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Tian F, Dong X, Yuan R, Hou X, Qing J, Li Y. Case Report: Two different acromelic dysplasia phenotypes in a Chinese family caused by a missense mutation in FBN1 and a literature review. Front Pediatr 2024; 12:1428513. [PMID: 39077065 PMCID: PMC11284092 DOI: 10.3389/fped.2024.1428513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 07/02/2024] [Indexed: 07/31/2024] Open
Abstract
Background Acromelic dysplasia caused by FBN1 mutation includes acromicric dysplasia (AD), geleophysic dysplasia 2 (GD2), and Weill-Marchesani syndrome 2 (WMS2). All three diseases share severe short stature and brachydactyly. Besides phenotypic similarity, there is a molecular genetic overlap among them, as identical FBN1 gene mutations have been identified in patients with AD, GD2, and WMS2. However, no family with different acromelic dysplasia phenotypes due to the same variant has been described in English reports. Case report The proband presented with typical facial features, severe short stature, short limbs, stubby hands and feet and radiological abnormalities. Her elder sister and mother had similar physical features. In addition, her elder sister was found to have aortic valve stenosis by echocardiography. Mutation analysis demonstrated a heterozygous missense mutation, c.5179C>T (p.Arg1727Trp) in exon 42 of the FBN1. The proband and her mother were diagnosed with AD, and her elder sister with GD2. The proband was treated with recombinant human growth hormone (rhGH) and had a body length gain of 0.72 SDS in half a year. Conclusion These findings expand the phenotypic spectrum of FBN1 gene mutations and highlight that identical FBN1 genotypes can result in different phenotypes of acromelic dysplasia in a family. The efficacy of rhGH therapy in patients with acromelic dysplasia is controversial. More follow-up is needed on the long-term efficacy of rhGH therapy.
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Affiliation(s)
- Fengyan Tian
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Arnaud P, Mougin Z, Baujat G, Drouin-Garraud V, El Chehadeh S, Gouya L, Odent S, Jondeau G, Boileau C, Hanna N, Le Goff C. Pathogenic variants affecting the TB5 domain of the fibrillin-1 protein: not only in geleophysic/acromicric dysplasias but also in Marfan syndrome. J Med Genet 2024; 61:469-476. [PMID: 38458756 DOI: 10.1136/jmg-2023-109646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 01/18/2024] [Indexed: 03/10/2024]
Abstract
BACKGROUND Marfan syndrome (MFS) is a multisystem disease with a unique combination of skeletal, cardiovascular and ocular features. Geleophysic/acromicric dysplasias (GPHYSD/ACMICD), characterised by short stature and extremities, are described as 'the mirror image' of MFS. The numerous FBN1 pathogenic variants identified in MFS are located all along the gene and lead to the same final pathogenic sequence. Conversely, in GPHYSD/ACMICD, the 28 known heterozygous FBN1 pathogenic variants all affect exons 41-42 encoding TGFβ-binding protein-like domain 5 (TB5). METHODS Since 1996, more than 5000 consecutive probands have been referred nationwide to our laboratory for molecular diagnosis of suspected MFS. RESULTS We identified five MFS probands carrying distinct heterozygous pathogenic in-frame variants affecting the TB5 domain of FBN1. The clinical data showed that the probands displayed a classical form of MFS. Strikingly, one missense variant affects an amino acid that was previously involved in GPHYSD. CONCLUSION Surprisingly, pathogenic variants in the TB5 domain of FBN1 can lead to two opposite phenotypes: GPHYSD/ACMICD and MFS, suggesting the existence of different pathogenic sequences with the involvement of tissue specificity. Further functional studies are ongoing to determine the precise role of this domain in the physiopathology of each disease.
