intrafamilial variability in fraser syndrome

PRENATAL DIAGNOSISPrenat Diagn 2007; 27: 778–782.Published online 4 June 2007 in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/pd.1774

SHORT COMMUNICATION

Intrafamilial variability in Fraser syndrome

Pankaj Prasun,* Mandakini Pradhan and Himanshu GoelSanjay Gandhi Postgraduate Institute of Medical Sciences, Medical Genetics, India

Fraser syndrome (OMIM 219000) is a rare, autosomal recessive disorder characterized by cryptophthalmos,cutanaeous syndactyly, malformations of the larynx and genitourinary tract, craniofacial dysmorphism, orofacialclefting, mental retardation and musculoskeletal anomalies. There is marked interfamilial clinical heterogeneity.However, there is strong phenotypic similarity and concordance of the degree of severity of the disease withina family. We report a family with two cases of Fraser syndrome with marked clinical heterogeneity. One casehad lethal phenotype with bilateral renal agenesis, while the other had mild phenotype with normal kidneys.It has not been reported before and highlights the importance of careful screening of pregnancies in familieswith Fraser syndrome. Copyright 2007 John Wiley & Sons, Ltd.

KEY WORDS: Fraser syndrome; cryptophthalmos syndrome; prenatal diagnosis

INTRODUCTION

Fraser syndrome, also known as cryptophthalmos syn-drome, is characterized by cryptophthalmos, cutaneoussyndactyly, abnormal genitalia, and other variable de-fects such as malformed ears, cleft lip, cleft palate,renal agenesis, and mental retardation. The inheritanceis autosomal recessive. Clinical expression of the dis-ease is very variable. Interfamilial clinical heterogeneityranges from lethal phenotypes with bilateral renal age-nesis to patients with only minor malformations. How-ever, there is strong phenotypic similarity and concor-dance of the degree of severity of the disease within afamily (Slavotinek and Tifft, 2002). Renal adysplasiais a common manifestation of the disease. The liter-ature search shows that renal adysplasia recurs con-stantly in families with severe form of Fraser syndrome(Burn and Marwood, 1982; Mortimer et al., 1985; Boydet al., 1988; Francannet et al., 1990; Rousseau et al.,2002).

Here we report a family with two cases of Frasersyndrome. One had lethal phenotype with bilateral renalagenesis, while the other had non lethal phenotypewith normal kidneys. Occurrence of lethal and nonlethal phenotypes of Fraser syndrome within a familyis very rare. There is no report of Fraser syndromewith bilateral renal agenesis occurring together withthe milder phenotype with normal kidneys in the samefamily.

Molecular basis of this disease is becoming clearer.We have tried to explain the marked clinical hetero-geneity of the disease and our observations in contextof the recent advances in molecular genetics of this dis-ease.

*Correspondence to: Dr. Pankaj Prasun, Department of MedicalGenetics, Sanjay Gandhi Postgraduate Institute of Medical Sci-ences, Lucknow, India - 226014.E-mail: [email protected]

CASE REPORT

The parents (27-year-old father and 24-year-old mother)were healthy and nonconsanguineous. There was nofamily history of malformations or recurrent sponta-neous abortions.

Case 1

A 13-day-old child was referred to the Genetic clinicof this hospital for facial dysmorphism and abnormalgenitalia. The baby weighed 1.77 kg (<5th centile) andhad head circumference of 31.4 cm (<5th centile) andlength of 43.2 cm (<5th centile). The right eye wascovered with skin (Figure 1). The eye globe could bepalpated underneath the skin. There was absence ofeyelids and eyebrow over that eye. In addition, therewere bifid nasal tip, low-set right ear, high archedpalate, micrognathia, tongue of hair over forehead,bilateral cutaneous syndactyly, and low umbilicus. Thegenitalia were ambiguous with clitoral hypertrophy andlarge labia major (Figure 2). There were no palpablegonads. Ultrasound abdomen showed presence of uterus.Kidneys were normal. The chromosome analysis wasnormal (46,XX). The child underwent lid reconstructionsurgery without much success. Her last visit to us was at15 months of age. She had global developmental delay.Renal function tests were normal.

