Acromicric Dysplasia Caused by a Novel Heterozygous Mutation of FBN1 and Effects of Growth Hormone Treatment.
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SUBMITTER: Jin HS
PROVIDER: S-EPMC5107629 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
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Acromicric Dysplasia Caused by a Novel Heterozygous Mutation of FBN1 and Effects of Growth Hormone Treatment.
Jin Hyung Suk HS Song Ho Young HY Cho Sung Yoon SY Ki Chang Seok CS Yang Song Hyun SH Kim Ok Hwa OH Kim Su Jin SJ
Annals of laboratory medicine 20170101 1
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Project description:Acromicric dysplasia (AD) and geleophysic dysplasia 2 (GD2) belong to the category of acromelic dysplasia syndromes, consisting of severe short stature, short hands and feet and skin thickening. Both can result from missense mutations in the transforming growth factor beta 5 domain of the fibrillin-1 gene (FBN1).Two patients (P1 age 10, and P2 age 7) from unrelated families presented to their endocrinologist with severe short stature (approx. -4 SDS). They were otherwise asymptomatic and only had mild facial dysmorphisms. Extensive endocrine work-up did not reveal an underlying etiology. Exome sequencing was performed in each family.Exome sequencing identified the presence of the same heterozygous missense variant c.C5183T (p.Ala1728Val) in the FBN1 gene in both P1 and P2. This variant was previously reported in a patient with GD2 and associated cardiac valvulopathy and hepatomegaly. Detailed clinical re-examination, cardiac and skeletal imaging did not reveal any abnormalities in P1 or P2 other than mild hip dysplasia.This report broadens the phenotypic spectrum of growth disorders associated with FBN1 mutations. Identical mutations give rise to a wide phenotypic spectrum, ranging from isolated short stature to a more classic picture of GD2 with cardiac involvement, distinct facial dysmorphisms and various skeletal anomalies.
| S-EPMC5135661 | biostudies-literature
Project description:BackgroundAcromicric 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 summaryWe 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.ConclusionFBN1-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.
| S-EPMC10044957 | biostudies-literature
Project description:BackgroundGeleophysic dysplasia (GD) presents the characterized clinical manifestations of acromelic dysplasia, including extremely short stature, short limbs, small hands and feet, stubby fingers and toes, joint stiffness and others. It is clinically distinct from the other acromelic dysplasia in terms of symptoms such as cardiac valvular abnormalities, progressive hepatomegaly and tracheal stenosis.Case summaryWe report on a Chinese 9-year-old girl with GD with the c.5243G>T (p.C1748F) mutation in FBN1 (fibrillin 1, OMIM 134797). She was born in Guangxi Zhuang Autonomous Region of China. The patient presented with typical clinical features of GD and recurrent respiratory tract infections over 6 years. Laboratory studies and chest computed tomography (CT) scan indicated bronchopneumonia. Her echocardiography revealed mild mitral valve thickening with regurgitation. Laryngopharyngeal CT and electronic bronchoscopy revealed severe glottic stenosis. Echocardiography examination displayed mild mitral valve thickening and regurgitation. Ophthalmic examination did not reveal myopia or lens dislocation. Treated with ceftriaxone sodium and methylprednisolone sodium succinate for injection as well as methylprednisolone orally, patient's symptoms had improved.ConclusionGD is a rare genetic condition that can cause life-threatening cardiovascular and respiratory problems. This study also found that the identified genotype of GD could be related to different clinical phenotypes.
