Atypical Werner syndrome refers to a small subset of individuals with a normal WRN gene sequence, normal WRN protein, and some signs and symptoms that sufficiently overlap with the Werner syndrome such that clinicians submit these cases to the International Registry. These individuals may give a history of comparatively early age of onset and a faster rate of progression than those with typical Werner syndrome. Among this group, 4 of 26 individuals so far investigated (15%) had novel heterozygous missense mutations in LMNA, which encodes the nuclear intermediate filament lamin A/C. These mutations are N-terminal to the canonical C-terminal mutations of the classical Hutchinson-Gilford progeria syndrome (HGPS) (see later).
Mandibuloacral dysplasia (MAD) is characterized by short stature; thin, hyperpigmented skin; partial alopecia, prominent eyes, beaked nose, tooth loss, small recessed chin, and short fingers. The Arg527His mutation in the C-terminal region of lamin A/C accounts for approximately 90% of the recessive MAD caused by LMNA mutations. A small subset of MAD is caused by mutations in the ZMPSTE24 gene, whose gene product is involved in the processing of lamin A.
The HGPS or progeria of childhood, like Werner syndrome, affects multiple organs with presentations suggestive of accelerated aging. Newborns with HGPS usually appear normal, but profound failure to thrive occurs during the first year. Characteristic facies, partial alopecia progressing to total alopecia, loss of subcutaneous fat, stiffness of joints, bone changes, and abnormal tightness of the skin over the abdomen and upper thighs usually become apparent during the second to third year. Motor and mental development is normal. Individuals with HGPS develop severe atherosclerosis. Death usually occurs as a result of complications of cardiac or cerebrovascular disease generally between age 6 and 20 years. Average life span is approximately 13 years. About 90% of individuals with HGPS have the same p.Gly608Gly in exon 11 of the LMNA gene, a mutation that creates a cryptic splice site. Inheritance is autosomal dominant. All individuals with HGPS have a de novo mutation, although inheritance via a mosaic testicular mutation is a potential mechanism.
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