November 1979
The J o u r n a l o f P E D I A T R I C S
701
A utosomal dominant microcephaly Four families with autosomal dominant microcephaly are reported Although the phenotype is , nondistinctive, several patients had receding or small foreheads, upslanted palpebral fissures, or prominent ears. The degree of intellectual dysfunction is not as severe as that recorded in atttosomal recessive microcephaly. It would appear that atttosomal dominant microcephaly is more common than previously recorded, and that head circumference measurements of siblings and parents of qffected patients should become a part of the initial investigation.
Robert H. A. H a s l a m , M.D., F.R.C.P.(C),* C a l g a r y , A l b e r t a , C a n a d a , and David W. Smith, M.D., S e a t t l e ,
Wash.
MICROCEPHALY, defined as a head circumference which measures more than 3 SD below the mean for age and sex. is a relatively common finding, particularly among the retarded. Causes of microcephaly during the prenatal period include intrauterine infections, chromosomal disorders, metabolic diseases, exposure to radiation, congenital malformations of the brain, and chronic hypoxia. Postnatal events contributing to microcephaly include birth trauma, meningitis, and toxic encephalopathy? Familial microcephaly occurs with an estimated incidence of 1:25.000 to 1:50,000 live births. ~ An autosomal recessive mode of inheritance has been suggested for the large number of subjects that have been studied? We report four unrelated families in which microcephaly appears to be transmitted in an autosomal dominant fashion. CASE REPORTS Family 1. The proposita is a 2-year-old girl, the only child of an unmarried, 19-year-old mother. The birth weight was 2.6 kg and the length 48.5 cm. Major motor convulsions began at the age of 7 months. At 2 years of age, the child's weight and height were at the tenth percentile. The cranium appeared small compared to the body size and measured 44 cm (-3.0 SD). The facial appearance was normal. The cranial nerve examination, From the Division of Pediatrics, University of' Calgat?'. and the University of Washington. *Reprint address: Department of Pediatrics. Foothills Hospital. Calgary, Alberta, Canada T2N 27"9.
0022-3476/79/110701 +05500.50/0 9 1979 The C. V. Mosby Co.
including the retina, was normal. There were a few beats of clonus in the lower extremities, associated with brisk reflexes and a left plantar extensor response. The electroencephalogram showed a minor abnormality consisting of independent sharp waves. The developmental assessment documented a minimal delay in language skills. The seizures have been readily controlled by anticonvulsant therapy.
See related article, p. 731. Abbreviations used EEG: electroencephalogram CAT: computed axial tomography The patient's mother had difficulty competing in a regular classroom and was informed that she was mildly retarded following testing by a school psychologist. She also had major motor convulsions as a child, but has been seizure free without medication for six years. The physical and neurologic examination was normal. The height and weight were at the tenth percentile and the head circumference of 49.5 cm was significantly below the third percentile (-4.2 SD). A skull radiograph was normal except for the small size of the cranial vault in the proposita and her mother. The maternal grandmother denied seizures as a child. She had difficulty learning in school and now works as a barmaid. She is of average stature, but her head appears small for her body size and measures 52 cm (-2.0 SD) (Fig. 1). Family 2. The proposita is a 19-month-old girl who was
Vol. 95, No. 5, part 1, pp. 701-705
702
Haslam and S m i t h
The Journal of Pediatrics November 1979
FAMILY 1
FAMILY 2
FAMILY 3
FAMILY 4
1
|1
3
10
11
912
3
2
2
3
3
IIl
IV
9 KEY
9 .~
affected dead sex unspecified
Q small head [ ] @ small head-not examined • propositus
Fig. 1. Pedigrees of four families with autosomal dominant microcephaly. admitted to the Foothills Hospital for investigation of microcephaly. Cardiac catheterization at 6 weeks of age showed a corrected transposition of the great vessels and a ventricular septal defect. The child's fine and gross motor milestones,were normal, but her vocabulary was l~mited to four to six single words. She has never had a convulsion. The cranium was small with minimal slanting of the forehead, and the ears wereprominent. The head circumference measured 42 cm ( 3.6 SD) (Fig. 2). The height and weight were at the fiftieth percentile. Examination of the cardiovascular system showed an active precordium with a widely radiating 4/6 holosystolic murmur. The neurologic examination was normal. An EEG, computed axial tomography scan, and TORCH titers (toxoplasmosis, rubella, cytomegalic inclusion disease, herpes), plasma amino acid analysis, and a karyotype (including Q banding) were all normal. The patient's father (Family 2, II-10) is 45 years of age. He failed many grades in elementary school and finally discontinued his education in grade seven at the age of 17. He is unable to read. He cannot recall if his parents or eight siblings had small heads, although one brother had recurrent seizures as a child. His head circumference measures 51.5 cm (-3,0 SD) and there is considerable slanting of the forehead: the height and weight are at the fiftieth percentile. The physical and neurologic examinations were otherwise normal. The EEG was within normal limits. The proposita's father had a son by/ilprevious spouse (Family 2, III-4) (Fig. 1). The child was the product of a 37-week gestation. A cesarean section was necessary because of placenta previa. The birth weight was 2.3 k g .
