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1.
J Med Genet ; 61(5): 469-476, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38458756

RESUMO

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 TGFß-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.


Assuntos
Doenças do Desenvolvimento Ósseo , Deformidades Congênitas dos Membros , Síndrome de Marfan , Humanos , Doenças do Desenvolvimento Ósseo/genética , Fibrilina-1/genética , Síndrome de Marfan/genética , Síndrome de Marfan/patologia , Mutação
2.
J Med Genet ; 60(4): 337-345, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-35927022

RESUMO

BACKGROUND: Ellis-Van Creveld (EVC) syndrome is one of the entities belonging to the skeletal ciliopathies short rib-polydactyly subgroup. Major signs are ectodermal dysplasia, chondrodysplasia, polydactyly and congenital cardiopathy, with a high degree of variability in phenotypes ranging from lethal to mild clinical presentations. The EVC and EVC2 genes are the major genes causative of EVC syndrome. However, an increased number of genes involved in the ciliopathy complex have been identified in EVC syndrome, leading to a better understanding of its physiopathology, namely, WDR35, GLI1, DYNC2LI1, PRKACA, PRKACB and SMO. They all code for proteins located in the primary cilia, playing a key role in signal transduction of the Hedgehog pathways. METHODS: The aim of this study was the analysis of 50 clinically identified EVC cases from 45 families to further define the phenotype and molecular bases of EVC. RESULTS: Our detection rate in the cohort of 45 families was of 91.11%, with variants identified in EVC/EVC2 (77.8%), DYNC2H1 (6.7%), DYNC2LI1 (2.2%), SMO (2.2%) or PRKACB (2.2%). No distinctive feature was remarkable of a specific genotype-phenotype correlation. Interestingly, we identified a high proportion of heterozygous deletions in EVC/EVC2 of variable sizes (26.92%), mostly inherited from the mother, and probably resulting from recombinations involving Alu sequences. CONCLUSION: We confirmed that EVC and EVC2 are the major genes involved in the EVC phenotype and highlighted the high prevalence of previously unreported CNVs (Copy Number Variation).


Assuntos
Síndrome de Ellis-Van Creveld , Polidactilia , Humanos , Proteínas Hedgehog/genética , Síndrome de Ellis-Van Creveld/genética , Síndrome de Ellis-Van Creveld/diagnóstico , Variações do Número de Cópias de DNA/genética , Fenótipo
3.
Am J Hum Genet ; 106(6): 779-792, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32413283

RESUMO

The evolutionarily conserved hedgehog (Hh) pathway is essential for organogenesis and plays critical roles in postnatal tissue maintenance and renewal. A unique feature of the vertebrate Hh pathway is that signal transduction requires the primary cilium (PC) where major pathway components are dynamically enriched. These factors include smoothened (SMO) and patched, which constitute the core reception system for sonic hedgehog (SHH) as well as GLI transcription factors, the key mediators of the pathway. Here, we report bi-allelic loss-of-function variations in SMO in seven individuals from five independent families; these variations cause a wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis). Cells derived from affected individuals showed normal ciliogenesis but severely altered Hh-signal transduction as a result of either altered PC trafficking or abnormal activation of the pathway downstream of SMO. In addition, Hh-independent GLI2 accumulation at the PC tip in cells from the affected individuals suggests a potential function of SMO in regulating basal ciliary trafficking of GLI2 when the pathway is off. Thus, loss of SMO function results in abnormal PC dynamics of key components of the Hh signaling pathway and leads to a large continuum of malformations in humans.


Assuntos
Alelos , Deficiências do Desenvolvimento/genética , Proteínas Hedgehog/metabolismo , Transdução de Sinais , Receptor Smoothened/genética , Sequência de Bases , Criança , Pré-Escolar , Cílios/fisiologia , Feminino , Humanos , Lactente , Masculino , Modelos Moleculares , Neoplasias/genética , Proteínas do Tecido Nervoso , Proteínas Nucleares , Linhagem , Proteína Gli2 com Dedos de Zinco , Proteína Gli3 com Dedos de Zinco
4.
Clin Genet ; 104(1): 114-120, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36951206

RESUMO

The NADSYN1 gene [MIM*608285] encodes the NAD synthetase 1 enzyme involved in the final step of NAD biosynthesis, crucial for cell metabolism and organ embryogenesis. Perturbating the role of NAD biosynthesis results in the association of vertebral, cardiac, renal, and limb anomalies (VCRL). This condition was initially characterized as severe with perinatal lethality or developmental delay and complex malformations in alive cases. Sixteen NADSYN1-associated patients have been published so far. This study illustrates the wide phenotypic variability in NADSYN1-associated NAD deficiency disorder. We report the clinical and molecular findings in three novel cases, two of them being siblings with the same homozygous variant and presenting with either a very severe prenatal lethal or a mild phenotypic form. In addition to an exhaustive literature, we validate the expansion of the spectrum of NAD deficiency disorder. Our findings indicate that NAD deficiency disorder should be suspected not only in the presence of the full spectrum of VCRL, but even a single of the aforementioned organs is affected. Decreased plasmatic levels of NAD should then strongly encourage the screening for any of the genes responsible for a NAD deficiency disorder.


