Aristotle University of Thessaloniki, Egntia St. 106, 54622 Thessaloniki, Greece. Tel.: +30 2310 241845, +30 6944 330587 (mobile); fax: +30 2310 241845. E-mail address: [email protected] (D.I. Zafeiriou).
http://dx.doi.org/10.1016/j.ghir.2014.10.001 1096-6374/© 2014 Elsevier Ltd. All rights reserved.
Various endocrine disorders, although not very often, have also been reported in patients with CS, including hypoglycaemia, hyperprolactinemia, growth hormone deficiency, ACTH deficiency, delayed puberty, cryptorchidism and hypothyroidism [1,3,4,17]. We report a case of Costello syndrome and growth hormone deficiency, cryptorchidism and hypothyroidism and evaluate the longterm safety and efficacy of growth hormone replacement therapy. 2. Case report The index patient is a male, born at 35 weeks' gestational age by phenotypically healthy, non-consanguineous parents. At birth he was macrosomic (BW 3450 g, N97th percentile) with relative macrocephaly (HC 36 cm, N97th percentile). He had prominent forehead, wide mouth, full lips, large tongue, low set pinnae with remarkably large ear lobes, a depressed nasal bridge, short neck and redundant skin folds across the limbs and neck. Hypotonia with increased tendon reflexes were also present. Clinical findings, suspected the diagnosis of hypothyroidism; however, subsequent assays of plasma T3, T4, and TSH were within normal range. At the age of 3 months the patient was admitted to the Department of Pediatrics for investigation of failure to thrive. Ultrasonography and endoscopic examination of the gastrointestinal tract did not reveal any pathological findings. Thyroid function tests revealed elevated plasma TSH (8.8 μIU/ml, normal range 0.4–4.0) with low plasma T4 (b0.65 ng/dl, normal range 0.65–2.3). Thyroid ultrasound scan demonstrated thyroid hypoplasia and thus the diagnosis of congenital hypothyroidism was confirmed and replacement therapy with L-T4 started at a dose of 50 μg/day. Further metabolic and karyotypic evaluation was normal. At six months of age the infant's weight and length were 4.5 kg and 59 cm respectively, both below 3rd percentile (− 5
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P. Triantafyllou et al. / Growth Hormone & IGF Research 24 (2014) 271–275
SD), while head circumference was 40 cm (5th percentile, − 1.6 SD). Neurodevelopmentally, the infant demonstrated psychomotor retardation, with central hypotonia and pyramidal tract dysfunction (bilateral increased tendon reflexes, clonus, positive Rossolimo's signs). Skeletal survey and cranial magnetic resonance imaging were normal. At the age of 3.5 years, he manifested the typical facial appearance of Costello syndrome, a prominent forehead with temporal narrowing, full cheeks, curly hair, epicanthal folds, short nose with full nasal tip, full lips, very wide mouth, low-set ears with thick lobes, short neck, short and flat hyperextensible fingers, dermatoglyphic findings consisting of deep plantar and palmar creases and papillomata around the mouth (Fig. 1). Serial two-dimensional echocardiograms have shown very mild thickening of the intraventricular septum. His weight and height remained below the 3rd percentile (−5 SD), whereas, head circumference was at the 5th percentile (−1.6 SD). He also diagnosed with cryptorchidism on the right and orchidopexy was performed. Sequencing analysis of DNA sample indentified a heterozygous mutation, c.34GNA (p.Gly12Ser), in exon 2 of HRAS which confirmed the diagnosis of Costello syndrome. At the age of 7 years, in order to evaluate growth hormone secretion we preceded to clonidine and glucagon stimulation tests, which revealed growth hormone deficiency (GHmax 0.7 and 6.95 ng/ml respectively). GH levels were measured by solid-phase, two-site chemiluminescent immunometric assay (IMMULITE 2000 Growth Hormone, recombinant 98/574). The solid phase of the method is coated with murine monoclonal anti-hGH antibody. IGF-1 level was low as well measured at 47 μg/L (− 2.5 SD). Hypothalamic–pituitary MRI scan revealed no pathology. Monitoring pre- and postprandial glucose levels didn't reveal any hypoglycemic episodes. Further hormonal investigation, including glucose metabolism was normal. Replacement therapy with rhGH was started with regular cardiological consultation and IGF-1 levels monitoring, given the existing cardiac hypertrophy and the risk of worsening. The initial rhGH dose was 0.21 mg/kg/week and it was adjusted thereafter maintaining IGF-1 levels in the normal range for age and gender. On follow-up the patient's height improved gradually without any signs of worsening cardiomyopathy or malignancies. In particular, he