| S-EPMC8409200 | biostudies-literature
Project description:BackgroundAcromicric dysplasia is a rare heritable short-stature syndrome with joint stiffness and varying degrees of cutaneous hardness. Stiff skin syndrome is a rare connective tissue disorder characterized by diffusely thick and hard skin from the time of birth. Heterozygous point mutations in the FBN1 have been proposed as the predominant cause of both diseases.MethodsBy performing skin biopsy, X-ray imaging, electrocardiography, as well as whole-genome sequencing and Sanger sequencing, we diagnosed an 8-year-old Chinese boy as acromicric dysplasia with severe skin stiffness caused by a heterogeneous mutation in the FBN1.ResultsThe patient presented with skin tightness, wrist and ankle stiffness, short stature and limbs, several deformed joints in the extremities, cone-shaped epiphyses, and distinct facial features. He also had a patent foramen ovale and frequent respiratory infections. Skin biopsy showed thickened dermis and excessive collagen aggregation. Alcian blue staining indicated dermal mucopolysaccharide deposition. Mutation analysis revealed a heterozygous missense mutation, c.5243G>A (p.Cys1748Tyr), in exon 42 of the FBN1.ConclusionThis is a report about acromicric dysplasia with stiff skin syndrome-like severe cutaneous presentation caused by a single hotspot mutation, further revealing the gene pleiotropy of FBN1.
| S-EPMC7336748 | biostudies-literature
Project description:Cleidocranial dysplasia (CCD) is a rare congenital autosomal dominant skeletal disorder that is characterized by hypoplasia or aplasia of clavicles, failure of cranial suture closure, dental anomalies, short stature and other changes in skeletal patterning and growth. The gene responsible for pathogenesis has been mapped to the short arm of chromosome 6p21, core binding factor alpha-1 (CBFA1) or runt related transcription factor-2 (RUNX2). Here we describe a CCD patient with a novel mutation in the RUNX2 gene. A five-and-a-half year old girl presented with severe short stature, dysmorphic facial appearance (hypertelorism, prominent forehead, high palate, midfacial hypoplasia), macrocephaly, large anterior fontanelle, increased anteroposterior chest diameter. Her shoulders were close to each other and her bilateral clavicles appeared short on physical examination. Bilateral hypoplastic clavicles, coxa valga, hypoplasia of iliac bones, wide symphysis pubis and phalangeal dysplastic features were detected on her skeletal X-ray examination. She was diagnosed as having CCD. Molecular analysis detected a novel heterozygous mutation ‘NM_001024630.3p.T155P(c.463A>C)’ in the RUNX2 gene. At age seven years and two months old, because of her severe short stature, growth hormone (GH) treatment was started and she responded well to GH therapy with no adverse effects. In conclusion, hypoplasia or aplasia of the clavicles, failure of cranial suture closure, dental anomalies and short stature should bring CCD to mind. We present a novel mutation in the RUNX2 gene for CCD. We obtained growth velocity gain with GH treatment in our patient.
| S-EPMC6745455 | biostudies-literature
Project description:Weiss-Kruszka syndrome (WSKA) is a rare disease most often caused by mutations in the ZNF462 gene. To screen for hereditary diseases, exons from the patient's genome were sequenced. Genomic PCR experiments followed by Sanger sequencing were used to confirm the mutated genomic regions in the patient and his parents. We report a new mutation site, a heterozygous mutation (NM_021224.6:c.6311dup) in ZNF462 in a male patient of 8 years old. The mutation in the ZNF462 gene caused WSKA. This patient is the first case with WSKA characterized by attention-deficit hyperactivity disorder and complete growth hormone deficiency without pituitary lesions. Our results suggest that the heterozygous mutation in ZNF462 is the direct cause of WSKA in this patient. Mutations in other genes interacting with ZNF462 result in similar symptoms of WSKA. Furthermore, ZNF462 and its interacting proteins ASXL2 and VPS13B may form a protein complex that is important for normal development but awaits more studies to reveal its detailed functions.
| S-EPMC9770794 | biostudies-literature
Project description:Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder, mostly caused by mutations in the fibrillin-1 (FBN1) gene. We, by using targeted next-generation sequence analysis, identified a novel intronic FBN1 mutation (the c.2678-15C>A variant) in a MFS patient with aortic dilatation. The computational predictions showed that the heterozygous c.2678-15C>A intronic variant might influence the splicing process by differentially affecting canonical versus cryptic splice site utilization within intron 22 of the FBN1 gene. RT-PCR and Western blot analyses, using FBN1 minigenes transfected into HeLa and COS-7 cells, revealed that the c.2678-15C>A variant disrupts normal splicing of intron 22 leading to aberrant 13-nt intron 22 inclusion, frameshift, and premature termination codon. Collectively, the results strongly suggest that the c.2678-15C>A variant could lead to haploinsufficiency of the FBN1 functional protein and structural connective tissue fragility in MFS complicated by aorta dilation, a finding that further expands on the genetic basis of aortic pathology.
