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PubMed2006

Differential diagnosis of fetal hyperechogenic cystic kidneys unrelated to renal tract anomalies: A multicenter study.

OBJECTIVES: To identify important factors in the differential diagnosis of renal cysts associated with hyperechogenic kidneys. METHODS: This was a retrospective multicenter study. We identified 93 fetuses presenting between 1990 and 2002 with hyperechogenic kidneys and which had a diagnosis of nephropathy confirmed later. We analyzed retrospectively the prenatal ultrasound findings of those fetuses which were found sonographically to have renal cysts. RESULTS: Of the 93 fetuses presenting with hyperechogenic kidneys and with a later diagnosis of nephropathy, there were 28 with autosomal dominant polycystic kidney disease (ADPKD), 31 with autosomal recessive polycystic kidney disease (ARPKD), 11 with Bardet-Biedl syndrome, nine with Meckel-Gruber syndrome, six with Ivemark II syndrome, one with Jarcho-Levin syndrome, one with Beemer syndrome and one with Meckel-like syndrome. One third of the fetuses (30/93) had renal cysts. Cystic characteristics (size, location, number) were not very useful for diagnosis; more useful was diagnosis of an associated malformation. Three (11%) of the fetuses with ADPKD had cysts, as did nine (29%) of those with ARPKD, three (27%) of those with Bardet-Biedl syndrome, all (100%) of those with Meckel-Gruber syndrome, three (50%) of those with Ivemark II syndrome, and each of the three cases with other syndromes (Jarcho-Levin, Beemer and Meckel-like syndromes). None of the cases with trisomy 13 had cysts. There were no associated malformations in the 12 cases with renal cysts and polycystic kidney disease; the other 18 cases with renal cysts were associated with malformations that were often specific, such as polydactyly in Bardet-Biedl and Beemer syndromes, occipital defect and Dandy-Walker malformation in Meckel-Gruber or Meckel-Gruber-like syndromes, and thoracic and/or vertebral abnormalities in Jarcho-Levin and Beemer syndromes. CONCLUSION: Renal cysts associated with hyperechogenic kidneys are not rare. The clue to diagnosis is the demonstration of an associated malformation. If no malformation is found, the main diagnosis remains polycystic kidney disease, i.e. ARPKD or ADPKD.

Bardet-Biedl Syndrome↗
PubMed2004

Fetal hydrops, associated with maternal propylthiouracil exposure, reversed by intrauterine therapy.

Thyroid hormone is essential for fetal neurological development. Among other etiologies, fetal hypothyroidism may be caused by maternal exposure to antithyroid drugs (ATDs). The most common presentation of fetal hypothyroidism is fetal goiter, which can cause dystocia, in addition to airway obstruction in the neonate. Intra-amniotic treatment with levothyroxine normalizes fetal thyroid status and reduces goiter size. We present a case of fetal hypothyroidism diagnosed in a patient who was treated with propylthiouracil (PTU) for Grave's disease. The fetus had marked hydrops fetalis and a large goiter. In addition, anal stenosis, vesicovaginal fistula, bilateral pyelectasia and polydactyly were diagnosed in the neonate. Intra-amniotic treatment with levothyroxine resulted in a regression of the hydrops and a reduction in the goiter size. A euthyroid, non-edematous, non-goitrous neonate was delivered. At the age of 27 months the child's psychomotor development was normal. The present case indicates that hydrops fetalis may be an unusual manifestation of fetal hypothyroidism, caused by intrauterine exposure to maternal antithyroid drugs (ATDs), and that it may be resolved by treatment with intra-amniotic levothyroxine.

Adult↗
PubMed1996

Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds.

The cation-dependent and cation-independent mannose 6-phosphate receptors (CD- and CI-MPRs) bind the phosphomannosyl recognition marker of lysosomal hydrolases, but in mammals the latter also interacts with insulin-like growth factor II (IGF-II). While IGF signaling is mediated by the type 1 IGF receptor (IGF1R), the type 2 receptor (IGF2R/CI-MPR) serves IGF-II turnover. Mouse mutants inheriting maternally a targeted disruption of the imprinted Igf2r gene, which is normally expressed only from the maternal allele, have increased serum and tissue levels of IGF-II and exhibit overgrowth (135% of normal birthweight) and generalized organomegaly, kinky tail, postaxial polydactyly, heart abnormalities, and edema. These mutants usually die perinatally, but a small minority can survive depending on genetic background and can occasionally reproduce, except for some females characterized by an imperforate vagina and hydrometrocolpos. Consistent with the hypothesis that lethality in the absence of IGF2R-mediated turnover is caused by excess of IGF-II overstimulating IGF1R, Igf2r mutants are completely rescued when they carry a second mutation eliminating either IGF-II or IGF1R. Normal embryonic development of the Igf1r/Igf2r double mutants, which differ from wild-type siblings only in the pattern of postnatal growth, appears to occur by signaling of IGF-II, being in excess, through a genetically identified unknown receptor, since triple mutants lacking IGF1R, IGF2R, and IGF-II are nonviable dwarfs (30% of normal size). In contrast with the Igf2r/Igf2 double mutants, mice lacking IGF2R/CI-MPR and CD-MPR survive in an IGF-II null background at a very low frequency and only for a few postnatal weeks, indicating that the mannose 6-phosphate-mediated lysosomal enzyme trafficking is essential for viability.

