RESUMO
DNA replication is fundamental for cell proliferation in all organisms. Nonetheless, components of the replisome have been implicated in human disease, and here we report PRIM1 encoding the catalytic subunit of DNA primase as a novel disease gene. Using a variant classification agnostic approach, biallelic mutations in PRIM1 were identified in five individuals. PRIM1 protein levels were markedly reduced in patient cells, accompanied by replication fork asymmetry, increased interorigin distances, replication stress, and prolonged S-phase duration. Consequently, cell proliferation was markedly impaired, explaining the patients' extreme growth failure. Notably, phenotypic features distinct from those previously reported with DNA polymerase genes were evident, highlighting differing developmental requirements for this core replisome component that warrant future investigation.
Assuntos
DNA Primase/genética , Nanismo/genética , Retardo do Crescimento Fetal/genética , DNA Primase/química , DNA Primase/deficiência , Nanismo/diagnóstico por imagem , Nanismo/patologia , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Retardo do Crescimento Fetal/patologia , Variação Genética , Humanos , Lactente , Masculino , Linhagem , SíndromeRESUMO
Due to abnormal prenatal ultrasound findings of femoral shortening and flattened facial profile, a G2P0 pregnant patient underwent an amniocentesis at 15 weeks of gestation for proband-only exome sequencing. Bioinformatic filtering for genes included on the laboratory's extended skeletal dysplasia panel identified a heterozygous, likely pathogenic, frameshift variant in DVL1 NM_001330311.2:c.1575_1582dup; (p.Pro528ArgfsTer149). Pathogenic variants in DVL1 are associated with autosomal dominant Robinow syndrome (ADRS), a genetic disorder characterized by skeletal dysplasia with genital and craniofacial abnormalities. Prenatal ultrasound in the third trimester noted shortened long bones (first percentile for gestational age), macrocephaly with frontal bossing, short and upturned nose with a wide nasal root, triangular mouth, low pedal arches concerning for rocker-bottom feet, and ambiguous genitalia. A postnatal exam by Medical Genetics confirmed the prenatal findings in addition to hypertelorism, brachydactyly with broad thumbs and halluces, clinodactyly of second fingers, rigid gums with a frontal frenulum, and a sacral dimple. This case describes a novel variant in DVL1 identified in a fetus with prenatal and postnatal phenotypic features consistent with ADRS. To our knowledge, this is the first reported case of a prenatal molecular diagnosis of the dominant form of Robinow syndrome and the third case to describe prenatal ultrasound findings associated with this diagnosis.
Assuntos
Anormalidades Craniofaciais , Proteínas Desgrenhadas , Deformidades Congênitas dos Membros , Fenótipo , Ultrassonografia Pré-Natal , Humanos , Feminino , Gravidez , Proteínas Desgrenhadas/genética , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/diagnóstico por imagem , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/diagnóstico por imagem , Adulto , Mutação da Fase de Leitura , Nanismo/genética , Nanismo/diagnóstico , Nanismo/diagnóstico por imagem , Anormalidades UrogenitaisRESUMO
BACKGROUND: Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC types 1 and 2) are rare spondyloepimetaphyseal dysplasias with identical radiological findings. The presence of intellectual disability in DMC and normal intellect in SMC differentiates the two. DMC and SMC1 are allelic and caused by homozygous or compound heterozygous variants in DYM. SMC2 is caused by variations in RAB33B. Both DYM and RAB33B are important in intravesicular transport and function in the Golgi apparatus. METHODS: Detailed clinical phenotyping and skeletal radiography followed by molecular testing were performed in all affected individuals. Next-generation sequencing and Sanger sequencing were used to confirm DYM and RAB33B variants. Sanger sequencing of familial variants was done in all parents. RESULTS: 24 affected individuals from seven centres are described. 18 had DMC and 6 had SMC2. Parental consanguinity was present in 15 of 19 (79%). Height <3 SD and gait abnormalities were seen in 20 and 14 individuals, respectively. The characteristic radiological findings of lacy iliac crests and double-humped vertebral bodies were seen in 96% and 88% of the affected. Radiological findings became attenuated with age. 23 individuals harboured biallelic variants in either DYM or RAB33B. Fourteen different variants were identified, out of which 10 were novel. The most frequently occurring variants in this group were c.719 C>A (3), c.1488_1489del (2), c.1484dup (2) and c.1563+2T>C (2) in DYM and c.400C>T (2) and c.186del (2) in RAB33B. The majority of these have not been reported previously. CONCLUSION: This large cohort from India contributes to the increasing knowledge of clinical and molecular findings in these rare 'Golgipathies'.
