Frem1 Autosomal Recessive Disorders
Summary
Clinical characteristics.
FREM1 autosomal recessive disorders include: Manitoba oculotrichoanal (MOTA) syndrome, bifid nose with or without anorectal and renal anomalies (BNAR syndrome), and isolated congenital anomalies of kidney and urinary tract (CAKUT).
- 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 (widely spaced eyes, anophthalmia/microphthalmia and/or cryptophthalmos, colobomas of the upper eyelid, and corneopalpebral synechiae), nose (bifid or broad nasal 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.
- BNAR syndrome is characterized by a bifid or wide nasal tip, anorectal anomalies, and renal malformations (e.g., renal agenesis, renal dysplasia). Typically the eye manifestations of MOTA syndrome are absent.
- FREM1-CAKUT was identified in one individual with bilateral vesicoureteral reflux (VUR) and a second individual with VUR and renal hypodysplasia.
Diagnosis/testing.
The diagnosis of a FREM1 autosomal recessive disorder is established in a proband by identification of biallelic pathogenic variants in FREM1 on molecular genetic testing.
Management.
Treatment of manifestations:
- Intensive ocular lubrication to avoid exposure keratopathy before surgery is performed; release of synechiae between the eyelid and cornea; surgical intervention and/or prostheses for anophthalmia/microphthalmia and cryptophthalmos if warranted; supportive care for those with visual impairment
- Rhinoplasty for notched ala nasi or bifid nose
- Surgical closure of omphalocele; surgical or conservative management of umbilical hernia
- Dilatation for anal stenosis
- Supportive treatment to preserve renal functions and electrolyte balance; dialysis and transplant if indicated in individuals with renal failure
- Psychosocial support
Genetic counseling.
MOTA, BNAR syndrome, and FREM1-CAKUT are 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 the FREM1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Diagnosis
Clinical Characteristics
Clinical Description
Manitoba Oculotrichoanal (MOTA) Syndrome
Ocular abnormalities include 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, also known as abortive cryptophthalmos), and microphthalmia/anophthalmia and/or cryptophthalmos. Anomalies may be unilateral or bilateral; the severity may differ between the two eyes.
Visual impairment may result directly from the ocular malformations or indirectly from exposure keratopathy. The long-term visual outcome depends on the severity of the ocular malformations and is poor for individuals with bilateral complete cryptophthalmos. In those with milder ocular malformations, such as upper eyelid colobomas, vision is typically intact.
Corneal clouding was described in one individual.
Anal anomalies include anal stenosis and/or anteriorly placed anus. No associated anomalies of the sacrum, vertebrae, or tethered cord have been reported. No affected individuals have had refractory constipation, fecal incontinence, or procedure-related stenosis or fistula.
Characteristic facial features include widely spaced eyes; an aberrant anterior hairline extending to the ipsilateral eye (unilateral or bilateral) that is often wedge-shaped but may also resemble a thin stripe or appear tongue-shaped; ipsilateral absent or interrupted eyebrow; and a broad nose or notched or bifid nasal tip.
Omphalocele or umbilical hernia has been reported in approximately one third of affected individuals. 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.
Other. Additional findings have been reported: renal pelviectasis, renal dysplasia, hydrometrocolpos and vaginal atresia, cutaneous syndactyly, and additional dysmorphic features (e.g., high forehead with a frontal upsweep of hair, dysplastic ears, maxillary hypoplasia, underdeveloped ala nasi, short philtrum, thin upper lip, and relative microstomia) [Slavotinek et al 2011, Mitter et al 2012, Nathanson et al 2013].
Growth and development. 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 that lead to visual impairment.
The manifestations and degree of severity vary even among affected members of the same family.
Bifid Nose with or without Anorectal and Renal Anomalies (BNAR) Syndrome
BNAR syndrome was described by Al-Gazali et al [2002] and Alazami et al [2009] in ten individuals from three consanguineous families of Egyptian, Afghani, and Pakistani origin.
- Craniofacial features. Broad and/or bifid nose (100%), widely spaced eyes, short and thick oral frenula
- Renal malformations (e.g., bilateral renal agenesis, unilateral renal agenesis) in 6/9 individuals evaluated
- Anorectal malformations (e.g., anteriorly placed anus, anal stenosis) in 2/9 individuals evaluated
- Airway malformations in 2/8 individuals evaluated
FREM1 Congenital Anomalies of Kidney and Urinary Tract (CAKUT)
FREM1-CAKUT phenotype has been reported in an individual with bilateral vesicoureteral reflux (VUR) grade III and in another individual with right-sided VUR grade V in conjunction with right-sided renal hypodysplasia [Kohl et al 2014].
Other Phenotypes
The following other phenotypes have been reported in individuals with biallelic FREM1 pathogenic variants:
- One individual with isolated congenital diaphragmatic hernia [Beck et al 2013]
- One fetus with severe hydrocephalus and shortened limbs associated with novel FREM1 pathogenic variants [Yang et al 2017]
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 of FREM1 autosomal recessive disorders are unknown. To date, the authors are aware of 27 published individuals with MOTA syndrome.
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 4,685 in 1996 and 2,020 in 2001 [First Nation Profiles 2004], the incidence of MOTA syndrome in that population is estimated at 2:1,000-6:1,000 births; however, this may be an underestimate in this population, as a few presumably affected individuals have also 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.