Assuntos
Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida , NAD , Feminino , Humanos , Gravidez , Homozigoto , Coluna Vertebral/anormalidades , Síndrome
5.
Clin Genet ; 104(5): 554-563, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37580112

RESUMO

The PIK3CA-related overgrowth spectrum (PROS) encompasses various conditions caused by mosaic activating PIK3CA variants. PIK3CA somatic variants are also involved in various cancer types. Some generalized overgrowth syndromes are associated with an increased risk of Wilms tumor (WT). In PROS, abdominal ultrasound surveillance has been advocated to detect WT. We aimed to determine the risk of embryonic and other types of tumors in patients with PROS in order to evaluate surveillance relevance. We searched the clinical charts from 267 PROS patients for the diagnosis of cancer, and reviewed the medical literature for the risk of cancer. In our cohort, six patients developed a cancer (2.2%), and Kaplan Meier analyses estimated cumulative probabilities of cancer occurrence at 45 years of age was 5.6% (95% CI = 1.35%-21.8%). The presence of the PIK3CA variant was only confirmed in two out of four tumor samples. In the literature and our cohort, six cases of Wilms tumor/nephrogenic rests (0.12%) and four cases of other cancers have been reported out of 483 proven PIK3CA patients, in particular the p.(His1047Leu/Arg) variant. The risk of WT in PROS being lower than 5%, this is insufficient evidence to recommend routine abdominal imaging. Long-term follow-up studies are needed to evaluate the risk of other cancer types, as well as the relationship with the extent of tissue mosaicism and the presence or not of the variant in the tumor samples.


Assuntos
Neoplasias Renais , Tumor de Wilms , Humanos , Mutação , Detecção Precoce de Câncer , Transtornos do Crescimento/diagnóstico , Tumor de Wilms/diagnóstico , Tumor de Wilms/epidemiologia , Tumor de Wilms/genética , Classe I de Fosfatidilinositol 3-Quinases/genética
6.
Am J Med Genet A ; 191(1): 77-83, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36271508

RESUMO

Developmental abnormalities provide a unique opportunity to seek for the molecular mechanisms underlying human organogenesis. Esophageal development remains incompletely understood and elucidating causes for esophageal atresia (EA) in humans would contribute to achieve a better comprehension. Prenatal detection, syndromic classification, molecular diagnosis, and prognostic factors in EA are challenging. Some syndromes have been described to frequently include EA, such as CHARGE, EFTUD2-mandibulofacial dysostosis, Feingold syndrome, trisomy 18, and Fanconi anemia. However, no molecular diagnosis is made in most cases, including frequent associations, such as Vertebral-Anal-Cardiac-Tracheo-Esophageal-Renal-Limb defects (VACTERL). This study evaluates the clinical and genetic test results of 139 neonates and 9 fetuses followed-up at the Necker-Enfants Malades Hospital over a 10-years period. Overall, 52 cases were isolated EA (35%), and 96 were associated with other anomalies (65%). The latter group is divided into three subgroups: EA with a known genomic cause (9/148, 6%); EA with Vertebral-Anal-Cardiac-Tracheo-Esophageal-Renal-Limb defects (VACTERL) or VACTERL/Oculo-Auriculo-Vertebral Dysplasia (VACTERL/OAV) (22/148, 14%); EA with associated malformations including congenital heart defects, duodenal atresia, and diaphragmatic hernia without known associations or syndromes yet described (65/148, 44%). Altogether, the molecular diagnostic rate remains very low and may underlie frequent non-Mendelian genetic models.


Assuntos
Atresia Esofágica , Cardiopatias Congênitas , Deformidades Congênitas dos Membros , Fístula Traqueoesofágica , Recém-Nascido , Gravidez , Feminino , Humanos , Atresia Esofágica/diagnóstico , Atresia Esofágica/genética , Estudos Retrospectivos , Fístula Traqueoesofágica/genética , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/complicações , Traqueia/anormalidades , Coluna Vertebral/anormalidades , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/complicações , Rim/anormalidades , Fatores de Alongamento de Peptídeos , Ribonucleoproteína Nuclear Pequena U5
7.
Am J Med Genet A ; 191(1): 52-63, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36196855