Assuntos
Nanismo , Deficiência Intelectual , Osteocondrodisplasias , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Mutação , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/genética , Nanismo/diagnóstico por imagem , Nanismo/genéticaRESUMO
Lamin B1 plays an important role in the nuclear envelope stability, the regulation of gene expression, and neural development. Duplication of LMNB1, or missense mutations increasing LMNB1 expression, are associated with autosomal-dominant leukodystrophy. On the basis of its role in neurogenesis, it has been postulated that LMNB1 variants could cause microcephaly. Here, we confirm this hypothesis with the identification of de novo mutations in LMNB1 in seven individuals with pronounced primary microcephaly (ranging from -3.6 to -12 SD) associated with relative short stature and variable degree of intellectual disability and neurological features as the core symptoms. Simplified gyral pattern of the cortex and abnormal corpus callosum were noted on MRI of three individuals, and these individuals also presented with a more severe phenotype. Functional analysis of the three missense mutations showed impaired formation of the LMNB1 nuclear lamina. The two variants located within the head group of LMNB1 result in a decrease in the nuclear localization of the protein and an increase in misshapen nuclei. We further demonstrate that another mutation, located in the coil region, leads to increased frequency of condensed nuclei and lower steady-state levels of lamin B1 in proband lymphoblasts. Our findings collectively indicate that de novo mutations in LMNB1 result in a dominant and damaging effect on nuclear envelope formation that correlates with microcephaly in humans. This adds LMNB1 to the growing list of genes implicated in severe autosomal-dominant microcephaly and broadens the phenotypic spectrum of the laminopathies.
Assuntos
Nanismo/genética , Deficiência Intelectual/genética , Lamina Tipo B/genética , Microcefalia/genética , Mutação , Lâmina Nuclear/genética , Sequência de Aminoácidos , Sequência de Bases , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Pré-Escolar , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Nanismo/diagnóstico por imagem , Nanismo/metabolismo , Nanismo/patologia , Feminino , Expressão Gênica , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Lamina Tipo B/metabolismo , Linfócitos/metabolismo , Linfócitos/patologia , Imageamento por Ressonância Magnética , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/metabolismo , Microcefalia/patologia , Lâmina Nuclear/metabolismo , Lâmina Nuclear/patologiaRESUMO
Biallelic variants in CHST3 gene result in congenital dislocation of large joints, club feet, short stature, rhizomelia, kypho-scoliosis, platyspondyly, epiphyseal dysplasia, flared metaphysis, in addition to minor cardiac lesions and hearing loss. Herein, we describe 14 new patients from 11 unrelated Egyptian families with CHST3-related skeletal dysplasia. All patients had spondyloepiphyseal changes that were progressive with age in addition to bifid distal ends of humeri which can be considered a diagnostic key in patients with CHST3 variants. They also shared peculiar facies with broad forehead, broad nasal tip, long philtrum and short neck. Rare unusual associated findings included microdontia, teeth spacing, delayed eruption, prominent angulation of the lumbar-sacral junction and atrial septal defect. Mutational analysis revealed 10 different homozygous CHST3 (NM_004273.5) variants including 7 missense, two frameshift and one nonsense variant. Of them, the c.384_391dup (p.Pro131Argfs*88) was recurrent in two families. Eight of these variants were not described before. Our study presents the largest series of patients with CHST3-related skeletal dysplasia from the same ethnic group. Furthermore, it reinforces that lethal cardiac involvement is a critical clinical finding of the disorder. Therefore, we believe that our study expands the phenotypic and mutational spectrum, and also highlights the importance of performing echocardiography in patients harboring CHST3 variants.
