Clinical characteristics.

Manitoba oculotrichoanal (MOTA) syndrome is characterized by an aberrant hairline (unilateral or bilateral wedge-shaped extension of the anterior hairline from the temple region to the ipsilateral eye) and anomalies of the eyes (ocular hypertelorism, anophthalmia/microphthalmia, cryptophthalmos, colobomas of the upper eyelid and corneopalpebral synechiae), nose (bifid or wide with a notched tip), abdominal wall (omphalocele or umbilical hernia), and anus (stenosis and/or anterior displacement of the anal opening). The manifestations and degree of severity vary even among affected members of the same family. Growth and psychomotor development are normal.

Diagnosis/testing.

Diagnosis is based on clinical findings and family history, and in many cases ethnicity is taken into account. FREM1 is the only gene in which mutation is known to cause MOTA syndrome.

Management.

Treatment of manifestations: Treatment consists primarily of surgical repair as needed, including closure of an omphalocele, dilatation for anal stenosis, release of synechiae between the eyelid and cornea, and craniofacial surgery for bifid nose. Supportive care is required for those with visual impairment.

Genetic counseling.

MOTA syndrome is inherited in an autosomal recessive manner. At conception, each full sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

Clinical Diagnosis

Diagnosis of Manitoba oculotrichoanal (MOTA) syndrome is based on the following [Marles et al 1992, Li et al 2007].

Clinical features present in 50% or more of individuals with MOTA syndrome diagnosed to date:

• Ocular hypertelorism
• Aberrant anterior hairline extending to the ipsilateral eye (unilateral or bilateral); often wedge-shaped, but may also resemble a thin stripe or appear tongue-shaped
• Wide nares, notched nares; bifid or broad nasal tip
• Ocular abnormalities including ipsilateral colobomas of the upper eyelid (sometimes referred to as a Tessier number 10 cleft by surgeons), corneopalpebral synechiae (i.e., adhesions between the eyelids and the cornea), microphthalmia/anophthalmia and/or cryptophthalmos. Corneal clouding was described in one individual.
  The upper-eyelid colobomas and cryptophthalmos are part of a spectrum of anomalies ranging from colobomas of the lid to eyelid coloboma plus corneopalpebral synechiae (also known as abortive cryptophthalmos) to complete cryptophthalmos [Nouby 2002]. Anomalies may be unilateral or bilateral; the severity may differ between the two eyes.
• Absent or interrupted eyebrow ipsilateral to the eye defect
• Anal stenosis and/or anteriorly placed anus
• Omphalocele or umbilical hernia in approximately one third of affected individuals

Minimum diagnostic criteria should include ocular hypertelorism and EITHER:

• Two or more additional features;
  OR
• One additional feature plus a previously affected full sib, parental consanguinity, or Island Lake aboriginal ethnicity.

Supportive findings include the following:

• A positive family history consistent with autosomal recessive inheritance (i.e., an affected full sib and/or consanguinity); helpful but not necessary for the diagnosis
• Ethnic origin of aboriginal Oji-Cree. To date, most (not all) affected individuals have been Oji-Cree, descended from the highly consanguineous population living in the Island Lake region of northern Manitoba, Canada (see Prevalence).

Molecular Genetic Testing

Gene. FREM1 is the only gene in which mutation is known to cause Manitoba oculotrichoanal syndrome [Slavotinek et al 2011].

Evidence for locus heterogeneity. No pathogenic variants in FREM1 were identified in two individuals with MOTA syndrome who were second cousins [Yeung et al 2009], suggesting genetic heterogeneity.

Testing

• Sequence analysis. FREM1 pathogenic variants were identified by genomic sequencing in 2/8 individuals with MOTA syndrome [Slavotinek et al 2011].
• Deletion/duplication analysis. In 6/8 individuals with FREM1-confirmed MOTA syndrome a deletion of exons 8 to 23 (c.824+631_c.3840-1311del) was identified as causative [Slavotinek et al 2011]; the deletion is unlikely to be detected by sequence analysis of the coding and flanking intronic regions of genomic DNA, as the breakpoints are intronic. The deletion was detected initially using a single nucleotide polymorphism (SNP) array capable of detecting copy number differences, but may be identified by a variety of deletion/duplication analysis methods (Table 1, footnote 3).

Testing Strategy

To confirm/establish the diagnosis in a proband

• The diagnosis is primarily established by clinical findings.
• In individuals with Oji-Cree ancestry, deletion analysis of FREM1 may be considered first.
• In those individuals of other ethnicities or in whom no deletion or duplication of FREM1 is found, sequence analysis of FREM1 may be considered.