Animals↗
PubMed2000

Targeted misexpression of constitutively active BMP receptor-IB causes bifurcation, duplication, and posterior transformation of digit in mouse limb.

Members of bone morphogenetic proteins (BMPs) play important roles in many aspects of vertebrate embryogenesis. In developing limbs, BMPs have been implicated in control of anterior-posterior patterning, outgrowth, chondrogenesis, and apoptosis. These diverse roles of BMPs in limb development are apparently mediated by different BMP receptors (BMPR). To identify the developmental processes in mouse limb possibly contributed by BMP receptor-IB (BMPR-IB), we generated transgenic mice misexpressing a constitutively active Bmpr-IB (caBmpr-IB). The transgene driven by the mouse Hoxb-6 promoter was ectopically expressed in the posterior mesenchyme of the forelimb bud, the lateral plate mesoderm, and the whole mesenchyme of the hindlimb bud. While the forelimbs appeared normal, the transgenic hindlimbs exhibited several phenotypes, including bifurcation, preaxial polydactyly, and posterior transformation of the anterior digit. However, the size of bones in the transgenic limbs seemed unaltered. Defects in sternum and ribs were also found. The bifurcation in the transgenic hindlimb occurred early in the limb development (E10.5) and was associated with extensive cell death in the mesenchyme and occasionally in the apical ectodermal ridge (AER). Sonic hedgehog (Shh) and Patched (Ptc) expression appeared unaffected in the transgenic limb buds, suggesting that the BMPR-IB mediated signaling pathway is downstream from Shh. However, ectopic Fgf4 expression was found in the anterior AER, which may account for the duplication of the anterior digit. An ectopic expression of Gremlin found in the transgenic limb bud would be responsible for the ectopic Fgf4 expression. The observations that Hoxd-12 and Hoxd-13 expression patterns were extended anteriorly provide a molecular basis for the posterior transformation of the anterior digit. Together these results suggest that BMPR-IB is the endogenous receptor to mediate the role of BMPs in anterior-posterior patterning and apoptosis in mouse developing limb. In addition, BMPR-IB may represent a critical component in the Shh/FGF4 feedback loop by regulating Gremlin expression.

Animals↗
PubMed2000

glypican-3 controls cellular responses to Bmp4 in limb patterning and skeletal development.

Glypicans represent a family of six cell surface heparan sulfate proteoglycans in vertebrates. Although no specific in vivo functions have thus far been described for these proteoglycans, spontaneous mutations in the human and induced deletions in the mouse glypican-3 (Gpc3) gene result in severe malformations and both pre- and postnatal overgrowth, known clinically as the Simpson-Golabi-Behmel syndrome (SGBS). Mice carrying mutant alleles of Gpc3 created by either targeted gene disruption or gene trapping display a wide range of phenotypes associated with SGBS including renal cystic dysplasia, ventral wall defects, and skeletal abnormalities that are consistent with the pattern of Gpc3 expression in the mouse embryo. Previous studies in Drosophila have implicated glypicans in the signaling of decapentaplegic, a BMP homolog. Our experiments with mice show a significant relationship between vertebrate BMP signaling and glypican function; GPC3-deficient animals were mated with mice haploinsufficient for bone morphogenetic protein-4 (Bmp4) and their offspring displayed a high penetrance of postaxial polydactyly and rib malformations not observed in either parent strain. This previously unknown link between glypican-3 and BMP4 function provides evidence of a role for glypicans in vertebrate limb patterning and skeletal development and suggests a mechanism for the skeletal defects seen in SGBS.

Animals↗
PubMed2000

csal1 is controlled by a combination of FGF and Wnt signals in developing limb buds.

