Hutchinson-Gilford Progeria Syndrome due to homozygous missense variant of LMNA gene
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction
Introduction: Hutchinson-Gilford Progeria Syndrome (HGPS; OMIM 176670) is a rare genetic disorder caused by specific mutations in the LMNA gene, which encodes the lamin A and lamin C proteins. The LMNA gene is located at chromosome 1q22. According to the Progeria Research Foundation, it is estimated that around 350-400 children worldwide are living with progeria, regardless of sex or race, affecting approximately 1 in 20 million individuals. In addition to HGPS, two pathogenic variants in the LMNA gene are associated with a severe condition known as restrictive dermopathy
Case Presentation
Methods: We describe the clinical characteristics, biochemical findings, and genetic diagnosis of two children with Hutchinson-Gilford Progeria Syndrome (HGPS). Genetic testing was performed using a next-generation sequencing panel that included 17 genes known to be associated with HGPS: AGPAT2, ALDH18A1, B4GALT7, BLM, BSCL2, COL3A1, ERCC2, ERCC4, ERCC5, ERCC6, ERCC8, GORAB, LMNA, PYCR1, RECQL4, WRN, and ZMPSTE24. Results: two siblings from unconsangunity family who are 9 years and 23 months. Case 1 is a girl. At the age of 3 months, she pesented with hair lost gradually and she could not sit cross-legged at 8 months. At 12 months, her fingers were swollen and hard, drumstick shaped and both knees bulge. At 8 years, she presented with tight, shiny, and hardened skin on limbs, limited movement and can not walk, she is difficulty swallow, only eat soup and milk, no hair and skin sclerosis at joints and Joint stiffness. On examination, she has failure to thrive with Poor weight gain and loss of subcutaneous fat. The skin is "Sclerodermatous" with taut, thickened, fibrotic, indurated, or rippled. Skin also displays abnormal pigmentation consisting of light or dark macules and patches along with some papules and skin mottling. She had total alopecia, lost of eyebrows and eyelashes. Fingernails and toenails become dystrophic. She has severe scoliosis and knee joint was hypertrophy, callosity and stiffness. Investigation showed normal hematology, biochemistry, normal adominal and heart ultrasound. Limbs scan showed subtacuneous calcification, curvature of the lumber spine. Case 2: presented with hair lost gradually from 3 months of age and hyperpigmentation, especialy at fold skin area at 9 months of age. At 21 months of age he had skin tightness on whole body, short fingers and drumstick shaped, abnormal teeth but he can walk, sit, eat and drink normally. Hematology, biochemistry, abdominal and heart ultrasound were normal. Both of them have homozygous missense variant of LMNA gen: c.1579C>T (p.Arg527Cys) (Chr1: 156137203). Their parents has carrier heterozygous missense variant. This variant is associated with various autosomal recessive disorders, including Hutchinson-Gilford Progeria Syndrome, which typically involve changes in lamin A/C structure affecting nuclear envelope stability
Diagnostic Workup
They were diagnosed with Hutchinson-Gilford Progeria Syndrome (HGPS)
Treatment and Management
Lonafarnib is approved by the U.S. Food and Drug Administration for children 1 year and older.
Outcome and Follow-Up
However, this medicine is not available in Vietnam so our cases were managed with supportive care, including rehabilitation, nutritional therapy, and regular follow-up visits to assess disease progression and associated complications.
Discussion
In our two siblings, the clinical presentation of HGPS, marked by accelerated aging, growth retardation, and severe musculoskeletal deformities, aligns with known pathological consequences of LMNA mutations, which destabilize nuclear lamina and lead to aberrant cellular aging and senescence. Comparatively, other reported cases of LMNA mutations affecting codon 527 underscore its critical role in maintaining nuclear structure and function, with pathogenic variants at this locus frequently linked to severe systemic involvement. The variant's homozygous state, as seen in our cases, likely exacerbates the phenotypic severity due to complete disruption of lamin A/C functionality. This variant-driven disease pathogenesis is characterized by progressive multisystem degeneration, emphasizing the need for further studies to elucidate the genotype-phenotype correlations and potential therapeutic interventions
Conclusion
Conclusion: The findings contribute to the understanding of atypical HGPS presentations and emphasize the significance of genetic counseling for affected families.
