1. Hutchinson-
Gilford Progeria
Syndrome
By
Dr mohammud Ibraheem

2. Defination

3. Hutchinson-Gilford progeria syndrome (HGPS) is characterized by
clinical features that develop in childhood and resemble some
features of accelerated aging. Death occurs as a result of
complications of severe atherosclerosis, either cardiac disease
(MI or HF) stroke, generally between ages six and 20 years.
Average life span is approximately 14.5 years.

5. Progeroid
syndromes

6. diseases associated with mutations in genes encoding DNA repair
disease discreption gene
Werner syndrome Short stature, skin tightness and ulcerations, hair
greying, lipodystrophy, osteoporosis, bilateral
cataracts, heart disease, and calcification of cardiac
valves
WRN
Bloom syndrome Prenatal growth retardation, light sensitivity,
telangiectatic skin lesions, reduced fertility,
predisposition to cancer, and immunodeficiency
BLM
Rothmund-Thomson
syndrome
Greying of hair, juvenile cataracts, and skin and
skeletal abnormalities
RECQL4
Cockayne syndrome Impaired development of the neural system,
microcephaly, photosensitivity and premature ageing
ERCC6,
ERCC8
Xeroderma
pigmentosum
Skin photosensitivity, photophobia and no neurological
abnormalities
XPA,
XPB,
XPC,
XPG
Ataxia telangectesia Progressive cerebellar degeneration, pigmentary ATM

7. diseases associated with mutations in genes encoding DNA repair
Disease discreption gene
Ataxia telangectesia
like disorder
Progressive cerebellar degeneration, ataxia and
oculomotor apraxia, but no immunodeficiency nor
telangiectases
MRE11
A
Nijmegen breakage
syndrome
Progressive microcephaly, intrauterine growth
retardation, short stature, recurrent sinopulmonary
infections, increased cancer risk and premature
ovarian failure
NBN
cerebroretinal
microangiopathy with
calcifications and
cysts
Progressive intracranial calcifications, brain cysts,
leukodystrophy, spasticity, ataxia, cognitive decline,
osteopenia and bone fractures
CTC1
dyskeratosis
congenita
Bone marrow failure, abnormal skin pigmentation,
cancer predisposition, pulmonary and hepatic fibrosis,
leukoplakia, nail dystrophy, thrombocytopenia,
premature hair greying, osteoporosis and testicular
atrophy
TERC,
TERT,
WRAP5
3
Seckel syndrome MR and postnatal dwarfism with a small, birdlike face ATR

8. Progeroid laminopathies
disease discreption Gene
HGPS
atypical progeroid syndromes Short stature, prominent nose,
premature hair greying, partial alopecia,
skin atrophy, lipodystrophy and skeletal
anomalies
LMNA
mandibuloacral dysplasia type A Growth retardation, skeletal and
craniofacial anomalies, osteolysis,
pigmentary skin changes and partial
lipodystrophy
LMNA

9. Other progeroid syndromes
disease discreption gene
restrictive dermopathy Intrauterine growth retardation, facial
deformities, enlarged fontanelles, tightly
adherent skin, low bone density,
dysplasia of clavicles and congenital
contractures
ZMPSTE24
mandibuloacral dysplasia
type B
Generalized lipodystrophy, prominent
eyes, beaked nose, hair loss, mottled
hyperpigmentation, acro-osteolysis and
joint contractures
ZMPSTE24
Néstor-Guillermo progeria
syndrome
Early onset, lipoatrophy, severe
osteolysis and alopecia
BANF1

10. Laminopathies

11. LMNAgene

12. A. Diseases of Striated Muscle
1. AD Emery-Dreifus Muscular Dystrophy
2. AR Emery-Dreifus Muscular Dystrophy
3. AD Cardiomyopathy Dilated 1A
4. AD Limb Girdle Muscular Dystrophy Type 1B
B. Peripheral Neuropathy
1. AR Charcot-Marie-Tooth Disorder Type 2B1
C. Lipodystrophy Syndromes
1. AD Dunnigan-type Familial Partial Lipodystrophy
2. AD Lipoatrophy with Diabetes, Hepatic Steatosis, Hypertrophic
Cardiomyopathy and Leukomelanodermic Papules
3. AR Mandibuloacral Dysplasia
D. Accelerated Aging Disorders
1. AD Atypical Werner Syndrome
2. AD Hutchinson-Gilford Progeria Syndrome
3. AD Restrictive Dermopathy Lethal