has been followed up by a pediatric cardiologist and had electrocardiogram and cardiac ultrasonography survey done every six months. Furthermore, he has abdominal ultrasound scan performed annually. He is currently 14-years-old and his height is 155 cm (10th percentile). Growth history is summarized in Figs. 2 and 3. His puberty started at the age of 10 years when testicular volume increased to 4 ml. He is currently G4 P4 A3 with testicular volume at 20 ml. Bone age was performed annually before the onset of puberty and in six-month intervals thereafter. We used the Greulich and Pyle method for its assessment. It was always correlated with chronological age and so it is at the age of 14. 3. Discussion The presentation and clinical findings of Costello syndrome follow two distinct phases: a) the in utero and immediate neonatal period when macrosomia is present, followed by b) the postnatal phase which is characterized by failure to thrive, short stature, developmental delay and the appearance of the characteristic phenotypic expression of the syndrome including the facial and skin manifestations [5]. CS belongs in the family of “RASopathies”, a group of genetic syndromes that share RAS/MAPK (mitogen-activated protein kinase) pathway disorders. Phenotypically similar syndromes are Noonan and cardio-facio-cutaneous syndrome, whereas Noonan syndrome with multiple lentigines (previously known as LEOPARD) and neurofibromatosis type I have less phenotypic overlap but similar pathogenic activation of RAS/MAPK pathway [16]. In pre-molecular era the diagnosis of CS was based on clinical findings, however in many cases it could be difficult to be certain especially during infancy. During the last ten years the identification of HRAS gene mutations as the underlying cause of CS enabled the differential and specific diagnosis of the syndrome. CS is caused by de novo heterozygous germline mutations in protooncogene HRAS, resulting in hyperactivation of RAS/MAPK signaling pathway [2]. The Ras/mitogen activated protein kinase pathway governs cell proliferation and differentiation, and its dysregulation affects cardiac and brain development, accounting for the significant overlap
Fig. 1. (a–b). Patient's clinical appearance. (a) Coarse facial features, broad nasal tip, thick lips, (b) deep palmar creases.
P. Triantafyllou et al. / Growth Hormone & IGF Research 24 (2014) 271–275
273
Fig. 2. Patient's height curve; MPH, mean parental height.
in physical and developmental differences and common medical problems among rasopathies. The most common mutation which is found in more than 80% of CS patients is p.G12S which is associated with the typical and rather homogenous phenotype followed by p.G12A seen in 7% of patients [6, 16]. Rarer mutations have either been associated with fatal forms or milder clinical presentation [15]. Endocrine disorders that have been reported in patients with CS include hypothyroidism, cryptorchidism, hyperprolactinaemia, parathyroid adenoma, hypoglycaemia due to ACTH deficiency or hyperinsulinism or growth hormone deficiency [1,3,4,17]. In the current patient there was documentation of hypothyroidism with low level of T3, T4 and thyroid hypoplasia, cryptorchidism and also a proven growth hormone deficiency. In patients with CS linear growth is slow and results in short stature. Short stature is a common feature in many genetic syndromes, however, only in few of them the underlying cause is known or it has been attributed to growth hormone deficiency. Regarding CS growth hormone
deficiency has been reported in up to 40% of cases [13,17]. On the other hand, growth hormone has been given successfully in non-GH deficient patients like the ones with Turner syndrome and lately with Noonan syndrome. Given the potential risk of malignancy and hypertrophic myocardiopathy in children with CS, along with considering mitogenic action of growth hormone and risk of worsening myocardial hypertrophy, growth hormone replacement treatment is controversial in children with CS [11]. Hypertrophic cardiomyopathy affects twothirds of patients. It is more severe and often lethal in infants and young children. Kobayashi et al. reported a case of worsening cardiomyopathy in a 6-year-old child with CS during growth hormone treatment and raise concerns about its use [12]. However, Lin et al. in a cohort of 61 patients reported no conclusive relationship between growth hormone replacement treatment and hypertrophic cardiomyopathy [14]. Growth hormone treatment could be beneficial in children with CS and growth hormone deficiency however these patients deserve close monitoring. In conclusion, the index patient is a paradigm of successful and safe treatment with growth hormone for almost 7 years. Given the limited
274
P. Triantafyllou et al. / Growth Hormone & IGF Research 24 (2014) 271–275
Fig. 3. Patient's weight curve.