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Affiliation(s)
- Pauline Arnaud
- Département de Génétique, Assistance Publique - Hopitaux de Paris, Paris, France
- U1148 LVTS, INSERM, Paris, Île-de-France, France
- Centre de Référence Maladies Rares Syndrome de Marfan et apparentés, Hôpital Bichat, APHP, Paris, Île-de-France, France
| | | | - Genevieve Baujat
- Département de Génétique, AP-HP, Hôpital Necker-Enfants malades, AP-HP, Paris, Île-de-France, France
| | | | - Salima El Chehadeh
- Service de Génétique Médicale, Hôpital de Hautepierre, CHU de Strasbourg, Strasbourg, Grand Est, France
| | - Laurent Gouya
- Centre de Référence Maladies Rares Syndrome de Marfan et apparentés, Hôpital Bichat, APHP, Paris, Île-de-France, France
| | - Sylvie Odent
- Service de Génétique Clinique, CLAD Ouest, CHU Rennes, Rennes, Bretagne, France
- UMR 6290, IGDR, Rennes, Bretagne, France
| | - Guillaume Jondeau
- U1148 LVTS, INSERM, Paris, Île-de-France, France
- Centre de Référence Maladies Rares Syndrome de Marfan et apparentés, Hôpital Bichat, APHP, Paris, Île-de-France, France
| | - Catherine Boileau
- Département de Génétique, Assistance Publique - Hopitaux de Paris, Paris, France
- U1148 LVTS, INSERM, Paris, Île-de-France, France
| | - Nadine Hanna
- Département de Génétique, Assistance Publique - Hopitaux de Paris, Paris, France
- U1148 LVTS, INSERM, Paris, Île-de-France, France
- Centre de Référence Maladies Rares Syndrome de Marfan et apparentés, Hôpital Bichat, APHP, Paris, Île-de-France, France
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Shen R, Feng JH, Yang SP. Acromicric dysplasia caused by a mutation of fibrillin 1 in a family: A case report. World J Clin Cases 2023; 11:2036-2042. [PMID: 36998968 PMCID: PMC10044957 DOI: 10.12998/wjcc.v11.i9.2036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/20/2023] [Accepted: 03/03/2023] [Indexed: 03/16/2023] Open
Abstract
BACKGROUND Acromicric dysplasia (AD) is a rare skeletal dysplasia. Its incidence is < 1/1000000, and only approximately 60 cases are reported worldwide. It is a disease characterized by severe short stature, short hands and feet, facial abnormalities, normal intelligence, and bone abnormalities. Unlike other skeletal dysplasia, AD has a mild clinical phenotype, mainly characterized by short stature. Extensive endocrine examination has not revealed a potential cause. The clinical effect of growth hormone therapy is still uncertain.
CASE SUMMARY We report a clinical phenotype of AD associated with mutations in the fibrillin 1 (FBN1) (OMIM 102370) gene c.5183C>T (p. Ala1728Val) in three people from a Chinese family. A 4-year-old member of the family first visited the hospital because of slow growth and short stature for 2 years, but no abnormalities were found after a series of laboratory tests, echocardiography, pituitary magnetic resonance imaging, and ophthalmological examination. Recombinant human growth hormone (rhGH) was used to treat the patient for > 5 years. The efficacy of rhGH was apparent in the first year of treatment; the height increased from -3.64 standard deviation score (SDS) to -2.88 SDS, while the efficacy weakened from the second year. However, long-term follow-up is required to clarify the efficacy of rhGH.
CONCLUSION FBN1-related AD has genetic heterogeneity and/or clinical variability, which brings challenges to the evaluation of clinical treatment. rhGH is effective for treatment of AD, but long-term follow-up is needed to clarify the effect.
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Affiliation(s)
- Ren Shen
- Department of Pediatrics, The People's Hospital of Yuhuan, Taizhou 317600, Zhejiang Province, China
| | - Jian-Hua Feng
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Shan-Pu Yang
- Department of Pediatrics, The People's Hospital of Yuhuan, Taizhou 317600, Zhejiang Province, China
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