Association of tracheoesophageal anomalies with visceral and parietal malformations in a human embryo (Carnegie stage 21)

A human embryo (Carnegie stage 21) with tracheoesophageal malformations (esophageal atresia and tracheoesophageal fistula) and anomalies at the caudal end of the embryo (anorectal atresia, rectovesical fistula, vertebral and notochordal defects, and agenesis of the metanephros) was studied. Other anomalies observed were: absence of right umbilical artery, fusion of spinal ganglia, and absence of cloacal outlet of mesonephric ducts. The possible pathogenesis of these associated malformations is discussed.     

Limb reduction defects in humans associated with prenatal isotretinoin exposure.

Retinoic acid has long been used to induce limb reductions defects in experimental animal studies. No limb malformations, however, have been reported among malformed retinoic acid-exposed human fetuses from case reports or epidemiologic studies. We report a child and a fetus with limb reduction malformations following maternal use of isotretinoin (13-cis-retinoic acid) during the first trimester of pregnancy. The child had a unilaterally absent clavicle and nearly absent scapula, with a short humerus and short, synostotic forearm bones. He also had ventriculomegaly and developmental delay, minor dysmorphic facial features, and a short sternum with a sterno-umbilical raphe. The fetus had a unilaterally absent thumb with normal proximal bony structures. Other findings included hydrocephalus, craniofacial anomalies, thymic agenesis, supracristal ventricular septal defect, single umbilical artery, anal and vaginal atresia, and urethral agenesis with dysplastic, multicystic kidneys. Although the limb malformations were quite dissimilar, a number of anomalies that are frequently found among isotretinoin-exposed fetuses/infants were present in both cases. This increases the probability that retinoic acid caused these limb defects, but a causal association cannot be conclusively drawn on the basis of these two retrospective case reports.     

Myasthenia gravis

Oesophageal atresia (OA) encompasses a group of congenital anomalies comprising of an interruption of the continuity of the oesophagus with or without a persistent communication with the trachea. In 86% of cases there is a distal tracheooesophageal fistula, in 7% there is no fistulous connection, while in 4% there is a tracheooesophageal fistula without atresia. OA occurs in 1 in 2500 live births. Infants with OA are unable to swallow saliva and are noted to have excessive salivation requiring repeated suctioning. Associated anomalies occur in 50% of cases, the majority involving one or more of the VACTERL association (vertebral, anorectal, cardiac, tracheooesophageal, renal and limb defects). The aetiology is largely unknown and is likely to be multifactorial, however, various clues have been uncovered in animal experiments particularly defects in the expression of the gene Sonic hedgehog (Shh). The vast majority of cases are sporadic and the recurrence risk for siblings is 1%. The diagnosis may be suspected prenatally by a small or absent stomach bubble on antenatal ultrasound scan at around 18 weeks gestation. The likelihood of an atresia is increased by the presence of polyhydramnios. A nasogastric tube should be passed at birth in all infants born to a mother with polyhydramnios as well as to infants who are excessively mucusy soon after delivery to establish or refute the diagnosis. In OA the tube will not progress beyond 10 cm from the mouth (confirmation is by plain X-ray of the chest and abdomen). Definitive management comprises disconnection of the tracheooesophageal fistula, closure of the tracheal defect and primary anastomosis of the oesophagus. Where there is a "long gap" between the ends of the oesophagus, delayed primary repair should be attempted. Only very rarely will an oesophageal replacement be required. Survival is directly related to birth weight and to the presence of a major cardiac defect. Infants weighing over 1500 g and having no major cardiac problem should have a near 100% survival, while the presence of one of the risk factors reduces survival to 80% and further to 30–50% in the presence of both risk factors.     

Severe congenital limb deficiencies,vertebral hypersegmentation,absent thymus and mirror polydactyly: A defect expression of a developmental control gene?

We describe two unrelated patients with a complex malformation pattern that may be a candidate for a developmental gene disorder. These two patients had severe, symmetrical upper and lower limb deficiencies, vertebral hypersegmentation, and duodenal atresia. Patient 1 also had mirror-image polydactyly of his feet; patient 2 was athymic. The concurrence in two unrelated patients of additional vertebrae with severe anomalies in limb development, including a symmetrical deficiency of the four limbs and either mirror-image duplication of some toes (only in patient 1) or absence of the thymus (only in patient 2), represents an early alteration in body-plan organization. Since limb development, thymus development and segmentation are possibly under the control of homeobox genes in the human embryo, it seems reasonable that the malformations observed in these two patients resulted from a defect of a gene controlling developmental pattern formation, possibly a homeobox gene or a paired-box gene. Severe limb deficiencies have been reported in other well-known genetic entities, such as Roberts syndrome, Baller-Gerold syndrome, X-linked amelia, and DK-phocomelia syndrome. However, since the specific pattern of anomalies observed in these patients makes the diagnosis of some of the abovementioned disorders unlikely, we conclude that our patients have a previously undescribed disorder.     

