Thanatophoric Dysplasia Research Articles

Fetal Skeletal System

ABSTRACT The prevalence of skeletal dysplasias is between 1 and 2000, and 1 and 4000 live births. While here are over 200 skeletal dysplasias approximately four disorders comprise 70% of the total: Achondroplasia, thanatophoric dysplasia, osteogenesis imperfecta, and achondrogenesis. The appropriate identification of lethal skeletal dysplasia is important not only for current pregnancy management, but also for genetic counseling concerning future pregnancies. Detection of skeletal dysplasias is usually possible by prenatal ultrasound, an accurate specific diagnosis is possible by radiologic, pathologic and molecular genetic examination. A total body ultrasound approach should include assessment of the following: Limbs, long bones and extremities, bone mineralization, any joint contractures, joint dislocations, fetal calvarium, spine and thorax.

PP-201. Thanatophoric dysplasia — The case report

PP-201. Thanatophoric dysplasia — The case report

First‐trimester molecular prenatal diagnosis of a thanatophoric dysplasia

First‐trimester molecular prenatal diagnosis of a thanatophoric dysplasia

Stippling: a first trimester marker for thanatophoric dysplasia type I

Stippling: a first trimester marker for thanatophoric dysplasia type I

Genetic inactivation of ERK1 and ERK2 in chondrocytes promotes bone growth and enlarges the spinal canal

Activating mutations in FGFR3 cause the most common forms of human dwarfism: achondroplasia and thanatophoric dysplasia. In mouse models of achondroplasia, recent studies have implicated the ERK MAPK pathway, a pathway activated by FGFR3, in creating reduced bone growth. Our recent studies have indicated that increased Fgfr3 and ERK MAPK signaling in chondrocytes also causes premature synchondrosis closure in the cranial base and vertebrae, accounting for the sometimes fatal stenosis of the foramen magnum and spinal canal in achondroplasia. Conversely, whether the decrease--or inactivation--of ERK1 and ERK2 promotes bone growth and delays synchondrosis closure remains to be investigated. In this study, we inactivated ERK2 in the chondrocytes of ERK1-null mice using the Col2a1-Cre and Col2a1-CreER transgenes. We found that the genetic inactivation of ERK1 and ERK2 in chondrocytes enhances the growth of cartilaginous skeletal elements. We also found that the postnatal inactivation of ERK1 and ERK2 in chondrocytes delays synchondrosis closure and enlarges the spinal canal. These observations make ERK1 and ERK2 an attractive target for the treatment of achondroplasia and other FGFR3-related skeletal syndromes.

THANATOPHORIC DYSPLASIA TYPE I ASSOCIATED WITH INCREASED NUCHAL TRANSLUCENCY IN THE FIRST TRIMESTER: Early Prenatal Diagnosis Using Combined Ultrasonography and Molecular Biology

A case of thanatophoric dysplasia (TD) type I associated with severely increased nuchal translucency at first trimester screening for Down syndrome is reported. A 38-year-old woman, G2P1, with previous uneventful pregnancy, was referred for amniocentesis at 16 weeks due to positive first trimester integrated test. Amniocentesis revealed a 46,XX fetus. At 16 weeks gestation, the ultrasound examination of the fetus revealed a narrow chest, short ribs, and a generalized severe shortening of the long bones. The patient underwent a follow-up scan at 19 weeks which demonstrated ultrasound findings consistent with severe rhizomelic micromelia. A wide prenatal panel of gene mutations related with skeletal dysplasia was performed. Nucleotidic sequence using QF-PCR on exons 7,10, 15, 19 of the fibroblast growth factor receptor 3 (FGFR3) demonstrated a 742 C>T (R248C) mutation, which resulted in an Arg248Cys substitution in heterozygous state, leading to a prenatal diagnosis of thanatophoric dysplasia type I. The early diagnosis of this lethal form of skeletal dysplasia directed the prenatal counseling and allowed appropriate obstetric management. Necropsy, post-mortem x-ray, and histologic analysis of the growth plate might aid the diagnosis of TD type I.