Case 2

The mother was referred again at 24 weeks gestationas there was gross oligohydramnios. Ultrasound exam-ination showed severe oligohydramnios and bilateralrenal agenesis. Umbilical cord insertion was low. Botheyeballs could be appreciated. Diagnosis of Fraser syn-drome was considered in view of renal agenesis, low

Copyright 2007 John Wiley & Sons, Ltd. Received: 19 January 2007Revised: 27 March 2007Accepted: 18 April 2007

Published online: 4 June 2007

INTRAFAMILIAL VARIABILITY IN FRASER SYNDROME 779

Figure 1—Case 1. Right cryptophthalmos, bifid nasal tip and tongueof hair over forehead

Figure 2—Case 1. Ambiguous genitalia: clitoral hypertrophy, largelabia major

cord insertion and previous affected child. After coun-seling the pregnancy was terminated at 24 weeks ofgestation. A male fetus was delivered weighing 675 gm(50th centile), with crown rump length of 22.3 cm (50th

Figure 3—Case 2. Right cryptophthalmos, low-set ears and low-setumbilical cord

centile) and head circumference of 21.7 cm (50th cen-tile). Autopsy was performed. There was right cryptoph-thalmos (Figure 3). The ears were low-set. Hands andfeet had cutanaeous syndactyly (Figure 4), and umbili-cal cord was inserted just above the pubic symphysis.Laryngeal stenosis was present. Abdominal examinationshowed bilateral renal agenesis (Figure 5). Urinary blad-der was vestigial. Postmortem chromosome analysis wasnormal (46,XY).

DISCUSSION

Thomas et al. (1986) proposed the diagnostic criteriaof Fraser syndrome. The presence of two major andone minor criterion, or one major and four minor cri-teria are compatible with the diagnosis (Table 1). The

Copyright 2007 John Wiley & Sons, Ltd. Prenat Diagn 2007; 27: 778–782.DOI: 10.1002/pd

780 P. PRASUN ET AL.

Figure 4—Case 2. Cutanaeous syndactyly of left hand and right foot

Figure 5—Case 2. Bilateral renal agenesis 97 × 110 mm (72 ×72 DPI)

main features are cryptophthalmos (∼90%), cutaneoussyndactyly (∼60%), ear abnormalities (∼60%), renalagenesis (∼45%) and congenital heart defects (∼10%).Surviving cases are often mentally retarded. In contrastto the marked interfamilial clinical heterogeneity, theexpression within a family tends to be similar. Particu-larly, the severe feature of the disease remains constantinside a family. Renal agenesis is a very common findingin Fraser syndrome. In previous reports of kindred withsevere forms of Fraser syndrome, bilateral renal agene-sis was found to recur constantly (Burn and Marwood,1982; Mortimer et al., 1985; Boyd et al., 1988).

Table 1—Diagnostic criteria forFraser syndrome from Thomaset al. (1986)

Major criteriaCryptophthalmosSyndactylyAbnormal genitaliaSib with Fraser syndromeMinor criteriaCongenital malformation of noseCongenital malformation of earsCongenital malformation of larynxCleft lip and/or palateSkeletal defectsUmbilical herniaRenal agenesisMental retardation

The present two cases were compatible with the diag-nosis of Fraser syndrome. However, there was markedphenotypic variability. The kidneys were normal in thefirst case and there was no malformation incompatiblefor survival. In contrast, the second case had bilateralrenal agenesis and laryngeal stenosis incompatible forlife. Intrafamilial variability is known but rare. Rousseauet al. (2002) described a family with two cases of Frasersyndrome with clinical variability. In one case, cryp-tiphthalmos was represented by bilateral and asymmet-ric absence of eyelids. The other case had symmetri-cal cryptophthalmos and multiple malformations includ-ing laryngeal stenosis, intestinal malrotation, and vagi-nal atresia. However, the condition was lethal in bothinstances due to renal adysplasia. There was bilateralrenal agenesis in one, while the other had unilateralrenal agenesis with multicystic dysplasia of the remain-ing kidney.