13. Epidemiology

14. HGPS is an ultra-rare, sporadic, AD orphan disease, without
gender or ethnic propensity.
This progressive, degenerative disorder has onset in early
childhood with an estimated overall prevalence of 1 in 6-8
millions, and therefore 300–350 children were estimated to be
living with progeria worldwide in 2014.

18. Pathophysiolog
y

19. HGPS is caused by an AD de novo mutation in the LMNA gene
(1q22) which encodes A-type lamins (An inner nuclear membrane
proteins that play roles in nuclear structure and shape), this
mutation amplifies a cryptic splice event in exon 11 leading to
deletion of 50 AA of the prelamin A precursor protein.
This deletion removes the recognition site for the
metalloproteinase ZMPSTE24 in the prelamin A and leads to the
production of a truncated protein called progerin. Progerin
production results in an aberrant nuclear shape and the
dysregulated expression of hundreds of genes

22. Clinical
presentation

23. 1. Features of accelerated aging
2. Growth deficiency. failure to thrive. Poor weight gain and loss
of subcutaneous fat. Stature decreases.
3. Characteristic facial features include
A. Head is disproportionately large for face
B. Narrow nasal ridge with a narrow nasal tip
C. Thin vermilion of the upper and lower lips
D. Small mouth, retrognathia, and micrognathia
E. A short, thick lingual frenulum limits tongue mobility
F. Narrow airway and rigid laryngeal structures cause a high-
pitched voice.

26. 4. Dental. Delayed eruption and delayed loss of primary teeth.
Dental crowding occurs as a result of a small mouth, lack of
primary tooth loss, and secondary tooth eruption behind the
primary teeth.
5. Skin. Skin findings may be evident at birth and are present in
all individuals by age two years. Sclerodermatous skin
changes, dimpling or irregular small out pouchings occur over
the lower abdomen and proximal thighs. Abnormal
pigmentation consisting of light or dark macules and patches
along with some papules.

29. 6. Hair. Partial alopecia progresses to total alopecia. Loss of
eyebrows and loss of eyelashes in some individuals.
7. Musculoskeletal
A. The coxa valga causes a wide based shuffling gait
B. Hip dislocation because of the progressive coxa valga
C. Avascular necrosis of the hip.
D. Osteolysis of the distal phalanges
E. Short clavicles
F. Pear-shaped thorax
G. Extra skeletal calcifications are present in 40% of cases

32. 8. Endocrine. Sexual immaturity. No cases of fertility have been
described. Insulin resistance occurs in 50%, without
development of DM.
9. Cardiovascular. severe atherosclerosis, usually without
obvious abnormalities in lipid profiles.
A. Diastolic dysfunction is detected beyond age 5 years
B. Ventricular hypertrophy
C. HT
D. Mitral and aortic valves calcification, stenosis, and
regurgitation
E. Coronary vascular insufficiency
F. Overt HF appear late

33. 10. Cerebrovascular TIAs, silent strokes, or symptomatic strokes
(The mean age of infarction identification on neuroimaging is
6.8 years (0.4 –10.7years)
11. Ophthalmologic. Nocturnal lagophthalmos (the inability to
fully close the eyes during sleep) is common.
12. Nails become dystrophic.
13. Hearing. Conductive hearing loss is highly prevalent at all
ages.
14. Tumor rate is not increased over that of the general
population. One individual died of a chondrosarcoma of the
chest wall at age 13 years .

