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Costello Syndrome

FCS Syndrome

Costello syndrome (CS) is a rare condition that presents with characteristic facies and affects multiple organ systems. It typically causes growth delay, mental impairment and failure to thrive in infants. Cardiac, neurological and musculoskeletal anomalies are also frequent.


Presentation

Costello syndrome (CS) is a genetic disease inherited through an autosomal dominant pattern. It is a rare condition caused by mutations in the KRAS gene (Kirsten rat sarcoma viral oncogene homolog) that results in a number of congenital abnormalities [1]. Cardiofaciocutaneous (CFC) syndrome has a similar genetic etiology and presents with significant phenotypical overlap with CS.

Children born with CS are usually macrosomic. In contrast, the neonatal period is characterized by failure to thrive, feeding difficulties, and eventually weight loss. Because of this, they may look marasmic and become irritable. Further challenges in infants involve hypotonia which varies in severity, nystagmus, and visual difficulties [2]. There is also an increased incidence of pyloric stenosis [3]. During development, there is usually mental impairment, growth retardation, as well as delayed puberty. Symptoms of CS are progressive, and older individuals may experience accelerated aging.

The clinical appearance of CS is coarse facies, which include a large mouth, low set ears, epicanthal folds, and upwards facing noses as well as macrocephaly. This is often accompanied by soft skin, fine, sparse hair, and facial warts [4].

Musculoskeletal complaints constitute lax joints, hip dysplasia, malformations of the hands and spine, and tight Achilles tendons in later childhood. Osteoporosis and osteopenia may be observed thereafter. Individuals with CS may also exhibit cardiac anomalies. These are a frequent feature of CS, with up to 87% of individuals with the condition reported to have cardiovascular malformations [5]. Lesions described in the literature are pulmonary stenosis, enlargement of ventricles, cardiomyopathy, and various arrhythmias. The central nervous system is also affected, producing phenomena such as Arnold-Chiari malformation type I, hydrocephalus, tethering and formation of fluid-filled cysts in the spinal cord, as well as the occurrence of seizures. Additionally, those with CS show a predisposition to certain tumors, namely, neuroblastoma, embryonal rhabdomyosarcoma, and transitional cell carcinoma.