Assuntos
Nanismo , Osteocondrodisplasias , Humanos , Nanismo/diagnóstico por imagem , Nanismo/genética , Homozigoto , Mutação , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/genética , Carboidrato SulfotransferasesRESUMO
Spondylo-epi-metaphyseal dysplasias (SEMDs) are a clinically and genetically heterogeneous group of skeletal dysplasias characterized by short stature and abnormal modeling of the spine and long bones. A novel form of rhizomelic skeletal dysplasia, Ain-Naz type, associated with a homozygous variant in GNPNAT1 was recently identified. Herein, we report an Egyptian patient, offspring of consanguineous parents, who presented with a severe form of unclassified SEMD. Whole exome sequencing identified a novel homozygous variant in exon 3, c.77T>G, (p.Phe26Cys) in GNPNAT1, that was confirmed by Sanger sequencing and both parents were found to be heterozygous for the identified variant. Main features included severe short stature, rhizomelic limb shortening, and wide flared metaphysis. Short broad long bones, brachydactyly, delayed epiphyseal ossification of long bones, advanced bone age, and immunodeficiency were additional findings expanding the clinical phenotype described in the previously reported family. We conclude that variants in the GNPNAT1 gene cause an autosomal recessive form of SEMD resembling Desbuquois like dysplasia caused by PGM3, which is involved in the same pathway as GNPNAT1.
Assuntos
Nanismo , Osteocondrodisplasias , Nanismo/diagnóstico por imagem , Nanismo/genética , Glucosamina 6-Fosfato N-Acetiltransferase/genética , Heterozigoto , Humanos , Hiperplasia , Osteocondrodisplasias/genética , Fosfoglucomutase/genética , Sequenciamento do ExomaRESUMO
A frameshift deletion variant in the Wnt pathway gene dishevelled 2 (DVL2) is associated with a truncated, kinked tail ("screw tail") in English Bulldogs, French Bulldogs and Boston Terriers. These breeds are also characterized by distinctive morphological traits, including a wide head, flat face and short-limbed dwarfism, which are characteristic of Robinow syndrome in humans, caused by defects in genes such as DVL1 and DVL3. Based on these phenotypic and genetic similarities, it has previously been hypothesized that the canine DVL2 variant results in a syndromic phenotype called the Robinow-like syndrome. In our study, we investigated the distribution of the DVL2 variant in 1954 dogs from 15 breeds, identifying breeds with allele variation and enabling the dissection of the genotype-phenotype correlation for the first time. With CT examinations in American Staffordshire Terriers, we confirmed that the DVL2 allele is associated with caudal vertebral malformations and a brachycephalic phenotype. We also hypothesize that the variant may be linked to additional health conditions, including brachycephalic obstructive airway syndrome and congenital heart defects. Altogether, our study strengthens the role of DVL2 as one of the contributors to the "bulldog type" morphology and features on the spectrum of human Robinow syndrome.
Assuntos
Craniossinostoses/veterinária , Proteínas Desgrenhadas/genética , Doenças do Cão/genética , Cães/genética , Coluna Vertebral/anormalidades , Animais , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/veterinária , Craniossinostoses/diagnóstico por imagem , Craniossinostoses/genética , Doenças do Cão/diagnóstico por imagem , Cães/anormalidades , Nanismo/diagnóstico por imagem , Nanismo/genética , Nanismo/veterinária , Feminino , Mutação da Fase de Leitura , Estudos de Associação Genética , Genótipo , Deformidades Congênitas dos Membros/diagnóstico por imagem , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/veterinária , Masculino , Fenótipo , Crânio/diagnóstico por imagem , Coluna Vertebral/diagnóstico por imagem , Cauda/anormalidades , Cauda/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Anormalidades Urogenitais/diagnóstico por imagem , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/veterináriaRESUMO
We report the clinical, biochemical and genetic findings from a Spanish boy of Caucasian origin who presented with fever-dependent RALF (recurrent acute liver failure) and osteogenesis imperfecta (OI). Whole-exome sequencing (WES) uncovered two compound heterozygous variants in NBAS (c.[1265 T > C];[1549C > T]:p.[(Leu422Pro)];[(Arg517Cys)]), and a heterozygous variant in P4HB (c.[194A > G];[194=]:p.[(Lys65Arg)];[(Lys65=)]) that was transmitted from the clinically unaffected mother who was mosaic carrier of the variant. Variants in NBAS protein have been associated with ILFS2 (infantile liver failure syndrome-2), SOPH syndrome (short stature, optic nerve atrophy, and Pelger-Huët anomaly syndrome), and multisystem diseases. Several patients showed clinical manifestations affecting the skeletal system, such as osteoporosis, pathologic fractures and OI. Experiments in the patient's fibroblasts demonstrated that mutated NBAS protein is overexpressed and thermally unstable, and reduces the expression of MGP, a regulator of bone homeostasis. Variant in PDI (protein encoded by P4HB) has been associated with CLCRP1 (Cole-Carpenter syndrome-1), a type of severe OI. An increase of COL1A2 protein retention was observed in the patient's fibroblasts. In order to study if the variant in P4HB was involved in the alteration in collagen trafficking, overexpression experiments of PDI were carried out. These experiments showed that overexpression of mutated PDI protein produces an increase in COL1A2 retention. In conclusion, these results corroborate that the variants in NBAS are responsible for the liver phenotype, and demonstrate that the variant in P4HB is involved in the bone phenotype, probably in synergy with NBAS variants.
