A C T A O P H T H A L M O L O G I C A VOL. 56 1 9 7 8
The Department of Ophthalmology (Head: N . Ehlers), drhus Kommiinehospital, Uniuersity of Aarliiis, Denmark
CRYPTOPHTHALMOS, DYSCEPHALY, SYNDACTYLY AND RENAL APLASIA Report of a Case BY
LISBETH VARNEK
A danish girl with incomplete, bilateral cryptophthalmos together with associated craniofacial malformations, laryngeal hypoplasia, syndactyly, unilateral renal aplasia and slight external genital abnormalities is reported. Chromosomal abnormalities or metabolic disorders were not demonstrated. As the condition is extremely rare, some clinical and pathological findings previously described in analogous cases are mentioned, together with a few pathogenetic mechanisms. Finally, a discussion regarding the aetiology of the condition is presented. Most authors are convinced that the malformative pattern is a syndrome with an autosomally recessive genetic basis. Added environmental influence explains the wide range of manifestations and the varying gene expressivity.
Key words: cryptophthalmos - orbital cyst - syndactyly - heredity dyscephaly - renal aplasia - laryngeal atresia.
Zehender 8c Manz (1872) described the first case of cryptopthalmia in an infant where the eyes covered with skin from the forehead to the cheek, the skin being fused with the anterior surface of the eyeballs. This child died at an age of six months. The autopsy revealed microphthalmos on one side and a colobomatous cyst on the other side. Systemic abnormalities including meningoencephalocele, nasal abnormalities, syndactyly and genital anomalies completed the malformative pattern. Received June 14, 1977. 302
Since then, more than fifty cases have been reported, the syndromal nature of the malformation being stressed by several authors (Makley & Battles 1969; Waring & Shields 1975), and most clearly and detailed classified by Franqois (1965). He considered the malformative pattern to have four characteristics: 1) cryptophthalmia, 2) dyscephaly, 3) syndactyly and 4) malformaticns of the urogenital system. All this does not always come to expression in the same patient, the cryptophthalmic anomaly sometimes standing alone, even in monolateral, incomplete or abortive forms. Most consistent are the eye symptoms conjoined with syndactyly and genital anomalies, namely in about 1/3 of the cases reported. The anomaly has been reported from all over the world. Many isolated cases have been reported, but, especially during the later years (Waring & Shields 1975), reports ccncerning several affected siblings have emerged. In these latter studies exact pedigrees have not been obtainable because of ethnic and geographical obstacles (foreign tribes), but in the affected areas there has been a tradition for consanguinous marriages, a fact in itself suggestive of a genetic aetiology, but not a convincing proof of this. A report is given below on a girl with malformations both of the eyes and of all the above-mentioned organ systems.
Case Report A danish girl was born without palpebral aperture on the right side and with an incomplete, medial cryptophthalmos c n the left side. There was no known family history of malformations or diseases, and the course of the pregnancy had been uncomplicated. Both parents were clinically healthy and young. There was no history of consanguinity. T h e delivery was uncomplicated. The birth weight was 3000 g, length 49 cm. Eyes
T h e supercilias were present, but sparse, and the hair of the scalp passed over the temples to the frontal region. The right eye was totally cryptophthalmic, with a dermal tag placed laterally at the site of the non-existing palpebral aperture (Fig. 1). Under the freely movable skin, only slightly adherent where the palpebral aperture should have been, was a pellucid, tense cyst measuring approximately 2 cm in diameter. There was no reaction to light. The left eye (Figs. 1 and 2) demonstrated a lower eyelid laterally. While medially, the skin of the brow swept over the eyeball to the malar eminence with complete abscence of the eyelid fold, caruncle and lacrimal puncta. T h e skin laterally passed directly into the semitranslucent cornea without forming an upper eyelid. The inferior conjunctival fornix was present laterally with a slightly everted lower eyelid with
303
Lisbeth Varnek
Fig. 1 . Craniofacial appearance at the age of 5 days. Note the right, bulging, hidden, cystic eye, the left partial cryptophthalmos and the coloboma of the naris as a result of the defective fusion of the right facial cleft. Also note the hair passing over the temples.
