American Journal of Medical Genetics 43:1030-1031 (1992)
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Microcephaly, Lymphedema, and Chorioretinal Dysplasia: A Distinct Syndrome? Murray Feingold and Louis Bartoshesky Professor of Pediatrics, Boston University School of Medicine, and Physician-in-Chief of the National Birth Defects Center, Boston, Massachusetts (M.F.); Associate Professor of Pediatrics, Thomas Jefferson University and Department of Pediatrics, Medical Center of Delaware (L.B.) ~~
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cept for a maternal aunt who has poor vision because of a reported unknown type of congenital infection. Development. He rolled over at 4 months, sat without support at 6% months, pulled to stand at 9 months, and walked well at 12 months. Verbally, he said a few words a t 12 months and combined 2 words a t 19 months. He was toilet trained at 2 years. He is presently in the fourth grade and does well in school. Physical examination. At age 6 days, the patient’s OFC was 31.5 cm, and he had a sloping forehead. The anterior fontanelle was fingertip size. Bilateral epi0 1992 Wiley-Liss,Inc. canthal folds and a flat nasal bridge were noted. An unusual retinal pigmentation was present bilaterally, KEY WORDS: dominant inheritance, autosobut could not be defined at that time. Neurologic examma1 recessive inheritance, conination was normal. There was lymphedema over the genital abnormalities dorsum of both feet without any tenderness or erythema. Nail dysplasia of the 2nd, 3rd, 4th, and 5th toes bilaterally was present. The puffiness of the feet INTRODUCTION was still present at the 4 , 6 , 8 , and 12 month examinaThe combination of microcephaly and lymphedema tions. His height and weight have remained normal and microcephaly and chorioretinal changes has been with his most recent height being at the 50th centile and described in a number of families. Inheritance was ei- weight a t the 20th centile. Head circumference, alther autosomal recessive or dominant. We report on 2 though growing steadily, remains below the 3rd centile, unrelated patients with microcephaly, lymphedema, and his measurement at age 6 was in the 50th centile for and chorioretinal changes. a 19-month-old. The chorioretinal changes have not changed. There were large areas of reticulated choCLINICAL REPORTS rioretinal atrophy in the superior and inferior fundus of Patient 1 both eyes. Mottled pigmentation was present in the The first patient, a 10-year-old boy, was the second areas of atrophy. Several atrophic yellow spots were child born to a 25-year-old mother and 28-year-old noted in the inferior portions of both fundi. The vitreous, father. Pregnancy was normal with no known exposures optic nerves, and posterior poles of both eyes were norto medication, radiation, nicotine, alcohol, or known mal. Mild optic atrophy on the right was observed. Vitoxins. Mother had a rash on her arms during the second sion was decreased bilaterally with the right eye (less trimester. Delivery was cephalic and birth weight was than 20/800 vision) more involved than the left, but 2,996 g, length 50 cm, and head circumference (OFC) improved with patching of the left eye. 31.5 cm. His mother does not recall when the lymphedema Family history. Father is of French and Native finally went away, but on examination at age 6 years, it American background and mother of French and Czecho- was no longer present. TORCH screening done during slovakian descent. An older sister is in good health. the newborn period was normal as was head ultrasound There is no family history of microcephaly, lymph- and computed tomographic (CT) scan. edema, mental retardation, or visual abnormalities exPatient 2 The second patient, a 9-year-old boy, was the sixth Received for publication October 21,1991; revision received Jan- child born to a 41-year-old mother. Pregnancy was normal and there were no known exposures to medication, uary 10,1992. Address reprint requests to Murray Feingold, M.D., National radiation, nicotine, alcohol, or toxins. Delivery was Birth Defects Center, 30 Warren Street, Brighton, M A 02135. cephalic, and birth weight 3 kg. The baby had no medi-
We report on 2 unrelated patients with microcephaly, lymphedema, and chorioretinal changes. They are compared with previously reported patients with microcephaly and lymphedema and microcephaly with chorioretinal changes. The question is raised whether all of these patients represent one entity or are separate syndromes. Until more data are available we propose that our patients represent a single entity.