While some of the signaling molecules that govern establishment of the limb axis have been characterized, little is known about the downstream effector genes that interpret these signals. In Drosophila, the spalt gene is involved in cell fate determination and pattern formation in different tissues. We have cloned a chick homologue of Drosophila spalt, which we have termed csal1, and this study focuses on the regulation of csal1 expression in the limb bud. csal1 is expressed in limb buds from HH 17 to 26, in both the apical ectodermal ridge and the distal mesenchyme. Signals from the apical ridge are essential for csal1 expression, while the dorsal ectoderm is required for csal1 expression at a distance from the ridge. Our data indicate that both FGF and Wnt signals are required for the regulation of csal1 expression in the limb. Mutations in the human homologue of csal1, termed Hsal1/SALL1, result in a condition known as Townes-Brocks syndrome (TBS), which is characterized by preaxial polydactyly. The developmental expression of csal1 together with the digit phenotype in TBS patients suggests that csal1 may play a role in some aspects of distal patterning.

Amino Acid Sequence↗
PubMed2002

Overgrowth of a mouse model of the Simpson-Golabi-Behmel syndrome is independent of IGF signaling.

The type 1 Simpson-Golabi-Behmel overgrowth syndrome (SGBS1) is caused by loss-of-function mutations of the X-linked GPC3 gene encoding glypican-3, a cell-surface heparan sulfate proteoglycan that apparently plays a negative role in growth control by an unknown mechanism. Mice carrying a Gpc3 gene knockout exhibited several phenotypic features that resemble clinical hallmarks of SGBS1, including somatic overgrowth, renal dysplasia, accessory spleens, polydactyly, and placentomegaly. In Gpc3/DeltaH19 double mutants (lacking GPC3 and also carrying a deletion around the H19 gene region that causes bialellic expression of the closely linked Igf2 gene by imprint relaxation), the Gpc3-null phenotype was exacerbated, while additional SGBS1 features (omphalocele and skeletal defects) were manifested. However, results from a detailed comparative analysis of growth patterns in double mutants lacking GPC3 and also IGF2, IGF1, or the type 1 IGF receptor (IGF1R) provided conclusive genetic evidence inconsistent with the hypothesis that GPC3 acts as a growth suppressor by sequestering or downregulating an IGF ligand. Nevertheless, our data are compatible with a model positing that there is downstream convergence of the independent signaling pathways in which either IGFs or (indirectly) GPC3 participate.

Abnormalities, Multiple↗
PubMed2002

In vivo evidence that BMP signaling is necessary for apoptosis in the mouse limb.

To determine the role of Bone morphogenetic protein (BMP) signaling in murine limb development in vivo, the keratin 14 promoter was used to drive expression of the BMP antagonist Noggin in transgenic mice. Phosphorylation and nuclear translocation of Smad1/5 were dramatically reduced in limbs of the transgenic animals, confirming the inhibition of BMP signaling. These mice developed extensive limb soft tissue syndactyly and postaxial polydactyly. Apoptosis in the developing limb necrotic zones was reduced with incomplete regression of the interdigital tissue. The postaxial extra digit is also consistent with a role for BMPs in regulating apoptosis. Furthermore, there was persistent expression of Fgf8, suggesting a delay in the regression of the AER. However, Msx1 and Msx2 expression was unchanged in these transgenic mice, implying that induction of these genes is not essential for mediating BMP-induced interdigital apoptosis in mice. These abnormalities were rescued by coexpressing BMP4 under the same promoter in double transgenic mice, suggesting that the limb abnormalities are a direct effect of inhibiting BMP signaling.

Animals↗
PubMed1997

BMP7 null mutation in mice: developmental defects in skeleton, kidney, and eye.

While generating bcl2 alpha transgenic mice, we found some F2 offspring of one of the transgenic lines which were very small and had closed eyes at the time of weaning. These pups died within 1 month after birth. In order to determine the molecular basis of this phenotype, we screened a genomic library of the above transgenic line with a transgene-specific probe and found that the Bmp7 gene, a member of the TGF beta superfamily, was inactivated by insertional mutagenesis due to transgene integration. The Bmp7 homozygous null condition in mice is a postnatal lethal mutation and is associated with various developmental defects: holes in the basisphenoid bone and the xyphoid cartilage, retarded ossification of bones, fused ribs and vertebrae, underdeveloped neural arches of the lumbar and sacral vertebrae, polydactyly of the hind limbs, a kinked tail, a reduced number of nephrons, polycystic kidney, lack of retinal pigmentation, and retarded lens development. These findings indicate that BMP7 is an important signaling molecule for normal development of the mammalian skeleton, kidney, and eye. Academic Press

Abnormalities, Multiple↗
PubMed1996

The gene for the Ellis-van Creveld syndrome is located on chromosome 4p16.

