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COL1A1 Mutations Presenting as Descending Perineum Syndrome in a Young Patient With Hypermobility Syndrome

      Abstract

      A 22-year-old woman presented with 12 years of progressive constipation; she had increased joint flexibility, hyperextensible skin, and excessive perineal descent on examination. Radiological studies confirmed evidence of rectal evacuation disorder due to descending perineum syndrome, enterocele, and rectocele. In a wide genetic screen (∼611,000 single nucleotide polymorphisms), 4 variations were identified in COL1A1 gene ([rs72656352, Chr17: 50,185,535-50,185,539, deletion], [rs72654794, Chr17: 50,188,575, deletion], [rs72667023, Chr17: 50,198,170, deletion], [rs67828806, Chr17: 50,198,177 G→C]). These mutations result in an increase in the number of base pairs in the C′ end, as well as replacement of the glycine amino acid in the N′ end, leading to incomplete cleavage of procollagen by proteases and resulting in collagen weakness. Our observations suggest that COL1A1 gene mutations are plausible biological factors predisposing to descending perineum syndrome in association with joint hypermobility in this patient.

      Abbreviations and Acronyms:

      DPS (descending perineum syndrome), EDS (Ehlers-Danlos syndrome), JHS (joint hypermobility syndrome), MRI (magnetic resonance imaging), OI (osteogenesis imperfecta), SNP (single nucleotide polymorphism)
      Hereditary connective tissue disorders, including joint hypermobility syndrome (JHS), Ehlers-Danlos syndrome (EDS), and osteogenesis imperfecta (OI), are characterized by varying degrees of hyperextensible or fragile skin and joint hypermobility.
      Two case series from tertiary referral centers have identified constipation and defecatory disorders in patients with JHS or EDS hypermobility.
      • Nelson A.D.
      • Mouchli M.A.
      • Valentin N.
      • et al.
      Ehlers Danlos syndrome and gastrointestinal manifestations: a 20-year experience at Mayo Clinic.
      • Mohammed S.D.
      • Lunniss P.J.
      • Zarate N.
      • et al.
      Joint hypermobility and rectal evacuatory dysfunction: an etiological link in abnormal connective tissue?.
      One series demonstrated that 31% of patients with JHS had pelvic organ prolapse, 58% rectal prolapse, and 11% enterocele.
      • Mohammed S.D.
      • Lunniss P.J.
      • Zarate N.
      • et al.
      Joint hypermobility and rectal evacuatory dysfunction: an etiological link in abnormal connective tissue?.
      In the Mayo Clinic series of 378 patients with EDS with gastrointestinal symptoms, 39% presented with constipation, 18 of 30 patients who underwent anorectal manometry had rectal evacuation disorder, and 3% had rectocele on magnetic resonance imaging (MRI) defecography.
      • Nelson A.D.
      • Mouchli M.A.
      • Valentin N.
      • et al.
      Ehlers Danlos syndrome and gastrointestinal manifestations: a 20-year experience at Mayo Clinic.
      Although there is evidence of pelvic floor dysfunction in patients with the spectrum of hypermobility syndromes, there are no reports of association with descending perineum syndrome (DPS). Descending perineum syndrome presents initially with constipation secondary to more than 4 cm perineal descent and associated decrease in the rectoanal angle, preventing stool passage.
      • Parks A.G.
      • Porter N.H.
      • Hardcastle J.
      The syndrome of the descending perineum.
      Over time, the pudendal nerve may be damaged from the increased perineal descent, with stretch neuropathy and loss of innervation of the external anal sphincter and the puborectalis muscle.
      • Surrenti E.
      • Rath D.M.
      • Pemberton J.H.
      • Camilleri M.
      Audit of constipation in a tertiary referral gastroenterology practice.
      When this occurs, patients with DPS may experience fecal incontinence.
      • Bartolo D.C.
      • Read N.W.
      • Jarratt J.A.
      • et al.
      Differences in anal sphincter function and clinical presentation in patients with pelvic floor descent.
      Descending perineum syndrome is associated with multiparity, middle or old age, and female sex as predisposing factors, and with evidence of pelvic floor trauma/stretching on examination.
      • El-Nashar S.A.
      • Occhino J.A.
      • Trabuco E.
      • Gebhart J.
      • Klingele C.
      Descending perineum syndrome: a fresh look at an interesting and complex pelvic floor disorder.
      There is no prior documentation of DPS in young adult females with EDS hypermobility; in addition, the pathobiology of the underlying ligament and pelvic floor laxity in association with DPS in young females is unknown.
      Our aim was to explore genetic variants as plausible biological factors associated with hypermobility syndrome in a young patient with DPS who presented with severe constipation.

