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The presented 6-year-old girl with Costello syndrome after 30 months of treatment with rhGH. The pictures show typical phenotypic features of the syndrome: loose skin with deep palmar creases (a); abnormal feet position as a result of excessive joint laxity (b)
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Costello syndrome is a rare syndrome of multiple congenital anomalies. The typical clinical traits include dysmorphic craniofacial features, skin hyperpigmentation and excess, feeding difficulties leading to severe postnatal growth retardation, short stature, joint hypermobility, and delayed psychomotor development. Additionally, Costello syndrome...
Context in source publication
Context 1
... the age of 2 years and 9 months Costello syndrome was suspected on the basis of phenotypic traits (large mouth, wide lips, short nasal bridge, loose skin deeply fissured on the palms and soles of the feet, joint laxity, and abnormal feet position, Fig. 1) and case history. The diagnosis was confirmed by molecular tests, which iden- tified c.35G > C (p.G12A) substitution in the HRAS gene, the second most common mutation responsible for Costello syndrome. Molecular studies in both par- ents revealed that this mutation occurred de novo ...
Citations
... Severe feeding problems, usually characterized by food aversion and swallowing difficulties, persist even beyond the first month of life Blachowska et al., 2016;Digilio et al., 2008;Kizilcan Cetin et al., 2020;Nwakalor et al., 2021;Piccione et al., 2009;Pratesi et al., 1998;van Eeghen, van Gelderen, & Hennekam, 1999) up to the second or third year due to the interaction of several possible causes ( Figure 1) (Box 1) (Leoni et al., 2016;Zampino et al., 1993). ...
... Later on in life (4-5 years of age) food aversion and feeding difficulties improve (Blachowska et al., 2016;Kawame et al., 2003) and artificial enteral nutrition in CS is usually discontinued Hiippala et al., 2016;Leoni et al., 2020;Schwartz et al., 2017) with an improvement in the oral-motor abilities (Leoni et al., 2020) (Box 1). ...
Noonan, Costello, and cardio‐facio‐cutaneous syndrome are neurodevelopmental disorders belonging to the RASopathies, a group of syndromes caused by alterations in the RAS/MAPK pathway. They are characterized by similar clinical features, among which feeding difficulties, growth delay, and gastro‐intestinal disorders are frequent, causing pain and discomfort in patients. Hereby, we describe the main nutritional and gastrointestinal issues reported in individuals with RASopathies, specifically in Noonan syndrome, Noonan syndrome‐related disorders, Costello, and cardio‐facio‐cutaneous syndromes. Fifty percent of children with Noonan syndrome may experience feeding difficulties that usually have a spontaneous resolution by the second year of life, especially associated to genes different than PTPN11 and SOS1. More severe manifestations often require artificial enteral nutrition in infancy are observed in Costello syndrome, mostly associated to c.34G>A substitution in the HRAS gene. In cardio‐facio‐cutaneous syndrome feeding issues are usually present (90–100% of cases), especially in individuals carrying variants in BRAF, MAP2K1, and MAP2K2 genes, and artificial enteral intervention, even after scholar age, may be required. Moreover, disorders associated with gastrointestinal dysmotility as gastro‐esophageal reflux and constipation are commonly reported in all the above‐mentioned syndromes. Given the impact on growth and on the quality of life of these patients, early evaluation and prompt personalized management plans are fundamental.
... the increase in serum levels of IGF-1 reflects a higher possibility of cancer development (17). In the literature about rhGH treatment of CS, patients with total GH deficiency responded successfully to rhGH without the development of tumors and cardiac abnormalities (18)(19)(20)(21), whereas those with partial GH deficiency and accompanying endocrinological problems such as hypoglycemia and cortisol deficiency, responded poorly to rhGH therapy (22). Two issues should be considered during the follow-up of rhGH treatment: cardiac hypertrophy and the risk of malignancy development. ...
Costello syndrome (CS) is a rare member of the group of neuro-cardio-facio-cutaneous diseases known as RASopathies. CS involves characteristic dysmorphic craniofacial features, cardiac defects, and increased cancer susceptibility, depending on the heterozygous activating germline mutations in HRAS. Polyhydramnios and high birth weight are the most common presentations in the perinatal and neonatal periods; while poor postnatal growth, short stature, and failure to thrive are significant issues in infancy. Possible mechanisms of short stature in CS include GH deficiency and feeding difficulties. Only a few reported cases of CS with GH deficiency exist in literature. Here, we describe the 5-yr follow-up of a CS patient with complete GH deficiency treated with recombinant human GH (rhGH) from the age of four years. No significant adverse events regarding progression of hypertrophic cardiomyopathy and tumor development were observed. She has been responsive to treatment with improved growth velocity and height standard deviation scores. She is still under continuous monitoring for concerns on the possible development of cardiac events and malignancies. This case indicated that rhGH therapy is effective for improving the height and growth velocity of CS patients with GH deficiency under close cardiac and oncological monitoring.
... Informed consent was obtained from the guardians of the patients (in cases 5 and 6, parents refused to publish photographs of their children). Three patients have previously individually reported by Schulz et al. (2008), Skórka et al. (2012), and Blachowska et al. (2016). ...
... In both cases, treatment led to excellent improvement of the height (− 1.6 SD); however, the echocardiogram performed in patient 2 after 2 years of GH treatment showed HCM. The effects of the GH treatment of patient 2 and patient 6 have been described by Skórka et al. (2012) and Blachowska et al. (2016), respectively. ...
