Fraser Syndrome: Case Report with Review of Literature

doi:10.4236/ojoph.2011.11001

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Open Journal of Ophthalmol ogy, 2011, 1, 1-3

doi:10.4236/ojoph.2011.11001 Published Online November 2011 (http://www.SciRP.org/journal/ojoph)

Fraser Syndrome: Case Report with Review of

Literature

Saruban Pasu1*, Luna Dhir2, Sarah Mackenzie3, Graham Thompson3

1Moorfields Eye Hospital NHS Foundation Trust, London, England; 2Chelsea and Westminster Hospital, London, England; 3Moor-

fields at St. George’s Hospital, Duke Elder Eye Centre, Tooting, London, England.

Email: [email protected]

Received September 26th, 2011; revised October 23rd, 2011; accepted November 3rd, 2011.

ABSTRACT

Fraser syndrome is a rare autosomal recessive multisystem disorder with a reported incidence of 0.043 per 10,0 00 live

born infants and 1.1 in 10,000 stillbirths [1]. The condition is cha racterised by cryptophtha lmos, cutaneous syndactyly,

laryngeal and genitourinary malformations, craniofacial dysmorphism, orofacial clefting, musculoskeletal anomalies

and mental retardation. The diagnosis can be made on prenatal scans, post natal clinical examination or on autopsy

findings. We present a case of Fraser syndrome and review of the ocular manifestations of this co ndition.

Keywords: Cryptophthalmos, Fraser Sy n dr o me

1. Case History

A one day old male infant was referred to the ophthal-

mology department for assessment of a fused right upper

and lower eyelid. He was the first child born to noncon-

sanguineous parents of south East Asian origin. He had a

birth weight of 2.8 Kg and was born via vaginal ventouse

delivery at 39 + 2 weeks. Antenatal scans at 20 weeks

had revealed unilateral right renal agenesis (see Figure

1(a)). An apparently normal left kidney was seen at this

stage (see Figure 1(b)). No other abnormalities were

noted on antenatal scanning.

Clinical examination revealed a normal anterior and

posterior segment of the left eye. Right complete cryp-

tophthalmos was noted with a palpable eyeball beneath

(see Figure 1(c)). Systemic examination findings were

an umbilical hernia, widely spaced fontanelle, bulbous

nose and clinodactyly of the right fourth and fifth toes.

The genitalia were normal, and no hypertelorism or oro-

facial clefting were noted. Further ultrasound scans and

biochemical investigations showed the left kidney to be

cystic, dyplastic and poorly functioning.

An MRI orbits and brain confirmed right cryptoph-

thalmos (see Figure 1(d)).

A diagnosis of Fraser syndrome was made based on

the clinical findings.

2. Discussion

The earliest reports of what is now known as cryptoph-

thalmos (hidden eye) date back to the first century A.D.

Pliny the Elder described the Lepidus family in which

three children were born with a membrane over the eye,

typical of this rare anomaly.

The term cryptophthalmos was introduced by Ze-

hender [2] et al. in 1872 who described a child whose

eyes were covered by continuous sheets of skin from

forehead to cheek, associated with additional malforma-

tions including hypertelorism, syndactyly, abnormal

genitalia, umbilical hernia , anal stenosis and hoarse voice.

George Fraser [3] in 1962 was the first to group these

features together under the term “cryptophthalmos syn-

drome”. In fact, cryptophthalmos is not always a feature

of this syndrome, and thus, the eponym Fraser syndrome

is preferable for the condition.

Fraser syndrome is a multiple malformation syndrome

with a probable autosomal recessive inheritance. It may

be caused by mutations in two genes FRAS1 [4] (chro-

mosome 4) and FREM2 [4]. The FRAS1 extracellular

matrix protein regulates epidermal-basement membrane

adhesion and organogenesis during development. The

FREM2 gene (chromosome 13) encodes the FRAS1-

related extracellular matrix protein 2.

Thomas et al. in 1986 were the first to publish diag-

nostic criteria (see Table 1) for Fraser syndrome. The

criteria were based upon a study of 124 cases. Two major

criteria and one minor criterion or one major and at least

four minor criteria were required for the diagnosis of

Fraser Syndrome: Case Report with Review of Literature

(a) (b) (c) (d)

#Written consent from the patient’ s mother has been obtaine d and she is happy to be contacted on ferhatuddin@hot mail.com

Figure 1. (a) Absent right kidney; (b) Apparently normal left kidney on antenatal ultrasound scan; (c) Clinical photograph

showing right eye complete cryptophthalmos; (d) T2 weighted axial MRI brain and orbits showing absence of right eye crys-

talline lens with cystic appearance to right eye anterior chamber. Extradural haematoma following ventouse delivery is also

present.

Table 1. Diagnostic criteria for Fraser syndrome: two ma-

jor criteria and one minor criterion or one major and at

least four minor criteria were required for the diagnosis of

Fraser syndrome. Asterisks mark the malformations pre-

sent in our case.

Cryptophthalmos *

Syndactyly

Abnormal genitali a

Major

Criteria

Sib with Fraser syndrome

Congenital malformation of nose *

Congenital malformation of ears

Congenital malformation of larynx

Cleft lip +/– palate

Skeletal defects *

Umbilical hernia *

Renal agenesis *

Minor

Criteria

Mental retardation

Fraser syndrome [5].

The patient we described fulfils the criteria for a diag-

nosis of Fraser syndrome. These criteria helped differen-

tiate Fraser syndrome from isolated cryptophthalmos.

Feldman et al. reported the first prenatal detection of

Fraser syndrome in 1985. Their diagnosis was based on

microphthalmia and hydrocephalus at 18 weeks of gesta-

tion, with a previous ly affected sibling [6].