Mutation Screening and Array Comparative Genomic Hybridization Using a 180K Oligonucleotide Array in VACTERL Association

In order to identify genetic causes of VACTERL association (V vertebral defects, A anorectal malformations, C cardiac defects, T tracheoesofageal fistula, E esophageal atresia, R renal anomalies, L limb deformities), we have collected DNA samples from 20 patients diagnosed with VACTERL or with a VACTERL-like phenotype as well as samples from 19 aborted fetal cases with VACTERL. To investigate the importance of gene dose alterations in the genetic etiology of VACTERL association we have performed a systematic analysis of this cohort using a 180K array comparative genomic hybridization (array-CGH) platform. In addition, to further clarify the significance of PCSK5, HOXD13 and CHD7 genes in the VACTERL phenotype, mutation screening has been performed. We identified pathogenic gene dose imbalances in two fetal cases; a hemizygous deletion of the FANCB gene and a (9;18)(p24;q12) unbalanced translocation. In addition, one pathogenic mutation in CHD7 was detected, while no apparent disease-causing mutations were found in HOXD13 or PCSK5. Our study shows that although large gene dose alterations do not seem to be a common cause in VACTERL association, array-CGH is still important in clinical diagnostics to identify disease cause in individual cases.     

Tracheal agenesis with broncho-esophageal fistula in VACTERL / TACRD association

Tracheal agenesis (TA) is an extremely rare malformation. We report here autopsy findings in a case of TA with bronchoesophageal fistula of Floyd type III. The other malformations present included laryngeal atresia, Right lung hypolobulation, ventricular septal defect in membranous portion, bilateral cystic renal dysplasia, spleninculus, Meckel''s diverticulum, and imperforate anus. The constellations of malformations present in our case have overlapping features with Vertebral anomalies, Anal atresia, Cardiovascular anomalies, Tracheo-esophageal fistula, Esophageal atresia, Renal anomalies, Limb anomalies and Tracheal atresia or laryngo tracheal atresia, Cardiac anomalies, Renal anomalies, Duodenal atresia association described previously in the literature.     

A boy with Weyers-like ulnar ray/oligodactyly reduction limb defects and split hand malformation: case report

Weyers ulnar ray/oligodactyly syndrome is characterized by variable ulnar, radial, or fibular ray limb reductions, single central incisor, and renal, splenic or cardiac anomalies. Split hand/split foot malformation is a central reduction defect of the hands and feet, and may occur either as an isolated malformation or as a part of syndrome. We describe a patient with Weyers-like ulnar ray/oligodactyly reduction limb defects and split hand malformation.     

National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999-2001

BACKGROUND: In the United States, birth defects affect approximately 3% of all births, are a leading cause of infant mortality, and contribute substantially to childhood morbidity. METHODS: Population-based data from the National Birth Defects Prevention Network were combined to estimate the prevalence of 21 selected defects for 1999-2001, stratified by surveillance system type. National prevalence was estimated for each defect by pooling data from 11 states with active case-finding, and adjusting for the racial/ethnic distribution of US live births. We also assessed racial/ethnic variation of the selected birth defects. RESULTS: National birth defect prevalence estimates ranged from 0.82 per 10,000 live births for truncus arteriosus to 13.65 per 10,000 live births for Down syndrome. Compared with infants of non-Hispanic (NH) white mothers, infants of NH black mothers had a significantly higher birth prevalence of tetralogy of Fallot, lower limb reduction defects, and trisomy 18, and a significantly lower birth prevalence of cleft palate, cleft lip with or without cleft palate, esophageal atresia/tracheoesophageal fistula, gastroschisis, and Down syndrome. Infants of Hispanic mothers, compared with infants of NH white mothers, had a significantly higher birth prevalence of anencephalus, spina bifida, encephalocele, gastroschisis, and Down syndrome, and a significantly lower birth prevalence of tetralogy of Fallot, hypoplastic left heart syndrome, cleft palate without cleft lip, and esophageal atresia/tracheoesophageal fistula. CONCLUSIONS: This study can be used to evaluate individual state surveillance data, and to help plan for public health care and educational needs. It also provides valuable data on racial/ethnic patterns of selected major birth defects.     

