American Journal of Medical Genetics 36:285-287 (1990)
Brief Clinical Report ~
Hypogonadotropic Hypogonadism in Mentally Retarded Adults With Microphthalmia and Clinical Anophthalmia Laura Davis Keppen, Michael C. Brodsky, Judith M. Michael, and Ann R. Poindexter Departments of Pediatrics (L.D.K.) and Ophthalmology (M.C.B.), University of Arkansas for Medical Sciences, Little Rock, and Human Development Center, Conway (J.M.M.,A.R.P.),Arkansas
Five of 13 patients with microphthalmia or clinical anophthalmia studied in an institution of 650 mentally retarded adults had hypogonadotropic hypogonadism. Four males had low testosterone levels and sexual infantilism, manifesting as micropenis with small testes or cryptorchidism. One female had primary amenorrhea. All 5 patients had low gonadotropin levels, confirming a hypothalamic or pituitary basis for their hypogonadism. Thyroxin, thyroid stimulating hormone, prolactin, and A.M. cortisol were also measured and were normal. All patients with hypogonadotropic hypogonadism were chromosomally normal and had variable central nervous system defects, suggesting that they comprise a heterogeneous group of disorders. Microphthalmia or anophthalmia in a mentally retarded patient is associated with hypogonadotropic hypogonadism. KEY WORDS: eye, genitalia, gonadotropins, mental retardation INTRODUCTION Mentally retarded individuals have a n unusually high incidence of visual problems [Jacobson, 1988; Warburg, 1971; Bankes, 19741. In a recent study of 228 adults with severe mental retardation, 60% had eye abnormalities including optic atrophy, cataract, retinal disease, keratoconus, microphthalmos, phthisis, glaucoma, neuroparalytic keratitis, and high myopia [Jacobson, 19881. This produced significant visual handicap in 23%of the study population. The coexistence of anophthalmia with clinical hypogonadism in 2 mentally retarded adults prompted us to review medical records of 650 adults with severe or pro-
found mental retardation a t the Human Development Center in Conway, Arkansas. Two percent of patients had microphthalmia or clinical anophthalmia. Clinical and laboratory findings of hypogonadotropic hypogonadism were found in 38%of patients who had microphthalmia or clinical anophthalmia. This report describes the ocular and systemic findings, endocrine studies, and chromosome analysis in 5 adults with profound mental retardation, microphthalmia or clinical anophthalmia, and hypogonadotropic hypogonadism. MATERIALS AND METHODS The charts of the 650 residents with mental retardation were reviewed. A total of 13 individuals with microphthalmia or clinical anophthalmia were identified. Each patient underwent a review of medical history, physical examination, and chromosome analysis on PHA-stimulated peripheral blood lymphocyte cultures using conventional trypsin-Giemsa banding. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and testosterone levels were measured in each individual with microphthalmia and hypogonadism to determine the cause of the hypogonadism. T4, TSH, prolactin, and A.M. cortisol levels were also measured to assess pituitary and hypothalamic function. Five patients who displayed abnormal pubertal development were found to have hypogonadotropic hypogonadism.
CLINICAL REPORTS Patient 1 A 21-year-old man with profound mental retardation and microcephaly had O.U. anophthalmia with small palpebral fissures. He had spastic quadriplegia and profound sensorineural hearing loss. He also had a history of a n epidermal cyst over the right eyebrow, a repaired cleft lip, and a cleft palate. Sense of smell could not be Received for publication May 31,1989; revision received Novem- assessed. He had a micropenis, measuring 3.5 cm; prepubertal testes, 1cm in length; and a n absence of pubic ber 13, 1989. Address reprint requests t o Laura Davis Keppen, M.D., Univer- hair. Testosterone was 6 ng/dl, LH was 3 mIU/ml, and FSH was 3 mIU/ml. sity of Arkansas, 800 Marshall Street, Little Rock, AR 72202.
0 1990 Wiley-Liss, Inc.
286
Keppen et al.
