American Journal of Medical Genetics 4075-76 (1991)
Brief Clinical Report 46,XX Gonadal Dysgenesis With Epibulbar Dermoid Sara A. Quayle and Kenneth C. Copeland Department of Pediatrics, University of Vermont College of Medicine, Burlington
Pure gonadal dysgenesis with 46,XX genotype is a rare abnormality with unknown etiology. Although sensorineural deafness has been described with 46,XX gonadal dysgenesis, the majority of reported cases of 46,XX gonadal dysgenesis have no associated physical abnormalities. We report a patient with 46,XX gonadal dysgenesis associated with epibulbar dermoids and preauricular skin tags, the classic ocular and skin manifestations of Goldenhar sequence (oculoauricular vertebral dysplasia).We propose that our patient may represent a new and previously unreported syndrome. KEY WORDS: Goldenhar sequence, gonadal dysgenesis 46,XX, oculoauricular vertebral dysplasia, Perrault syndrome
INTRODUCTION Gonadal dysgenesis with 46,XX genotype is a rare condition, in which a phenotypically female individual is found to have streak gonads and normal karyotype. Its precise etiology is not known. When it occurs in isolation, it is termed pure gonadal dysgenesis. It is usually diagnosed at puberty, when the patient fails to develop secondary sexual characteristics and undergo menarche. Although some females with gonadal dysgenesis and 46,XX karyotype may also have one or more of the physical stigmata of classic Ullrich-Turner syndrome, the vast majority of these girls also will have a detectable 45,XO cell line in blood, skin, or other tissues [Simpson, 19761. Gonadal dysgenesis with 46,XX karyotype has also been associated with sensorineural deafness [Perrault et al., 19511. Perrault syndrome has been described in numerous kinships, apparently transmitted in an autosomal recessive fashion. To our knowledge 46,XX gonadal dysgenesis has not been associated with other anomalies or syndromes. Received for publication May 23,1990;revision received October 22, 1990. Address reprint requests to Sara A. Quayle, M.D., Timber Lane Pediatric Associates, 51 Timber Lane, So. Burlington, VT 05403.
0 1991 Wiley-Liss, Inc.
We report a female patient with 46,XX gonadal dysgenesis in association with epibulbar dermoids and preauricular skin tags. The latter anomalies are found in patients with Goldenhar sequence, which classically consists of epibulbar dermoid, external ear anomalies and vertebral anomalies, and frequently includes preauricular skin tags.
CLINICAL REPORT S.M. was born in 1972, at 40 weeks gestation, to a 25year-old multiparous mother, following a healthy pregnancy. Her father was age 34. There was no known family history of congenital anomalies. The parents were not consanguineous. At birth, numerous bilateral preauricular skin tags were present. At age 2 weeks, bulbar dermoids, 2 on the left cornea and one on the right, and left lid ptosis were noted. The diagnosis of Goldenhar “syndrome” was made at that time. The child was generally healthy throughout infancy and childhood, with normal growth and development. Hearing tests were normal. Clinical examinations of the spine were consistently normal and spinal radiographs were never obtained. At age 163/12 years, menarche had not occurred. Physical exam was normal except for absence of breast development, scant downy pubic hair, and infantile external genitalia. Height was 170 cm (85th centile) and weight was 72 kg (90th centile). Laboratory testing showed a serum estradiol level less than 20 mIU/ml. Serum FSH and LH were 68 mIU/ml and 34 mIU/ml. T4 and TSH were normal. Peripheral blood and skin fibroblast karyotyping were both 46,XX. Thyroid, ovarian and adrenal antibodies were all negative. Pelvic ultrasound showed an infantile uterus and bilateral small, indistinct gonads. The patient responded well to therapy with ethinyl estradiol and medroxyprogesterone acetate, attaining Tanner IV breast and Tanner I1 pubic hair development upon followup 5 months after the initiation of therapy. DISCUSSION Our patient presented with epibulbar dermoids, preauricular skin tags, and gonadal dysgenesis with 46,XX chromosome constitution. The presence of epibulbar dermoid and preauricular skin tags suggests a partially expressed oculoauricular vertebral dysplasia (Goldenhar sequence). To our knowledge, these eye and ear