Assuntos
Colágeno Tipo I/genética , Falência Hepática Aguda/genética , Proteínas de Neoplasias/genética , Osteogênese Imperfeita/genética , Pró-Colágeno-Prolina Dioxigenase/genética , Isomerases de Dissulfetos de Proteínas/genética , Criança , Pré-Escolar , Craniossinostoses/complicações , Craniossinostoses/genética , Craniossinostoses/patologia , Nanismo/diagnóstico por imagem , Nanismo/genética , Nanismo/patologia , Anormalidades do Olho/complicações , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Febre/complicações , Febre/genética , Heterozigoto , Humanos , Hidrocefalia/complicações , Hidrocefalia/genética , Hidrocefalia/patologia , Lactente , Recém-Nascido , Fígado/diagnóstico por imagem , Fígado/patologia , Falência Hepática Aguda/complicações , Falência Hepática Aguda/diagnóstico por imagem , Falência Hepática Aguda/patologia , Masculino , Mutação/genética , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/patologia , Fenótipo , Sequenciamento do ExomaRESUMO
3M syndrome is a rare autosomal recessive genetic disorder characterized by severe growth retardation, dysmorphic facial features, skeletal dysplasia, and normal intelligence. Variants in CUL7, OBSL1, and CCDC8 genes have been reported to be responsible for this syndrome. In this study, the clinical and molecular findings of four 3M syndrome cases from three families are presented. All cases had growth retardation, relative macrocephaly, and typical dysmorphic facial features. Their neurological developments were normal. Sequencing of CUL7, OBSL1, and CCDC8 genes revealed two different novel homozygous variants in CUL7 in Families 1 and 3 and a previously reported homozygous pathogenic variant in OBSL1 in Family 2. In conclusion, a comprehensive dysmorphological evaluation should be obtained in individuals presenting with short stature and in such individuals with typical facial and skeletal findings, 3M syndrome should be considered. Our report expands the genotype of 3M syndrome and emphasizes the importance of thorough physical and dysmorphological examination.
Assuntos
Proteínas de Transporte/genética , Proteínas Culina/genética , Proteínas do Citoesqueleto/genética , Nanismo/genética , Hipotonia Muscular/genética , Coluna Vertebral/anormalidades , Adolescente , Criança , Pré-Escolar , Nanismo/diagnóstico por imagem , Nanismo/patologia , Feminino , Predisposição Genética para Doença , Genótipo , Homozigoto , Humanos , Lactente , Masculino , Hipotonia Muscular/diagnóstico por imagem , Hipotonia Muscular/patologia , Mutação , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/patologiaRESUMO
Biallelic pathogenic variants in RNU4ATAC have been linked to microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1). Although children with MOPD1 have been reported to show profound, life-limiting clinical decompensation at the time of a febrile illness, these episodes including magnetic resonance imaging (MRI) findings have not been well characterized. We present acute MRI brain findings for a 10-year-old girl with homozygous variants in RNU4ATAC (NR_023343.1) n.55G>A, who presented with two episodes of clinical decompensation associated with a febrile illness in early childhood. The pathogenic variants were identified by whole genome sequencing as RNU4ATAC is not captured in most exome products. Her MRI of the brain revealed symmetric, diffusion restriction of the deep gray nuclei that initially pointed to a mitochondrial disease or acute necrotizing encephalopathy. Her phenotype included microcephaly and profound cognitive impairment that can be seen with MOPD1. However, she did not demonstrate clinical or radiographic evidence of a spondyloepimetaphyseal dysplasia or "primordial dwarfism" that is characteristic of this disease. As such, the predominant neurological presentation of this child represents an atypical variant of RNU4ATAC-associated disease and should be a diagnostic consideration for geneticists and neurologists caring for children, particularly in the event of an acute clinical decline.
