Cutis Laxa

C ut i s l ax a 497 The question of cryptic splice site activation can distill to one of context. The outcome of a mutation within a normal splice site may depend on the proximity and strength of a nearby cryptic site. Since most disease genes are well characterized, potential cryptic splice sites could be identified within their nucleotide sequence. This approach could permit the awareness of risk of cryptic splicing. In summary, the clinical interpretation of genetic variants that could impact splicing in disease genes is problematic. Definitive genetic and biochemical approaches are beyond the scope of clinical laboratories, while attempting to model the effects of mutations for all but the most conserved bases within the normal splice sites is uncertain. See also: Alternative Splicing; Eukaryotic Genes; Pre-mRNA Splicing

ct DNA Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.1815

ct DNA is the abbreviation for chloroplast DNA. See also: Chloroplasts, Genetics of

CTP (Cytidine Triphosphate)

Cutis laxa F M Pope Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.1747

Cutis laxa (CL) is a clinical term referring to the overstretched and inelastic skin, which forms loose folds, especially of the neck, face, and flexures. Whilst common in old age, it is very abnormal any earlier, especially when generalized or very widespread as opposed to more localized forms of sagginess. For a long time, CL was confused with cutis hyperelastica, which characterizes most Ehlers±Danlos syndrome (EDS) variants (Pope, 1993). Early cases of EDS were often described as showing `cutis laxa,' as was the original description of EDS by Danlos himself. Here, in contrast to the bloodhound-like jowly melted-wax appearance and loss of elasticity of true cutis laxa, the skin isoverextensible.Afterbeing stretched or otherwise deformed, it immediately snaps back to normal. Rather confusingly, some EDS subtypes also show genuine CL, either very early, as in EDS types VII a±c or very much later as a late complication after middle age in some EDS I/II variants. CL is classified into three subsets; primary CL of which there are several variants; secondary CL, in which the lax skin complicates other inherited defects of connective tissue; and acquired CL in which disorders of systems other than primary connective tissue components induce obvious cutaneous laxity and redundancy (Pope, 1993, 1995).

E J Murgola Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0298

Cytidine-50 -triphosphate (CTP) is an energy-rich, activated precursor for RNA synthesis. It is formed in the cell by amination of uridine triphosphate (UTP). The carbonyl oxygen at C4 of the uracil moiety is replaced by an amino group. The amide donors differ among organisms. In mammals, for example, glutamine is the amide donor, but, in the bacterium Escherichia coli, the ammonium ion is used in this reaction. For the synthesis of deoxycytidine triphosphate (dCTP), a precursor of DNA, the 20 hydroxyl group of the ribose moiety of CTP is replaced by a hydrogen atom. The final step in this conversion is catalyzed by ribonucleotide reductase. See also: RNA

Primary Cutis Laxa Classical Types

This was first described in the late nineteenth century under a variety of names, such as generalized dermatolysis, geomorphisme cutane, atrophie idiopathique de la peau, peau rideÂe senile, etc. Published in 1887, Dubreuilh's case showed the striking premature aging of an adolescent French girl, who looked old enough to be her own grandmother. Other contemporary cases were confused with progeria and even when recognized as different from EDS, CL was not easily differentiated from neurofibromatosis, calcinosis, and various types of scleroderma (Pope, 1993). In 1972, Beighton clearly distinguished autosomal dominant and recessive variants, observing that in general the recessive variant was both earlier in onset and more dangerous. He studied a large autosomal dominant family, in which the CL occurred from infancy onwards. Emphysema had been recognized as early as 1938 and in general is

498

Cutis l axa depletion or less frequently proliferation. Mutations of the elastin gene have now been demonstrated in both variants (Zhang et al., 1997).

Other Primary Variants

These include CL with joint laxity and developmental delay, also called autosomal recessive cutis laxa type II. Another variant includes wormian bones and generalized osteoporosis, to which when combined with corneal clouding and developmental delay with CL, the eponym De Barsey syndrome is applied.

Secondary to other Disorders Cutis Laxa Complicating other Inherited Connective Tissue Syndromes

Figure 1 (See Plate 6) Two examples of generalized CL complicating pseudoxanthoma elasticum (PXE). (A) Predominantly in a female of Afro-Caribbean origin; (B) generalized in a Japanese female. much more severe in the recessive form, who can die from respiratory failure in teenage. Beighton's original autosomal dominant proband survived to late middle age before requiring lung transplantation to treat her progressive emphysema. Her skin histology showed elastic fragmentation. In the autosomal recessive forms, elastic stains of the skin show either elastic

Generalized CL is a rare complication of both the Ehlers±Danlos syndrome and pseudoxanthoma elasticum (PXE) (Figure 1A, B) whilst more localized forms are very much commoner. It is also a well-recognized complication of the occipital horn syndrome. In EDS types VII a±c there is premature cutis laxa, which ranges from generalized in EDS VIIc to more subtle localized CL, usually most obvious of the face and less so of the trunk in EDS types VII a and b. The degree of laxity correlates with the severity of the mispacked collagen fibres, caused by mutations of either the NB propeptide cleavage sequence or of its cleavage N propeptidase. Unlike in true primary CL, the skin is hyperelastic. Transient CL has also been occasionally observed in babies with EDS IV caused by collagen type III mutations. Late-onset laxity complicates EDS types I and II. A beautiful example was illustrated by Beighton, who showed the contrast between the smooth-skinned hypermobile youth and his very weathered facial appearance in old age. Here a bloodhound-like appearance very similar to that of premature autosomal dominant CL occurs, except that in EDS this is a problem of old age. PXE produces true cutis laxa, in which the affected axillary, neck, and flexural skin becomes truly lax and inelastic. As proof of such laxity, it looks like plucked-chicken skin and here the abnormal skin contains degenerate, fragmented, mid-dermal deposits of abnormal elastic fibres. The latter equally will induce abnormalities of blood vessels and the retina. Very occasionally there is snowstorm calcification of the lungs. Cutis laxa also complicates the occipital horn syndrome where lysyl oxidase deficiency is caused by abnormal copper metabolism. Bladder diverticulae and dilatation of the urinary tract are also features and there may be phenotypical overlap with Menke's syndrome. However since the lysyl oxidase gene is autosomal the linked inheritance of lysyl oxidase