      Case Report

      A 22-year-old woman presented with 12 years of progressive constipation with up to 3 weeks without spontaneous bowel movements, “rock hard” stools, excessive straining, bilateral lower quadrant abdominal pain, and bloating. She denied having upper gastrointestinal symptoms. Constipation had not responded to osmotic or secretory laxatives or enemas; stimulant laxatives provided some relief for the bowel dysfunction.
      Physical examination demonstrated hyperextensible skin along the anterior thighs and no finger, knee, or elbow hyperextension; however, she was able to place both palms flat on the floor without bending her knees (Figure 1A). Abdominal examination demonstrated bilateral lower quadrant abdominal tenderness. Rectal examination in the left lateral position demonstrated perineal descent of more than 3 cm, normal anal sphincter pressures, and levator ani tenderness.
      Figure thumbnail gr1
      Figure 1A, Physical examination findings consistent with EDS. Patient is able to lay her palms flat on the ground without flexion of her knees. B, Upright abdominal radiograph demonstrating mild scoliosis (∼10° angle), with black lines demonstrating a version of the Cobb angle. C, Upright abdominal x-ray demonstrating increased rectal gas, indicative of rectal evacuation disorder. D, Scintigraphic colonic transit demonstrating no movement in radiotracer between 24 hour and 48 hours, and overall slow colonic transit. EDS = Ehlers-Danlos syndrome.
      Upright abdominal radiograph demonstrated mild scoliosis (Figure 1B) and increased rectal gas area of 16 cm2 (Figure 1C). Anorectal manometry was unremarkable (normal sphincter pressures and balloon expulsion). Colonic transit was delayed, with radiotracer not passing beyond the transverse colon and no isotope movement between the 24- and 48-hour scans (Figure 1D). Magnetic resonance imaging defecography revealed a large enterocele, 2.8-cm anterior rectocele, approximately 5 cm perineal descent, and rectoanal angle of 115° resting and 120° during stimulated defecation, consistent with failure of rectoanal angle opening as a result of the excessive perineal descent (Figure 2A). An abdominal vascular Doppler ultrasound demonstrated patent celiac and mesenteric arteries with no aneurysm or dissection (Figure 2B).
      Figure thumbnail gr2
      Figure 2A, Magnetic resonance imaging defecography in 3 different settings: during anal squeeze (left), during straining (middle), and post-evacuation (right) phases. Note that there is evidence of approximately 5 cm perineal descent and anterior rectocele as compared with the rectal and perineum appearance during the anal squeeze phase. B, Abdominal vascular Doppler ultrasound demonstrated normal blood flow, with no aneurysm or dissection in the celiac (left), superior mesenteric (middle), and inferior mesenteric (right) arteries. IMA = inferior mesenteric artery; SMA = superior mesenteric artery.
      On the basis of her physical examination (perineal descent >3 cm) and MRI defecography, she had evidence of DPS. Intense biofeedback therapy did not relieve abdominal or defecatory symptoms.

      Genetic Studies

      The unique aspect of this case was the absence of pelvic floor trauma in a young, nulliparous woman with DPS with features of hypermobility. In view of the lack of a clear etiology for the DPS, we explored evidence for genetic variation in the synthesis of collagen, particularly because previous literature of hypermobility syndromes has not documented an association with DPS.
      Before presentation to Mayo Clinic, the patient had undergone genotyping (∼611,000 single nucleotide polymorphisms [SNPs]) performed by a commercial, Clinical Laboratory Improvement Amendments-certified laboratory using a V4 chip. We identified 4 SNP variations of potential interest in COL1A1 gene ([rs72656352, Chr17: 50,185,535-50,185,539, deletion], [rs72654794, Chr17: 50,188,575, deletion], [rs72667023, Chr17: 50,198,170, deletion], [rs67828806, Chr17: 50,198,177 G→C]). Of note, the gene location is on build 38 reference genome (Figure 3).
      Figure thumbnail gr3
      Figure 3Representation of the COL1A1 gene structure with exomes (dark blocks) and introns (lines) and the genetic variant location, nuclear variant or mutation, and subsequent protein change for the 4 mutations identified in this patient. Obtained from the University of California Santa Cruz Genome Browser database for the COL1A1 gene. The source for the Genome Browser, Blat, liftOver, and other utilities is free for nonprofit academic research and for personal use.