RESUMO

A small but growing body of scientific literature is emerging about clinical findings in patients with 19p13.3 microdeletion or duplication. Recently, a proximal 19p13.3 microduplication syndrome was described, associated with growth delay, microcephaly, psychomotor delay and dysmorphic features. The aim of our study was to better characterize the syndrome associated with duplications in the proximal 19p13.3 region (prox 19p13.3 dup), and to propose a comprehensive analysis of the underlying genomic mechanism. We report the largest cohort of patients with prox 19p13.3 dup through a collaborative study. We collected 24 new patients with terminal or interstitial 19p13.3 duplication characterized by array-based Comparative Genomic Hybridization (aCGH). We performed mapping, phenotype-genotype correlations analysis, critical region delineation and explored three-dimensional chromatin interactions by analyzing Topologically Associating Domains (TADs). We define a new 377 kb critical region (CR 1) in chr19: 3,116,922-3,494,377, GRCh37, different from the previously described critical region (CR 2). The new 377 kb CR 1 includes a TAD boundary and two enhancers whose common target is PIAS4. We hypothesize that duplications of CR 1 are responsible for tridimensional structural abnormalities by TAD disruption and misregulation of genes essentials for the control of head circumference during development, by breaking down the interactions between enhancers and the corresponding targeted gene.


Assuntos
Anormalidades Múltiplas , Microcefalia , Humanos , Hibridização Genômica Comparativa , Anormalidades Múltiplas/genética , Microcefalia/genética , Síndrome , Estudos de Associação Genética
8.
BMC Med Res Methodol ; 23(1): 269, 2023 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-37957586

RESUMO

BACKGROUND: The design of clinical trials in rare diseases is often complicated by a lack of real-world translational knowledge. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by skeletal malformations and progressive heterotopic ossification (HO). Palovarotene is a selective retinoic acid receptor gamma agonist. Here, we describe the methodology of three studies in the palovarotene clinical development program in FOP and discuss insights that could inform future research, including endpoint suitability and the impact of trial design. METHODS: PVO-1A-001 (NCT02322255) was a prospective, protocol-specified, longitudinal FOP natural history study (NHS). PVO-1A-201 (NCT02190747) was a randomized, double-blind, placebo-controlled phase II trial; PVO-1A-202 (NCT02279095) was its open-label extension. Trial designs, including treatment regimens and imaging assessments, were refined between PVO-1A-201 and PVO-|1A-202, and within PVO-1A-202, based on emerging data as the studies progressed. Palovarotene doses were administered using a flare-up treatment regimen (higher dose for 2/4 weeks, followed by lower dose for 4/≥8 weeks; from flare-up onset), with or without accompanying chronic (daily) treatment. Flare-up and disease progression outcomes were assessed, including incidence and volume of new HO during flare-ups and/or annually, as well as other clinical, patient-reported, and exploratory outcomes. Safety was monitored throughout all studies. RESULTS: Overall, 114 and 58 individuals with FOP were enrolled in the NHS and phase II trials, respectively. Results of the NHS and PVO-1A-201 were published in 2022; complete results of PVO-1A-202 will be publicly available in due course. Together the studies yielded important information on endpoint suitability, including that low-dose whole-body computed tomography was the optimum imaging modality for assessing HO progression annually and that long study durations are needed to detect substantial changes in functional and patient-reported outcomes. CONCLUSIONS: A flexible clinical development program is necessary for underexplored rare diseases to overcome the many challenges faced. Here, the NHS provided a longitudinal evaluation of FOP progression and interventional trials were based on emerging data. The studies described informed the design and endpoints implemented in the phase III MOVE trial (NCT03312634) and provide a foundation for future clinical trial development. TRIAL REGISTRATION: NCT02322255 (registered 23/12/2014); NCT02190747 (registered 15/07/2014); NCT02279095 (registered 30/10/2014).


Assuntos
Miosite Ossificante , Ossificação Heterotópica , Humanos , Miosite Ossificante/tratamento farmacológico , Ossificação Heterotópica/tratamento farmacológico , Estudos Prospectivos , Doenças Raras , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase II como Assunto
9.
Clin Orthop Relat Res ; 481(12): 2447-2458, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37156007