Short Stature
  • Costello syndrome is characterized by facial dysmorphia, hyperpigmented skin, palmar and plantar hyperkeratosis, curly hair, perioral and nasal papillomata (more rarely localized anally and on vocal cords), short stature, mental retardation and sociable[ncbi.nlm.nih.gov]
  • Fewer individuals with p.G13C had short stature (height below -2 SD) without use of growth hormone (P 0.001). The noteworthy absence of malignant tumors did not reach statistical significance.[ncbi.nlm.nih.gov]
  • It affects multiple organ systems and includes severe failure-to-thrive, short stature, and macrocephaly. The goal of this study was to develop Costello syndrome-specific growth curves.[ncbi.nlm.nih.gov]
  • Costello syndrome (CS) was described in 1977 by Costello who reported two unrelated children with a new syndrome comprising short stature, redundant skin of the neck, palms, soles, and fingers, curly hair, papillomata around the mouth and nares, and mental[ncbi.nlm.nih.gov]
  • This congenital disorder is characterised by multiple congenital abnormalities, such as psychomotor retardation, short stature, redundant skin, papillomata, curly hair, relative macroencephaly, distinctive face and various defects of internal organs.[ncbi.nlm.nih.gov]
Barrel Chest
  • Both had relative macrocephaly at birth, curly hair, large ear lobes, epicanthic folds, a low nasal bridge, thick lips, a short and wide nose, a short neck, a barrel chest, redundant skin, tight Achilles tendons, and pes equinovarus.[link.springer.com]
Hypertrophic Pyloric Stenosis
  • Thus we add hypertrophic pyloric stenosis to the abnormalities seen with increased frequency in Costello syndrome.[ncbi.nlm.nih.gov]
Sparse Hair
  • Cutaneous manifestations are: loose skin of the hands and feet "washer woman's hand", hyperkeratosis palmoplantaris, curly or sparse hair, acanthosis nigricans, papillomata nasi.[ncbi.nlm.nih.gov]
  • The facial and hair abnormalities of the HRAS p.Gly13Asp individuals differ from the typical pattern observed in those showing the common HRAS (p.Gly12Ser) mutation, with less coarse facial features and slow growing, sparse hair with abnormal texture,[ncbi.nlm.nih.gov]
  • This is often accompanied by soft skin, fine, sparse hair, and facial warts. Musculoskeletal complaints constitute lax joints, hip dysplasia, malformations of the hands and spine, and tight Achilles tendons in later childhood.[symptoma.com]
  • Affected children show characteristic symptoms such as specific craniofacial and musculosceletal features, curly or sparse hair; loose, soft skin, increased pigmentation, diffuse hypotonia, macrocephaly and cardiac diseases, short stature as well as intellectual[notube.com]
Increased Birth Weight
  • The patient presented with the typical clinical findings of Costello syndrome such as increased birth weight, severe failure to thrive, characteristic facial appearance, and skin abnormalities.[ncbi.nlm.nih.gov]
  • Cardiac hypertrophy has not been reported, but fetal atrial tachycardia has been detected in at least five fetuses subsequently diagnosed with Costello syndrome, and it increases the index of suspicion for this diagnosis. 26 Increased birth weight and[nature.com]
Thick Lips
  • Ultrasonographic morphological fetal face analysis found abnormal thickness of the skin in the prefrontal area, thick dysplastic ears, thick lips and deep-set creases in the hands and feet.[ncbi.nlm.nih.gov]
  • lips, thick lobes, ears set low and large head), mental retardation, dry and thick leg, arm, feet and hand skin, and excessively flexible finger joints.[ic.steadyhealth.com]
  • Both had relative macrocephaly at birth, curly hair, large ear lobes, epicanthic folds, a low nasal bridge, thick lips, a short and wide nose, a short neck, a barrel chest, redundant skin, tight Achilles tendons, and pes equinovarus.[link.springer.com]
  • Major Features Dysphagia / Feeding difficulty / Gastrostomy tube (g-tube) (95%) Postnatal short stature (97%) Characteristic facial features (98%) Thick lips (95%) Loose skin (94%) Abnormal palmar skin creases (99%) DD (developmental delay) / MR (mental[web.archive.org]
  • lips, and/or wide nostrils Mental retardation Thickened, dry skin on the hands and feet or arms and legs (hyperkeratosis) Abnormally flexible joints of the fingers.[verywellhealth.com]
Coarse Face
  • Costello syndrome is a multiple congenital anomaly and mental retardation syndrome characterized by coarse face, loose skin, cardiomyopathy and predisposition to tumors.[ncbi.nlm.nih.gov]
  • We describe a 34-year-old woman with mental retardation, short stature, macrocephaly, a "coarse" face, hoarse voice, and redundant skin with deep palmar and plantar creases who had evident Costello syndrome.[ncbi.nlm.nih.gov]
  • Costello syndrome (CS) is a rare multiple congenital anomaly/mental retardation syndrome characterized by coarse face, loose skin and cardiomyopathy. It is often associated with benign and malignant tumors.[ncbi.nlm.nih.gov]
  • We describe a girl with motor and mental retardation, macrocephaly, a "coarse" face, choanal atresia, postnatal feeding difficulty, redundant skin with deep palmar and plantar creases, and histopathological evidence of altered elastic fibers, who died[ncbi.nlm.nih.gov]
  • A 2-year-old Japanese boy presented with a 'coarse' face, curly hair and loose skin of the dorsal aspect of the hands and feet with dark pigmentation.[ncbi.nlm.nih.gov]
Short Neck
  • His clinical findings were sparse, thin, and light-colored hair, bilateral ptosis, low-set ears, depressed nasal bridge, bulbous nose, short neck, loose pigmented skin with deep palmar and plantar creases, bilateral cryptorchidism, and delays in growth[ncbi.nlm.nih.gov]
  • Of primary concern to anaesthesiologists are potential airway difficulties related a short neck, macroglossia, hypertrophied tonsillar and supraglottic tissues, laryngeal papillomata and choanal atresia.[ncbi.nlm.nih.gov]
  • Both had relative macrocephaly at birth, curly hair, large ear lobes, epicanthic folds, a low nasal bridge, thick lips, a short and wide nose, a short neck, a barrel chest, redundant skin, tight Achilles tendons, and pes equinovarus.[link.springer.com]
  • neck Costello syndrome is an autosomal dominant disorder.[forgottendiseases.org]
Secondary Amenorrhea
  • In addition to the classic features, the patient had endocrine disturbances including secondary amenorrhea, goiter, and adrenal insufficiency. This last abnormality may be the cause of the hypoglycemic episodes seen in CS.[ncbi.nlm.nih.gov]