Assuntos
Nanismo/genética , Encefalite/genética , Retardo do Crescimento Fetal/genética , Microcefalia/genética , Osteocondrodisplasias/genética , RNA Nuclear Pequeno/genética , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Pré-Escolar , Nanismo/diagnóstico por imagem , Nanismo/patologia , Encefalite/diagnóstico por imagem , Encefalite/patologia , Exoma/genética , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Retardo do Crescimento Fetal/patologia , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/patologia , Mutação/genética , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/patologia , Fenótipo , Sequenciamento do Exoma , Sequenciamento Completo do GenomaRESUMO
Hypochondroplasia (HCH) is a rare autosomal dominant skeletal dysplasia condition caused by FGFR3 mutations leading to disproportionate short stature. Classically HCH presents in toddlers or school-age children, as limb-to-trunk disproportion and is often mild and easily overlooked during infancy. We report experiences from a single-center UK HCH-cohort of 31 patients, the rate of antenatal HCH detection in our cohort (13/31, 41.9%) and describe relevant case-data for this subset of 13 patients. Inclusion criteria were patients with confirmed molecular HCH diagnosis (by age 3 years) and presenting with short long-bones or large head size on antenatal ultrasound scan. We then conducted a systematic literature review using PUBMED and MEDLINE, analyzing patients with HCH and related antenatal findings. Antenatally suspected (with subsequent molecular confirmation) HCH has been reported 15 times in the literature (2004-2019). Key markers (consistent in both groups) included reduced; femur length, humeral length and increased; biparietal diameter and head circumference. HCH is increasingly detected both antenatally and in infancy, contrary to previous descriptions. This is likely due to greater HCH awareness, improved imaging, and easier molecular testing. Thus, one should consider HCH outside the classical presenting period. Studying the natural history of younger patients with HCH is important with the advent of several targeted FGFR3 therapies currently in trials for Achondroplasia, that may soon be trialed in HCH.
Assuntos
Acondroplasia/diagnóstico , Osso e Ossos/anormalidades , Nanismo/diagnóstico , Diagnóstico Precoce , Deformidades Congênitas dos Membros/diagnóstico , Lordose/diagnóstico , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Acondroplasia/genética , Acondroplasia/patologia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Nanismo/diagnóstico por imagem , Nanismo/genética , Nanismo/patologia , Feminino , Fêmur/diagnóstico por imagem , Fêmur/patologia , Humanos , Deformidades Congênitas dos Membros/diagnóstico por imagem , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/patologia , Lordose/diagnóstico por imagem , Lordose/genética , Lordose/patologia , Mutação/genética , Gravidez , Reino UnidoRESUMO
Robinow syndrome (RS) is a rare heterogeneous disorder characterized by short stature, short-limbs, craniofacial, oro-dental abnormalities, vertebral segmentation defects, and frequently genital hypoplasia. Both autosomal dominant and recessive patterns of inheritance are observed with many causative genes. Here, we present the phenotypes and genotypes of four children with RS from different Indian families. Sequence variants were identified in genes ROR2, DVL1, and DVL3. Our results expand the mutational spectrum of RS and we also highlight the radiological changes in the radius and ulna in patients with ROR2 sequence variants which are primarily characteristic for ROR2 related RS but have been reported in WNT5A related RS.
Assuntos
Anormalidades Craniofaciais/genética , Proteínas Desgrenhadas/genética , Nanismo/genética , Deformidades Congênitas dos Membros/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Anormalidades Urogenitais/genética , Proteína Wnt-5a/genética , Criança , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/patologia , Nanismo/diagnóstico , Nanismo/diagnóstico por imagem , Nanismo/patologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Índia/epidemiologia , Lactente , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/diagnóstico por imagem , Deformidades Congênitas dos Membros/patologia , Masculino , Mutação/genética , Fenótipo , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/diagnóstico por imagem , Anormalidades Urogenitais/patologiaRESUMO
3-M syndrome is a rare autosomal recessive disorder, characterized by short stature, characteristic facies and absence of microcephaly and intellectual disability. 3-M syndrome 2 (MIM# 612921) is caused by biallelic disease causing variants in OBSL1. In this study, we identified two probands from two families with homozygous, c.1534 + 5G > T and compound heterozygous variants, c.35dup and c.1273dup in OBSL1, respectively. We herein highlight the clinical and molecular findings of the first reported cases from Indian ethnicity.
