Congenital diaphragmatic hernia in the Brachmann-de Lange syndrome

We present 12 children with typical Brachmann-de Lange syndrome and congenital diaphragmatic hernia. Affected children were more likely to be of low birth weight and to have major upper limb malformations. Hernia repair was attempted in 4 of these children, and only one survived past 12 months, Newborn infants with congenital diaphragmatic hernia should be examined carefully for evidence of the Brachmann-de Lange syndrome because diagnosis of thes condition may influence their clinical management and prognosis. © 1993 Wiley-Liss, Inc.     

Congenital diaphragmatic hernia in older children

The incidence of congenital diaphragmatic hernia (CDH) is about 4.8/10,000 live births. Its typical clinical presentation is respiratory distress occurring immediately after birth or in the first few hours or days of a child's life. It is characterized by a high mortality rate. Exceptionally, CDH can occur at an older age, its symptoms then frequently reflecting gastrointestinal obstruction or mild respiratory symptoms. In such cases CDH presents a far more complex diagnostic problem. The paper presents the cases of two girls without typical symptomatology, aged 5.5 and 10 years, in whom CDH was detected incidentally upon thorough physical examination and chest x-rays. Further radiographic evaluation, which included barium contrast study and spiral computed tomography, confirmed the suspicion of a left-sided posterolateral diaphragmatic hernia with associated intestinal malrotation. Surgical intervention conclusively confirmed a diaphragmatic defect at the site of Bochdalek's foramen in both cases. The vital capacity of the older girl, which was low before the surgery (VC 1.66 L; 69% of predicted), was significantly increased a month after the surgical treatment (VC 2.25 L; 92% of predicted). The generally expressed view that the clinical onset of CDH is rare after the neonatal period seems to be erroneous. Some papers report on the clinical presentation of CDH after the neonatal period in as many as 13%-14% of infants and young children suffering from CDH. Infants and young children with a delayed clinical occurrence of CDH can present with respiratory or gastrointestinal symptomatology. Children presenting with gastrointestinal symptoms have been shown to be significantly older than those presenting with respiratory symptoms. In older children and adolescents, the symptoms and signs of CDH, which include acute hernial incarceration, nausea, recurrent vomiting, diarrhea, obstipation, acute gastric dilatation, subcostal pain, failure to thrive and recurrent chest infections, habitually present a significant diagnostic problem. Diagnostic errors are mainly due to the fact that the possibility of CDH in that age is totally neglected. The most recurrent diagnostic misinterpretations in such cases are pneumonia or massive pleuropneumonia, empyema, pneumothorax, lung cysts and bullae, and gastric volvulus. Thus, whenever a child presents with uncommon respiratory or gastrointestinal symptoms and an anomalous chest x-ray, a differential diagnosis of CDH should be considered. Otherwise, an accurate diagnosis in both young and older children will most probably be only reached at autopsy. In conclusion, the presented cases corroborate the finding that CDH in older children may present with scarce symptoms, mostly gastrointestinal, or may be altogether asymptomatic and unrecognized until as late as adolescence. However, when a diagnosis of CDH has been established, albeit asymptomatic, it must be promptly treated surgically in order to prevent complications, such as strangulation or bowel perforation, and thus avert a potentially fatal outcome. The size itself of the herniac foramen is unlikely to be a determining factor at the time of clinical presentation of CDH. Surgical occlusion of CDH may in older children result in an improved vital capacity, as such cases are rarely associated with major pulmonary hypoplasia. Complications resulting from surgical treatment of CDH in older children are more likely to occur in the gastrointestinal system, as a consequence of the associated bowel malrotation and inadequate bowel fixation. Finally, these two cases corroborate the diagnostic value of accurate history taking and thorough physical examination.     

Congenital diaphragmatic hernia in half sibs.

Half brothers from the same mother had congenital left sided posterolateral diaphragmatic hernias repaired in the neonatal period. The inheritance of diaphragmatic hernia should probably be based on the multifactorial hypothesis.     

Congenital diaphragmatic hernia in Coffin Siris syndrome: Further evidence from two cases

Coffin-Siris Syndrome (CSS) is a rare multi-system dominant condition with a variable clinical presentation mainly characterized by hypoplasia/aplasia of the nail and/or distal phalanx of the fifth digit, coarse facies, hirsutism/hypertrichosis, developmental delay and intellectual disability of variable degree and growth impairment. Congenital anomalies may include cardiac, genitourinary and central nervous system malformations whereas congenital diaphragmatic hernia (CDH) is rarely reported. The genes usually involved in CSS pathogenesis are ARID1B (most frequently), SMARCA4, SMARCB1, ARID1A, SMARCE1, DPF2, and PHF6. Here, we present two cases of CSS presenting with CDH, for whom Whole Exome Sequencing (WES) identified two distinct de novo heterozygous causative variants, one in ARID1B (case 1) and one in SMARCA4 (case 2). Due to the rarity of CDH in CSS, in both cases the occurrence of CDH did not represent a predictive sign of CSS but, on the other hand, prompted genetic testing before (case 1) or independently (case 2) from the clinical hypothesis of CSS. We provide further evidence of the association between CSS and CDH, reviewed previous cases from literature and discuss possible functional links to related conditions.     