Fraser syndrome has been equated with ‘blebbed’mice models. These mice have overlapping phenotypescharacterized by combinations of subepidermal blister-ing, syndactyly, cryptophthalmos, and renal anomalies(Smyth and Scambler, 2005). Fras1, Frem2, Grip1,


INTRAFAMILIAL VARIABILITY IN FRASER SYNDROME 781

Table 2—Similarity between Fraser syndrome and Bardet-Biedl syndrome

Features Bardet–Biedl syndrome Fraser syndrome

Clinical Marked clinical heterogeneity; significantinterfamilial and intrafamilial variability.

Marked clinical heterogeneity;interfamilial and intrafamilial variability.

Genetic Initially modeled as purely autosomalrecessive trait.

An autosomal recessive trait.

Eight BBS loci have been mapped, andsix BBS genes are known (Katsanis,2004).

Mice models suggest at least five loci.

Oligogenic inheritance has been provedin some families.

Two genes (FRAS1 and FREM2 ) havebeen identified in human families.Oligogenic inheritance is a strongpossibility.

Cellular and biochemical The various BBS proteins are supposedto be involved in formation of amultiprotein complex which plays a rolein function of basal body of ciliatedcells.

The various Fraser syndrome associatedproteins are supposed to be involved information of a multiprotein complexwhich participates inepithelial–mesenchymal interactions.

Basal body dysfunction has beenimplicated in the pathogenesis of BBS(Ansley et al., 2003).

Impaired epithelial–mesenchymalinteractions have been implicated in thepathogenesis of Fraser syndrome.

and Qbrick/Frem1 have been recognized as the genesmutated in these mice models. Mutations in FRAS1and FREM2 genes have been identified in human fam-ilies with Fraser syndrome (McGregor et al., 2003;Jadeja et al., 2005). Fras1, Frem2, and Qbrick/Frem1encode members of a family of extracellular matrix(ECM) proteins (Kiyozumi et al., 2006). ECM pro-teins control cellular behaviors including, adhesion,migration, differentiation, and proliferation. They arealso instrumental in intercellular communication andepithelial–mesenchymal interactions during develop-ment. Metanephric kidney development is dependenton inductive interactions between the epithelium ofthe ureteric bud and the adjacent mesenchyme inwhich ECM proteins are involved (Vrontou et al.,2003). Similarly, cryptophthalmos and syndactyly arethought to arise as a consequence of interruptedepithelial–mesenchymal interactions between the eye-lid epithelia or limb apical ectodermal ridge (AER)and the underlying mesenchyme. Defective epithe-lial–mesenchymal interaction is thought to be the under-lying pathogenic mechanism of Fraser syndrome. In fact,the blebs genes are highly expressed in tissues in whicha differentiating or remodeling epidermis is interactingwith mesenchyme, suggesting their role in tissue dif-ferentiation (Smyth and Scambler, 2005). The strikingphenotypic similarity of mutant mice led to specula-tion that the deficits caused by mutations in the iden-tified genes might affect a common process. Indeed,it has been suggested that Fraser syndrome associatedECM proteins become functional after their coordi-nated assembly into the basement membrane (Kiyozumiet al., 2006). This complex is thought to participatein epithelial–mesenchymal interactions during develop-ment. Incomplete assembly of this complex secondaryto impaired expression of any component will lead toan unstable unit.

The accumulating clinical, genetic and biochemicaldata suggest that Fraser syndrome may have oligogenic

properties. Mutations at different Fraser syndrome locican interact to cause and/or modify the phenotype. Evi-dence suggests that different Fraser syndrome associatedproteins participate in a common pathway (Kiyozumiet al., 2006). Thus, presence of additional mutation orpolymorphism may modify the severity or pleiotropyof the disease even inside a family. It is interestingto mention here that Fraser syndrome resemble Bardet-Biedl syndrome (BBS) in many aspects (Table 2). BBSwas initially portrayed as purely autosomal recessivetrait. The oligogenic nature of BBS has become obviousafter identification of several BBS loci which in someinstances have been shown to interact and modify thephenotype (Badano et al., 2003; Katsanis, 2004).

