Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).

A unilateral form of agenesis of the kidney.

Agenesis, that is, failure of the kidney to develop during embryogenesis and development.

Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.

The presence of developmental dysplasia of the kidney.

Multicystic dysplasia of the kidney is characterized by multiple cysts of varying size in the kidney and the absence of a normal pelvicaliceal system. The condition is associated with ureteral or ureteropelvic atresia, and the affected kidney is nonfunctional.

A condition in which middle parts of the hands and/or feet (digits and meta-carpals and -tarsals) are missing giving a cleft appearance. The severity is very variable ranging from slightly hypoplastic 3rd toe/fingers over absent 2nd or 3rd toes/fingers as far as oligo- or monodactyl hands and/or feet.

Supernumerary digits located at the ulnar side of the hand (that is, on the side with the fifth finger).

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.

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

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).

A deficiency or slowing down of growth pre- and postnatally.

A decreased magnitude of the sensory perception of sound.

Chiari malformation consists of a downward displacement of the cerebellar tonsils and the medulla through the foramen magnum, sometimes causing hydrocephalus as a result of obstruction of CSF outflow.

The disorder described by Hirschsprung (1888) and known as Hirschsprung disease or aganglionic megacolon is characterized by congenital absence of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the gastrointestinal tract. Patients are diagnosed with the short-segment form (S-HSCR, approximately 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and with the long-segment form (L-HSCR) when aganglionosis extends proximal to the sigmoid (Amiel et al., 2008). Total colonic aganglionosis and total intestinal HSCR also occur. Genetic Heterogeneity of Hirschsprung Disease Several additional loci for isolated Hirschsprung disease have been mapped. HSCR2 (600155) is associated with variation in the EDNRB gene (131244) on 13q22; HSCR3 (613711) is associated with variation in the GDNF gene (600837) on 5p13; HSCR4 (613712) is associated with variation in the EDN3 gene (131242) on 20q13; HSCR5 (600156) maps to 9q31; HSCR6 (606874) maps to 3p21; HSCR7 (606875) maps to 19q12; HSCR8 (608462) maps to 16q23; and HSCR9 (611644) maps to 4q31-q32. HSCR also occurs as a feature of several syndromes including the Waardenburg-Shah syndrome (277580), Mowat-Wilson syndrome (235730), Goldberg-Shprintzen syndrome (609460), and congenital central hypoventilation syndrome (CCHS; 209880). Whereas mendelian modes of inheritance have been described for syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. Isolated HSCR appears to be of complex nonmendelian inheritance with low sex-dependent penetrance and variable expression according to the length of the aganglionic segment, suggestive of the involvement of one or more genes with low penetrance. The development of surgical procedures decreased mortality and morbidity, which allowed the emergence of familial cases. HSCR occurs as an isolated trait in 70% of patients, is associated with chromosomal anomaly in 12% of cases, and occurs with additional congenital anomalies in 18% of cases (summary by Amiel et al., 2008).

Neuronal degeneration in the cerebellum, pontine nuclei, and inferior olivary nucleus.

A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.

Excessive sensitivity to light with the sensation of discomfort or pain in the eyes due to exposure to bright light.

Dilation of central canal from incomplete fusion of the posterior columns or persistence of the primitive large canal of the embryo.

Underdevelopment of the corpus callosum.

A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.

A type of Developmental delay characterized by a delay in acquiring motor skills.

An increase in size of the ventricular system of the brain.

Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.

Partial or complete wasting (loss) of brain tissue that was once present.

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.

Displacement of the femur from its normal location in the hip joint.

The presence of an abnormal lateral curvature of the spine.

An omphalocele is an abdominal wall defect limited to an open umbilical ring, and is characterized by the herniation of membrane-covered internal organs into the open base of the umbilical cord. Omphalocele is distinguished from gastroschisis (230750), in which the abdominal wall defect is located laterally to a normally closed umbilical ring with herniation of organs that are uncovered by membranes (summary by Bugge, 2010). On the basis of clinical manifestations, epidemiologic characteristics, and the presence of additional malformations, Yang et al. (1992) concluded that omphalocele and gastroschisis are casually and pathogenetically distinct abdominal wall defects. Omphalocele can be a feature of genetic disorders, such as Beckwith-Wiedemann syndrome (130650) and the Shprintzen-Goldberg syndrome (182210).

Head circumference below 2 standard deviations below the mean for age and gender.

A butterfly vertebra (sagittal cleft vertebra or anterior rachischisis) is a sagittal defect in the vertebral body caused by failure of fusion of the two lateral chondrification centers during embryogenesis. The name is based on the appearance of the two hemivertebrae emerging as butterfly wings from the central cleft on x-ray.

An increased susceptibility to upper respiratory tract infections as manifested by a history of recurrent upper respiratory tract infections (running ears - otitis, sinusitis, pharyngitis, tonsillitis).

An inflammatory exfoliative dermatosis involving nearly all of the surface of the skin. Erythroderma develops suddenly. A patchy erythema may generalize and spread to affect most of the skin. Scaling may appear in 2-6 days and be accompanied by hot, red, dry skin, malaise, and fever.

Eczema is a form of dermatitis that is characterized by scaly, pruritic, erythematous lesions located on flexural surfaces.

Inflammation of the cornea.

Infections of the skin that happen multiple times.

Absence of the eyebrow.

Abnormal narrowing of the choana (the posterior nasal aperture).

Decreased number of hairs per unit area of skin of the scalp.

Cleft palate is a developmental defect of the palate resulting from a failure of fusion of the palatine processes and manifesting as a separation of the roof of the mouth (soft and hard palate).

A noncongenital process of hair loss, which may progress to partial or complete baldness.

Ectodermal dysplasia is a group of conditions in which there is abnormal development of the skin, hair, nails, teeth, or sweat glands.

Abnormally diminished capacity to sweat.

A thickening of the stratum corneum in the region beneath the nails.

Skin characterized by the lack of natural or normal moisture.

Onychodystrophy (nail dystrophy) refers to nail changes apart from changes of the color (nail dyschromia) and involves partial or complete disruption of the various keratinous layers of the nail plate.

Refers to the loss of the outer layer of the epidermis in large, scale-like flakes.

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.

The most dramatic and severe form of hair loss characterized by an absence of hair follicles.

Hyperkeratosis is thickening of the outer layer of the skin, the stratum corneum, which is composed of large, polyhedral, plate-like envelopes filled with keratin which are the dead cells that have migrated up from the stratum granulosum.

Erythema (Redness of the skin caused by hyperemia of the capillaries in the lower layers of the skin) localized to the region surrounding the anus.

The presence of developmental dysplasia of the nail.

Lack of eyelashes.

Erythema (redness of the skin caused by hyperemia in superficial capillaries) in the region surrounding a fingernail or toe nail.

The presence of misshapen or partially destroyed nail plates, often with accumulation of soft, yellow keratin between the dystrophic nail plate and nail bed, resulting in elevation of the nail plate.

Ichthyosis follicularis is characterized by widespread non inflammatory thorn-like follicular projections. Dyskeratotic papules are most pronounced over the extensor extremities and scalp and are symmetrically distributed.

Diminished amniotic fluid volume in pregnancy.

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).

Ingrowth of new blood vessels into the cornea.

The presence of recurrent corneal epithelial erosions. Although most corneal epithelial defects heal quickly, some may show recurrent ulcerations.

Reduced transparency of the stroma of cornea.