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Relevant diseases: - Noonan syndrome - Noonan syndrome plus other features - Cardio-facio-cutaneous syndrome - LEOPARD syndrome - Costello syndrome - Legius syndrome
Inclusion Criteria
- At least 2 of the suggestive clinical features: - Early feeding difficulty/ failure to thrive - Relative macrocephaly - Short stature - Developmental disability - At least 1 of: - Cardiomyopathy - Congenital heart disease - Arrhythmia - Suggestive malignancy ( bladder carcinoma, Rhabdomyosarcoma, Leukaemia, phaeochromocytoma) - Skin abnormalities (hyperkeratosis, cafe au lait patches, ulerythema oophorogenes, keratosis pilaris, excess palmar skin)
Exclusion Criteria
- Low birth weight for gestation
Prior Genetic Testing
- Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing. PLEASE NOTE: The sensitivity of WGS compared to current diagnostic genetic testing has not yet been established. It is therefore important that tests which are clinically indicated under local standard practice continue to be carried out.
Genes
Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - PTPN11, RAF1, BRAF, SOS1, KRAS, HRAS, NRAS, SHOC2, CBL, SPRED1, MAP2K1, MAP2K2
Closing Statement
These requirements will be kept under continual review during the main programme and may be subject to change.
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Increased nuchal translucency
The presence of an abnormally large hypoechoic space in the posterior fetal neck (usually detected on prenatal ultrasound examination). Comment: Increased nuchal translucency may be related to a cystic hygroma or to mesenchymal edema. Increased nuchal translucency can be classified into three categories: 1) cardiac abnormalities, combined with abnormal ductus venosus flow velocities, is found, leading to the theory that cardiac failure causes nuchal translucency enlargement; 2) various types of abnormalities are found in the extracellular matrix of the nuchal skin of fetuses with increased nuchal translucency; 3) abnormal lymphatic development is demonstrated in fetuses with increased nuchal translucency.
Nonimmune hydrops fetalis
A type of hydrops fetalis in which there is no identifiable circulating antibody to red blood cell antigens .
Polyhydramnios
The presence of excess amniotic fluid in the uterus during pregnancy. Comment: Polyhydramnios is diagnosed if the deepest vertical pool of amniotic fluid is more than 8 cm or amniotic fluid index is more than 95th percentile for the corresponding gestational age.
Failure to thrive in infancy
Feeding difficulties
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Pulmonic stenosis
A narrowing of the right ventricular outflow tract that can occur at the pulmonary valve (valvular stenosis) or just below the pulmonary valve (infundibular stenosis). Comment: Infundibular pulmonic stenosis is mostly caused by overgrowth of the heart muscle wall (hypertrophy of the septoparietal trabeculae). Pulmonic stenosis is often seen as a part of Fallot' s tetralogy, in which case the events leading to the formation of the overriding aorta are also believed to be a cause of the pulmonic stenosis. The pulmonic stenosis is the major cause of the malformations seen in patients with Fallot tetralogy, with the other associated malformations acting as compensatory mechanisms to the pulmonic stenosis. The degree of stenosis varies between individuals with TOF, and is the primary determinant of symptoms and severity. This malformation is infrequently described as sub-pulmonary stenosis or subpulmonary obstruction.
Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Abnormality of the atrioventricular valves
An abnormality of an atrioventricular valve.
Atrial septal defect
Atrial septal defect (ASD) is a congenital abnormality of the interatrial septum that enables blood flow between the left and right atria via the interatrial septum.
Ventricular septal defect
A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum.
Arrhythmia
Any cardiac rhythm other than the normal sinus rhythm. Such a rhythm may be either of sinus or ectopic origin and either regular or irregular. An arrhythmia may be due to a disturbance in impulse formation or conduction or both.
Lymphedema
Localized fluid retention and tissue swelling caused by a compromised lymphatic system.
Pleural effusion
The presence of an excessive amount of fluid in the pleural cavity.
Intellectual disability
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70. Comment: This term should be used for children at least five years old. For younger children, consider the term Global developmental delay (HP:0001263).
Specific learning disability
Impairment of certain skills such as reading or writing, coordination, self-control, or attention that interfere with the ability to learn. The impairment is not related to a global deficiency of intelligence. Comment: The term learning disability is used with different meanings in different contexts. Significant impairments of mental functioning with a reduction in IQ below 70 should be coded as mental retardation.
Delayed gross motor development
A type of motor delay characterized by an delay in acquiring the ability to control the large muscles of the body for walking, running, sitting, and crawling.
Delayed speech and language development
A degree of language development that is significantly below the norm for a child of a specified age. Comment: Language delay can be characterized by a failure to meet the developmental milestones for language development, an inability to follow directions, or slow or incomprehensible speech after the age of three years, as well as with severe problems with syntax or articulation.
Abnormality of the kidney
An abnormality of the kidney. Comment: The kidney is a paired organ whose primary function is the production of urine.
Delayed puberty
Passing the age when puberty normally occurs with no physical or hormonal signs of the onset of puberty. Comment: The age at which delayed puberty may be diagnosed in a person without signs of secondary sexual development is 13 years in a girl or 14 years in a boy.
Cryptorchidism
Testis in inguinal canal. That is, absence of one or both testes from the scrotum owing to failure of the testis or testes to descend through the inguinal canal to the testis. Comment: The gonad is mobile and can be retracted superiorly by the cremaster muscle reflex stimulated, for instance, by cold or touch. A retracted testis is not cryptorchidism. An abdominal testis cannot be distinguished by physical examination from an (Apparently) absent testis and requires radiological (or, rarely, surgical) procedures for assessment.
Decreased fertility
Abnormality of hair texture
An abnormality of the texture of the hair.
