Search

Urorectal septum malformation sequence (URSMS) is characterized by a spectrum of anomalies of the urogenital system, hindgut and perineum. It is presumed to be a constellation of an embryonic defect. Herein, we analyzed the clinically diverse syndromes associated with URSMS in our perinatal evaluation unit. We reviewed fetuses with URSMS in referrals for perinatal autopsy over a period of 3 years. Chromosomal microarray and genome sequencing were performed whenever feasible. Literature was reviewed for syndromes or malformations with URSMS. We ascertained URSMS in 12 of the 215 (5%) fetuses. Nine fetuses (75%) had complete URSMS and remainder had partial/intermediate URSMS. Eleven fetuses had malformations of other systems that included: cerebral ventriculomegaly; right aortic arch with double outlet right ventricle; microcephaly with fetal akinesia deformation sequence; ventricular septal defect and radial ray anomaly; thoraco-abdominoschisis and limb defects; myelomeningocele; spina bifida and fused iliac bones; omphalocele; occipital encephalocele; lower limb amelia and cleft foot. We report on six fetuses with recurrent and five fetuses with unique malformations/patterns where URSMS is a component. Exome sequencing (one family) and genome sequencing (eight families) were performed and were nondiagnostic. Additionally, we review the literature for genetic basis of this condition. URMS is a clinically heterogeneous condition and is a component of several multiple malformation syndromes. We describe several unique and recurrent malformations associated with URSMS.

Roberts syndrome (also known as Roberts-SC phocomelia syndrome) is an autosomal recessive developmental disorder, characterized by pre- and postnatal growth retardation, limb malformations including bilateral symmetric tetraphocomelia or mesomelia, and craniofacial dysmorphism. Biallelic loss-of-function variants in ESCO2, which codes for establishment of sister chromatid cohesion N-acetyltransferase 2, cause Roberts syndrome. Phenotypic spectrum among patients is broad, challenging clinical diagnosis in mildly affected individuals. Here we report a 3-year-old boy with a mild phenotype of Roberts syndrome with bilateral elbow contractures, humeroradial synostosis, mild lower limb disparity, and facial dysmorphism. Trio whole-exome sequencing identified the novel biallelic splice variant c.1673+1G>A in ESCO2 in the patient. Aberrant ESCO2 pre-mRNA splicing, reduced relative ESCO2 mRNA amount, and characteristic cytogenetic defects, such as premature centromere separation, heterochromatin repulsion, and chromosome breaks, in patient cells strongly supported pathogenicity of the ESCO2 variant affecting one of the highly conserved guanine-thymine dinucleotide of the donor splice site. Our case highlights the difficulty in establishing a clinical diagnosis in individuals with minor clinical features of Roberts syndrome and normal intellectual and social development. However, next-generation sequencing tools allow for molecular diagnosis in cases presenting with mild developmental defects.

Homozygous variants in PPP2R3C have been reported to cause a syndromic 46,XY complete gonadal dysgenesis phenotype with extragonadal manifestations (GDRM, MIM# 618419) in patients from four unrelated families, whereas heterozygous variants have been linked to reduced fertility with teratozoospermia (SPGF36, MIM# 618420) in male carriers. We present eight patients from four unrelated families of Turkish and Indian descent with three different germline homozygous PPP2R3C variants including a novel in-frame duplication (c.639_647dupTTTCTACTC, p.Ser216_Tyr218dup). All patients exhibit recognizable facial dysmorphisms allowing gestalt diagnosis. In two 46,XX patients with hypergonadotropic hypogonadism and non-visualized gonads, primary amenorrhea along with absence of secondary sexual characteristics and/or unique facial gestalt led to the diagnosis. 46,XY affected individuals displayed a spectrum of external genital phenotypes from ambiguous genitalia to complete female. We expand the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to both XY and XX gonadal dysgenesis. Our findings supported neither ocular nor muscular involvement as major criteria of the syndrome. We also did not encounter infertility problems in the carriers. Since both XX and XY individuals were affected, we hypothesize that PPP2R3C is essential in the early signalling cascades controlling sex determination in humans.

