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.
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 . 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 . There is also an increased incidence of pyloric stenosis . 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 .
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 . 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.
Entire Body System
- Sparse Hair
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]
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]
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]
- 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]
Face, Head & Neck
- 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]
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]
Distinctive facial feature such as a broad mouth with thick lips, loose folds of extra skin (especially on the hands and feet), and unusually flexible joints. Remarkably pleasant, social, and easy-going personality. [costellosyndromeusa.com]
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
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]
- Short Neck
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]
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 . In some cases, craniofacial abnormalities may be observable on ultrasound . 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  .
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Lo IF, Brewer C, Shannon N. Severe neonatal manifestations of Costello syndrome. J Med Genet. 2008;45(3):167-171.