Extrahepatic biliary atresia with laterality sequence anomalies

The patient was the first child of first cousin parents. He was born at term after an uneventful pregnancy with normal height, weight and head circumference. Jaundice appeared at 15 days of age. Ventricular septal defects and valvular pulmonary stenosis were diagnosed. An hepatic workup revealed extrahepatic biliary atresia and abdominal situs inversus. Hepatic biopsy showed cirrhosis with intrahepatic cholestasis. Genetic factors are suggested in extrahepatic biliary atresia. Analysis of segregation patterns suggested the existence of two major groups, one with various combinations of anomalies within the laterality sequence and the other with one or two anomalies mostly involving the cardiac, gastrointestinal, and urinary systems. This patient belongs to the first group.     

The Antley-Bixler syndrome. Review of the literature. Apropos of a personal case

A female newborn presenting multiple congenital anomalies with acrocephalosynanky, external auditory canals atresia, vertebral anomalies, is described as being affected of an Antley-Bixler Syndrome. The authors compare this case with the eight others reported with this disorder, of whom two are sisters.     

Multiple endocrine neoplasia type 1

Solitary median maxillary central incisor syndrome (SMMCI) is a complex disorder consisting of multiple, mainly midline defects of development resulting from unknown factor(s) operating in utero about the 35th–38th day(s) from conception. It is estimated to occur in 1:50,000 live births. Aetiology is uncertain. Missense mutation in the SHH gene (I111F) at 7q36 may be associated with SMMCI. The SMMCI tooth differs from the normal central incisor, in that the crown form is symmetric; it develops and erupts precisely in the midline of the maxillary dental arch in both primary and permanent dentitions. Congenital nasal malformation (choanal atresia, midnasal stenosis or congenital pyriform aperture stenosis) is positively associated with SMMCI. The presence of an SMMCI tooth can predict associated anomalies and in particular the serious anomaly holoprosencephaly. Common congenital anomalies associated with SMMCI are: severe to mild intellectual disability, congenital heart disease, cleft lip and/or palate and less frequently, microcephaly, hypopituitarism, hypotelorism, convergent strabismus, oesophageal and duodenal atresia, cervical hemivertebrae, cervical dermoid, hypothyroidism, scoliosis, absent kidney, micropenis and ambiguous genitalia. Short stature is present in half the children. Diagnosis should be made by eight months of age, but can be made at birth and even prenatally at 18–22 weeks from the routine mid-trimester ultrasound scan. Management depends upon the individual anomalies present. Choanal stenosis requires emergency surgical treatment. Short stature may require growth hormone therapy. SMMCI tooth itself is mainly an aesthetic problem, which is ideally managed by combined orthodontic, prosthodontic and oral surgical treatment; alternatively, it can be left untreated.     

Unilateral absence of the trapezius and pectoralis major muscle: a variant of Poland syndrome

We report a female patient with unilateral absence of the trapezius and pectoralis major muscles without other associated limb abnormalities. We believe that this anomaly belongs to the spectrum of anomalies resulting from disruption of the blood supply in the embryonic subclavian and vertebral arteries, as suggested in Poland syndrome.     

VACTERL association and maternal diabetes: A possible causal relationship?

BACKGROUND: Some factors(s)/features(s) of maternal insulin‐dependent diabetes mellitus are considered common human teratogens. Although the variable association of cardiac, renal, and skeletal anomalies are commonly observed in infants from diabetic mothers, the relationship between VACTERL (i.e., the association of vertebral and cardiac defects, tracheo‐esophageal fistula, renal/radial malformations, and other limb anomalies) and maternal diabetes has not been sufficiently emphasized in the literature. CASE: We report on a 3‐year‐old boy presenting with a constellation of blastogenetic malformations strongly suggestive of VACTERL association. His mother was affected by insulin‐dependent diabetes since she was 7 years old and pregnancy history disclosed very high glucose and HbA1c levels, especially during the first 2 gestational months. CONCLUSIONS: In an attempt to properly counsel the parents, we reviewed the literature and identified four additional patients with VACTERL and first trimester exposure to maternal diabetes mellitus. Although this evidence does not strongly support a causal relationship between these two conditions, additional arguments may substantiate this hypothesis. The pathogenesis of diabetic embryopathy in relation to the VACTERL phenotype is also discussed. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

