KISSCHILD WITH STUNTED GROWTH, BALD HEAD AND BIRD LIKE FACIES.
Progeria is a rare disorder of premature aging, which manifests as retarded physical development and abnormal facies, skeletal abnormalities and senile appearance1. There is onset of scleroderma in early childhood. The major changes are in the skin, bone and cardiovascular tissues2. Progressive senile degeneration occurs and death usually occurs in the second decade of life, the most common cause being coronary artery disease1. The patient may first present to the dermatologist due to the appearance of the skin, hence it is an important dermatological diagnosis not to be missed. We report the case of a 13 year old girl who was referred to us for diagnosis; along with discussion on its salient features.
Our patient, a girl currently 13 years of age, is the second child of unrelated parents. She was born at 38 weeks of gestation by vaginal delivery following an uncomplicated pregnancy. She was completely normal at birth with 3.5 kg birth weight and normal head circumference. By the second year of life the parents noticed delayed milestones of development, with stunted physical and skeletal growth. However according to them the mental status of the patient was normal. The patient did not have proper growth of scalp hair, eyebrows and eyelashes, since her early childhood. Her nail growth was poor, and her teeth were also not developing properly. The skin over her arms and legs was progressively getting thin and atrophic with contactures developing at the fingers. There was no history of photosensitivity, visual changes or acral blistering.
Three siblings of the child were completely normal and there was no history of similar problem in any other family member.
On examination the girl had prominent and disproportionately large cranium with small extremities. There was loss of subcutaneous fat especially over the limbs. The abdomen was protuberant. The eyes were prominent and she had a thin beaked nose, low set ears and micrognathia. The nipples were hypoplastic and the external genitalia were also not well developed (Fig. 1 and 2).
Dermatological examination revealed prominent scalp veins with thin and sparse scalp hair (Fig 1 and 3).
The eyebrows were thin and eyelashes were very scanty and thin (Fig 1). The skin overall was thin, smooth and shiny. Over the extremities, especially the hands, the skin was sclerotic and bound down resulting in contractures of the finger joints (Fig 4). There were linear sclerotic bands over the lower legs extending on the dorsa of the feet bilaterally (Fig 5). There was mottled pigmentation especially over the trunk (Fig 6). All the nails were dystrophic (Fig 4 and 5).
The dentition was very poor (Fig 3).
The body was proportionately small and the joints were prominent. However, there were no obvious skeletal abnormalities. Her mental development was normal for her age.
Based on the findings of stunted physical growth, large bald head, abnormal facies, thin atrophic skin and scleroderma like changes on the extremities, a diagnosis of progeria was made. In view of the association of the condition with cardiovascular complications especially atheroma formation, she was referred for a cardiology review, which was normal. Ophthalomological examination was normal, and there were no senile changes in eyes. Skeletal radiology did not reveal any bone deformities.
The parents were counselled about the nature of the disease, its course and the possible complications, which might occur. They were encouraged for a regular follow up of the child and periodic review by a paediatrician, dermatologist, dentist and orthopaedic surgeon.
Progeria (also known as "Hutchinson-Gilford progeria syndrome" and "Hutchinson-Gilford syndrome"1) is a rare and severe genetic condition in which symptoms of aging are manifested at an early age. Progeria was first described in 1886 by Jonathan Hutchinson2 and also described independently in 1897 by Hastings Gilford.3 The condition was later named Hutchinson-Gilford Progeria syndrome (HGPS). The first case of progeria in Pakistan was reported in 20084.
The incidence of the disorder is very low and it occurs one per eight million live births5. The average age of survival is about thirteen years, although many patients have been known to survive till their late teens and early twenties and rarely individuals may even reach their forties6.
It is a genetic condition that occurs as a de novo mutation and is not usually inherited, although there is a uniquely inheritable form. This is in contrast to another rare but similar premature aging syndrome, dyskeratosis congenita (DKC), which is inheritable and will often be expressed multiple times in a family line7.