Carrier testing for at-risk relatives requires prior identification of both pathogenic variants in an affected family member.

Note: Carriers are heterozygotes for this autosomal recessive disorder and to date are not known to be at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.

Clinical Description

Manitoba oculotrichoanal (MOTA) syndrome is characterized by the findings detailed in Diagnosis. Additional findings have been reported in one individual each [Slavotinek et al 2011]: renal pelviectasis; vaginal atresia; and mild craniofacial dysmorphism (high forehead with a frontal upsweep of hair, maxillary hypoplasia, small nasal alae with colobomas and a bifid nasal tip, short philtrum, thin upper lip, and relative microstomia).

The manifestations and degree of severity vary even among affected members of the same family. Not all features are observed in all affected individuals.

Pregnancy of an affected infant is usually uneventful and birth weight, length, and head circumference are appropriate for gestational age. In one instance oligohydramnios was detected on prenatal ultrasound for an individual given a postnatal clinical diagnosis of MOTA syndrome with no detectable FREM1 pathogenic variant [Slavotinek et al 2011].

Visual impairment may result directly from ocular malformation or indirectly from exposure keratopathy. The long-term visual outcome depends on the severity of the ocular malformation and is poor for individuals with bilateral complete cryptophthalmos. In those with milder ocular malformations, such as upper eyelid colobomas, vision is typically intact.

Conservative management or surgical intervention for omphalocele or umbilical hernia is usually well tolerated and outcomes are excellent. Long-term intestinal complications have not been described.

The anteriorly displaced anus and anal stenosis are not associated with anomalies of the sacrum, vertebrae, or a tethered cord. No affected individuals have had refractory constipation, fecal incontinence, or procedure-related stenosis or fistula.

Individuals with MOTA syndrome assessed at various ages appear generally healthy with age-appropriate growth and cognition. Motor, social, and speech and language skills are typically normal, although development may be influenced by the presence of severe eye defects leading to visual impairment.

Individuals with MOTA syndrome have not had malformations of the limbs, spine, heart, lungs, or other internal organs. They have had normal skull x-rays with no evidence of cranium bifidum, a midline defect in the frontal bone found in the related condition, frontonasal dysplasia (FND) sequence.

Genotype-Phenotype Correlations

Genotype-phenotype correlations have not been possible to date given the rarity of the condition and limited number of pathogenic variants described.

Prevalence

The prevalence in the general population is unknown; MOTA syndrome is likely very rare.

To date, the authors are aware of 20 published individuals with MOTA syndrome: 16 from Manitoba [Marles et al 1992; Li et al 2007; several also reported in Slavotinek et al 2011]; two from Australia [Yeung et al 2009; also reported in Slavotinek et al 2011]; one from Belgium [Fryns 2001; also reported in Slavotinek et al 2011]; and one from the Netherlands [Li et al 2007, also reported in Slavotinek et al 2011]. Similar clinical findings have been identified in several individuals in an unpublished Turkish kindred [Tukun, personal communication].

Based on the number of individuals identified to date in the aboriginal Oji-Cree community of the Island Lake region of northern Manitoba, Canada, which had a population of 4685 in 1996 and 2020 in 2001 [First Nation Profiles 2004], the incidence of MOTA syndrome in that population is estimated at 2:1000-6:1000 births; however, this may be an underestimate in this population, as a few presumably affected individuals have been identified through family histories of affected individuals, and some milder cases may not have come to medical attention. All affected individuals from the Island Lake region identified to date are presumed to be related.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Manitoba oculotrichoanal (MOTA) syndrome, the following are recommended:

• Ophthalmologic evaluation
• Surgical evaluation of omphalocele and umbilical hernia, if present, and of anal abnormalities
• ENT (ear-nose-throat) evaluation for bifid nose/notched nares
• Plastic surgery evaluation
• Clinical genetics consultation

Treatment of Manifestations

A multidisciplinary team comprising a clinical geneticist, general surgeon, ophthalmologist, otolaryngologist, plastic surgeon, and social worker is preferred for optimal management of individuals with MOTA syndrome.

Treatment consists primarily of surgical intervention with procedures tailored to the specific needs of the individual.

Eye anomalies

• Colobomas of the upper eyelids and synechiae are managed conservatively with intensive ocular lubrication to avoid exposure keratopathy before surgery is performed.
• Anophthalmia/microphthalmia and cryptophthalmos may warrant surgical intervention and insertion of prostheses to facilitate the development of the ocular region [Seah et al 2002].
• Visual impairment, such as refractive errors, may be associated with colobomas and corneopalpebral synechiae.

Notched or bifid nose. Rhinoplasty may be performed for cosmetic purposes.

