In 1886, Hutchinson described a boy with congenital alopecia, wrinkled atrophic skin, an odd facies, joint contractures, and nor- mal intelligence. Subsequently in 1904, Gilford reported a second patient with similar features and suggested the term progeria, from the Greek word geras meaning old age, to describe the pre- mature senile characteristics of the patients. Thus, the syndrome is also known as Hutchinson-Gilford progeria syndrome (HGPS).
Progeria is an extremely rare condition with characteristic clinical findings of premature and accelerated aging. Its inci- dence was estimated to be 1 per 8 million live births in the United States. Males to females ratio is about 1.5 to 1. Most reported patients are Caucasians.
GENETICS/BASIC DEFECTS
1. Inheritance: autosomal dominant inheritance a. Advanced paternal age effect observed
b. Germinal mosaicism responsible for rare instances of affected sibs
2. Basic defects
a. Caused by mutations in lamin A (LMNA) gene i. LMNA gene encodes two protein products, lamin
A/C (lamin A and lamin C), representing major constituent of the inner nuclear membrane lamina ii. Mutations in LMNA
a) About 90% of patients have an identifiable mutation
b) Most common mutation: a de novo single- base substitution, G608G (GGC>GGT) in exon 11. G608G mutation responsible for the majority of progeria arises in the pater- nal germline
c) A second mutation in the same codon, G608S (GGC>AGC)
d) E145K (exon 2) observed in a phenotypically unusual HGPS
iii. Mutations in LMNA also cause the following dif- ferent recessive and dominant disorders:
a) Emery-Dreifuss muscular dystrophy type 1 (EMD1) (autosomal dominant)
b) Emery-Dreifuss muscular dystrophy type 2 (EMD2) (autosomal recessive)
c) A familial dilated cardiomyopathy and con- duction system defects (CMD1A) (autoso- mal dominant)
d) Dunnigan type familial partial lipodystrophy (FPLD) (autosomal dominant)
e) Limb girdle muscular dystrophy type 1B (LGMD1B) (autosomal dominant)
f) Charcot-Marie-Tooth disorder type 2B1 (CMT2B1) (autosomal recessive axonal neuropathy)
g) Mandibuloacral dysplasia (MAD) (autoso- mal recessive)
b. Hutchinson-Gilford progeria syndrome gene local- ized to chromosome 1q by observing two cases of uniparental isodisomy of 1q and one case with a 6- megabase paternal interstitial deletion
c. Increased hyaluronic acid production by progeric fibroblasts postulated as the underlying metabolic abnormality in progeria
i. Urinary excretion of hyaluronic acid found to be increased in some patients
ii. Elevated levels of hyaluronic acid may result in growth failure and accelerated senescence by inhibiting the growth of blood vessels
d. Accumulation of type IV collagen due to an interac- tion between activated T lymphocytes and fibroblasts e. Current results of microarray analysis: further support the notion that patients with progeria experience an accelerated form of aging
f. Reduced growth capacity in vitro in the skin fibrob- lasts from progeria patients with conflicting evidence on whether progeric cells can repair single-strand DNA breaks induced by X- or gamma-irradiation g. Fibroblasts from progeric tissue
i. Inability to subculture ii. Having short telomeres
iii. Uncertain as to whether aging is the conse- quence of shortened telomeres with reduced cell replication, impaired telomerase activity, or the culmination of the effects of reactive oxygen species
h. Del(1)(q23) reported in a patient with Hutchinson- Gilford progeria
i. Inv ins(1;1)(q32;q44q23) reported in the postmortem skin biopsy specimens from identical twins raising the possibility that a gene for progeria may be located at the break point site of the inserted chromosome segment
CLINICAL FEATURES
1. General features
a. Normal appearance at birth
b. Normal intelligence and personality c. High-pitched voice
2. Growth
a. Profound growth failure/failure to thrive starting around 6 month to one year of age
b. Extreme short stature
c. No rapid growth during puberty
d. Markedly diminished subcutaneous fat, especially on the face and limbs
e. Absent sexual maturation 3. Skin
a. Unremarkable at birth
b. Generalized non-pitting edema suggestive of sclero- derma shortly after birth
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c. “Sclerodermatous” skin over lower abdomen and proximal thighs, in which irregular bumps give appearance of lipodystrophy
