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Case Reports in Pediatrics 2022Thanatophoric dysplasia (TD) is a rare but uniformly lethal inherited disorder of the skeletal system resulting from defects in the fibroblast growth factor receptor-3...
Thanatophoric dysplasia (TD) is a rare but uniformly lethal inherited disorder of the skeletal system resulting from defects in the fibroblast growth factor receptor-3 gene on the short arm of chromosome ##4. It is characterised by pronounced shortening of the tubular bones resulting in significant short stature, macrocephaly, a funnel-shaped chest, protuberant abdomen, redundant skin in the limbs, and typical facies among others. The two clinical types of TD are differentiated by typical cranial and tubular bone configurations. Antenatal diagnosis is usually made in the last trimester and corroborated at birth. We present 2 cases of TD seen at Barau Dikko Teaching Hospital (BDTH) between January and August 2021 to highlight the potential difficulty with antenatal diagnosis, its diagnostic features, and associated early postnatal fatality. The antenatal diagnosis was missed in both cases in spite of repeated 2 and 3-trimester sonographic examinations. Both babies presented with remarkable micromelic short stature with the telephone-handle appearance of the femoral bones characteristic of type 1 TD, developed progressive respiratory distress at birth, and died within 36 hours of life despite respiratory support with Bubble CPAP. These cases are discussed along with a review of existing relevant literature.
PubMed: 36213390
DOI: 10.1155/2022/3056324 -
American Journal of Medical Genetics.... Sep 2008There have been no large population-based studies of the prevalence of achondroplasia and thanatophroic dysplasia in the United States. This study compared data from...
There have been no large population-based studies of the prevalence of achondroplasia and thanatophroic dysplasia in the United States. This study compared data from seven population-based birth defects monitoring programs in the United States. We also present data on the association between older paternal age and these birth defects, which has been described in earlier studies. The prevalence of achondroplasia ranged from 0.36 to 0.60 per 10,000 livebirths (1/27,780-1/16,670 livebirths). The prevalence of thanatophoric dysplasia ranged from 0.21 to 0.30 per 10,000 livebirths (1/33,330-1/47,620 livebirths). In Texas, fathers that were 25-29, 30-34, 35-39, and > or =40 years of age had significantly increased rates of de novo achondroplasia among their offspring compared with younger fathers. The adjusted prevalence odds ratios were 2.8 (95% CI; 1.2, 6.7), 2.8 (95% CI; 1.0, 7.6), 4.9 (95% CI; 1.7, 14.3), and 5.0 (95% CI; 1.5, 16.1), respectively. Using the same age categories, the crude prevalence odds ratios for de novo cases of thanatophoric dysplasia in Texas were 5.8 (95% CI; 1.7, 9.8), 3.9 (95% CI; 1.1, 6.7), 6.1 (95% CI; 1.6, 10.6), and 10.2 (95% CI; 2.6, 17.8), respectively. These data suggest that thanatophoric dysplasia is one-third to one-half as frequent as achondroplasia. The differences in the prevalence of these conditions across monitoring programs were consistent with random fluctuation. Birth defects monitoring programs may be a good source of ascertainment for population-based studies of achondroplasia and thanatophoric dysplasia, provided that diagnoses are confirmed by review of medical records.
Topics: Achondroplasia; Adult; Confidence Intervals; Humans; Infant, Newborn; Male; Odds Ratio; Paternal Age; Prevalence; Sentinel Surveillance; Texas; Thanatophoric Dysplasia; United States
PubMed: 18698630
DOI: 10.1002/ajmg.a.32485 -
The Ulster Medical Journal Sep 2010The minimum prevalence of lethal Osteogenesis imperfecta type II, thanatophoric dysplasia and achondroplasia were derived following detailed case note review of all...
The minimum prevalence of lethal Osteogenesis imperfecta type II, thanatophoric dysplasia and achondroplasia were derived following detailed case note review of all perinatal lethal skeletal dysplasias (SD) in Northern Ireland over a 12 year period. Multiple sources of ascertainment, including genetic notes, radiological reports and post mortem findings, were used. 39 cases were identified. Thanatophoric dysplasia was the commonest diagnosis made (22), followed by osteogenesis imperfecta type II (four children) and achondroplasia (two children). Eleven other diagnoses each occurred once in the 12 year period. The minimum prevalence range, per live births, of each of the common skeletal dysplasias in Northern Ireland has been calculated; thanatophoric dysplasia 0.80/10,000, osteogenesis imperfecta type II 0.15/10,000 and achondroplasia 0.07/10,000. The prevalence range for thanatophoric dysplasia is much higher than reported in previous studies. We discuss reasons for the prevalence figures obtained.
