The syndromes associated with an accelerated or premature aging
(often called progeroid) phenotype represent an uncommon but medically
and biologically important class of disorders. These conditions
are characterized by physical manifestations that produce a prematurely
aged appearance or symptoms suggesting accelerated aging unexpected
for a child or adolescent. Although one of these conditions, Hutchinson-Gilford
progeria (HGP), is the prototype for this community of diseases,
there are at least 20 human syndromes that have been labeled as
progeroid. It is a common mistake for both the clinician and the
media to incorrectly lump all of these disorders under the heading
of progeria, even though there are several discrete entities. Making
an accurate diagnosis of the correct accelerated/premature
aging syndrome is crucial because all of these conditions vary in
inheritance pattern, natural history and prognosis. The plan of
management and health care supervision is informed by the diagnosis
here, as is the case of all genetic syndromes.
Table 184-1 (modified from a recent commentary
by Neilan in 20091) classifies the commonly described
progeroid syndromes by the pathogenetic category of the disorder.
Hutchinson-Gilford progeria, the mandibuloacral dysplasias (MAD),
and the connective tissue dysplasias with signs of premature aging
will be discussed in more detail in subsequent section. Table 184-1 provides a listing of clinical
manifestations of the conditions, as well as the inheritance pattern
and the gene locus, gene name, and encoded protein if known. Of
note, different mutations of the gene LAMA cause
multiple different phenotypes, including HGP and a form of MAD as
well as several nonclassical progeroid phenotypes1-3 displaying
the genetic principle of allelic heterogeneity. It is also interesting
that MAD is genetically heterogeneous (locus heterogeneity) and
can be caused by mutations of LAMA or the gene ZMPSTE24,
which encodes a peptide that is involved in the posttranslational modification
of lamin A/C.4
Table 184-1. Syndromes with
an Accelerated Aging (Progeroid) Phenotype |Favorite Table|Download (.pdf)
Table 184-1. Syndromes with
an Accelerated Aging (Progeroid) Phenotype
|Category/Disorder||Major Manifestations||Inheritance (OMIM number)||Gene Locus/Gene/Product|
|Hutchinson-Gilford progeria||Growth delay, sparse hair, distinctive face, osteopenia,
premature coronary disease||AD (176670)||1q21/ LAMA/lamin A/C|
|Mandibuloacral dyplasia with type A lipodystrophy||Sparse hair, micrognathia, atrophy of skin on hands, lipodystrophy
type A, acro-osteolysis, insulin resistance||AR (248370)||1q21/LAMA/lamin A/C|
|Mandibuloacral dysplasia with type B lipodystrophy||Sparse hair, micrognathia, atrophy of skin on hands, lipodystrophy
type B, acro-osteolysis, insulin resistance||AR (608612)||1p34/ZMPSTE24*/zinc
|Other LMNA-related progeroid disorders||Nonclassical progeria: milder manifestations overlapping
with HGP||AD (176670)||1q21/LAMA/lamin A/C|
|Barraquer-Simons syndrome||Acquired childhood-onset partial lipodystrophy of face, renal
dysfunction||Sporadic (608709)||19p13/LAMB/lamin B|
|XFE progeroid syndrome||Short stature, microcephaly, skin sensitivity, aged face,
hearing loss||AR (610965)||16p13/ERCC4/excision repair
cross complementing protein 4|
|Cockayne syndromes||Postnatal short stature, progressive neurologic condition,
photosensitivity, pigmentary retinopathy, hearing loss, joint limitations||AR (216400, ...|
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