Prenatal diagnosis of campomelic dysplasia by ultrasonography

Consanguineous partners had a boy with campomelic dysplasia who died of increasing respiratory distress soon after birth. The next pregnancy was monitored frequently by ultrasonography and a healthy male infant was born at term. During a further pregnancy, ultrasonography suggested campomelic dysplasia in the 16th week of gestation. This was confirmed in the 18th week. The pregnancy was terminated and the fetus showed the typical radiological, anatomical and histological findings.     

Campomelic acampomelic dysplasia presenting with increased nuchal translucency in the first trimester

This is the first report of a fetus affected with campomelic acampomelic dysplasia presenting with increased nuchal translucency. Ultrasonography at 13 weeks of amenorrhea showed a nuchal translucency 5.6 mm thick. The karyotype performed on amniotic fluid cells was normal (46,XY). Ultrasonography at 22 weeks revealed a normal femoral length and female genitalia. A second amniocentesis was performed to confirm the karyotype and for dosage of steroid hormones. Testosterone dosage was low, corresponding to a female fetus. Ultrasonography at 32 weeks showed growth retardation of the long bones (<3rd centile) that were not curved. A severe malformation syndrome was suspected and the pregnancy was terminated at 33 weeks. The fetus displayed macrocephaly, facial dysmorphism and female external genitalia. X ray showed straight and thickened long bones, hypoplastic scapulae and moderate platyspondyly. In view of the association of sex reversal, hypoplasia of the scapulae, and the presence of straight long bones, campomelic acampomelic dysplasia was suspected and confirmed by the finding of a SOX9 mutation. This case shows the importance of a careful echographic survey in a fetus with a nuchal translucency > 4 mm, especially if there is discordance between phenotypic and genotypic sex, since growth retardation may occur later during the pregnancy. Copyright © 2004 John Wiley & Sons, Ltd.     

Prenatal transvaginal diagnosis of the ectrodactyly,ectodermal dysplasia,cleft palate (EEC) syndrome

Transvaginal ultrasonography performed at 14 weeks' gestation demonstrated a bilateral cleft lip and lobster-claw deformities of the hands and feet, in keeping with the diagnosis of EEC syndrome (ectrodactyly or lobster-claw deformity, ectodermal dysplasia, and cleft lip and palate). The fetus was aborted and the diagnosis of EEC syndrome was confirmed.     

Antenatal ultrasonic diagnosis of dyssegmental dysplasia: A case report

Sonographic prenatal diagnosis and management of a pregnancy complicated by dys-segmental dysplasia of the Silverman-Handmaker type are presented. This is a documented case of this type of short-limbed dwarfism presenting in a family of Hispanic-American ancestry.     

Prenatal ultrasound diagnosis of frontonasal dysplasia

We report a case of prenatal ultrasound diagnosis of frontonasal dysplasia. This represents a very rare disorder involving the face (hypertelorism, median cleft lip, absence of the nasal tip) and often the central nervous system (CNS) (cranium bifidum occultum, ethmoidal cephalocele, agenesis of the corpus callosum). Although several of the typical anomalies are diagnosable by ultrasound in utero (hypertelorism, median cleft lip, anterior cephalocele), very few cases have been reported prenatally, the present being only the third. In the present case, hemimegalencephaly is first reported among the anomalies possibly associated with frontonasal dysplasia. The diagnosis was made at 22 weeks' gestation and was confirmed by necropsy following termination of pregnancy. Copyright © 2002 John Wiley & Sons, Ltd.     

Radiographic and genetic diagnosis of sporadic hypochondroplasia early in the neonatal period

Hypochondroplasia is an autosomal dominant skeletal dysplasia expressing postnatal onset of short stature with mild rhizomelic shortening of the limbs. This manifestation leads to restricted prenatal diagnosis of the disorder. We report here on a sporadic case of a hypochondroplastic baby, whose prenatal sonographic measurements were serially recorded from 19 weeks of gestation. Mild shortening of the limbs became manifest after 26 weeks of gestation. Biparietal diameter was within the normal range throughout gestation. Both parents were of average stature. A tentative diagnosis of a nonlethal short-limb skeletal dysplasia was made. At birth, the clinical manifestations of the neonate were not characteristic, but the radiographic features raised the possibility of hypochondroplasia. Molecular analyses revealed a C to G mutation at nucleotide 1659 of the fibroblast growth factor receptor 3 (FGFR3) gene, a common mutation in hypochondroplasia. Copyright © 2004 John Wiley & Sons, Ltd.     