Topics: Genetic Testing; Humans; Northern Ireland; Osteogenesis Imperfecta; Receptor, Fibroblast Growth Factor, Type 3; Retrospective Studies; Risk Assessment; Thanatophoric Dysplasia
PubMed: 22375084
DOI: No ID Found -
Seminars in Perinatology Feb 2015Disorders of brain overgrowth are significant causes of intractable epilepsy, intellectual disability, autism, and other complex neurological problems. The pathology of... (Review)
Review
Disorders of brain overgrowth are significant causes of intractable epilepsy, intellectual disability, autism, and other complex neurological problems. The pathology of these disorders is sometimes striking and characteristic, as in hemimegalencephaly, but can also be subtle, as in autism. Recent genetic studies have shown that many diverse forms of brain overgrowth are caused by de novo mutations that increase activity in the receptor tyrosine kinase (RTK)-phosphatidylinositol-3-kinase (PI3K)-AKT signaling pathway, a key mediator of signaling by growth factors in the developing brain, such as fibroblast growth factors. In cases where mutations arise in postzygotic embryos, brain regions exhibit mosaic pathology that reflects the distribution of mutant cells, ranging from focal cortical dysplasia to lobar or hemispheric overgrowth. In turn, the histopathology of these disorders is also remarkably varied. The common underlying mechanisms of RTK-PI3K-AKT overactivation suggest new possibilities for drugs that inhibit this pathway.
Topics: Brain; Humans; Malformations of Cortical Development; Megalencephaly; Mutation; Neuroimaging; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptor Protein-Tyrosine Kinases; Signal Transduction
PubMed: 25432429
DOI: 10.1053/j.semperi.2014.10.006 -
International Medical Case Reports... 2022Spontaneous uterine rupture, especially in an unscarred uterus, is a rare pregnancy complication that can cause severe morbidity and mortality in both the mother and...
BACKGROUND AND IMPORTANCE
Spontaneous uterine rupture, especially in an unscarred uterus, is a rare pregnancy complication that can cause severe morbidity and mortality in both the mother and the fetus. The vast majority of uterine ruptures occur in the presence of a previous uterine scar, most commonly from a previous cesarean delivery. To our knowledge, here we reported the first case of spontaneous rupture of unscarred uterus in a term primigravida secondary to lethal skeletal dysplasia fetus (Type 1 Thanatophoric dysplasia) faced by a practicing clinician in an underdeveloped country (Somalia) with a successful outcome.
CASE PRESENTATION
The patient was 24 yrs. Old Primagravida, at 40 weeks gestation by LMP, presented with abdominal pain and active vaginal bleeding; she did not receive antenatal care during pregnancy; after initial abdominal ultrasonography and vaginal examination, laparotomy was performed due to high suspicion of uterine rupture. After dead fresh fetal extraction, the uterine defect was repaired successfully, and the patient was discharged home in good condition after several days.
CONCLUSION
Through this case, we would like to highlight the urgent need to focus on and recognize the importance of receiving antenatal care in the community so that the burden of thousands of lives lost each year can be reduced.
PubMed: 36225974
DOI: 10.2147/IMCRJ.S383195 -
American Journal of Human Genetics Feb 2012Advanced paternal age has been associated with an increased risk for spontaneous congenital disorders and common complex diseases (such as some cancers, schizophrenia,... (Review)
Review
Advanced paternal age has been associated with an increased risk for spontaneous congenital disorders and common complex diseases (such as some cancers, schizophrenia, and autism), but the mechanisms that mediate this effect have been poorly understood. A small group of disorders, including Apert syndrome (caused by FGFR2 mutations), achondroplasia, and thanatophoric dysplasia (FGFR3), and Costello syndrome (HRAS), which we collectively term "paternal age effect" (PAE) disorders, provides a good model to study the biological and molecular basis of this phenomenon. Recent evidence from direct quantification of PAE mutations in sperm and testes suggests that the common factor in the paternal age effect lies in the dysregulation of spermatogonial cell behavior, an effect mediated molecularly through the growth factor receptor-RAS signal transduction pathway. The data show that PAE mutations, although arising rarely, are positively selected and expand clonally in normal testes through a process akin to oncogenesis. This clonal expansion, which is likely to take place in the testes of all men, leads to the relative enrichment of mutant sperm over time-explaining the observed paternal age effect associated with these disorders-and in rare cases to the formation of testicular tumors. As regulation of RAS and other mediators of cellular proliferation and survival is important in many different biological contexts, for example during tumorigenesis, organ homeostasis and neurogenesis, the consequences of selfish mutations that hijack this process within the testis are likely to extend far beyond congenital skeletal disorders to include complex diseases, such as neurocognitive disorders and cancer predisposition.
Topics: Animals; Genetic Predisposition to Disease; Humans; Male; Mutation; Paternal Age; Spermatogonia; Spermatozoa; Testis
PubMed: 22325359
DOI: 10.1016/j.ajhg.2011.12.017 -
Osteoarthritis and Cartilage Apr 2015
Topics: Achondroplasia; Animals; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Receptor, Fibroblast Growth Factor, Type 3; Thanatophoric Dysplasia
PubMed: 25595698
DOI: 10.1016/j.joca.2015.01.002 -
Journal of Clinical and Diagnostic... Nov 2015Thanatophoric Dysplasia (TD) is a congenital, sporadic and the most lethal skeletal dysplasia caused by new mutation in the FGFR3 gene. At birth, it is characterized by...