d. Becoming thin, dry, taut, and shiny in some areas, but lax and wrinkled in others, most commonly over the fingers and toes, by the second year
e. Striking loss of subcutaneous tissue f. Prominent venous pattern
g. Easy bruising
h. Diminished eccrine sweating in some cases
i. Progressive freckle-like hyperpigmentation (most evident in sun-exposed areas) and thickened sclerotic areas (usually on the lower parts of the trunk or thighs) after several years
4. Hair
a. Partial alopecia progressing to generalized alopecia often beginning at birth or in the first year and becom- ing prominent by the end of the second year
b. Few remaining hairs: white or blond, fine, and fuzzy c. Body hair as well as scalp and facial hair: equally
affected 5. Nails
a. Short, thin, and dystrophic fingernails and toenails b. Koilonychia (spoon nails)
c. Onychogryphosis (deformed overgrowth of the nails) 6. A striking facies after few months of life
a. Typical “plucked-bird” appearance related to dispro- portionate craniofacial growth
b. Disproportionately large cranium c. Relatively small face
d. Prominent eyes e. Prominent scalp veins
f. Sparse to absent scalp hair (alopecia, balding, hypotrichosis)
g. Absent eyebrows and eyelashes h. Thin lips
i. Circumoral cyanosis
j. Protruded ears with absent earlobes k. “Beaked”, pinched nose with sculptured tip
l. Micrognathia 7. Teeth
a. Anodontia/hypodontia, especially permanent teeth b. Delayed and incomplete dentition
c. Discoloration (yellowish brownish)
d. Crowded, rotated, displaced, overlapped, and maloc- cluded, especially the anterior teeth
e. High incidence of caries f. Poor oral hygiene/gingivitis
g. Irregularity in size and shape of the odontoblasts h. Delayed in ossification of the crown of the permanent
teeth
i. Narrow pulp chambers and root canals j. Reticular atrophy of pulp
k. Calcification along the nerve fibers and the vascular walls
l. Irregular width of predentin, secondary dentin and cemetum
m. Osteoclastic resorption at apical portion
n. Incompletely formation of roots of deciduous molars
8. Endocrine manifestations a. Incomplete sexual maturation b. Occasional hypoplastic nipples 9. Cardiovascular disease.
a. Premature severe atherosclerosis b. Premature coronary artery disease
c. Death from coronary artery disease frequent and may occur before 10 years of age
d. Angina pectoris e. Myocardial infarction
f. Congestive heart failure
g. Epidural hematoma formation after a mild head injury possibly due to progressive atherosclerosis of intracranial vessels
10. Musculoskeletal abnormalities
a. Generalized osteoporosis with pathologic fractures b. Marked delay in bone-healing after fractures c. Short/dystrophic clavicles
d. Coxa valga e. Arthropathy
f. Avascular necrosis of the femoral capital epiphysis g. Distal phalangeal osteolysis
h. Delayed closure and persistently patent anterior fontanelle
i. Joint contractures with contracted hands, elbows, and knees
j. Dislocation of the hip
k. Mild flexion of the knees resulting in a wide-gaited horse-riding stance and wide-based shuffling gait l. Short, tapered distal phalanges
m. Thin limbs n. Muscle atrophy 11. Prognosis
a. Absence of other factors associated with aging such as cancers, cataracts, and senility (not considered to be a phenocopy of normal aging)
b. Death due to cardiovascular abnormalities in approx- imately 75% of patients
c. Main cause of death due to cardiovascular complica- tions
i. Myocardial infarction ii. Congestive heart failure d. Other causes of death
i. Marasmus ii. Inanition iii. Convulsions
iv. Accidental head trauma due to thinned cortical bones
e. Average life expectancy: 13 years (7–27 years)
DIAGNOSTIC INVESTIGATIONS
1. Histopathology
a. Skin lesions indistinguishable from scleroderma i. Progressive hyalinization of dermal collagen
(hyaline fibrosis)
ii. Loss of subcutaneous tissue
iii. Decreased sebaceous and sweat glands and hair follicles
b. Bone lesions i. Osteoporosis
ii. Osteolysis prominent in distal phalanges and clavicles
iii. Skeletal dysplasia manifesting as coxa plana, coxa valga, and attenuated diaphyses with dys- trophic metaphyses
iv. Avascular hip necrosis v. Nonunion of fractures vi. Hip dislocations c. Cardiovascular lesions
i. Severe, progressive atherosclerosis with widely variable age of clinical manifestation
ii. Presence of atherosclerotic plaques in the large and small arteries
iii. Calcifications in the mitral and aortic valves as well as aorta, coronary, cerebral, subclavian, and axillary arteries