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abnormalities have never been described in association with 46,XX gonadal dysgenesis. Oculoauricular vertebral dysplasia was first described by von Arlt in 1845. However, it derives its common name of Goldenhar “syndrome” from a report by Goldenhar [1952],in which he reviewed 16previously published cases and described 3 new cases with epibulbar dermoids, preauricular skin tags and external ear abnormalities. Gorlin et al. [ 19631later described 40 cases in which vertebral anomalies were recognized in association with the ocular and auricular components, and they renamed the syndrome oculoauricular vertebral dysplasia. Both sporadic [Pashayan et al., 19701 and familial [Summitt, 1969; Mellor et al., 19731 cases suggesting both autosomal recessive and autosomal dominant inheritance have since been described. There are case reports in the literature which lack the presence of epibulbar dermoid (Pashayan et al., 1970) or vertebral anomalies [Summitt, 19691. This suggests partial or variable expressivity in some individuals. While the full sequence is generally characterized by epibulbar dermoids and lipodermoids of the eye, preauricular skin tags and external ear malformations (generally on the same side as auricular anomalies when unilateral), and vertebral anomalies, most commonly cervical, other associated abnormalities have been recognized. These include colobomata of the upper eyelids, facial asymmetry and hemifacial microsomia, micrognathia, cleft lip and palate, conduction deafness, and a variety of cardiac defects [Smith, 19821. Abnormalities of the genitourinary system have rarely been reported [Rollnick et al., 19871. Both genetic and environmental causes have been proposed for failure of embryonic gonadal development resulting in streak gonads. Sporadic cases may result from a single genetic mutation or from an environmental factor affecting the fetus at the time of genital ridge formation or even earlier in gonadal development [Simpson, 19801. The most common cause of gonadal dysgenesis is XO chromosomal abnormality (UllrichTurner syndrome), and most girls with the classic stigmata of Ullrich-Turner syndrome and apparent 46,XX karyotype also have a 45,XO cell line if a diligent search is made [Simpson, 19761. To date, however, over 130 cases of pure 46,XX gonadal dysgenesis have been reported [Bercu and Schulman, 19801. Numerous family studies with affected sibs or parental consanguinity suggest autosomal recessive inheritance [Simpson, 1980; Granat et al., 19831. While it is possible that our patient with 46,XX gonadal dysgenesis is an individual with partially expressed Goldenhar sequence, she does not have the typically associated external ear malformations or vertebral anomalies. We suspect that this patient with epibulbar dermoids, preauricular skin tags, and 46,XX gonadal dysgenesis instead represents a previously un-
reported syndrome. In the absence of a positive family history for any of these abnormalities, she appears to represent a sporadic case. With the development of DNA technology capable of detecting minor genetic abnormalities of the sex chromosomes [Simpson et al., 19871, it soon may be possible to define clearly any relationships with these or other similar conditions, not on the basis of physical findings alone, but on the basis of closely linked chromosomal abnormalities.