Patient 2 A 23-year-old man with severe mental retardation had microphthalmos O.S. The cornea O.D. was small; however, the globe was buphthalmic from a long history of uncontrolled glaucoma. A retro-corneal scar was seen through the clear right cornea. The globe was firm to palpation. The patient was 190.5 cm tall with long limbs, arachnodactyly, large ears, and gynecomastia. Sense of smell was normal. He had a small penis 3 cm long, bilateral cryptorchidism, and a horizontal female escutcheon. Testosterone and gonadotropin levels were low.
Patient 3 A 36-year-old man with profound mental retardation and microcephaly had microphthalmos O.S. In the left eye, the iris was adherent to the corneal endothelium peripherally, and the peripheral cornea was vascularized. The central cornea remained clear. The right cornea was of normal size and diffusely hazy. He had severe to profound sensorineural hearing loss and external ears were normal. Index fingers were ulnar deviated and short with rudimentary proximal and middle phalanges. Sense of smell could not be assessed. Penis length was 4 cm and there was bilateral cryptorchidism. He had a female escutcheon. Serum testosterone level was 15 ngldl and serum gonadotropins were low. Patient 4 A 23-year-old man with severe mental retardation and microcephaly had bilateral clinical microphthalmia. He had spastic diplegia and flexion contractures. He had a micropenis, prepubertal testes, and Tanner stage 2 pubic hair. Testosterone and gonadotropin levels were low. Patient 5 A 35-year-old woman with moderate mental retardation and microcephaly had bilateral clinical anophthalmia. Other systemic abnormalities were absent. Hearing was normal and she had normal external ears. Sense of smell was grossly assessed as normal. She had primary amenorrhea. She had Tanner stage 4 breast
development, Tanner stage 4 pubic hair, and normal pelvic structure. Gonadotropin levels were low.
RESULTS All 4 males had micropenis, small testes or cryptorchidism, very low testosterone levels, and absence of gonadotropin elevations. The adult female had primary amenorrhea without elevation of gonadotropins. Family history of these patients was unremarkable. Chromosomes were normal in all 5 individuals. The endocrine results obtained on these individuals are shown in Table I. Thyroxin, thyroid-stimulating hormone, prolactin, and A.M. cortisol were also measured. There were no additional endocrine abnormalities. The 8 individuals with microphthalmia and normal genital development included: 3 profoundly mentally retarded individuals with microcephaly and unilateral microphthalmia; a woman with profound mental retardation, unilateral microphthalmia, ventricular dilatation, and vertebral abnormalities; a n individual with severe mental retardation, bilateral microphthalmia, and congenital leucoma secondary to mesodermal dysgenesis; one with profound mental retardation and autosoma1 dominant bilateral microphthalmia without associated systemic malformations; and one with profound mental retardation and bilateral congenital cystic microphthalmia. A 13-year-old boy profoundly mentally retarded with right microphthalmia and cataract of the left eye was found to have duplication of chromosome 13q (13q21- 13qter). DISCUSSION Five of the 13 (38%)mentally retarded adults with severe microphthalmia or clinical anophthalmia had abnormal pubertal development and hypogonadotropic hypogonadism. This was manifest clinically as sexual infantilism in 4 males and as primary amenorrhea in one female. Luteinizing and follicle-stimulating hormone levels were normal in all patients, confirming that hypogonadism was of hypothalamic or pituitary origin [Kaplan, 1982; Wilson and Foster, 19851. Microphthalmia is a congenital malformation in which the volume of one or both eyes is reduced [Bate-
TABLE I. Endocrine Evaluation on Patients With Hypogonadotropic Hypogonadism
LHiFSH Normal v a l u e s Clinical manifestations Male with micropenis, prepubertal testes, absent pubic hair Male with micropenis, cryptorchidism, female escutcheon Male with micropenis, cryptorchidism, female escutcheon Male with micropenis, prepubertal testes, Tanner 2 pubic hair Female with 1"amenorrhea
3-18 mIUiml
Testosterone male 270-1,100 ngidl
~~
Estrogen male 40-115, female 61-437 pgiml ~~
A.M.