Prenatal diagnosis of metatropic dwarfism

We present a case of prenatal diagnosis of severe metatropic dysplasia at 20 weeks' gestation. The characteristic prenatal features of this rare autosomal recessive chondrodysplasia appear to be significant dwarfism with an enlarged head and a narrow thorax associated with enlargement of the hands and feet, and the radiographic ‘dumb-bell’ appearance of the long bones.     

Three-dimensional ultrasound in prenatal diagnosis of skeletal dysplasia

A lethal form of bone dysplasia, platylospondylic lethal chondrodysplasia, was diagnosed prenatally using three-dimensional ultrasound. The various types of three-dimensional imaging mode provided diagnostic details not available by conventional two-dimensional ultrasound. The diagnosis was made after referral in the 23rd week of gestation, allowing termination of pregnancy due to the poor prognosis. Prenatal sonograms were compared with postnatal radiographs.     

Further predictors of renal dysplasia in fetal obstructive uropathy: Bladder pressure and biochemistry of ‘fresh’ urine

Urine was aspirated on two consecutive days from the dilated bladder of nine fetuses with lower urinary tract obstruction. Gestational age ranged from 17 to 35 weeks. Renal dysplasia was diagnosed histologically in four fetuses, whereas the other five had normal renal histology or only partial dysplasia. Urinary sodium (Na⁺) and osmolality (Osm) decreased significantly in the second urine sample 1 day after bladder emptying (median decrease: Na⁺ = −11.3 per cent; Osm= −13.3 per cent). Although there were no significant differences between fetuses with or without renal dysplasia, normalization of an initially raised urine Na ⁺ concentration occurred at the second sample in a fetus with partially normal renal histology, thus correcting a false-positive diagnosis of dysplasia. Bladder pressure was measured at the time of the first urine sampling in seven fetuses and in a further eight with bladder outlet obstruction undergoing a single urine aspiration at 18–28 weeks. Bladder pressure was increased above the reference range in 8 of 15 fetuses with urinary obstruction, but there was no correlation between pressure and the degree of impairment of renal function. Although no conclusive clinical guidelines can be drawn from this study for the evaluation of fetal renal function, these findings suggest that, in lower urinary tract obstruction, tubular reabsorption is impeded by the standing pressure in the urinary tract and that improvement of renal function may occur following relief of obstruction.     

Prenatal ultrasound diagnosis of rhizomelic chondrodysplasia punctata in a primigravida

Rhizomelic chondrodysplasia punctata (RCDP) is a sublethal autosomal recessive disorder characterized by skeletal dysplasia, microcephaly, mental retardation, congenital cataracts, joint contractures, skin changes, and failure to thrive. Prenatal ultrasound diagnosis has been reported during the second trimester of pregnancy. Prenatal diagnosis is also possible from the first trimester onwards by demonstration of peroxisomal dysfunction in cultured chorionic villous or amniotic fluid cells. In all cases reported hitherto, the prenatal diagnosis was established after the birth of a previous affected child. In contrast to these studies in pregnant multiparous women at risk for RCDP, we report on the first case of prenatal ultrasound diagnosis of RCDP at 19 weeks' gestation in a primigravida. In addition, a complex cardiac malformation associated with hypoplasia of the thymus (DiGeorge anomaly) is described.     

Prenatal diagnosis of chondroectodermal dysplasia with fetoscopy

Chondroectodermal dysplasia (Ellis-van Creveld syndrome) has previously been diagnosed prenatally only once, using fetoscopy. We report on two consecutive pregnancies in a woman at risk of having a child with the syndrome during which fetoscopic visualization was performed. Ellis-van Creveld syndrome was diagnosed prenatally in one instance, while it could be excluded in the other one. Non-invasive prenatal diagnosis of the syndrome is discussed.     

