CASE REPORT Pediatric Dermatology 1–5, 2014
Hutchinson–Gilford Progeria Syndrome Caused by an LMNA Mutation: A Case Report Yan Chu, M.D., Zi-Gang Xu, M.D., Zhe Xu, M.D., Ph.D., and Lin Ma, M.D. Department of Dermatology, Beijing Children’s Hospital, Capital Medical University, Beijing, China
Abstract: Hutchinson–Gilford progeria syndrome is a rare genetic disorder characterized by premature aging of the skin, bones, heart, and blood vessels. We report a 6-year-old boy who was born at full term but presented with scleroderma-like appearance at 1 month of age and gradually developed clinical manifestations of progeria. He had characteristic facial features of prominent eyes, scalp, and leg veins; loss of scalp hair, eyebrows, and eyelashes; stunted growth; scleroderma-like changes of the skin; and a premature aged appearance. Metabolic investigations showed transient methylmalonic aciduria, and genetic testing of the peripheral blood identified the c.1824C>T heterozygous LMNA mutation. The present case is reported because of its rarity.
Hutchinson first reported Hutchinson–Gilford progeria syndrome (HGPS) in 1886 as a case of “congenital absence of hair and its appendages,” and Gilford introduced the term progeria in 1904 (1). Clinical features of accelerated aging that develop in childhood characterize HGPS. Although signs and symptoms vary in terms of the age of onset and severity, they are remarkably consistent overall. It is a rare hereditary disorder, with approximately 100 cases reported in the medical literature (2). CASE REPORT A 6-year-old boy presented with loss of scalp hair, eyebrows, and eyelashes since 1 month of age, along with stunted growth. The boy was the result of a fullterm normal delivery and appeared normal at birth, with a birthweight of 3,500 g, but he soon failed to
thrive and his skin appeared swollen and sclerodermatous on the trunk and legs at 1 month of age (Fig. 1). The swollen skin subsequently resolved at 10 months of age, but the stunted growth and loss of hair did not improve. On examination, he had distinctive facial features, with prominent eyes and scalp veins, delayed closure of the anterior fontanelle, generalized alopecia with sparse downy hairs, narrow nasal bridge, thin lips, micrognathia, and small ear lobes (Fig. 2). He also had a protuberant abdomen with mottled pigmentation and scleroderma-like changes. He had a varus deformity of the knees with prominent superficial leg veins (Fig. 3). His teeth were eroded. His hands and feet were short and stubby, with small, dystrophic nails (Figs. 4 and 5). His genitalia were normal. His voice was high-pitched, and he was short and malnourished. He was 96 cm tall (A (p.Gly6 08Ser), c.1821G>A (p.Val607Val), or c.1968+1G> A—in atypical HGPS (7,8). There were classic manifestations of progeria and the LMNA mutation in the classic form of HGPS in the present case. Lamin A is an inner nuclear membrane protein with structural and cell-signaling effects. The single C to T transition at nucleotide 1824 of LMNA does not change the translated amino acid (Gly608Gly) but activates a cryptic splice site, resulting in the deletion of 150 base pairs in the 30 portion of exon 11. Translation followed by post-translational processing of this altered mRNA produces a shortened abnormal prelamin A with a 50 amino acid deletion near its
C-terminal end. The 50 amino acid deletion leads to proteolytic cleavage of the terminal 18 amino acids of prelamin A, along with the phosphorylation site(s) involved in the dissociation and reassociation of the nuclear membrane at each cell division. A key to disease in HGPS is the presumable farnesylation of progerin, which permanently intercalates it into the inner nuclear membrane, where it accumulates and exerts progressively more damage to cells as they age. Studies of cell and mouse models that have been engineered to produce a nonfarnesylated progerin product or treated with a drug that inhibits farnesylation, rendering a nonfarnesylated progerin product, strongly support the idea that LMNA gene mutation inducing the lack of mature farnesylation of prelamin A is responsible, at least in part, for the phenotypes observed in HGPS (9). In vitro studies in mice suggest a possible role for the use of farnesyltransferase inhibitors (FTIs) in progeria. FTIs allow prelamin A to be correctly incorporated into the nuclear lamina, correcting the structural and functional nuclear defects (10–13). This case demonstrates the transient high urine level of methylmalonic acid, which was high when he first came in, but normal after 1 week. Methylmalonic aciduria (MMA) is a rare disorder in which a deficiency of malonyl-CoA decarboxylase impairs the body’s ability to convert fatty acids into energy. MMA is related to dysfunction of multiple systems, such as ketoacidosis, hypotonia, hypertension, atherosclerosis and nephropathy. Many of these may be related to inadequate protein and energy intake rather than the pathology of the disease (14). The main manifestations include developmental delay, poor muscle tone, enlarged heart muscle, and metabolic acidosis. MMA is commonly coincidental and not associated with systematic abnormalities. In our case, this boy had a transient high methylmalonic acid urine level without any other symptoms. He has not had any discomfort or symptoms of MMA. By the recent follow-up, repeat metabolic urine screening showed normal amino acid levels, serum folic acid levels had fallen, and gene mutation of MMA was not detected, so MMA cannot be diagnosed in just one urine screening. Long-term follow-up of the patient should be planned. Treatments are available for complications of HGPS, but not for the disease itself. Long-term follow-up is needed to observe cardiovascular and skeletal abnormalities in these patients. Because cutaneous manifestations appear earlier, followed by the skeletal and cardiovascular systems, dermatolo-
Chu et al: Hutchinson-Gilford Progeria Syndrome 5
gists should pay close attention to these symptoms. The present case is reported because of the rarity of the syndrome. ACKNOWLEDGMENT We would like to thank the family of the patient for their cooperation and for consenting to the publication of photographs. REFERENCES 1. Agarwal US, Sitaraman S, Mehta S et al. HutchinsonGilford progeria syndrome. Indian J Dermatol Venematol Leprol 2010;76:591. 2. Shinton RA, Sarkar PK. Hutchinson-Gilford progeria syndrome. Postgrad Med J 2001;77:312–317. 3. Mazereeuw-Hautier J, Wilson LC, Mohammed S 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;156:1308–1314. 4. Gordon LB, McCarten KM, Giobbie-Hurder A et al. Disease progression in Hutchinson-Gilford progeria syndrome: impact on growth and development. Pediatrics 2007;120:824–833. 5. Merideth MA, Gordon LB, Clauss S et al. Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med 2008;358:592–604.