Cortisol 5-25 pgidl ~~
~
6.1
3.8
4.5
9.8
4.2
9.8
7.5
6
8.4
1.6
7.7
4.8
10
11
2/
Brief Clinical Report ~
Hypogonadotropic Hypogonadism in Mentally Retarded Adults With Microphthalmia and Clinical Anophthalmia Laura Davis Keppen, Michael C. Brodsky, Judith M. Michael, and Ann R. Poindexter Departments of Pediatrics (L.D.K.) and Ophthalmology (M.C.B.), University of Arkansas for Medical Sciences, Little Rock, and Human Development Center, Conway (J.M.M.,A.R.P.),Arkansas
Five of 13 patients with microphthalmia or clinical anophthalmia studied in an institution of 650 mentally retarded adults had hypogonadotropic hypogonadism. Four males had low testosterone levels and sexual infantilism, manifesting as micropenis with small testes or cryptorchidism. One female had primary amenorrhea. All 5 patients had low gonadotropin levels, confirming a hypothalamic or pituitary basis for their hypogonadism. Thyroxin, thyroid stimulating hormone, prolactin, and A.M. cortisol were also measured and were normal. All patients with hypogonadotropic hypogonadism were chromosomally normal and had variable central nervous system defects, suggesting that they comprise a heterogeneous group of disorders. Microphthalmia or anophthalmia in a mentally retarded patient is associated with hypogonadotropic hypogonadism. KEY WORDS: eye, genitalia, gonadotropins, mental retardation INTRODUCTION Mentally retarded individuals have a n unusually high incidence of visual problems [Jacobson, 1988; Warburg, 1971; Bankes, 19741. In a recent study of 228 adults with severe mental retardation, 60% had eye abnormalities including optic atrophy, cataract, retinal disease, keratoconus, microphthalmos, phthisis, glaucoma, neuroparalytic keratitis, and high myopia [Jacobson, 19881. This produced significant visual handicap in 23%of the study population. The coexistence of anophthalmia with clinical hypogonadism in 2 mentally retarded adults prompted us to review medical records of 650 adults with severe or pro-
found mental retardation a t the Human Development Center in Conway, Arkansas. Two percent of patients had microphthalmia or clinical anophthalmia. Clinical and laboratory findings of hypogonadotropic hypogonadism were found in 38%of patients who had microphthalmia or clinical anophthalmia. This report describes the ocular and systemic findings, endocrine studies, and chromosome analysis in 5 adults with profound mental retardation, microphthalmia or clinical anophthalmia, and hypogonadotropic hypogonadism. MATERIALS AND METHODS The charts of the 650 residents with mental retardation were reviewed. A total of 13 individuals with microphthalmia or clinical anophthalmia were identified. Each patient underwent a review of medical history, physical examination, and chromosome analysis on PHA-stimulated peripheral blood lymphocyte cultures using conventional trypsin-Giemsa banding. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and testosterone levels were measured in each individual with microphthalmia and hypogonadism to determine the cause of the hypogonadism. T4, TSH, prolactin, and A.M. cortisol levels were also measured to assess pituitary and hypothalamic function. Five patients who displayed abnormal pubertal development were found to have hypogonadotropic hypogonadism.
CLINICAL REPORTS Patient 1 A 21-year-old man with profound mental retardation and microcephaly had O.U. anophthalmia with small palpebral fissures. He had spastic quadriplegia and profound sensorineural hearing loss. He also had a history of a n epidermal cyst over the right eyebrow, a repaired cleft lip, and a cleft palate. Sense of smell could not be Received for publication May 31,1989; revision received Novem- assessed. He had a micropenis, measuring 3.5 cm; prepubertal testes, 1cm in length; and a n absence of pubic ber 13, 1989. Address reprint requests t o Laura Davis Keppen, M.D., Univer- hair. Testosterone was 6 ng/dl, LH was 3 mIU/ml, and FSH was 3 mIU/ml. sity of Arkansas, 800 Marshall Street, Little Rock, AR 72202.
0 1990 Wiley-Liss, Inc.
286
Keppen et al.