Significant hyperbilirubinemia resulted in an exchange transfusion on the third day. The developmental milestones were delayed. The child had a series of major motor convulsions at the age of 2 years. The physical examination at the age of 6 years was striking because of the small cranium, which measured 45 cm (-5.2 SD). The forehead was not receding. Except for bilateral simian creases, the physical and neurologic examinations were normal. The height and weight were at the tenth percentile. A psychometric evaluation placed the patient's intelligence quotient at 55. An EEG, CAT scan, TORCH titers, plasma amino acid analysis, and a karyotype (including Q-banding) were all normal. The skull radiograph was unremarkable except for small size of the vault, a trait seen in all family members. Family 3. The proposita was admitted to the Children's Orthopedic HospitaJ+at 9 months of age for evaluation of a congenital heart defect which was shown by catheterization studies to be a small ventricular septal defect. Her birth weight was 2.9 kg and at 9 months she was at the fifth percentile for length and third percentile for weight. Her developmental progress had been slow and was estimated at the six- to seven-month level at 9 months of age. Her neurologic status was otherwise normal. The cranium was small with a receding frontal region and there Were upslanting palpebral fissures. The head circumference of 39 cm was 3.95 SD below the mean for age. The sutures were open and skull radiographs showed no abnormality other than small size. Chromosome studies were normal. There was no family history for heart defect, but the history was notable for "familial small head" (Fig, 1). The mother and maternal grandmother
Volume 95 Number 5, part i
A utosomal dominant microcephaly
70 3
Fig. 2. Microcephalic father with his affected children. The proposita, a 19-monthgirl is on the right and her 6-year-old half-brother on the left. Note the father's receding forehead and the proposita's prominent ears (Family 2). had noticeably small heads which measured 4.1 and 4.2 SDs below normal, with a sloping forehead in both and upslanfing palpebral fissures in the case of the mother (Fig. 3). The mother discontinued high school in the eleventh grade. She was found to be of low-average intelligence and stated that her mother was of normal intelligence. Neither had any obvious neurologic dysfunction, nor was there a family history of seizures. Their stature was within normal limits. The head sizes of the other family members were within the normal range, varying from -0.2 SD to -1.5 SD below the mean for age. Family 4. The proposita is a 2-year-old girl with a symmetrically small head whose performance level of 20 months is only mildly retarded as contrasted to her -2.3 SD head circumference (44.7 cm) for age. She was born following a term gestation and weighed 3 kg. A small head Was evident at birth. Other than eye surgery for alternating strabismus and mild!y slow developmental progress, no other abnormalities have been noted. She is in the twenty-fifth percentile for height at two years. She shows no neurologic or behavioral abnormalities, and has had no seizures. The optic fundi appear normal. Studies did not reveal a cause for the significantly small head. The mother, who has a noi'mal cranium, provided the family history and stated that her husband and his mother and maternal grandmother had "very small heads." The father, who works as a warehouseman clerk, has required special hats in the armed services because the smallest standard hat Size was too large for his head. Neither he
nor other affected individuals are known to have any neurologic or unusual behavior problems. The one sibling of the proposita and those of the father and paternal grandmother are said to have normal head sizes (Fig. 1). DISCUSSION Patients with autosomal recessive type of microcephaly present a rather striking appearance. The patients are often very short, the forehead inclines acutely, and the scalp may be excessively furrowed owing to wrinkling of the skin. The chin is hypoplastic: the nose and ears are prominent. Neurologic abnormalities include spastic diplegia and seizures. Severe mental retardation is the usual rule. The brain weight of adult subjects may not exceed 500 gm, the average size of a two-month-old infant's brain? The surface convolutional markings are undifferentiated and there are heterotopic clusters of nerve cells within the subcortical white matter. Characteristically, the cortical nerve cells are arranged in linear columns separated by patches of acellular tissue? An autosomal recessive mode of inheritance has been implicated in several large studies of familial microcephaly. ~- ~ Qazi and Reed s examined 13 families and found a significant incidence of mental retardation in parents and nonaffected siblings of microcephalic children. In spite of the fact that head circumference measurements of the parents were not provided, the finding suggests that partial expression of the microcephaly gene may be evident as mental retardation in the heterozygote.
