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The Official Scientific Journal of Delhi Ophthalmological Society
Manitoba Oculotrichoanal Syndrome: First Case Report From India
Sai Rani Karanam, Vinay Kumar Konana, Shruthi Sreenivasaiah, Sudhakar Potti
Sankara Eye Hospital, Guntur, Andhra Pradesh, India
Corresponding Author:
Vinaya Kumar Konana
Resident, Sankara Eye Hospital,
Vijayawada-Guntur express highway, Pedakakani,
Guntur District-522509, Andhra Pradesh, India.
Email id: dr.vini69@gmail.com
Received: 25-OCT-2015 Accepted: 16-JAN-2016 Published Online: 09-SEP-2016
DOI: http://dx.doi.org/10.7869/djo.220
Abstract
Manitoba-oculo-tricho-anal (MOTA) syndrome is very rare syndrome characterized by aberrant hairline, eye anomalies (ocular hypertelorism, cryptophthalmos, and upper eyelid colobomas), bifid nose, omphalocele and anorectal anomalies. MOTA syndrome was first reported in 1992 in Oji-cree community from the Island Lake region of Manitoba, Canada. Till date very few cases of MOTA have been reported and none from India. We report first case of MOTA syndrome from India. A two month old male baby was brought with complaints of defect in right upper eye lid since birth. He was the second born child of a second degree consanguineously married couple at 37 weeks of gestation. On physical examination, the baby had right upper eyelid coloboma, ocular hypertelorism, bifid nose, small nasal ala and bilateral undescended testis. Investigations revealed high anorectal anomaly and right renal agenesis. Whole exome sequencing showed homozygous nonsense variation in exon 25 of the FREM1 gene that resulted in a stop codon. This case gains importance as it is the first case of MOTA being reported from India and bilateral undescended testis which was seen this case is an addition to the variable clinical spectrum of MOTA. 
Keywords : MOTA, BNAR, consanguinity, multisystem
Manitoba-oculo-tricho-anal (MOTA) syndrome is a very rare syndrome characterized by an aberrant hairline, eye anomalies (ocular hypertelorism, cryptophthalmos, upper eyelid coloboma and corneopalpebral synechiae), bifid nose, abdominal wall (omphalocele or umbilical hernia) and anorectal anomalies.[1,2] During embryogenesis the adhesion between the basement membrane and the epithelium is maintained by a complex called FRAS/FREM complex which comprises proteins FRAS1, FREM1 and FREM[2,3,4] Mutation in FRAS/FREM complex results in syndromes like MOTA, bifid nose renal agenesis and anorectal malformations (BNAR) syndrome and FRASER syndrome.[5-7] As these syndromes result from closely related genes there is considerable overlapping of clinical features. FRAS1 and FREM2 gene mutation causes Fraser syndrome and mutation in FREM1 gene causes MOTA and BNAR syndrome.[5,6] MOTA syndrome was first reported in 1992 in Oji-cree community from the Island Lake region of Manitoba, Canada.[1] Till date very few cases of MOTA have been reported in the world and none from India. We report first case of MOTA syndrome from India that also has bilateral undescended testis which is not reported in the literature so far.

Case Report

A baby was brought with complaints of defect in right upper eye lid since birth. Baby was the second born child of a second degree consanguineously married couple at 37 weeks of gestation. History of consanguinity was present. Pre-natal period was uneventful. No similar complaints in parents or sibling. On ocular examination right upper eyelid coloboma and hypertelorism were noted (Figure 1A). Baby had abdominal distension on first day of life and was found to have high anorectal anomaly in X ray invertogram. On general physical examination baby had bifid nose, small nasal ala and bilateral undescended testis. Eye brows and hair line were normal, no associated limb and ear anomalies were noted. Developmental milestones were normal. Ultrasound abdomen and pelvis showed right renal agenesis (Figure 2), bilateral undescended testis (Figure 3), mildly prominent rectum and other bowel loops in lower abdomen and minimal inter bowel ascites was noted. Child was operated for right upper lid coloboma (Figure 1B) Whole exome sequencing of the proband, parents and elder sister was performed. In proband a homozygous nonsense variation in exon 25 of the FREM1 gene that results in a stop codon and premature truncation of the protein. This variation was not detected in his unaffected elder sister and was detected in heterozygous state in both his unaffected parents. Based on the above findings baby was diagnosed to have Manitoba-oculo-tricho-anal syndrome.