Fetal akinesia deformation sequence (FADS) is a clinically and genetically heterogeneous condition. Pathogenic variants in DOK7 are known to cause myasthenic syndrome, congenital, 10 (MIM#254300) and, rarely (reported in a single family) lethal FADS. Herein, we describe a biallelic variant c.1263dupC in DOK7, known to cause congenital myasthenic syndrome 10, causing lethal FADS in a consanguineous family. The present report illustrates wide phenotypic variability caused by biallelic pathogenic variants in DOK7. We also describe the second family with FADS due to pathogenic variants in DOK7.

Meckel syndrome (MKS) is a perinatally lethal, genetically heterogeneous, autosomal recessive condition caused by defective primary cilium formation leading to polydactyly, multiple cysts in kidneys and malformations of nervous system. We performed exome sequencing in six fetuses from six unrelated families with MKS. We identified seven novel variants in B9D2, TNXDC15, CC2D2A, CEP290 and TMEM67. We describe the second family with MKS due to a homozygous variant in B9D2 and fifth family with bi-allelic variant in TXNDC15. Our data validates the causation of MKS by pathogenic variation in B9D2 and TXNDC15 and also adds novel variants in CC2D2A, CEP290 and TMEM67 to the literature.

International audience; Dysregulated transforming growth factor TGF-beta signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. Importin 8 belongs to the karyopherin family of nuclear transport receptors and was previously shown to mediate TGF-beta-dependent SMADs trafficking to the nucleus in vitro. The important in vivo role of IPO8 in pSMAD nuclear translocation was demonstrated by CRISPR/Cas9-mediated inactivation in zebrafish. Consistent with IPO8's role in BMP/TGF-beta signaling, ipo8(-/-) zebrafish presented mild to severe dorso-ventral patterning defects during early embryonic development. Moreover, ipo8(-/-) zebrafish displayed severe cardiovascular and skeletal defects that mirrored the human phenotype. Our work thus provides evidence that IPO8 plays a critical and non-redundant role in TGF-beta signaling during development and reinforces the existing link between TGF-beta signaling and connective tissue defects.

Biallelic loss of function variants in TRIP11 encoding for the Golgi microtubule-associated protein 210 (GMAP-210) cause the lethal chondrodysplasia achondrogenesis type 1A (ACG1A). Loss of TRIP11 activity has been shown to impair Golgi structure, vesicular transport and results in loss of IFT20 anchorage to the Golgi that is vital for ciliary trafficking and ciliogenesis. Here we report four fetuses, two each from two families, who were ascertained antenatally with ACG1A. Affected fetuses in both families are homozygous for the deep intronic TRIP11 variant, c.5457+81T>A that was found in a shared region of homozygosity. This variant was found to cause aberrant transcript splicing and the retention of 77 base-pairs of intron 18. The TRIP11 messenger RNA and protein levels were drastically reduced in fibroblast cells derived from one of the affected fetuses. Using immunofluorescence we also detected highly compacted Golgi apparatus in affected fibroblasts. Further we observed significant reduction in the frequency of ciliated cells and in the length of primary cilia in subject derived cell-lines, not reported so far in patient cells with TRIP11 null or hypomorphic variants. Our findings illustrate how pathogenic variants in intronic regions of TRIP11 can impact transcript splicing, expression and activity resulting in ACG1A. This article is protected by copyright. All rights reserved.

Skeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including bone dysplasia and internal abnormalities. To date, pathogenic variants in at least 30 genes, coding for different structural cilia proteins, are reported to cause skeletal ciliopathies. Here, we summarize genetic and phenotypic features of 34 affected individuals from 29 families with skeletal ciliopathies. Molecular diagnostic testing was performed using massively parallel sequencing (MPS) in combination with copy number variant (CNV) analyses and in silico filtering for variants in known skeletal ciliopathy genes. We identified biallelic disease-causing variants in seven genes: DYNC2H1, KIAA0753, WDR19, C2CD3, TTC21B, EVC, and EVC2. Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA. Furthermore, CNV analyses showed an intragenic deletion of DYNC2H1 in one individual and a 6.7 Mb de novo deletion on chromosome 1q24q25 in another. In five unsolved cases, MPS was performed in family setting. In one proband we identified a de novo variant in PRKACA and in another we found a homozygous intragenic deletion of IFT74, removing the first coding exon and leading to expression of a shorter message predicted to result in loss of 40 amino acids at the N-terminus. These findings establish IFT74 as a new skeletal ciliopathy gene. In conclusion, combined single nucleotide variant, CNV and cDNA analyses lead to a high yield of genetic diagnoses (90%) in a cohort of patients with skeletal ciliopathies.