Anorectal anomalies, diaphragmatic defect, cleft palate, lower lip pits, hypopigmentation and hypogammaglobulinemia A in Kabuki syndrome: a rare combination

We report a rare combination of anomalies in an Egyptian girl with Kabuki syndrome (KS). The 26-month-old girl had imperforate anus with rectovestibular fistula, diaphragmatic defect, congenital heart defects, cleft palate, lower lip pits, hypopigmentation, seizures, hypogammaglobulinemia A, hyperlaxity of joints and premature breast development. This unique combination of anomalies, proposes to carefully investigate cases with KS patient in an attempt to determine their real frequency and in order to improve clinical management. Further, it raises a question about factors determining the variability in phenotypic expression among cases with KS. To our knowledge, this is the first case of KS to be reported from Egypt.     

Unusual presentation of biliary atresia splenic malformation syndrome with autosomal dominant hypospadias

Biliary atresia is associated with polysplenia in 2-10% of cases and is defined as Biliary Atresia Splenic Malformation syndrome (BASM). The main features of BASM syndrome include extrahepatic biliary atresia and polysplenia besides the characteristic findings of laterality anomalies, cardiac anomalies, intraabdominal vascular anomalies, pancreatic anomalies and malrotation. Here we present a 6-month-old male patient with BASM having atrial septal defect, umblical hernia, inguinal hernia, and hypospadias. Clinical history revealed that his father also had hypospadias which showed a rare form of autosomal dominant inheritance. The karyotype was normal and the molecular analysis of CFC1 gene revealed no mutation. We emphasize the importance of a detailed physical examination in cases with BASM.     

Histological study of timing and embryology of notochordal abnormalities in rat exposed in utero to Doxorubicin

Experimental Doxorubicin-exposure in utero is correlated with foetal oesophageal atresia, tracheo-oesophageal fistula, axial alterations. While gastrointestinal and respiratory defects have been largely investigated, only sporadic data have been published to date on notochordal and vertebral defects. The aim of this work was the study of the genesis of chordal and vertebral abnormalities in rat embryos and foetuses exposed to Doxorubicin and the study of their correlation with oesophageal and tracheal defects. For this purpose, pregnant rats were i.p. injected with saline (control) or with 4 mg/Kg b.w. Doxorubicin on days 9.5 and 10.5 of gestation. Embryos and foetuses were morphologically analysed on days 10.5-15 and 16, 18, 20 of gestation respectively, fixed in formaldehyde and histologically processed. Slides were routinely stained with haematoxylin-eosin (11-15 days post coitum embryos and all foetuses) or specifically stained with aniline blue for the staining of basal laminae (10.5 days post coitum embryos). Moreover, some foetuses at term (20 days post coitum) were processed for bone and cartilage staining. The data obtained in the present work confirm the specificity of Doxorubicin in inducing gastro-intestinal and tracheal defects, describe the genesis of these defects step by step, describe the type and the genesis of notochordal abnormalities and their fate and exclude the role of Doxorubicin in inducing axial skeletal malformations.     

Anomalies of the forebrain with radial limb defects: Garcia‐Lurie‐Steinfeld syndrome?

BACKGROUND: Severe anomalies of the forebrain together with radial limb anomalies have been reported in Steinfeld syndrome, XK aprosencephaly, and partial monosomy 13q. Steinfeld syndrome is an extremely variable autosomal dominant condition that, in severe cases, is characterized by holoprosencephaly, radial limb defects, and renal and/or cardiac defects. In mild cases there may be only thumb hypoplasia, ocular coloboma, or oral clefts. XK aprosencephaly, also called Garcia-Lurie syndrome (GLS), is a usually sporadic disorder with radial limb defects and aprosencephaly/atelencephaly. Based on two atypical sibships, autosomal recessive inheritance has been suggested. Two patients with variations of monosomy 13q have been described with atelencephaly but, generally, Steinfeld and XK aprosencephaly patients are chromosomally normal. Holoprosencephaly in 13q deletion patients appears to be due to ZIC2 mutations, but ZIC2 has not been previously tested in Steinfeld syndrome or GLS patients. CASES: We report three sporadic cases with clinical features intermediate between Steinfeld and GLS, including severe forebrain malformations and radial limb defects. All had normal karyotypes, and mutations in ZIC2 were absent in the two cases tested. CONCLUSIONS: In our cases and in the literature there is significant clinical overlap between Steinfeld syndrome and GLS. We propose these conditions may not be nosologically or etiologically distinct. The spectrum of severe forebrain anomalies in these conditions is broader than previously thought and may include some neural tube defects. Mild cases are difficult to identify and the full range of expression remains unknown. Autosomal dominant inheritance with incomplete penetrance and frequent new mutations is postulated. Thorough clinical evaluation is recommended for children with severe forebrain and radial limb defects.     