Prenatal diagnosis of thanatophoric dysplasia and obstetrical challenges

Thanatophoric dysplasia (TD) was first described in 1967 (Maroteaux et al. 1967). It occurs in approximately 1/20,000 to 1/50,000 births (Sawaia et al. 1999). The birth rate in the United Arab Emir...

Fibroblast growth receptor-3 (FGFR3) G375C mutation in a case of achondroplasia and thanatophoric dysplasia phenotypic overlap

Barton, Christophera; Sweeney, Elizabethc; Roberts, Devenderd; McPartland, Job Author Information

Thanatophoric Dysplasia: Role of 3D Sonography

Thanatophoric Dysplasia: Role of 3D SonographyLourens R. Pistorius, Gwendolyn T. R. Manten and Peter G. NikkelsAudio Available | Share

Seborrhoeic keratoses and acanthosis nigricans in a long-term survivor of thanatophoric dysplasia

Seborrhoeic keratoses and acanthosis nigricans in a long-term survivor of thanatophoric dysplasia

Malformation of the fetal brain in thanatophoric dysplasia: US and MRI findings

We present a case in which the unusual cerebral malformations of thanatophoric dysplasia (TD) were identified on a 21-week fetal US and confirmed by antenatal MRI, postmortem imaging and autopsy. TD is the most common lethal skeletal dysplasia and is characterized by short long bones, which are often bowed (type 1), a small thorax, and skull deformities. There is also a recognised constellation of abnormalities of the brain primarily affecting the temporal lobes that, although well described in the postmortem setting, are not widely recognized in fetal imaging. Familiarity with this appearance will facilitate accurate antenatal diagnosis.

Pattern and prenatal diagnosis of skeletal dysplasias in Qatar population

Objective. To determine the pattern of skeletal dysplasias in Qatar population and to assess the accuracy of prenatal diagnosis and prognosis.Methods. This was a retrospective descriptive study of 30 women with high risk for skeletal dysplasias. The recruited women were submitted to clinical assessment, ultrasound scanning using 2-dimensional, 3-dimensional/4-dimensional and colour Doppler technique with possible molecular diagnosis. The findings were compared with the postnatal or postmortem assessments. Final diagnosis was based on clinical examination, skeletal survey, autopsy and molecular testing as deemed necessary.Results. Thirty cases of skeletal dysplasia were antenatally diagnosed over 4-year period with family history in few cases. Among many entities thanatophoric dysplasia showed largest prevalence [7(23%)]. Prenatal diagnosis was accurate in 76% of foetuses while the first indicator of abnormality was a suspected anomaly found during routine ultrasound assessment in most cases [17(56%)]. Prediction of lethality based on ultrasound findings was 100% accurate.Conclusions. This study confirmed the possibility of good prenatal diagnosis of skeletal dysplasias present among Qatar population. Diagnosis based on ultrasound assessment will improve by adding molecular techniques with positive impact on prenatal care.

A case of thanatophoric dysplasia type I with an R248C mutation in theFGFR3gene

Thanatophoric dysplasia (TD) is a short-limb neonatal dwarfism syndrome that is usually lethal in the perinatal period. It is characterized by shortening of the limbs, severely small thorax, large head with a prominent forehead, macrocephaly, curved femur, and flattened vertebral bodies. These malformations result from the mutation in fibroblast growth factor receptor 3 (FGFR-3) gene which is located on the short arm of chromosome 4. A definite diagnosis should be established by molecular genetic analysis to find out the abnormal mutations in the FGFR3 gene. We confirmed by detection of a R248C mutation in the FGFR3 gene in DNA analysis.