Early prenatal detection of diastrophic dysplasia

Diastrophic dysplasia, an autosomal recessive disorder, results in severe short-limbed dwarfism, progressive spinal and joint problems, and secondary psychosocial disability. The results of treatments are unsatisfactory. Four pregnant mothers at risk for an affected fetus were studied with an ultrasound scanner at 16 and 19 weeks of gestation. Each mother had a previous child with diastrophic dysplasia. The biparietal distance and the length of the long bones of the extremities were normal in three fetuses, whereas in one fetus there was a 30 per cent shortening of all long bones. The biparietal distance corresponded with the gestational age in all fetuses. In one fetus, diastrophic dysplasia was confirmed by fetoscopy and fetal radiograph at 19 weeks of gestation after the parents had decided to terminate the pregnancy. The skeletal radiograph and autopsy findings of the fetus verified the diagnosis. All other mothers were followed with repeated ultrasound examinations, and they delivered healthy babies. The retrospective follow-up of the four previous pregnancies and of the present one with affected fetuses disclosed that two mothers had had vaginal bleeding, two lymphedema, one abdominal pains, and one mother had had polyhydramnios. These complications were, however, mild and transient, and they could not be regarded as specific for pregnancies with affected fetuses.     

The BOR syndrome and renal agenesis-prenatal diagnosis andfurther clinical delineation

This is the first report of prenatal diagnosis of a fetus with brachio-oto-renal dysplasia (BOR) syndrome with right-sided renal agenesis and severe left hypoplasia. The father of this fetus had malformed external ears, a left-sided preauricular pit and branchial cyst, and bilateral mild to moderate deafness without a demonstrable renal anomaly. This family highlights the variable expressivity seen in the autosomal dominant BOR syndrome, the importance of genetic counselling for families with BOR syndrome, and the aetiologic heterogeneity of renal agenesis.     

Metaphyseal chondrodysplasia McKusick type in a Chinese fetus,caused by novel compound heterozygosity 64T> A and 79G >T in RMRPgene

We present the first confirmed case by molecular analysis of a metaphyseal chondrodysplasia, McKusick type, in a 22-week fetus. Two novel compound heterozygous mutations, 64T> A and 79G > T, were found in the highly conserved regions of the RMRP gene. Twenty-two heterozygous g.1018 T> C mutations, two homozygous g.1018 T> C mutations, two heterozygous insertion mutations g.799_g.800insC and one heterozygous insertion mutation g.849_g.850insT were found among 100 normal controls. Careful radiological examination of the fetus for skeletal dysplasia allowed definitive diagnosis, proper genetic counselling and future prenatal diagnosis. Copyright © 2006 John Wiley & Sons, Ltd.     

Rapid whole exome sequencing in pregnancies to identify the underlying genetic cause in fetuses with congenital anomalies detected by ultrasound imaging

Objective

The purpose of this study was to explore the diagnostic yield and clinical utility of trio-based rapid whole exome sequencing (rWES) in pregnancies of fetuses with a wide range of congenital anomalies detected by ultrasound imaging.

Methods

In this observational study, we analyzed the first 54 cases referred to our laboratory for prenatal rWES to support clinical decision making, after the sonographic detection of fetal congenital anomalies. The most common identified congenital anomalies were skeletal dysplasia (n = 20), multiple major fetal congenital anomalies (n = 17) and intracerebral structural anomalies (n = 7).

Results

A conclusive diagnosis was identified in 18 of the 54 cases (33%). Pathogenic variants were detected most often in fetuses with skeletal dysplasia (n = 11) followed by fetuses with multiple major fetal congenital anomalies (n = 4) and intracerebral structural anomalies (n = 3). A survey, completed by the physicians for 37 of 54 cases, indicated that the rWES results impacted clinical decision making in 68% of cases.

Conclusions

These results suggest that rWES improves prenatal diagnosis of fetuses with congenital anomalies, and has an important impact on prenatal and peripartum parental and clinical decision making.     

Prenatal diagnosis of anhidrotic ectodermal dysplasia

This paper reports on successful prenatal diagnosis of X-linked anhidrotic ectodermal dysplasia (AED) by means of light and electron microscopy on fetal skin biopsies obtained under fetoscopy. In the present family two brothers of the proband were severely affected with the full symptomatology of AED, the pregnant female and her mother revealed minor symptoms with patches of skin lacking vellus hair. Control of lesional skin of the affected family members by electron microscopy revealed no ultrastructural abnormalities. However, all biopsies lacked skin appendages including hair follicles, sebaceous glands, and sweat glands. The lack of pilosebaceous follicles can be used as a diagnostic criterion since these structures are fully developed in normal fetuses of 20 weeks whereas the development of sweat glands does not start before week 20 to 24 of fetal life. Skin biopsies were taken from various regions of the fetus at risk via fetoscopy in week 20 and processed for light and electron microscopy. All samples revealed complete absence of all skin appendages in contrast to a total of 61 non-AED fetuses. Thus positive prenatal diagnosis of AED was made and the pregnancy was terminated. Control investigations after abortion confirmed the diagnosis.     