We identified ten persons in six consanguineous families with Distal Arthrogryposis (DA) who had congenital contractures, scoliosis, and short stature. Exome sequencing revealed that each affected person was homozygous for one of two different rare variants (c.470G>T, p.(Cys157Phe) or c.469T>C, p.(Cys157Arg)) affecting the same residue ofmyosin light chain, phosphorylatable, fast skeletal muscle(MYLPF). In a seventh family, a c.487G>A, p.(Gly163Ser) variant inMYLPFarosede novoin a father, who transmitted it to his son. In an eighth family comprised of seven individuals with dominantly-inherited DA, a c.98C>T, p.(Ala33Val) variant segregated in all four persons tested. Variants inMYLPFunderlie both dominant and recessively inherited DA. Mylpf protein models suggest that the residues associated with dominant DA interact with myosin whereas the residues altered in families with recessive DA only indirectly impair this interaction. Pathological and histological exam of a foot amputated from an affected child revealed complete absence of skeletal muscle (i.e., segmental amyoplasia). To investigate the mechanism for this finding, we generated an animal model for partial MYLPF impairment by knocking out zebrafishmylpfa. Themylpfamutant had reduced trunk contractile force and complete pectoral fin paralysis, demonstrating thatmylpfimpairment most severely affects limb movement.mylpfamutant muscle weakness was most pronounced in an appendicular muscle and was explained by reduced myosin activity and fiber degeneration. Collectively, our findings demonstrate that partial loss of MYLPF function can lead to congenital contractures, likely as a result of degeneration of skeletal muscle in the distal limb.

Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.

15-Hydroxyprostaglandin dehydrogenase is NAD-dependent catalytic enzyme involved in prostaglandin biosynthesis pathway encoded by HPGD. The pathogenic variations in HPGD cause primary hypertrophic osteoarthropathy (PHO). The objective of the present study is to identify the genetic basis in patients with digital clubbing due to PHO. We performed detailed clinical and radiographic evaluation and exome sequencing in patients from three unrelated Indian families with PHO. Exome sequencing revealed two novel, c.34G>A (p.Gly12Ser) and c.313C>T (p.Gln105*) and a known variant, c.418G>C (p.Ala140Pro) in HPGD. Herein, we add three Indian families to HPGD mutation spectrum and review the literature on variants in this gene.

Aneuploidies occur in about 5% of clinically recognized pregnancies. Facial gestalt is a vital tool for the clinical diagnosis of trisomy 21. Facial anomalies are subtle in fetal life and challenging for a clinician not familiar with perinatal dysmorphology. Here, we present the facial profile and additional features in six fetuses with Down syndrome as a visual aid. We present the facial photographs of six fetuses with genetically confirmed trisomy 21. These photographs will serve as a diagnostic aid for trisomy 21 in perinatal dysmorphology. We noted punctate calcifications in two fetuses with trisomy 21.

Urorectal septum malformation sequence (URSMS) is a rare spectrum of malformations involving various organ systems. Here, we present eight cases of URSMS, noted in autopsy, with different degrees of complexity, seven being the complete type and one being the partial type. All cases had gastrointestinal tract malformation in the form of the imperforate anus and indeterminate genitalia. Other gastrointestinal tract anomalies were anal agenesis in two cases, anorectal agenesis in two cases, and malformed lower intestinal tract in four cases. The associated renal abnormality was noted in five cases, which were unilateral renal agenesis, dysplastic kidney, hydronephrosis, horseshoe kidney, and unilateral hypoplastic ectopic kidney. External genital malformation, present in both male and female fetuses, included a knob-like structure at perineum in female fetuses, genital fold hypoplasia and penile aplasia or hypoplasia in male fetuses. Skeletal abnormalities included two cases of sacral agenesis and one case of lumbosacral dysraphism. Other anomalies included a case with alobar holoprosencephaly, truncus arteriosus with hypoplastic lungs in one case, and three cases with abdominal wall defects. It is our attempt to delineate a spectrum of abnormalities associated with URSMS.