Generation of Fgfr3 Conditional Knockout Mice

Fibroblast growth factor receptor 3 (FGFR3), highly conserved in both humans and murine, is one of key tyrosine kinase receptors for FGF. FGFR3 is expressed in different tissues, including cartilage, brain, kidney, and intestine at different development stages. Conventional knockout of Fgfr3 alleles leads to short life span, and overgrowth of bone. In clinic, human FGFR3 mutations are responsible for three different types of chondrodysplasia syndromes including achondroplasia (ACH), hypochondroplasia (HCH) and thanatophoric dysplasia (TD). For better understanding of the roles of FGFR3 in different tissues at different stages of development and in pathological conditions, we generated Fgfr3 conditional knockout mice in which loxp sites flank exons 9-10 in the Fgfr3 allele. We also demonstrated that Cre-mediated recombination using Col2a1-Cre, a Cre line expressed in chondrocyte during bone development, results in specific deletion of the gene in tissues containing cartilage. This animal model will be useful to study distinct roles of FGFR3 in different tissues at different ages.

Comment on Trujillo-Tiebas MJ et al. J Assist Reprod Genet DOI 10.1007/s10815-009-9339-1

Dear Dr. Dong-Zhi Li, Firstly, we thank you for the interest with which you have read our article as well as the remarks you have made in response [1]. As you mention, skeletal dysplasias are indeed a very diverse group of pathologies for which ultrasound prenatal diagnosis is a difficult prospect that poses a substantial challenge for professionals. For this reason, our Clinical Genetics Service is made up of a consultation section and both a cytogenetics and molecular laboratory. The aim of our paper was to give an account of our experience over a nine-year period in a GENETICS laboratory while summarizing the laboratory’s results in providing molecular diagnosis based on samples coming in from both our own institution as well as other accredited centers. Our intent was to stress the great advantages offered by a comprehensive service which, in addition to molecular diagnosis, provides both genetic counseling and cytogenetic and molecular studies. In Spain, termination of pregnancy is currently permitted by law until the twenty-second week. One of the causes justifying lawful pregnancy termination is the detection of ultrasound-documented alterations which render the developing fetus inviable as well as those causing severe fetal illness. Our hospitals do not perform pregnancy-termination procedures, and the abortuses received by our service are sent to us by legal institutions specializing in such operations. All the samples that become part of our studies are the product of fetuses deemed by the law as suitable for such purposes. The time elapsed between detection and gestation is a limiting factor. It can be assumed that, in the near future, prenatal diagnosis of the most common types of bone dysplasia will be performed by means of a screening process carried out in a timely and cost-effective manner, thus limiting the number of pregnancies terminated because of severe skeletal alterations. Couples seeking genetic counseling in our center are informed of the risks associated with invasive techniques and the options open to them under Spanish law at the moment they receive information on the most likely diagnosis. Therefore, couples choose to pursue prenatal diagnosis of their pregnancy and then are free to decide whether to continue the pregnancy or not based on the findings of ultrasound testing and genetic studies. Orphanet suggests in genetic counseling for thanatophoric dysplasia that > [2] Our experience has shown there to be two main types of situations: Previous pregnancy diagnosed with bone dysplasia: recurrence has been shown to be low prevalent in these pathologies [3] but the risk of repeated mutations may be greater than in the general population since it cannot be proven that no de novo mutation in the fetus has occurred [4]. Because it is the patients themselves who defend their right to know, they fund these studies themselves. (This information is not contained in the article.) therefore, these individuals take on the risk of losing the fetus, though our center has a low incidence of fetal loss (<1.5/% in chorionic villi). When the time of gestation has surpassed the period during which it is legal to terminate the pregnancy: The study is requested as a part of the pregnancy plan, the perinatal follow-up program, and by virtue of the right of parents to have this information. Some couples who receive ultrasound prenatal diagnoses without molecular confirmation though having been given previous genetic counseling continue with the pregnancy. Many times, these pregnancies result in other diagnoses (referred to in the article as post-natal diagnosis, such as renal polycystosis, cardiopathy, etc.). Other couples, having gone through a follow-up process adapted to the pathological findings of ultrasound testing, opted to discontinue pregnancy in a lawful manner. It is true that the article has a typographical error, since the STR markers used in the QF-PCR assay included chromosome 21 rather than chromosome 15. Nonetheless, this information appeared in accurate form in the bibliographical reference [5]. We agree with Dr. Li in that prenatal identification of skeletal dysplasias is quite challenging, and that it would be much more effective if there were interdisciplinary efforts made between all the specialties involved. Complementary radiological, anatomic pathology, and molecular studies must be made available for there to be conclusive diagnoses. We also believe that conducting a study on abortuses found via ultrasound to have skeletal alterations may assist in expanding the knowledge of these pathologies.