Assuntos
Proteínas do Citoesqueleto/genética , Nanismo/genética , Deficiência Intelectual/genética , Microcefalia/genética , Hipotonia Muscular/genética , Criança , Pré-Escolar , Nanismo/complicações , Nanismo/diagnóstico por imagem , Nanismo/patologia , Fácies , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Índia/epidemiologia , Deficiência Intelectual/complicações , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/patologia , Masculino , Microcefalia/complicações , Microcefalia/diagnóstico por imagem , Microcefalia/patologia , Hipotonia Muscular/complicações , Hipotonia Muscular/diagnóstico por imagem , Hipotonia Muscular/patologia , Mutação/genética , Linhagem , FenótipoRESUMO
Robinow syndrome, a rare genetic disorder, is characterized by skeletal dysplasia with, among other anomalies, extremity and hand anomalies. There is locus heterogeneity and both dominant and recessive inheritance. A detailed description of associated extremity and hand anomalies does not currently exist due to the rarity of this syndrome. This study seeks to document the hand anomalies present in Robinow syndrome to allow for improved rates of timely and accurate diagnosis. A focused assessment of the extremities and stature was performed using clinical examination and standard photographic images. A total of 13 patients with clinical and molecular diagnosis consistent with dominant Robinow syndrome or recessive Robinow syndrome were evaluated. All patients had limb shortening, the most common of which was mesomelia; however, rhizomelia and micromelia were also seen. These findings are relevant to clinical characterization, particularly as Robinow syndrome has classically been defined as a "mesomelic disorder." A total of eight distinct hand anomalies were identified in 12 patients with both autosomal recessive and dominant forms of Robinow syndrome. One patient did not present with any hand differences. The most common hand findings included brachydactyly, broad thumbs, and clinodactyly. A thorough understanding of the breadth of Robinow syndrome-associated extremity and hand anomalies can aid in early patient identification, improving rates of timely diagnosis and allowing for proactive management of sequelae.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Craniofaciais/diagnóstico , Nanismo/diagnóstico , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas dos Membros/diagnóstico , Anormalidades Urogenitais/diagnóstico , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/fisiopatologia , Nanismo/diagnóstico por imagem , Nanismo/genética , Nanismo/fisiopatologia , Extremidades/diagnóstico por imagem , Extremidades/fisiopatologia , Feminino , Mãos/diagnóstico por imagem , Mãos/fisiopatologia , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/fisiopatologia , Humanos , Deformidades Congênitas dos Membros/diagnóstico por imagem , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Fenótipo , Anormalidades Urogenitais/diagnóstico por imagem , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/fisiopatologia , Adulto JovemRESUMO
Kenny-Caffey syndrome type 2 (KCS2) and osteocraniostenosis (OCS) are allelic disorders caused by heterozygous pathogenic variants in the FAM111A gene. Both conditions are characterized by gracile bones, characteristic facial features, hypomineralized skull with delayed closure of fontanelles and hypoparathyroidism. OCS and KCS2 are often referred to as FAM111A-related syndromes as a group; although OCS presents with a more severe, perinatal lethal phenotype. We report a novel FAM111A mutation in a fetus with poorly ossified skull, proportionate long extremities with thin diaphysis, and hypoplastic spleen consistent with FAM111A-related syndromes. Trio whole exome sequencing identified a p.Y562S de novo missense variant in the FAM111A gene. The variant shows significant similarity to other reported pathogenic mutations fitting proposed pathophysiologic mechanism which provide sufficient evidence for classification as likely pathogenic. Our report contributed a novel variant to the handful of OCS and KCS2 cases reported with pathogenic variants.
Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Nanismo/genética , Hiperostose Cortical Congênita/genética , Hipocalcemia/genética , Receptores Virais/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/patologia , Anormalidades Cardiovasculares/diagnóstico , Anormalidades Cardiovasculares/genética , Anormalidades Cardiovasculares/patologia , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/patologia , Nanismo/diagnóstico , Nanismo/diagnóstico por imagem , Nanismo/patologia , Ossos Faciais/anormalidades , Ossos Faciais/patologia , Feminino , Feto , Predisposição Genética para Doença , Heterozigoto , Humanos , Hiperostose Cortical Congênita/diagnóstico , Hiperostose Cortical Congênita/diagnóstico por imagem , Hiperostose Cortical Congênita/patologia , Hipocalcemia/diagnóstico , Hipocalcemia/diagnóstico por imagem , Hipocalcemia/patologia , Masculino , Mutação/genética , Gravidez , Crânio/anormalidades , Crânio/patologia , Baço/anormalidades , Baço/diagnóstico por imagem , Sequenciamento do ExomaRESUMO
BACKGROUND: Orthopedic complications can cause issues and severe disability in patients with dwarfism. Thus, these individuals frequently undergo total hip arthroplasty to mitigate decline in daily functioning. Although studies have reported on the difficulties of orthopedic surgery in patients with dwarfism, many do not clearly define dwarfism and have a short follow-up period. We aimed to retrospectively investigate the clinical and radiographic results of total hip arthroplasty for patients with dwarfism. METHODS: A total of 68 hips of 49 patients with height <140 cm and at least 10-year follow-up periods were enrolled. All patients had conventional cementless implants. All hips were evaluated using the Japanese Orthopaedic Association hip score. RESULTS: The main hip disease etiologies were primary hip osteoarthritis (58%) and secondary osteoarthritis due to developmental dysplasia (31%). Rheumatoid arthritis, rapidly destructive coxarthrosis, spondyloepiphyseal dysplasia, childhood infection, and femoral head aseptic necrosis were also causative pathologies. Hip scores significantly improved from 44 to 82 out of 100. Overall implant-associated survival rate after 10 years was 94.1%. Cup loosening was observed in 2 hips, and subsidence >5 mm was observed in 9 hips. Presence of Crowe IV in hips was a significant risk factor for total hip arthroplasty in patients with dwarfism (p < 0.05); leg lengthening had a weak but significant correlation (r = 0.253, p < 0.05). CONCLUSIONS: Total hip arthroplasty using conventional cementless implants for patients with dwarfism shows good clinical and radiological outcomes and has a relatively low perioperative risk.
Assuntos
Artroplastia de Quadril , Nanismo , Prótese de Quadril , Artroplastia de Quadril/efeitos adversos , Criança , Nanismo/complicações , Nanismo/diagnóstico por imagem , Nanismo/cirurgia , Seguimentos , Humanos , Desenho de Prótese , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Processing of Precursor RNA 1 (POP1) is a core protein component shared by two essential closely related eukaryotic ribonucleoprotein complexes: RNase MRP (the mitochondrial RNA processing ribonuclease) and RNase P. Recently, five patients harboring mutations in POP1 have been reported with severe spondylo-epi-metaphyseal dysplasia and extremely short stature. We report a unique clinical phenotype resulting from the novel homozygous R211Q POP1 mutation in three patients from one family, presenting with severe short stature but only subtle skeletal dysplastic changes that are merely metaphyseal. The RNA moiety of the RNase-MRP complex quantified in RNA extracted from peripheral lymphocytes was dramatically reduced in affected patients indicating instability of the enzymatic complex. However, pre5.8s rRNA, a substrate of RNase-MRP complex, was not accumulated in patients' RNA unlike in the previously reported POP1 mutations; this may explain the uniquely mild phenotype in our cases, and questions the assumption that alteration in ribosomal biogenesis is the pathophysiological basis for skeletal disorders caused by POP1 mutations. Finally, POP1 mutations should be considered in familial cases with severe short stature even when skeletal dysplasia is not strongly evident.