Thanatophoric Dysplasia (TD) is a congenital, sporadic and the most lethal skeletal dysplasia caused by new mutation in the FGFR3 gene. At birth, it is characterized by shortening of the limbs (micromelia), small conical thorax, platyspondyly (flat vertebral bodies) and macrocephaly. TD is divided into two clinically defined subtypes: type I and II with some clinical overlap between the two subtypes. They can be differentiated by the skull shape and femur morphology. Ultrasound examination in the second trimester is often straight forward in diagnosing the congenital anomaly. We report a case of pre term fresh stillborn baby with dysmorphic facies, macrocephaly, micromelia with short stubby fingers and deep skin creases, narrow thorax and protuberant abdomen which delivered at our hospital. The ultrasound examination showed shortening of long bones with femur shaped like telephone receiver. Dysmorphic facial features and skeletal abnormalities in the baby lead us to make the diagnosis of TD type I. Because of the rarity of this condition we report this case of thanatophoric dysplasia with a short review of literature.
PubMed: 26675119
DOI: 10.7860/JCDR/2015/13201.6702 -
Fetal Diagnosis and Therapy 2008To present the early 2D and 3D ultrasound findings and the molecular confirmation in a case of thanatophoric dysplasia.
OBJECTIVE
To present the early 2D and 3D ultrasound findings and the molecular confirmation in a case of thanatophoric dysplasia.
METHODS
On ultrasound examination, there was frontal bossing, increased nuchal translucency and short limbs at 12 weeks' gestation and a small thorax and short and bowed long bones on 3D at 16 weeks. Amniocentesis and DNA analysis confirmed the mutation of FGFR3 gene indicating thanatophoric dysplasia.
RESULTS
After medical termination of pregnancy, the postmortem X-ray and pathology examination findings were consistent with the diagnosis.
CONCLUSION
3D anatomy scan and molecular confirmation may be helpful in early diagnosis and genetic counseling of thanatophoric dysplasia.
Topics: Adult; Female; Humans; Imaging, Three-Dimensional; Mutation; Pregnancy; Receptor, Fibroblast Growth Factor, Type 3; Thanatophoric Dysplasia; Ultrasonography, Prenatal
PubMed: 18504386
DOI: 10.1159/000132411 -
Frontiers in Genetics 2023Prenatal diagnosis of fetal short long bones (SLBs) was reported to be associated with skeletal dysplasias, chromosomal abnormalities, and genetic syndromes. This study...
Prenatal diagnosis of fetal short long bones (SLBs) was reported to be associated with skeletal dysplasias, chromosomal abnormalities, and genetic syndromes. This study aims to identify the genetic causes for fetal short long bones, and retrospectively evaluate the additional diagnostic yield of exome sequencing (ES) for short long bones following the use of conventional genetic testing. A cohort of ninety-four fetuses with sonographically identified short long bones was analyzed by trio-exome sequencing between January 2016 and June 2021. Fetuses with abnormal results of karyotype or chromosomal microarray analysis were excluded. Variants were interpreted based on ACMG/AMP guidelines. All diagnostic variants were validated by Sanger sequencing. Of the 94 fetuses, 38 (40.4%) were found to carry causal genetic variants (pathogenic or likely pathogenic) in sixteen genes with 38 variants. Five fetuses (5.3%) had variant(s) of uncertain significance. Thirty-five cases (37.2%) were diagnosed as genetic skeletal dysplasias including 14 different diseases that were classified into 10 groups according to the Nosology and Classification of Genetic Skeletal Disorders. The most common disease in the cohort was achondroplasia (28.9%), followed by osteogenesis imperfecta (18.4%), thanatophoric dysplasia (10.5%), chondrogenesis (7.9%), and 3-M syndrome (5.3%). The diagnostic yield in fetuses with isolated short long bones was lower than the fetuses with non-isolated short long bones, but not reached statistical significance (27.3% vs. 44.4%; = 0.151). Whereas, the rate in the fetuses with other skeletal abnormalities was significantly higher than those with non-skeletal abnormalities (59.4% vs. 32.5%, = 0.023), and the diagnostic rate was significantly higher in femur length (FL) below -4SDs group compared with FL 2-4SDs below GA group (72.5% vs. 16.7%; < 0.001). A long-term follow-up showed that outcomes for fetuses with FL 2-4SDs below GA were significantly better than those with FL below -4SDs. Additionally, fourteen (36.8%) novel short long bones-related variants were identified in the present study. The findings suggest that in fetuses with short long bones routine genetic tests failed to determine the underlying causes, exome sequencing could add clinically relevant information that could assist the clinical management of pregnancies. Novel pathogenic variants identified may broaden the mutation spectrum for the disorders and contributes to clinical consultation and subsequent pregnancy examination.
PubMed: 36923788
DOI: 10.3389/fgene.2023.1032346