0 1992 Wiley-Liss, Inc.
Microcephaly, Lymphedema, and Chorioretinal Dysplasia cal problems during his 2-day stay in the nursery, except that it was noted that his head was small, and he had puffiness of his feet. Family history. There are 6 healthy sibs, and no family history of microcephaly, lymphedema, mental retardation, visual abnormalities, or consanguinity. Development. He has had some difficulty learning in school, and psychological testing documented a full scale I& of 78. His expressive language abilities, including vocabulary and grammar, were in the normal range, but his receptive language skills were mildly reduced. Significantly decreased was his abstract verbal reasoning. Physical examination. Patient’s head was always considered to be small, and our first measurement, at age 9 months, was 40.8 cm (50th centile for a 3-monthold). Length was normal, but weight was 6.6 kg (50th centile for a 4-month-old). His face was not abnormal. External eye examination was normal, but fundi were not well visualized. Chest was clear, and no cardiac murmurs were heard. Abdominal examination did not show any enlarged organs or masses. There was lymphedema on the dorsum of both feet. Neurologic examination was normal. His height has remained at the 25th centile, and weight a t the 5th centile. Head circumference, although growing steadily, has remained below the 3rd centile and at 8% years of age was 47 cm (50th centile for an 11-month-old). Because we were aware of the chorioretinal changes present in patient 1, he was referred to an ophthalmologist at age 2 years. The ophthalmologist’simpression at that time was “apparently a normal ocular examination, but because the patient was not cooperative, a good view was not obtained.” On follow-upvisit to our Clinic a t age 6 years, a routine fundoscopicexamination showed “pigmented lesions.” Examination by an ophthalmologist documented pallor in the area of the optic nerve. There was a poor foveae reflex with a granular pigment pattern on the macula. Multiple hypopigmented spots with surrounding pigment clumping were seen in the equatorial zone bilaterally with an additional large atrophic area inferiorly on the left. Electroretinographic findings of the right eye were compatible with focal retinal degeneration affecting the photopic system more than the scotopic (rod) system. The impression of the ophthalmologist was equatorial chorioretinal pigmentary changes with mild optic disc pallor, and pigment granularity of the macula that had the appearance of being congenital. His vision has subsequently remained stable. Laboratory data. Results of the following studies were normal: chromosomes, TORCH studies, head CT scan, lipid profile, phytanic acid, and retinol esters.
DISCUSSION In 1985,Leung described 4 generations (5relatives) of a Chinese family with microcephaly and congenital lymphedema involving mainly the feet. Mental retardation was not present and there was no mention of chorioretinal dysplasia. The following year 5 individuals in 3 generations were reported with either microcephaly (3 relatives), or microcephaly and lymphedema (2 relatives) [Crowe and Dickerman, 19861.None of these pa-
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tients were retarded, and there was no mention of any eye abnormalities. McKusick et al. [19661 reported 8 patients in 2 sibships with microcephaly and chorioretinopathy. No lymphedema or mental retardation was present, but they did have short stature. The suggested mode of inheritance was autosomal recessive. Subsequently, there have been 2 other reports of autosoma1 recessively inherited microcephaly and chorioretinal dysplasia [Par et al., 1975;Cantu et al., 19771, and 2 reports of the same combination with autosomal dominant inheritance [Alzial et al., 1980;Tenconi et al., 19811. Although short stature and mental retardation were present in some of the affected patients, lymphedema was not. The cause remains unknown in most patients with microcephaly, although there are infectious (intrauterine), teratogenic, genetic, chromosomal, and syndromic causes. Lymphedema has been associated with intestinal lymphangiectasia, distichiasis (double row of eye lashes), yellow nails, and Ullrich-lbrner syndrome. None of these findings were present in our 2 patients. The chorioretinal changes present in these patients are not typical of the chorioretinitis seen in intrauterine infections or retinitis pigmentosa. In all of the patients discussed above, including our 2 patients, microcephaly is the constant finding. The question is whether all of these patients represent just one entity (microcephaly, lymphedema, and chorioretinal dysplasia with or without retardation) or are 3 distinct entities (microcephaly and lymphedema; microcephaly and chorioretinal dysplasia; and microcephaly, chorioretinal dysplasia, and lymphedema with or without mental retardation). For the time being and until more data are available, we propose that the combination of microcephaly, lymphedema, and chorioretinal dysplasia represents a single syndrome.