| S-EPMC5996431 | biostudies-literature
Project description:Background Cleidocranial dysplasia (CCD, #MIM119600) is an autosomal-dominant skeletal dysplasia characterized by delayed closure of the cranial sutures, aplasia, or hypoplasia of the clavicles and dental abnormalities. These findings were accompanied by mobile and drooping shoulders, frontal and parietal bossing, hypertelorism, brachycephaly, short stature, supernumerary, and late erupting teeth. Radiographic studies can reveal involvement of multiple bones including skull, chest, pelvis, and limbs. CCD can be diagnosed with clinical and radiological evaluation and validated by molecular studies. Heterozygous loss of function RUNX2 gene, which plays an important role in osteogenesis and differentiation of precursor cells, causes CCD phenotype. Methods In this article, we reported five cases from three unrelated families with CCD phenotype. All exons and exonic-intronic boundary regions of RUNX2 gene from five patients were analyzed by polymerase chain reaction amplification and direct Sanger-sequencing. Results Our patients had classical CCD phenotype and we detected three different previously described mutations including c.1171C > T, IVS4 + 4delAAGT and c.676G > A. However, nail dysplasia has never been associated with these mutations. Our patients had varying degrees of nail dysplasia. Two of three mutations are related with Runt DNA-binding domain of RUNX2 protein in Wnt signaling and c.1171C > T had effect on proline/serine/threonine-rich (PST) domain. Recently, Wnt signaling pathway was presented as a key regulator of digit and nail differentiation. Our data suggest that RUNX2 gene may have an essential role on embryogenesis of nails, probably by protecting their integrity.
| S-EPMC8837417 | biostudies-literature
Project description:BackgroundThyroid hormone resistance syndrome (THRS) is a rare disorder with increased concentrations of free thyroxine (FT4) and triiodothyronine (FT3), but normal or slightly increased thyroid-stimulating hormone (TSH). The mutations in the thyroid hormone receptor β (THRβ) gene are thought to be the main pathogenesis.ObjectivesThe aims of this study were to present 1 pedigree of Chinese THRS, summarize their clinical characteristics, and analyze the gene mutation.MethodsThe clinical characteristics and thyroid function of the proband and his family members were collected. Gene mutations were analyzed by DNA sequencing.ResultsThe proband and his mother exhibited symptoms of hyperthyroidism, such as palpitations, heat intolerance, and perspiration. The mother also had atrial fibrillation. The rest of the kindred did not display clinical manifestations of hyper- or hypothyroidism. DNA sequencing revealed a heterozygous G>A missense mutation at position 949 in Exon 9 of THRβ both in the patient and his mother, which led to the transition from alanine to threonine at position 317 of THRβ protein (A317T), whereas the rest of the kindred did not share this mutation. The proband and his mother were diagnosed with pituitary resistance to thyroid hormone. Oral administration of methimazole was stopped and β-receptor blockers were administrated.ConclusionsWe present 1 pedigree of THRS with heterozygous A317T mutation in THRβ gene in the proband and his mother, which is the first reported mutation in Chinese and provides a comprehensive review of available literature.
| S-EPMC5370793 | biostudies-literature
Project description:There are urgent demands for efficient treatment of heritable genetic diseases. The base editing technology has displayed its efficiency and precision in base substitution in human embryos, providing a potential early-stage treatment for genetic diseases. Taking advantage of this technology, we corrected a Marfan syndrome pathogenic mutation, FBN1T7498C. We first tested the feasibility in mutant cells, then successfully achieved genetic correction in heterozygous human embryos. The results showed that the BE3 mediated perfect correction at the efficiency of about 89%. Importantly, no off-target and indels were detected in any tested sites in samples by high-throughput deep sequencing combined with whole-genome sequencing analysis. Our study therefore suggests the efficiency and genetic safety of correcting a Marfan syndrome (MFS) pathogenic mutation in embryos by base editing.
| S-EPMC6224777 | biostudies-literature