Pathology & Genetics

• AD: Vertical

AR: Horizontal

XR: Oblique

·         The 5p– syndrome is also called the cri-du-chat syndrome, as affected infants characteristically have a high-pitched cry similar to that of a kitten. Additional findings in this disorder include severe mental retardation, microcephaly, and congenital heart disease.

 4p–, also called Wolf-Hirschhorn syndrome, is characterized by pre- and postnatal growth retardation and severe hypotonia. Affected infants have many defects including micrognathia and a prominent forehead.

 The 11p– syndrome is characterized by the congenital absence of the iris (aniridia) and is often accompanied by Wilms tumor of the kidney.

The 13q– syndrome is associated with the loss of the Rb suppressor gene and the development of retinoblastoma.

15q– may result in either Prader-Willi syndrome or Angelman’s syndrome depending on whether the defect involves the paternal or the maternal chromosome (genetic imprinting).

17p–, also known as Smith-Margens syndrome, is associated with self-destructive behavior.

·         Inheriting two copies of paternal chromosome 11 results in Beckwith-Wiedemann syndrome. This is not a trisomy, as the maternal chromosome is lost, and therefore this would be a paternal uniparental disomy for chromosome 11. This syndrome is characterized by exomphalos, macroglossia, and gigantism (EMG).

·         Reduced penetrance is commonly seen in dominantly inherited conditions that have relatively high fitness such as Huntington's disease or polycystic kidney disease.

·         This explains the much higher incidence of mental retardation in grandsons rather than brothers of normal transmitting males (Sherman’s paradox), as the permutation is amplified in females but not in males.

·         CHS: docking protein def, abnormal fusion of phagosomes with lysosomes

CGD: NADPH def

LAD: B2-integrin def

·         There are also some non-immunologic activators of the classic complement pathway, such as urate crystals, which may be part of the pathophysiologic process of gout.

In the alternate pathway, the early complement components (C1, C4, and C2) are bypassed and C3 is activated directly by such things as bacterial endotoxins, cobra venom factor, lipopolysaccharide, and aggregated immunoglobulin (mainly IgA, but also IgE). C3 nephritic factor is an unusual substance capable of activating the alternate complement system within the glomerulus, producing glomerular injury.

·         Type IV EDS is related to abnormal type III collagen, and as such is associated with ruptured intestinal organs and blood vessels.

Type IX EDS involves abnormalities of copper metabolism. There is increased copper in cells, but a decreased copper level in the blood.

Type VI EDS is characterized by decreased lysyl hydroxylation of collagen, which causes decreased cross-linking of collagen. Only collagen types I and III are affected