Assuntos
Proteínas Reguladoras de Apoptose/genética , Nanismo/genética , Predisposição Genética para Doença , Osteocondrodisplasias/genética , Ribonucleoproteínas/genética , Criança , Consanguinidade , Nanismo/diagnóstico por imagem , Nanismo/patologia , Homozigoto , Humanos , Masculino , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Anormalidades Musculoesqueléticas , Mutação/genética , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/patologia , Precursores de RNA/genética , Ribossomos/genéticaRESUMO
Saul-Wilson syndrome (SWS) is a rare autosomal recessive disorder characterized by microcephalic primordial dwarfism, spondyloepimetaphyseal dysplasia, characteristic facial findings, clubfoot, brachydactyly, bilateral cataracts, and hearing loss. Recently, recurrent mutations in COG4, encoding a component of the Conserved Oligomeric Golgi (COG) complex, were identified. We created detailed growth curves for stature, weight, and head circumference, as well as weight-for-length and weight velocity charts for younger children, derived from hundreds of data points obtained by retrospective chart review from 14 individuals with molecularly-confirmed SWS. In addition, we performed statistical comparisons of height-for-age model fits before and after initiation of growth hormone supplementation, and found that this therapy does not appear to influence height in individuals with SWS. We hope that these charts will represent valuable tools for clinicians, both in assessing whether SWS seems an appropriate diagnosis, as well as to monitor growth of affected individuals. In particular, we hope that our detailed growth characterization will reduce morbidity resulting from unnecessarily aggressive nutritional interventions by well-intentioned physicians trying to promote weight gain, an unrealistic goal in this genetically-determined cause of primordial dwarfism.
Assuntos
Nanismo/genética , Retardo do Crescimento Fetal/genética , Microcefalia/genética , Osteocondrodisplasias/genética , Proteínas de Transporte Vesicular/genética , Adolescente , Adulto , Estatura/genética , Estatura/fisiologia , Criança , Pré-Escolar , Pé Torto Equinovaro/diagnóstico por imagem , Pé Torto Equinovaro/genética , Pé Torto Equinovaro/patologia , Nanismo/diagnóstico por imagem , Nanismo/patologia , Fácies , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Retardo do Crescimento Fetal/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/patologia , Mutação/genética , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/patologia , Adulto JovemRESUMO
Microcephalic osteodysplastic primordial dwarfism (MOPD) type II is a rare disorder characterized by skeletal dysplasia, severe proportionate short stature, insulin resistance and cerebrovascular abnormalities including cerebral aneurysms and moyamoya disease. MOPD type II is caused by mutations in the pericentrin (PCNT) gene, which encodes a protein involved in centrosomes function. We report a 2 year old girl affected by MOPD type II caused by two compound heterozygous loss-of-function variants in PCNT gene, of which one is a novel variant (c.5304delT; p.Gly1769AlafsTer34). The patient presented atypical brain magnetic resonance imaging (MRI) findings consistent with pachygyria. This was confirmed by morphometric analysis of cortical thickness (CT) and gyrification index by comparing MRI data of the patient with a group of eight age-matched healthy controls. The statistical analysis revealed a significant and diffuse increase of CT with an anterior-predominant pattern and diffuse reduced gyrification (p < .05). These findings provide new evidences to the emergent concept that malformations of cortical development are complex disorders and that new genetic findings contribute to the fading of classification borders.
Assuntos
Antígenos/genética , Nanismo/genética , Retardo do Crescimento Fetal/genética , Lisencefalia/genética , Microcefalia/genética , Osteocondrodisplasias/genética , Pré-Escolar , Nanismo/diagnóstico por imagem , Nanismo/patologia , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Retardo do Crescimento Fetal/patologia , Humanos , Lisencefalia/diagnóstico por imagem , Lisencefalia/patologia , Imageamento por Ressonância Magnética , Microcefalia/diagnóstico por imagem , Microcefalia/patologia , Mutação/genética , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/patologiaRESUMO
Kenny-Caffey Syndrome Type 2 (KCS2) is a rare genetic disorder characterized by short stature, skeletal dysplasia, primary hypoparathyroidism, and delayed closure of the anterior fontanelle. Patients with KCS2 typically require multidisciplinary management due to numerous craniofacial and skeletal anomalies. Craniosynostosis, however, has not yet been identified in a patient with KCS2 to the best of our knowledge. We present the first case of craniosynostosis in the setting of KCS2 and provide a comprehensive analysis of the associated craniofacial findings to date. The authors will describe the craniofacial features specific to our patient and review the characteristic morphological features in a manner relevant to early recognition and focused evaluation.