sparse cilias. There was no lid closure. On light stimulation there was distinct wrinkling of the skin of the forehead. Furthermore, the eye was seen to move. Because of the opaque condition of the cornea, ophthalmoscopy proved impossible. Associated deformities
The skull was normally shaped and sized. There was an osseous defect, 4 x 5 cm, situated between the right parietal and right occipital bones, continuing into the triangular fontanelle, which was wider than normal. There was no encephalo- or myelomeningocele. The face showed incomplete closure of the right fissura naso-orbitalis (right facial cleft), resulting in coloboma of the naris. The external ears on both sides were abnormal in size and shape. They were low set, small and rotated backwards with deficiently developed lobes. The external auditory meatuses were narrow, but patent, and on both sides normal light reflexes from the ear-drums were seen, without further demonstrable details. Clinically, the child had normal hearing. Anterior rhinoscopy revealed normal conchae on both sides. The voice was weak and high-picthed at birth, and on direct laryngoscopic investigation under general anaesthesia at the age of 5 weeks a n abnormal diaphragm was observed spanning between the vocal cords near the anterior commisure. T h e endolarynx otherwise appeared normal. A spontaneous normalisation of the voice occurred at the age of six months.
304
Cryptophthalmos Syndrome
Fig. 1. Close up view of the left eye a t the age of 11 weeks. Note the partial, medial cryptophthalmos with upper symblepharon, and the semitranslucent cornea.
There was cutaneous syndactyly of both hands, the left foot and the four lateral toes on the right foot (Figs. 3, 4, 8 and 9). The external genitalia showed clitoral hypertrophy, but were otherwise normal The anus was normal. There was no bladder ectopy, but intravenous urography revealed no renal shadow on the left side, indicating either an aplasia of the left kidney or a severely reduced function. The right renal shadow was normal. General examination
Normal respiration, with no cyanosis, dyspnoea or oedema. Motor functions and reflexes were normal. There was no palpable enlargement of the abdominal organs (Fig. 5 ) . Course
From the start the child thrived well, gained weight normally and presented no feeding problems. Throughout an observation time of ten months her mental and physical development was followed and estimated as normal. At four months of age, il lateral tarsorrhaphy was performed on the left side in an attempt to protect the cornea. Until the age of six months the prominence of the right
305
Lisbeth Varnek
Figs. 3 and 4. Cutaneous syndactyly of hands and feet at the age of 5 days.
306
Cryptophthalrnos Syndrome
Fig. 5. Overall body view a t the age of 5 days. Normal proportions, good nutritional state and normal limbs, apart from syndactyly.
orbital region did not increase further, but then a rapid growth of the cyst occurred, necessitating surgical intervention. When opened, a small, malformed eye-anlage was found in the bottom of the cyst. Four months post-operatively no signs of cyst-recurrence were apparent.
Special investigations
Rlood. Blood type A Rh pos. Erythrocyte sedimentation rate 4 mm/h. Leucocytes 10.7 x lo3 per mm3. Differential count normal. Wassermann reaction negative. Glucose 4.1 mM/1 (normal range 3.5-5.5 m d l ) . Serum creatinine 0.053 mM/1 (normal value < 0.1 15 m d l ) . Urine. No glucosuria or proteinuria. Fellings reaction negative. Urine-microscopy normal. The chromatographic pattern of the amino acids showed general hypoaminoaciduria. Radiography. The skull was of normal thickness. Sella turcica was normal. There was an osseous malformation in the skull (defect 4 x 5 cm between the right parietal and occipital squamas) (Fig. 6). No defects concerning the orbitae and maxillary sinuses were seen, more especially there was no abnormal communication on the right side, but moderate hypertelorism was found. There were no pathological intracranial calcifications (Fig. 7). There was an osseous cleft palate.
307
Lisbeth Varnek
Fig. 6. Skull radiography, right side view. Note 4 x 5 cm osseous defect between the parietal and occipital squamas.
