Intestinal Pseudoobstruction, Neuronal, Chronic Idiopathic, X-Linked

A number sign (#) is used with this entry because of evidence that the disorder can be caused by mutation or duplication in the gene encoding filamin A (FLNA; 300017).

Description

Chronic idiopathic intestinal pseudoobstruction (CIIP) is caused by severe abnormality of gastrointestinal motility. Patients have recurrent symptoms and signs of intestinal obstruction without any mechanical lesion (Auricchio et al., 1996).

Some primary forms of CIIP are caused by defects of enteric neuronal cells: see Hirschsprung disease (see, e.g., HSCR1; 142623) and autosomal recessive visceral neuropathy (243180) (Tanner et al., 1976).

Clinical Features

FitzPatrick et al. (1997) reported 2 brothers and a maternal uncle with CIIP. All 3 had a patent duct arteriosus (see 607411), an association which FitzPatrick et al. (1997) pointed out had been reported by Harris et al. (1976). The 2 brothers had chronic thrombocytopenia with large platelets which, again, FitzPatrick et al. (1997) reported was described by Pollock et al. (1991) in association with CIIP. The 2 brothers had mild facial dysmorphism. One of the brothers and maternal uncle had gut malrotation, which FitzPatrick et al. (1997) noted was present in the cases described by Harris et al. (1976), Pollock et al. (1991), and in some members of the Italian family described by Auricchio et al. (1996). FitzPatrick et al. (1997) suggested that gut malrotation may be a useful phenotypic marker for an X-linked form of CIIP. FitzPatrick et al. (1997) concluded that the additional clinical features in this family may be the result of an Xq28 microdeletion, or that the CIIPX gene may have a role in developmental regulation of multiple systems, with different mutations causing a different spectrum of abnormalities.

Gargiulo et al. (2007) described an affected male in the Italian family with X-linked chronic idiopathic intestinal pseudoobstruction reported by Auricchio et al. (1996). The patient presented at 3 days of life with bilious vomiting, and laparotomy showed a short small bowel with intestinal malrotation, pyloric hypertrophy, and an ileal volvulus. Fifteen days later, he required additional surgery for intestinal obstruction, and an ileostomy was created. Other surgical procedures were required including an ileorectal anastomosis to restore bowel continuity at age 3 years. In addition to the severe CIIP, by age 7 years, an asymmetric spastic diplegia with impairment of fine finger movements became apparent. MRI of the brain showed an abnormal intermediate signal in the peritrigonal white matter. The patient required lengthening operations for both Achilles tendons. He also had seizures, the first time after surgery during his first month of life, then again at ages 8 and 18 years. He required supplemental parenteral nutrition to maintain good health. Of the 10 affected males in 4 generations in this family, all except this patient died in the first months of life.

Congenital Short Bowel Syndrome

Kern et al. (1990) reported a nonconsanguineous Italian family in which 3 male sibs were born with a short small bowel, malrotation, and functional bowel obstruction. One child was a long-term survivor. Two of the sibs presented with bilious vomiting at 1 month and 6 days of age, respectively; the latter sib passed frank blood rectally. Both had midgut volvulus. Length of the small intestine in the first sib was 112 cm from the ligament of Trietz to the ileocecal valve. The second sib required resection of a 15-cm necrotic segment of jejunum, after which the remaining small bowel measured only 55 cm from the ligament of Trietz to the ileocecal valve. Both of these sibs died in infancy. The third sib was the second male child of the couple. He presented at 3 months of age with failure to thrive, but had a formula change and did well. Following the birth of his younger brother he was reinvestigated and found to have a malrotation, for which the parents refused surgical treatment. At age 14 he had developed partial duodenal and jejunal obstruction. At laparotomy, the small intestine was found to be short (235 cm from ligament of Trietz to the ileocecal valve), dilated, and thick-walled. After Ladd's procedure and a second laparotomy, the patient was well for the subsequent 3 years.

Siva et al. (2002) reported a 35-year-old male with synovial lipomatosis and congenital short bowel syndrome. At 15 years of age the length of his small intestine was found to be 90 inches, about one-third of normal. At more than 40 years of age, the patient was doing well and the arthropathy had resolved spontaneously (van der Werf et al., 2013).

