Prenatal diagnosis of hypochondroplasia: three-dimensional multislice computed tomography findings and molecular analysis

We report the first case of sporadic hypochondroplasia diagnosed in utero by computed tomography (CT) three-dimensional (3D) imaging and molecular analysis at 38 weeks' gestation. Prenatal sonographic examinations performed at 32 and 35 weeks' gestation revealed a rhizomelic shortness of the long bones (femur and humerus) with macrocephaly. Based on these findings, a nonlethal form of skeletal dysplasia was suspected and a multislice CT imaging with 3D reconstruction was performed depicting skeletal abnormalities which suggested hypochondroplasia. The prenatal diagnosis was confirmed by DNA mutation analysis of the fibroblast growth receptor 3 gene.     

Prenatal diagnosis of Kniest dysplasia with three-dimensional helical computed tomography

Objective.?Fetal three-dimensional helical computed tomography (3D-CT) has attracted attention in the diagnosis of fetal skeletal dysplasias because of limited diagnostic capabilities of standard ultrasonography to delineate the skeleton. Here we report the first instance of diagnosing Kniest dysplasia with 3D-CT.

Methods.?Fetal 3D-CT was performed for a fetus at 28 weeks' gestation after ultrasonography at 24 weeks had shown moderate shortening of the limbs, mild narrow thorax, and polyhydramnios. The imaging parameters were set so as to reduce estimated fetal irradiation dose to 12.39 mGy of the CT dose index volume and 442 of the dose length product.

Results.?Fetal 3D-CT revealed dumbbell-shaped femora and platyspondyly with coronal cleft of the lumbar vertebral body. This warranted a diagnosis of Kniest dysplasia and corresponded well with postnatal radiographic findings. In retrospect, however, spinal deformation was somewhat underestimated due to image smoothing associated with image processing in 3D-CT. Genetic testing for COL2A1 confirmed Kniest dysplasia; i.e., a de novo mutation of A–C transversion at the splice acceptor site of the 3′ end of intron 16.

Conclusions.?The combined use of 3D-CT with ultrasonography is a power tool for the prenatal diagnosis of congenital skeletal dysplasias.     

In utero ultrasonographic features of campomelic dysplasia

A prenatal diagnosis of campomelic dysplasia in a primigravida is described. First level fetal ultrasonography demonstrated bowing and shortening of lower limbs. Second level examination allowed the correct diagnosis by demonstrating several skeletal anomalies pathognomonic of campomelic dysplasia.     

First-trimester prenatal diagnosis of Ellis–van Creveld syndrome

ObjectiveTo present the perinatal findings and first-trimester molecular and transabdominal ultrasound diagnosis of a fetus with Ellis–van Creveld (EvC) syndrome.Case ReportA 35-year-old woman was referred for genetic counseling at 13 weeks of gestation because of a family history of skeletal dysplasia. She had experienced one spontaneous abortion, and delivered one male fetus and one female fetus with EvC syndrome. During this pregnancy, a prenatal transabdominal ultrasound at 13⁺⁴ weeks of gestation revealed a nuchal translucency (NT) thickness of 2.0 mm, an endocardial cushion defect, postaxial polydactyly of bilateral hands, and mesomelic dysplasia of the long bones. Amniocentesis was performed at 13⁺⁵ weeks of gestation. Results of a cytogenetic analysis revealed a karyotype of 46,XX and that of a molecular analysis revealed compound heterozygous mutations of c.1195C>T and c.871-2_894del26 in the EVC2 gene. Prenatal ultrasound at 16 weeks of gestation showed a fetus with short limbs, an endocardial cushion defect, and postaxial polydactyly of bilateral hands. The parents decided to terminate the pregnancy, and a 116-g female fetus was delivered with a narrow thorax, shortening limbs, and postaxial polydactyly of the hands.ConclusionPrenatal diagnosis of an endocardial cushion defect with postaxial polydactyly should include a differential diagnosis of EvC syndrome in addition to short rib–polydactyly syndrome, Bardet–Biedl syndrome, orofaciodigital syndrome, Smith–Lemli–Opitz syndrome, and hydrolethalus syndrome.     

