Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia.

The development of hindlimbs in tetrapod species relies specifically on the transcription factor TBX4. In humans, heterozygous loss-of-function TBX4 mutations cause dominant small patella syndrome (SPS) due to haploinsufficiency. Here, we characterize a striking clinical entity in four fetuses with complete posterior amelia with pelvis and pulmonary hypoplasia (PAPPA). Through exome sequencing, we find that PAPPA syndrome is caused by homozygous TBX4 inactivating mutations during embryogenesis in humans. In two consanguineous couples, we uncover distinct germline TBX4 coding mutations, p.Tyr113∗ and p.Tyr127Asn, that segregated with SPS in heterozygous parents and with posterior amelia with pelvis and pulmonary hypoplasia syndrome (PAPPAS) in one available homozygous fetus. A complete absence of TBX4 transcripts in this proband with biallelic p.Tyr113∗ stop-gain mutations revealed nonsense-mediated decay of the endogenous mRNA. CRISPR/Cas9-mediated TBX4 deletion in Xenopus embryos confirmed its restricted role during leg development. We conclude that SPS and PAPPAS are allelic diseases of TBX4 deficiency and that TBX4 is an essential transcription factor for organogenesis of the lungs, pelvis, and hindlimbs in humans.

Caudal dysplasia syndrome and sirenomelia: are they part of a spectrum?

Caudal dysplasia syndrome (CDS) is associated with hypoplastic lower extremities, caudal vertebrae, sacrum, neural tube, and urogenital organs. Sirenomelia is characterized by a single lower extremity, absent sacrum, urogenital anomalies, and imperforate anus. There is controversy in the medical literature about whether sirenomelia and CDS are part of the spectrum of the same malformation. Patients with CDS and sirenomelia were identified from our pathology files from 1991 to 2006. Maternal history, pathologic examination, and radiographs were collected and tabulated. We found 9 cases with CDS and 6 with sirenomelia. Fully 7 of 9 patients with CDS (77.7%) versus none of sirenomelic babies were infants of diabetic mothers. Congenital heart disease was present in 5 patients with CDS (55.5%) and none of the infants with sirenomelia. Of 9 children with CDS 2 (22.2%) had bilateral renal agenesis versus 66% of sirenomelics. Single umbilical artery was found in 33% of cases with CDS and 100% of children with sirenomelia. External genitalia were ambiguous in 2 of 9 patients (22.2%) with CDS and in all patients with sirenomelia. Imperforate anus was found in 10 cases (66.6%) divided as 4 of 9 babies with CDS (44.4%) and all patients with sirenomelia. Three patients with CDS had concomitant maternal diabetes mellitus and chronic hypertension. These babies also had cleft lip and palate. Congenital heart disease was found in 55.5% of cases with CDS and none of the children with sirenomelia. We conclude that although CDS and sirenomelia share many similar features, they are two different entities.

Beyond the myth: the mermaid syndrome from Homerus to Andersen. A tribute to Hans Christian Andersen's bicentennial of birth.

Mermaid or sirens have been part of the cultural tradition of the sailors during the first expeditions in the western world. The Siren's Myth appeared for a first time with Homer, who described in the Odyssey some singing creatures that lured the enchanted sailors to death. More frequently described with a bird body and a female head, sometimes the female part was extended to torso, with arms prolonged in sturdy claws. In the Latin literature Publius Ovidius Naso presented in the Métamorphoses these creatures. Proposed ethymology for the word "siren" seems to confirm the prerogatives of these creatures, related to magnetism, seduction, charm. The first figuration of Sirens resembling to fish-women was in the second century bc. Hans Christian Andersen provided to leave us the strongest legend of Siren in the well-known fairy tale "The Little Mermaid". Following this story, Sirens are definitely considered as beautiful half-fish women who lived in the bottom of the sea, having a lovely voice to be used when they rise up to allow sweeter the agony of the wrecked sailors. Beyond the Myth, may the Siren really exist? It can be hypothesized that these creatures probably were individuals affected by sirenomelia. In our literature and medical review, we describe the etiology of the disease, and we illustrated the anatomical features of fetuses affected by this pathology using MDCT 3D reconstructions. Syrenomelia is a condition not compatible with the normal life, however nine cases of "mermaid" survived to reconstructive surgery have been reported until now. In our report we also presented a case of survival baby girl affected by sirenomelia, before and after surgery, with correlative radiologic imaging findings. The most important characteristic that seems to allow survival of the affected individuals is the presence of one functional kidney, displaced in pelvis. As so dramatically tragic was the history of the Andersen Little Mermaid, so unattended pleasant would be the destiny of a modern mermaid, who can hope to finally marry her prince, without the risk to "loose her head", as the Copenhagen City's Symbol did in the past years, for a story beyond the Myth.