Ellis-van Creveld syndrome (EVC) is an autosomal recessive disorder characterized by disproportionate dwarfism, polydactyly, and congenital heart disease. This rare disorder is found with increased frequency among the Old Order Amish community in Lancaster County, Pennsylvania. We have used linkage analysis to localize the gene responsible for the EVC phenotype in nine interrelated Amish pedigrees and three unrelated families from Mexico, Ecuador, and Brazil. We now report the linkage for the Ellis-van Creveld syndrome gene to markers on the distal short arm of human chromosome 4, with Zmax = 6.91 at theta = 0.02 for marker HOX7, in a region proximal to the FGFR3 gene responsible for the achondroplasia phenotype.

Brazil↗
PubMed1998

Cloning of a novel C-terminal kinesin (KIFC3) that maps to human chromosome 16q13-q21 and thus is a candidate gene for Bardet-Biedl syndrome.

Kinesins are a large superfamily of microtubule motors that mediate specific motile processes. In a previous study, we identified 11 kinesin family members in the retina and retinal pigment epithelium (RPE) of the striped bass, Morone saxatilus. We have now identified, cloned, and sequenced the human homologue (KIFC3) of the most abundantly expressed retinal kinesin from that study, the C-terminal kinesin FKIF2. An antibody raised against an FKIF2 peptide cross-reacted with an approximately 80-kDa protein in human retina, RPE, kidney, and lung. Since microtubule-dependent processes are critical to the function and morphogenesis of the photoreceptors and RPE, the abundantly expressed KIFC3 was considered to be a potential candidate gene for causing human retinal degeneration. Chromosomal localization of the KIFC3 gene revealed that it maps to chromosome 16q13-q21, within the critical region for a Bardet-Biedl syndrome locus (BBS2). Bardet-Biedl syndrome is a genetically heterogeneous, autosomal recessive disorder characterized by retinal dystrophy, polydactyly, obesity, hypogonadism, renal abnormalities, and mental retardation. The chromosomal localization and expression pattern of KIFC3 suggest that it may be an excellent candidate for families linked to BBS2.

Amino Acid Sequence↗
PubMed1999

The cloning and developmental expression of unconventional myosin IXA (MYO9A) a gene in the Bardet-Biedl syndrome (BBS4) region at chromosome 15q22-q23.

Bardet-Biedl Syndrome (BBS) is a heterogeneous, autosomal recessive disorder characterized by mental retardation, obesity, retinitis pigmentosa, syndactyly and/or polydactyly, short stature, and hypogenitalism and is caused by mutations at a number of distinct loci. Using a positional cloning approach for identifying the BBS4 (chromosome 15) gene, we identified and cloned an unconventional myosin gene, myosin IXA (HGMW-approved symbol MYO9A). Since mutations in unconventional myosins are known to cause several human diseases, and since mutations of unconventional myosin VIIa cause retinal degeneration, we evaluated myosin IXA as a candidate for BBS. We exploited PCR-based techniques to clone a 8473-nt cDNA for myosin IXA. A 7644-bp open reading frame predicts a protein with all the hallmarks of class IX unconventional myosins. Human Northern blot analysis and in situ hybridization of mouse embryos reveal that myosin IXA is expressed in many tissues consistent with BBS. Intron/exon boundaries were identified, and myosin IXA DNA and RNA from BBS4 patients were evaluated for mutation.

Amino Acid Sequence↗
PubMed2001

A high-resolution genetic, physical, and comparative gene map of the doublefoot (Dbf) region of mouse chromosome 1 and the region of conserved synteny on human chromosome 2q35.

The mouse doublefoot (Dbf) mutant exhibits preaxial polydactyly in association with craniofacial defects. This mutation has previously been mapped to mouse chromosome 1. We have used a positional cloning strategy, coupled with a comparative sequencing approach using available human draft sequence, to identify putative candidates for the Dbf gene in the mouse and in homologous human region. We have constructed a high-resolution genetic map of the region, localizing the mutation to a 0.4-cM (+/-0.0061) interval on mouse chromosome 1. Furthermore, we have constructed contiguous BAC/PAC clone maps across the mouse and human Dbf region. Using existing markers and additional sequence tagged sites, which we have generated, we have anchored the physical map to the genetic map. Through the comparative sequencing of these clones we have identified 35 genes within this interval, indicating that the region is gene-rich. From this we have identified several genes that are known to be differentially expressed in the developing mid-gestation mouse embryo, some in the developing embryonic limb buds. These genes include those encoding known developmental signaling molecules such as WNT proteins and IHH, and we provide evidence that these genes are candidates for the Dbf mutation.