REFERENCES Baum JL, Feingold M (1973):Ocular aspects of Goldenhar’s syndrome. Am J Ophthalmol 75:250-257. Bercu BB, Schulman J D (1980): Genetics of abnormalities of sexual differentiation and female reproductive failure. Obstet Gynecol Surv 35:l-11. Budden SS, Robinson GC (1973):Oculoauricular vertebral dysplasiaits association with sensorineural deafness and other abnormalities. Am J Dis Child 125:431-433. Goldenhar M (1952):Associations malformations de l’oeilet de l’oreille en particulier le syndrome dermoids epibulbaire-appendices auriculaires fistula auris congenita et ses relations avec la dysostose mandibulofaciale. J Genet Hum 1:243-288. Gorlin R J , Jue KL, Jacobsen U, Goldschmidt E (1963): Oculoauriculovertebral dysplasia. J Pediatr 63:991-999. Granat M, Amar A, Mor-Yosef S, Brautbar C, Schenker J (1983): Familial gonadal germinative failure: endocrine and human leukocyte antigen studies. Fertil Steril 40:215-219. Mellor DH, Richardson J E , Douglas DM (1973): Goldenhar’s syndrome-oculoauriculo-vertebral dysplasia. Arch Dis Child 48: 537-541. Pashayan J , Pinsky L, Fraser FC (1970): Hemifacial microsomiaoculo-auriculo-vertebraldysplasia-a patient with overlappingfeatures. J Med Genet 7:185-188. Perrault M, Klotz B, Housset E (1951):Deux cas de syndrome de Turner avec Surdi-mutite dans une meme fratrie. Bull Mem SOC Med Hop Paris 16:79-84. Portuondo JA, Neyro JL, Benito JA, de 10s Rios A, Barral A (1987): Familial 46,XX gonadal dysgenesis. Int J Fertil 32:56-58. Rollnick BR, Kaye CI, Nagatoshi K, Hauck W, Martin A 0 (1987): Oculovertebral dysplasia and variants: phenotypic characteristics of 294 patients. Am J Med Genet 26:361-375. Simpson J L (1976):Gonadal dysgenesis. In Simpson J L (ed): “Disorders of Sexual Differentiation.” New York: Academic Press,p 293. Simpson J L (1979):Gonadal dysgenesis, XX type. In Bergsma D (ed): “Birth Defects Compendium,” Second Edition. New York Alan R. Liss, Inc. Simpson J L (1980):Genes, chromosomes and reproductive failure. Ferti1 Steril 33:107-116. Simpson E, Chandler P, Goulmy E, Disteche CM, Ferguson-Smith MA, Page DC (1987):Separation of the genetic loci for the H-Y antigen and for testis determination on human Y chromosome. Nature 326:876-878. Smith DW (1982): “Fkcognizable Patterns of Human Malformation,” Third ed. Philadelphia: Saunders Company, pp 497-500. Summitt R (1969):Familial Goldenhar syndrome. In Bergsma D (ed): “Birth Defects: Original Article Series.” New York: The National Foundation-March of Dimes, BD:OAS 5 (2):106-109. von Arlt CF (1845):Klinische darstellung der krankheiten des auges. Vienna 3:376. Youlton R, Michelsen H, Be C, Cruz-Coke R (1982):Pure XX gonadal dysgenesis in identical twins. Clin Genet 21262-265.
Brief Clinical Report 46,XX Gonadal Dysgenesis With Epibulbar Dermoid Sara A. Quayle and Kenneth C. Copeland Department of Pediatrics, University of Vermont College of Medicine, Burlington
Pure gonadal dysgenesis with 46,XX genotype is a rare abnormality with unknown etiology. Although sensorineural deafness has been described with 46,XX gonadal dysgenesis, the majority of reported cases of 46,XX gonadal dysgenesis have no associated physical abnormalities. We report a patient with 46,XX gonadal dysgenesis associated with epibulbar dermoids and preauricular skin tags, the classic ocular and skin manifestations of Goldenhar sequence (oculoauricular vertebral dysplasia).We propose that our patient may represent a new and previously unreported syndrome. KEY WORDS: Goldenhar sequence, gonadal dysgenesis 46,XX, oculoauricular vertebral dysplasia, Perrault syndrome
INTRODUCTION Gonadal dysgenesis with 46,XX genotype is a rare condition, in which a phenotypically female individual is found to have streak gonads and normal karyotype. Its precise etiology is not known. When it occurs in isolation, it is termed pure gonadal dysgenesis. It is usually diagnosed at puberty, when the patient fails to develop secondary sexual characteristics and undergo menarche. Although some females with gonadal dysgenesis and 46,XX karyotype may also have one or more of the physical stigmata of classic Ullrich-Turner syndrome, the vast majority of these girls also will have a detectable 45,XO cell line in blood, skin, or other tissues [Simpson, 19761. Gonadal dysgenesis with 46,XX karyotype has also been associated with sensorineural deafness [Perrault et al., 19511. Perrault syndrome has been described in numerous kinships, apparently transmitted in an autosomal recessive fashion. To our knowledge 46,XX gonadal dysgenesis has not been associated with other anomalies or syndromes. Received for publication May 23,1990;revision received October 22, 1990. Address reprint requests to Sara A. Quayle, M.D., Timber Lane Pediatric Associates, 51 Timber Lane, So. Burlington, VT 05403.
0 1991 Wiley-Liss, Inc.