RESUMO

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder with episodic and progressive heterotopic ossification. Tissue trauma is a major risk factor for flareups, heterotopic ossification (HO), and loss of mobility in patients with FOP. The International Clinical Council on FOP generally recommends avoiding surgery in patients with FOP unless the situation is life-threatening, because soft tissue injury can trigger an FOP flareup. Surprisingly little is known about flareups, HO formation, and loss of mobility after fractures of the normotopic (occurring in the normal place, distinct from heterotopic) skeleton when treated nonoperatively in patients with FOP. QUESTIONS/PURPOSES: (1) What proportion of fractures had radiographic evidence of union (defined as radiographic evidence of healing at 6 weeks) or nonunion (defined as the radiographic absence of a bridging callus at 3 years after the fracture)? (2) What proportion of patients had clinical symptoms of an FOP flareup because of the fracture (defined by increased pain or swelling at the fracture site within several days after closed immobilization)? (3) What proportion of patients with fractures had radiographic evidence of HO? (4) What proportion of patients lost movement after a fracture? METHODS: We retrospectively identified 36 patients with FOP from five continents who sustained 48 fractures of the normotopic skeleton from January 2001 to February 2021, who were treated nonoperatively, and who were followed for a minimum of 18 months after the fracture and for as long as 20 years, depending on when they sustained their fracture during the study period. Five patients (seven fractures) were excluded from the analysis to minimize cotreatment bias because these patients were enrolled in palovarotene clinical trials (NCT02190747 and NCT03312634) at the time of their fractures. Thus, we analyzed 31 patients (13 male, 18 female, median age 22 years, range 5 to 57 years) who sustained 41 fractures of the normotopic skeleton that were treated nonoperatively. Patients were analyzed at a median follow-up of 6 years (range 18 months to 20 years), and none was lost to follow-up. Clinical records for each patient were reviewed by the referring physician-author and the following data for each fracture were recorded: biological sex, ACVR1 gene pathogenic variant, age at the time of fracture, fracture mechanism, fracture location, initial treatment modality, prednisone use at the time of the fracture as indicated in the FOP Treatment Guidelines for flare prevention (2 mg/kg once daily for 4 days), patient-reported flareups (episodic inflammatory lesions of muscle and deep soft connective tissue characterized variably by swelling, escalating pain, stiffness, and immobility) after the fracture, follow-up radiographs of the fracture if available, HO formation (yes or no) as a result of the fracture determined at a minimum of 6 weeks after the fracture, and patient-reported loss of motion at least 6 months after and as long as 20 years after the fracture. Postfracture radiographs were available in 76% (31 of 41) of fractures in 25 patients and were independently reviewed by the referring physician-author and senior author for radiographic criteria of fracture healing and HO. RESULTS: Radiographic healing was noted in 97% (30 of 31) of fractures at 6 weeks after the incident fracture. Painless nonunion was noted in one patient who sustained a displaced patellar fracture and HO. In seven percent (three of 41) of fractures, patients reported increased pain or swelling at or near the fracture site within several days after fracture immobilization that likely indicated a site-specific FOP flareup. The same three patients reported a residual loss of motion 1 year after the fracture compared with their prefracture status. HO developed in 10% (three of 31) of the fractures for which follow-up radiographs were available. Patient-reported loss of motion occurred in 10% (four of 41) of fractures. Two of the four patients reported noticeable loss of motion and the other two patients reported that the joint was completely immobile (ankylosis). CONCLUSION: Most fractures treated nonoperatively in individuals with FOP healed with few flareups, little or no HO, and preservation of mobility, suggesting an uncoupling of fracture repair and HO, which are two inflammation-induced processes of endochondral ossification. These findings underscore the importance of considering nonoperative treatment for fractures in individuals with FOP. Physicians who treat fractures in patients with FOP should consult with a member of the International Clinical Council listed in the FOP Treatment Guidelines ( https://www.iccfop.org ). LEVEL OF EVIDENCE: Level IV, therapeutic study.


Assuntos
Fraturas Ósseas , Miosite Ossificante , Ossificação Heterotópica , Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Recém-Nascido , Miosite Ossificante/diagnóstico por imagem , Miosite Ossificante/genética , Miosite Ossificante/terapia , Estudos Retrospectivos , Ossificação Heterotópica/diagnóstico por imagem , Ossificação Heterotópica/etiologia , Ossificação Heterotópica/terapia , Dor/complicações
10.
Int Orthop ; 47(7): 1863-1869, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37171515

RESUMO

PURPOSE: Osteogenesis imperfecta (OI) is a genetic disorder responsible for various symptoms including deformities and frequent fractures. Bone allografting is poorly documented in this condition. The objective of this study was to describe our experience and assessments in a consecutive series of OI patients. METHODS: Thirty-nine lower limb allograft procedures (28 femurs, 11 tibias) were performed in 26OI patients (mean age, 12.9 years). They were classified as type III of Sillence (17), type IV (6), and 3 recessive forms. The indications for surgery were correction of deformity (19), fracture (16), and non-union (4). In all cases, bone allografting was added to reinforce areas of fragility and in 28 cases for osteosynthesis to lock the rotations at the osteotomy site and to avoid screwed metallic plate. The duration of bone consolidation and allograft fusion was assessed. Complications and Gillette functional score were reported. RESULTS: The mean follow-up was 6.7years (range, 2 to 10 years). On average, bone consolidation was achieved after 3.3 months and graft fusion after 7.7 months. No bone allograft-related complications were observed and there was any secondary displacement. The Gillette functional score was improved in 23 patients and stable in three cases. Complications were reported in two cases: one partial allograft resorption and one delayed consolidation of a non-union. One refracture was observed but after a significant trauma in a child who had regained significant physical activity. CONCLUSIONS: Bone allografting in children with OI is a reliable method of biological fixation, allowing efficient fusion and contributing to increased bone capital and functional outcome.


