The first adolescent case of Fraser syndrome 3, with a novel nonsense variant in GRIP1.

Fraser syndrome is characterized by cryptophthalmos, syndactyly and other autopod defects, and abnormalities of the respiratory and urogenital tracts. Biallelic variants in GRIP1 can cause Fraser syndrome 3 (FRASRS3), and five unrelated FRASRS3 cases have been reported to date. Four cases are fetuses with homozygous truncating variants. The remaining case is an almost 9-year-old Turkish girl compound heterozygous for a truncation variant and a possibly frame-shift intragenic deletion. We present a 15.5-year old Pakistani boy with homozygous truncating variant c.1774C>T (p.Gln592Ter). Of the hallmarks of the disease, the boy has cryptophthalmia, midface retrusion, very low anterior hairline, hair growth on temples extending to the supraorbital line and also on alae nasi, agenesis of right kidney, and cutaneous syndactyly of fingers and toes but no symptoms in any other organs, including lungs, anorectal system, genitalia, and umbilical system. This case is the oldest known individual with FRASRS3, and our findings show that a homozygous GRIP1 truncating variant can manifest with a non-lethal phenotype than in the reported cases with such variants, expanding the phenotypic and mutational spectrum of GRIP1.

Bilateral anophthalmia and intrahepatic biliary atresia, two unusual components of Fraser syndrome: a case report.

BACKGROUND: Fraser syndrome or "cryptophthalmos syndrome" is a rare autosomal recessive disease. It is characterized by a group of congenital malformations such as: crytophthalmos, syndactyly, abnormal genitalia, and malformations of the nose, ears, and larynx. Although cryptophthalmos is considered as a main feature of Fraser syndrome, its absence does not exclude the diagnosis. Clinical diagnosis can be made by Thomas Criteria. Here we present the first documented case of Fraser Syndrome in Aleppo, Syria that is characterized by bilateral anophthalmia and intrahepatic biliary atresia. CASE PRESENTATION: During pregnancy, several ultrasound scans revealed hyperechoic lungs, ascites, and unremarkable right kidney at the 19th-week visit; bilateral syndactyly on both hands and feet at the 32nd-week visit. On the 39th week of gestation, the stillborn was delivered by cesarean section due to cephalopelvic disproportion. Gross examination showed bilateral anophthalmia, bilateral syndactyly on hands and feet, low set ears, and ambiguous genitalia. Microscopic examination of the lung, spleen, liver, ovary, and kidneys revealed abnormalities in these organs. CONCLUSION: The diagnosis of Fraser syndrome can be made prenatally and postnatally; prenatally by ultrasound at 18 weeks of gestation and postnatally by clinical examination using Thomas criteria. Moreover, intrahepatic biliary atresia was not described previously with Fraser syndrome; this recommends a more detailed pathologic study for Fraser syndrome cases.

Two unrelated families with variable expression of Fraser syndrome due to the same pathogenic variant in the FRAS1 gene.

We report on two unrelated families of Polish origin with variable expression of Fraser syndrome (FS; MIM#219000) due to homozygosity for the same pathogenic variant, c.6963_6964dup, of FRAS1. In one family, the disorder presented with perinatal and prenatal lethality. One affected female from family 2 who was followed-up for 32 years, represented a relatively favorable long-term outcome. She displayed the typical craniofacial dysmorphism, including right cryptophthalmos, cutaneous syndactyly, abnormalities of the stomathognatic system, bilateral atresia of the external ear canals resulting in conductive hearing loss, and malformations of the larynx, spleen, kidney, and genitourinary tract. Her intellectual capacities were normal. Our observations illustrate that expression and severity of FS, even when caused by the same pathogenic variant, may be quite different ranging from a lethal disorder to a condition with multiple physical malformations but normal psychomotor development. In addition, we propose that the FRAS1 c.6963_6964dup variant may be a founder mutation in the Polish population. Therefore, it would be reasonable to test specifically for this variant first in any FS1 patient of Polish ancestry.

Genetic mutation of Frem3 does not causeFraser syndrome in mice.

QBRICK, FRAS1, and FREM2 compose a family of extracellular matrix proteins characterized by twelve consecutive CSPG repeats and single or multiple Calx-ß motifs. Dysfunction of these proteins have been associated with Fraser syndrome, which is characterized by malformation of skin, eyes, digits, and kidneys. FREM3 is another member of the 12-CSPG protein family. However, it remains unknown whether genetic dysfunction of FREM3 also causes Fraser syndrome or another developmental disorder. Here we investigated a Frem3 mutant mouse line generated by CRISPR/Cas9-mediated genome editing. The FREM3 mutant homozygotes were born at the expected Mendelian ratio and did not possess any defects characteristic of Fraser syndrome. These results indicate that the dysfunction of FREM3 is not associated with Fraser syndrome.