We report a female patient with 46,XX gonadal dysgenesis in association with epibulbar dermoids and preauricular skin tags. The latter anomalies are found in patients with Goldenhar sequence, which classically consists of epibulbar dermoid, external ear anomalies and vertebral anomalies, and frequently includes preauricular skin tags.
CLINICAL REPORT S.M. was born in 1972, at 40 weeks gestation, to a 25year-old multiparous mother, following a healthy pregnancy. Her father was age 34. There was no known family history of congenital anomalies. The parents were not consanguineous. At birth, numerous bilateral preauricular skin tags were present. At age 2 weeks, bulbar dermoids, 2 on the left cornea and one on the right, and left lid ptosis were noted. The diagnosis of Goldenhar “syndrome” was made at that time. The child was generally healthy throughout infancy and childhood, with normal growth and development. Hearing tests were normal. Clinical examinations of the spine were consistently normal and spinal radiographs were never obtained. At age 163/12 years, menarche had not occurred. Physical exam was normal except for absence of breast development, scant downy pubic hair, and infantile external genitalia. Height was 170 cm (85th centile) and weight was 72 kg (90th centile). Laboratory testing showed a serum estradiol level less than 20 mIU/ml. Serum FSH and LH were 68 mIU/ml and 34 mIU/ml. T4 and TSH were normal. Peripheral blood and skin fibroblast karyotyping were both 46,XX. Thyroid, ovarian and adrenal antibodies were all negative. Pelvic ultrasound showed an infantile uterus and bilateral small, indistinct gonads. The patient responded well to therapy with ethinyl estradiol and medroxyprogesterone acetate, attaining Tanner IV breast and Tanner I1 pubic hair development upon followup 5 months after the initiation of therapy. DISCUSSION Our patient presented with epibulbar dermoids, preauricular skin tags, and gonadal dysgenesis with 46,XX chromosome constitution. The presence of epibulbar dermoid and preauricular skin tags suggests a partially expressed oculoauricular vertebral dysplasia (Goldenhar sequence). To our knowledge, these eye and ear
76
Quayle and Copeland
abnormalities have never been described in association with 46,XX gonadal dysgenesis. Oculoauricular vertebral dysplasia was first described by von Arlt in 1845. However, it derives its common name of Goldenhar “syndrome” from a report by Goldenhar [1952],in which he reviewed 16previously published cases and described 3 new cases with epibulbar dermoids, preauricular skin tags and external ear abnormalities. Gorlin et al. [ 19631later described 40 cases in which vertebral anomalies were recognized in association with the ocular and auricular components, and they renamed the syndrome oculoauricular vertebral dysplasia. Both sporadic [Pashayan et al., 19701 and familial [Summitt, 1969; Mellor et al., 19731 cases suggesting both autosomal recessive and autosomal dominant inheritance have since been described. There are case reports in the literature which lack the presence of epibulbar dermoid (Pashayan et al., 1970) or vertebral anomalies [Summitt, 19691. This suggests partial or variable expressivity in some individuals. While the full sequence is generally characterized by epibulbar dermoids and lipodermoids of the eye, preauricular skin tags and external ear malformations (generally on the same side as auricular anomalies when unilateral), and vertebral anomalies, most commonly cervical, other associated abnormalities have been recognized. These include colobomata of the upper eyelids, facial asymmetry and hemifacial microsomia, micrognathia, cleft lip and palate, conduction deafness, and a variety of cardiac defects [Smith, 19821. Abnormalities of the genitourinary system have rarely been reported [Rollnick et al., 19871. Both genetic and environmental causes have been proposed for failure of embryonic gonadal development resulting in streak gonads. Sporadic cases may result from a single genetic mutation or from an environmental factor affecting the fetus at the time of genital ridge formation or even earlier in gonadal development [Simpson, 19801. The most common cause of gonadal dysgenesis is XO chromosomal abnormality (UllrichTurner syndrome), and most girls with the classic stigmata of Ullrich-Turner syndrome and apparent 46,XX karyotype also have a 45,XO cell line if a diligent search is made [Simpson, 19761. To date, however, over 130 cases of pure 46,XX gonadal dysgenesis have been reported [Bercu and Schulman, 19801. Numerous family studies with affected sibs or parental consanguinity suggest autosomal recessive inheritance [Simpson, 1980; Granat et al., 19831. While it is possible that our patient with 46,XX gonadal dysgenesis is an individual with partially expressed Goldenhar sequence, she does not have the typically associated external ear malformations or vertebral anomalies. We suspect that this patient with epibulbar dermoids, preauricular skin tags, and 46,XX gonadal dysgenesis instead represents a previously un-
reported syndrome. In the absence of a positive family history for any of these abnormalities, she appears to represent a sporadic case. With the development of DNA technology capable of detecting minor genetic abnormalities of the sex chromosomes [Simpson et al., 19871, it soon may be possible to define clearly any relationships with these or other similar conditions, not on the basis of physical findings alone, but on the basis of closely linked chromosomal abnormalities.