literature on growth hormone deficiency in patients with CS the current case adds useful information on this field. Since patients with CS are at increased risk for cardiac myopathy and tumor development they deserve close monitoring during treatment. Conflict of interest The authors confirm that they do not have any potential conflict of interest. References [1] S. Alexander, D. Ramadan, H. Alkayyat, I. Al Sartawi, K.C. Backer, F. El-Sabban, K. Hussian, Costello syndrome and hyperinsulinemic hypoglycemia, Am. J. Med. Genet. A 139 (2005) 227–230. [2] Y. Aoki, T. Niihori, H. Kawame, K. Kurosawa, H. Ohashi, Y. Tanaka, M. Filocamo, K. Kato, Y. Suzuki, S. Kure, Y. Matsubara, Germline mutations in HRAS proto-oncogene cause Costello syndrome, Nat. Genet. 37 (2005) 1038–1040. [3] M. Cakir, C. Arici, S. Tacoy, U. Karayalcin, A case of Costello with parathyroid adenoma and hyperprolactinemia, Am. J. Med. Genet. A 124A (2004) 196–199.
[4] N. Gregersen, D. Viljohen, Costello syndrome with growth hormone deficiency and hypoglycemia: a new report and review of the endocrine associations, Am. J. Med. Genet. A 129 (2004) 171–175. [5] K.W. Gripp, A.E. Lin, Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations, Genet. Med. 14 (2012) 285–292. [6] K.W. Gripp, A.E. Lin, D.L. Stabley, L. Nicholson, I. Charles, C.I. Scott Jr., D. Doyle, Y. Aoki, Y. Matsubara, E.H. Zackai, P. Lapunzina, A. Gonzalez-Meneses, J. Holbrook, C.A. Agresta, I.L. Gonzalez, K. Sol-Church, HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation, Am. J. Med. Genet. A 140A (2006) 1–7. [7] K.W. Gripp, Tumor predisposition in Costello syndrome, Am. J. Med. Genet. C: Semin. Med. Genet. 137C (2005) 72–77. [8] K.W. Gripp, C.I. Scott, L. Nicholson, D.M. McDonnald-McGinn, J.D. Ozeram, M.C. Jones, A.E. Lin, E.H. Zackai, Five additional Costello syndrome patients with rhabdomyoarcoma: proposal for a tumor screening protocol, Am. J. Med. Genet. 108 (2002) 80–87. [9] R.C.M. Hennekam, Costello syndrome: an overview, Am. J. Med. Genet. C: Semin. Med. Genet. 117C (2003) 42–48. [10] E. Hopkins, D. Doyle, W.B. Dobyns, High incidence of progressive postnatal cerebellar enlargement in Costello Syndrome: brain overgrowth associated with HRAS mutations as the likely cause of structural brain and spinal cord abnormalities, Am. J. Med. Genet. A 152A (2010) 1161–1168. [11] B. Kerr, M.A. Einaudi, P. Clayton, G. Gladman, T. Eden, P. Saunier, D. Genevieve, N. Philip, Is growth hormone treatment beneficial or harmful in Costello syndrome? J. Med. Genet. 40 (6) (2003) e74.