Patient 2 A 23-year-old man with severe mental retardation had microphthalmos O.S. The cornea O.D. was small; however, the globe was buphthalmic from a long history of uncontrolled glaucoma. A retro-corneal scar was seen through the clear right cornea. The globe was firm to palpation. The patient was 190.5 cm tall with long limbs, arachnodactyly, large ears, and gynecomastia. Sense of smell was normal. He had a small penis 3 cm long, bilateral cryptorchidism, and a horizontal female escutcheon. Testosterone and gonadotropin levels were low.
Patient 3 A 36-year-old man with profound mental retardation and microcephaly had microphthalmos O.S. In the left eye, the iris was adherent to the corneal endothelium peripherally, and the peripheral cornea was vascularized. The central cornea remained clear. The right cornea was of normal size and diffusely hazy. He had severe to profound sensorineural hearing loss and external ears were normal. Index fingers were ulnar deviated and short with rudimentary proximal and middle phalanges. Sense of smell could not be assessed. Penis length was 4 cm and there was bilateral cryptorchidism. He had a female escutcheon. Serum testosterone level was 15 ngldl and serum gonadotropins were low. Patient 4 A 23-year-old man with severe mental retardation and microcephaly had bilateral clinical microphthalmia. He had spastic diplegia and flexion contractures. He had a micropenis, prepubertal testes, and Tanner stage 2 pubic hair. Testosterone and gonadotropin levels were low. Patient 5 A 35-year-old woman with moderate mental retardation and microcephaly had bilateral clinical anophthalmia. Other systemic abnormalities were absent. Hearing was normal and she had normal external ears. Sense of smell was grossly assessed as normal. She had primary amenorrhea. She had Tanner stage 4 breast
development, Tanner stage 4 pubic hair, and normal pelvic structure. Gonadotropin levels were low.
RESULTS All 4 males had micropenis, small testes or cryptorchidism, very low testosterone levels, and absence of gonadotropin elevations. The adult female had primary amenorrhea without elevation of gonadotropins. Family history of these patients was unremarkable. Chromosomes were normal in all 5 individuals. The endocrine results obtained on these individuals are shown in Table I. Thyroxin, thyroid-stimulating hormone, prolactin, and A.M. cortisol were also measured. There were no additional endocrine abnormalities. The 8 individuals with microphthalmia and normal genital development included: 3 profoundly mentally retarded individuals with microcephaly and unilateral microphthalmia; a woman with profound mental retardation, unilateral microphthalmia, ventricular dilatation, and vertebral abnormalities; a n individual with severe mental retardation, bilateral microphthalmia, and congenital leucoma secondary to mesodermal dysgenesis; one with profound mental retardation and autosoma1 dominant bilateral microphthalmia without associated systemic malformations; and one with profound mental retardation and bilateral congenital cystic microphthalmia. A 13-year-old boy profoundly mentally retarded with right microphthalmia and cataract of the left eye was found to have duplication of chromosome 13q (13q21- 13qter). DISCUSSION Five of the 13 (38%)mentally retarded adults with severe microphthalmia or clinical anophthalmia had abnormal pubertal development and hypogonadotropic hypogonadism. This was manifest clinically as sexual infantilism in 4 males and as primary amenorrhea in one female. Luteinizing and follicle-stimulating hormone levels were normal in all patients, confirming that hypogonadism was of hypothalamic or pituitary origin [Kaplan, 1982; Wilson and Foster, 19851. Microphthalmia is a congenital malformation in which the volume of one or both eyes is reduced [Bate-
TABLE I. Endocrine Evaluation on Patients With Hypogonadotropic Hypogonadism
LHiFSH Normal v a l u e s Clinical manifestations Male with micropenis, prepubertal testes, absent pubic hair Male with micropenis, cryptorchidism, female escutcheon Male with micropenis, cryptorchidism, female escutcheon Male with micropenis, prepubertal testes, Tanner 2 pubic hair Female with 1"amenorrhea
3-18 mIUiml
Testosterone male 270-1,100 ngidl
~~
Estrogen male 40-115, female 61-437 pgiml ~~
A.M.
Cortisol 5-25 pgidl ~~
~
6.1
3.8
4.5
9.8
4.2
9.8
7.5
6
8.4
1.6
7.7
4.8
10
11
2/
