Hutchinson-Gilford Progeria Syndrome: Case Report of a RareDevastating Malady

Introduction

Hutchinson-Gilford Progeria Syndrome is an exceptionally, unheard of, calamitous genetic disease, based on the name of Dr. Hutchinson and Dr. Hastings Gilford, who first reported it in 1886 in England.¹ The recorded prevalence is one in eight million and if unreported cases are taken into consideration, the estimated birth prevalence comes out to be one in four million.² According to the estimate of Progeria Research Foundation database, there are 200–250 children living with Progeria worldwide at a point of time, and 172 of them have been identified as of 31st March 2020 residing in 53 countries.³ It is a severe premature aging syndrome, characterized by retarded growth, dwarfism and abnormal onset of scleroderma.⁴ De novo Sporadic autosomal dominant mutation in LMNA genes is responsible for majority of the cases and inheritance is quite rare.⁵ It affects males more than females with a ratio of 1.5:1, and Caucasians show strong racial susceptiveness, representing 97% patients.⁶ The average survival age is 13.5 years (life expectancy about 8–21 years) with associated significant morbidity and premature death due to stroke, myocardial infarction, heart failure, or atherosclerosis.⁷ We present a rare and interesting case of Progeria with essentially all the imaging findings described in literature till date.

Case Report

A 10-year-old male child presented with progressive history of skin coarsening, sclerodermatous changes over whole body and tendon contractures resulting in fixed flexion deformities of hands and feet. This child was born to non-consanguineous parents with an uneventful antenatal and perinatal history. The abnormal features were apparent before the age of one year. General examination revealed short stature, characteristic facial appearance with beaked nose, retracted mandible, crowded irregularly erupted teeth with micrognathia and loss of subcutaneous fat (Figure 1a & b). The child also had sclerodermatous changes and mottled discoloration all over the trunk and lower limbs along with tendon contractures resulting in fixed flexion deformities of hands and feet (Figure 2). The terminal ends of the fingers of hand and feet appeared stubby (Figure 3). However, the genitals were normal and mental age was corresponding to the chronological age. Biochemical investigations were normal except for elevated serum cholesterol. Based on the history and clinical findings, an interim diagnosis of Progeria was made.

Further, skeletal survey of the patient was planned. Radiographs of the skull showed disproportionate large calvarium with hypoplastic facial bones, small mandible, retrognathia and overcrowding of teeth (Figure 4a & b). Frontal chest radiograph showed sloping slender posterior ribs and resorption of lateral ends of clavicle (Figure 5). Lateral radiograph of the dorso-lumbar spine showed mild concavity along the anterior aspect of vertebral bodies (“fish mouth” vertebra) (Figure 6). Radiograph of both hands and feet antero-posterior view showed resorption of terminal phalanges with preservation of soft tissue along with flexion deformities at interphalangeal and ankle joints (Figure 7a & b). Radiograph of pelvis with both hip joints anteroposterior view showed increased neck shaft angle (coxa valga deformity), abnormal outline of bilateral femoral head and slender proximal femoral shafts (Figure 8). Radiograph of both knee joints in antero-posterior view showed mild genu valgum deformity (Figure 9). The bones appeared mildly osteopenic in all the radiographs.

Based on the clinical and imaging findings, a diagnosis of Hutchinson-Gilford Progeria syndrome was made. Typical clinical and imaging findings help differentiating it from other premature aging syndromes.

Discussion

Progeria is a premature aging syndrome. The term Progeria, derived from the Greek word “geros” meaning old was framed by Gilford in 1904. De Busk in 1972 renamed this condition as “Hutchinson-Gilford Progeria syndrome”. As compared to normal individuals, the ageing process is seven times faster in affected individuals. De novo autosomal dominant mutation in the LMNA gene (located on band 1q21.1-1q21.3) is responsible for majority of the cases.⁸ Rarely, autosomal recessive or maternal transmission could be seen. This mutant gene causes aberrant cell division along with abnormal formation and remodelling of collagen and extra cellular matrix. The hyaluronic acid levels are abnormally high, leading to cardiovascular abnormalities and sclerodermatous changes. Also, there are high levels of serum triglycerides, total cholesterol, LDL cholesterol and reduced levels of HDL cholesterol.⁹

The earliest manifestation is growth deficiency during infancy. These patients exhibit short stature, characteristic facies which include beaked nose with “sculptured nasal tip”, abnormal dentition, receding chin, exophthalmos alopecia and prominent scalp veins in first two years of life.⁶ Sclerodermatous changes manifest initially in the gluteal region and proximal extremities. Cutaneous manifestations precede the involvement of skeletal and cardiovascular systems. Muscular atrophy with joint deformities are additional features. Lower limb involvement with valgus deformity and mid flexion leads to a “horse riding” stance.¹⁰ However, bone age and intellect remains normal.¹¹ With all these features the child had a distinctive physiognomy of “a wizened little old man.”

Radiographic changes manifest within the second year of life. A review of the previously published imaging findings in progeria revealed marked synonymity.¹² Typical skull radiograph findings are fragile, gigantic calvarium, shallow diploe space, wormian bones, small mandible with infantile obtuse angle, short ascending rami, hypo plastic facial bones, open cranial fontanelles and prominent vascular markings. Chest radiograph reveals thin short clavicles and abnormal delicate ribs involving the posterior segments of the upper ribs. Limb radiographs show frail long bones, coxa valga, and gradual acroosteolysis of the terminal phalanges. All these findings were observed in the present case, except wormian bones. The common hip manifestations include coxa magna, coxa valga, acetabular dysplasia, bizarre greater trochanters, hip subluxation and dislocation.¹³ Rarely, avascular necrosis of the femoral head, splayed long bone metaphysis/epiphysis, expanded capitulum of the distal humerus have also been reported. Bilateral coxa valga deformity was seen in the present case.

Differential diagnosis would include Werner syndrome (Progeria adultorum), Rothmund-Thomson syndrome, Acrogeria and Cockayne syndrome, which can be comprehended and differentiated by their clinical findings (Table 1).

Long-duration follow-up is needed to monitor the cardiovascular and skeletal abnormalities in these patients. Survival is unlikely after the second decade and cause of death is commonly myocardial infarction or congestive heart failure. Other common complications include decreased bone density, pathological fractures, aberrant dentition and malnourishment. Till date, no definitive treatment is available and patients are managed conservatively.

Conclusion

Hutchinson-Gilford progeria syndrome is a rare premature aging syndrome with distinctive clinical and radiographic findings. Typical imaging findings can help differentiating it from other premature aging syndromes. We have illustrated typical radiographic features of progeria syndrome which is an extremely rare genetic disorder. Intriguing insight into the radiological features can guide in excluding progeria mimics. The oddity of this malady and finite scope of literature prompted us to report this case.

Abbreviations

Hutchinson-Gilford Progeria Syndrome (HGPS)

Conflict of Interest

None.