Cyclic AMP ( cAMP) 499 deficient CL is doubtful. Our two recently reported cases presented with infantile CL, later developing wormian bones. One had severe obstructive uropathy with renal failure. This phenotype resembles autosomal recessive CL with wormian bones (OMIM 219200).

Acquired Cutis Laxa Caused by Other Systemic Disorders

Here the end result is the same, i.e, there is true laxity of the skin, but the cause is of incidental systemic disease, which happens to infiltrate dermal connective tissue. Good examples are amyloid disease, either as a primary disorder or occurring secondary to multiple myeloma. In hereditary neuropathic amyloidosis of the Finnish type, the CL is predominantly facial. Similar generalized elastolysis can also occasionally complicate urticaria, generalized eczema or Sweet syndrome (Pope, 1993, 1995). None of these have anything in common pathogenetically except for a general predisposition to affect the skin. Idiopathic generalized elastolysis occurs in the absence of any of the listed secondary causes. Unlike primary cutis laxa, it is of adult onset, from the third to the sixth decades. Characteristic changes include esophageal diverticulae, esophogeal or inguinal hernias, severe generalized emphysema, colonic diverticulae, and progressive joint laxity. Pulmonary hypertension or aortic dilatation and rupture have been documented in various patients. Whether this is sometimes a lateonset allelic variant of primary CL is unknown.

Blepharochalasis

Although strictly speaking confined to the orbits, eyelids, and eyebrows, blepharochalasis often accomponies generalized CL. It can also segregate as specific autosomal dominant traits, with or without lip involvement (OMIM 109900 and 11000).

Pathogenesis of Cutis Laxa In most varieties of CL, elastin itself, or another component of elastic fibres is either fundamentally fragile or degraded by virtue of other secondary factors. Otherwise, the closely related microfibrillar constituents are abnormal, as is the case in lysyl oxidase deficiency (Khakoo et al., 1997) and in some cases of acquired CL. Less commonly, collagen fibres are distorted as occurs in those EDS variants with CL, whilst in amyloidosis other elastic microfibrillar abnormalities are produced by amyloid microfibrils. Structurally, elastic fragmentation or even gross deficiency is very obvious in primary autosomal CL, whilst the changes vary in the other primary autosomal recessive CL.

References

Beighton P (1972) The dominant and recessive forms of cutis laxa. Journal of Medical Genetics 9: 216±221. Khakoo A, Thomas R, Trompeter DP Price R, and Pope FM (1997) Congenital cutis laxa with lysyl oxidase deficiency: a phenotypic description of two cases. Clinical Genetics 51: 109±114. Pope FM (1993) Cutis laxa. In: McKusick's Heritable Disorders of Connective Tissue, 5th edn, pp. 253±279. St Louis, MO: Mosby. Pope FM (1995) Pseudoxanthoma elasticum, cutis laxa and other disorders of connective tissue. In: Rimoin DL, Connor JM and Pyeritz RE (eds) Emery & Rimion's Principles, pp. 1083± 1119. Edinburgh, UK: Churchill Livingstone. Zhang MC, He L, Yong SL et al. (1997) Cutis laxa arising from a frame-shift mutation in the elastin gene, Abstract 2068. American Journal of Human Genetics. 61(4): A353

See also: Ehlers±Danlos Syndrome

Cyclic AMP (cAMP) R Somerville Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0303

Cyclic AMP was discovered in the 1950s by Earl Sutherland in the course of studying how certain hormones elicit the conversion in liver cells of glucose to glycogen. In essence, the binding of a hormone to the external face of a highly specific transmembrane receptor triggers the action of an intracellular enzyme, adenylate cyclase. This enzyme then converts ATP to cyclic AMP. The latter compound (sometimes referred to as a `second messenger') acts in variety of ways, most notably by stimulating the activity of various broad-specificity protein kinases. The phosphoprotein products of the kinase reactions participate in signal transduction cascades in such a way as to greatly amplify the effect of very slight amounts of hormone. Cyclic AMP was identified in bacteria in 1965, also by Sutherland. As in animal cells, the precursor molecule is ATP. The best-understood role of cyclic AMP in bacteria is to modulate the utilization of carbon sources. This is accomplished via the action of an accessory protein, the cyclic AMP binding protein (CAPorCRP).Thisproteincanpotentiallyactasatranscription factor by engaging specific target sequences in DNA. When physiological circumstances lead to a rise in cyclic AMP, the concentration of binding protein±cyclic AMP complexes also increases. As a result, there is enhanced occupancy of a set of target sites in DNA, many of which are situated within or