Cytogenetics

Clayton-Smith et al. (2009) reported 20 males from 10 families with intestinal pseudoobstruction associated with duplications of chromosome Xq28 including the FLNA gene. The duplication was restricted to the FLNA gene alone in 2 families, including the family reported by FitzPatrick et al. (1997). The phenotype in these patients was restricted to intestinal pseudoobstruction, patent ductus arteriosus, and thrombocytopenia with giant platelets. None of these patients had mental retardation, spasticity, or chest infections, although some had mild facial dysmorphism. The Xq28 duplication was larger in the remaining 8 families reported by Clayton-Smith et al. (2009), and may have included the MECP2 (300005), SLC6A8 (300036), L1CAM (308840) genes in addition to FLNA, although detailed mapping was not reported. The phenotype in all patients with larger Xq28 duplications included pseudoobstruction with severe constipation from infancy and clearly dysmorphic facies. Other common but variable features included recurrent chest infections, mental retardation, some evidence of periventricular nodular heterotopia or abnormalities of the corpus callosum, hypotonia, and spasticity. Many of these features overlapped with that of the MECP2 duplication syndrome (300260). Clayton-Smith et al. (2009) also commented on a facial phenotype associated with Xq28 duplications: a narrow pinched appearance of the nose, deep-set eyes, prominent chin, small everted lower lip, and flat nasal bridge. The authors concluded that involvement of the FLNA gene was responsible for intestinal pseudoobstruction in these patients.

Mapping

Auricchio et al. (1996) described a family in which the disorder appeared to be segregating as an X-linked recessive trait and in which they were able to map the disease locus (symbolized CIIPX by them) to Xq28. The microsatellite marker DXYS154, located in the distal part of Xq28, showed no recombination with a maximum lod score of 2.32. Multipoint analysis excluded linkage with markers spanning other regions of the X chromosome. On the basis of analysis of recombinants, Auricchio et al. (1996) concluded that the critical region for the disease gene is limited by DXS15 toward the centromere and by the pseudoautosomal boundary toward the telomere. Auricchio et al. (1996) raised the intriguing hypothesis that CIIPX may represent an additional susceptibility locus in Hirschsprung disease (142623). (Hirschsprung disease is the most common form of neuronal intestinal pseudoobstruction.) A higher penetrance of Hirschsprung disease has been observed in males compared to females in the case of both RET (164761) and EDNRB (131244) mutations (Badner et al., 1990).

In the family reported by them with CIIP, FitzPatrick et al. (1997) demonstrated cosegregation of a maternal grandmaternal Xq28 haplotype with the disease by DNA analysis of the brothers, their unaffected mother, and maternal grandmother using markers DXS1108, DXS15, F8C, and DXYS154.

Molecular Genetics

To select candidate genes for the CIIP in the Italian family of Auricchio et al. (1996), Gargiulo et al. (2007) analyzed the expression in murine fetal brain and intestine of 56 genes from the critical region. They selected and sequenced 7 genes and found that 1 affected male from the Italian kindred bore a 2-bp deletion in exon 2 of the FLNA gene that was present in heterozygous state in the carrier females of the family (300017.0025).

Because X-linked dominant nodular ventricular heterotopia (PVNH; 300049), a central nervous system migration defect that presents with seizures in females and lethality in males, has been associated with loss-of-function FLNA mutations, Gargiulo et al. (2007) considered it notable that the male bearing the FLNA mutation had signs of central nervous system (CNS) involvement and possibly PVNH. They noted that, different from the male with PVNH and constipation described by Hehr et al. (2006) (see 300017.0024), the phenotype in the family originally described by Auricchio et al. (1996) was most distinguished by severe CIIP, present at birth, that was lethal unless promptly corrected by surgery.

Congenital Short Bowel Syndrome

Van der Werf et al. (2013) reported that the sibs reported by Kern et al. (1990) and the unrelated singleton reported by Siva et al. (2002) with X-linked congenital short bowel syndrome all had the same 2-basepair deletion in FLNA (300017.0035). In the family, all obligate carriers were heterozygous for the mutation; in the isolated male, the mutation had occurred as a de novo event. Van der Werf et al. (2013) stated that they could not exclude involvement of the central nervous system in these patients because no magnetic resonance imaging brain scans were available.