Prenatal diagnosis of thanatophoric dysplasia in the second trimester: ultrasonography and other diagnostic modalities

Thanatophoric dysplasia is the most common type of neonatal lethal osteochondrodysplasias, with an estimated frequency of nearly of 1 in 20,000 births. It is a disorder characterized by extremely short ribs, tubular bones and macrocephaly. The prenatal diagnosis of thanatophoric dysplasia has been well established by ultrasonography in the second trimester; however it is not always possible to differentiate the thanatophoric dysplasia fetuses from the others with skeletal dysplasias like fibrochondrogenesis or atelosteogenesis by ultrasonography. Recently, mutations in the fibroblast growth factor receptor 3 gene, located on the short arm of chromosome 4 have been identified as a cause of thanatophoric dysplasia. In this article we described the prenatal diagnosis of two fetuses with thanatophoric dysplasia at 18 and 24 weeks of gestation by ultrasonography. Postpartum radiological and histological analysis confirmed our prenatal diagnosis. Our purpose was to remind the differential prenatal diagnosis with other skeletal dysplasias and new prenatal diagnostic modalities.     

Rapid detection of K650E mutation in FGFR3 using uncultured amniocytes in a pregnancy affected with fetal cloverleaf skull,occipital pseudoencephalocele,ventriculomegaly, straight short femurs,and thanatophoric dysplasia type II

ObjectiveTo present the ultrasound and molecular genetic diagnosis of thanatophoric dysplasia type II (TD2).Case ReportA 35-year-old, primigravid woman was referred to our institution for genetic counseling and amniocentesis at 19 weeks of gestation because of advanced maternal age and sonographic abnormalities in the fetus. The prenatal ultrasound showed short straight femurs, prominent forehead, narrow chest, skin edema, short limbs, and cloverleaf skull consistent with the diagnosis of TD2. Amniocentesis revealed a karyotype of 46,XX. DNA testing for the FGFR3 gene using uncultured amniocytes revealed a heterozygous c.1948A>G, AAG>GAG transversion leading to a p.Lys650Glu(K650E) mutation in the FGFR3 gene. A prenatal ultrasound at 21 weeks of gestation showed ventriculomegaly, cloverleaf skull, straight femurs, micromelia, narrow chest, and pseudoencephalocele with a bulging occipital bone mimicking encephalocele. The pregnancy was subsequently terminated, and a 480-g malformed fetus was delivered with macrocephaly, depressed nasal bridge, short upturned nasal tip, hypoplastic midface, frontal bossing, short digits, trident-shaped hands, short limbs, cloverleaf skull, narrow chest, brachydactyly, nuchal edema, and bulging occipital bone.ConclusionA prenatal diagnosis of cloverleaf skull, short limbs, straight femurs, and occipital pseudoencephalocele should include a differential diagnosis of TD2. A molecular analysis of FGFR3 using uncultured amniocytes is useful for the rapid confirmation of TD2 at prenatal diagnosis.     

Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia

Thanatophoric dysplasia (TD) is one of the most common neonatal lethal skeletal dysplasias. Prenatal sonographic and molecular genetic diagnoses of three cases of TD type I (TD1) and one case of TD type II (TD2) are presented here. Two fetuses of TD1 were characterized by polyhydramnios, macrocephaly, short limbs, a narrow thoracic cage and curved short femora, but without a cloverleaf skull at 27 and 31 weeks' gestation, respectively. The third fetus with TD1 was, however, not associated with macrocephaly, polyhydramnios, chest narrowing and severe femoral bowing on prenatal ultrasound at 18 weeks' gestation. The TD2 fetus was characterized by polyhydramnios, short limbs, a narrow thoracic cage, straight short femora, hydrocephalus and a cloverleaf skull at 24 weeks' gestation. Three-dimensional ultrasound was able to enhance the visualization of thickened, redundant skin folds and craniofacial and limb deformities associated with TD. Molecular analysis of the fibroblast growth factor receptor 3 (FGFR3) gene by restriction enzyme digestion analysis and direct sequencing using cultured amniotic fluid cells or cord blood cells revealed a missense mutation of 742C-->T (Arg248Cys) in all cases with TD1 and a missense mutation of 1948A-->G (Lys650Glu) in the case with TD2. The present report shows that adjunctive applications of molecular genetic analysis of the FGFR3 gene and three-dimensional ultrasound are useful for prenatal diagnosis of TD.     

