Case Series of Fraser Syndrome

Abstract

Fraser syndrome is an autosomal recessive multiple malformation syndrome. It has a recurrence risk of 25% among siblings; therefore, prenatal diagnosis is important for counseling of affected families. We describe three prenatal cases of Fraser syndrome. Based on new diagnostic criteria, three major, two major, and two minor criteria or one major and three minor criteria are needed for diagnosis of Fraser syndrome. It includes six “major” manifestations, including syndactyly, cryptophthalmos spectrum, ambiguous genitalia, urinary tract abnormalities, laryngeal and tracheal anomalies, and positive family history with five “minor” defects, including anorectal defects, dysplastic ears, skull ossification defects, umbilical defects, and nasal anomalies. In all three of our cases, congenital high airway obstruction syndrome (CHAOS) was a constant finding. Renal system anomalies, including renal agenesis and dysplastic kidneys, anhydramnios, and ascites, were also found in all three cases. Prenatal diagnosis of Fraser syndrome was confirmed genetically postnatally in two out of the three patients, with an excellent correlation of antenatal sonographic findings with postnatal features of the abortus. Certain anomalies like syndactyly and cryptophthalmos, which were not possible to detect antenatally because of anhydramnios, were confirmed postnatally. We conclude that cases with antenatal diagnosis of CHAOS and bilateral renal agenesis/dysplastic kidneys must be advised for meticulous postnatal examination for the remaining features of Fraser syndrome, especially ambiguous genitalia, cryptophthalmos, and syndactyly and then confirm genetically to ensure appropriate counseling of the couple for future pregnancy.

Keywords

ambiguous genitalia - bilateral renal agenesis - CHAOS - Fraser syndrome - syndactyly - upper airway malformations - cryptophthalmos spectrum

Case 1

A 30 year old second gravida showed ultrasound findings of anhydramnios, bilateral renal agenesis, bilaterally large, hyperinflated uniformly echogenic lungs with dilated trachea and bronchi flattening of the diaphragm, and an anterior displacement of the heart, indicating congenital high airway obstruction syndrome (CHAOS) and gross ascites at 20 weeks. The first trimester scan was normal, with a low risk on combined first trimester screening. The patient's first pregnancy was terminated in the second trimester with a history of similar anomalies. Previous pregnancy reports were suggestive of CHAOS with bilateral renal agenesis and postabortal findings were a male fetus with cryptophthalmos and syndactyly in the left hand. There was no significant family or past medical history or history of consanguineous marriage.

The history of similar findings in the previous pregnancy raised a strong suspicion of Fraser syndrome and the parents were counseled about the poor prognosis and advised genetic testing. The patient decided to continue the pregnancy and went into spontaneous preterm labor at 7 months of gestation. The baby was examined by a pediatrician and ophthalmologist. Postnatal findings were syndactyly in the left hand between the middle and ring fingers, ambiguous genitalia, and a small chin. There was no cryptophthalmos ([Fig. 1]).

Fig. 1 Shows antenatal and postabortal images. (A) Image shows large echogenic lungs flattening the diaphragm. Dilated trachea and bronchi are also seen. (B) Gross ascites with free floating bowel loops. (C) The heart is squeezed and pushed anteriorly. (D) Normal eyes with small chin. (E) Ambiguous genitalia. (F) Syndactyly of the middle and ring fingers.

Comparison of Previous and Present Pregnancy Findings

CHAOS, bilateral renal agenesis, anhydramnios, syndactyly, and ambiguous genitalia were present in both the present fetus and previous pregnancy. Cryptophthalmos was present only in the previous pregnancy.

The newborn's blood was sent for molecular diagnosis (target mutation) of Fraser syndrome. A homozygous mutation in gene FRAS1 was detected, which is pathogenic for FRASER syndrome. Parents were also tested and were found (heterozygous) carriers for gene FRAS1.

• Genetic report of abortus: a homozygous variant was detected in exon 28 of gene FRAS1 of abortus, which is the pathogenic variant for Fraser syndrome.

• Genetic reports of parents: both parents were heterozygous for the tested variant, c3648G, in the FRAS1 gene.

Case 2

A young primigravida with first degree consanguinity was referred for a second opinion scan at 23 weeks for bilateral renal agenesis and anhydramnios. There was no relevant past or family history. The present scan showed bilateral hyperinflated, uniformly echogenic lungs with dilated trachea and bronchi. The heart was squeezed and pushed anteriorly with a flattened diaphragm and gross ascites. The kidneys and urinary bladder were not seen. The findings indicated CHAOS.