Unusual case of epigastric heteropagus twinning.

Asymmetrical conjoined twins or heteropagus twins are extremely rare. They are characterized by an incomplete component (parasite) that is normally smaller and dependent on the host (autosite). In cases of an epigastric heteropagus twin, the insertion occurs in the epigastrium. There are few reports of epigastric heteropagus twinning in the English-language literature. The authors report an extremely rare case of epigastric heteropagus twinning in which the parasite presented with head, thorax, and a rudimentary heart.

Caudal dysplasia sequence: severe phenotype presenting in offspring of patients with gestational and pregestational diabetes.

The association of maternal diabetes mellitus and congenital anomalies is well established. Children of insulin-dependent diabetic women have an increased risk of congenital malformations, especially major multiorgan defects. The cardiovascular, central nervous, gastrointestinal, genitourinary and musculoskeletal are the most affected body systems. Studies also show that offspring of women with gestational diabetes (specially those with fasting hyperglycaemia) tend to have higher rates of congenital anomalies. We report two cases of infants born to unrelated mothers: one with diabetes mellitus first detected during pregnancy (gestational diabetes) and the other with pregestational diabetes. Both infants had amelia of the lower limbs (suggestive of caudal dysplasia sequence), together with cardiovascular, skeletal, urinary and gastrointestinal defects. While pregestational diabetes seems to leave no doubt about its teratogenicity, the association of gestational diabetes and fetal/newborn malformations is still under discussion. Complete absence of the lower limbs has not been reported in association with gestational diabetes, but it may represent a spectrum of the caudal dysplasia sequence. The presentation of two cases with the same clinical phenotype of mothers with gestational and pregestational diabetes supports the evidence that gestational diabetes can be responsible for the development of the most severe form of the caudal dysplasia sequence.

Orthopaedic manifestations of Brachmann-de Lange syndrome: a report of 34 patients.

Brachmann-de Lange syndrome (BDLS) is a disorder of unknown cause that is recognized on the basis of characteristic facies in association with growth retardation, mental retardation and, in many cases, upper limb anomalies. Because of its association with skeletal anomalies, patients with the syndrome are often referred to the paediatric orthopaedic surgeon. Thirty-four patients with Brachmann-de Lange syndrome were evaluated for the prevalence and pattern of musculoskeletal involvement. The average age of the patients was 10.2 years (range, 1 month to 44 years). Both sexes were affected equally. The common orthopaedic manifestation affected the hand (100%), elbow (47%), and the heel cord (26%). Severe bony anomalies included complete absence of the hand in one case, and ulna hemimelia in two cases. In two patients bilateral Legg-Perthes-like changes were noted. Scoliosis presented in four cases, all before the age of 10 years. Surgery was performed in two patients with severe bilateral equinovarus feet. Despite the constellation of musculoskeletal findings, most of the patients did not have surgical intervention for their deformities.

A surviving infant with sirenomelia (Mermaid syndrome) associated with absent bladder.

The authors report a case of a surviving infant with sirenomelia (Mermaid syndrome). The child is now 4 years of age. The authors believe that this is only the fourth reported case of an infant with sirenomelia surviving beyond the neonatal period and the first associated with absent bladder. The abnormal distal aorta shown in this case supports the theory that sirenomelia is an extreme form of caudal dysgenesis rather than occurring secondary to vascular steal.

Sirenomelia, the mermaid syndrome--detection in the first trimester.

The sirenomelia sequence with fusion, rotation, hypotrophy or atrophy of the lower limbs in combination with severe urogenital and gastrointestinal malformations is a rare and usually lethal disorder. We present the case of a 28-year-old woman, who was referred to our department because of an intraabdominal cystic structure in the 9th week of gestation. Subsequent scans confirmed the diagnosis of a sirenomelia sequence with the fusion of the lower extremities without fusion of the bones according to Stocker I classification. The size of the intraabdominal cyst decreased during follow-up. After counseling, termination of pregnancy was induced. The postmortem X-ray confirmed the ultrasound diagnosis. The exact etiological mechanism of this malformation is still unknown. An early alteration of the embryological vascular network damaging the caudal mesoderm is thought to lead to arrested development of the lower limbs and other affected organs. The cyst we saw in the 9th week might fit with this theory, either as an expression of the complex malformation of the lower abdomen or as the sonographic appearance of necrosis.