P. Triantafyllou et al. / Growth Hormone & IGF Research 24 (2014) 271–275 [12] D. Kobayashi, A.L. Cook, D.A. Williams, Progressively worsening hypertrophic cardiomyopathy in a child with newly diagnosed Costello syndrome while receiving growth hormone therapy, Cardiol. Young 20 (2010) 459–461. [13] L. Legault, C. Cagnon, Growth hormone deficiency in Costello syndrome: a possible explanation for the short stature, J. Pediatr. 138 (2001) 151–152. [14] A.E. Lin, M.E. Alexander, S.D. Colan, B. Kerr, K.A. Rauen, J. Noonan, J. Baffa, E. Hopkins, K. Sol-Church, G. Limongelli, M.C. Digilio, B. Marino, A.M. Innes, Y. Aoki, M. Silberbach, M.A. Delrue, S.M. White, R.M. Hamilton, W. O'Connor, P.D. Grossfeld, L.B. Smoot, R.F. Padera, K.W. Gripp, Clinical, pathological, and molecular analyses of cardiovascular
275
abnormalities in Costello syndrome: a Ras/MAPK pathway syndrome, Am. J. Med. Genet. A 155A (2011) 486–507. [15] S. Lorenz, C. Petersen, U. Kordaß, H. Seidel, M. Zenker, K. Kutsche, Two cases with severe lethal course of Costello syndrome associated with HRAS p.G12C and p.G12D, Eur. J. Med. Genet. 55 (2012) 615–619. [16] K.A. Rauen, The RASopathies, Annu. Rev. Genomics Hum. Genet. 14 (2013) 355–369. [17] R.I. Stein, L. Legault, D. Daneman, R. Weksberg, J. Hamilton, Growth hormone deficiency in Costello syndrome, Am. J. Med. Genet. A 129A (2004) 166–170.
Contents lists available at ScienceDirect
Growth Hormone & IGF Research journal homepage: www.elsevier.com/locate/ghir
Growth hormone replacement therapy in Costello syndrome Panagiota Triantafyllou, Athanasios Christoforidis, Euthymia Vargiami, Dimitrios I. Zafeiriou ⁎ 1st Department of Pediatrics, Aristotle University, Thessaloniki, Greece
a r t i c l e
i n f o
Article history: Received 17 June 2014 Received in revised form 26 August 2014 Accepted 12 October 2014 Available online 30 October 2014 Keywords: Costello syndrome Growth hormone deficiency Hypothyroidism Endocrine disorders
a b s t r a c t Costello syndrome (CS) is considered an overgrowth disorder given the macrosomia that is present at birth. However, shortly after birth the weight drops dramatically and the patients are usually referred for failure to thrive. Subsequently, affected patients develop the distinctive coarse facial appearance and are at risk for cardiac anomalies and solid tumor malignancies. Various endocrine disorders, although not very often, have been reported in patients with CS, including growth hormone deficiency, hypoglycemia, ACTH deficiency, cryptorchidism and hypothyroidism. We report a case of Costello syndrome with hypothyroidism, cryptorchidism and growth hormone deficiency and we evaluate the long-term safety and efficacy of growth hormone replacement therapy. The index patient is a paradigm of successful and safe treatment with growth hormone for almost 7 years. Since patients with CS are at increased risk for cardiac myopathy and tumor development they deserve close monitoring during treatment. © 2014 Elsevier Ltd. All rights reserved.
1. Introduction Costello syndrome (CS, OMIM 218040) is considered an overgrowth disorder given the macrosomia that is present at birth in 89% of the cases. However, shortly after birth the weight drops dramatically and the patients are usually referred for failure to thrive. Subsequently, affected patients develop the distinctive coarse facial appearance of CS, including relative macrocephaly, hirsute forehead, curly and often sparely implanted hair, thick eyebrows, epicanthal folds, strabismus, downward slanted palpebral fissures, low-set pinnae with large ear lobes, and a depressed nasal bridge. Dermatological manifestations include redundant skin with deep creases on the palms and soles, generalized hyperpigmentation, acanthosis nigricans and papillomata around the mouth, nares and anus [9]. Cardiac involvement is commonly seen, either as congenital heart defects or later presenting valvular defects, dysarhythmias and hypertrophic cardiomyopathy [14]. Central nervous system manifestations include mental retardation, which is one of the main features of the syndrome, and various structural defects as brain atrophy, ventricular dilatation, white matter hypodensity, Arnold–Chiari malformation type I and frontal lobe hypoplasia [10]. Predisposition to tumor development has been associated with CS [7]. Rhabdomyosarcoma bladder carcinoma, acoustic neuromas and neuroblastoma have more commonly been reported and proposals for tumor screening protocols have been suggested [8]. ⁎ Corresponding author at: 1st Department of Pediatrics, Aristotle University of Thessaloniki, Egntia St. 106, 54622 Thessaloniki, Greece. Tel.: +30 2310 241845, +30 6944 330587 (mobile); fax: +30 2310 241845. E-mail address: [email protected] (D.I. Zafeiriou).
http://dx.doi.org/10.1016/j.ghir.2014.10.001 1096-6374/© 2014 Elsevier Ltd. All rights reserved.
