Rapid and unexpected death.

Lack of the ability to control the urinary bladder leading to involuntary urination at an age where control of the bladder should already be possible.

Abnormally high level of calcium in the urine.

Nephrocalcinosis is the deposition of calcium salts in renal parenchyma.

Abnormal narrowing of the urethra.

Vesicoureteral reflux (VUR) is characterized by the reflux of urine from the bladder into the ureters and sometimes into the kidneys. It is a risk factor for urinary tract infections. Primary VUR results from a developmental defect of the ureterovesical junction (UVJ). In combination with intrarenal reflux, the resulting inflammatory reaction may result in renal injury or scarring, also called reflux nephropathy (RN). Extensive renal scarring impairs renal function and may predispose patients to hypertension, proteinuria, and renal insufficiency (summary by Lu et al., 2007). Genetic Heterogeneity of Vesicoureteral Reflux A locus designated VUR1 maps to chromosome 1p13. VUR2 (610878) is caused by mutation in the ROBO2 gene (602431) on chromosome 3p12; VUR3 (613674) is caused by mutation in the SOX17 gene (610928) on chromosome 8q11; VUR4 (614317) maps to chromosome 5; VUR5 (614318) maps to chromosome 13; VUR6 (614319) maps to chromosome 18; VUR7 (615390) maps to chromosome 12; and VUR8 (615963) is caused by mutation in the TNXB gene (600985) on chromosome 6p21. A possible X-linked form has been reported (VURX; 314550).

Diverticulum (sac or pouch) in the wall of the urinary bladder.

A developmental defect in which a kidney is located in an abnormal anatomic position within the pelvis.

Repeated infections of the urinary tract.

Hypoplasia of the kidney.

A reduction in the level of performance of the kidneys in areas of function comprising the concentration of urine, removal of wastes, the maintenance of electrolyte balance, homeostasis of blood pressure, and calcium metabolism.

Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.

Any structural anomaly of the kidney.

Lateral deviation of the great toe (i.e., in the direction of the little toe).

Clinodactyly refers to a bending or curvature of the fifth finger in the radial direction (i.e., towards the 4th finger).

Supravalvular aortic stenosis (SVAS) is a heart defect that develops before birth. This defect is a narrowing (stenosis) of the large blood vessel that carries blood from the heart to the rest of the body (the aorta). The condition is described as supravalvular because the section of the aorta that is narrowed is located just above the valve that connects the aorta with the heart (the aortic valve). Some people with SVAS also have defects in other blood vessels, most commonly stenosis of the artery from the heart to the lungs (the pulmonary artery). An abnormal heart sound during a heartbeat (heart murmur) can often be heard during a chest exam. If SVAS is not treated, the aortic narrowing can lead to shortness of breath, chest pain, and ultimately heart failure.\n\nThe severity of SVAS varies considerably, even among family members. Some affected individuals die in infancy, while others never experience symptoms of the disorder.

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.

A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum.

The presence of chronic increased pressure in the systemic arterial system.

Increased pressure in the portal vein.

An abnormality of the mitral valve characterized by insufficiency or incompetence of the mitral valve resulting in retrograde leaking of blood through the mitral valve upon ventricular contraction.

One or both of the leaflets (cusps) of the mitral valve bulges back into the left atrium upon contraction of the left ventricle.

The presence of stenosis of the renal artery.

Sudden impairment of blood flow to a part of the brain due to occlusion or rupture of an artery to the brain.

Bicuspid, or bicommissural, aortic valve (BAV) describes an aortic valve with 2 rather than 3 leaflets (Cripe et al., 2004). In 1 to 2% of the population a bicuspid aortic valve is present. Bicuspid aortic valve is frequently an antecedent to aortic valve stenosis or insufficiency. In extreme cases the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome (241550) (Garg et al., 2005). The valve calcification often observed in bicuspid aortic valve is a result of inappropriate activation of osteoblast-specific gene expression. Mutations in the signaling and transcription regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in nonsyndromic autosomal dominant human pedigrees. Genetic Heterogeneity of Aortic Valve Disease Also see AOVD2 (614823), caused by mutation in the SMAD6 gene (602931) on chromosome 15q22, and AOVD3 (618496), caused by mutation in the ROBO4 gene (607528) on chromosome 11q24. There is evidence for additional genetic heterogeneity (see MAPPING).

