Etiologic complexities of diaphragmatic defects: Right diaphragmatic hernia,pulmonary hypoplasia/agenesis,and hydrocephalus in sibs

Here we review the complexities of diaphragmatic defects and describe sibs with small, right diaphragmatic defects with pulmonary hypoplasia/agenesis and hydrocephalus. Despite a poor initial prognosis, the propositus has progressed remarkably well. Antenatal sonographic study detected hydrocephalus but not the diaphragmatic defect in the sib of the propositus. Because diaphragmatic defects are most commonly found in association with other anomalies and may occur in association with chromosome anomalies careful workup of all affected infants is crucial for accurate genetic counseling.     

Anencephaly with diaphragmatic hernia in sibs.

Two sibs who both had anencephaly and diaphragmatic hernia are reported. The type of diaphragmatic defect seen in anencephaly may differ from the defect seen in other babies. It is important to perform a necropsy in anencephaly.     

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.     

Discordant, non-syndromic, congenital diaphragmatic defects in sibs.

We report an Arab sibship of two brothers with non-syndromic, congenital diaphragmatic defects (CDD). The first had an extensive, left, Bochdalek-type hernia and the second hemidiaphragmatic agenesis; these were verified by surgical exploration and necropsy respectively. The parents are healthy second cousins. Other reported discordant cases of CDD are briefly reviewed.     

Dual-hit hypothesis explains pulmonary hypoplasia in the nitrofen model of congenital diaphragmatic hernia

Pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH) remains a major therapeutic problem. Moreover, the pathogenesis of pulmonary hypoplasia in case of CDH is controversial. In particular, little is known about early lung development in this anomaly. To investigate lung development separate from diaphragm development we used an in vitro modification of the 2, 4-dichlorophenyl-p-nitrophenylether (Nitrofen) animal model for CDH. This enabled us to investigate the direct effects of Nitrofen on early lung development and branching morphogenesis in an organotypic explant system without the influence of impaired diaphragm development. Epithelial cell differentiation of the lung explants was assessed using surfactant protein-C and Clara cell secretory protein-10 mRNA expression as markers. Furthermore, cell proliferation and apoptosis were investigated. Our results indicate that Nitrofen negatively influences branching morphogenesis of the lung. Initial lung anlage formation is not affected. In addition, epithelial cell differentiation and cell proliferation are attenuated in lungs exposed to Nitrofen. These data indicate that Nitrofen interferes with early lung development before and separate from (aberrant) diaphragm development. Therefore, we postulate the dual-hit hypothesis, which explains pulmonary hypoplasia in CDH by two insults, one affecting both lungs before diaphragm development and one affecting the ipsilateral lung after defective diaphragm development.     

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.     

Down-regulation of sonic hedgehog expression in pulmonary hypoplasia is associated with congenital diaphragmatic hernia

The pathogenesis of pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH) is unknown. The sonic hedgehog (Shh) cascade is crucial for the patterning of the early respiratory system in mice. To establish whether Shh plays a role in the pathogenesis of lung hypoplasia in CDH, we investigated the gestation-specific expression of Shh in normal rat and human lungs using in situ hybridization and immunohistochemistry. The expression pattern was compared with that of age-matched samples of hypoplastic lungs associated with CDH in humans and in the 2,4-dichlorophenyl-p-nitrophenylether (nitrofen) rat model. Our results showed that in normal controls the expression of Shh increased with advancing gestation, peaked in the late pseudoglandular stage, and declined thereafter. The expression of Shh is initially down-regulated in pulmonary hypoplasia associated with CDH and peaks instead during the late canalicular stage. These data indicate that maximal expression of Shh occurs when respiratory bronchioles develop and thinning of the interstitium takes place, suggesting that Shh may play a role in these processes. Furthermore, we observed that Shh inhibited fetal lung fibroblast proliferation in vitro. Therefore, it is tempting to speculate that alterations in Shh expression may affect these developmental processes, thereby contributing to the pulmonary abnormality in CDH.     

Congenital diaphragmatic hernia associated with ipsilateral upper limb reduction defects: report of a case with thumb hypoplasia.

Four unrelated cases of congenital diaphragmatic hernia associated with ipsilateral upper limb reduction defects were reported by McCredie and Reid in 1978 (J Pediatr 92: 762-765). As contiguous segments of the cervical neural crest are involved in the development of diaphragm and arms, the authors suggested that an early injury to the cervical neural crest might be the common underlying pathogenesis. We describe here a further example of this malformation complex: a newborn with a left posterolateral diaphragmatic hernia associated with ipsilateral thumb hypoplasia.     