Assuntos
Fraturas Ósseas , Osteogênese Imperfeita , Humanos , Criança , Osteogênese Imperfeita/cirurgia , Osteogênese Imperfeita/complicações , Fraturas Ósseas/cirurgia , Fixação Interna de Fraturas/efeitos adversos , Fêmur/cirurgia , Transplante Homólogo/efeitos adversos
11.
Genet Med ; 24(12): 2422-2433, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36152026

RESUMO

PURPOSE: We report the first prospective, international, natural history study of the ultra-rare genetic disorder fibrodysplasia ossificans progressiva (FOP). FOP is characterized by painful, recurrent flare-ups, and disabling, cumulative heterotopic ossification (HO) in soft tissues. METHODS: Individuals aged ≤65 years with classical FOP (ACVR1R206H variant) were assessed at baseline and over 36 months. RESULTS: In total, 114 individuals participated; 33 completed the study (mean follow up: 26.8 months). Median age was 15.0 (range: 4-56) years; 54.4% were male. During the study, 82 (71.9%) individuals reported 229 flare-ups (upper back: 17.9%, hip: 14.8%, shoulder: 10.9%). After 84 days, 14 of 52 (26.9%) imaged flare-ups had new HO at the flare-up site (mean new HO volume: 28.8 × 103 mm3). Mean baseline low-dose whole-body computed tomography (excluding head) HO volume was 314.4 × 103 mm3; lowest at 2 to <8 years (68.8 × 103 mm3) and increasing by age (25-65 years: 575.2 × 103 mm3). The mean annualized volume of new HO was 23.6 × 103 mm3/year; highest at 8 to <15 and 15 to <25 years (21.9 × 103 and 41.5 × 103 mm3/year, respectively) and lowest at 25 to 65 years (4.6 × 103 mm3/year). CONCLUSION: Results from individuals receiving standard care for up to 3 years in this natural history study show the debilitating effect and progressive nature of FOP cross-sectionally and longitudinally, with greatest progression during childhood and early adulthood.


Assuntos
Miosite Ossificante , Ossificação Heterotópica , Adolescente , Adulto , Feminino , Humanos , Masculino , Miosite Ossificante/diagnóstico por imagem , Miosite Ossificante/epidemiologia , Ossificação Heterotópica/diagnóstico por imagem , Ossificação Heterotópica/genética , Dor , Estudos Prospectivos , Pré-Escolar , Criança , Adulto Jovem , Pessoa de Meia-Idade
12.
Genet Med ; 24(8): 1708-1721, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35583550

RESUMO

PURPOSE: LEF1 encodes a transcription factor acting downstream of the WNT-ß-catenin signaling pathway. It was recently suspected as a candidate for ectodermal dysplasia in 2 individuals carrying 4q35 microdeletions. We report on 12 individuals harboring LEF1 variants. METHODS: High-throughput sequencing was employed to delineate the genetic underpinnings of the disease. Cellular consequences were characterized by immunofluorescence, immunoblotting, pulldown assays, and/or RNA sequencing. RESULTS: Monoallelic variants in LEF1 were detected in 11 affected individuals from 4 unrelated families, and a biallelic variant was detected in an affected individual from a consanguineous family. The phenotypic spectrum includes various limb malformations, such as radial ray defects, polydactyly or split hand/foot, and ectodermal dysplasia. Depending on the type and location of LEF1 variants, the inheritance of this novel Mendelian condition can be either autosomal dominant or recessive. Our functional data indicate that 2 molecular mechanisms are at play: haploinsufficiency or loss of DNA binding are responsible for a mild to moderate phenotype, whereas loss of ß-catenin binding caused by biallelic variants is associated with a severe phenotype. Transcriptomic studies reveal an alteration of WNT signaling. CONCLUSION: Our findings establish mono- and biallelic variants in LEF1 as a cause for a novel syndrome comprising limb malformations and ectodermal dysplasia.


Assuntos
Displasia Ectodérmica , Fator 1 de Ligação ao Facilitador Linfoide/genética , Via de Sinalização Wnt , Consanguinidade , Displasia Ectodérmica/genética , Humanos , Deformidades Congênitas dos Membros , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Síndrome , beta Catenina/genética , beta Catenina/metabolismo
13.
Genet Med ; 24(12): 2444-2452, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36107167

RESUMO

PURPOSE: This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control. METHODS: In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing. RESULTS: A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants <1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants <1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged <1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward. CONCLUSION: This study represents one of the largest datasets of prospectively collected medical and longitudinal growth data in children with achondroplasia. It serves as a robust historical control to measure therapeutic interventions against and to further delineate the natural history of this condition.