Glycogen storage disease IV (GSD IV), caused by a defect in GBE1, is a clinically heterogeneous disorder. A classical hepatic form and a neuromuscular form have been described. The severe neuromuscular form presents as a fetal akinesia deformation sequence or a congenital subtype. We ascertained three unrelated families with fetuses/neonates who presented with fetal akinesia deformation sequence to our clinic for genetic counseling. We performed a detailed clinical evaluation, exome sequencing, and histopathology examination of two fetuses and two neonates from three unrelated families presenting with these perinatally lethal neuromuscular forms of GSD IV. Exome sequencing in the affected fetuses/neonates identified four novel pathogenic variants (c.1459G>T, c.144-1G>A, c.1680C>G, and c.1843G>C) in GBE1 (NM_000158). Histopathology examination of tissues from the affected fetuses/neonate was consistent with the diagnosis. Here, we add three more families with the severe perinatally lethal neuromuscular forms of GSD IV to the GBE1 mutation spectrum.

A 27-year-old primigravida at 19 weeks of gestation with suspected hydrops fetalis. There were characteristic ultrasonographic features like hyper inflated and enlarged lungs, flattened diaphragm, small centrally displaced heart, and hydrops suggestive of CHAOS. Congenital high airway obstruction syndrome is a rare fetal anomaly causing nonimmune hydrops. Prenatal ultrasound features are characteristic. Meticulous system wise fetal imaging in the presence of hydrops would help in early diagnosis of the condition, helping in appropriate management of pregnancy. How to cite this article Mundkur A, Nayak SS, Vasudeva A, Katta GM, Kumar P. Congenital High Airway Obstruction Syndrome presenting as Nonimmune Hydrops in a 19-week Fetus. Int J Infertil Fetal Med 2016;7(3):99-102.

Objectives We aimed to analyze the utility of fetal autopsy in terms of its contribution to establishing a definitive diagnosis and its impact on genetic counseling.Subjects and methods Detailed fetal autopsy was carried out in fetuses referred for examination. Clinical utility of fetal autopsy and its impact on counseling were measured by adapting previously published parameters.Results We performed autopsy in 230 fetuses. There were 106 cases with single system and 92 cases with multisystem involvement. We confirmed prenatal findings in 23% of cases and observed additional findings in 37% of cases. In 23% of cases, autopsy findings differed enough to change the diagnosis. However, in 17% of fetuses, no cause of fetal loss was determined. Risk of recurrence became clear in 30.3% of the fetuses, and risk remained the same, but the diagnosis was different in 4.8% of cases after autopsy. Hence, autopsy led to refinement of the risk of recurrence in 36% of cases. Autopsy aided prenatal counseling of couples in 7 % of cases by either confirming the prenatal findings (35%) or providing new information/ruling out a diagnosis (42%).Conclusion The present study quantifies the utility of fetal autopsy in reproductive genetic counseling in a large.

We evaluated 214 fetuses sent for autopsy with gestational ages ranging from 12 to 39 weeks. Of these, seventeen fetuses (7.9%) had single umbilical artery. Thirteen of these fetuses were aborted after antenatal detection of severe malformations and 4 died in utero. Genito-urinary system (n=6) and central nervous system (n=4) were the most common sites of involvement. Presence of single umbilical artery warrants a detailed evaluation of the fetus for other anomalies.