Prenatal diagnosis of hydrancephaly and enlarged cerebellum and cisterna magna in a fetus with thanatophoric dysplasia type II and a review of prenatal diagnosis of brain anomalies associated with thanatophoric dysplasia

Objective

We present prenatal diagnosis of hydrancephaly and enlarged cerebellum and cisterna magna in a fetus with thanatophoric dysplasia type II (TD2) and a review of prenatal diagnosis of brain anomalies associated with TD.

Prenatal diagnosis of thanatophoric dysplasia by mutational analysis of the fibroblast growth factor receptor 3 gene and a proposed correction of previously published PCR results

Thanatophoric dysplasia (TD) is the most frequent form of neonatal lethal skeletal dysplasia. Recently. mutations in the fibroblast growth factor receptor 3 (FGFR3) gene that cause two subtypes of this disorder, type I (TDI) and type II (TDII), have been identified. This discovery has now made it possible to make a definite diagnosis of TD by molecular methods. To date, prenatal diagnosis of TD has been accomplished by ultrasonography in the second trimester. However, it is not always possible to distinguish TD fetuses it utero from the other osteochondrodysplasias by ultrasonography or radiography. We report on the prenatal diagnosis of a TD fetus, showing severe shortness of limbs and polyhydramnios, by identification of a mutation in the FGFR3 gene. Genomic DNA was isolated from the amniotic fluid and then subjected to PCR amplification. The common TDI mutation, C-->T transition at nucleotide 742 in the FGFR3 gene, was identified using restriction enzyme analysis. This information was critical in obstetric management decisions later in pregnancy. However, although the mutation responsible for TDI was detected previously, we noticed some inconsistencies in the published PCR results and have proposed a correction.     

Sonographic diagnosis of SEDC and double heterozygote of SEDC and achondroplasia--a report of six pregnancies

OBJECTIVE: To define the sonographic features of spondyloepiphyseal dysplasia congenita (SEDC) and the double heterozygote for SEDC and achondroplasia. METHODS: A retrospective review of 6 pregnancies in one family where one parent has achondroplasia and the other SEDC. RESULTS: There were 4 double heterozygote pregnancies and 2 where the fetus had SEDC. Shortening of long bones was evident in both conditions from around 16 weeks gestation. Other findings such as an increased nuchal translucency were more variable. CONCLUSIONS: Molecular analysis of the FGFR3 and COL2AI gene once mutations are known in a family such as reported here can inform prenatal diagnosis and help to distinguish between the double heterozygote and a fetus which has inherited a single mutation. The data presented here on the growth of the long bones and other sonographic features associated with SEDC may aid prenatal diagnosis in cases where the mutation is not known.     

Prenatal and postnatal findings in a case with the autosomal recessive type of Robinow syndrome

OBJECTIVE: Our aim was to present a prenatally diagnosed case with Robinow syndrome in a consanguineous couple and discuss possible differential diagnosis in view of the literature. METHODS: A 28-year-old pregnant woman gravida 2 para 1 was referred to the obstetric clinic of Kahramanmaras Sutcu Imam University presenting with a fetus having shortened upper and lower limbs at 33 weeks of gestation. Her medical history was unremarkable except for consanguinity. Prenatal ultrasonographic examination revealed a reduced humerus and femur length. Further, shortening of the forearm, frontal bossing, mild hypertelorism, reduced thoracic perimeter and hemivertebrae at the thoracic level were present. RESULTS: Meticulous neonatal examination was performed following an uncomplicated vaginal delivery at 39 weeks of gestation. Distinct facial appearance in addition to the prenatal findings argued in favor of the diagnosis of Robinow syndrome. Additionally, radiological survey revealed and confirmed shortening of the upper extremities and thoracic hemivertebrae. CONCLUSION: We are documenting the case on the account of its rarity and additional features. The main approach in the differential diagnosis of Robinow syndrome should determine whether hemivertebrae is isolated or part of a syndrome or association.     