Assuntos
Acondroplasia , Criança , Masculino , Feminino , Humanos , Pré-Escolar , Estudos Prospectivos , Acondroplasia/epidemiologia , Acondroplasia/genética , Acondroplasia/diagnóstico , Estatura
14.
Genet Med ; 24(1): 179-191, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34906456

RESUMO

PURPOSE: Haploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS. METHODS: We report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status. RESULTS: The expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes. CONCLUSION: We refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature.


Assuntos
Deficiência Intelectual , Transtornos do Desenvolvimento da Linguagem , Anormalidades Musculoesqueléticas , Haploinsuficiência , Humanos , Deficiência Intelectual/diagnóstico , Transtornos do Desenvolvimento da Linguagem/genética , Anormalidades Musculoesqueléticas/genética , Fenótipo
15.
Am J Med Genet A ; 188(7): 2036-2047, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35445792

RESUMO

Unique or multiple congenital facial skin polyps are features of several rare syndromes, from the most well-known Pai syndrome (PS), to the less recognized oculoauriculofrontonasal syndrome (OAFNS), encephalocraniocutaneous lipomatosis (ECCL), or Sakoda complex (SC). We set up a research project aiming to identify the molecular bases of PS. We reviewed 27 individuals presenting with a syndromic frontonasal polyp and initially referred for PS. Based on strict clinical classification criteria, we could confirm only nine (33%) typical and two (7%) atypical PS individuals. The remaining ones were either OAFNS (11/27-41%) or presenting with an overlapping syndrome (5/27-19%). Because of the phenotypic overlap between these entities, OAFNS, ECCL, and SC can be either considered as differential diagnosis of PS or part of the same spectrum. Exome and/or genome sequencing from blood DNA in 12 patients and from affected tissue in one patient failed to identify any replication in candidate genes. Taken together, our data suggest that conventional approaches routinely utilized for the identification of molecular etiologies responsible for Mendelian disorders are inconclusive. Future studies on affected tissues and multiomics studies will thus be required in order to address either the contribution of mosaic or noncoding variation in these diseases.


Assuntos
Anormalidades do Olho , Lipomatose , Síndromes Neurocutâneas , Agenesia do Corpo Caloso , Fenda Labial , Coloboma , Anormalidades Craniofaciais , Diagnóstico Diferencial , Orelha Externa/anormalidades , Anormalidades do Olho/genética , Oftalmopatias , Face/anormalidades , Humanos , Lipoma , Lipomatose/genética , Pólipos Nasais , Síndromes Neurocutâneas/genética , Anormalidades do Sistema Respiratório , Dermatopatias , Coluna Vertebral/anormalidades
16.
J Pediatr Orthop ; 42(1): 47-52, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34723894

RESUMO

BACKGROUND: Osteosynthesis of leg fractures and deformities in children with osteogenesis imperfecta should align the skeleton and overcome its fragility during growth with a telescopic effect. A high rate of mechanical complications is associated with various surgical techniques described in the literature. PURPOSE: The objective of this work was to assess the long-term clinical and radiologic outcomes of tibial sliding elastic nailing technique. METHODS: A total of 22 children with an average age of 4.7 years were operated using the technique between 2004 and 2018 unilaterally (6) or bilaterally (16), that is, 38 operations. They were listed according to the Sillence classification into type I (3), III (17), or V (2). The nails were introduced percutaneously at the distal tibial epiphysis through the medial malleolus, and in the prespinal area for the proximal tibial epiphysis. The stainless-steel rods diameter was 1.5 to 2.5 mm, adapted to the size and weight of the patient. Realignment osteotomies were performed if necessary. Radiographic data including the correction of the deformation in the frontal and sagittal planes, as well as the width at mid-shaft of the tibia in the frontal and sagittal planes, were reviewed. Gillette Functional Score, assessment of pain, mechanical and infectious complications were collected. RESULTS: The average follow-up was 8.6 years. In the frontal plane, preoperative average varus was 8 degrees (maximum, 40 degrees), 5 degrees (maximum, 13 degrees) postoperatively, and 6 degrees (maximum, 12 degrees) at last follow-up. Preoperative valgus was 11 degrees (maximum, 22 degrees), 9 degrees (maximum, 15 degrees) postoperatively, and 9 degrees (maximum, 14 degrees) at the last follow-up. In the sagittal plane, the mean sagittal bowling of the tibia was 32 degrees (4 to 75 degrees) preoperatively, 9 degree (1 to 26 degrees) postoperatively, and 9 degrees (1 to 24 degrees) at last follow-up. The width at mid-shaft of the tibia in the frontal plane was 1.1 cm (0.6 to 1.8 cm) preoperatively and 1.3 cm at the last follow-up (0.7 to 2.0 cm). In the sagittal plane, it was 1.25 cm (0.7 to 2.7 cm) preoperatively and 1.27 cm (0.8 to 2.8 cm) at the last follow-up. Ten patients did not require revision surgery during their follow-up. Sixteen mechanical complications occurred in 12 patients (12 fractures or deformities following a lack of overlap of the 2 rods at an average time of 4.9 years after the initial surgery, 3 prominence of the nail, 1 pseudarthrosis). No infectious complication was reported. Gillette Functional Score was 20.54/65. Fifteen patients were able to walk at last follow-up, and 18 had no painful discomfort. CONCLUSIONS: The tibial sliding elastic nailing technique provides satisfactory clinical and radiologic results over time. Performed in case of fracture or as a preventive treatment, it allows a good correction of angular deformations. It is particularly suitable for young patients with a narrow medullary shaft. LEVEL OF EVIDENCE: Level IV-therapeutic study.