ACKNOWLEDGMENTS We thank Lory C. Snady-McCoy, M.D., and John Killion, M.D., for their assistance. This work was supported by a grant from the Genesis Fund. REFERENCES Alzial C, Dufier JL, Brasnu C, Aicardi J, de Grouchy J (1980): Microcephalie vraie avec dysplasie chorioretinienne B h6r6dit6 dominante. Ann Genet 23:91-94. Cantu JM, Rojas JA, Garcia-Cruz D, Hernandez A, Pagan P, Fragoso R, Manzano C (1977): Autosomal recessive microcephaly associated with chorioretinopathy. Hum Genet 36:243-247. Crowe CA, Dickerman LH (1986):Brief clinical report: A genetic association between microcephaly and lymphedema. Am J Med Genet 24131-135. Leung AKC (1985): Dominantly inherited syndrome of microcephaly and congenital lymphedema. Clin Genet 27:611-612. McKusick VA, Stauffer M, Knox DL, Clark DB (1966): Chorioretinopathy with hereditary microcephaly. Arch Ophthalmol 75597-600. Par MM, Cordier P, ’Ridon A, Raspeller A, Stehlen B (1975): Microcephalies g6n6tiques et dysplasies chorio-retiniennes dans une meme fratrie. Bull SOCOphthalmol F’r 75473-477. Tenconi R, Clementi M, Moschini GB, Casara G, Baccichetti C (1981): Chorio-retinal dysplasia, microcephaly and mental retardation. An autosomal dominant syndrome. Clin Genet 20:347-351.
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Microcephaly, Lymphedema, and Chorioretinal Dysplasia: A Distinct Syndrome? Murray Feingold and Louis Bartoshesky Professor of Pediatrics, Boston University School of Medicine, and Physician-in-Chief of the National Birth Defects Center, Boston, Massachusetts (M.F.); Associate Professor of Pediatrics, Thomas Jefferson University and Department of Pediatrics, Medical Center of Delaware (L.B.) ~~
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cept for a maternal aunt who has poor vision because of a reported unknown type of congenital infection. Development. He rolled over at 4 months, sat without support at 6% months, pulled to stand at 9 months, and walked well at 12 months. Verbally, he said a few words a t 12 months and combined 2 words a t 19 months. He was toilet trained at 2 years. He is presently in the fourth grade and does well in school. Physical examination. At age 6 days, the patient’s OFC was 31.5 cm, and he had a sloping forehead. The anterior fontanelle was fingertip size. Bilateral epi0 1992 Wiley-Liss,Inc. canthal folds and a flat nasal bridge were noted. An unusual retinal pigmentation was present bilaterally, KEY WORDS: dominant inheritance, autosobut could not be defined at that time. Neurologic examma1 recessive inheritance, conination was normal. There was lymphedema over the genital abnormalities dorsum of both feet without any tenderness or erythema. Nail dysplasia of the 2nd, 3rd, 4th, and 5th toes bilaterally was present. The puffiness of the feet INTRODUCTION was still present at the 4 , 6 , 8 , and 12 month examinaThe combination of microcephaly and lymphedema tions. His height and weight have remained normal and microcephaly and chorioretinal changes has been with his most recent height being at the 50th centile and described in a number of families. Inheritance was ei- weight a t the 20th centile. Head circumference, alther autosomal recessive or dominant. We report on 2 though growing steadily, remains below the 3rd centile, unrelated patients with microcephaly, lymphedema, and his measurement at age 6 was in the 50th centile for and chorioretinal changes. a 19-month-old. The chorioretinal changes have not changed. There were large areas of reticulated choCLINICAL REPORTS rioretinal atrophy in the superior and inferior fundus of Patient 1 both eyes. Mottled pigmentation was present in the The first patient, a 10-year-old boy, was the second areas of atrophy. Several atrophic yellow spots were child born to a 25-year-old mother and 28-year-old noted in the inferior portions of both fundi. The vitreous, father. Pregnancy was normal with no known exposures optic nerves, and posterior poles of both eyes were norto medication, radiation, nicotine, alcohol, or known mal. Mild optic atrophy on the right was observed. Vitoxins. Mother had a rash on her arms during the second sion was decreased bilaterally with the right eye (less trimester. Delivery was cephalic and birth weight was than 20/800 vision) more