Abnormal narrowing of the coronary artery.

Myxomatous mitral valve is defined as the presence of excess leaflet tissue and leaflet thickening greater than 5 mm, resulting in a prolapse greater than 2 mm into the left atrium on parasternal long axis view.

Stenosis of a peripheral branch of the pulmonary artery.

A narrowing of the right ventricular outflow tract that can occur at the pulmonary valve (valvular stenosis), below the pulmonary valve (infundibular stenosis), or above the pulmonary valve (supravalvar stenosis).

An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.

Accumulation of substantial excess body fat.

A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).

Infrequent or difficult evacuation of feces.

The presence of multiple diverticula of the colon.

Protrusion of the rectal mucous membrane through the anus.

Constipation for longer than three months with fewer than 3 bowel movements per week, straining, lumpy or hard stools, and a sensation of anorectal obstruction or incomplete defecation.

Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.

A condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter.

A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.

Increased volume of the earlobe, that is, abnormally prominent ear lobules.

Intense feelings of nervousness, tenseness, or panic, often in reaction to interpersonal stresses; worry about the negative effects of past unpleasant experiences and future negative possibilities; feeling fearful, apprehensive, or threatened by uncertainty; fears of falling apart or losing control.

Over-sensitivity to certain frequency ranges of sound.

An abnormality of sleep including such phenomena as 1) insomnia/hypersomnia, 2) non-restorative sleep, 3) sleep schedule disorder, 4) excessive daytime somnolence, 5) sleep apnea, and 6) restlessness.

Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.

An abnormality of mental functioning including various affective, behavioural, cognitive and perceptual abnormalities.

Reduced attention span characterized by distractibility and impulsivity but not necessarily satisfying the diagnostic criteria for attention deficit hyperactivity disorder.

Cerebellar hypoplasia is a descriptive term implying a cerebellum with a reduced volume, but a normal shape and is stable over time.

Arnold-Chiari type I malformation refers to a relatively mild degree of herniation of the posteroinferior region of the cerebellum (the cerebellar tonsils) into the cervical canal with little or no displacement of the fourth ventricle. It is characterized by one or both pointed (not rounded) cerebellar tonsils that project 5 mm below the foramen magnum, measured by a line drawn from the basion to the opisthion (McRae Line)

An abnormally heightened sensitivity to loud sounds.

Attention deficit-hyperactivity disorder (ADHD) is the most common childhood-onset behavioral disorder, affecting approximately 5 to 10% of children and adolescents (Wolraich et al., 1996). In this condition, persistent inattention and/or hyperactive-impulsive behavior results in impaired social and/or academic functioning. Boys are affected about 8 times more frequently than girls (Zametkin et al., 1990). Genetic Heterogeneity of Attention Deficit-Hyperactivity Disorder Susceptibility to ADHD7 (607478) may be conferred by variation in the TPH2 gene (607478) on chromosome 12q21. ADHD8 (619957) is caused by mutation in the CDH2 gene (114020) on chromosome 18q12. Several loci for susceptibility to ADHD have been mapped, including ADHD1 (608903) on chromosome 16p13, ADHD2 (608904) on chromosome 17p11, ADHD3 (608905) on chromosome 6q12, ADHD4 (608906) on chromosome 5p13, ADHD5 (612311) on 2q21.1, and ADHD6 (612312) on 13q12.11. Also see MOLECULAR GENETICS.

The presence of one or more obsessive-compulsive personality traits. Obsessions refer to persistent intrusive thoughts, and compulsions to intrusive behaviors, which the affected person experiences as involuntary, senseless, or repugnant.