Omphalocele and umbilical hernia may be managed conservatively or by surgery. To date, all individuals with MOTA syndrome who have been managed surgically have tolerated the procedure well without procedure-related complications.

Anal stenosis is generally managed by serial dilatations.

Anteriorly placed anus is managed conservatively or with surgical intervention, as determined on a case-by-case basis.

Psychosocial support may be indicated for the parents and the affected child.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Manitoba oculotrichoanal (MOTA) syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutated allele).
• Heterozygotes (carriers) have been asymptomatic (i.e., no known evidence of anomalies).

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with MOTA syndrome are obligate heterozygotes (carriers) for a pathogenic variant.

Carrier Detection

Carrier status can be ascertained in some instances by pedigree analysis.

If the pathogenic variants in the family have been identified, carrier testing for at-risk family members is possible using molecular genetic techniques through laboratories offering either testing for the gene of interest or custom testing.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Pregnancies at high a priori risk. Ultrasound examination may be diagnostic of MOTA syndrome if findings such as omphalocele, cryptophthalmos, anophthalmia/microphthalmia, ocular hypertelorism, and/or a wide nose are detected. However, mild findings may be difficult to detect on prenatal imaging.

Pregnancies at low a priori risk. Chromosome analysis and possibly DNA-based testing for other specific disorders with findings similar to MOTA syndrome should be considered when omphalocele and craniofacial features associated with MOTA syndrome are identified on fetal ultrasound examination in a pregnancy not known to be at risk for MOTA syndrome.

Molecular Genetic Pathogenesis

Homozygosity for an intragenic deletion of FREM1 at chromosome 9p22.3 was recently found in two separate Oji-Cree families with MOTA syndrome [Slavotinek et al 2011]. The deletion (c.824+631_c.3840-1311del) removed exons 8 to 23 of FREM1 and was consistent with loss of gene function. Homozygosity for the deletion was found in an affected brother and sister from one previously reported family [Li et al 2007] and in a severely affected male with bilateral cryptophthalmos, bilateral aberrant anterior hairlines, omphalocele, renal pelviectasis in the neonatal period, and anal stenosis. He had three affected female second cousins who were heterozygous for the same deletion that was inherited from their father; they had also inherited the same maternal allele but a pathogenic variant on the maternal allele was not identified in these patients [Slavotinek et al 2011]. Sequencing of FREM1 in other families with MOTA syndrome identified a 4-bp deletion, c.2097_2100delATTA, in a previously reported female [Fryns 2001] and the pathogenic variants c.3971T>G and c.6271G>A in another female patient [Li et al 2007, Slavotinek et al 2011]. However, in two patients with MOTA syndrome who were second cousins [Yeung et al 2009], no pathogenic variants in FREM1 were identified, suggesting genetic heterogeneity.

Normal allelic variants. There are few published single nucleotide allelic variants (SNPs) in FREM1. c.5556A>G in exon 31 of FREM1 did not result in an amino acid substitution but was predicted to abolish the donor splice site for exon 31; however, this sequence variant was found in normal controls and was not considered to be pathogenic [Slavotinek et al 2011].

Pathogenic allelic variants. FREM1 variants resulting in MOTA syndrome identified to date are listed in Table 2.

Note: The deletion of exons 8 to 23 found in families with MOTA syndrome affects the chondroitin sulfate proteoglycan (CSPG) domains of FREM1 [Slavotinek et al 2011].

Normal gene product. The human FREM1 protein has a putative signal sequence, 12 chondroitin sulfate proteoglycan (CSPG) repeats, a Calx-β domain, and a C-terminal type C lectin-like domain [Alazami et al 2009].

In the mouse, Frem1 is thought to function in a ternary complex with Fras1 and Frem2 to ensure integrity of the basement membrane of the skin [Short et al 2007]. Absence of Fras1 or Frem2 causes complete loss of the ternary complex, but in mouse mutants with loss of Frem1, deposition of Fras1 and Frem2 can be unaffected or present at lower levels [Smyth et al 2004]. In the adult mouse, Frem1 is considered unnecessary for stabilization of the ternary complex.

The partial redundancy of Frem1 is thought to confer greater phenotypic variability to mutants with loss of Frem1 function and to ensure a less severe phenotype than that which results from loss of Fras1 or Frem2 (Fraser syndrome), as there is some preservation of Fras1 and Frem2 function in Frem1 mutants.

Abnormal gene product. All pathogenic variants reported to date in FREM1 are hypothesized to result in loss of function.

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Revision History

• 13 October 2011 (me) Comprehensive update posted live
• 9 July 2008 (me) Review posted to live Web site
• 16 May 2008 (cl) Original submission