[Polyostotic fibrous dyplasia: a case report of a diffuse form with hemimelic predominance]. / Dysplasie fibreuse polyostotique: à propos d'une forme diffuse à prédominance hémimélique.

Fibrous dysplasia is an uncommon condition characterized by the presence of mesenchymatous tissue in bone. There are various risks. We describe the clinical and radiological features observed in a patient with fibrous polyostotic fibrous dysplasia and discuss risks. A 37-year-old man suffered from bone pain and multiple fractures without endocrine disorder since the age of 10 years. At admission in 1998, he presented limb deformities and hyperchromic spots on the thorax. Calciuria was low and alkaline phosphatase was 1274 IU/ml. Endocrine tests were normal. Radiographs showed polyostotic defects in the right hemibody and in the skull. They also showed a right subtrochanteric fissure. CT scan of the face and skull did not demonstrate nerve compression. Histology analysis identified fibrous dysplasia. Vitamin and calcium supplementation and preventive measures were instituted. No deformity led to surgical correction despite the early beginning. Polyostotic fibrous dysplasia is a congenital disease. Radiological aspects are variable. There is a risk of deformities, fractures, osteomalacia (as in our case), neurological compression, and finally a risk of sarcomatous transformation. Recently introduced biphosphonate therapy appears to provide effective pain relief and probably satisfactory prevention of fractures.

Case of complex craniofacial anomalies, bilateral nasal proboscides, palatal pituitary, upper limbs reduction, and amnion rupture sequence: disorganization phenotype?

We report a case of a dizygotic twin with complex abnormalities of head, body, and limbs. The anomalies include the following: lateral and midline cleft upper lip, ectopic palatal pituitary, natal teeth, bilateral nasal proboscides with an absent nose, left microphthalmia with conjunctival-lined cyst, right ocular dysgenesis, bilateral retinal dysplasia, platybasia with skull asymmetry, hydrocephalus secondary to aqueductal atresia, brain hemispheric asymmetry with a parietal-occipital cortical flap, agenesis of posterior corpus callosum, absence of the olfactory nerves and left anterior cerebral artery, leptomeningeal and intraventricular heterotopias, right radial longitudinal terminal meromelia with constriction rings of fingers, partial syndactyly of the third and fourth left fingers, dorsiflexed great toes and pes equinovarus bilaterally, and multiple skin tags with a sacral appendage. Additionally, this twin's placental disc and extraplacental membranes were devoid of amnion. We regard these anomalies as a possible expression of the human homologue of the disorganization phenotype or another gene mutation. Nevertheless, an abnormality of blastogenesis with early damage to organizing tissues of the frontonasal region and limbs, or a vascular disruption, cannot be excluded. Early amnion rupture sequence (possible extraamniotic pregnancy with amniotic bands, limb reduction defects with Streeter bands, and multiple skin tags tapering into amniotic bands) was also present in this case, and may have acted as a contributing factor.

Sirenomelia / Sirenomelia

Se presenta un caso clínico de sirenomelia, diagnosticado en el parto, en una paciente de 37 años. Se comenta frecuencia, etiopatogenia y diagnóstico

Síndrome de Potter / Potterïs syndrome

Se comunican 24 casos con diagnóstico prenatal de síndrome de Potter, reunidos en la Unidad de Ultrasonografía del Servicio y Departamento de Ginecología y Obstetricia del Hospital San Juan de Dios, en el período comprendido entre enero de 1992 y diciembre de 1997. Se destacan los aspectos clínicos, ecográficos y las malformaciones asociadas. Es importante recalcar que el síndrome tiene una mortalidad de 100 por ciento y enfatiza la necesidad de asesoramiento genético para embarazos posteriores

Vascular anastomoses leading to amelia and cutis aplasia in a dizygotic twin pregnancy.