Follicular hyperkeratosis
A skin condition characterized by excessive development of keratin in hair follicles, resulting in rough, cone-shaped, elevated papules resulting from closure of hair follicles with a white plug of sebum.
Cafe-au-lait spot
Cafe-au-lait spots are hyperpigmented lesions that can vary in color from light brown to dark brown with smooth borders and having a size of 1.5 cm or more in adults and 0.5 cm or more in children. Comment: The phrase cafe-au-lait comes from the French word for milk-coffee. A single cafe-au-lait spot can be an isolated finding in otherwise normal individuals. Multiple cafe-au-lait spots often indicate the presence of neurofibromatosis type 1 but may also be seen in other diseases including McCune-Albright syndrome, tuberous sclerosis, and Fanconi anemia.
Multiple lentigines
Presence of an unusually high number of lentigines (singular: lentigo), which are flat, tan to brown oval spots. Comment: Lentigines are commonly (but not always) due to chronic sun exposure (solar lentigines; sometimes called liver spots) and occur most frequently on the face and back of the hands.
Hemangioma
A hemangioma is a benign tumor characterized by blood-filled spaces lined by benign endothelial cells. A hemangioma characterized by large endothelial spaces (caverns) is called a cavernous hemangioma (in contrast to a hemangioma with small endothelial spaces, which is called capillary hemangioma).
Papilloma
A tumor of the skin or mucous membrane with finger-like projections. Comment: The vast majority of papillomas are benign. Papillomas on the skin (cutaneous papillomas) are commonly referred to as warts.
Pectus carinatum
A deformity of the chest caused by overgrowth of the ribs and characterized by protrusion of the sternum.
Pectus excavatum
A defect of the chest wall characterized by a depression of the sternum, giving the chest ("pectus") a caved-in ("excavatum") appearance.
Wide intermamillary distance
A larger than usual distance between the left and right nipple.
Webbed neck
Pterygium colli is a congenital skin fold that runs along the sides of the neck down to the shoulders. It involves an ectopic fibrotic facial band superficial to the trapezius muscle. Excess hair-bearing skin is also present and extends down the cervical region well beyond the normal hairline.
Abnormality of the coagulation cascade
An abnormality of the coagulation cascade, which is comprised of the contact activation pathway (also known as the intrinsic pathway) and the tissue factor pathway (also known as the extrinsic pathway) as well as cofactors and regulators.
Abnormality of thrombocytes
An abnormality of platelets. Comment: Platelets, also known as thrombocytes, are non-nucleated disk-shaped cells mainly involved in blood coagulation.
Neoplasm
An organ or organ-system abnormality that consists of uncontrolled autonomous cell-proliferation which can occur in any part of the body as a benign or malignant neoplasm (tumour). Comment: The World Health Organization (WHO) classifies neoplasms into four main groups: (i) benign neoplasm, (ii) in situ neoplasm, (iii) malignant neoplasm, and (iv) neoplasm of uncertain or unknown behavior. A malignant neoplasm is also known as cancer.
Immunodeficiency
Autoimmunity
The occurrence of an immune reaction against the organism's own cells or tissues.
Abnormality of brain morphology
A structural abnormality of the brain, which has as its parts the forebrain, midbrain, and hindbrain.
Seizures
Seizures are an intermittent abnormality of the central nervous system due to a sudden, excessive, disorderly discharge of cerebral neurons and characterized clinically by some combination of disturbance of sensation, loss of consciousness, impairment of psychic function, or convulsive movements. The term epilepsy is used to describe chronic, recurrent seizures. Comment: The term epilepsy is not used to describe recurrent febrile seizures. Epilepsy presumably reflects an abnormally reduced seizure threshold.
Autism
Autism is a neurodevelopmental disorder characterized by impaired social interaction and communication, and by restricted and repetitive behavior. Autism begins in childhood. It is marked by the presence of markedly abnormal or impaired development in social interaction and communication and a markedly restricted repertoire of activity and interest. Manifestations of the disorder vary greatly depending on the developmental level and chronological age of the individual (DSM-IV). Comment: The term refers to the diagnosis of autism and is left for convenience. However, it is preferable to annotate the exact phenotypic abnormalities rather than merely the diagnostic category autism.
Depression
A condition characterized by pervasive dysphoric mood, loss of interests, and inability to experience pleasure.
Schizophrenia
A mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social or occupational dysfunction. The onset of symptoms typically occurs in young adulthood, with a global lifetime prevalence of about 0.3-0.7%. Comment: Positive symptoms, such as delusions and hallucinations (especially of voices), are common, and any Schneiderian first-rank symptoms are particularly indicative of the illness. Negative symptoms include social withdrawal, impairment of ego boundaries, and loss of energy and initiative. Schizophrenia is diagnosed only if symptoms persist for at least one month. The illness can spontaneously remit, run a course with infrequent or frequent relapses, or become chronic. The prognosis has improved with antipsychotic drugs and with vigorous psychological and social management and rehabilitation. The many causes include genetic factors, environmental stress, and various triggering factors.
Ptosis
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Abnormality of refraction
An abnormality in the process of focusing of light by the eye in order to produce a sharp image on the retina.
Strabismus
Strabismus (also known as squint) is a condition in which the eyes are not properly aligned with each other.
Hearing abnormality
An abnormality of the sensory perception of sound. Comment: According to the World Health Organization, deafness refers to the complete loss of hearing ability in one or two ears. Hearing impairment refers to both complete and partial loss of the ability to hear.
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- Intelligence Quotient Assessment
- Additional body measurements
- General Imaging Diagnostics
General imaging diagnostics report to capture reports that aren't included in the specific subclasses. Inherits all the elements in the abstract Imaging Diagnostics class and the abstract Investigation Class.