iv. Myocardial ischemia and infarction resulting from the coronary artery disease
v. Diffuse interstitial myocardial fibrosis vi. Ventricular dilatation and hypertrophy
d. Increased lipofuscin in the brain, adrenal cortex, kid- ney, testis, liver, and heart
e. Gonads
i. Aspermatogenesis in males
ii. Presence of primordial follicles and corpora albi- cans in females with evidence of ovulation f. Arterial biopsy
i. Premature atherosclerosis ii. Subintimal fibrosis 2. Radiography
a. Widespread degenerative changes of bone in the first or second year of life
b. Skull and facial bones
i. Craniofacial disproportion ii. Patent fontanelles
iii. Wormian bones with fractures iv. Facial bone hypoplasia
v. Mandibular hypoplasia with dental crowding vi. Delayed and abnormal dentition
c. Thorax
i. Clavicular resorption ii. Rib tapering
d. Long bones i. Indentations ii. Attenuated cortices iii. Widened metaphyses
iv. Coxa valga v. Genu valgum e. Phalanges
i. Distal resorption, one of the hallmarks of the disease ii. Radiolucent terminal phalanges (acro-osteolysis) f. Other
i. Osteoporosis
ii. Fish-mouthed vertebral bodies iii. Soft-tissue loss
3. Blood chemistry for hyperlipidemia a. Increased low-density lipoprotein levels
b. Increased β-lipoprotein and pre-β-lipoprotein levels of high-density lipoprotein
c. Increased serum cholesterol levels 4. Metabolic work-up: inconsistent results
a. Insulin resistance
b. Abnormal collagen formation
c. Increased metabolic rate: could be the cause of the failure to thrive seen in progeria
d. Elevated growth hormone levels 5. Urine test
a. Excessive excretion of glycosaminoglycans b. Excessive excretion of hyaluronic acid (unreliable) 6. Cultured skin fibroblasts
a. Exhibit 76.1% DNA repair capacity compared to normal
b. Decreased cell growth in culture c. Short telomeres
d. Whether aging is the consequence of shortened telomeres with reduced cell replication, impaired telomerase activity, or the culmination of the effects of reactive oxygen species is uncertain
7. Immunofluorescence of cultured fibroblasts with antibod- ies directed against lamin A demonstrating visible abnor- malities of the nuclear membrane in many cells
8. Molecular genetic analysis: polymerase chain reaction amplification of all of the exons of the LMNA gene, fol- lowed by direct sequencing
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. The lamin A gene mutations not found in patient’s parents suggesting that it occurs sponta- neously in each patient and does not pass from parent to child
ii. Recurrence risk very low, estimated at 1 in 500 with each subsequent pregnancy due to germ line mutations
iii. Rare reports of siblings with progeria from con- sanguineous or nonconsanguineous marriages iv. Reported cases of monozygous twins with progeria b. Patient’s offspring: inability of patients to reproduce 2. Prenatal diagnosis: possible in families in which the disease-
causing mutation has been identified in a family member 3. Management
a. Regular diet
b. Combined nutritional treatment and growth hormone treatment
i. Improve growth
ii. Increase the levels of growth factors iii. Paradoxically result in a decreased BMR
iv. Response decreases over time
v. Do not prevent the progression of atherosclerotic disease
c. Early and definitive surgical intervention for sympto- matic oral pathosis
i. Abnormal facial morphology ii. Dermal inelasticity
iii. Potential anaesthetic difficulties
iv. Progressive ongoing deterioration in the medical condition
d. Orthopedic cares for musculoskeletal abnormalities i. Routine treatment of fractures
ii. Conservative treatment for hip dislocation.
Avoid surgery if possible
iii. Routine physical therapy to maintain joint range of motion
e. Management of cardiovascular complications i. Routine anticongestive therapy for congestive
heart failure
ii. Nitroglycerin for angina
iii. Low doses of aspirin help delay heart attacks and strokes
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Fig. 1. A boy with progeria showing short stature, senile appearance, small face in comparison with large cranial vault (craniofacial dispro- portion), alopecia with prominent scalp veins, absent eyelashes and eyebrows, prominent eyes, beaklike nose, mandibular hypoplasia, absent earlobes, contracted hands, elbows, and knees, short tapered terminal phalanges, enlarged joints, and dry brittle hypoplastic nails.
