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

  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. [unboundmedicine.com]

  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]

  […] fibromata Breast papilloma Hyperkeratosis, hyperpigmentation Short stature Skeletal and orthopedic problems DD (developmental delay) MR (mental retardation) [web.archive.org]

• Pneumonia

  Most conspicuous was the depositing of abnormal collagen and elastic fibres and the development of endogenous lipid pneumonia. [ncbi.nlm.nih.gov]

  Continuous aspiration of lipids, virus pneumonia and malignancy were excluded. [erj.ersjournals.com]

  Treatment Infants born with Jarcho-Levin syndrome have difficulty breathing due to their small, malformed chests, and therefore are prone to repeated respiratory infections ( pneumonia ). [verywellhealth.com]

  Cardiac problems, failure to thrive, and pneumonia are the main reasons for early death. [accessanesthesiology.mhmedical.com]

• Barrel Chest

  chest, pectus excavatum/ carinatum, scoliosis, broad hands and feet, limited extension in elbow and wrist, pes equinovarus, subluxation of hip and elbow, osteoporosis), the skin (redundant skin on hands and feet leading to deep palmar and plantar creases [accessanesthesiology.mhmedical.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]

• Gingival Hypertrophy

  All four patients showed true/relative macrocephaly with facial bone hypoplasia and gingival hypertrophy. Occlusal attrition, malocclusion, small dental arches, microdontia, and convex face were noted in three patients. [ncbi.nlm.nih.gov]

  Mucosa An oral examination for gingival hypertrophy and mucocutaneous lip papules is important, as these are both distinct features of Costello syndrome. [dermnetnz.org]

• 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]

  Respiratory distress immediately after birth has been reported in a few patients. Characteristically, patients are born with increased birth weight and macrocephaly, which is followed by postnatal growth retardation and failure to thrive. [accessanesthesiology.mhmedical.com]

  Her father was 34 years old at his birth. The parents were healthy and alert. Birth weight was 4300 gr and Apgar score was low because of that he had been admitted with respiratory distress over 1 week in hospital. [amhsr.org]

  Although it may be classified as an "overgrowth" syndrome due to slightly increased birth weight and relative macrocephaly, it is characterized by severe postnatal failure to thrive and short stature. [cancerindex.org]

• Hyperkeratosis

  A chaotic atrial tachyarrhythmia, hypertrophic cardiomyopathy, papillomatosis and hyperkeratosis, and fuller eyebrows and curly hair are more common in Costello syndrome than in Noonan syndrome cardio-facio-cutaneous syndrome. [dermnetnz.org]

  A skin biopsy of the dorsal aspect of the left hand revealed hyperkeratosis and papillomatosis of the epidermis, hyperpigmentation of the basal layer, and shortening and rupture of elastic fibers of the dermis. [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]

  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]

• Kinky Hair

  Hair Changes to the hair in Costello syndrome can include: Hair that may be blonde or pigmented, but different in type from that of other family members Thin and kinky hair with tight curls that give a frizzy ‘cloud of curls’ appearance Thick eyebrows [dermnetnz.org]

  Infants are usually born at term and have normal birth length and weight, but this is followed by postnatal growth failure resulting in short stature. [2],[3] They have a distinctive coarse face with relative macrocephaly, fine, sparse, curly, kinky hair [ijdvl.com]

• Papule

  Skin lesions: Facial and perianal localized skin-coloured, wart-like papules and plaques, diffuse palmo-plantar hyperkeratosis with rhagades on the heels, hyperhidrosis palmaris et plantaris; hyperpigmented rough, hyperkeratotic plaques on the back of [altmeyers.org]

  Mucosa An oral examination for gingival hypertrophy and mucocutaneous lip papules is important, as these are both distinct features of Costello syndrome. [dermnetnz.org]

• 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]

  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]

  The characteristic facial profile includes low set ears, thick lips, macrocephaly, depressed nasal bridge and widening of nostrils. Pathology HRAS gene mutation is reported in almost all cases of costello syndrome. [radiopaedia.org]

  This period is called the marasmic phase, which is followed by the pseudo-thesaurismotic phase that is characterized by a storage disease-like picture with macrocephaly, full cheeks, large mouth with thick lips, macroglossia, and gingival hyperplasia. [accessanesthesiology.mhmedical.com]

  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]

• Coarse Face

  Costello syndrome is a mental retardation syndrome characterized by high birth weight, postnatal growth retardation, coarse face, loose skin, cardiovascular problems, and tumor predisposition. [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]

  […] with bulbous nose and anteverted nostrils, full cheeks, micrognathia, retrognathia, large mouth with macroglossia, high arched palate, bifid uvula, abnormal teeth, short neck), the skeleton (short stature with adult height between 118 and 148 cm, barrel [accessanesthesiology.mhmedical.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]

• Global Developmental Delay

  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 [ncbi.nlm.nih.gov]

  The patient has a mild ventriculomegaly and moderate global developmental delay. Unilateral strabismus (esotropia) of the right eye was noted. [nature.com]

  Independent walking was acquired at the age of three years, after Achilles tendons resection; global developmental delay was delineated with particular impairment of gross motor and fine motor abilities. [mdpi.com]

  He had failure to thrive and moderate global developmental delay. Brain MRI at 9 months showed an arachnoid cyst at the left posterior cranial fossa. [fdna.health]

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].

• Hypoglycemia

  Hypoglycemia has been documented due to growth hormone and cortisol deficiency. We report on two patients with Costello syndrome and persistent hyperinsulinemic hypoglycemia and review the endocrine manifestations of Costello syndrome. [ncbi.nlm.nih.gov]

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]

Treatment and Management Treatment There is no “cure” for Costello syndrome, but there are treatments and therapies. Each treatment plan is tailored to the patient, based on their medical issues. [cincinnatichildrens.org]

Fig. 1 The presented 6-year-old girl with Costello syndrome after 30 months of treatment with rhGH. [ijponline.biomedcentral.com]

Clinical management should be informed by knowledge of the poor prognosis of this condition. [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]

Although the cause is currently unknown, Costello syndrome is interesting because of a potential genetic-metabolic etiology. [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]

This is the first epidemiological study of Costello syndrome and CFC syndrome. [ncbi.nlm.nih.gov]

You might also be interested in Internal medicine Occurrence/Epidemiology This section has been translated automatically. m:w=1:1; so far less than 300 cases have been described worldwide. [altmeyers.org]

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]

Miller was Chief of the Epidemiology Branch at the National Cancer Institute in Bethesda, MD from 1961-1976, and Chief of the Institute’s Clinical Epidemiology Branch from 1976-1994. [sarcomahelp.org]

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]

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]

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]

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.