Congenital diaphragmatic hernia is part of the new 15q24 microdeletion syndrome

The recurrent microdeletion 15q24 syndrome is rare with only 5 cases reported thus far. Here we describe an additional patient with this deletion, presenting with many features common to this syndrome, including developmental delay, loose connective tissue, digital and genital anomalies and a distinct facial gestalt. Interestingly, in addition, this patient has a large congenital diaphragmatic hernia, as was described in one other patient with a 15q24 microdeletion, indicating that this feature might be part of the syndrome. Chromosome 15q24 has a highly polymorphic architecture that is prone to genomic rearrangements underlying this novel microdeletion syndrome.     

Congenital diaphragmatic hernia, coarse facies, and acral hypoplasia: Fryns syndrome

We describe five patients with Fryns syndrome. Four presented with diaphragmatic hernia and died in the neonatal period. One did not have diaphragmatic involvement and survived but is severely mentally retarded. All patients had "coarse" faces, microretrognathia, macrostomia, and distal digital hypoplasia. In addition to previously reported traits, our patients had clinical manifestations that have not previously been described, including omphalocele, broad clavicles, Hirschsprung "disease," and anal anomalies. The condition was detected antenatally in three of the cases. The patients include two sib pairs, further supporting autosomal recessive inheritance.     

Congenital diaphragmatic hernia and early lethality in PIGL-related disorder

We report on three male siblings who presented prenatally with a nearly identical combination of congenital anomalies and who died shortly after preterm birth. The first baby was a singleton pregnancy, and the other two babies were dichorionic diamniotic twins. Key features included: left-sided congenital diaphragmatic hernia, inferior vermian dysgenesis/hypoplasia, prenasal edema, cleft palate, micropenis/ambiguous genitalia (in 2 of 3 babies), bilateral renal pelvic dilatation (in twins, first baby showed slightly enlarged kidneys) and polyhydramnios (in 2 of 3). Whole genome sequencing performed on DNA from all three babies revealed homozygous missense PIGL gene variants: c.438C>A, p.(Phe146Leu). Both parents were heterozygous carriers of the variant. The reporting clinical laboratory classified the change as a variant of uncertain significance (VUS), and concluded “A genetic diagnosis of autosomal recessive CHIME syndrome is possible”. The PIGL gene has been reported to cause two different autosomal recessive conditions: CHIME syndrome and Mabry syndrome. CHIME (Zunich neuroectodermal syndrome) is characterized by ocular Colobomas, Heart defects, Ichthyosiform dermatosis, Mental retardation (intellectual disability), and Ear anomalies, including conductive hearing loss. Mabry [aka hyperphosphatasia mental retardation syndrome (HPMRS)] is characterized by severe developmental delay, moderate to severe intellectual disability, distinctive facial features, brachytelephalangy, increased serum levels of alkaline phosphatase (ALP), and recurrent seizures. Neonatal demise and lack of postmortem examination precluded assessment of some key features (including seizures, developmental delay, ALP levels, colobomas and deafness), but overlapping features observed included cleft palate, brain anomalies, genitourinary abnormalities and prenasal edema. Notably, diaphragmatic hernia is not a common feature of either condition, but is a cardinal feature of Fryns syndrome. The genetic etiology of Fryns syndrome has not been definitively established, although, much like CHIME and Mabry syndrome, can be caused by variants in glycosylphosphatidylinositol (GPI) anchor pathway genes. Our findings suggest further overlap between inherited GPI deficiencies, and possible expansion of the clinical phenotype of PIGL-related disorders to include prenatal presentations with congenital diaphragmatic hernia. Although reported as a VUS, we present phenotypic and familial segregation evidence that supports likely pathogenicity of the c.438C>A variant.     

Congenital diaphragmatic hernia in Smith-Magenis syndrome: a possible locus at chromosome 17p11.2

We report on a 7-month-old girl with Smith-Magenis syndrome (SMS) due to a 4.76-Mb deletion of 17p12-17p11.2 detected by array comparative genomic hybridization. She was also affected with a left-sided congenital diaphragmatic hernia (CDH) and cardiac anomalies including an atypical atrioventricular canal defect and a cleft mitral valve. To our knowledge, this is the first reported case of a patient with both SMS and CDH. There are numerous chromosomal regions in which duplications, deletions, inversions, or translocations have been associated with CDH, but none have previously been reported at or close to 17p11.2. We discuss candidate genes for the diaphragmatic defect in this patient. Our case demonstrates that it is important to consider the possibility of SMS in non-isolated cases of diaphragmatic hernia.     