Various endocrine disorders, although not very often, have also been reported in patients with CS, including hypoglycaemia, hyperprolactinemia, growth hormone deficiency, ACTH deficiency, delayed puberty, cryptorchidism and hypothyroidism [1,3,4,17]. We report a case of Costello syndrome and growth hormone deficiency, cryptorchidism and hypothyroidism and evaluate the longterm safety and efficacy of growth hormone replacement therapy. 2. Case report The index patient is a male, born at 35 weeks' gestational age by phenotypically healthy, non-consanguineous parents. At birth he was macrosomic (BW 3450 g, N97th percentile) with relative macrocephaly (HC 36 cm, N97th percentile). He had prominent forehead, wide mouth, full lips, large tongue, low set pinnae with remarkably large ear lobes, a depressed nasal bridge, short neck and redundant skin folds across the limbs and neck. Hypotonia with increased tendon reflexes were also present. Clinical findings, suspected the diagnosis of hypothyroidism; however, subsequent assays of plasma T3, T4, and TSH were within normal range. At the age of 3 months the patient was admitted to the Department of Pediatrics for investigation of failure to thrive. Ultrasonography and endoscopic examination of the gastrointestinal tract did not reveal any pathological findings. Thyroid function tests revealed elevated plasma TSH (8.8 μIU/ml, normal range 0.4–4.0) with low plasma T4 (b0.65 ng/dl, normal range 0.65–2.3). Thyroid ultrasound scan demonstrated thyroid hypoplasia and thus the diagnosis of congenital hypothyroidism was confirmed and replacement therapy with L-T4 started at a dose of 50 μg/day. Further metabolic and karyotypic evaluation was normal. At six months of age the infant's weight and length were 4.5 kg and 59 cm respectively, both below 3rd percentile (− 5
272
P. Triantafyllou et al. / Growth Hormone & IGF Research 24 (2014) 271–275
SD), while head circumference was 40 cm (5th percentile, − 1.6 SD). Neurodevelopmentally, the infant demonstrated psychomotor retardation, with central hypotonia and pyramidal tract dysfunction (bilateral increased tendon reflexes, clonus, positive Rossolimo's signs). Skeletal survey and cranial magnetic resonance imaging were normal. At the age of 3.5 years, he manifested the typical facial appearance of Costello syndrome, a prominent forehead with temporal narrowing, full cheeks, curly hair, epicanthal folds, short nose with full nasal tip, full lips, very wide mouth, low-set ears with thick lobes, short neck, short and flat hyperextensible fingers, dermatoglyphic findings consisting of deep plantar and palmar creases and papillomata around the mouth (Fig. 1). Serial two-dimensional echocardiograms have shown very mild thickening of the intraventricular septum. His weight and height remained below the 3rd percentile (−5 SD), whereas, head circumference was at the 5th percentile (−1.6 SD). He also diagnosed with cryptorchidism on the right and orchidopexy was performed. Sequencing analysis of DNA sample indentified a heterozygous mutation, c.34GNA (p.Gly12Ser), in exon 2 of HRAS which confirmed the diagnosis of Costello syndrome. At the age of 7 years, in order to evaluate growth hormone secretion we preceded to clonidine and glucagon stimulation tests, which revealed growth hormone deficiency (GHmax 0.7 and 6.95 ng/ml respectively). GH levels were measured by solid-phase, two-site chemiluminescent immunometric assay (IMMULITE 2000 Growth Hormone, recombinant 98/574). The solid phase of the method is coated with murine monoclonal anti-hGH antibody. IGF-1 level was low as well measured at 47 μg/L (− 2.5 SD). Hypothalamic–pituitary MRI scan revealed no pathology. Monitoring pre- and postprandial glucose levels didn't reveal any hypoglycemic episodes. Further hormonal investigation, including glucose metabolism was normal. Replacement therapy with rhGH was started with regular cardiological consultation and IGF-1 levels monitoring, given the existing cardiac hypertrophy and the risk of worsening. The initial rhGH dose was 0.21 mg/kg/week and it was adjusted thereafter maintaining IGF-1 levels in the normal range for age and gender. On follow-up the patient's height improved gradually without any signs of worsening cardiomyopathy or malignancies. In particular, he