involved than the left, but 2,996 g, length 50 cm, and head circumference (OFC) improved with patching of the left eye. 31.5 cm. His mother does not recall when the lymphedema Family history. Father is of French and Native finally went away, but on examination at age 6 years, it American background and mother of French and Czecho- was no longer present. TORCH screening done during slovakian descent. An older sister is in good health. the newborn period was normal as was head ultrasound There is no family history of microcephaly, lymph- and computed tomographic (CT) scan. edema, mental retardation, or visual abnormalities exPatient 2 The second patient, a 9-year-old boy, was the sixth Received for publication October 21,1991; revision received Jan- child born to a 41-year-old mother. Pregnancy was normal and there were no known exposures to medication, uary 10,1992. Address reprint requests to Murray Feingold, M.D., National radiation, nicotine, alcohol, or toxins. Delivery was Birth Defects Center, 30 Warren Street, Brighton, M A 02135. cephalic, and birth weight 3 kg. The baby had no medi-
We report on 2 unrelated patients with microcephaly, lymphedema, and chorioretinal changes. They are compared with previously reported patients with microcephaly and lymphedema and microcephaly with chorioretinal changes. The question is raised whether all of these patients represent one entity or are separate syndromes. Until more data are available we propose that our patients represent a single entity.
0 1992 Wiley-Liss, Inc.
Microcephaly, Lymphedema, and Chorioretinal Dysplasia cal problems during his 2-day stay in the nursery, except that it was noted that his head was small, and he had puffiness of his feet. Family history. There are 6 healthy sibs, and no family history of microcephaly, lymphedema, mental retardation, visual abnormalities, or consanguinity. Development. He has had some difficulty learning in school, and psychological testing documented a full scale I& of 78. His expressive language abilities, including vocabulary and grammar, were in the normal range, but his receptive language skills were mildly reduced. Significantly decreased was his abstract verbal reasoning. Physical examination. Patient’s head was always considered to be small, and our first measurement, at age 9 months, was 40.8 cm (50th centile for a 3-monthold). Length was normal, but weight was 6.6 kg (50th centile for a 4-month-old). His face was not abnormal. External eye examination was normal, but fundi were not well visualized. Chest was clear, and no cardiac murmurs were heard. Abdominal examination did not show any enlarged organs or masses. There was lymphedema on the dorsum of both feet. Neurologic examination was normal. His height has remained at the 25th centile, and weight a t the 5th centile. Head circumference, although growing steadily, has remained below the 3rd centile and at 8% years of age was 47 cm (50th centile for an 11-month-old). Because we were aware of the chorioretinal changes present in patient 1, he was referred to an ophthalmologist at age 2 years. The ophthalmologist’simpression at that time was “apparently a normal ocular examination, but because the patient was not cooperative, a good view was not obtained.” On follow-upvisit to our Clinic a t age 6 years, a routine fundoscopicexamination showed “pigmented lesions.” Examination by an ophthalmologist documented pallor in the area of the optic nerve. There was a poor foveae reflex with a granular pigment pattern on the macula. Multiple hypopigmented spots with surrounding pigment clumping were seen in the equatorial zone bilaterally with an additional large atrophic area inferiorly on the left. Electroretinographic findings of the right eye were compatible with focal retinal degeneration affecting the photopic system more than the scotopic (rod) system. The impression of the ophthalmologist was equatorial chorioretinal pigmentary changes with mild optic disc pallor, and pigment granularity of the macula that had the appearance of being congenital. His vision has subsequently remained stable. Laboratory data. Results of the following studies were normal: chromosomes, TORCH studies, head CT scan, lipid profile, phytanic acid, and retinol esters.