704
Haslam and S m i t h
The Journal o f Pediatrics November 1979
Fig. 3, A, Mother and maternal grandmother of the protSosita. B, The proposita at 9 months of age with her mother. Note the relatively small frontal region and the upslant of the palpebral fissures (Family 3).
Penrose "~'noted an increased incidence of severe psYchiatric disorders among the parents of microcephalic children, peihaps another manifestation of the heterozygote. To our knowledge, these four families represent the first reported examples of autosomal dominant microcephaly. They differ in many respects from those with autosomal recessive microcephaly, and x-linked inheritance is excluded by the male-to-male transmission in Family 2. (Fig..1). The Stature of our patients was usually in the average range, whereas most individuals with autosomal recessive microcephaly have short stature. The facial appearance of these patients with autosomal dominant microcephaly is not characteristic, although some children and their parents have receding foreheads, upslanting of the paipebral fissures, and large prominent ears. The facies associated with the autosomal recessive form of microcephaly is much more distinctive. Convulsions may occur in both, but patients with autos0mal dominant microcephaly appear to be seizure free as adults. The finding of congenital heart disease in two i~atients suggests that the gene for dominant microcephaly could have an effect on the deve~0ping heart. The karyotype was normal in both children:., The most significant difference betwee,g the two groups of microcephalic patients is their intellectual potential. Individuals with the autosomal dominant type of micro-
cephaly can be identified by their poor school performance. Upon testing, most fall into the mild or borderline retarded range. 'Many are capable of leading relatively normal lives. The vast majority of patients with autosomal recessive microcephaly are severely retarded and are therefore placed in institutions for the mentally retarded. A recent study of such patients found their mean intelligence quotient to be 34? ~ The majority of autosomal, dominantly inherited conditions produce less significant disabilities than those common to most autosomal recessive conditions, including microcephaly:l(~he discovery of less severe defects, particularly mild or borderline mental retardation in our patients, is in keeping with this concept. Further case reports will likely demonstrate considerable variation in the expressivity of autosomal dominant microcephaly. Autosomal dominant microcephaly may be a relatively common form of heritable microcephaly. Our study would s~ggcst that the head circumference of Siblings and parents should be recorded during the initial investigation of the microcephalic patient. The authors are grateful to Drs. W. A. Proudfoot, D. F. McPhersom and K. Jernberg for referring the patients. We thank Elizabeth McRobbie for secretarial assistance and Dr. Brian Lowry for his helpful comments.
Volume 95 Number 5, part 1
A utosomal dominant microcephaly
REFERENCES I.
Menkes JH: Textbook of child neurology, Philadelphia, 1974, Lea & Febiger, Publishers, pp 148-150. 2. B66k JA, Schut JW, and Reed SC: A clinical and genetical study of microcephaly, Am J Ment Defic 57:637, 1953. 3. McKusick VA: Mendelian inheritance in man, Baltimore, 1978, The Johns Hopkins Press, pp 588-589. 4. Lemire RJ, Loeser JD, Leech RW, and Alvord EC: Normal and abnormal development of the human nervous system, Hagerstown, Md., 1975, Harper & Row, Publishers~ p 47. 5. Blackwood W, McMenemey WH, Meyer A, Norman RM, and Russell DS: Greenfield's neuropathology, London, 1963, Edward Arnold (Publishers) Ltd., pp 348-349. 6. Komai T, Kishimoto K, and Ozaki Y: Genetic study of
7. 8.
9. 10. 11.
705
microcephaly based on Japanese material, Am J Hum Genet 7:51, 1955. Koch G: Genetics of microcephaly in man, Acta Genet Med Gemellol (Roma) 8:75, 1959. Qazi QH, and Reed TE: A possible major contribution to mental retardation in the general population by the gene for microcephaly, Clin Genet 7:85, 1975. Penrose LS: Biology of mental defect, London, 1954, Sidgwick & Jackson Ltd. Qazi QH, and Reed TE: A problem in diagnosis of primary versus secondary microcephaly, Clin Genet 4:46, 1973. Porter IH: Heredity and disease, New York, 1968, McGrawHill Book Company, p 88.