A homozygous mutation p.Arg2167Trp in FREM2 causes isolated cryptophthalmos.

Cryptophthalmos (CO, MIM: 123570) is rare congenital anomalies of eyelid formation, which can occur alone or in combination with multiple congenital anomalies as part of Fraser syndrome (FS) or Manitoba Oculotrichoanal syndrome. Causal mutations have been identified for these syndromes but not in the isolated cases. Here, we described two patients from two unrelated Chinese families: one with unilateral isolated CO, while the other with unilateral CO and renal agenesis. A novel homozygous mutation (c.6499C>T: p.Arg2167Trp) and compound heterozygote mutations (c.15delG; c.6499C>T: p.Arg2167Trp) in FREM2 (NM_172862) were identified for the two patients, respectively. The deletion mutation c.15delG resulted in a frameshift and triggered the nonsense-mediated mRNA decay. For the shared missense mutation, p.Arg2167Trp altered a conserved residue and was predicted to affect protein structure by in silico analysis. Functional analysis revealed that Arg2167Trp mutant decreased its interaction with FRAS1 related extracellular matrix 1 (FREM1) and impaired the function of the FRAS1-FRAS1 related extracellular matrix 1 (FREM2)-FREM1 ternary complex required for normal embryogenesis. Furthermore, considering that mutation (c.5914C>T: p.Glu1972Lys) in FREM2 causes FS, a severe systemic disorder, we also compared these two different missense mutations. Our results showed that p.Arg2167Trp had a weaker effect in interrupting interactions between FREM2 and FREM1 than FS-associated missense mutation p.Glu1972Lys. Overall, our data demonstrate that the homozygous mutation p.Arg2167Trp in FREM2 causes isolated CO, which will facilitate our better understanding of the molecular mechanisms underlying the disease.

Expanding the mutation spectrum for Fraser syndrome: identification of a novel heterozygous deletion in FRAS1.

Fraser syndrome (FS) is a rare autosomal recessive inherited disorder characterized by cryptophthalmos, laryngeal defects and oral clefting, mental retardation, syndactyly, and urogenital defects. To date, 250 patients have been described in the literature. Mutations in the FRAS1 gene on chromosome 4 have been identified in patients with Fraser syndrome. So far, 26 mutations have been identified, most of them are truncating mutations. The mutational spectrum includes nucleotide substitutions, splicing defects, a large insertion, and small deletions/insertions. Moreover, single heterozygous missense mutations in FRAS1 seem to be responsible for non-syndromic unilateral renal agenesis. Here we report the first case of a family with two patients affected by Fraser syndrome due to a deletion of 64 kb (deletion 4q21.21) and an additional novel frameshift mutation in exon 66 of the FRAS1 gene. To date, large deletions of the FRAS1 gene have not yet been described. Large deletions seem to be a rare cause for Fraser syndrome, but should be considered in patients with a single heterozygous mutation.

A puzzle over several decades: eye anomalies with FRAS1 and STRA6 mutations in the same family.

Fraser syndrome (FS) and microphthalmia syndromic 9 (MCOPS9) are autosomal recessive conditions with distinct, and some overlapping features affecting the ocular, respiratory and cardiac systems. Mutations in FRAS1 and FREM2 occur in FS, and mutations in STRA6 occur in MCOPS9. We report two sibships, in the same family, where four deceased offspring had ocular, respiratory and cardiac abnormalities. Two sibs with microphthalmia had syndactyly and laryngeal stenosis, suggesting a clinical diagnosis of FS. Our results indicate that they were compound heterozygotes for novel FRAS1 mutations, p.Cys729Phe and p.Leu3813Pro. The other two sibs, first cousins to the first sib pair, had anophthalmia, lung hypoplasia and cardiac anomalies, suggesting a retrospective diagnosis of MCOPS9. Our results indicate compound heterozygous STRA6 mutations, a novel frameshift leading to p.Tyr18* and a p.Thr644Met mutation. The one surviving individual from these sibships is heterozygous for the p.Tyr18*STRA6 mutation and has bilateral ocular colobomata and microphthalmia. This work emphasises the need for careful phenotypic characterisation to determine genes for assessment in ocular syndromic conditions. It also indicates that heterozygous STRA6 mutations may rarely contribute to microphthalmia and coloboma.

Mutations in GRIP1 cause Fraser syndrome.

