Fraser syndrome in three consecutive siblings.

Fraser syndrome (FS) is a rare disorder characterized by a combination of acrofacial and urogenital malformations with or without cryptophthalmos. We report a newborn and its two elder siblings who had multiple congenital anomalies and clinico-radiological features consistent with FS.

Introduction

Fraser syndrome (FS; cryptophthalmos syndrome) is a rare inherited disorder characterized by cryptophthalmos, cutaneous syndactyly, craniofacial dysmorphism, orofacial clefting, mental retardation, malformations of the larynx and genitourinary tract, and musculoskeletal anomalies.[1] To the best of our knowledge, till now, less than 100 cases have been reported worldwide. C. R. Fraser, a Canadian geneticist, first described the syndrome in 1962.[2] The incidence of this syndrome is 0.043 per 10,000 live born infants and 1.1 in 10,000 stillbirths, making it a rare syndrome.[3] Since cryptophthalmos is not an obligate feature of this disorder, it is more appropriately termed as FS.[4] It has an autosomal recessive inheritance pattern with marked variability of expression. Mutations in the FRAS1 gene or in the FREM2 gene located on the long arm of chromosome 4 (4q21) have been reported to underlie FS, indicating genetic heterogeneity.[5] Cases with isolated cryptophthalmos which do not have FS have also been reported. We report three consecutive siblings affected with this rare disorder. In medical literature, FS has been reported in siblings.[6-8]

Case Report

A full-term female baby of Indian origin, the third child of non-consanguineous healthy parents, was born in our hospital by vaginal delivery. An antenatal scan at 30 weeks of gestation showed multiple anomalies – microphthalmia, cryptophthalmos on right side, right renal agenesis and oligohydramnios. There was a positive history of similar anomalies in two previous siblings and no history in any of the paternal or maternal relatives [Figure 1].

Figure 1

Pedigree chart of the patients in three generations

The first sibling was a boy, born full-term 2 years ago, with complete bilateral cryptophthalmos of both eyes, midline cleft lip and palate and noisy breathing. The child subsequently died on day 15 of life during an ophthalmic corrective surgery elsewhere.

The second sibling was antenatally diagnosed with bilateral renal agenesis and anhydramnios at 20 weeks of gestation and was aborted at 21 weeks in our hospital a year ago. The aborted fetus also had findings suggestive of FS [Figure 2] – bilateral cryptophthalmos, opaque right cornea, ventriculomegaly of the brain, absent both kidneys and ureters, absent uterus, vagina and proximal fallopian tubes, clitoromegaly, bifid nasal tip with depressed nasal bridge, low-set conical ears, abnormal anterior hairline, and a high arched palate. The heart, lungs, other abdominal organs and limbs were normal.

Figure 2

Aborted second sibling fetus with features suggestive of Fraser syndrome

This third newborn was vigorous at birth with a birth weight of 3.3 kg and crown-rump length of 52 cm. Examination revealed absent eyelids and eyebrow over the right eye, with the eyeball completely covered with skin (complete cryptophthalmos). The eyeball was palpable underneath [Figure 3]. On the left side, the upper eyelid was fused to the cornea and sclera and was devoid of eyelashes (incomplete or partial cryptophthalmos). The lens appeared clear; the pupil was normal and reacted to light in the left side. Blink reflex was present in both eyes. The hairline on the lateral forehead extended to the lateral eyebrow. Head circumference was 34 cm. The baby had malformed and low-set ears, wide nasal bridge, pseudo-hypertelorism, widely spaced nipples and fused labia with adhesion. The oral cavity, limbs, digits, spine and vertebrae and other systems were normal.

Figure 3

Complete “cryptophthalmos” on the right side – the underlying right eye was developmentally abnormal; partial “cryptophthalmos” on the left side, absence of eyelashes and eyebrows, abnormal hairline and a broad, depressed nasal bridge

The blood parameters were normal. A screening ultrasonogram of abdomen and pelvis showed right renal agenesis [Figure 4] and a unicornuate uterus with absent fallopian tube on the right side [Figure 5]. Other abdominal organs were normal. Neurosonogram and echocardiogram were normal. Chest radiograph and skeletal survey did not reveal any significant abnormality. A clinico-radiological diagnosis of FS was made. Conventional karyotyping done on both parents did not show any chromosomal abnormalities. Molecular studies could not be done due to financial constraints.

Figure 4

Ultrasound abdomen suggestive of right renal agenesis

Figure 5

Ultrasound abdomen is suggestive of unicornuate uterus to the left side

Discussion

Thomas et al. in 1986 proposed the diagnostic criteria for FS which included four major criteria (i) cryptophthalmos, (ii) syndactyly (fused or partially fused fingers and/or toes), (iii) genital anomalies, and (iv) a sibling history of FS; and eight minor criteria including (i) alterations of the nose, ears, larynx, (ii) cleft lip and/or palate, (iii) umbilical hernia, (iv) renal agenesis (bilateral or unilateral), (v) skeletal anomalies and (vi) mental retardation. A diagnosis of FS is suggested if there are at least two major and one minor criteria, or one major and four minor criteria. The findings in the newborn and her elder siblings reported in this paper are compatible with the diagnosis of FS according to the criteria proposed above.[9] According to the revised diagnostic criteria proposed by Van Haelst et al. in 2007,[10] the airway tract and urogenital anomalies were included in the major criteria and mental retardation and clefting were removed as criteria. The diagnosis can be made if either three major criteria, or two major and two minor criteria, or one major and three minor criteria are present in a patient.

The exact etiopathogenesis of FS is not known. It is believed to be related to a failure of programmed cell necrosis or a defect in metabolism of retinoids.[11] The developmental defects observed suggest that these defects arise from disruption of the epithelial–mesenchymal interactions required for normal morphogenetic processes.[5]

Cryptophthalmos (covered or hidden eye) is a failure of eyelid separation and absence of palpebral fissure mostly with varying absence of eyelashes and eyebrows and defects of the eye, especially the anterior part.[12] It can be unilateral or bilateral, and is classified into three types: complete (the eyelid is completely fused over an existing eye), incomplete (the eyelid is only partially fused over the underlying eye), and abortive (the eyelid is completely fused and the underlying eye does not form).[12] In FS, the defect of eyelid development is frequently accompanied by ocular anomalies; hence, achieving adequate visual perception is poor.[4]

Hair growth pattern may be abnormal. Hearing is usually normal. No affected individual has been reported to have reproduced.[1] The parents of affected children are sometimes, but not always consanguineous. Consanguinity is reported in 15–24% of cases and the recurrence rate among siblings is 25%.[1] Prenatal diagnosis by means of fetoscopy and antenatal ultrasonography (level II) is suggested as early as 18 weeks of gestation, particularly in families with affected siblings.[13] FS should be suspected in all cases of stillbirths with renal agenesis.[14] The type and severity of the renal or laryngeal malformations determines the prognosis and chances of survival – 25% of affected fetuses are stillborn and 25% die during the first few weeks of life and death is usually secondary to renal agenesis and laryngeal stenosis.[1413] With cryptophthalmos, prognosis with regard to sight is uniformly poor. Prevention by genetic counseling would be the best approach for recurrent cases.