This disease is of interest to the scientists and the research workers because it might reveal clues about the normal process of aging8,9. HGPS is caused by a point mutation in position 1824 of the LMNA gene. This mutation replaces cytosine with thymine which creates an unusable form of the protein Lamin10, which is part of the building blocks of the nuclear envelope. Other studies show that mutations in a second gene ZMPSTE24, have been found in patients with HGPS11. The pG608G LMNA mutation is the most commonly reported mutation11.
Unlike most other "accelerated aging diseases" (such as Werner's syndrome, Cockayne's syndrome, or xeroderma pigmentosum), progeria is not caused by defective DNA repair. These diseases are called "segmental progerias" or segmental aging syndromes12 as diseases display different aspects of aging but never every aspect.
There is a period of hyperproliferationin the fibroblasts of the patients with progeria, which characterizes the cellular aging and terminates with a large increase in the rate of apoptosis13. This cellular division results in cells with abnormal nuclear morphology and the fraction of these abnormalities increase with cellular age13.
Patients can be subdivided as classical and non-classical HGPS14. Classical progeria follows an autosomal dominant pattern of inheritance, and almost all cases represent spontaneous mutations14. In the non-classical progeria, pattern of inheritance is most probably autosomal recessive. In this pattern there is less retardation of the growth, there is more slow progression of lipodystrophy, scalp hair remains present for a longer time and there is more expression of osteolysis except in the face14.
The earliest distinctive clinical finding in progeria is the skin changes, and careful physical and radiological examination for other features of HGPS15. The presentation is usually in late infancy and early childhood. These patients have a characteristic phenotype of abnormal skin, nails and teeth, alopecia; short stature; failure to thrive; beaked nose and loss of subcutaneous fat16.
The facial features resemble aged persons. Cardiovascular compromise and coronary artery disease leads to early death1,14. Cognitive development is normal. There is extreme variation in the age of onset and nature of the cardiovascular problems17. The most frequent are stroke and coronary dysfunctioning14,17. The coronaries and aorta pathologically show findings that resemble sometimes those in elderly persons, but can also be much more limited17. The most important pathological finding seems to be the loss of smooth muscle cells14. Mean age of survival has been reported to be 12.6 years14.
Recently oral and craniofacial types have been described. Anomalies of dentition, oral and gnathic bones have been described. Hypodontia, steep mandibular angles, dysmorphic teeth, and thin basal bone are the most common radiologigal findings that have been identified in such patients18. Soft tissue findings include ankyloglossia, ogival palatal arch and median sagittal palatal fissure18.
The bony and skeletal deformities that have been described are avascular necrosis of the femoral head, clavicular resorption, abnormalities in modeling of long bones with slender diaphyses, coxavalga, flared metaphyses, and overgrown epiphyses19. It has been shown that long bones show normal cortical thickness in the centre and progressive focal demineralization in periphery19.
Intelligence is normal but sexual maturation is absent1. Somatic and gonadal mosaicisms have been found in progeria20.
Diagnosis of progeria is mainly clinical. Laboratory findings show an increased excretion of hyaluronic acid in urine16. Skin biopsy for histology is not a useful investigation for dignosing this condition15.
No specific and effective treatment is available16, however clinical trials are been carried out for the possible therapeutic modalities. A clinical review showed that the pathway of modifications in the processing of prelamina through alterations in farnesylation offers a possible drug target21. Since the gene defect has been identified, experiments have been done on animal models with drugs that target the primary disease pathway21, and clinically significant baseline data have been obtained. Studies have been performed on mouse models and it has been shown that the combination of statins with bisphosphonates has makedly improved many aging related phenotypes in mice including hair loss, lipodystrophy, growth retardation, bone defects and loss of weight22.
1. N.P. Burrows, C.R. Lovell. Disorders of connective tissue. In: Champion RH, Burton, Burns DA, Breathnach SM, editors.Rook'sText book of Dermatology. Volume 3. 7th edition. Oxford: Blackwell scientific, 2004; 59-60.
2. Hutchinson J .Case of congenital absence of hair, with atrophic condition of the skin and its appendages, in a boy whose mother had been almost wholly bald from alopecia areata from the age of six. Lancet1886; I: 923.