Features raised a strong suspicion of Fraser syndrome and parents were counseled about the poor prognosis and advised genetic testing. Postabortal findings were syndactyly in both hands and feet between the middle and ring fingers, ambiguous genitalia, and a small chin. There was no cryptophthalmos ([Fig. 2]).

Fig. 2 Shows antenatal and postabortal images. (A) Hyperinflated lungs, flattened diaphragm, and gross ascites. (B) Echogenic hyperinflated lungs with heart squeezed and pushed anteriorly. (C) Complete absence of liquor amnii around fetus with gross ascites. (D) Syndactyly in the feet. (E) Small chin with an absence of cryptophthalmos. (F) Syndactyly in the hand. (G) Ambiguous genitalia.

The sample was sent for a target mutation for Fraser syndrome and showed two mutations, FREM 1 and FREM 2.

• Genetic report: a heterozygous variant in intron 19 of gene FRAM1 and on exome 1 of gene FRAM2 are both pathogenic for Fraser syndrome. The parents refused genetic testing.

Case 3

A young primigravida with a history of first degree consanguineous marriage visited for an anomaly scan at 22 weeks with no significant past or medical history. Ultrasound showed severe edema all over the body with gross ascites, distended echogenic lungs with dilated trachea and bronchus, and anteriorly displaced heart indicating CHAOS. The cerebellum was small and hypoplastic. There was an outflow ventricular septal defect, and the aorta appeared very small with a vertical course without forming an arch, suggesting an interrupted aortic arch. The pulmonary artery was dilated. Both kidneys were small, measuring 14 mm in length and showed cortical cysts, suggesting dysplastic kidneys. The urinary bladder was persistently empty. There was a bilateral talipes deformity, single umbilical artery, and anhydramnios ([Fig. 3]).

Fig. 3 (A) Tomographic ultrasound imaging (TUI) view of the thorax and abdomen showing hyperinflated lungs with gross ascites. (B) Image shows convex diaphragm with heart pushed anteriorly and gross ascites. (C) Shows postabortal pictures. 1. Bilateral talipes deformity. 2. Syndactyly of the hand. 3. Micrognathia. 4. Ambiguous genitalia with vertical slit anus. 5. Cryptophthalmos. 6. Syndactyly of the foot.

As there was a strong suspicion of Fraser syndrome, parents were counseled about the poor prognosis and were advised for genetic testing. The patient decided to terminate the pregnancy. Postabortal findings were cryptophthalmos, ambiguous genitalia, vertical slit like anus, syndactyly of feet between the second, third, and fourth fingers, micrognathia, talipes, and single umbilical artery ([Table 1]).

Table 1 Comparison of the three cases in the form of ultrasound findings, postabortal findings, history, and genetic mutation

US findings	Patient 1	Patient 2	Patient 3
CHAOS	Yes	Yes	Yes
Ascites	Yes	Yes	Yes
Renal system	Bilateral renal agenesis	Bilateral renal agenesis	Bilateral dysplastic kidneys
Other			Hydrops, Dandy walker malformation talipes, IAA, Micrognathia
Postabortal findings
Cryptophthalmos	No	No	Yes
Syndactyly	Yes	Yes	Yes
Ambiguous genitalia	Yes	Yes	Yes
Anal atresia	No	No	Yes
Micrognathia/Small chin	Yes	Yes	Yes
H/O in sibling	Yes	No	No

Abbreviations: CHAOS, congenital high airway obstruction syndrome; H/O, history of; IAA, interrupted aortic arch; US, ultrasound.

Note: CHAOS, ascites, renal system abnormalities, syndactyly, ambiguous genitalia, and micrognathia were present in all three cases.

Discussion

Fraser syndrome is a rare autosomal recessive multisystem syndrome caused by mutations in different genes. These include FRAS1 (on chromosome 4q21 called Fraser syndrome-1), FRAM2 (on chromosome 13q13 called Fraser syndrome-2), and GRIP1 (on chromosome 12q14 called Fraser syndrome-3).[1] [2] [3] It is phenotypically characterized by multiple malformations with a prevalence of 0.43:100,000 at birth and 1:10,000 in stillbirths.[4] Mutations in FRAS1, FREM2, and GRIP1 are the cause of this pathogenesis. These genes encode the proteins of the extracellular matrix (ECM) that are essential for the adhesion between the basement membrane of the epidermis and connective tissues of the dermis layer during embryological development.[5] [6] FRAS1 and FREM2 are multidomain extracellular transmembrane proteins, and GRIP1 is required to present the FRAS/FREM complex at the basal membrane of epithelial cells. ECM proteins are important for cell adhesion and migration, basement membrane integrity, and epithelial mesenchymal interactions during development. Metanephric kidney development depends on interactions between the ureteric bud epithelium and adjacent mesenchyme, during which ECM proteins are involved. Cryptophthalmos and syndactyly arise from the loss of epidermal adhesion, causing interrupted epidermal/mesenchymal interactions between the eyelid epithelial or limb apical ectodermal ridge and the underlying mesenchyme. It is characterized by variable expression of cryptophthalmos, syndactyly, abnormal genitalia, malformations of the nose, ear, and larynx, renal agenesis, clefting, skeletal defects, umbilical hernia, and mental retardation in survivors. Other anomalies associated with Fraser syndrome are heart defects, major vascular anomalies, imperforate anus, intestinal hypoplasia, thymic aplasia, and cerebral malformations. Fraser syndrome has a recurrence risk of 25% among siblings; therefore, prenatal diagnosis is important for the counseling of affected families. Many researchers have given different criteria for diagnosis. Based on new diagnostic criteria,[7] three major or two major and two minor criteria or one major and three minor criteria are needed for the diagnosis of Fraser syndrome.[8] [9] [10]