Tomography of the temporal bones showed normal auditory external meatuses, tympanic cavities and ossicles on both sides, and the semicircular canal system was also normal. Chest roetgenogram showed normal conditions. Intravenous urography revealed no excretion from the left kidney. Roetgenograms of the bones in the hands, feet and spinal column were normal (Figs. 8 and 9). Chromosome analyses of leukocytes showed 46 chromosomes. More detailed studies showed normal autosomes and XX-constitution. Histopathology. Microscopic investigation of that part of the specimen which included the eyeball (Fig. lo), revealed a thickened scleral envelope containing coarse collagen fibres. There was some chorioidal fibrosis and a vascular malformation of the cavernous type in the chorioidea. The retinal pigment epithelium (Fig. 11) adhered to the choroid,
Fig. 7. Radiography of the skull, front view. Note normal orbits and nasal cavity, and slight hypertelorism.
308
Cryfitophthalmos Syndrome
Figs. 8 and 9. Radiography of bones in the left hand and the feet. Note the normal bone condition without osseous syndactyly.
Fig. 10. Thickened sclera, fibrotic chorioidea with a vascular malformation of the cavernous type. Stain haematoxylin-eosin (10 x).
309
Lisbeth Varnek
Fig. 11. Sensory retina. Normal nuclear and reticular layers, invisible ganglional layer with cystic degeneration. Stain haematoxylin-eosin (250 x).
F i g . 12. Anterior cyst wall. N o corneal structures demonstrable. Stain haematoxylin-eosin (100 x).
310
Cryptophthalmos Syndrome while the sensory retina was only partially adherent. The nuclear and reticular layers in the retina appeared normal. There was some degree of abnormal vascularisation in the nerve fibre layer. The ganglional layer was invisible, but a pronounced cystic degeneration was found in that area. The cyst vesicle seemed to comprise a grossly dilated anterior chamber, yet no ccrneal structures were demonstrable in the cyst wall (Fig. 12). No signs of inflammation were found.
Cyst fluid. Leukocyte count 0. Erythrocyte count 0. Glucose 2.2 m d l . Total protein 342 pg/g. Prealbumin 5.6 !‘gig. Albumin 154.7 Ifgig. a,-globulin 15.6 !tg/g. a?-globulin 56.8 yg/g. fil-globulin 56.8 {‘gig. &globulin 0. y-globulin 57.9 !ig/g. Electroencephalograp/zy showed a dominant 4-6 hz activity with slight depression during both wake- and sleepphases over the left hemisphere. Conclusion: Slightly abnormal.
Discussion Cryptophthalmia designates a ccndition where skin passes directly from the forehead to the cheek. Although often bilateral (Sugar 1968), unilateral or incomplete forms occur, including partial cryptophthalmos (Waring & Shields 1975) where the lateral portion of the eyelid is normal with fusion of the facial skin to the cornea medially, and superior symblepharon where the upper eyelid fuses with the globe. In about 1/3 of the cases reported the condition has been asymmetric (Waring & Shields 1975). Histopathological investigations of about 17 cases (Fransois 1965; Ehlers 1966; Sugar 1968) has revealed that the eyelid malformation can be combined with malformations of the eyeball itself, especially concerning its anterior half. About 1/5 of the cases (Ehlers 1966) are associated with microphthalmos and colobomatous cysts. The cryptophthalmos-syndrome includes, apart from the eye malformations described, dyscephalia with cranial defects and fusional defects of the face (in about 2 5 0 / 0 of the cases, Gorlin & Sedano 1969), cleft palate and earabnormalities, syndactyly, and malformations o f the genito-urinary system, including small penis, hypospadia, non-descended testes in the male and hypertrophia of the clitoris with or without vaginal atresia and inccmplete labial development to the point approximating pseudohermaphroditism in the female. The urinary apparatus can have defects concerning the vesica and especially partial renal agenesia, often extreme and incompatible with postnatal survival (Fraser 1974). Less constantly, namely in about 100/0 of the cases, laryngeal hypoplasia or atresia has been found (Gorlin & Sedano 1969). The pathogenesis of cryptophthalmos is unknown (Ehlers 1966; Makley & Battles 1969), and many theories have been put forward. These include primary 31 1