3. Gilford H. Ateleiosis and progeria: continuous youth and premature old age. Brit. Med. J. 1904; 2: 914-8.
4. Iqbal M, Iftikhar A. Progeria-first case report from Pakistan. Rawal Med J.2008; 33(2): 266-7.
5. Russo-Menna I, Arancibias C. The Hutchison-GlifordProgeria Syndrome: a case report.Minerva Anestesiol 2010; 76 (2): 151-4.
6. Ewell Steve Roach, Van S. Miller. Neurocutaneous Disorders. Cambridge University Press 2004: 150.
7. Heiss NS, Knight SW, Vulliamy TJ. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet.1998;19(1): 32-8.
8. Korf B. Hutchinson-Gilford progeria syndrome, aging, and the nuclear lamina.. N. Engl. J. Med.2008; 358: 552-5.
9. Merideth MA, Gordon LB, Clauss S, et al.Phenotype and course of Hutchinson-Gilford progeria syndrome . N. Engl. J. Med. 2008;358 (6): 592-604.
10. Pollex RL, Hegele EA. Hutchinson-Gilford progeria syndrome. Clin Genet. 2004; 66(5): 375-81.
11. Coutinho HD, Falcao-Silva VS, Goncalves GF, da Nobrega RB. Molecular aging in progeroid syndromes: Hutchison-Glifordprogeria syndrome as a model.Immun Aging 2009; 6: 4.
12. Shalev SA, De Sandre-Giovannoli A, Shani AA, Levy N. An association of Hutchinson-Gilford progeria and malignancy. Am J Med Genet A. 2007; 143A(16):1821-6
13. Bridger JM, Kill IR. Aging of Hutchinson-Gilford progeria syndrome fibroblasts is characterised by hyperproliferation and increased apoptosis. Exp Gerontol. 2004; 39(5): 717-24.
14. Hennekam RC. Hutchinson-Gilford progeria syndrome: review of the phenotype. Am J Med Genet A. 2006; 140(23): 2603-24.
15. Mazereeuw-Hautier J, Wilson LC, Mohammed S, Smallwood D, Shackleton S, Atherton DJ et al. Hutchinson-Gilford progeria syndrome: clinical findings in three patients carrying the G608G mutation in LMNA and review of the literature.Br J Dermatol. 2007; 156(6): 1308-14.
16. Ackerman J, Gilbert-Barness E. Hutchinson-Gilford progeria syndrome: a pathologic study.PediatrPathol Mol Med. 2002; 21(1): 1-13.
17. Capell BC, Collins FS, Nabel EG.Mechanisms of cardiovascular disease in accelerated aging syndromes. Circ Res. 2007; 101(1): 13-26.
18. Domingo DL, Trujillo MI, Council SE, Merideth MA, Gordon LB, Wu T et al. Hutchison-Glifordprogeria syndrome: oral and craniofacial phenotypes. Oral Dis.2009;15(3):187-95.
19. Gordon LB, McCarten KM, Giobbie-Hurder A, Machan JT, Campbell SE, Berns SD. Disease progression in Hutchinson-Gilford progeria syndrome: impact on growth and development. Pediatrics 2007; 120(4): 824-33.
20. Wuyts W, Biervliet M, Reyniers E, ,D'Apice MR, Novelli G, Storm K. Somatic and gonadal mosaicism in Hutchinson-Gilford progeria. Am J Med Genet A. 2005; 135 (1):66-8.
21. Kieran MW, Gordon L, Kleinman M. New approaches to progeria. Pediatrics. 2007; 120(4): 834-41.
22. Varela I, Pereira S, Ugalde AP. Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nat. Med. 2008; 14 (7): 767-72.
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|Author:||Alvi, Rehanud din; Hafeez, Javeria; Rizvi, Dilawar Abbas|
|Publication:||Pakistan Armed Forces Medical Journal|
|Article Type:||Clinical report|
|Date:||Mar 31, 2012|
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