Costello syndrome (CS) is a rare congenital disorder from the group of RASopathies, characterized by a distinctive facial appearance, failure to thrive, cardiac and skin anomalies, intellectual disability, and a predisposition to neoplasia. CS is associated with germline mutations in the proto-oncogene HRAS, a small GTPase from the Ras family. In this study, a molecular and clinical analysis was carried out in eight Polish patients with the Costello phenotype. A molecular test showed two known heterozygous mutations in the first coding exon of the gene in seven patients: p.G12S (n=4) and p.G12A (n=3), and a novel pathogenic variant p.G60V in one child with an unusually severe, lethal course of the syndrome. In addition, a fatal course of CS was present in one patient with the p.G12A mutation and in another with p.G12S, there was a co-occurrence of Turner syndrome because of the distal Xp deletion. A severe clinical manifestation with a lethal outcome in an individual with p.G60V in HRAS and contrary observations of an attenuated phenotype in CS patients with other mutations at glycine-60 residue may suggest that the nature of the substituted amino acid plays a significant role in the clinical variability observed in some CS cases.
Background
Data on dermatological manifestations of Costello syndrome (CS) remain heterogeneous and lack in validated description.
Objectives
To describe the dermatological manifestations of CS; compare them with the literature findings; assess those discriminating CS from other RASopathies, including cardiofaciocutaneous syndrome (CFCS) and the main types of Noonan syndrome (NS); and test for dermatological phenotype–genotype correlations.
Methods
We performed a 10‐year, large, prospective, multicentric, collaborative dermatological and genetic study.
Results
Thirty‐one patients were enrolled. Hair abnormalities were ubiquitous, including wavy or curly hair and excessive eyebrows, respectively in 68% and 56%. Acral excessive skin (AES), papillomas and keratotic papules (PKP), acanthosis nigricans (AN), palmoplantar hyperkeratosis (PPHK) and ‘cobblestone’ papillomatous papules of the upper lip (CPPUL), were noted respectively in 84%, 61%, 65%, 55% and 32%. Excessive eyebrows, PKP, AN, CCPUL and AES best differentiated CS from CFCS and NS. Multiple melanocytic naevi (>50) may constitute a new marker of attenuated CS associated with intragenic duplication in HRAS . Oral acitretin may be highly beneficial for therapeutic management of PPHK. No significant dermatological phenotype–genotype correlation was determined between patients with and without HRAS c.34G>A (p.G12S).
Conclusions and Relevance
This validated phenotypic characterization of a large number of patients with CS will allow future researchers to make a positive diagnosis, and to differentiate CS from CFCS and NS.
De novo germline mutations in HRAS cause Costello syndrome, with >95% of the mutations causing Costello syndrome affecting amino acid position 12 (p.Gly12) or 13 (p.Gly13). We report on a patient with de novo missense mutation causing an amino acid change at codon 146 of HRAS, c.436G > C:p.Ala146Pro, who presented with subtle dysmorphic features, failure to thrive, global developmental delay, and hypertrophic obstructive cardiomyopathy. Mutations affecting codon 146 are observed in <1% of patients with Costello syndrome. From literature search, there were only two other patients reported with mutations involving the same location. We summarized and updated their findings, and discussed evidence to show that these patients with less obvious signs of Costello syndrome may not necessarily run a more benign clinical course.
Introduction: Skeletal dysplasias, also termed as osteochondrodysplasias, are a large heterogeneous group of disorders characterized by abnormalities of bone or cartilage growth or texture. They occur due to genetic mutations and their phenotype continues to evolve throughout life. Reduced growth is a common feature.
Objective: To evaluate and discuss data about growth and growth hormone axis in patients with the main common skeletal dysplasias, such as achondroplasia, hypochondroplasia, 3M syndrome, and Leri-Weill syndrome.
Design: Evaluate retrospectively the data on growth, final height (FH), height velocity (HV), growth hormone deficiency, and growth hormone response after growth hormone (GH) treatment in patients with these disorders. However, this chapter provides an updated picture of growth hormone axis and endocrinological features in skeletal dysplasia.
The growth hormone (GH) is a polypeptide made by 191 amino acids, synthesized by somatotrope cells and stored in the anterior pituitary gland. GH is encoded by GH1 gene situated on the long arm of chromosome 17 at position 24.2 (OMIM *139250), even if this function is regulated by a cluster of five genes strictly related. Mutations or deletions of one of these genes lead to growth hormone deficiency, resulting in short stature.
While researchers make progress in understanding the molecular mechanisms behind these disorders and identify possible therapeutic interventions in patients with skeletal dysplasia, it remains to be identified which treatments may allow a better improvement in stature. For example, for those with achondroplasia and related disorders, fibroblast growth factor receptor 3 (FGFR3) has been identified as a critical regulator of endochondral bone growth, and in these patients mutations in the coding sequence of the FGFR3 gene have been identified [36, 37]. In these patients, several approaches to reduce FGFR3 signalling by blocking receptor activation or inhibiting downstream signals have been proposed, some promising in preclinical animal models and other in humans [38]. In this regard, more data are available on the GH-IGF-1 axis in patients with skeletal dysplasias and genetic syndrome and GH treatment (Table 3). So, in this section of the chapter, we try to critically evaluate the data available on the endocrine characteristics and response to GH treatment of these patients, considering the great diversity of the studies performed as well as length of observation, the sample size and GH dosage used (Table 3).