Slavotinek [7] et al.’s work in 2002 aimed to validate

the published diagnostic criteria and delineate the phe-

notype associated with this syndrome. Based on their

review of 117 cases, cryptophthalmos was present in

88% of cases (unilateral in 27.4%, bilateral in 47.9%).

This is consistent with previous reports, Thomas et al. [5]

reported 85% and Gattuso et al. [8] 93% (unilateral 25%,

bilateral 57%).

Numerous ocular manifestations of Fraser syndrome

have been reported. The findings from the Slavotinek

review are summarised in Table 2.

Francois’ [9] review of 43 cryptophthalmos cases lead

to this ophthalmic sign being divided into 3 groups.

Complete (typical) cryptophthalmos is usually bilateral

structure with a sheet of skin running from forehead to-

and is characterised by replacement of normal eye lid

Table 2. Other ocular complications in Fraser syndr ome .

Tongue of hair extending from scalp to lateral eye brow 34.20%

Absent eye lashes 29.10%

Coloboma of eyelid 17.90%

Groove in frontal bone/fur row to forehead/temporal depression8.50%

Microphthalmia 21.40%

Anophthalmia 6%

Corneal opacification/ corneal clouding/sclerocornea 10.30%

Microcornea /absence of the cornea/corneal epithelial defect 2.60%

Abnormal anteri or chamber/absence of the anterior str uctu res 5.10%

Hypoplasia of the optic nerve/atrophy of optic nerve 5.10%

Symblepharon /oculop a lp e b ral synechiae 14.50%

Fraser Syndrome: Case Report with Review of Literature 3

cheek. There can be absence or poor development of the

eyebrows, eyelashes, gland structures and conjunctival

sac. The skin is adherent to the underlying cornea. Mi-

crophthalmia, symblepharon and abnormalities of the

anterior chamber are common.

Incomplete (atypical) cryptophthalmos refers to rudi-

mentary lid structures that are present with small con-

junctival sacs placed laterally, Small palpebral fissures,

micophthalmia and symblepharon [10].

Abortive cryptophthalmos or congenital symblepharon

described an upper lid without a well defined margin that

is adherent to the cornea. Slavotinek also suggests sym-

plepharon is part of the ocular manifestations of Fraser

syndrome [7].

We suggest utmost vigilance when clinicians are en

countered with one fetal anomaly o n antenatal ultrasou nd.

Rare multisystem disorders like Fraser syndrome should

be considered, so adequate parental counselling can be

delivered.

3. Literature Search

A MEDLINE search covering the years 1950 to the pre-

sent was conducted using the following terms: Fraser

syndrome, cryptophthalmos syndrome, and cryptoph-

thalmos. Articles cited in the reference lists of other arti-

cles were also searched.

The authors declare no conflicts of interest.

REFERENCES

[1] M. Narang, M. Kumar and D. Shah, “Fraser-Crypto-

phthalmos Syndrome with Colonic Atresia,” Indian Jour-

nal of Pediatrics, Vol. 75, No. 2, 2008, pp. 89-91.

doi:10.1007/s12098-008-0030-9

[2] W. Zehender, “Eine Missge burt mit Hautueberwachsenen

Augen oder Kryptophthalmus,” Klin Monatsbl Augen-

heilkd, Vol. 10, 1872, pp. 225-234.

doi:10.1007/s12098-008-0030-9

[3] G. R. Fraser, “Our Genetical ‘Load’: A Review of Some

Aspects of Genetic Variation,” Annals of Human Genetics,

Vol. 25, 1962, pp. 387-415.

[4] I. Smyth and P. Scambler, “The Genetics of Fraser Syn-

drome and the Blebs Mouse Mutants,” Human Molecular

Genetics, Vol. 14, No. 2, 2005, pp. R269-274.

doi:10.1093/hmg/ddi262

[5] I. T. Thomas, J. L. Frias, V. Felix, L. Sanchex de Leon, R.

A. Hernandex and M. C. Jones, “Isolated and Syndromic

Cryptophthalmos,” American Journal of Medical Genet-

ics, Vol. 25, 1986, pp. 85-98.

doi:10.1002/ajmg.1320250111

[6] E. Feldman, E. Shalev, E. Weiner, H. Cohen and H.

Zuckerman, “Microphthalmia B Prenatal Ultrasonic Di-

agnosis: A Case Report,” Prenatal Diagnosis, Vol. 5,

1985, pp. 205-207. doi:10.1002/pd.1970050307

[7] A. M. Slavotinek and C. J. Tifft, “Fraser Syndrome and

Cryptophthalmos: A Review of the Diagnostic Criteria

and Evidence of Phenotypic Modules,” Journal of Medi-

cal Genetics, Vol. 39, 2002, pp. 623-633.

doi:10.1136/jmg.39.9.623

[8] J. Gattuso, M. A. Patton and M. Baraitser, “The Clinical

Spectrum of Fraser Syndrome: Report of Three New

Cases and Review, ” Journal of Medical Genetics, Vol. 24,

1987, pp. 549-555. doi:10.1136/jmg.24.9.549

[9] J. Francois, “Syndrome Malformatif avec Cryptophthal-

mie,” Annals Genertics Medical Gemellol, Vol. 18, 1969,

pp. 18-50.

[10] D. J. Brazier, S. J. Hardman-Lea and J. R. O. Collin,

“Cryp- tophthalmos: Surgical Treatment of the Congenital

Symblepharon Variant,” British Journal of Ophthalmol-

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doi:10.1136/bjo.70.5.391