      Synthesis of Collagen and Potential Functional Consequences of COL1A1 Variations

      The type I collagen fiber is an important component in tendons, ligaments, bone, and skin. As depicted in Figure 4, it is a trihelical structure consisting of 2 α(1) and 1 α(2) fibrils. The tight, stable trihelical structure is dependent on every third amino acid being glycine. Long collagen fibers are constructed in the extracellular space by connecting shorter collagen molecules. These collagen molecules, known as procollagen, are synthesized within the endoplasmic reticulum of fibroblasts. To ensure that the procollagen molecules do not connect prematurely to form the large collagen fiber within the cell, N′ and C′ ends are added to the procollagen. Once the procollagen reaches the extracellular space, proteases cleave the N′ and C′ ends, forming the collagen molecule and allowing it to create a collagen fiber. In OI and EDS type VII, the N′ area of the procollagen is incompletely or inappropriately cleaved by proteases because of mutations in the glycine amino acid or the proteases, resulting in partial retention of the N′ within the collagen fiber.
      • Makareeva E.
      • Cabral W.A.
      • Marini J.C.
      • Leikin S.
      Molecular mechanism of alpha 1(I)-osteogenesis imperfecta/Ehlers-Danlos syndrome: unfolding of an N-anchor domain at the N-terminal end of the type I collagen triple helix.
      Failure of N-proteinase cleavage at misfolded sites in the procollagen leads to incorporation of pN-collagen into fibrils; such fibrils containing pN-collagen are thinner and weaker, causing laxity of large and small joints and paraspinal ligament. The mutations identified in this patient are likely to result in incomplete or inappropriate cleavage of procollagen by proteases because of mutations in the glycine amino acid. Thus, failure to cleave the N′ end could result in collagen weakness.
      Figure thumbnail gr4
      Figure 4The left panel demonstrates normal trihelical structure of procollagen with every third amino acid being glycine. Protease digestion at both C terminus and N terminus results in normal collagen structure with bonds binding the collagen fibrils. The right panel depicts abnormal trihelical structure near the N′ end due to loss of glycine in every third position of the amino acid structure. As a result, the N′ is not cleaved appropriately and results in decreased number of bonds within the collagen fiber and, hence, the collagen weakness.
      In our patient, there were 4 mutations in the COL1A1 gene, which encodes α(1) fibril. Chr17:50,198,170 deletion and Chr17:50,198,177 G→C are found on the 5′ end of the COL1A1 gene and encode the N′ end of the procollagen, changing both the amino acids from glycine to either alanine or valine. Two previous studies have reported these mutations in humans, both associated with Chr17:50,198,170 deletion (build 38 reference genome). The first describes the same mutation noted in an infant with features characteristic of OI type III.
      • Venturi G.
      • Tedeschi E.
      • Mottes M.
      • et al.
      Osteogenesis imperfecta: clinical, biochemical and molecular findings.
      The second report evaluated 7 patients with the OI/EDS phenotype. Genetic analysis demonstrated 2 patients with a similar mutation and noted that cleavage of the N′ end of the procollagen protein was reduced to 70% compared with healthy controls. In addition, patients with this genetic mutation had a smaller collagen fibril (diameter 50 nm compared with 81 nm in controls).
      • Cabral W.A.
      • Makareeva E.
      • Colige A.
      • et al.
      Mutations near amino end of alpha1(I) collagen cause combined osteogenesis imperfecta/Ehlers-Danlos syndrome by interference with N-propeptide processing.
      The remaining 2 mutations are on the 3′ end of the COL1A1 gene, corresponding to the C′ end of the procollagen protein (Chr17:50,185,535-50,185,539 5 base-pair deletion and Chr17:50,188,575 deletion on build 38 reference genome). Interestingly, the 5 base-pair deletion seen at Chr17:50,185,535-50,185,539 was reported in 20 family members over 3 generations with a mild phenotype of OI. These family members had an additional 84 amino acids on the C′ end of collagen, indicating inappropriate cleavage.
      • Willing M.C.
      • Cohn D.H.
      • Byers P.H.
      Frameshift mutation near the 3′ end of the COL1A1 gene of type I collagen predicts an elongated Pro alpha 1(I) chain and results in osteogenesis imperfecta type I.
      It is important to note that our evaluation of the genotyping did not identify any of the variants or mutations previously reported to be related to JHS(s), OI, or EDS. However, we have identified in this patient the presence of SNPs at both the 3′ and 5′ ends of the COL1A1 gene that putatively prevents appropriate collagen fibril formation and may lead to the observed DPS.