Workup

Costello syndrome can be diagnosed clinically, provided there are multiple features suggestive of the condition. Molecular genetic testing is carried out in order to make a definitive diagnosis. Amniocentesis may be carried out during pregnancy, to enable prenatal genetic analysis.

Moreover, before birth, ultrasound is instrumental in the diagnostic process, as there are certain features that are made visible with this technique. These entail fetal macrosomia, polyhydramnios, and macrocephaly, which may lead to the suspicion of maternal diabetes [6]. In some cases, craniofacial abnormalities may be observable on ultrasound [7]. It is estimated that about 40% of children with CS are delivered prematurely. Furthermore, most of these infants are born with birth weights above the 90th percentile for the average newborn. Severe forms of the disease can lead to early neonatal death [7] [8].

Shortened Long Bone
  • Less frequent were nuchal thickening, ascites, shortened long bones, abnormal hand posture, ventriculomegaly, macrosomia, and macrocephaly.[ncbi.nlm.nih.gov]

Treatment

  • 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.[ncbi.nlm.nih.gov]
  • In addition, thickening of the aortic valve was also rescued by captopril treatment, although 24 weeks of treatment time were needed (Figure 7, G–L).[doi.org]
  • There have been no detailed reports of severe spinal deformities requiring surgical treatment as a complication of Costello syndrome. We report a case of a 10-year-old girl with progressive scoliosis associated with Costello syndrome.[ncbi.nlm.nih.gov]
  • The possibility of growth hormone (GH) treatment can be considered in cases of documented GH deficiency in patients with Costello syndrome, but only under close oncologic and cardiologic supervision.[ncbi.nlm.nih.gov]
  • These additional features improve phenotype delineation in individuals with rare HRAS mutations, facilitating the development of specific behavioral treatments which could lead to improvement in cases of autism spectrum disorder.[ncbi.nlm.nih.gov]

Prognosis

  • Clinical management should be informed by knowledge of the poor prognosis of this condition.[ncbi.nlm.nih.gov]
  • This case provides new information on the endocrine features and prognosis of CS.[ncbi.nlm.nih.gov]
  • In order to assess the prevalence, natural history, prognosis, and tumor incidence associated with these diseases, we conducted a nationwide prevalence study of patients with Costello and CFC syndromes in Japan.[ncbi.nlm.nih.gov]
  • Prognosis The risk of neoplasia and severe hypertrophic cardiomyopathy negatively affects the prognosis. The prognosis varies by the specific missense mutations, with neonatal lethal phenotypes and attenuated phenotypes reported.[orpha.net]

Etiology

  • Although the cause is currently unknown, Costello syndrome is interesting because of a potential genetic-metabolic etiology.[ncbi.nlm.nih.gov]
  • Costello syndrome is a rare but increasingly recognized syndrome of unknown etiology. Neurological abnormalities are not rare in this syndrome and consist of structural and electrophysiological disorders.[ncbi.nlm.nih.gov]
  • Our hope is that these data will potentially add to our knowledge of the etiology of both Costello syndrome and Chiari I malformation and potentially aid in the definition of a genetic locus for both entities.[ncbi.nlm.nih.gov]
  • These mice should help in elucidating the etiology of CS symptoms, identifying additional defects, and evaluating potential therapeutic strategies.[ncbi.nlm.nih.gov]
  • Cardiofaciocutaneous (CFC) syndrome has a similar genetic etiology and presents with significant phenotypical overlap with CS. Children born with CS are usually macrosomic.[symptoma.com]