34. suspicious
findings

35. 1. Ectodermal
i. Dental. Delayed eruption and
delayed loss of primary teeth,
partial secondary tooth eruption,
dental crowding
ii. Skin. variably pigmented,
sclerodermatous, skin
outpouchings over lower
abdomen and/or proximal thighs
iii. Hair. Total alopecia, with very
sparse downy immature hair
remaining; loss of eyebrows
iv. Dystrophic nails
2. Musculoskeletal
i. Coxa valga with wide-based,
shuffling gait, sometimes
accompanied by avascular
necrosis of the femoral head
ii. Osteolysis of the distal phalanges
iii. Short clavicles with distal
resorption
iv. Pear-shaped thorax
3. Growth deficiency
i. Short stature (<3rd percentile)
ii. Poor weight gain (<3rd
percentile), weight distinctly
low for height
iii. Diminished subcutaneous body
fat globally
4. Facial features
i. Head disproportionately large
for face
ii. Long narrow nose
iii. Thin vermilion of the upper and
lower lips
iv. Retrognathia and micrognathia
5. Other
I. Thin, high-pitched voice
II. Low-frequency conductive
hearing loss
III. Nocturnal lagophthalmos

36. Investigations

37. 1. Weight and height plotted on standard growth charts to evaluate
growth over time
2. ECG and echocardiogram
3. Carotid artery duplex
4. MRI/MRA of the brain and neck
5. Skeletal x-rays to evaluate for characteristic findings: acroosteolysis,
clavicular resorption, coxa valga, and extraskeletal calcifications
6. Dual-energy x-ray absorptiometry (DXA) to assess bone mineral
density.
7. Occupational and physical therapy assessments, including six-
minute walk test, goniometry to assess joint mobility, and
assessment of activities of daily living
8. Nutritional assessment, although dietary intake is generally not
compromised in these patients
9. Audiologic, ophthalmologic, and dental examinations

38. A, Chronic watershed (white arrows) and white matter infarcts (black arrow)
B, Acute gyral infarcts (black arrows).Bright signal in the sulci indicates slow
cortical collateral flow (white arrows).

39. Arterial calcification. CTA reformatted images of the same patient demonstrate
right VA calcification (A) and ICA and external carotid artery (B) calcifications.

40.  Progerin levels in plasma (351±251 pg/mL) from
untreated patients with HGPS were on average 95-fold
higher than in non-HGPS plasma
 A multigene panel that includes LMNA, ZMPSTE24, and
other genes of interest is most likely to identify the genetic
cause of the condition while limiting identification of
variants of uncertain significance and pathogenic variants
in genes that do not explain the underlying phenotype.

41. Diagnosis

42. HGPS is usually diagnosed during the second year of life or
later, when progeroid features begin to be noticeable. The
diagnosis is based upon a thorough clinical evaluation,
characteristic physical findings, a careful patient history and
diagnostic genetic testing which is available through the
Progeria Research Foundation (www.progeriaresearch.org).

43. Treatment

44. Lonafarnib
Lonafarnib is an orally active
farnesyltransferase inhibitor
is developed for the
treatment of
1) Hepatitis D virus (HDV)
infections
2) Progeria

45. Mechanism of action
Development of lonafarnib for oncology has been
discontinued due to lack of efficacy. In progeria, lonafarnib
inhibits farnesyltransferase to prevent farnesylation and
subsequent accumulation of progerin and progerin-like
proteins in the nucleus and cellular cytoskeleton.
Lonafarnib therapy significantly decreased plasma progerin
levels within 4 months

47. Dose
The starting dosage of lonafarnib for patients with a BSA of
≥ 0.39 m2 is 115 mg/m2 twice daily taken with morning and
evening meals to reduce the risk of GIT adverse reactions;
after 4 months of treatment, lonafarnib dosage is to be
increased to 150 mg/m2 twice daily with morning and
evening meals. The dosage of lonafarnib dosage should be
rounded to the nearest 25 mg increment.

48. Adverse reactions
The most common adverse reactions (incidence > 50%) with
lonafarnib:
a) Vomiting (90%)
b) Diarrhoea (81%)
c) Infection (78%)
d) Nausea (56%)
e) Decreased appetite (53%)
f) Fatigue (51%)

49. Multidisciplenary team
1. Growth retardation
2. Orthopedic
3. Cardiovascular and neurological
4. Dental
5. Ophthalmological
6. Hearing aid

50. THANK YOU