Detection of a de novo Y278C mutation in FGFR3 in a pregnancy with severe fetal hypochondroplasia: Prenatal diagnosis and literature review

ObjectiveWe describe a prenatal molecular diagnosis of hypochondroplasia (HCH) in a pregnancy not at risk of HCH and review the literature on prenatal diagnosis of HCH.Case reportA 28-year-old primigravid woman was referred for genetic counseling at 30 weeks of gestation because of short-limbed dwarfism in the fetus. The woman had a body height of 152 cm. Her husband had a body height of 180 cm. Level II ultrasound showed a normal amount of amniotic fluid and a singleton fetus with fetal biometry equivalent to 30 weeks except for short limbs. Fetal biometry measurements were as follows: biparietal diameter = 7.38 cm (30 weeks); head circumference = 28.14 cm (30 weeks); abdominal circumference (AC) = 24.64 cm (30 weeks); femur length (FL) = 3.97 cm (<5th centile); FL/AC ratio = 0.161 (normal > 0.18); humerus = 3.64 cm (<5th centile); radius = 3.49 cm (30 weeks); ulna = 3.76 cm (<5^th centile); tibia = 3.67 cm (<5th centile); and fibula = 3.72 cm (<5th centile). The digits and craniofacial appearance were normal. A tentative diagnosis of achondroplasia (ACH) was made. DNA testing for the FGFR3 gene and whole-genome array comparative genomic hybridization (aCGH) analysis were performed using cord blood DNA obtained by cordocentesis. FGFR3 mutation analysis revealed a de novo heterozygous c.833A > G, TAC > TGC transversion in exon 7 leading to a p.Tyr278Cys (Y278C) mutation in the FGFR3 protein. aCGH analysis revealed no genomic imbalance in cord blood. After delivery, the fetus had short limbs, a narrow thorax, brachydactyly, and relative macrocephaly. Cytogenetic analysis of cultured placental cells revealed a karyotype of 46,XX.ConclusionPrenatal diagnosis of abnormal ultrasound findings suspicious of ACH should include a differential diagnosis of HCH by molecular analysis of FGFR3.     

Prenatal diagnosis of Meckel syndrome: a case report.

OBJECTIVE: To demonstrate the major sonographic findings associated with Meckel syndrome and to emphasize the importance of prenatal sonography in helping to establish the correct diagnosis. SUBJECTS: Two fetuses with prenatal diagnosis of Meckel syndrome were sonographically evaluated. RESULTS: Both fetuses were demonstrated to have evidence of renal cystic dysplasia, occipital cephalocele and postaxial polydactyly. One case was diagnosed at 16 weeks of gestation whereas the other was detected at 36 weeks. Of interest, the first case had only unilateral renal cystic dysplasia and contralateral renal agenesis and mild degree of oligohydramnios. The other related anomalies which were not detected prenatally included cerebellar hypoplasia in case 1 and micrognathia in case 2. CONCLUSION: The main sonographic findings included renal cystic dysplasia, occipital cephalocele and postaxial polydactyly.     

New clinical findings in the Richieri-Costa/Pereira type of acrofacial dysostosis

The Richieri-Costa/Pereira form of acrofacial dysostosis is an autosomal-recessive condition characterized by short stature, Pierre-Robin sequence, preaxial and postaxial abnormalities in hands, congenital talipes, cleft mandible and malformations of the larynx. We report female infant presenting with severe micrognathia, a hypoplasic clavicle, median mandible cleft, bilateral hand abnormalities and talipes, laryngeal malformations, hip subluxation with acetabular dysplasia and mesomelic shortening of limbs. A few reported patients have clavicular hyploplasia but hip subluxation with acetabular dysplasia and mesomelic shortening of limbs have not been described.     