6. De Sandre-Giovannoli A, Bernard R, Cau P et al. Lamin A truncation in Hutchinson-Gilford progeria. Science 2003;300:2055. 7. Kieran MW, Gordon L, Kleinman M. New approaches to progeria. Pediatrics 2007;120:834–841. 8. Moulson CL, Fong LG, Gardner JM et al. Increased progerin expression associated with unusual LMNA mutation causes severe progeroid syndromes. Hum Mutat 2007;28:882–889. 9. Eriksson M, Brown WT, Gordon LB et al. Recurrent de novo point mutations in lamin A cause HutchinsonGilford progeria syndrome. Nature 2003;423:293–298. 10. Julia I. Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes. Proc Natl Acad Sci USA 2005;10:12873– 12878. 11. Yang SH. Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation. Proc Natl Acad Sci USA 2005;102:10291–10296. 12. Brian C. Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of HutchinsonGilford progeria syndrome. Proc Natl Acad Sci USA 2005;102:12879–12884. 13. Monica P. Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci USA 2005;102:14416–14421. 14. Yannicelli S. Nutrition therapy of organic acidaemias with amino acid-based formulas: emphasis on methylmalonic and propionic acidaemia. J Inherit Metab Dis 2006;29:281–287.
Hutchinson–Gilford Progeria Syndrome Caused by an LMNA Mutation: A Case Report Yan Chu, M.D., Zi-Gang Xu, M.D., Zhe Xu, M.D., Ph.D., and Lin Ma, M.D. Department of Dermatology, Beijing Children’s Hospital, Capital Medical University, Beijing, China
Abstract: Hutchinson–Gilford progeria syndrome is a rare genetic disorder characterized by premature aging of the skin, bones, heart, and blood vessels. We report a 6-year-old boy who was born at full term but presented with scleroderma-like appearance at 1 month of age and gradually developed clinical manifestations of progeria. He had characteristic facial features of prominent eyes, scalp, and leg veins; loss of scalp hair, eyebrows, and eyelashes; stunted growth; scleroderma-like changes of the skin; and a premature aged appearance. Metabolic investigations showed transient methylmalonic aciduria, and genetic testing of the peripheral blood identified the c.1824C>T heterozygous LMNA mutation. The present case is reported because of its rarity.