Shortened fetal long bones: A notable intrauterine phenotypic feature in SHOX-associated skeletal dysplasia

Objective

To explore the intrauterine phenotypic spectrum of short stature homeobox-containing (SHOX) gene-associated skeletal dysplasia and provide genetic counseling at-risk pregnancies.

Method

We analyzed the fetuses with SHOX-microdeletions identified by single nucleotide polymorphism (SNP)-array. The intrauterine phenotypes and outcomes were further elaborated.

Results

Nine fetuses carrying a single SHOX-microdeletion were reported, with deletion sizes ranging from 0.134 to 1.35 Mb. Shortened long bones were observed in all fetuses, varying from −2.0 standard deviation (SD) to −5.3 SD. Moreover, all cases had a femur length/foot ratio less than 0.87 and a femur/abdominal circumference ratio greater than 0.16, suggesting that non-lethal skeletal dysplasia may be involved. Two fetuses showed intrauterine growth restriction, and two had nasal bone hypoplasia. Prenatal ultrasonography did not reveal other obvious anomalies, including the Madelung deformity. Five microdeletions were inherited and one was de novo. Five terminations and four newborns were recorded. Two newborns had normal stature, and two were short-statured (height <3rd percentile), with one having inflexible wrists.

Conclusions

SHOX haploinsufficiency may manifest with shortened fetal long bones. The combination of history taking, prenatal ultrasonography, and SNP-array can prompt early prenatal diagnosis and timely postnatal treatment of SHOX-associated skeletal dysplasia.     

A rare case of isolated right atrial enlargement and TBX5 mutation associated with Holt–Oram syndrome

Holt–Oram syndrome or atriodigital dysplasia is commonly associated with cardiac malformations, most often with defects of the muscular septum. We describe the case of a fetus referred for fetal cardiology evaluation in the setting of right atrial enlargement without tricuspid valve abnormalities with small muscular VSDs, and without other significant cardiac lesions. On serial fetal echocardiograms, isolated right atrial enlargement was persistent as was relative fetal bradycardia without apparent AV block or other signs of abnormal conduction. Limb or other anatomic abnormalities were also not visualized on prenatal scans. A postnatal diagnosis of Holt–Oram Syndrome was made. In the setting of isolated right atrial enlargement, we suggest a comprehensive sonographic search for upper limb abnormalities as well as genetic evaluation.     

Sonographic depiction of fetal tooth germs

Recently, sonography of the fetal face has gained increasing importance in prenatal diagnosis. It is not yet clear whether sonographic depiction of fetal tooth germs would have an influence on the prenatal diagnosis of ectodermal dysplasia syndromes. During routine malformation screening, horizontal sections of fetal jaws were visualized and examined for tooth germs in 124 pregnant women following sonographic ‘facing’. Histological jaw sections of fetuses that had died in utero at various gestational ages were produced in order to examine the degree of correspondence between the sonographic and histological findings. At least four tooth germs were found in the jaws of all fetuses between 19 and 34 gestational weeks (n=104). Although jaw visualization was possible between 14 and 18 gestational weeks (n=20), the exact number and location of the tooth germs could not be determined. Assessment of tooth germs may become increasingly important, as aplasia of the tooth germs is one of the principal signs of various hereditary ectodermal diseases.     

Prenatal diagnosis of Fukuyama congenital muscular dystrophy

Fukuyama congenital muscular dystrophy (FCMD) is characterized by infantile hypotonia, symmetrical generalized muscle weakness, and neuronal migration disturbances that result in changes consistent with cobblestone lissencephaly with cerebral and cerebellar cortical dysplasia. FCMD is recognized as an autosomal recessive genetic defect. Genetic counselling is recommended for parents at risk of having a child with FCMD. Given the high risk and overwhelming prospect of having another child with this incurable devastating condition leads many couples to consider prenatal diagnosis. In Japanese families, haplotype analysis using microsatellite markers is available. In non-Japanese families, DNA sequence analysis is available. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed. Copyright © 2006 John Wiley & Sons, Ltd.