Recurrent tetraamelia and pulmonary hypoplasia with multiple malformations in sibs

A term amelic female infant was born to an apparently nonconsanguineous Arab Moslem couple. This was followed by the birth of 4 normal children. Afterwards, in 2 subsequent pregnancies, 2 amelic fetuses were diagnosed by transabdominal ultrasonography in the 18th and 12th week of gestation. Pregnancies were terminated and on autopsy both amelic fetuses had severe lung hypoplasia and aplasia of the peripheral pulmonary vessels. The first fetus also had apparently low-set ears and micrognathia, whereas the last had hydrocephaly and left cleft lip beside the lung hypoplasia and aberrant pulmonary artery. This appears to be a new autosomal recessive malformation syndrome.     

新生儿先天性膈疝并肺发育不良1例

患者为女婴,妊娠40周于2004年5月27日16时经剖宫产术娩出.胎儿娩出后逐渐出现呼吸困难,皮肤发绀,肌张力减弱,阿氏评分8-6-6.立即给予加压给氧、气管插管、脐静脉推注0.1%盐酸肾上腺素、胸外按压等治疗,经抢救无效死亡。     

Lung development and implications for hypoplasia found in congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) is associated with various degrees of pulmonary hypoplasia and severe persistent pulmonary hypertension in the newborn. These conditions have significant implications for the outcome for the patient. Defects in early lung development are likely to be central to the generation of hypoplasia. A number of mouse models with defects in pathways that are central to lung development were found to have CDH. Understanding all aspects of early lung development will provide fresh insight into the pathogenesis of CDH and its associated conditions.     

The PDAC syndrome (pulmonary hypoplasia/agenesis, diaphragmatic hernia/eventration, anophthalmia/microphthalmia, and cardiac defect) (Spear syndrome, Matthew-Wood syndrome): report of eight cases including a living child and further evidence for autosomal recessive inheritance

The combination of pulmonary agenesis/dysgenesis/hypoplasia, microphthalmia/anophthalmia, and a diaphragmatic defect (agenesis or eventration) is a rare syndrome presumed to have an autosomal recessive mode of inheritance based on a report of affected siblings born to unaffected parents [Seller et al., 1996]. The condition is known as Spear syndrome and Matthew-Wood syndrome, although genetic heterogeneity cannot be ruled out. We report on eight patients with this condition including a living child, three sibs and three isolated cases. Most presented with fetal ultrasound findings of microphthalmia/anophthalmia, and diaphragmatic eventration/hernia and in five, cardiac abnormalities were also found. The earliest detection was at 20 weeks gestation. This is the second report of sibs affected with this condition, which supports an autosomal recessive mode of inheritance. We present the first and only reported living patient with this condition and expand the intrafamilial, interfamilial, and ethnic variability of this condition. We suggest changing the condition's name to PDAC to reflect the most important components of this condition.     

Unknown syndrome: radial ray defects, omphalocele, diaphragmatic hernia, and hepatic cyst

We present a male infant with a giant omphalocele, diaphragmatic hernia, hepatic cyst, bilateral radioulnar synostosis, absent left thumb, and triphalangeal right thumb.     

Unusual association of two unilateral anomalies present in adulthood: pulmonary hypoplasia and renal agenesis

Summary We report a case of pulmonary hypoplasia associated with renal agenesia diagnosed in a 46-year-old woman admitted to hospital because of a viral pleuro-pericarditis. The chest x-ray raised the suspicion of left pulmonary hypolasia. The CT scan and the Magnetic Resonance Image confirmed the presence of the congenital lung malformation and detected the absence of the left kidney. The clinical presentation, radiological diagnosis and embryological basis are described.

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Association inhabituelle de deux anomalies unilatérales chez l'adulte : hypoplasie pulmonaire et agénésie rénale. Aspects embryologique et clinique

Résumé Nous présentons un cas d'hypoplasie pulmonaire associée à une agénésie rénale diagnostiquées chez une femme de 46 ans admise à l'hôpital pour une pleuro-péricardite virale. Le cliché radiologique du thorax fait suspecter une hypoplasie pulmonaire gauche. La tomodensitométrie et l'image par résonance magnétique nucléaire confirment la présence d'une malformation pulmonaire et montrent l'absence du rein gauche. La présentation clinique, le diagnostic radiologique et les bases embryologiques sont décrites.

     

Sensorineural hearing loss,enamel hypoplasia,and nail abnormalities in sibs

A brother and sister born to normal, nonconsanguineous parents have a syndrome of profound sensorineural hearing deficiency, enamel hypoplasia limited to the permanent dentition, and nail abnormalities. This appears to be a previously unreported inherited syndrome.     

The Fryns syndrome: diaphragmatic defects, craniofacial dysmorphism, and distal digital hypoplasia Further evidence for autosomal recessive inheritance

A further example of the Fryns syndrome is reported. The female infant presented a malformation syndrome with coarse facies including cleft lip and palate, distal limb hypoplasia, a diaphragmatic defect, and excessive body hair, most pronounced on the face. She died 5 days after birth. Consanguinity in the parents supports the hypothesis of autosomal recessive inheritance. Considering the severity of the internal malformations and the poor prognosis of this syndrome, prenatal ultrasound diagnosis in the 2nd trimester of pregnancies at risk should be attempted.