Shalini S. Nayak

Clinical utility of fetal autopsy and its impact on genetic counseling.

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.

Fetal Akinesia Deformation Sequence: Expanding the Phenotypic Spectrum

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.

RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6

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.

Jejunal atresia and postaxial polydactyly: a newly recognized phenotype.

Clinical summary Fetal anomalies were detected by ultrasound scan in a 26-year-old G3 P2 + 0 and she was referred for counseling at 28 weeks of gestation. She has a consanguineous marriage; her first pregnancy ended in intrauterine death of the fetus at 26 weeks of gestation, which was not investigated further, and her next pregnancy resulted in the birth of a healthy male, now 3 years old. There were no antenatal illnesses, no evidence of maternal diabetes mellitus, and no exposure to known teratogens. Echogenic bowel loops with a cystic lesion measuring 2.5 2.2 cm along with a rim of calcification, located anterior to the stomach bubble, were visualized on antenatal ultrasonography (Fig. 1). Polyhydramnios and a two-vessel cord were also noted. Following intrauterine fetal death at 33 weeks of gestation, a perinatal autopsy was requested. The female fetus weighed 1284 g (5th centile) and measured 37 cm in length (– 2 SD). The fetus had postaxial polydactyly of both feet and the right hand (Fig. 2). There was a sacral pit (Fig. 3a) and a single umbilical artery (Fig. 3b) was also noted. An intraabdominal mass on the left side (Fig. 4a) was found to comprise a distended duodenum and jejunum with a gangrenous mass of 3 4.5 cm diameter filled with meconium in the middle of the jejunum. An abrupt narrowing of the jejunum distal to the mass suggested type I atresia (Fig. 4b). There was no facial dysmorphism. The lungs, heart, major vessels, diaphragm, stomach, liver, kidneys, adrenals, ureters, urinary bladder, ovaries, uterus, vagina, and rectum of the fetus were normal. Fetal radiographs were unremarkable. Fetal chromosomal analysis could not be carried out. Both parents were healthy and neither had polydactyly nor any known history of this. The study received the approval of the institutional ethics committee.

Symmetrical Terminal Transverse Limb Deficiencies

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

Prenatal diagnosis of absent pulmonary valve confirmed by autopsy

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.

Author Correction: RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6

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.

Occurrence of Synpolydactyly and Omphalocele in a Fetus with a HOXD13 Mutation

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.

Variable presentation of Fraser syndrome in two fetuses and a novel mutation in FRAS1

We report on a consanguineous family with three pregnancies affected with Fraser syndrome. We note severe brachydactyly is a manifestation of Fraser syndrome and found a novel homozygous splice site variation c.3293‐2A>T in FRAS1. We would like to highlight variable manifestations of Fraser syndrome and the presence of oligohydramnios in the antenatal period often makes prenatal diagnosis clinically challenging.

Spectrum of urorectal septum malformation sequence.

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.