Animals↗
PubMed1999

Outcome of pregnancies occurring before completion of human chorionic gonadotropin follow-up in patients with persistent gestational trophoblastic tumor.

OBJECTIVE: To determine the outcome of pregnancies occurring before completion of human chorionic gonadotropin follow-up in patients treated with chemotherapy for gestational trophoblastic tumor. METHODS: Retrospective record review of patients with gestational trophoblastic tumor who conceived before standard hCG follow-up was completed during 1973-1998. RESULTS: Forty-three patients treated for gestational trophoblastic tumors conceived before human chorionic gonadotropin follow-up was completed. The antecedent pregnancy was complete mole in 31 (72.1%) and partial mole in 12 (27. 9%) patients. Of the 43 patients, 39 (90.7%) had stage I, 1 had stage II, and 3 had stage III disease. The mean interval from human chorionic gonadotropin remission to new pregnancy was 6.3 months (range 1-11 months). Ten patients underwent elective termination and four patients were lost to follow-up. Of the remaining 29 patients, 22 (75.9%) had term live births, 3 (10.3%) had preterm delivery, 3 had spontaneous abortion, and 1 (3.5%) had a repeat mole. Two cases of fetal anomalies were detected; one was inherited polydactyly and the other was hydronephrosis. One patient developed choriocarcinoma with lung involvement and underwent cesarean section at 28 weeks; a normal fetus was delivered and no choriocarcinoma was detected in the placenta. CONCLUSION: Pregnancies occurring in patients treated for gestational trophoblastic tumor before standard human chorionic gonadotropin follow-up is completed may continue under close clinical surveillance since the majority have a favorable outcome. However, patients should also be advised of the low but important risk of delayed diagnosis in case tumor relapse develops during early subsequent pregnancy.

Adult↗
PubMed1993

The prevalence of congenital orthopaedic anomalies in a rural community.

A rural Indian population of 50,055 was studied for the detection of congenital orthopaedic anomalies by a door-to-door survey. An incidence of 2.25 cases per 1000 population was found. Club foot was the commonest anomaly at 0.9 per 1000, followed by polydactyly and syndactyly at 0.45 and 0.38 cases per 1000. The most common anomaly found in females was a congenital short 4th metatarsal (0.24 per 1000).

Bone and Bones↗
PubMed1985

Aplasia of tibia with split-hand/split-foot deformity. Report of six families with 35 cases and considerations about variability and penetrance.

Six families with a total of 34 affected persons with the syndrome of tibial aplasia and ectrodactyly are reported. The spectrum of malformations is compared to that of 99 familial cases from the literature. The full-blown syndrome consists of bilateral aplasia of tibiae and split-hand/split-foot deformity. Additional malformations may be distal hypoplasia or bifurcation of femora, hypo- or aplasia of ulnae, and minor anomalies such as aplasia of patellae, hypoplastic big toes, postaxial and intermediate polydactyly in connection with split-hand deformity, and cup-shaped ears. The mildest visible manifestation may be hypoplastic big toes, the severest is tetramonodactyly or transverse hemimelia. This disorder is autosomal dominantly inherited. The penetrance is markedly reduced.

Abnormalities, Multiple↗
PubMed1978

Prenatal diagnosis of Meckel syndrome.

The three main features of Meckel syndrome are encephalocele, polycystic kidneys, and polydactyly. Prenatal diagnosis of a fetus with Meckel syndrome was made in the 16th week of gestation by means of amniotic fluid alpha1 fetoprotein estimation. The indication for amniocentesis was a previous child with an occipital meningocele and polycystic kidneys. Interpretation of the alpha1-fetoprotein value (240 microgram/ml) was difficult due to fetal blood contamination. Prenatal diagnosis is indicated in any pregnancy following the birth of a child with only two major symptoms of Meckel syndrome.

Amniotic Fluid↗
PubMed1983

Interstitial deletion for a region in the long arm of chromosome 16.

An infant with an interstitial deletion of chromosome 16 is reported. He showed severe psychomotor retardation and multiple congenital anomalies (craniofacial dysmorphism, cleft palate, endocardial cushion defect, preaxial polydactyly of one hand, low total ridge count). Unbanded chromosome studies following amniocentesis failed to identify the deletion. This case is very similar to other cases in the literature which were reported first by Fryns et al. (1977).

Abnormalities, Multiple↗