Hutchinson first reported Hutchinson–Gilford progeria syndrome (HGPS) in 1886 as a case of “congenital absence of hair and its appendages,” and Gilford introduced the term progeria in 1904 (1). Clinical features of accelerated aging that develop in childhood characterize HGPS. Although signs and symptoms vary in terms of the age of onset and severity, they are remarkably consistent overall. It is a rare hereditary disorder, with approximately 100 cases reported in the medical literature (2). CASE REPORT A 6-year-old boy presented with loss of scalp hair, eyebrows, and eyelashes since 1 month of age, along with stunted growth. The boy was the result of a fullterm normal delivery and appeared normal at birth, with a birthweight of 3,500 g, but he soon failed to
thrive and his skin appeared swollen and sclerodermatous on the trunk and legs at 1 month of age (Fig. 1). The swollen skin subsequently resolved at 10 months of age, but the stunted growth and loss of hair did not improve. On examination, he had distinctive facial features, with prominent eyes and scalp veins, delayed closure of the anterior fontanelle, generalized alopecia with sparse downy hairs, narrow nasal bridge, thin lips, micrognathia, and small ear lobes (Fig. 2). He also had a protuberant abdomen with mottled pigmentation and scleroderma-like changes. He had a varus deformity of the knees with prominent superficial leg veins (Fig. 3). His teeth were eroded. His hands and feet were short and stubby, with small, dystrophic nails (Figs. 4 and 5). His genitalia were normal. His voice was high-pitched, and he was short and malnourished. He was 96 cm tall (A (p.Gly6 08Ser), c.1821G>A (p.Val607Val), or c.1968+1G> A—in atypical HGPS (7,8). There were classic manifestations of progeria and the LMNA mutation in the classic form of HGPS in the present case. Lamin A is an inner nuclear membrane protein with structural and cell-signaling effects. The single C to T transition at nucleotide 1824 of LMNA does not change the translated amino acid (Gly608Gly) but activates a cryptic splice site, resulting in the deletion of 150 base pairs in the 30 portion of exon 11. Translation followed by post-translational processing of this altered mRNA produces a shortened abnormal prelamin A with a 50 amino acid deletion near its
C-terminal end. The 50 amino acid deletion leads to proteolytic cleavage of the terminal 18 amino acids of prelamin A, along with the phosphorylation site(s) involved in the dissociation and reassociation of the nuclear membrane at each cell division. A key to disease in HGPS is the presumable farnesylation of progerin, which permanently intercalates it into the inner nuclear membrane, where it accumulates and exerts progressively more damage to cells as they age. Studies of cell and mouse models that have been engineered to produce a nonfarnesylated progerin product or treated with a drug that inhibits farnesylation, rendering a nonfarnesylated progerin product, strongly support the idea that LMNA gene mutation inducing the lack of mature farnesylation of prelamin A is responsible, at least in part, for the phenotypes observed in HGPS (9). In vitro studies in mice suggest a possible role for the use of farnesyltransferase inhibitors (FTIs) in progeria. FTIs allow prelamin A to be correctly incorporated into the nuclear lamina, correcting the structural and functional nuclear defects (10–13). This case demonstrates the transient high urine level of methylmalonic acid, which was high when he first came in, but normal after 1 week. Methylmalonic aciduria (MMA) is a rare disorder in which a deficiency of malonyl-CoA decarboxylase impairs the body’s ability to convert fatty acids into energy. MMA is related to dysfunction of multiple systems, such as ketoacidosis, hypotonia, hypertension, atherosclerosis and nephropathy. Many of these may be related to inadequate protein and energy intake rather than the pathology of the disease (14). The main manifestations include developmental delay, poor muscle tone, enlarged heart muscle, and metabolic acidosis. MMA is commonly coincidental and not associated with systematic abnormalities. In our case, this boy had a transient high methylmalonic acid urine level without any other symptoms. He has not had any discomfort or symptoms of MMA. By the recent follow-up, repeat metabolic urine screening showed normal amino acid levels, serum folic acid levels had fallen, and gene mutation of MMA was not detected, so MMA cannot be diagnosed in just one urine screening. Long-term follow-up of the patient should be planned. Treatments are available for complications of HGPS, but not for the disease itself. Long-term follow-up is needed to observe cardiovascular and skeletal abnormalities in these patients. Because cutaneous manifestations appear earlier, followed by the skeletal and cardiovascular systems, dermatolo-
Chu et al: Hutchinson-Gilford Progeria Syndrome 5
gists should pay close attention to these symptoms. The present case is reported because of the rarity of the syndrome. ACKNOWLEDGMENT We would like to thank the family of the patient for their cooperation and for consenting to the publication of photographs. REFERENCES 1. Agarwal US, Sitaraman S, Mehta S et al. HutchinsonGilford progeria syndrome. Indian J Dermatol Venematol Leprol 2010;76:591. 2. Shinton RA, Sarkar PK. Hutchinson-Gilford progeria syndrome. Postgrad Med J 2001;77:312–317. 3. Mazereeuw-Hautier J, Wilson LC, Mohammed S 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;156:1308–1314. 4. Gordon LB, McCarten KM, Giobbie-Hurder A et al. Disease progression in Hutchinson-Gilford progeria syndrome: impact on growth and development. Pediatrics 2007;120:824–833. 5. Merideth MA, Gordon LB, Clauss S et al. Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med 2008;358:592–604.
6. De Sandre-Giovannoli A, Bernard R, Cau P et al. Lamin A truncation in Hutchinson-Gilford progeria. Science 2003;300:2055. 7. Kieran MW, Gordon L, Kleinman M. New approaches to progeria. Pediatrics 2007;120:834–841. 8. Moulson CL, Fong LG, Gardner JM et al. Increased progerin expression associated with unusual LMNA mutation causes severe progeroid syndromes. Hum Mutat 2007;28:882–889. 9. Eriksson M, Brown WT, Gordon LB et al. Recurrent de novo point mutations in lamin A cause HutchinsonGilford progeria syndrome. Nature 2003;423:293–298. 10. Julia I. Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes. Proc Natl Acad Sci USA 2005;10:12873– 12878. 11. Yang SH. Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation. Proc Natl Acad Sci USA 2005;102:10291–10296. 12. Brian C. Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of HutchinsonGilford progeria syndrome. Proc Natl Acad Sci USA 2005;102:12879–12884. 13. Monica P. Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci USA 2005;102:14416–14421. 14. Yannicelli S. Nutrition therapy of organic acidaemias with amino acid-based formulas: emphasis on methylmalonic and propionic acidaemia. J Inherit Metab Dis 2006;29:281–287.