Perinatal imaging findings and molecular genetic analysis of thanatophoric dysplasia type 1 in a fetus with a c.2419T>G (p.Ter807Gly) (X807G) mutation in FGFR3

Objective

We present perinatal imaging findings and molecular genetic analysis of thanatophoric dysplasia type I (TD1) in a fetus.

Short rib polydactyly syndrome type 3 with absence of fibulae (Verma-Naumoff syndrome)

Short rib polydactyly syndrome (SRPS) is a group of skeletal dysplasias manifested by short-limb dwarfism, short ribs with thoracic dysplasia and polydactyly. SRPS is an inherited autosomal-recessive disorder with different prenatal sonographic and postnatal clinical, histological and radiologic findings. SRPS type 1 (Saldino-Noonan) and type 3 (Verma-Naumoff) are very similar and frequently get mixed. In this report, we present a case of SRPS with hydrops, thoracic hypoplasia, short limbs and postaxial polydactyly in a 27-week fetus. The visceral findings in the fetus including the central nervous system were normal. The karyotype was 46XY. The prenatal diagnosis was thought to be type 1 because of the absence of fibulae at ultrasonography. However, postmortem autopsy, histologic, and radiologic findings were reviewed and the diagnosis was type 3 SRPS because of absence of visceral anomalies, presence of fan-shaped iliac bones and short tubular bones with metaphyseal widening. We concluded that detailed ultrasonography performed in the prenatal period is very important in the diagnosis and differential diagnosis of SRPS.     

Prenatal ultrasonographic diagnosis of diastrophic dysplasia at 13 weeks of gestation

Diastrophic dwarfism is a skeletal dysplasia that can be identified by ultrasound usually during the second trimester of pregnancy. This severe but non-lethal disorder of the cartilage can be diagnosed earlier using transvaginal sonography (TVS). We present a case of diastrophic dysplasia diagnosed at 13 weeks of gestation by TVS. The early TVS evaluation of the fetal biometric parameters and the accurate study of the morphological features of the fetal long bones and extremities allowed an early diagnosis of this rare pathology that leads to a progressive physical handicap, due mainly to severe kyphoscoliosis and arthropathies. Recently, the routine use of TVS at 11–14 weeks of gestation has permitted an earlier diagnosis to be reached of a great number of congenital anomalies. Patients at risk for skeletal dysplasia could benefit from the enhancements of ultrasound techniques. An early diagnosis of diastrophic dysplasia can be reached at the and of the first trimester of pregnancy, using TVS.     

Prenatal diagnosis of osteogenesis imperfecta type III

Ultrasonographic and radiographic evaluation of a fetus at risk for osteogenesis imperfecta (O.I) type III was performed. Real-time ultrasound measurements at 15 weeks gestation were interpreted as normal, but at 20 and 22 weeks of gestation revealed marked shortening of the long bones and deformity of the femurs. The findings were confirmed by fetal radiography at 22 weeks gestation. Radiographic and histologic changes characteristic of O.I. were observed in the aborted fetus. Thus the antenatal manifestations of O.I. type III maybe severe enough to make prenatal diagnosis possible in the second trimester for families at risk for recurrence of this disorder.     

Typical isolated ectrodactyly of hands and feet: early antenatal diagnosis.

Ectrodactyly is a rare dominant autosomal malformation with variable expression. Herein we report a case early diagnosed by ultrasound at 15 weeks of gestation of isolated ectrodactyly involving the four limbs. The sonographic findings were bilateral split hands and split foot. Diagnosis of typical isolated ectrodactyly was pathologically confirmed. Clinical forms, pathogenesis, differential diagnosis, and early prenatal diagnosis are discussed.     

Typical isolated ectrodactyly of hands and feet: Early antenatal diagnosis

Ectrodactyly is a rare dominant autosomal malformation with variable expression. Herein we report a case early diagnosed by ultrasound at 15 weeks of gestation of isolated ectrodactyly involving the four limbs. The sonographic findings were bilateral split hands and split foot. Diagnosis of typical isolated ectrodactyly was pathologically confirmed. Clinical forms, pathogenesis, differential diagnosis, and early prenatal diagnosis are discussed.