Fraser syndrome.A Chattopadhyay, AS Kher, AD Udwadia, SV Sharma, BA Bharucha, AD Nicholson
Dept of Paediatrics, Seth GS Medical College, Parel, Bombay, Maharashtra.
Fraser Syndrome is a rare disorder with only a few cases having been described in Indian literature. We report here a case of a patient aged 16 yr present with primary amenorrhea which is a very unusual mode of presentation. Multiple associated anomalies were present including those of eyelids, eyebrow, face, fingers and genitalia. Chromosome analysis revealed a normal female karyotype. Pituitary gonadotropins were within normal range.
Keywords: Abnormalities, Multiple, diagnosis,epidemiology,genetics,pathology,Adolescent, Amenorrhea, etiology,Case Report, Eye Abnormalities, diagnosis,epidemiology,genetics,pathology,Face, abnormalities,Female, Genitalia, Female, abnormalities,Human, Skull, abnormalities,Syndactyly, diagnosis,epidemiology,genetics,pathology,Syndrome,
Cryptophthalmos (hidden eye) was first described by Zehender (1872), as an isolated abnormality in which there is a failure of development of the eyelid folds. Over the last century, the association between cryptophthalmos and multiple congenital malformations has been well documented. Fraser in 1962 identified two sibships, in each of which two sisters had cryptophthalmos with multiple abnormalities. Numerous authors have described cases as the cryptophthalmos - syndactyl syndrome. Franacois assigned four characteristics to the syndrome: (1) cryptophthalmia, (2) dyscephaly (including meningocele, cleft lip and palate, ear and nasal deformities), (3) syndactyly, and (4) genital abnormalities. Reports of cases without cryptophthalmos have led several authors to use the eponymic designation-Fraser syndrome,,.
Fraser syndrome shows an equal sex distribution, and reports strongly suggest an autosomal recessive mode of inheritance. The pathogenesis of this syndrome is still unclear. A large number of characteristic abnormalities in Fraser syndrome have now been reported,,,.
This patient of Fraser syndrome presented with primary amenorrhea, which is an unusual presentation.
KSM, a 16-year-old girl presented with primary amenorrhea and multiple associated anomalies. She was referred for genetic evaluation. She was the first child of a nonconsanguinous marriage. Birth history and family history were normal. A skin tag over the left eye medially was noticed at birth and surgically removed at the age of six years.
The physical examination revealed a height of 141 cms (5th percentile), weight of 28.5 kg (below the 5th percentile), and head circumference of 47 cms (less than 2 SD below the mean). The anomalies were [Figure - 1]: narrow forehead, a tongue of hair across the brow descending into the medial end of the left eyebrow and beyond; pseudo hype rteloris m; medial groove of the nasal tip; fine hair over the nose; high arched palate; ‘V’ shaped upper dental arch, microstomia, low posterior hair line, marked soft tissue syndactyly of the fingers and of the toes [Figure - 2]; hypoplastic clitoris; labia majora and minora with vaginal aplasia. Her sexual maturity rating was normal for her age.
Examination of the left eye revealed the eyebrow at a higher level with extension onto the nose, upward slant of the palpebral fissure, outward displacement of the inner canthus, belpharophimosis posterior symblepharon in upper nasal quadrant and concomitant uniocular exotropia of 7-100. Trichiasis and districhiasis of both lids and bilateral sclerocornea were also present. The pupil, lens and fundus were normal in both eyes. Visual acuity in the right eye was normal and reduced to finger counting at 3 feet in the left eye. ENT manifestations included small ears with folded antihelix, a narrow left external auditory meatus, a high deviated nasal septum to the left and absence of anterior pillar of left tonsil.
Bone survey of extremities revealed normal osseous structures. There was no separation of pubic bones. Skull and chest roentgenograms were normal. Intravenous urography was normal. 2 D echocardiography showed osteurn secundum atrial septal defect with no evidence of pulmonary stenosis or pulmonary hypertension. Ultrasongraphy of abdomen showed a hematocolpos with normal uterine architecture. Audiometry indicated moderate to severe conductive loss at 500 Hz. Chromosome analysis revealed a normal female karyotype. On the Kamat scale, she had an I.Q. of 75. Pituitary gonadotropins (LH and FSH) were within normal range.
Over a hundred cases of Fraser syndrome have been reported. [Table - 1] lists the classical anomalies reported thus far. Thomas, et al (1986) have proposed diagnostic criteria [Table - 2], wherein atleast two major and one minor, or one major and four minor criteria should be fulfilled. This patient satisfied all these requirements.
There is a wide spectrum of severity of eye manifestations in the disorder. In the most complete form of typical cryptophthalmia, the eyelids are absent or replaced by skin covering the orbit, extending from forehead to cheek. Various anatomical structures of the eyelids are nonexistent or incompletely developed. In incomplete or partial forms, formation of the eyelids is abortive, with varying fusion of lid to globe. The eyeball may be partially or totally covered by skin and the globes are usually microphthalmic. Cornea may be covered by membranes or scleral like tissue with some clear cornea .
Abnormalities of the genital tract have been widely reported of which the commonest abnormality in female patients has been clitoral hypertrophy. In spite of the high frequency of genital abnormalities, there have been no endocrinal studies in this syndrome. In this patient, gonadotropins were normal. This probably means that the genital abnormalities are structural in origin and not hormone dependent. None of the patients thus far reported have reproduced which can be attributed to the genital malformations.
Cardiovascular malformations are unusual and have been reported in 4 cases: dextrocardia, univentricular heart, atrial septal defect and ventricular septal defect. This patient had an atrial septal defect.
From the genetic view point, there is an autosomal recessive inheritance of the syndrome in half of the reported cases. The remainder are probably sporadic, as seems likely in this patient.
About one-quarter of the cases are stillborn and another quarter die within the first year of life due to renal ageneis or laryngeal stenosis. It becomes very important therefore for the physician to be aware of the clinical manifestations. He must not only establish the diagnosis and anticipate the complications, but also render advice on prognosis, which depends on the severity of mental retardation and associated anomalies. Treatment includes use of artificial tears and cosmetic surgery. Prenatal diagnosis of the severe forms is possible by detection of anomalies of the eyes, digits and kidneys on ultrasound. Genetic counselling must be based on a high probability or recurrence.
We wish to thank Dr PM Pai, Dean Seth GS Medical College and King Edward Memorial Hospital for granting permission to publish this report.
[Figure - 1], [Figure - 2][Table - 1], [Table - 2]