Assuntos
Fixação Intramedular de Fraturas , Osteogênese Imperfeita , Fraturas da Tíbia , Pinos Ortopédicos , Criança , Pré-Escolar , Fixação Intramedular de Fraturas/efeitos adversos , Humanos , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/cirurgia , Tíbia/diagnóstico por imagem , Tíbia/cirurgia , Fraturas da Tíbia/diagnóstico por imagem , Fraturas da Tíbia/cirurgia , Resultado do Tratamento
17.
Br J Haematol ; 192(5): 909-921, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33528045

RESUMO

Lowe syndrome (LS) is an oculocerebrorenal syndrome of Lowe (OCRL1) genetic disorder resulting in a defect of the OCRL protein, a phosphatidylinositol-4,5-bisphosphate 5-phosphatase containing various domains including a Rho GTPase-activating protein (RhoGAP) homology domain catalytically inactive. We previously reported surgery-associated bleeding in patients with LS, suggestive of platelet dysfunction, accompanied with a mild thrombocytopenia in several patients. To decipher the role of OCRL in platelet functions and in megakaryocyte (MK) maturation, we conducted a case-control study on 15 patients with LS (NCT01314560). While all had a drastically reduced expression of OCRL, this deficiency did not affect platelet aggregability, but resulted in delayed thrombus formation on collagen under flow conditions, defective platelet spreading on fibrinogen and impaired clot retraction. We evidenced alterations of the myosin light chain phosphorylation (P-MLC), with defective Rac1 activity and, inversely, elevated active RhoA. Altered cytoskeleton dynamics was also observed in cultured patient MKs showing deficient proplatelet extension with increased P-MLC that was confirmed using control MKs transfected with OCRL-specific small interfering(si)RNA (siOCRL). Patients with LS also had an increased proportion of circulating barbell-shaped proplatelets. Our present study establishes that a deficiency of the OCRL protein results in a defective actomyosin cytoskeleton reorganisation in both MKs and platelets, altering both thrombopoiesis and some platelet responses to activation necessary to ensure haemostasis.


Assuntos
Plaquetas/citologia , Megacariócitos/citologia , Síndrome Oculocerebrorrenal/genética , Monoéster Fosfórico Hidrolases/fisiologia , Trombopoese/fisiologia , Actomiosina/análise , Adolescente , Adulto , Anemia/etiologia , Coagulação Sanguínea , Plaquetas/ultraestrutura , Estudos de Casos e Controles , Forma Celular , Criança , Colágeno , Citoesqueleto/ultraestrutura , Feminino , Inativação Gênica , Humanos , Masculino , Megacariócitos/ultraestrutura , Pessoa de Meia-Idade , Mutação , Cadeias Leves de Miosina/metabolismo , Síndrome Oculocerebrorrenal/sangue , Síndrome Oculocerebrorrenal/patologia , Monoéster Fosfórico Hidrolases/deficiência , Monoéster Fosfórico Hidrolases/genética , Fosforilação , Domínios Proteicos , Processamento de Proteína Pós-Traducional , RNA Interferente Pequeno/genética , Transdução de Sinais , Trombocitopenia/etiologia , Adulto Jovem
18.
Genet Med ; 23(2): 331-340, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33082559

RESUMO

PURPOSE: Geleophysic dysplasia (GD) and acromicric dysplasia (AD) are characterized by short stature, short extremities, and progressive joint limitation. In GD, cardiorespiratory involvement can result in poor prognosis. Dominant variants in the FBN1 and LTBP3 genes are responsible for AD or GD, whereas recessive variants in the ADAMTSL2 gene are responsible for GD only. The aim of this study was to define the natural history of these disorders and to establish genotype-phenotype correlations. METHODS: This monocentric retrospective study was conducted between January 2008 and December 2018 in a pediatric tertiary care center and included patients with AD or GD with identified variants (FBN1, LTBP3, or ADAMTSL2). RESULTS: Twenty-two patients with GD (12 ADAMTSL2, 8 FBN1, 2 LTBP3) and 16 patients with AD (15 FBN1, 1 LTBP3) were included. Early death occurred in eight GD and one AD. Among GD patients, 68% presented with heart valve disease and 25% developed upper airway obstruction. No AD patient developed life-threatening cardiorespiratory issues. A greater proportion of patients with either a FBN1 cysteine variant or ADAMTSL2 variants had a poor outcome. CONCLUSION: GD and AD are progressive multisystemic disorders with life-threatening complications associated with specific genotype. A careful multidisciplinary follow-up is needed.