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.

Reduced ability affecting mainly visuospatial cognition which may be tested using pattern construction (for example by Differential Ability Scales, which test a person's strengths and weaknesses across a range of intellectual abilities).

Protrusion of the contents of the abdominal cavity through the inguinal canal.

Protrusion of abdominal contents through a defect in the abdominal wall musculature around the umbilicus. Skin and subcutaneous tissue overlie the defect.

Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.

Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.

Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility. According to the WHO criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviations or more below the average value for young healthy adults (a T-score below -2.5 SD).

Lack of stability of a joint.

There are 2 types of radioulnar synostosis: in type 1, there is a proximal, smooth fusion of 2 to 6 cm between the radius and ulna and the radial head is absent; in type 2, there is a fusion just distal to the proximal radial epiphysis in association with congenital dislocation of the radial head (Bauer and Jonsson, 1988). Both types result in a limitation of pronation and supination of the forearm, and in type 2 there is also a restriction of extension at the elbow. Dominant inheritance through several lines in several generations was demonstrated by a family reported by Davenport et al. (1924). Hansen and Andersen (1970) found a positive family history in 5 of 37 cases. Radioulnar synostosis is a feature of certain chromosome abnormalities, notably the triple X-Y syndrome (XXXY). See pronation-supination of the forearm, impairment of (176800). Radioulnar synostosis occurs in an autosomal dominant syndrome with amegakaryocytic thrombocytopenia; see RUSAT1, 605432.

A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.

An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.

Low set, steeply sloping shoulders.

Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.

Generalized muscular hypotonia (abnormally low muscle tone).

A defect of the chest wall characterized by a depression of the sternum, giving the chest ("pectus") a caved-in ("excavatum") appearance.

Celiac disease is a systemic autoimmune disease that can be associated with gastrointestinal findings (diarrhea, malabsorption, abdominal pain and distension, bloating, vomiting, and weight loss) and/or highly variable non-gastrointestinal findings (dermatitis herpetiformis, chronic fatigue, joint pain/inflammation, iron deficiency anemia, migraines, depression, attention-deficit disorder, epilepsy, osteoporosis/osteopenia, infertility and/or recurrent fetal loss, vitamin deficiencies, short stature, failure to thrive, delayed puberty, dental enamel defects, and autoimmune disorders). Classic celiac disease, characterized by mild to severe gastrointestinal symptoms, is less common than non-classic celiac disease, characterized by absence of gastrointestinal symptoms.

Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.

A group of abnormalities characterized by hyperglycemia and glucose intolerance.

An abnormally increased calcium concentration in the blood.

A detrimental reaction to a food, beverage, food additive, or compound found in foods that produces symptoms in one or more body organs and systems that is not mediated by an immune reaction.

Glucose intolerance (GI) can be defined as dysglycemia that comprises both prediabetes and diabetes. It includes the conditions of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) and diabetes mellitus (DM).

Hoarseness refers to a change in the pitch or quality of the voice, with the voice sounding weak, very breathy, scratchy, or husky.

A loss of the ability to move the vocal folds.

A fixed reduction in the vertical distance between the upper and lower eyelids with short palpebral fissures.