failure of mesodermal and ectodermal differentiation in formation of the eyelid (ablepharon by agenesis) with normal projection of the eyelids, but with arrest in the development of the furrow between the eyelids and the cornea, which should have further developed into the conjunctival sac. When comparing the cryptophthalmic anomaly with the anomalies from the other organ systems, with which it is often combined, especially with the anomaly of syndactyly, it is clear that a designation applicable to all the malformations is nzalformation of arrest. In the case described, the influence of an existing eyeball on the eyelid malformaticn seems probable. The total cryptophthalmos on the right side is combined with a cyst on that side, indicating that lack of a normal eyeball may be a factor governing eyelid formation, and that this could totally fail. In contrast, the partial cryptophthalmos on the left side is combined with an eye. This suggests that the presence of an eye, however small, could stimulate a more normal eyelid development. The composition of the cyst fluid in this case neither corresponds to cerebrospinal fluid nor to aqueous humour, thereby permitting no possible clues as to its origin. In general, it must be stressed that there is by no means a constant relation between the condition of the eyeball and of the eyelids, since both microphthalmos, buphthalmos and orbitopalpebral cysts (Ehlers 1966) have occurred without cryptophthalmos, and since pronounced cryptophthalmos has been combined with the presence of a normal eye (ankyloblepharon, Zehender & Manz 1872). Most authors (Sugar 1968; Chovet et al. 1972; Fraser 1974) consider the syndrome to be genetically determined. Although chromosomal defects have never been observed, and although exact pedigrees are still lacking, the existence of parental consanguinity in 15-18 O/O of the reported cases (Gorlin et al. 1976) strongly indicates a genetic disorder with an autosomal recessive mode of inheritance. T h e great variety in the symptomatology does not contravene with the genetic concept, but may represent the added infiuence of environmental factors on the gene expressivity. In the reported case, no chromosomal defects or parental consanguinity were found. The clinical findings all corresponded to some developmental arrest exerting its maximum effect about the end of the 7th and the start of the 8th foetal week (Streeter 1951; Allan 1969). This might seemingly indicate the existence of some environmental factor (infectious, malnutritive, anoxic, iatrogenic, immunologic) which is at least partially responsible for the resulting malformations in this particular case.
312
Cryptophthalmos Syndrome
References Allan F. D. (1969) Essentials of Human E m b ~ y o l o g y ,2. Ed. Oxford University Press, New York. Azevedo E. S., Biondi J. & Ramalho L. M. (1973) Cryptopthalmos in two families from Bahia, Brazil. J. med. Genet. 10, 389-392. Chovet M., Dufour J. & Degabriel J. (1972) Cryptophthalmies et malformations associees en milieu africain consanguin (Mauritanie du Sud). Med. t r o p . 32, 419-426. Ehlers N. (1966) Cryptophthalmos with orbilopalpebral cyst and microphthalmos. Acta oplithal. (Kbh.) 44, 84-94. F r a n ~ o i sJ. (1965) Malformation syndrome with cryptophthalmie. Ophthalmologica 150, 2 15-2 18. Fraser G. R. (1974) Genetic and Metabolic Eye Diseases. Little, Brown and Company. Boston. Gorlin R. J., Pindborg J. J. & McKusick V. A. (1976) Syndromes of the Head and Neck, 2. Ed. Mc. Graw-Hill. New York, Toronto, London. Gorlin J. R. & Sedano H . (1969) Cryptophthalmia syndrome. Modern Medicine, 156-157. Makley J. R. & Battles M. (1969) Microphthalmos with cyst, report of two cases in the same family. Surv. Ophtlial. 13, 200-206. Streeter G. L. (1951) Developmental Horizonts in Human Embryos, Vol. 2. Washington, Carnegie Institution of Washington 1951. Sugar H. S. (1968) T h e cryptophthalmos - syndactyly-syndrome. Amer. J. Ofihthal. 66, 897-899. Waring G. 0. & Shields J. A. (1975) Partial, unilateral cryptophthalmos with syndactyly, brachycephaly and renal anomalies. Amer. /. Ophtlzal. 79, 437-440. Zehender W. & Manz ? (1872) Eine Missgeburt mit hautiberwachsenen Augen oder Kryptopthalmus. Klin. Mbl. Augenheilk. 10, 225-249.
Author’s address: Lisbeth Varnek, 0jenafdelingen, Rigshospitalet, Blegdamsvej 9, DK-2100 K ~ b e n h a v n0 .