DISCUSSION In 1985,Leung described 4 generations (5relatives) of a Chinese family with microcephaly and congenital lymphedema involving mainly the feet. Mental retardation was not present and there was no mention of chorioretinal dysplasia. The following year 5 individuals in 3 generations were reported with either microcephaly (3 relatives), or microcephaly and lymphedema (2 relatives) [Crowe and Dickerman, 19861.None of these pa-
1031
tients were retarded, and there was no mention of any eye abnormalities. McKusick et al. [19661 reported 8 patients in 2 sibships with microcephaly and chorioretinopathy. No lymphedema or mental retardation was present, but they did have short stature. The suggested mode of inheritance was autosomal recessive. Subsequently, there have been 2 other reports of autosoma1 recessively inherited microcephaly and chorioretinal dysplasia [Par et al., 1975;Cantu et al., 19771, and 2 reports of the same combination with autosomal dominant inheritance [Alzial et al., 1980;Tenconi et al., 19811. Although short stature and mental retardation were present in some of the affected patients, lymphedema was not. The cause remains unknown in most patients with microcephaly, although there are infectious (intrauterine), teratogenic, genetic, chromosomal, and syndromic causes. Lymphedema has been associated with intestinal lymphangiectasia, distichiasis (double row of eye lashes), yellow nails, and Ullrich-lbrner syndrome. None of these findings were present in our 2 patients. The chorioretinal changes present in these patients are not typical of the chorioretinitis seen in intrauterine infections or retinitis pigmentosa. In all of the patients discussed above, including our 2 patients, microcephaly is the constant finding. The question is whether all of these patients represent just one entity (microcephaly, lymphedema, and chorioretinal dysplasia with or without retardation) or are 3 distinct entities (microcephaly and lymphedema; microcephaly and chorioretinal dysplasia; and microcephaly, chorioretinal dysplasia, and lymphedema with or without mental retardation). For the time being and until more data are available, we propose that the combination of microcephaly, lymphedema, and chorioretinal dysplasia represents a single syndrome.
ACKNOWLEDGMENTS We thank Lory C. Snady-McCoy, M.D., and John Killion, M.D., for their assistance. This work was supported by a grant from the Genesis Fund. REFERENCES Alzial C, Dufier JL, Brasnu C, Aicardi J, de Grouchy J (1980): Microcephalie vraie avec dysplasie chorioretinienne B h6r6dit6 dominante. Ann Genet 23:91-94. Cantu JM, Rojas JA, Garcia-Cruz D, Hernandez A, Pagan P, Fragoso R, Manzano C (1977): Autosomal recessive microcephaly associated with chorioretinopathy. Hum Genet 36:243-247. Crowe CA, Dickerman LH (1986):Brief clinical report: A genetic association between microcephaly and lymphedema. Am J Med Genet 24131-135. Leung AKC (1985): Dominantly inherited syndrome of microcephaly and congenital lymphedema. Clin Genet 27:611-612. McKusick VA, Stauffer M, Knox DL, Clark DB (1966): Chorioretinopathy with hereditary microcephaly. Arch Ophthalmol 75597-600. Par MM, Cordier P, ’Ridon A, Raspeller A, Stehlen B (1975): Microcephalies g6n6tiques et dysplasies chorio-retiniennes dans une meme fratrie. Bull SOCOphthalmol F’r 75473-477. Tenconi R, Clementi M, Moschini GB, Casara G, Baccichetti C (1981): Chorio-retinal dysplasia, microcephaly and mental retardation. An autosomal dominant syndrome. Clin Genet 20:347-351.