It includes:

Six major manifestations	Five minor symptoms
1. Syndactyly	1. Anorectal defects
2. Cryptophthalmos spectrum	2. Dysplastic ears
3. Ambiguous genitalia	3. Skull ossification defects
4. Urinary tract abnormalities	4. Umbilical defects
5. Laryngeal and tracheal anomalies	5. Nasal anomalies
6. Positive family history

Differential Diagnosis

The differential diagnosis includes:

• Bilateral renal agenesis (isolated)

• CHAOS (isolated)

• Ablepharon-macrostomia (mutation in TWIST 2 gene-AD)

• Meckel syndrome (mutation in MKS1, MKS2, or MKS 3 gene-AR)

• Syndromic microphthalmia caused by heterozygous mutations of the SOX2 gene

Conclusion

Fraser syndrome/cryptophthalmos/syndactyly syndrome is an extremely rare congenital syndromic anomaly with autosomal recessive inheritance. Prenatal diagnosis of Fraser syndrome was confirmed genetically postnatally in two out of the three patients, with an excellent correlation of antenatal sonographic findings with postnatal features of the abortus. Certain anomalies like syndactyly and cryptophthalmos, which were not possible to detect antenatally due to anhydramnios, were confirmed postnatally. We conclude that cases with antenatal diagnosis of CHAOS and bilateral renal agenesis/dysplastic kidneys must be advised proper postnatal examination for the remaining features of Fraser syndrome, especially ambiguous genitalia and syndactyly, and then confirmed genetically. This will improve genetic counseling, prenatal molecular diagnosis, and sonographic screening in subsequent pregnancies.

Conflict of Interest

None declared.

• References

• 1 Fraser syndrome. Genetics Home Reference. June 2014. Accessed December 7, 2016 at: https://ghr.nlm.nih.gov/condition/fraser-syndrome . 2a
• 2 Thomas IT, Frias JL, Felix V, Sanchez de Leon L, Hernandez RA, Jones MC. Isolated and syndromic cryptophthalmos. Am J Med Genet 1986; 25 (01) 85-98
• 3 Bouaoud J, Olivetto M, Testelin S, Dakpé S, Bettoni J, Devauchelle B. Fraser syndrome: review of the literature illustrated by a historical adult case. Int J Oral Maxillofac Implants 2020; 49 (10) 1245-1253
• 4 Martínez-Frías ML, Bermejo Sánchez E, Félix V, Calvo Celada R, Ayala Garcés A, Hernández Ramón F. Fraser syndrome: frequency in our environment and clinical-epidemiological aspects of a consecutive series of cases [in Spanish]. An Esp Pediatr 1998; 48 (06) 634-638
• 5 McGregor L, Makela V, Darling SM. et al. Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. Nat Genet 2003; 34 (02) 203-208
• 6 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 (04) 487-495
• 7 van Haelst MM, Scambler PJ, Hennekam RC. Fraser Syndrome Collaboration Group. Fraser syndrome: a clinical study of 59 cases and evaluation of diagnostic criteria. Am J Med Genet A 2007; 143A (24) 3194-3203
• 8 McKusick VA. Fraser syndrome. OMIM. 10/05/2015. Accessed December 7, 2016 at: http://www.omim.org/entry/219000
• 9 Tessier A, Sarreau M, Pelluard F. et al. Fraser syndrome: features suggestive of prenatal diagnosis in a review of 38 cases. Prenat Diagn 2016; 36 (13) 1270-1275
• 10 De Bernardo G, Giordano M, Di Toro A, Sordino D, De Brasi D. Prenatal diagnosis of Fraser syndrome: a matter of life or death?. Ital J Pediatr 2015; 41: 86

Publication History

Article published online:
28 May 2025