has been followed up by a pediatric cardiologist and had electrocardiogram and cardiac ultrasonography survey done every six months. Furthermore, he has abdominal ultrasound scan performed annually. He is currently 14-years-old and his height is 155 cm (10th percentile). Growth history is summarized in Figs. 2 and 3. His puberty started at the age of 10 years when testicular volume increased to 4 ml. He is currently G4 P4 A3 with testicular volume at 20 ml. Bone age was performed annually before the onset of puberty and in six-month intervals thereafter. We used the Greulich and Pyle method for its assessment. It was always correlated with chronological age and so it is at the age of 14. 3. Discussion The presentation and clinical findings of Costello syndrome follow two distinct phases: a) the in utero and immediate neonatal period when macrosomia is present, followed by b) the postnatal phase which is characterized by failure to thrive, short stature, developmental delay and the appearance of the characteristic phenotypic expression of the syndrome including the facial and skin manifestations [5]. CS belongs in the family of “RASopathies”, a group of genetic syndromes that share RAS/MAPK (mitogen-activated protein kinase) pathway disorders. Phenotypically similar syndromes are Noonan and cardio-facio-cutaneous syndrome, whereas Noonan syndrome with multiple lentigines (previously known as LEOPARD) and neurofibromatosis type I have less phenotypic overlap but similar pathogenic activation of RAS/MAPK pathway [16]. In pre-molecular era the diagnosis of CS was based on clinical findings, however in many cases it could be difficult to be certain especially during infancy. During the last ten years the identification of HRAS gene mutations as the underlying cause of CS enabled the differential and specific diagnosis of the syndrome. CS is caused by de novo heterozygous germline mutations in protooncogene HRAS, resulting in hyperactivation of RAS/MAPK signaling pathway [2]. The Ras/mitogen activated protein kinase pathway governs cell proliferation and differentiation, and its dysregulation affects cardiac and brain development, accounting for the significant overlap
Fig. 1. (a–b). Patient's clinical appearance. (a) Coarse facial features, broad nasal tip, thick lips, (b) deep palmar creases.
P. Triantafyllou et al. / Growth Hormone & IGF Research 24 (2014) 271–275
273
Fig. 2. Patient's height curve; MPH, mean parental height.
in physical and developmental differences and common medical problems among rasopathies. The most common mutation which is found in more than 80% of CS patients is p.G12S which is associated with the typical and rather homogenous phenotype followed by p.G12A seen in 7% of patients [6, 16]. Rarer mutations have either been associated with fatal forms or milder clinical presentation [15]. Endocrine disorders that have been reported in patients with CS include hypothyroidism, cryptorchidism, hyperprolactinaemia, parathyroid adenoma, hypoglycaemia due to ACTH deficiency or hyperinsulinism or growth hormone deficiency [1,3,4,17]. In the current patient there was documentation of hypothyroidism with low level of T3, T4 and thyroid hypoplasia, cryptorchidism and also a proven growth hormone deficiency. In patients with CS linear growth is slow and results in short stature. Short stature is a common feature in many genetic syndromes, however, only in few of them the underlying cause is known or it has been attributed to growth hormone deficiency. Regarding CS growth hormone
deficiency has been reported in up to 40% of cases [13,17]. On the other hand, growth hormone has been given successfully in non-GH deficient patients like the ones with Turner syndrome and lately with Noonan syndrome. Given the potential risk of malignancy and hypertrophic myocardiopathy in children with CS, along with considering mitogenic action of growth hormone and risk of worsening myocardial hypertrophy, growth hormone replacement treatment is controversial in children with CS [11]. Hypertrophic cardiomyopathy affects twothirds of patients. It is more severe and often lethal in infants and young children. Kobayashi et al. reported a case of worsening cardiomyopathy in a 6-year-old child with CS during growth hormone treatment and raise concerns about its use [12]. However, Lin et al. in a cohort of 61 patients reported no conclusive relationship between growth hormone replacement treatment and hypertrophic cardiomyopathy [14]. Growth hormone treatment could be beneficial in children with CS and growth hormone deficiency however these patients deserve close monitoring. In conclusion, the index patient is a paradigm of successful and safe treatment with growth hormone for almost 7 years. Given the limited
274
P. Triantafyllou et al. / Growth Hormone & IGF Research 24 (2014) 271–275
Fig. 3. Patient's weight curve.
