A number sign (#) is used with this entry because of evidence that X-linked diaphragmatic hernia-5 (DIH5) is caused by hemizygous or heterozygous mutation in the PLS3 gene (300131) on chromosome Xq23.

Diaphragmatic hernia-5 (DIH5) is an X-linked disorder characterized by congenital diaphragmatic hernia (CDH), diaphragmatic agenesis, and abdominal wall defects. The disorder is usually transmitted in an X-linked recessive pattern with males being severely affected; many die in early childhood. Although the diaphragmatic features are variable, posterolateral diaphragmatic defects are common. Additional features include hypertelorism, sometimes with more severe dysmorphic facial features, and some affected males may show genitourinary, cardiac, pulmonary, or neurodevelopmental abnormalities. Most carrier females show hypertelorism, although a few have mild abdominal wall defects. Some of the features of DIH5 overlap with those of the X-linked disorder thoracoabdominal syndrome (THAS; 313850) (Petit et al., 2023).

For a discussion of genetic heterogeneity of congenital diaphragmatic hernia (CDH), see DIH1 (142340).

Petit et al. (2023) reported 22 patients, including 21 males and 1 female, from 8 unrelated families with congenital diaphragmatic hernia. Twelve male patients died of the disorder, although only 6 of these individuals were confirmed to carry a hemizygous PLS3 mutation. Family 1 was a large European family with 8 affected males and several mildly affected females. Most affected males died of diaphragmatic weakness and respiratory failure; 1 affected pregnancy was terminated. Affected males also showed hypertelorism. One living affected male had a supraumbilical abdominal hernia, but no diaphragmatic anomalies. He also had hypertelorism, high bone mineral density, and genu valgum. Two other living affected males in this family with an unknown genotype had intellectual disability. In this family, 8 female mutation carriers had hypertelorism, but only 2 had supraumbilical abdominal hernias. Affected males and carrier females in the other 7 smaller families showed similar features. These included unspecified CDH, left posterolateral CDH, right CDH, diaphragmatic agenesis, diaphragmatic eventration, and left/right/ventral CDH with hernia sac. Body-wall defects included supraumbilical abdominal hernia or muscle deficiency, umbilical hernia, omphalocele, and skin-covered abdominal-wall defect. Two living male patients had more complex dysmorphic features, including hypertelorism, prominent forehead, flattened nasal bridge, wide nasal root, anteverted nares, downslanting palpebral fissures, low-set ears, micrognathia, widely spaced teeth, and high-arched palate. Some affected males had additional rare findings, including dextrocardia, cardiac septal defects, lung segmentation defects, bicuspid aortic valve, choroid cysts, cystic hygroma, hydronephrosis, renal pelvis dilation, ureteral abnormalities, cryptorchidism, and 2-vessel umbilical cord. Six affected males (including 4 in family 1) were noted to have neurodevelopmental abnormalities, including intellectual disability, hypotonia, seizures, and hypoplasia of the corpus callosum. One of these patients had impaired intellectual development, speech delay, autism, seizures, dilated lateral ventricles, sensorineural hearing loss, and nystagmus. Most female carriers had hypertelorism, but none had neurodevelopmental abnormalities or other systemic features.

The transmission pattern of CDH5 in the families reported by Petit et al. (2023) was consistent with X-linked recessive inheritance; some carrier females showed mild features.

In affected males and several mildly affected or unaffected female carriers from 8 unrelated families with DIH5, Petit et al. (2023) identified hemizygous (in males) or heterozygous (in females) missense mutations in the PLS3 gene (see, e.g., E270K, 300131.0004; W499C, 300131.0005; and M592V, 300131.0006). The mutations, which were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families, with incomplete penetrance in heterozygous female carriers. None of the variants was present in the gnomAD database. All mutations occurred at conserved residues in one of the 2 actin-binding domains (ABD1 or ABD2), and were not predicted to cause a conformational change in the protein. Molecular modeling predicted that most of the mutations could alter actin binding. Functional studies of the variants and studies of patient cells were not performed, but a knockin mouse model with the W499C mutation recapitulated clinical features of the disorder (see ANIMAL MODEL). The authors concluded that these mutations affect the plastin-actin interaction in a way that affects critical cellular processes during development, possibly through a gain-of-function effect.

Petit et al. (2023) generated 2 Pls3 mutant mouse models: a knockin strain expressing the missense W499C mutation (300131.0005) observed in a family with DIH5, and a strain carrying a 14-bp deletion causing a loss-of-function effect. Hemizygous W499C male mice and homozygous W499C female mice showed increased death within the first 2 days of life, whereas mice with the deletion mutation were viable and fertile. W499C mutant mice displayed diaphragmatic abnormalities and anterior body-wall defects late in gestation and in the neonatal period, including amuscular diaphragmatic regions at the posterolateral edge and anterior region and anterior wall defects, both with reduced penetrance. These amuscular regions had a thin layer of connective tissue reminiscent of a sac-type hernia in humans. Less commonly, complete holes in the diaphragm with herniation of the liver were observed. Abdominal wall defects included omphalocele and thinning of the abdominal wall muscles. These defects were not observed in mice with the 14-bp deletion mutation. W499C mice did not show major lung abnormalities, and fibroblasts from these animals did not show structural abnormalities of the actin cytoskeleton or defects in wound healing. W499C mice had increased bone mineral density compared to controls, whereas mice with the 14-bp deletion had lower bone mineral density. The authors hypothesized that the W499C mutation may cause abnormal plastin-actin interactions and possibly have a gain-of-function effect, whereas Pls3 loss-of-function variants cause osteoporosis without defects in body-wall development (see BMND18, 300910).

Lilly et al. (1974) described a family in which 2 brothers and their maternal uncle had congenital, anterior diaphragmatic hernia. Two of the 3 died in infancy of complications.

Crane (1979) favored multifactorial inheritance with high male:female sex ratio. Twelve multiplex families were analyzed.