Acta ophthal. 51i, 2
21
The Department of Ophthalmology (Head: N . Ehlers), drhus Kommiinehospital, Uniuersity of Aarliiis, Denmark
CRYPTOPHTHALMOS, DYSCEPHALY, SYNDACTYLY AND RENAL APLASIA Report of a Case BY
LISBETH VARNEK
A danish girl with incomplete, bilateral cryptophthalmos together with associated craniofacial malformations, laryngeal hypoplasia, syndactyly, unilateral renal aplasia and slight external genital abnormalities is reported. Chromosomal abnormalities or metabolic disorders were not demonstrated. As the condition is extremely rare, some clinical and pathological findings previously described in analogous cases are mentioned, together with a few pathogenetic mechanisms. Finally, a discussion regarding the aetiology of the condition is presented. Most authors are convinced that the malformative pattern is a syndrome with an autosomally recessive genetic basis. Added environmental influence explains the wide range of manifestations and the varying gene expressivity.
Key words: cryptophthalmos - orbital cyst - syndactyly - heredity dyscephaly - renal aplasia - laryngeal atresia.
Zehender 8c Manz (1872) described the first case of cryptopthalmia in an infant where the eyes covered with skin from the forehead to the cheek, the skin being fused with the anterior surface of the eyeballs. This child died at an age of six months. The autopsy revealed microphthalmos on one side and a colobomatous cyst on the other side. Systemic abnormalities including meningoencephalocele, nasal abnormalities, syndactyly and genital anomalies completed the malformative pattern. Received June 14, 1977. 302
Since then, more than fifty cases have been reported, the syndromal nature of the malformation being stressed by several authors (Makley & Battles 1969; Waring & Shields 1975), and most clearly and detailed classified by Franqois (1965). He considered the malformative pattern to have four characteristics: 1) cryptophthalmia, 2) dyscephaly, 3) syndactyly and 4) malformaticns of the urogenital system. All this does not always come to expression in the same patient, the cryptophthalmic anomaly sometimes standing alone, even in monolateral, incomplete or abortive forms. Most consistent are the eye symptoms conjoined with syndactyly and genital anomalies, namely in about 1/3 of the cases reported. The anomaly has been reported from all over the world. Many isolated cases have been reported, but, especially during the later years (Waring & Shields 1975), reports ccncerning several affected siblings have emerged. In these latter studies exact pedigrees have not been obtainable because of ethnic and geographical obstacles (foreign tribes), but in the affected areas there has been a tradition for consanguinous marriages, a fact in itself suggestive of a genetic aetiology, but not a convincing proof of this. A report is given below on a girl with malformations both of the eyes and of all the above-mentioned organ systems.
Case Report A danish girl was born without palpebral aperture on the right side and with an incomplete, medial cryptophthalmos c n the left side. There was no known family history of malformations or diseases, and the course of the pregnancy had been uncomplicated. Both parents were clinically healthy and young. There was no history of consanguinity. T h e delivery was uncomplicated. The birth weight was 3000 g, length 49 cm. Eyes
T h e supercilias were present, but sparse, and the hair of the scalp passed over the temples to the frontal region. The right eye was totally cryptophthalmic, with a dermal tag placed laterally at the site of the non-existing palpebral aperture (Fig. 1). Under the freely movable skin, only slightly adherent where the palpebral aperture should have been, was a pellucid, tense cyst measuring approximately 2 cm in diameter. There was no reaction to light. The left eye (Figs. 1 and 2) demonstrated a lower eyelid laterally. While medially, the skin of the brow swept over the eyeball to the malar eminence with complete abscence of the eyelid fold, caruncle and lacrimal puncta. T h e skin laterally passed directly into the semitranslucent cornea without forming an upper eyelid. The inferior conjunctival fornix was present laterally with a slightly everted lower eyelid with
303
Lisbeth Varnek
Fig. 1 . Craniofacial appearance at the age of 5 days. Note the right, bulging, hidden, cystic eye, the left partial cryptophthalmos and the coloboma of the naris as a result of the defective fusion of the right facial cleft. Also note the hair passing over the temples.