Additive effect of TAp63 deficiency on the adrenocortical dysplasia (acd) phenotype

Adrenocortical dysplasia (acd) is a spontaneous autosomal recessive mouse mutation exhibiting caudal truncation, vertebral segmentation defects, hydronephrosis, limb hypoplasia, and perinatal lethality. Acd encodes TPP1, a component of the shelterin complex that maintains telomere integrity, and consequently acd mutant mice have telomere dysfunction and genomic instability. We previously showed that apoptosis is the primary mechanism causing the acd skeletal phenotype, and that p53 deficiency rescues the skeletal defects of the acd phenotype but has no effect on the perinatal lethality. The Trp63 gene encodes multiple isoforms, which play a role in proliferation, apoptosis, and stem/progenitor cell maintenance. Different p63 isoforms exhibit both proapoptotic (TAp63) and antiapoptotic (ΔNp63) functions. We hypothesized that deficiency of proapoptotic TAp63 isoforms might rescue the acd skeletal phenotype, similar to our previous observations with deficiency of p53. Mice heterozygous for a null allele of TAp63 were crossed to heterozygous acd mice to determine the effect of TAp63 deficiency on the acd mutant phenotype. In contrast to our results with the acd?×?p53 cross, skeletal anomalies were not rescued by deficiency of TAp63. In fact, the limb and vertebral anomalies observed in double-mutant embryos were more severe than those of embryos with the acd mutation alone, demonstrating a dose-dependent effect. These studies suggest that TAp63 isoforms do not facilitate p53-like apoptosis during development in response to acd-mediated telomere dysfunction and are consistent with the proposed roles of TAp63 in maintaining genomic stability.     

Duane anomaly, meningomyelocele, dextroposition of heart and localized vertebrocostal alterations with associated anomalies in a girl

Vertebral and rib anomalies occur because of defects at different stages of embryo development and result in different malformations. Developmental field defects are the term to describe the alterations in the biological units which occur because of defects in the pattern formation. Short trunk dwarfism associated with vertebral and rib anomalies is one of the well-known conditions described under various names. Here we report on a 20-month-old female with short trunk dwarfism involving an asymmetrically malformed thorax with kyphoscoliosis presenting skeletal anomalies of spine and ribs and additional multiple associated anomalies such as downslanting palpebral fissures, long philtrum, high palate, rocker bottom feet, dextroposition of heart, cascade stomach, retroposition of bulbi duodeni and bilateral renal cortical thinning. Ophthalmological examination revealed Duane anomaly. No mutation was detected in the analysis of the DLL3 gene. The malformations in the patient are related to different progenitor fields in the early development of the embryo and the presented combination of Duane anomaly with the associated anomalies has not been reported in the literature.     

Dystrophic Spinal Deformities in a Neurofibromatosis Type 1 Murine Model

Despite the high prevalence and significant morbidity of spinal anomalies in neurofibromatosis type 1 (NF1), the pathogenesis of these defects remains largely unknown. Here, we present two murine models: Nf1^flox/−;PeriCre and Nf1^flox/−;Col.2.3Cre mice, which recapitulate spinal deformities seen in the human disease. Dynamic histomorphometry and microtomographic studies show recalcitrant bone remodeling and distorted bone microarchitecture within the vertebral spine of Nf1^flox/−;PeriCre and Nf1^flox/−;Col2.3Cre mice, with analogous histological features present in a human patient with dystrophic scoliosis. Intriguingly, 36–60% of Nf1^flox/−;PeriCre and Nf1^flox/−;Col2.3Cre mice exhibit segmental vertebral fusion anomalies with boney obliteration of the intervertebral disc (IVD). While analogous findings have not yet been reported in the NF1 patient population, we herein present two case reports of IVD defects and interarticular vertebral fusion in patients with NF1. Collectively, these data provide novel insights regarding the pathophysiology of dystrophic spinal anomalies in NF1, and provide impetus for future radiographic analyses of larger patient cohorts to determine whether IVD and vertebral fusion defects may have been previously overlooked or underreported in the NF1 patient population.