Discussion

MOTA syndrome is a rare autosomal recessively inherited syndrome, which was initially thought to be confined to children born to consanguineous married Oji –cree community couples of northern Manitoba, Canada. Li et al in 2007 reported new case outside Manitoba born to non-consanguineously married couple.[2] Till date very few cases of MOTA syndrome are reported outside Oji-Cree community and none from India. Our case was diagnosed to have MOTA syndrome based on features like upper eyelid coloboma, hypertelorism, high anorectal anomaly, bifid nose, small nasal ala. In addition to above features our case also had bilateral undescended testis and right renal agenesis. Renal agenesis was more characteristic of BNAR syndrome but Slavotinek et al stated that “eye defects occurred consistently with MOTA syndrome than BNAR syndrome and patients with MOTA and BNAR exhibit more clinical overlap and could be diagnosed with either syndrome”.[8]

The presenting features of MOTA syndrome are variable, which include Ocular hypertelorism, aberrant anterior hairline, wide nares, notched nares; bifid or broad nasal tip, ipsilateral colobomas of the upper eyelid, microphthalmia/anophthalmia and/or cryptophthalmos. Anal stenosis and/or anteriorly placed anus, Omphalocele or umbilical hernia in approximately one third of affected individuals.[1,2] Minimum diagnostic criteria for MOTA syndrome should include ocular hypertelorism and either two or more additional features or one additional feature plus a previously affected full sibling, parental consanguinity, or Island Lake aboriginal ethnicity.[1,2] According to Li et al the manifestations and degree of severity vary even among affected members of the same family. Not all features are observed in all affected individuals.[1] Hence in our case even though the baby had normal hairline it can still be diagnosed as MOTA syndrome based on the above stated diagnostic criteria. Though our case has genitourinary malformations, other features of FRASER syndrome like cryptophthalmos, syndactyly, ambiguous genitalia, laryngeal, oral clefting were absent and hence FRASER syndrome was ruled out.10 Our case supports the hypothesis that MOTA is not confined to just Oji- cree community. It also shows that a case of MOTA can have overlapping features of MOTA and BNAR.8 MOTA is associated with abdominal problems like omphalocele or umbilical hernia but bilateral undescended testis has not been reported so far either with MOTA or with BNAR.

Conclusion

This is the first case of MOTA syndrome being reported from India and fifth outside Oji- cree community. Bilateral undescended testis is an addition to the widely variable clinical spectrum of MOTA. Occurrence of such cases outside Oji-cree community highlights the need to explore the pathogenesis of MOTA syndrome further.

References
  1. Marles SL, Greenberg CR, Persaud TV, Shuckett EP, Chudley AE. New familial syndrome of unilateral upper eyelid coloboma, aberrant anterior hairline pattern, and anal anomalies in Manitoba Indians. Am J Med Genet 1992; 42:793–9.
  2. Li C, Marles SL, Greenberg CR, Chodirker BN, van de Kamp J, Slavotinek A, Chudley AE. Manitoba Oculotrichoanal (MOTA) syndrome: report of eight new cases. Am J Med Genet A 2007; 143A:853-7.
  3. Short K , Wiradjaja F, Smyth I. Let’s stick together: the role of the Fras1 and Frem proteins in epidermal adhesion. IUBMB Life 2007; 59:42735.
  4. Pavlakis E , Chiotaki R, Chalepakis G. The role of Fras1/Frem proteins in the structure and function of basement membrane. Int J Biochem Cell Biol 2011; 43:487-95.
  5. Alazami AM, Shaheen R, Alzahrani F, Snape K, Saggar A, Brinkmann B, et al. FREM1 Mutations Cause Bifid Nose, Renal Agenesis, and Anorectal Malformations Syndrome. Am J Hum Genet. 2009; 85:414–8.
  6. AlGazali, Bakir, Hamud, Gerami. An autosomal recessive syndrome of nasal anomalies associated with renal and anorectal malformations. Clin Dysmorphol 2002; 11:33-38
  7. Van Haelst MM, Maiburg M, Baujat G, Jadeja S, Monti E, Bland E, et al. Molecular study of 33 families with Fraser syndrome new data and mutation review. Am J Med Genet A 2008; 146A: 2252-7.
  8. Slavotinek AM, Baranzini SE, Schanze D, LabelleDumais C, Short KM, Chao R, et al. Manitobaoculotrichoanal (MOTA) syndrome is caused by mutations in FREM1. J Med Genet 2011; 48:375–82.
  9. Li C, Slavotinek A, Chudley AE. Manitoba oculotrichoanal syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. GeneReviews. Seattle (WA): University of Washington; 1993.
  10. Slavotinek AM, Tifft CJ. Fraser syndrome and cryptophthalmos: review of the diagnostic criteria and evidence for phenotypic modules in complex malformation syndromes. J Med Genet 2002; 39:623–33.
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Sai Rani Karanam, Vinay Kumar Konana, Shruthi Sreenivasaiah, Sudhakar PottiManitoba Oculotrichoanal Syndrome: First Case Report From India.DJO 2016;27:111-113
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Sai Rani Karanam, Vinay Kumar Konana, Shruthi Sreenivasaiah, Sudhakar PottiManitoba Oculotrichoanal Syndrome: First Case Report From India.DJO [serial online] 2016[cited 2019 Feb 20];27:111-113. Available from: http://www.djo.org.in/articles/27/2/manitoba-oculotrichoanal.html
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