sparse cilias. There was no lid closure. On light stimulation there was distinct wrinkling of the skin of the forehead. Furthermore, the eye was seen to move. Because of the opaque condition of the cornea, ophthalmoscopy proved impossible. Associated deformities
The skull was normally shaped and sized. There was an osseous defect, 4 x 5 cm, situated between the right parietal and right occipital bones, continuing into the triangular fontanelle, which was wider than normal. There was no encephalo- or myelomeningocele. The face showed incomplete closure of the right fissura naso-orbitalis (right facial cleft), resulting in coloboma of the naris. The external ears on both sides were abnormal in size and shape. They were low set, small and rotated backwards with deficiently developed lobes. The external auditory meatuses were narrow, but patent, and on both sides normal light reflexes from the ear-drums were seen, without further demonstrable details. Clinically, the child had normal hearing. Anterior rhinoscopy revealed normal conchae on both sides. The voice was weak and high-picthed at birth, and on direct laryngoscopic investigation under general anaesthesia at the age of 5 weeks a n abnormal diaphragm was observed spanning between the vocal cords near the anterior commisure. T h e endolarynx otherwise appeared normal. A spontaneous normalisation of the voice occurred at the age of six months.
304
Cryptophthalmos Syndrome
Fig. 1. Close up view of the left eye a t the age of 11 weeks. Note the partial, medial cryptophthalmos with upper symblepharon, and the semitranslucent cornea.
There was cutaneous syndactyly of both hands, the left foot and the four lateral toes on the right foot (Figs. 3, 4, 8 and 9). The external genitalia showed clitoral hypertrophy, but were otherwise normal The anus was normal. There was no bladder ectopy, but intravenous urography revealed no renal shadow on the left side, indicating either an aplasia of the left kidney or a severely reduced function. The right renal shadow was normal. General examination
Normal respiration, with no cyanosis, dyspnoea or oedema. Motor functions and reflexes were normal. There was no palpable enlargement of the abdominal organs (Fig. 5 ) . Course
From the start the child thrived well, gained weight normally and presented no feeding problems. Throughout an observation time of ten months her mental and physical development was followed and estimated as normal. At four months of age, il lateral tarsorrhaphy was performed on the left side in an attempt to protect the cornea. Until the age of six months the prominence of the right
305
Lisbeth Varnek
Figs. 3 and 4. Cutaneous syndactyly of hands and feet at the age of 5 days.
306
Cryptophthalrnos Syndrome
Fig. 5. Overall body view a t the age of 5 days. Normal proportions, good nutritional state and normal limbs, apart from syndactyly.
orbital region did not increase further, but then a rapid growth of the cyst occurred, necessitating surgical intervention. When opened, a small, malformed eye-anlage was found in the bottom of the cyst. Four months post-operatively no signs of cyst-recurrence were apparent.
Special investigations
Rlood. Blood type A Rh pos. Erythrocyte sedimentation rate 4 mm/h. Leucocytes 10.7 x lo3 per mm3. Differential count normal. Wassermann reaction negative. Glucose 4.1 mM/1 (normal range 3.5-5.5 m d l ) . Serum creatinine 0.053 mM/1 (normal value < 0.1 15 m d l ) . Urine. No glucosuria or proteinuria. Fellings reaction negative. Urine-microscopy normal. The chromatographic pattern of the amino acids showed general hypoaminoaciduria. Radiography. The skull was of normal thickness. Sella turcica was normal. There was an osseous malformation in the skull (defect 4 x 5 cm between the right parietal and occipital squamas) (Fig. 6). No defects concerning the orbitae and maxillary sinuses were seen, more especially there was no abnormal communication on the right side, but moderate hypertelorism was found. There were no pathological intracranial calcifications (Fig. 7). There was an osseous cleft palate.
307
Lisbeth Varnek
Fig. 6. Skull radiography, right side view. Note 4 x 5 cm osseous defect between the parietal and occipital squamas.