The intrafamilial variability present in this family maybe due to additional mutation in another Fraser syndromeassociated gene in one of the cases which might havemodified the phenotype. But, in the absence of molecularevidence, this is only a speculation. However, intrafamil-ial variability is a rare but genuine possibility in Frasersyndrome. This issue is relevant in the prenatal diagno-sis of this condition. In the case of an affected child in afamily, all the features of this condition should be lookedfor during prenatal imaging of the next pregnancy. Con-centrating only on those features which are present inthe proband may miss the diagnosis.

REFERENCES

Ansley SJ, Badano JL, Blacque OE, et al. 2003. Basal bodydysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome.Nature 425(6958): 628–633.

Badano JL, Kim JC, Hoskins BE, et al. 2003. Heterozygousmutations in BBS1, BBS2 and BBS6 have a potential epistatic effecton Bardet-Biedl patients with two mutations at a second BBS locus.Hum Mol Genet 12: 1651–1659.

Boyd PA, Keeling JW, Lindenbaum RH. 1988. Fraser syndrome(cryptophthalmos-syndactyly syndrome): a review of eleven caseswith postmortem findings. Am J Med Genet 31: 159–168.


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Burn J, Marwood RP. 1982. Fraser syndrome presenting as bilateralrenal agenesis in three sibs. J Med Genet 19: 360–361.

Francannet C, Lefrancois P, Dechelotte P, Robert E, Malpuech G,Robert JM. 1990. Fraser syndrome with renal agenesis in twoconsanguineous Turkish families. Am J Med Genet 36: 477–479.

Jadeja S, Smyth I, Pitera JE, et al. 2005. Identification of a new genemutated in Fraser syndrome and mouse myelencephalic blebs. NatGenet 37: 520–525.

Katsanis N. 2004. The oligogenic properties of Bardet-Biedlsyndrome. Hum Mol Genet 13: R65–R71, Spec No 1.

Kiyozumi D, Sugimoto N, Sekiguchi K. 2006. Breakdown of thereciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 at thebasement membrane provokes Fraser syndrome-like defects. ProcNatl Acad Sci U S A 103: 11981–11986.

McGregor L, Makela V, Darling SM, et al. 2003. Fraser syndromeand mouse blebbed phenotype caused by mutations in FRAS1/Fras1encoding a putative extracellular matrix protein. Nat Genet 34:203–208.

Mortimer G, Mc Ewan HP, Yates JR. 1985. Fraser syndromepresenting as monozygotic twins with bilateral renal agenesis. JMed Genet 22: 76–78.

Rousseau T, Laurent N, Thauvin-Robinet C, et al. 2002. Prenataldiagnosis and intrafamilial clinical heterogeneity of Frasersyndrome. Prenat Diagn 22: 692–696.

Slavotinek AM, Tifft CJ. 2002. Fraser syndrome and cryptophthal-mos: review of the diagnostic criteria and evidence for phenotypicmodules in complex malformation syndromes. J Med Genet 39:623–633.

Smyth I, Scambler P. 2005. The genetics of Fraser syndrome and theblebs mouse mutants. Hum Mol Genet 14: R269–R274, Spec No.2.

Thomas IT, Frias JL, Felix V, Sanchez de Leon L, Hernandez RA,Jones MC. 1986. Isolated and syndromic cryptophthalmos. Am JMed Genet 25: 85–98.

Vrontou S, Petrou P, Meyer BI, et al. 2003. Fras1 deficiency resultsin cryptophthalmos, renal agenesis and blebbed phenotype in mice.Nat Genet 34: 209–214.


intrafamilial variability in fraser syndrome

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