The J o u r n a l o f P E D I A T R I C S
701
A utosomal dominant microcephaly Four families with autosomal dominant microcephaly are reported Although the phenotype is , nondistinctive, several patients had receding or small foreheads, upslanted palpebral fissures, or prominent ears. The degree of intellectual dysfunction is not as severe as that recorded in atttosomal recessive microcephaly. It would appear that atttosomal dominant microcephaly is more common than previously recorded, and that head circumference measurements of siblings and parents of qffected patients should become a part of the initial investigation.
Robert H. A. H a s l a m , M.D., F.R.C.P.(C),* C a l g a r y , A l b e r t a , C a n a d a , and David W. Smith, M.D., S e a t t l e ,
Wash.
MICROCEPHALY, defined as a head circumference which measures more than 3 SD below the mean for age and sex. is a relatively common finding, particularly among the retarded. Causes of microcephaly during the prenatal period include intrauterine infections, chromosomal disorders, metabolic diseases, exposure to radiation, congenital malformations of the brain, and chronic hypoxia. Postnatal events contributing to microcephaly include birth trauma, meningitis, and toxic encephalopathy? Familial microcephaly occurs with an estimated incidence of 1:25.000 to 1:50,000 live births. ~ An autosomal recessive mode of inheritance has been suggested for the large number of subjects that have been studied? We report four unrelated families in which microcephaly appears to be transmitted in an autosomal dominant fashion. CASE REPORTS Family 1. The proposita is a 2-year-old girl, the only child of an unmarried, 19-year-old mother. The birth weight was 2.6 kg and the length 48.5 cm. Major motor convulsions began at the age of 7 months. At 2 years of age, the child's weight and height were at the tenth percentile. The cranium appeared small compared to the body size and measured 44 cm (-3.0 SD). The facial appearance was normal. The cranial nerve examination, From the Division of Pediatrics, University of' Calgat?'. and the University of Washington. *Reprint address: Department of Pediatrics. Foothills Hospital. Calgary, Alberta, Canada T2N 27"9.
0022-3476/79/110701 +05500.50/0 9 1979 The C. V. Mosby Co.
including the retina, was normal. There were a few beats of clonus in the lower extremities, associated with brisk reflexes and a left plantar extensor response. The electroencephalogram showed a minor abnormality consisting of independent sharp waves. The developmental assessment documented a minimal delay in language skills. The seizures have been readily controlled by anticonvulsant therapy.
See related article, p. 731. Abbreviations used EEG: electroencephalogram CAT: computed axial tomography The patient's mother had difficulty competing in a regular classroom and was informed that she was mildly retarded following testing by a school psychologist. She also had major motor convulsions as a child, but has been seizure free without medication for six years. The physical and neurologic examination was normal. The height and weight were at the tenth percentile and the head circumference of 49.5 cm was significantly below the third percentile (-4.2 SD). A skull radiograph was normal except for the small size of the cranial vault in the proposita and her mother. The maternal grandmother denied seizures as a child. She had difficulty learning in school and now works as a barmaid. She is of average stature, but her head appears small for her body size and measures 52 cm (-2.0 SD) (Fig. 1). Family 2. The proposita is a 19-month-old girl who was
Vol. 95, No. 5, part 1, pp. 701-705
702
Haslam and S m i t h
The Journal of Pediatrics November 1979
FAMILY 1
FAMILY 2
FAMILY 3
FAMILY 4
1
|1
3
10
11
912
3
2
2
3
3
IIl
IV
9 KEY
9 .~
affected dead sex unspecified
Q small head [ ] @ small head-not examined • propositus
Fig. 1. Pedigrees of four families with autosomal dominant microcephaly. admitted to the Foothills Hospital for investigation of microcephaly. Cardiac catheterization at 6 weeks of age showed a corrected transposition of the great vessels and a ventricular septal defect. The child's fine and gross motor milestones,were normal, but her vocabulary was l~mited to four to six single words. She has never had a convulsion. The cranium was small with minimal slanting of the forehead, and the ears wereprominent. The head circumference measured 42 cm ( 3.6 SD) (Fig. 2). The height and weight were at the fiftieth percentile. Examination of the cardiovascular system showed an active precordium with a widely radiating 4/6 holosystolic murmur. The neurologic examination was normal. An EEG, computed axial tomography scan, and TORCH titers (toxoplasmosis, rubella, cytomegalic inclusion disease, herpes), plasma amino acid analysis, and a karyotype (including Q banding) were all normal. The patient's father (Family 2, II-10) is 45 years of age. He failed many grades in elementary school and finally discontinued his education in grade seven at the age of 17. He is unable to read. He cannot recall if his parents or eight siblings had small heads, although one brother had recurrent seizures as a child. His head circumference measures 51.5 cm (-3,0 SD) and there is considerable slanting of the forehead: the height and weight are at the fiftieth percentile. The physical and neurologic examinations were otherwise normal. The EEG was within normal limits. The proposita's father had a son by/ilprevious spouse (Family 2, III-4) (Fig. 1). The child was the product of a 37-week gestation. A cesarean section was necessary because of placenta previa. The birth weight was 2.3 k g .