      Discussion

      This young patient was diagnosed with DPS on the basis of excessive perineal descent (>4 cm)
      • Harewood G.C.
      • Coulie B.
      • Camilleri M.
      • Rath-Harvey D.
      • Pemberton J.H.
      Descending perineum syndrome: audit of clinical and laboratory features and outcome of pelvic floor retraining.
      (both on physical examination and on MRI defecography) and evidence of rectal evacuation disorder, supported by large rectal gas area on upright abdominal x-ray, although the rectal balloon expulsion was normal, as has been observed in previous studies in other patients with DPS.
      • Harewood G.C.
      • Coulie B.
      • Camilleri M.
      • Rath-Harvey D.
      • Pemberton J.H.
      Descending perineum syndrome: audit of clinical and laboratory features and outcome of pelvic floor retraining.
      Rectal gas area greater than 9 cm2 on scout film is suggestive of rectal evacuation disorder.
      • Park S.Y.
      • Khemani D.
      • Acosta A.
      • Eckert D.
      • Camilleri M.
      Rectal gas volume: defining cut-offs for screening for evacuation disorders in patients with constipation.
      Importantly, rectal prolapse is in the differential diagnosis for constipation in patients with features of hypermobility. Rectal prolapse was ruled out on the basis of physical examination and MRI defecography.
      • Mohammed S.D.
      • Lunniss P.J.
      • Zarate N.
      • et al.
      Joint hypermobility and rectal evacuatory dysfunction: an etiological link in abnormal connective tissue?.
      The identified genetic variations appear to explain the molecular weakening of the collagen fiber chain (trihelical structure and the retention of N′)
      • Makareeva E.
      • Cabral W.A.
      • Marini J.C.
      • Leikin S.
      Molecular mechanism of alpha 1(I)-osteogenesis imperfecta/Ehlers-Danlos syndrome: unfolding of an N-anchor domain at the N-terminal end of the type I collagen triple helix.
      and provide a likely molecular explanation for the elasticity of the patient's skin, mild scoliosis, and DPS. Although her Beighton score was 1/9, there are previous reports in the literature describing this genetic abnormality in collagen in patients with a combined phenotype of OI and EDS.
      • Makareeva E.
      • Cabral W.A.
      • Marini J.C.
      • Leikin S.
      Molecular mechanism of alpha 1(I)-osteogenesis imperfecta/Ehlers-Danlos syndrome: unfolding of an N-anchor domain at the N-terminal end of the type I collagen triple helix.
      This patient did not manifest features of OI. One limitation of our report is that the patient did not undergo whole-exome DNA sequencing; therefore, we do not know whether there are variants of unknown significance in any genes associated with EDS or other collagen disorders that would predispose to the DPS.

      Conclusion

      In conclusion, COL1A1 gene mutations are plausible biological factors predisposing to DPS in association with increased flexibility. Our clinical observation suggests that young females diagnosed with DPS with no obvious pelvic trauma should be screened for connective tissue disorders with detailed history, physical examination, exclusion of rectal mucosal prolapse, and a search for genetic variation in collagen synthesis.

      Supplemental Online Material

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