Synpolydactyly (SPD) is an autosomal dominant congenital limb disorder due to mutations in HOXD13. It is a phenotypically heterogeneous condition characterized by syndactyly of the third finger (F3), fourth finger (F4) and/or fourth toe (T4), and fifth toe (T5) with variably associated polydactyly. We report on a mother and fetus with SPD. The mother has a novel mutation (c.708_708delC) in the HOXD13 gene that was also seen in the fetus. However, the fetus had congenital omphalocele in addition to SPD that is an association not reported to date. A chromosomal microarray in the fetus was normal. We report a novel mutation in HOXD13 and document co-occurrence of an omphalocele and SPD in a fetus.

We report on two unrelated fetuses born to nonconsanguineous couples with fetal akinesia deformation sequence (FADS). The fetuses shared facial features, micrognathia, fetal finger pads, bulbous digital tips, pterygia, clubfeet, ventriculomegaly, and cerebellar anomalies. Both had loss/absence of Purkinje cells in cerebellum. The first family had a similarly affected previous pregnancy suggesting an autosomal recessive inheritance. The second fetus, in addition to the findings in the first, had cleft palate and defective lobulation of lungs. These fetuses appear to have the Pena-Shokeir phenotype (PSP) or FADS. These two cases seem to define a newly recognizable subtype of FADS with bulbous digital tips, prominent digit pads and cerebellar anomalies, and highlight the phenotypic diversity of syndromes with multiple congenital contractures manifesting in utero.

The four R-spondin secreted ligands (RSPO1–RSPO4) act via their cognate LGR4, LGR5 and LGR6 receptors to amplify WNT signalling1–3. Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs. Functional studies revealed impaired binding to the LGR4/5/6 receptors and the RNF43 and ZNRF3 transmembrane ligases, and reduced WNT potentiation, which correlated with allele severity. Unexpectedly, however, the triple and ubiquitous knockout of Lgr4, Lgr5 and Lgr6 in mice did not recapitulate the known Rspo2 or Rspo3 loss-of-function phenotypes. Moreover, endogenous depletion or addition of exogenous RSPO2 or RSPO3 in triple-knockout Lgr4/5/6 cells could still affect WNT responsiveness. Instead, we found that the concurrent deletion of rnf43 and znrf3 in Xenopus embryos was sufficient to trigger the outgrowth of supernumerary limbs. Our results establish that RSPO2, without the LGR4/5/6 receptors, serves as a direct antagonistic ligand to RNF43 and ZNRF3, which together constitute a master switch that governs limb specification. These findings have direct implications for regenerative medicine and WNT-associated cancers. Independently of the LGR4/5/6 receptors, RSPO2 acts as a direct antagonistic ligand to RNF43 and ZNRF3 during embryogenesis, and specifies the position and number of limbs that an embryo should form.

In this Letter, the surname of author Lena Vlaminck was misspelled 'Vlaeminck'. In addition, author Kris Vleminckx should have been associated with affiliation 16 (Center for Medical Genetics, Ghent University, Ghent, Belgium). These have been corrected online.

Objective: We aimed to determine the value of autopsy in fetuses with antenatally diagnosed oligohydramnios. Patients and methods: We evaluated all fetal losses over a period of 6.5 years. Those with oligohydramnios on antenatal scan were critically analyzed. Oligohydramnios was defined as amniotic fluid index of less than five objectively or as an obvious lack of liquor at subjective assessment. A detailed postmortem examination was carried out in all the fetuses after obtaining an informed consent. Results: Fetal autopsy was conducted in 255 cases. Fifty-five (21.5%) fetuses were diagnosed to have oligohydramnios on antenatal ultrasonography. On analysis of antenatal causes of oligohydramnios, maternal/placental factors were noted in 18%, ultrasound findings known to affect amniotic fluid in 27% while cause remained unidentified in 54.5% of cases. On autopsy, fetal malformations were noted in 61.8% cases, intrauterine growth retardation in 21.8% fetuses and no obvious malformations in 16.3% fetuses. Renal anomalies were noted in 40% cases and non-renal malformations in 21.8% cases. Conclusion: The postmortem examination helped us to identify the cause of fetal loss in 46 (83.6%) fetuses with antenatal oligohydramnios. A working diagnosis could not have been established without autopsy in 19 (34.5%) cases.