Dichorionic placentation is observed in both monozygotic (MZ) and dizygotic (DZ) twinning, while monochorionic placentation is unique to MZ twinning. Examinations of monochorionic twin placentas frequently reveal the presence of vascular anastomoses between the two fetal circulations; such anastomoses rarely occur in dichorionic placentas. Consequently, abnormalities resulting from placental vascular communications are almost exclusively observed in MZ twin pairs with monochorionic placentas. We report opposite-sex DZ twins in which vascular anastomoses occurred within a fused dichorionic placenta and were associated with vascular disruptions in one twin. The liveborn male twin had amelia, cutis aplasia, and XX/XY blood chimerism; the female twin died in utero.

[Severe anomaly of fetal limbs after early and failed voluntary interruption of pregnancy]. / Severa anomalia degli arti fetali dopo precoce e fallita interruzione volontaria di gravidanza.

The authors report the case of a patient who underwent a failed legal abortion at the 7th week of pregnancy via vacuum aspiration. A follow-up ultrasound survey done at the 14th week demonstrated the continuance of pregnancy and the presence of a serious fetal deformity consisting of the amelia of the two upper limbs, complete phocomelia of the right lower limb and distal phocomelia of the left lower limb. In the light of recent findings of a high incidence of fetal limb abnormalities in women subjected to chorionic villus sampling, before the 9th week of gestation, the Authors hypothesize that chorionic villus sampling, occurring during the abortion attempt, could probably be the cause of the fetal limb abnormalities in the present case study.

Combined pentalogy of Cantrell and sirenomelia: a case report with speculation about a common etiology.

A case of combined pentalogy of Cantrell with sirenomelia in a monozygotic twin is described. Similar cases from the world literature are reviewed. Current concepts on the etiology of anterior midline ventral wall defects and sirenomelia are detailed. It has been proposed that anterior midline ventral wall defects may be caused by either monozygotic twinning or vascular dysplasia. Likewise, a vascular steal phenomenon causes sirenomelia. A common etiology for these defects, an alteration in vascular development, is proposed.

Case reports of malformations associated with maternal diabetes: history and critique.

Several malformations and malformation complexes have been alleged to be associated with maternal type 1 diabetes mellitus: in particular, sacral dysplasia, caudal regression/sirenomelia, femoral dysplasia, and holoprosencephaly. For some of the malformations the claim rests on case material, and for others on theoretical considerations. The history and evolution of these ideas are presented.

Sirenomelia: presentación de un caso / Sirenomelia: report of a case

Se reporta un caso de Sirenomelia diagnosticado en la Unidad de Perinatología del H.U.C., cuya evaluación antenatal reportó aligoamnios severo, retardo de crecimiento intrauterino y ausencia de imagen ecográfica renal. El diagnóstico se hizo en la etapa postnatal. Dentro de la clasificación de Forster, el caso en cuestión se trata del tipo Symelia Apus. Presentó además defecto abierto del tubo renal. Es de hacer notar la dificultad diagnóstica que detérmina la presencia de oligoamnios severo en estos casos, lo cual limita la evaluación de la anatomía fetal por ultrasonido. Se brinda una revisión de la literatura sobre etiopatogenia y manejo diagnóstico de los casos de Sirenomelia

[Pathogenesis of radiation-induced abnormalities of the bones and joints of white rat embryos]. / Patogenez luchevykh anomalii skeleta i sustavov zarodyshei beloi krysy.

After X-radiation of pregnant rats on the 10th day of pregnancy, in 50% of the fetuses studied subtotal aplasia of the tibial bone anlage and decreasing number of the metatarsus and finger phalanges anlages are observed. Radiation on the 11th day of embryogenesis does not result in anomaly formation of the thoracic and pelvic extremities. After radiation on the 12th day of embryogenesis, the most specific anomaly of the pelvic extremity is phocomelia. The thoracic extremity skeleton lesions are revealed as an ulnar type of distal ectromelia, or axial ectromelia. After radiation on the 13th--14th day, hypoplasia of the bone anlages, that make zeugopodium, autopodium, is observed. After radiation on the 13th day, a partial or total aplasia of the fibular bone anlage can take place. In all the fetuses a sharp decrease in number of the hand and foot bone anlages is observed; it is connected with a total aplasia of some of them and with fusion of the others. A specific feature for radiation lesions of the extremity skeleton is that the oppositely situated anlages of the bones do not separate from each other. This results from certain disturbances in the joint interzone formation at early stages of embryogenesis and from underdevelopment of the joint cleft. Qualitatively different radiation anomalies of the extremity skeleton development are formed as consequence of disturbances in morphogenetic processes of determination: migration, proliferation, morphogenetic cell death and differentiation.