literature on growth hormone deficiency in patients with CS the current case adds useful information on this field. Since patients with CS are at increased risk for cardiac myopathy and tumor development they deserve close monitoring during treatment. Conflict of interest The authors confirm that they do not have any potential conflict of interest. References [1] S. Alexander, D. Ramadan, H. Alkayyat, I. Al Sartawi, K.C. Backer, F. El-Sabban, K. Hussian, Costello syndrome and hyperinsulinemic hypoglycemia, Am. J. Med. Genet. A 139 (2005) 227–230. [2] Y. Aoki, T. Niihori, H. Kawame, K. Kurosawa, H. Ohashi, Y. Tanaka, M. Filocamo, K. Kato, Y. Suzuki, S. Kure, Y. Matsubara, Germline mutations in HRAS proto-oncogene cause Costello syndrome, Nat. Genet. 37 (2005) 1038–1040. [3] M. Cakir, C. Arici, S. Tacoy, U. Karayalcin, A case of Costello with parathyroid adenoma and hyperprolactinemia, Am. J. Med. Genet. A 124A (2004) 196–199.
[4] N. Gregersen, D. Viljohen, Costello syndrome with growth hormone deficiency and hypoglycemia: a new report and review of the endocrine associations, Am. J. Med. Genet. A 129 (2004) 171–175. [5] K.W. Gripp, A.E. Lin, Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations, Genet. Med. 14 (2012) 285–292. [6] K.W. Gripp, A.E. Lin, D.L. Stabley, L. Nicholson, I. Charles, C.I. Scott Jr., D. Doyle, Y. Aoki, Y. Matsubara, E.H. Zackai, P. Lapunzina, A. Gonzalez-Meneses, J. Holbrook, C.A. Agresta, I.L. Gonzalez, K. Sol-Church, HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation, Am. J. Med. Genet. A 140A (2006) 1–7. [7] K.W. Gripp, Tumor predisposition in Costello syndrome, Am. J. Med. Genet. C: Semin. Med. Genet. 137C (2005) 72–77. [8] K.W. Gripp, C.I. Scott, L. Nicholson, D.M. McDonnald-McGinn, J.D. Ozeram, M.C. Jones, A.E. Lin, E.H. Zackai, Five additional Costello syndrome patients with rhabdomyoarcoma: proposal for a tumor screening protocol, Am. J. Med. Genet. 108 (2002) 80–87. [9] R.C.M. Hennekam, Costello syndrome: an overview, Am. J. Med. Genet. C: Semin. Med. Genet. 117C (2003) 42–48. [10] E. Hopkins, D. Doyle, W.B. Dobyns, High incidence of progressive postnatal cerebellar enlargement in Costello Syndrome: brain overgrowth associated with HRAS mutations as the likely cause of structural brain and spinal cord abnormalities, Am. J. Med. Genet. A 152A (2010) 1161–1168. [11] B. Kerr, M.A. Einaudi, P. Clayton, G. Gladman, T. Eden, P. Saunier, D. Genevieve, N. Philip, Is growth hormone treatment beneficial or harmful in Costello syndrome? J. Med. Genet. 40 (6) (2003) e74.
P. Triantafyllou et al. / Growth Hormone & IGF Research 24 (2014) 271–275 [12] D. Kobayashi, A.L. Cook, D.A. Williams, Progressively worsening hypertrophic cardiomyopathy in a child with newly diagnosed Costello syndrome while receiving growth hormone therapy, Cardiol. Young 20 (2010) 459–461. [13] L. Legault, C. Cagnon, Growth hormone deficiency in Costello syndrome: a possible explanation for the short stature, J. Pediatr. 138 (2001) 151–152. [14] A.E. Lin, M.E. Alexander, S.D. Colan, B. Kerr, K.A. Rauen, J. Noonan, J. Baffa, E. Hopkins, K. Sol-Church, G. Limongelli, M.C. Digilio, B. Marino, A.M. Innes, Y. Aoki, M. Silberbach, M.A. Delrue, S.M. White, R.M. Hamilton, W. O'Connor, P.D. Grossfeld, L.B. Smoot, R.F. Padera, K.W. Gripp, Clinical, pathological, and molecular analyses of cardiovascular
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