REFERENCES Baum JL, Feingold M (1973):Ocular aspects of Goldenhar’s syndrome. Am J Ophthalmol 75:250-257. Bercu BB, Schulman J D (1980): Genetics of abnormalities of sexual differentiation and female reproductive failure. Obstet Gynecol Surv 35:l-11. Budden SS, Robinson GC (1973):Oculoauricular vertebral dysplasiaits association with sensorineural deafness and other abnormalities. Am J Dis Child 125:431-433. Goldenhar M (1952):Associations malformations de l’oeilet de l’oreille en particulier le syndrome dermoids epibulbaire-appendices auriculaires fistula auris congenita et ses relations avec la dysostose mandibulofaciale. J Genet Hum 1:243-288. Gorlin R J , Jue KL, Jacobsen U, Goldschmidt E (1963): Oculoauriculovertebral dysplasia. J Pediatr 63:991-999. Granat M, Amar A, Mor-Yosef S, Brautbar C, Schenker J (1983): Familial gonadal germinative failure: endocrine and human leukocyte antigen studies. Fertil Steril 40:215-219. Mellor DH, Richardson J E , Douglas DM (1973): Goldenhar’s syndrome-oculoauriculo-vertebral dysplasia. Arch Dis Child 48: 537-541. Pashayan J , Pinsky L, Fraser FC (1970): Hemifacial microsomiaoculo-auriculo-vertebraldysplasia-a patient with overlappingfeatures. J Med Genet 7:185-188. Perrault M, Klotz B, Housset E (1951):Deux cas de syndrome de Turner avec Surdi-mutite dans une meme fratrie. Bull Mem SOC Med Hop Paris 16:79-84. Portuondo JA, Neyro JL, Benito JA, de 10s Rios A, Barral A (1987): Familial 46,XX gonadal dysgenesis. Int J Fertil 32:56-58. Rollnick BR, Kaye CI, Nagatoshi K, Hauck W, Martin A 0 (1987): Oculovertebral dysplasia and variants: phenotypic characteristics of 294 patients. Am J Med Genet 26:361-375. Simpson J L (1976):Gonadal dysgenesis. In Simpson J L (ed): “Disorders of Sexual Differentiation.” New York: Academic Press,p 293. Simpson J L (1979):Gonadal dysgenesis, XX type. In Bergsma D (ed): “Birth Defects Compendium,” Second Edition. New York Alan R. Liss, Inc. Simpson J L (1980):Genes, chromosomes and reproductive failure. Ferti1 Steril 33:107-116. Simpson E, Chandler P, Goulmy E, Disteche CM, Ferguson-Smith MA, Page DC (1987):Separation of the genetic loci for the H-Y antigen and for testis determination on human Y chromosome. Nature 326:876-878. Smith DW (1982): “Fkcognizable Patterns of Human Malformation,” Third ed. Philadelphia: Saunders Company, pp 497-500. Summitt R (1969):Familial Goldenhar syndrome. In Bergsma D (ed): “Birth Defects: Original Article Series.” New York: The National Foundation-March of Dimes, BD:OAS 5 (2):106-109. von Arlt CF (1845):Klinische darstellung der krankheiten des auges. Vienna 3:376. Youlton R, Michelsen H, Be C, Cruz-Coke R (1982):Pure XX gonadal dysgenesis in identical twins. Clin Genet 21262-265.