Significant hyperbilirubinemia resulted in an exchange transfusion on the third day. The developmental milestones were delayed. The child had a series of major motor convulsions at the age of 2 years. The physical examination at the age of 6 years was striking because of the small cranium, which measured 45 cm (-5.2 SD). The forehead was not receding. Except for bilateral simian creases, the physical and neurologic examinations were normal. The height and weight were at the tenth percentile. A psychometric evaluation placed the patient's intelligence quotient at 55. An EEG, CAT scan, TORCH titers, plasma amino acid analysis, and a karyotype (including Q-banding) were all normal. The skull radiograph was unremarkable except for small size of the vault, a trait seen in all family members. Family 3. The proposita was admitted to the Children's Orthopedic HospitaJ+at 9 months of age for evaluation of a congenital heart defect which was shown by catheterization studies to be a small ventricular septal defect. Her birth weight was 2.9 kg and at 9 months she was at the fifth percentile for length and third percentile for weight. Her developmental progress had been slow and was estimated at the six- to seven-month level at 9 months of age. Her neurologic status was otherwise normal. The cranium was small with a receding frontal region and there Were upslanting palpebral fissures. The head circumference of 39 cm was 3.95 SD below the mean for age. The sutures were open and skull radiographs showed no abnormality other than small size. Chromosome studies were normal. There was no family history for heart defect, but the history was notable for "familial small head" (Fig, 1). The mother and maternal grandmother
Volume 95 Number 5, part i
A utosomal dominant microcephaly
70 3
Fig. 2. Microcephalic father with his affected children. The proposita, a 19-monthgirl is on the right and her 6-year-old half-brother on the left. Note the father's receding forehead and the proposita's prominent ears (Family 2). had noticeably small heads which measured 4.1 and 4.2 SDs below normal, with a sloping forehead in both and upslanfing palpebral fissures in the case of the mother (Fig. 3). The mother discontinued high school in the eleventh grade. She was found to be of low-average intelligence and stated that her mother was of normal intelligence. Neither had any obvious neurologic dysfunction, nor was there a family history of seizures. Their stature was within normal limits. The head sizes of the other family members were within the normal range, varying from -0.2 SD to -1.5 SD below the mean for age. Family 4. The proposita is a 2-year-old girl with a symmetrically small head whose performance level of 20 months is only mildly retarded as contrasted to her -2.3 SD head circumference (44.7 cm) for age. She was born following a term gestation and weighed 3 kg. A small head Was evident at birth. Other than eye surgery for alternating strabismus and mild!y slow developmental progress, no other abnormalities have been noted. She is in the twenty-fifth percentile for height at two years. She shows no neurologic or behavioral abnormalities, and has had no seizures. The optic fundi appear normal. Studies did not reveal a cause for the significantly small head. The mother, who has a noi'mal cranium, provided the family history and stated that her husband and his mother and maternal grandmother had "very small heads." The father, who works as a warehouseman clerk, has required special hats in the armed services because the smallest standard hat Size was too large for his head. Neither he
nor other affected individuals are known to have any neurologic or unusual behavior problems. The one sibling of the proposita and those of the father and paternal grandmother are said to have normal head sizes (Fig. 1). DISCUSSION Patients with autosomal recessive type of microcephaly present a rather striking appearance. The patients are often very short, the forehead inclines acutely, and the scalp may be excessively furrowed owing to wrinkling of the skin. The chin is hypoplastic: the nose and ears are prominent. Neurologic abnormalities include spastic diplegia and seizures. Severe mental retardation is the usual rule. The brain weight of adult subjects may not exceed 500 gm, the average size of a two-month-old infant's brain? The surface convolutional markings are undifferentiated and there are heterotopic clusters of nerve cells within the subcortical white matter. Characteristically, the cortical nerve cells are arranged in linear columns separated by patches of acellular tissue? An autosomal recessive mode of inheritance has been implicated in several large studies of familial microcephaly. ~- ~ Qazi and Reed s examined 13 families and found a significant incidence of mental retardation in parents and nonaffected siblings of microcephalic children. In spite of the fact that head circumference measurements of the parents were not provided, the finding suggests that partial expression of the microcephaly gene may be evident as mental retardation in the heterozygote.