Differential Diagnosis
The following disorders should be considered in the differential diagnosis of Manitoba oculotrichoanal (MOTA) syndrome and bifid nose with or without anorectal and renal anomalies (BNAR) syndrome (Table 2).
Table 2.
Disorders to Consider in the Differential Diagnosis of MOTA Syndrome and BNAR Syndrome
| DiffDx Disorder | Gene(s) | MOI | Clinical Features of DiffDx Disorder | |
|---|---|---|---|---|
| Overlapping w/MOTA &/or BNAR syndrome | Distinguishing from MOTA & BNAR syndromes | |||
| Fraser syndrome (OMIM PS219000) | FRAS1 REM2 GRIP1 | AR |
|
|
| Frontonasal dysplasia (FND) (OMIM PS136760) | ALX1 ALX3 ALX4 | AR |
|
|
| Craniofrontonasal dysplasia (CFND) (OMIM 304110) | EFNB1 | XL | In females w/CFND: 4
|
|
| Oculoauriculofrontonasal syndrome (OMIM 601452) | Unknown | Unknown |
|
|
| FG syndrome type 1 (see MED12-Related Disorders) | MED12 | XL | In a male infant:
| Often, additional findings such as:
|
| Townes-Brocks syndrome | SALL1 | AD | Anteriorly placed anus, anal stenosis | |
| VACTERL (OMIM 192350) | Unknown | Unknown | ||
| Donnai-Barrow syndrome | LRP2 | AR |
|
|
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance; VACTERL = vertebral abnormalities, anal abnormalities, cardiac defects, tracheoesophageal fistula, renal and/or radial ray abnormalities, and limb anomalies; XL = X-linked
- 1.
Slavotinek & Tifft [2002], McGregor et al [2003], Vrontou et al [2003]
- 2.
Jones [2006]
- 3.
Cranium bifidum is a midline defect of the frontal bone detected on skull x-rays.
- 4.
CFND is inherited in a unique X-linked manner that paradoxically shows greater severity in heterozygous females than in hemizygous males. Typically, females have FND, craniofacial asymmetry, craniosynostosis, a bifid nasal tip, and grooved nails; they may also have skeletal abnormalities. In contrast, males typically show only widely spaced eyes [Twigg et al 2004, Wieland et al 2004].
FREM1 congenital anomalies of kidney and urinary tract (CAKUT). Isolated CAKUT has been associated with more than 20 genes to date and may be inherited in an autosomal dominant, autosomal recessive, or multifactorial manner [Nicolaou et al 2015]. The genetic etiology in most individuals with isolated CAKUT is unknown [Kohl et al 2014].
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a FREM1 autosomal recessive disorder, the evaluations summarized in Table 3, Table 4, or Table 5 (depending on the phenotype) are recommended if they have not already been performed as part of the evaluation that led to the diagnosis:
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with MOTA Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Ocular | Ophthalmologic eval | For coloboma &/or keratopathy |
| Gastrointestinal | Referral to surgeon | For omphalocele, umbilical hernia, &/or anal anomalies if present |
| ENT | Eval for bifid nose / notched ala nasi | Referral to plastic surgeon as needed |
| Other | Consultation w/clinical geneticist &/or genetic counselor |
Table 4.
Recommended Evaluations Following Initial Diagnosis in Individuals with BNAR Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Renal | Renal imaging & renal functional analysis | |
| Gastrointestinal | Referral to surgeon | For omphalocele, umbilical hernia, &/or anal anomalies if present |
| Respiratory |
| Referral to plastic surgeon as needed |
| Other | Consultation w/clinical geneticist &/or genetic counselor |
Table 5.
Recommended Evaluations Following Initial Diagnosis in Individuals with FREM1-CAKUT
| System/Concern | Evaluation |
|---|---|
| Genitourinary | Clinical exam, imaging & surgical eval |
| Other | Consultation w/clinical geneticist &/or genetic counselor |
Treatment of Manifestations
Treatment of FREM1 autosomal recessive disorders consists primarily of surgical intervention with procedures tailored to the specific needs of the individual. A multidisciplinary team comprising a clinical geneticist, general surgeon, ophthalmologist, otolaryngologist, plastic surgeon, and social worker is preferred for optimal management.
Table 6.
Treatment of Manifestations in Individuals with FREM1 Autosomal Recessive Disorders
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| Colobomas of the upper eyelids & synechiae |
| To avoid exposure keratopathy before surgery is performed |
| Anophthalmia/microphthalmia & cryptophthalmos | May warrant surgical intervention & insertion of prostheses | To facilitate development of ocular region 1 |
| Visual impairment (e.g., refractive errors) | Per ophthalmologist | May be assoc w/colobomas & corneopalpebral synechiae |
| Notched ala nasi or bifid nose | Rhinoplasty | May be performed for cosmetic purposes |
| Omphalocele & umbilical hernia | May be managed conservatively or surgically | To date, all persons w/a FREM1 AR disorder managed surgically have tolerated the procedure w/out complications. |
| Anal stenosis | Serial dilatations | |
| Anteriorly placed anus | Managed conservatively or w/surgical intervention | As determined on an individual basis |
| Renal malformations |
| Dialysis & transplant may be indicated in persons w/renal failure. |
| Psychosocial stressors | Psychosocial support | May be indicated for parents & affected child |
AR = autosomal recessive
- 1.
Seah et al [2002]
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 in the US and EU Clinical Trials Register in Europe 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.