Review of the recently defined molecular mechanisms underlying thanatophoric dysplasia and their potential therapeutic implications for achondroplasia

Achondroplasia (ACH), thanatophoric dysplasia (TD) types I and II, hypochondroplasia (HCH), and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) are all due to activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. We review the clinical, epidemiological, radiological, molecular aspects, and signaling pathways involved in these conditions. It is known that FGFR3 signaling is essential to regulate bone growth. The signal transducers and activators of transcription (STAT1) pathway is involved in the inhibition of chondrocyte proliferation, and the mitogen-activated protein kinase (MAPK) pathways are involved in chondrocyte differentiation. Hence, FGFR3 signaling is pivotal in chondrocyte differentiation and proliferation through these two different active pathways. Recent studies on the molecular mechanisms involved in chondrocyte differentiation and proliferation, demonstrated that Snail1 participates in the control of longitudinal bone growth and appears to be essential to transduce FGFR3 signaling during chondrogenesis. This result was confirmed in a newborn infant with TD, and suggests new non-surgical therapeutic approaches, that is, Snail1 as a new encouraging therapeutic target.

Lung hypoplasia and its associated major congenital abnormalities in perinatal death: An autopsy study of 850 cases

To determine the relative frequency of causes of lung hypoplasia (LH) and its associated congenital malformations among perinatal deaths. 850 medical reports of perinatal autopsies, in a 25-year period, assessed for LH as a cause of death. LH found in 96 (11.3%) cases, 89 (92.7%) were associated with major congenital malformation (secondary type) and primary type was seen in 7 cases (7.3%). Fourteen cases were associated with multiple congenital anomalies. 32 cases (33.3%) with Genito-urinary anomalies were the most common associated major malformations, followed by 19 cases (19.8%) of diaphragmatic impairment, 15 cases (15.6%) of musculoskeletal abnormalities and 11 cases (11.4%) of kidney agenesis. The most common musculoskletal abnormality was thanatophoric dwarfism in 10 cases (10.4%). Meckle-Gruber syndrome with 7 affected fetuses (7.3%) was the most common malformation syndrome associated with LH. More than ninety percent of LH was secondary to pathology outside the respiratory tract. Renal agenesis is the most common association observed in LH, followed by diaphragmatic hernia and thanatophoric dysplasia.

New Insight on FGFR3-Related Chondrodysplasias Molecular Physiopathology Revealed by Human Chondrocyte Gene Expression Profiling

Endochondral ossification is the process by which the appendicular skeleton, facial bones, vertebrae and medial clavicles are formed and relies on the tight control of chondrocyte maturation. Fibroblast growth factor receptor (FGFR)3 plays a role in bone development and maintenance and belongs to a family of proteins which differ in their ligand affinities and tissue distribution. Activating mutations of the FGFR3 gene lead to craniosynostosis and multiple types of skeletal dysplasia with varying degrees of severity: thanatophoric dysplasia (TD), achondroplasia and hypochondroplasia. Despite progress in the characterization of FGFR3-mediated regulation of cartilage development, many aspects remain unclear. The aim and the novelty of our study was to examine whole gene expression differences occurring in primary human chondrocytes isolated from normal cartilage or pathological cartilage from TD-affected fetuses, using Affymetrix technology. The phenotype of the primary cells was confirmed by the high expression of chondrocytic markers. Altered expression of genes associated with many cellular processes was observed, including cell growth and proliferation, cell cycle, cell adhesion, cell motility, metabolic pathways, signal transduction, cell cycle process and cell signaling. Most of the cell cycle process genes were down-regulated and consisted of genes involved in cell cycle progression, DNA biosynthesis, spindle dynamics and cytokinesis. About eight percent of all modulated genes were found to impact extracellular matrix (ECM) structure and turnover, especially glycosaminoglycan (GAG) and proteoglycan biosynthesis and sulfation. Altogether, the gene expression analyses provide new insight into the consequences of FGFR3 mutations in cell cycle regulation, onset of pre-hypertrophic differentiation and concomitant metabolism changes. Moreover, impaired motility and ECM properties may also provide clues about growth plate disorganization. These results also suggest that many signaling pathways may be directly or indirectly altered by FGFR3 and confirm the crucial role of FGFR3 in the control of growth plate development.

Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors.

Genes mutated in congenital malformation syndromes are frequently implicated in oncogenesis1,2, but the causative germline and somatic mutations occur in separate cells at different times of an organism’s life. Here we unify these processes for mutations arising in male germ cells that show a paternal age effect3. Screening of 30 spermatocytic seminomas4,5 for oncogenic mutations in 17 genes identified 2 mutations in FGFR3 (both 1948A>G encoding K650E, which causes thanatophoric dysplasia in the germline)6 and 5 mutations in HRAS. Massively parallel sequencing of sperm DNA showed that the FGFR3 mutation increases with paternal age, with a similar mutation spectrum at the K650 codon to that in bladder cancer7,8. Most spermatocytic seminomas show increased immunoreactivity for FGFR3 and/or HRAS. We propose that paternal age effect mutations activate a common “selfish” pathway supporting proliferation in the testis, leading to diverse phenotypes in the next generation including fetal lethality, congenital syndromes and cancer.

Maternal Age-Specific Risk of Nonchromosomal Anomalies

With a continuing rise in the average maternal age in industrialized societies, accurate data are needed on maternal age-related obstetric risks. Although it is well known that the risk of fetal aneuploidy increases along with maternal age, it is unclear whether older mothers are at increased risk of having a fetus with nonchromosomal congenital anomalies (NCA). Much of the data on the risk data for NCA among older European mothers are either difficult to interpret or come from studies with small sample size, and little data are available on the overall risk of NCA in younger (teenage) mothers. This population-based prevalence study compared the age-specific risk of NCA among mothers in 15 European countries. Data from 1.75 million infants born between 2000 and 2004 were obtained from the EUROCAT database, a network of population-based congenital anomaly registers in 15 European countries. The primary outcome measures were the prevalence of NCA at increasing maternal ages and the relative risk (RR) of any NCA and 84 standard NCA subgroups. Included among the 38,958 cases of NCA were live births, fetal deaths ≥20 weeks’ gestation, and pregnancy terminations following prenatal diagnosis of malformation. The highest crude prevalence of all NCAs was among mothers <20 years old (26.5 per 1000 births). With increasing maternal age, the overall prevalence of NCA decreased: the crude prevalence per 1000 births for mothers 20 to 24, 25 to 29, 30 to 34, 35 to 39, and 40 to 44 years was 23.8, 22.5, 21.5, 21.4, and 22.6, respectively. Compared to mothers age 25 to 29, the RR of NCA adjusted for country was 1.11 (95% confidence interval [CI], 1.06–1.17) for mothers age <20 years, 0.99 (95% CI, 0.96–1.02) for mothers age 35 to 39, and 1.01 (95% CI, 0.95–1.07) for mothers age 40 to 44. There was significant variation in the pattern of maternal age-related risk between countries: the RR was higher for teenage mothers in France, Ireland, and Portugal, whereas the RR was higher for older mothers in Germany and Poland. The maternal age-specific RR was also different for specific NCAs among the 84 subgroups analyzed. Mothers <20 years old were at a significantly greater risk of nervous system abnormalities including anencephaly, tricuspid atresia, digestive system anomalies including gastroschisis, and maternal infection syndromes. Older mothers aged from 35 to 39 and 40 to 44 years were at a significantly greater risk of encephalocele, esophageal atresia, thanatophoric dwarfism, and fetal alcohol syndrome (all values P < 0.01). These findings indicate that, while teenage mothers are at increased risk of having offspring with NCAs, older maternal age is a negligible risk factor for NCAs overall, although the risk of a few specific anomalies appears to increase with age.