704
Haslam and S m i t h
The Journal o f Pediatrics November 1979
Fig. 3, A, Mother and maternal grandmother of the protSosita. B, The proposita at 9 months of age with her mother. Note the relatively small frontal region and the upslant of the palpebral fissures (Family 3).
Penrose "~'noted an increased incidence of severe psYchiatric disorders among the parents of microcephalic children, peihaps another manifestation of the heterozygote. To our knowledge, these four families represent the first reported examples of autosomal dominant microcephaly. They differ in many respects from those with autosomal recessive microcephaly, and x-linked inheritance is excluded by the male-to-male transmission in Family 2. (Fig..1). The Stature of our patients was usually in the average range, whereas most individuals with autosomal recessive microcephaly have short stature. The facial appearance of these patients with autosomal dominant microcephaly is not characteristic, although some children and their parents have receding foreheads, upslanting of the paipebral fissures, and large prominent ears. The facies associated with the autosomal recessive form of microcephaly is much more distinctive. Convulsions may occur in both, but patients with autos0mal dominant microcephaly appear to be seizure free as adults. The finding of congenital heart disease in two i~atients suggests that the gene for dominant microcephaly could have an effect on the deve~0ping heart. The karyotype was normal in both children:., The most significant difference betwee,g the two groups of microcephalic patients is their intellectual potential. Individuals with the autosomal dominant type of micro-
cephaly can be identified by their poor school performance. Upon testing, most fall into the mild or borderline retarded range. 'Many are capable of leading relatively normal lives. The vast majority of patients with autosomal recessive microcephaly are severely retarded and are therefore placed in institutions for the mentally retarded. A recent study of such patients found their mean intelligence quotient to be 34? ~ The majority of autosomal, dominantly inherited conditions produce less significant disabilities than those common to most autosomal recessive conditions, including microcephaly:l(~he discovery of less severe defects, particularly mild or borderline mental retardation in our patients, is in keeping with this concept. Further case reports will likely demonstrate considerable variation in the expressivity of autosomal dominant microcephaly. Autosomal dominant microcephaly may be a relatively common form of heritable microcephaly. Our study would s~ggcst that the head circumference of Siblings and parents should be recorded during the initial investigation of the microcephalic patient. The authors are grateful to Drs. W. A. Proudfoot, D. F. McPhersom and K. Jernberg for referring the patients. We thank Elizabeth McRobbie for secretarial assistance and Dr. Brian Lowry for his helpful comments.
Volume 95 Number 5, part 1
A utosomal dominant microcephaly
REFERENCES I.
Menkes JH: Textbook of child neurology, Philadelphia, 1974, Lea & Febiger, Publishers, pp 148-150. 2. B66k JA, Schut JW, and Reed SC: A clinical and genetical study of microcephaly, Am J Ment Defic 57:637, 1953. 3. McKusick VA: Mendelian inheritance in man, Baltimore, 1978, The Johns Hopkins Press, pp 588-589. 4. Lemire RJ, Loeser JD, Leech RW, and Alvord EC: Normal and abnormal development of the human nervous system, Hagerstown, Md., 1975, Harper & Row, Publishers~ p 47. 5. Blackwood W, McMenemey WH, Meyer A, Norman RM, and Russell DS: Greenfield's neuropathology, London, 1963, Edward Arnold (Publishers) Ltd., pp 348-349. 6. Komai T, Kishimoto K, and Ozaki Y: Genetic study of
7. 8.
9. 10. 11.
705
microcephaly based on Japanese material, Am J Hum Genet 7:51, 1955. Koch G: Genetics of microcephaly in man, Acta Genet Med Gemellol (Roma) 8:75, 1959. Qazi QH, and Reed TE: A possible major contribution to mental retardation in the general population by the gene for microcephaly, Clin Genet 7:85, 1975. Penrose LS: Biology of mental defect, London, 1954, Sidgwick & Jackson Ltd. Qazi QH, and Reed TE: A problem in diagnosis of primary versus secondary microcephaly, Clin Genet 4:46, 1973. Porter IH: Heredity and disease, New York, 1968, McGrawHill Book Company, p 88.