Assuntos
Proteínas ADAMTS , Proteínas dos Microfilamentos , Proteínas ADAMTS/genética , Doenças do Desenvolvimento Ósseo , Criança , Fibrilina-1/genética , Fibrilinas , Estudos de Associação Genética , Humanos , Deformidades Congênitas dos Membros , Proteínas dos Microfilamentos/genética , Mutação , Estudos Retrospectivos
19.
Am J Med Genet A ; 185(7): 2108-2118, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33908178

RESUMO

Sleep-disordered breathing (SDB) is common in patients with skeletal dysplasias. The aim of our study was to analyze SDB and respiratory management in children with rare skeletal dysplasias. We performed a retrospective analysis of patients with spondyloepiphyseal dysplasia congenita (SEDC), metatropic dysplasia (MD), spondyloepimetaphyseal dysplasia (SEMD), acrodysostosis (ADO), geleophysic dysplasia (GD), acromicric dysplasia (AD), and spondylocostal dysplasia (SCD) between April 2014 and October 2020. Polygraphic data, clinical management, and patients' outcome were analyzed. Thirty-one patients were included (8 SEDC, 3 MD, 4 SEMD, 1 ADO, 4 GD, 3 AD, and 8 SCD). Sixteen patients had obstructive sleep apnea (OSA): 11 patients (2 with SEDC, 1 with SEMD, 1 with ADO, 1 with GD, 2 with AD, and 4 with SCD) had mild OSA, 2 (1 SEMD and 1 GD) had moderate OSA, and 3 (1 SEDC, 1 MD, 1 SEMD) had severe OSA. Adenotonsillectomy was performed in one patient with SCD and mild OSA, and at a later age in two other patients with ADO and AD. The two patients with moderate OSA were treated with noninvasive ventilation (NIV) because of nocturnal hypoxemia. The three patients with severe OSA were treated with adenotonsillectomy (1 SEDC), adeno-turbinectomy and continuous positive airway pressure (CPAP; 1 MD), and with NIV (1 SEMD) because of nocturnal hypoventilation. OSA and/or alveolar hypoventilation is common in patients with skeletal dysplasias, underlining the importance of systematic screening for SDB. CPAP and NIV are effective treatments for OSA and nocturnal hypoventilation/hypoxemia.


Assuntos
Disostoses/congênito , Deficiência Intelectual/terapia , Osteocondrodisplasias/congênito , Costelas/anormalidades , Síndromes da Apneia do Sono/terapia , Apneia Obstrutiva do Sono/terapia , Coluna Vertebral/anormalidades , Adenoidectomia , Adolescente , Adulto , Criança , Pré-Escolar , Pressão Positiva Contínua nas Vias Aéreas/métodos , Disostoses/diagnóstico por imagem , Disostoses/patologia , Disostoses/terapia , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Masculino , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/patologia , Osteocondrodisplasias/terapia , Polissonografia , Costelas/diagnóstico por imagem , Costelas/patologia , Síndromes da Apneia do Sono/diagnóstico por imagem , Síndromes da Apneia do Sono/patologia , Apneia Obstrutiva do Sono/diagnóstico por imagem , Apneia Obstrutiva do Sono/patologia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/patologia , Tonsilectomia , Resultado do Tratamento , Adulto Jovem
20.
J Med Genet ; 57(7): 466-474, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32277047

RESUMO

PURPOSE: Marfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan-Fryns syndrome explain no more than 20% of subjects. METHODS: To further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic. RESULTS: We identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2). Using simulation models, we showed that five genes (DLG4, NFIX, EHMT1, ZEB2 and ATP1A1) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including NSD1 and NFIX, which are known to be mutated in overgrowth syndromes. CONCLUSION: We demonstrated that DNVs were enriched in chromatin remodelling (p=2×10-4) and genes regulated by the fragile X mental retardation protein (p=3×10-8), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.


Assuntos
Anormalidades Craniofaciais/genética , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Síndrome de Marfan/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Fatores de Transcrição NFI/genética , Adolescente , Adulto , Criança , Montagem e Desmontagem da Cromatina , Anormalidades Craniofaciais/patologia , Exoma/genética , Feminino , Predisposição Genética para Doença , Humanos , Deficiência Intelectual/patologia , Masculino , Síndrome de Marfan/patologia , Deficiência Intelectual Ligada ao Cromossomo X/patologia , Pessoa de Meia-Idade , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Sequenciamento do Exoma , Adulto Jovem
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