Epidemiology

  • This is the first epidemiological study of Costello syndrome and CFC syndrome.[ncbi.nlm.nih.gov]
  • Summary Epidemiology The estimated number of patients worldwide is 300. Estimated birth prevalence has been reported to be 1/300,000 to 1/1.25 million.[orpha.net]
  • Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan: findings from a nationwide epidemiological survey. Am J Med Genet A. 2012 May;158A(5):1083-94. doi: 10.1002/ajmg.a.35292. Epub 2012 Apr 11.[ghr.nlm.nih.gov]
  • Summary Epidemiology The prevalence and incidence of Donnai-Barrow syndrome (DBS) are difficult to estimate. Fewer than 50 individuals from about 20 families have been reported.[orpha.net]
Sex distribution
Age distribution

Pathophysiology

  • We review the pathophysiology of Costello syndrome and highlight the recent recommendations of tumor screening and cardiac surveillance in this population, of particular relevance to those receiving GH therapy.[ncbi.nlm.nih.gov]
  • Abnormal hand posture has been reported as a typical feature of Costello Syndrome but the pathophysiology of this is unclear.[ncbi.nlm.nih.gov]
  • The pathophysiology for the catecholamine metabolite abnormality in these patients with Costello syndrome remains unclear.[ncbi.nlm.nih.gov]

Prevention

  • Treatment with captopril, an inhibitor of Ang II biosynthesis, prevented development of the hypertension condition, vascular remodeling, and heart and kidney fibrosis. In addition, it partially alleviated the observed cardiomyopathies.[ncbi.nlm.nih.gov]
  • These mice represent the first mouse model for CS, offering an experimental tool to study the molecular and physiological alterations underlying the neurological manifestations of CS and to test new therapies aimed at preventing or ameliorating the cognitive[ncbi.nlm.nih.gov]
  • The significant decrease in BMD and low levels of vitamin D documented in the present cohort, along with the risk for pathologic fractures reported in adult individuals with CS, testifies the requirement for a preventive treatment to alleviate evolutive[ncbi.nlm.nih.gov]
  • Children require enhanced preventive dental care and frequent visits to the dentist. In certain cases and to prevent possible problems, antibiotics can be given to people with heart defects prior to dental treatment which may cause bleeding.[socialstyrelsen.se]

References

Article

  1. Zenker M, Lehmann K, Schulz AL, et al. Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Med Genet. 2007;44(2):131-135.
  2. van der Burgt I, Kupsky W, Stassou S, et al. Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive HRas activation. J Med Genet. 2007;44(7):459-462.
  3. Gripp KW, Innes AM, Axelrad ME, et al. Costello syndrome associated with novel germline HRAS mutations: an attenuated phenotype? Am J Med Genet A. 2008;146A(6):683-690.
  4. Kerr B, Delrue M, Sigaudy S, et al. Genotype‐phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006;43(5):401-405.
  5. Lin AE, Alexander ME, Colan SD, et al. Clinical, pathological and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK Pathway syndrome. Am J Med Genet A. 2006;140(1):1-7.
  6. Smith LP, Podraza J, Proud VK. Polyhydramnios, fetal overgrowth, and macrocephaly: prenatal ultrasound findings of Costello syndrome. Am J Med Genet A. 2009;149A(4):779-784.
  7. Kuniba H, Pooh RK, Sasaki K. Prenatal diagnosis of Costello syndrome using 3D ultrasonography amniocentesis confirmation of the rare HRAS mutation G12D. Am J Med Genet A. 2009;149A(4):785-787.
  8. Lo IF, Brewer C, Shannon N. Severe neonatal manifestations of Costello syndrome. J Med Genet. 2008;45(3):167-171.

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Last updated: 2019-07-11 21:33