Hutchinson-Gilford progeria syndrome with severe calcific aortic valve stenosis.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging syndrome that results from mutation in the Laminin A gene. This case report of a 12-year-old girl with HGPS is presented for the rarity of the syndrome and the classical clinical features that were observed in the patient. All patients with this condition should undergo early and periodic evaluation for cardiovascular diseases. However, the prognosis is poor and management is mainly conservative. There is no proven therapy available. Mortality in this uniformly fatal condition is primarily due to myocardial infarction, strokes or congestive cardiac failure between ages 7 and 21 years due to the rapidly progressive arteriosclerosis involving the large vessels.

INTRODUCTION

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature ageing syndrome that is uniformly fatal and affects a variety of organ systems. Death in HGPS is caused primarily by myocardial infarction usually between ages 7 and 21 years as a result of rapidly progressive arteriosclerosis.[1] Death is often preceded by hypertension, transient ischemic attacks and strokes. This case report of a child with HGPS is presented because of the rarity of this syndrome and the classical clinical findings that were observed.

CASE REPORT

A 12-year-old girl, the youngest of three siblings, born of a nonconsanguineous marriage, and who had a normal perinatal history, was referred for evaluation of an incidentally detected cardiac murmur. There was failure to thrive but otherwise the patient was asymptomatic. There was no history of chest pain, syncope or palpitations. There was no family history of cardiac disease or genetic syndromes. The child had normal motor and mental development with normal intelligence. She had not attained menarche and her physical examination revealed short stature, craniofacial disproportion, shrunken facies, alopecia, prominent scalp veins, prominent eyes, micrognathia, a “beaked” nose, prominent and stiff joints, dystrophic nails, thin wrinkled skin and absent secondary sexual characteristics suggestive of a premature ageing syndrome [Figures 1 and 2]. The above-mentioned abnormal features were noted to appear after infancy.

Figure 1

Side Photograph of the child showing the typical phenotypic features of the Hutchinson–Gilford progeria syndrome

Figure 2

Front Photograph of the child showing the typical phenotypic features of the Hutchinson–Gilford progeria syndrome

The blood pressure was 128/92 mmHg, and all pulses were palpable, but feeble. There was bilateral carotid shudder. There was no brachiofemoral delay and clinical findings suggestive of severe aortic stenosis were present. Electrocardiography revealed left ventricular hypertrophy with a strain pattern. Echocardiography showed calcified aortic cusps with severe aortic stenosis (peak systolic gradient of 72 mmHg, mean gradient of 52 mmHg), mild aortic regurgitation and moderate mitral regurgitation [Figure 3]. There was concentric left ventricular hypertrophy with normal function (ejection fraction 57%). The aortic valve area was estimated to be 0.7 cm2. The patient's lipid profile revealed hypercholesterolemia with elevated low-density lipoprotein cholesterol and normal high-density lipoprotein cholesterol. It was decided to manage the patient conservatively as the outcome of aortic valve balloon dilatation/surgical replacement in this condition is not well documented and also because of the extremely fragile general condition of the patient.

Figure 3

Echocardiographic image in an apical five-chamber view showing severe aortic stenosis with turbulence across the valve on color Doppler echocardiography

DISCUSSION

HGPS has long been a source of fascination and curiosity. Since its first description, about 100 cases have been documented worldwide. HGPS is characterized by features reminiscent of normal ageing such as alopecia, skin wrinkling and osteoporosis. The most devastating aspect of this disease, however, is accelerated, premature cardiovascular disease that leads to fatal myocardial infarction or stroke by an average age of 13 years.[2] It is caused by a single base mutation in the LMNA gene, a laminopathy, which results in the production of a mutant lamin A protein product, progerin.[1-3] Laminin A is an essential scaffolding component of the nuclear envelope, which is the membrane that surrounds the nucleus. The altered protein in HGPS makes the nuclear envelope unstable and progressively damages the nucleus, making cells more likely to die prematurely.

The diagnosis of HGPS is essentially clinical,[4] as in the present patient, although other diseases may phenotypically mimic HGPS early in life (i.e., Wiedemann–Rautenstrauch Syndrome and restrictive dermopathy).[5] The characteristic features are usually recognized during the second year of life.[4] Most of the signs and symptoms, as well as the cause of death, result from the complications of sclerosis.

Cardiac involvement manifests as coronary artery disease, valvar stenosis and hypertension.[67] In a review of 32 cases of progeria, Makous et al.[7] observed cardiovascular system involvement in 31 patients who were aged from 2 to 26 years. A highly accelerated calcific deposition was seen to occur in the coronary, aortic, cerebral, subclavian and axillary arteries, mitral annulus and aortic valve cusps.[4] The calcific aortic valve sclerosis represents a degenerative change that is an exaggeration of normal ageing and involves principally the anterior mitral valve cusp and the proximal aortic valve cusps.[68] Death usually occurs within 4 years after the onset of angina pectoris as a result of acute coronary insufficiency with or without myocardial infarction. Heart failure may precede death.[5] Systemic hypertension is common and may appear before the patient reaches the age of 5 years. The condition carries a poor prognosis and no effective therapy is currently approved. However, some experimental drugs are undergoing trials.[8] One of them is Lonafarnib, a farnesyltransferase inhibitor that blocks the posttranslational farnesylation of prelamin A. Farnesylation is essential for the function of both mutant and nonmutant lamin A proteins, including progerin (ClinicalTrials.gov number, NCT000425607). Another treatment attempted is the combination of two molecules – zoledronic acid and pravastatin (ClinicalTrials.gov number, NCT00731016). Presently, the average life expectancy in progeria is 13 years (range: 7–27 years),[9] with death resulting from cardiovascular abnormalities, usually myocardial infarction, stroke or congestive cardiac failure, in 75% of the cases.[2]

In conclusion Hutchinson–Gilford progeria is a rare disease characterized by accelerated signs of ageing.that result from mutation in lMNA gene. Cardiovascular involvement is the commonest cause of death and prognosis remains poor.