Introduction: Hutchinson-Gilford Progeria Syndrome (HGPS; OMIM 176670) is a rare genetic disorder caused by specific mutations in the LMNA gene, which encodes the lamin A and lamin C proteins. The LMNA gene is located at chromosome 1q22. According to the Progeria Research Foundation, it is estimated that around 350-400 children worldwide are living with progeria, regardless of sex or race, affecting approximately 1 in 20 million individuals. In addition to HGPS, two pathogenic variants in the LMNA gene are associated with a severe condition known as restrictive dermopathy
Case Presentation
Methods: We describe the clinical characteristics, biochemical findings, and genetic diagnosis of two children with Hutchinson-Gilford Progeria Syndrome (HGPS). Genetic testing was performed using a next-generation sequencing panel that included 17 genes known to be associated with HGPS: AGPAT2, ALDH18A1, B4GALT7, BLM, BSCL2, COL3A1, ERCC2, ERCC4, ERCC5, ERCC6, ERCC8, GORAB, LMNA, PYCR1, RECQL4, WRN, and ZMPSTE24. Results: two siblings from unconsangunity family who are 9 years and 23 months. Case 1 is a girl. At the age of 3 months, she pesented with hair lost gradually and she could not sit cross-legged at 8 months. At 12 months, her fingers were swollen and hard, drumstick shaped and both knees bulge. At 8 years, she presented with tight, shiny, and hardened skin on limbs, limited movement and can not walk, she is difficulty swallow, only eat soup and milk, no hair and skin sclerosis at joints and Joint stiffness. On examination, she has failure to thrive with Poor weight gain and loss of subcutaneous fat. The skin is "Sclerodermatous" with taut, thickened, fibrotic, indurated, or rippled. Skin also displays abnormal pigmentation consisting of light or dark macules and patches along with some papules and skin mottling. She had total alopecia, lost of eyebrows and eyelashes. Fingernails and toenails become dystrophic. She has severe scoliosis and knee joint was hypertrophy, callosity and stiffness. Investigation showed normal hematology, biochemistry, normal adominal and heart ultrasound. Limbs scan showed subtacuneous calcification, curvature of the lumber spine. Case 2: presented with hair lost gradually from 3 months of age and hyperpigmentation, especialy at fold skin area at 9 months of age. At 21 months of age he had skin tightness on whole body, short fingers and drumstick shaped, abnormal teeth but he can walk, sit, eat and drink normally. Hematology, biochemistry, abdominal and heart ultrasound were normal. Both of them have homozygous missense variant of LMNA gen: c.1579C>T (p.Arg527Cys) (Chr1: 156137203). Their parents has carrier heterozygous missense variant. This variant is associated with various autosomal recessive disorders, including Hutchinson-Gilford Progeria Syndrome, which typically involve changes in lamin A/C structure affecting nuclear envelope stability
Diagnostic Workup
They were diagnosed with Hutchinson-Gilford Progeria Syndrome (HGPS)
Treatment and Management
Lonafarnib is approved by the U.S. Food and Drug Administration for children 1 year and older.
Outcome and Follow-Up
However, this medicine is not available in Vietnam so our cases were managed with supportive care, including rehabilitation, nutritional therapy, and regular follow-up visits to assess disease progression and associated complications.
Discussion
In our two siblings, the clinical presentation of HGPS, marked by accelerated aging, growth retardation, and severe musculoskeletal deformities, aligns with known pathological consequences of LMNA mutations, which destabilize nuclear lamina and lead to aberrant cellular aging and senescence. Comparatively, other reported cases of LMNA mutations affecting codon 527 underscore its critical role in maintaining nuclear structure and function, with pathogenic variants at this locus frequently linked to severe systemic involvement. The variant's homozygous state, as seen in our cases, likely exacerbates the phenotypic severity due to complete disruption of lamin A/C functionality. This variant-driven disease pathogenesis is characterized by progressive multisystem degeneration, emphasizing the need for further studies to elucidate the genotype-phenotype correlations and potential therapeutic interventions
Conclusion
Conclusion: The findings contribute to the understanding of atypical HGPS presentations and emphasize the significance of genetic counseling for affected families.