Fryns syndrome without diaphragmatic hernia?

We report on a child with Fryns syndrome including lung hypoplasia, characteristic facial appearance, cleft palate, cardiac anomaly, distal limb abnormalities, absent nipples, bicornuate uterus and early death. In contrast to most patients with Fryns syndrome, diaphragmatic hernia was absent in our patient. However, the diaphragm was reduced to a fibrous web with reduced muscular component.     

Congenital diaphragmatic hernia associated with duplication of 11q23-qter

Congenital diaphragmatic hernia (CDH) is a relatively common birth defect with a high mortality. Although little is known about its etiology, there is increasing evidence for a strong genetic contribution. Both numerical and structural chromosomal abnormalities have been described in patients with CDH. Partial trisomy 11q and partial trisomy 22 associated with the common t(11;22) has been reported in several cases of CDH. It has been assumed that the diaphragmatic defect seen in these individuals was primarily due to duplication of material from chromosome 22q11. However, in this report we describe a family with a t(11;12) in which one of two brothers with partial trisomy 11q has a left sided posterolateral CDH. This is the second case of CDH in partial trisomy 11q due to an unbalanced translocation other than t(11;22). Using array-based comparative genomic hybridization and fluorescent in situ hybridization, we mapped the breakpoints in both brothers and their mother who is a balanced translocation carrier. Our results suggest that duplication of one or more genes on a approximately 19 Mb region of 11q23.3-qter predisposes to the development of CDH. These effects may be the primary cause of CDH in individuals t(11;22) or may be additive to effects from the duplication of chromosome 22 material. We also conclude that the partial trisomy 11q syndrome has a variable phenotype and that CDH should be added to the spectrum of anomalies that can be present in this syndrome.     

Simpson-Golabi-Behmel syndrome: Congenital diaphragmatic hernia and radiologic findings in two patients and follow-up of a previously reported case

This report suggests the association of congenital diaphragmatic hernia in Simpson-Golabi-Behmel syndrome by describing two unrelated males with this malformation. One male was the maternal half-nephew of our previously reported 8-year-old boy with this syndrome. Review of the skeletal roentgenograms of these 2 affected males, and those of the previously reported 8-year-old, documents flare of the iliac wings, narrow sacroiliac notches, and the presence of two carpal ossification centers as a newborn (“advanced bone age”). We also report the follow-up of the 8-year-old boy, now 16 years old, who continues to have significant overgrowth and speech, dental, developmental, and adjustment problems. © 1993 Wiley-Liss, Inc.     

Congenital diaphragmatic hernia (CDH) etiology as revealed by pathway genetics

Congenital diaphragmatic hernia (CDH) is a common birth defect with high mortality and morbidity. Two hundred seventy CDH patients were ascertained, carefully phenotyped, and classified as isolated (diaphragm defects alone) or complex (with additional anomalies) cases. We established different strategies to reveal CDH-critical chromosome loci and genes in humans. Candidate genes for sequencing analyses were selected from CDH animal models, genetic intervals of recurrent chromosomal aberration in humans, such as 15q26.1-q26.2 or 1q41-q42.12, as well as genes in the retinoic acid and related pathways and those known to be involved in embryonic lung development. For instance, FOG2, GATA4, and COUP-TFII are all needed for both normal diaphragm and lung development and are likely all in the same genetic and molecular pathway. Linkage analysis was applied first in a large inbred family and then in four multiplex families with Donnai-Barrow syndrome (DBS) associated with CDH. 10K SNP chip and microsatellite markers revealed a DBS locus on chromosome 2q23.3-q31.1. We applied array-based comparative genomic hybridization (aCGH) techniques to over 30, mostly complex, CDH patients and found a de novo microdeletion in a patient with Fryns syndrome related to CDH. Fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) techniques allowed us to further define the deletion interval. Our aim is to identify genetic intervals and, in those, to prioritize genes that might reveal molecular pathways, mutations in any step of which, might contribute to the same phenotype. More important, the elucidation of pathways may ultimately provide clues to treatment strategies.     

Traumatic diaphragmatic hernia

A review of ten years of experience with traumatic diaphragmatic hernia, an often-missed injury, is presented. The unusual occurrence of a right diaphragmatic hernia following blunt trauma, which occurred in one patient, prompted this retrospective review. A high index of suspicion is still a safeguard against missing this injury. The mechanism of diaphragmatic tear with blunt trauma is described and modes of diagnosis and treatment are discussed.