BACKGROUND: Fraser syndrome (FS) is a autosomal recessive malformation syndrome characterised by cryptophthalmos, syndactyly and urogenital defects. FS is a genetically heterogeneous condition. Thus far, mutations in FRAS1 and FREM2 have been identified as cause of FS. Both FRAS1 and FREM2 encode extracellular matrix proteins that are essential for the adhesion between epidermal basement membrane and the underlying dermal connective tissues during embryonic development. Mutations in murine Grip1, which encodes a scaffolding protein that interacts with Fras1/Frem proteins, result in FS-like defects in mice. OBJECTIVE: To test GRIP1 for genetic variants in FS families that do not have mutations in FRAS1 and FREM2. METHODS AND RESULTS: In three unrelated families with parental consanguinity, GRIP1 mutations were found to segregate with the disease in an autosomal recessive manner (donor splice site mutation NM_021150.3:c.2113+1G→C in two families and a 4-bp deletion, NM_021150.3:c.1181_1184del in the third). RT-PCR analysis of the GRIP1 mRNA showed that the c.2113+1G→C splice mutation causes skipping of exon 17, leading to a frame shift and a premature stop of translation. CONCLUSION: Mutations in GRIP1 cause classic FS in humans.

Expression of Fraser syndrome genes in normal and polycystic murine kidneys.

BACKGROUND: Fraser syndrome (FS) features renal agenesis and cystic kidneys. Mutations of FRAS1 (Fraser syndrome 1)and FREM2 (FRAS1-related extracellular matrix protein 2)cause FS. They code for basement membrane proteins expressed in metanephric epithelia where they mediate epithelial/mesenchymal signalling. Little is known about whether and where these molecules are expressed in more mature kidneys. METHODS: In healthy and congenital polycystic kidney (cpk)mouse kidneys we sought Frem2 expression using a LacZ reporter gene and quantified Fras family transcripts. Fras1 immunohistochemistry was undertaken in cystic kidneys from cpk mice and PCK (Pkhd1 mutant) rats (models of autosomal recessive polycystic kidney disease) and in wildtype metanephroi rendered cystic by dexamethasone. RESULTS: Nascent nephrons transiently expressed Frem2 in both tubule and podocyte epithelia. Maturing and adult collecting ducts also expressed Frem2. Frem2 was expressed in cpk cystic epithelia although Frem2 haploinsufficiency did not significantly modify cystogenesis in vivo. Fras1 transcripts were significantly upregulated, and Frem3 downregulated, in polycystic kidneys versus the non-cystic kidneys of littermates. Fras1 was immunodetected in cpk, PCK and dexamethasone-induced cystepithelia. CONCLUSIONS: These descriptive results are consistent with the hypothesis that Fras family molecules play diverse roles in kidney epithelia. In future, this should be tested by conditional deletion of FS genes in nephron segments and collecting ducts.

[Bilateral anophthalmia and left-sided orbital tumor : case of an eight-month-old infant]. / Beidseitiger Anophthalmus und linksseitiger Orbitatumor : Fall eines acht Monate alten Säuglings.

An 8-month-old infant from Russia with bilateral anophthalmia presented with an expanding orbital tumor. The tumor was extirpated and the histological examination revealed a non-malignant pseudocystic process with residual neuro-ectodermal structures.

Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1.

BACKGROUND: Manitoba-oculo-tricho-anal (MOTA) syndrome is a rare condition defined by eyelid colobomas, cryptophthalmos and anophthalmia/microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. Autosomal recessive inheritance had been assumed because of consanguinity in the Oji-Cre population of Manitoba and reports of affected siblings, but no locus or cytogenetic aberration had previously been described. METHODS AND RESULTS: This study shows that MOTA syndrome is caused by mutations in FREM1, a gene previously mutated in bifid nose, renal agenesis, and anorectal malformations (BNAR) syndrome. MOTA syndrome and BNAR syndrome can therefore be considered as part of a phenotypic spectrum that is similar to, but distinct from and less severe than, Fraser syndrome. Re-examination of Frem1(bat/bat) mutant mice found new evidence that Frem1 is involved in anal and craniofacial development, with anal prolapse, eyelid colobomas, telecanthus, a shortened snout and reduced philtral height present in the mutant mice, similar to the human phenotype in MOTA syndrome. CONCLUSIONS: The milder phenotypes associated with FREM1 deficiency in humans (MOTA syndrome and BNAR syndrome) compared to that resulting from FRAS1 and FREM2 loss of function (Fraser syndrome) are also consistent with the less severe phenotypes resulting from Frem1 loss of function in mice. Together, Fraser, BNAR and MOTA syndromes constitute a clinically overlapping group of FRAS-FREM complex diseases.