Tomography of the temporal bones showed normal auditory external meatuses, tympanic cavities and ossicles on both sides, and the semicircular canal system was also normal. Chest roetgenogram showed normal conditions. Intravenous urography revealed no excretion from the left kidney. Roetgenograms of the bones in the hands, feet and spinal column were normal (Figs. 8 and 9). Chromosome analyses of leukocytes showed 46 chromosomes. More detailed studies showed normal autosomes and XX-constitution. Histopathology. Microscopic investigation of that part of the specimen which included the eyeball (Fig. lo), revealed a thickened scleral envelope containing coarse collagen fibres. There was some chorioidal fibrosis and a vascular malformation of the cavernous type in the chorioidea. The retinal pigment epithelium (Fig. 11) adhered to the choroid,
Fig. 7. Radiography of the skull, front view. Note normal orbits and nasal cavity, and slight hypertelorism.
308
Cryfitophthalmos Syndrome
Figs. 8 and 9. Radiography of bones in the left hand and the feet. Note the normal bone condition without osseous syndactyly.
Fig. 10. Thickened sclera, fibrotic chorioidea with a vascular malformation of the cavernous type. Stain haematoxylin-eosin (10 x).
309
Lisbeth Varnek
Fig. 11. Sensory retina. Normal nuclear and reticular layers, invisible ganglional layer with cystic degeneration. Stain haematoxylin-eosin (250 x).
F i g . 12. Anterior cyst wall. N o corneal structures demonstrable. Stain haematoxylin-eosin (100 x).
310
Cryptophthalmos Syndrome while the sensory retina was only partially adherent. The nuclear and reticular layers in the retina appeared normal. There was some degree of abnormal vascularisation in the nerve fibre layer. The ganglional layer was invisible, but a pronounced cystic degeneration was found in that area. The cyst vesicle seemed to comprise a grossly dilated anterior chamber, yet no ccrneal structures were demonstrable in the cyst wall (Fig. 12). No signs of inflammation were found.
Cyst fluid. Leukocyte count 0. Erythrocyte count 0. Glucose 2.2 m d l . Total protein 342 pg/g. Prealbumin 5.6 !‘gig. Albumin 154.7 Ifgig. a,-globulin 15.6 !tg/g. a?-globulin 56.8 yg/g. fil-globulin 56.8 {‘gig. &globulin 0. y-globulin 57.9 !ig/g. Electroencephalograp/zy showed a dominant 4-6 hz activity with slight depression during both wake- and sleepphases over the left hemisphere. Conclusion: Slightly abnormal.
Discussion Cryptophthalmia designates a ccndition where skin passes directly from the forehead to the cheek. Although often bilateral (Sugar 1968), unilateral or incomplete forms occur, including partial cryptophthalmos (Waring & Shields 1975) where the lateral portion of the eyelid is normal with fusion of the facial skin to the cornea medially, and superior symblepharon where the upper eyelid fuses with the globe. In about 1/3 of the cases reported the condition has been asymmetric (Waring & Shields 1975). Histopathological investigations of about 17 cases (Fransois 1965; Ehlers 1966; Sugar 1968) has revealed that the eyelid malformation can be combined with malformations of the eyeball itself, especially concerning its anterior half. About 1/5 of the cases (Ehlers 1966) are associated with microphthalmos and colobomatous cysts. The cryptophthalmos-syndrome includes, apart from the eye malformations described, dyscephalia with cranial defects and fusional defects of the face (in about 2 5 0 / 0 of the cases, Gorlin & Sedano 1969), cleft palate and earabnormalities, syndactyly, and malformations o f the genito-urinary system, including small penis, hypospadia, non-descended testes in the male and hypertrophia of the clitoris with or without vaginal atresia and inccmplete labial development to the point approximating pseudohermaphroditism in the female. The urinary apparatus can have defects concerning the vesica and especially partial renal agenesia, often extreme and incompatible with postnatal survival (Fraser 1974). Less constantly, namely in about 100/0 of the cases, laryngeal hypoplasia or atresia has been found (Gorlin & Sedano 1969). The pathogenesis of cryptophthalmos is unknown (Ehlers 1966; Makley & Battles 1969), and many theories have been put forward. These include primary 31 1