Tooth agenesis in some form is a common human anomaly that affects approximately 20% of the population. Although tooth agenesis is associated with numerous syndromes, several case reports describe nonsyndromic forms that are either sporadic or familial in nature, as reviewed by Gorlin et al. (1990). The incidence of familial tooth agenesis varies with each class of teeth. Most commonly affected are third molars (wisdom teeth), followed by either upper lateral incisors or lower second premolars; agenesis involving first and second molars is very rare. Also see 114600 and 302400. Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth). Faulty use of the terms, however, have confounded their use. The term 'partial anodontia' is obsolete (Salinas, 1978). Genetic Heterogeneity of Selective Tooth Agenesis Other forms of selective tooth agenesis include STHAG2 (602639), mapped to chromosome 16q12; STHAG3 (604625), caused by mutation in the PAX9 gene (167416) on chromosome 14q12; STHAG4 (150400), caused by mutation in the WNT10A gene (606268) on chromosome 2q35; STHAG5 (610926), mapped to chromosome 10q11; STHAG7 (616724), caused by mutation in the LRP6 gene (603507) on chromosome 12p13; STHAG8 (617073), caused by mutation in the WNT10B gene (601906) on chromosome 12q13; STHAG9 (617275), caused by mutation in the GREM2 gene (608832) on chromosome 1q43; STHAG10 (620173), caused by mutation in the TSPEAR gene (612920) on chromosome 21q22; and STHAGX1 (313500), caused by mutation in the EDA gene (300451) on chromosome Xq13. A type of selective tooth agenesis that was formerly designated STHAG6 has been incorporated into the dental anomalies and short stature syndrome (DASS; 601216). Of 34 unrelated patients with nonsyndromic tooth agenesis, van den Boogaard et al. (2012) found that 56% (19 patients) had mutations in the WNT10A gene (STHAG4), whereas only 3% and 9% had mutations in the MSX1 (STHAG1) and PAX9 (STHAG3) genes, respectively. The authors concluded that WNT10A is a major gene in the etiology of isolated hypodontia. Genotype-Phenotype Correlations Yu et al. (2016) observed that the most frequently missing permanent teeth in WNT10B-associated oligodontia were the lateral incisors (83.3%), whereas premolars were missing only 51.4% of the time, which they noted was a pattern 'clearly different' from the oligodontia patterns resulting from WNT10A mutations. They also stated that the selective pattern in WNT10B mutants was different from that associated with mutations in other genes, such as MSX1, in which second premolars are missing, and PAX9, in which there is agenesis of molars.

Dental malocclusion refers to an abnormality of the occlusion, or alignment, of the teeth and the way the upper and lower teeth fit together, resulting in overcrowding of teeth or in abnormal bite patterns.

Decreased size of the teeth, which can be defined as a mesiodistal tooth diameter (width) more than 2 SD below mean. Alternatively, an apparently decreased maximum width of tooth.

A facial appearance characterized by a permanently or nearly permanently opened mouth.

Increase in width of the nasal tip.

Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).

Posterior positioning of the nasal root in relation to the overall facial profile for age.

Increased thickness of the lower lip, leading to a prominent appearance of the lower lip. The height of the vermilion of the lower lip in the midline is more than 2 SD above the mean. Alternatively, an apparently increased height of the vermilion of the lower lip in the frontal view (subjective).

Width of the forehead or distance between the frontotemporales is more than two standard deviations below the mean (objective); or apparently narrow intertemporal region (subjective).

Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).

An abnormal distribution of eyebrow hair growth in the medial direction.

Posterior positions and/or vertical shortening of the infraorbital and perialar regions, or increased concavity of the face and/or reduced nasolabial angle.

Distance from nasion to subnasale more than two standard deviations below the mean, or alternatively, an apparently decreased length from the nasal root to the nasal tip.

Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border.

Increased prominence or roundness of soft tissues between zygomata and mandible.

Increase in periorbital soft tissue.

Wrinkled, redundant, inelastic and sagging skin.

Development of gray hair at a younger than normal age.

A nail that is diminished in length and width, i.e., underdeveloped nail.

Subjective impression of increased softness upon palpation of the skin.

Deficiency of thyroid hormone.

An early onset of puberty, in this case early does not refer to precocious.

Reduced visual acuity that is uncorrectable by lenses in the absence of detectable anatomic defects in the eye or visual pathways.

A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.

Interpupillary distance less than 2 SD below the mean (alternatively, the appearance of an decreased interpupillary distance or closely spaced eyes).

A markedly blue coloration of the iris.

An abnormality in the process of focusing of light by the eye in order to produce a sharp image on the retina.

The presence of an increased number of twists and turns of the retinal arterioles.