FREM1 Autosomal Recessive Disorders

Excerpt

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 kidney malformations (e.g., renal agenesis, renal dysplasia). Typically, the eye manifestations of MOTA syndrome are absent.

FREM1-related CAKUT has been reported in two boys from Macedonia with isolated CAKUT who had the same homozygous FREM1 pathogenic variants.

Diagnosis/testing: The diagnosis of a FREM1 autosomal recessive disorder is established in a proband with biallelic pathogenic variants in FREM1 identified by 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. Dilation for anal stenosis. Surgical closure of omphalocele; surgical or conservative management of umbilical hernia. Supportive treatment to preserve kidney function and electrolyte balance; dialysis and transplant if indicated in individuals with kidney failure. Psychosocial support and care coordination as needed.

Surveillance: Assess kidney function in those with kidney disease with frequency per nephrologist; social work and family support at each visit.

Genetic counseling: Phenotypes caused by biallelic FREM1 pathogenic variants – including MOTA syndrome, BNAR syndrome, and FREM1-related CAKUT – are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a FREM1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a 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, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.