Urorectal septum malformation sequence (URSMS) is a rare spectrum of malformations involving various organ systems. Here, we present eight cases of URSMS, noted in autopsy, with different degrees of complexity, seven being the complete type and one being the partial type. All cases had gastrointestinal tract malformation in the form of the imperforate anus and indeterminate genitalia. Other gastrointestinal tract anomalies were anal agenesis in two cases, anorectal agenesis in two cases, and malformed lower intestinal tract in four cases. The associated renal abnormality was noted in five cases, which were unilateral renal agenesis, dysplastic kidney, hydronephrosis, horseshoe kidney, and unilateral hypoplastic ectopic kidney. External genital malformation, present in both male and female fetuses, included a knob-like structure at perineum in female fetuses, genital fold hypoplasia and penile aplasia or hypoplasia in male fetuses. Skeletal abnormalities included two cases of sacral agenesis and one case of lumbosacral dysraphism. Other anomalies included a case with alobar holoprosencephaly, truncus arteriosus with hypoplastic lungs in one case, and three cases with abdominal wall defects. It is our attempt to delineate a spectrum of abnormalities associated with URSMS.

We evaluated 214 fetuses sent for autopsy with gestational ages ranging from 12 to 39 weeks. Of these, seventeen fetuses (7.9%) had single umbilical artery. Thirteen of these fetuses were aborted after antenatal detection of severe malformations and 4 died in utero. Genito-urinary system (n=6) and central nervous system (n=4) were the most common sites of involvement. Presence of single umbilical artery warrants a detailed evaluation of the fetus for other anomalies.

To the Editor: Two fetuses were evaluated following abortion (fetus 1) or intrauterine demise (fetus 2). In both cases, mothers were primigravidae with no antenatal history of teratogenic exposure. The family history was unremarkable and the couples were non-consanguineous. In fetus 1, antenatal sonography revealed all fetal parameters at 22 wk of gestation. However, hands were not visualized. On examination, the fetus had micrognathia (Fig. 1a and b). There was symmetrical absence of hands and digits with preservation of dorsoventral differentiation of skin at the limb terminus (Fig. 1a). Lower limbs were normal and internal examination was unremarkable. Radiograph of the hands revealed bilateral absence of metacarpals and phalanges (Fig. 1c). The anthropometric measurements of fetus 2 corresponded to 15 wk of gestation. Fetus had significant nuchal edema. Both hands were underdeveloped with absence of all fingers. Both feet were completely absent (Fig. 2a and b). There were no other external or internal anomalies. Radiographs showed normal long bones. Metacarpals and phalanges in both hands were small. Metatarsals and phalanges in both feet were completely absent (Fig. 2c and d). Unfortunately, due to non-availability of DNA, we were not able to perform any molecular studies. We hereby report on two fetuses with symmetrical, bilateral and isolated terminal transverse limb reduction defects. These defects are rare anomalies referring to absence or hypoplasia of distal structures of limbs with normal proximal parts. In most cases it is difficult to ascertain a cause. Unilateral defects that occur more frequently are often thought to arise from disruptive forces like amniotic bands, thromboembolic phenomenon, vasospastic drug exposure and they are rarely familial [1, 2]. Bilateral, symmetrical and apparently non-syndromic transverse limb defects have been reported extremely rarely [3]. Saeed et al., identified 9 cases of isolated transverse limb defect [4]. The abnormality in these cases ranged in severity and in only one case there was bilateral involvement. To the best of our knowledge, there have been no reports similar to the pattern described here. The current understanding of genetic basis for limb development has essentially evolved from

Absent pulmonary valve syndrome (APVS) is a rare congenital cardiac anomaly. This syndrome is comprised of subtotal or total absence of pulmonary valve leaflets, stenosis of the pulmonary artery orifice, aneurysmal dilation of the main pulmonary artery and ventricular septal defect. We report a case of APVS with neural tube defect detected prenatally at 22 weeks of gestation by echocardiography, and subsequently confirmed by autopsy of the still born fetus. The common presentations, means of diagnosis and variants of APVS are discussed in brief.