failure of mesodermal and ectodermal differentiation in formation of the eyelid (ablepharon by agenesis) with normal projection of the eyelids, but with arrest in the development of the furrow between the eyelids and the cornea, which should have further developed into the conjunctival sac. When comparing the cryptophthalmic anomaly with the anomalies from the other organ systems, with which it is often combined, especially with the anomaly of syndactyly, it is clear that a designation applicable to all the malformations is nzalformation of arrest. In the case described, the influence of an existing eyeball on the eyelid malformaticn seems probable. The total cryptophthalmos on the right side is combined with a cyst on that side, indicating that lack of a normal eyeball may be a factor governing eyelid formation, and that this could totally fail. In contrast, the partial cryptophthalmos on the left side is combined with an eye. This suggests that the presence of an eye, however small, could stimulate a more normal eyelid development. The composition of the cyst fluid in this case neither corresponds to cerebrospinal fluid nor to aqueous humour, thereby permitting no possible clues as to its origin. In general, it must be stressed that there is by no means a constant relation between the condition of the eyeball and of the eyelids, since both microphthalmos, buphthalmos and orbitopalpebral cysts (Ehlers 1966) have occurred without cryptophthalmos, and since pronounced cryptophthalmos has been combined with the presence of a normal eye (ankyloblepharon, Zehender & Manz 1872). Most authors (Sugar 1968; Chovet et al. 1972; Fraser 1974) consider the syndrome to be genetically determined. Although chromosomal defects have never been observed, and although exact pedigrees are still lacking, the existence of parental consanguinity in 15-18 O/O of the reported cases (Gorlin et al. 1976) strongly indicates a genetic disorder with an autosomal recessive mode of inheritance. T h e great variety in the symptomatology does not contravene with the genetic concept, but may represent the added infiuence of environmental factors on the gene expressivity. In the reported case, no chromosomal defects or parental consanguinity were found. The clinical findings all corresponded to some developmental arrest exerting its maximum effect about the end of the 7th and the start of the 8th foetal week (Streeter 1951; Allan 1969). This might seemingly indicate the existence of some environmental factor (infectious, malnutritive, anoxic, iatrogenic, immunologic) which is at least partially responsible for the resulting malformations in this particular case.
312
Cryptophthalmos Syndrome
References Allan F. D. (1969) Essentials of Human E m b ~ y o l o g y ,2. Ed. Oxford University Press, New York. Azevedo E. S., Biondi J. & Ramalho L. M. (1973) Cryptopthalmos in two families from Bahia, Brazil. J. med. Genet. 10, 389-392. Chovet M., Dufour J. & Degabriel J. (1972) Cryptophthalmies et malformations associees en milieu africain consanguin (Mauritanie du Sud). Med. t r o p . 32, 419-426. Ehlers N. (1966) Cryptophthalmos with orbilopalpebral cyst and microphthalmos. Acta oplithal. (Kbh.) 44, 84-94. F r a n ~ o i sJ. (1965) Malformation syndrome with cryptophthalmie. Ophthalmologica 150, 2 15-2 18. Fraser G. R. (1974) Genetic and Metabolic Eye Diseases. Little, Brown and Company. Boston. Gorlin R. J., Pindborg J. J. & McKusick V. A. (1976) Syndromes of the Head and Neck, 2. Ed. Mc. Graw-Hill. New York, Toronto, London. Gorlin J. R. & Sedano H . (1969) Cryptophthalmia syndrome. Modern Medicine, 156-157. Makley J. R. & Battles M. (1969) Microphthalmos with cyst, report of two cases in the same family. Surv. Ophtlial. 13, 200-206. Streeter G. L. (1951) Developmental Horizonts in Human Embryos, Vol. 2. Washington, Carnegie Institution of Washington 1951. Sugar H. S. (1968) T h e cryptophthalmos - syndactyly-syndrome. Amer. J. Ofihthal. 66, 897-899. Waring G. 0. & Shields J. A. (1975) Partial, unilateral cryptophthalmos with syndactyly, brachycephaly and renal anomalies. Amer. /. Ophtlzal. 79, 437-440. Zehender W. & Manz ? (1872) Eine Missgeburt mit hautiberwachsenen Augen oder Kryptopthalmus. Klin. Mbl. Augenheilk. 10, 225-249.
Author’s address: Lisbeth Varnek, 0jenafdelingen, Rigshospitalet, Blegdamsvej 9, DK-2100 K ~ b e n h a v n0 .
Acta ophthal. 51i, 2
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