Basal Cell Nevus Syndrome

In basal cell nevus syndrome (BCNS) there is an increased frequency of neoplasms, the result of excessive activation of segments of the Hedgehog pathway.

Patched is a target gene in the Hedgehog signalling network. Patched (Ptch1) encodes a transmembrane protein that acts as a negative regulator of hedgehog (Hh) signalling (Fig. 1). [Note: There is a general move toward abandoning the acronyms Ptc and PTC in favor of Ptch and PTCH, thereby avoiding confusion with phenylthiocarbamide tasting (PTC; OMIM 171200)]. The 1500-amino acid glycoprotein has 12 hydrophobic, membrane-spanning domains, intracellular amino- and carboxy-terminal regions, and two large hydrophilic extracellular loops where Hh ligand binding occurs.

Ptch has dual roles in sequestering and transducing Hh. When the second large extracellular loop, essential for ligand binding, is deleted by a Ptch1 mutation, Hh binding to Ptch cannot occur, but repression of Smoothened (Smo) by Ptch is unaffected. When a C-terminal truncation is caused by a Ptch1 mutation, Ptch can no longer repress Smo, but Hh binding to Ptch is unaffected.

In the Hedgehog signalling network, mutations result in various phenotypes, including, among others, holopro-sencephaly, BCNS, Pallister-Hall syndrome, Greig ceph-alopolysyndactyly, Rubinstein-Taybi syndrome, isolated BCCs, and desmoplastic medulloblastoma.

Human PTCH1, a tumor suppressor gene, maps to 9q22.3. Most mutations in PTCH1 result in protein truncation. However, four rare PTCH missense mutations have resulted in holoprosencephaly—two in the extracellular loops required for SHH binding and two in the intracellular loops that may be involved in PTCH-SMO interaction.1-4-1

Four features of Hedgehog signalling are noteworthy. First, autoprocessing generates an active Hedgehog ligand with a C-terminal cholesterol moiety. Then, palmitoyla-tion results in an N-terminal palmitate. The active Hedgehog ligand therefore becomes double lipid modified. Second, most membrane-bound receptors activate downstream signalling on ligand binding. However, Ptch is repressed by its Hedgehog ligand, freeing Smoothened for downstream signalling.

Table 1 Diagnostic criteria for BCNS

Diagnosis of BCNS made in the presence of two major, or one major and two minor criteria

Major criteria

2. Histologically confirmed odontogenic keratocysts of jaw

3. > 3 palmar or plantar pits

4. Bilamellar calcification of falx cerebri

5. Bifid, fused, or markedly splayed ribs

6. First-degree relative with BCNS syndrome

7. Desmoplastic medulloblastoma

Minor criteria

Any two of the following features:

1. Macrocephaly determined after adjustment for height

2. Congenital malformations: cleft lip or palate, frontal bossing, ''coarse face,'' moderate or severe hypertelorism

3. Other skeletal abnormalities: Sprengel deformity, marked pectus deformity, marked syndactyly of digits

4. Radiological abnormalities: bridging of the sella turcica vertebral anomalies such as hemivertebrae, fusion or elongation of the vertebral bodies, modeling defects of the hands and feet, or flame-shaped lucencies of hands or feet Ovarian fibroma

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Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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