Prevention of developmental disabilities
http://www.100md.com
《美国医学杂志》
Departments of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
Abstract
People with developmental disabilities have problems with major life activities such as language, mobility, learning, self-help, and independent living. Developmental disabilities begin anytime during development upto 22 years of age and usually last throughout a person's lifetime. It reflects the person's need for a combination and sequence of special interdisciplinary or generic care, treatment or other services that are of life-long or extended duration and that are individually planned and coordinated. They currently represent a large proportion of the childhood illnesses and disorders. The causes can be environmental, genetic or multifactorial. Prevention is important to reduce the neuromorbidity in the society. Strategies for prevention are discussed which take into account the possible causal associations.
Keywords: Developmental disabilities; Prevention; Prenatal, Post natal
Developmental disabilities are a diverse group of severe chronic conditions caused due to mental and/or physical impairments. People with developmental disabilities have problems with major life activities such as language, mobility, learning, self-help, and independent living. They begin anytime during development upto 22 years of age and usually last throughout a person's lifetime.[1] It also indicates a person who has a diagnosed physical or mental condition with a high probability of resulting into developmental delay. It reflects the person's need for a combination and sequence of special interdisciplinary or generic care, treatment or other services that are of life- long or extended duration and that are individually planned and coordinated.
Before this definition was developed, the following specific conditions or syndromes were considered to define developmental disabilities.
Mental retardation
Autistic spectrum disorders
Attention deficit hyperactivity disorder
Cerebral palsy
Learning disorders
Epilepsy
Hearing impairment
Vision impairment
Neuromuscular disorders
Magnitude of the Problem
The developmental disabilities currently represent a large proportion of the childhood illnesses and disorders commonly seen by the general pediatrician, the public health worker, the social service worker, and the teacher in daily practice. The World Health Organization (WHO) estimates that, worldwide, 15%-20% of children have disabilities; Kohler et al suggest a prevalence of 5%-20%.[2]
Causes of developmental disabilities
The cause of developmental disabilities can be environmental, genetic or multifactorial and are detailed in table1.
Prevention Strategies
In every age, man has recognized the special importance of the child's role in society. If children are the indicators of the general health of society, it follows that steps for primary prevention and care must logically begin in childhood, where the task is to so enhance the child's environment, that mental health is maintained and promoted and pathology is aborted at the primary source.
Environmental
It is said that the secret of national health lies in the homes of the people. Primary prevention operates on a community basis. Availability and acceptability of services are usually related to the overall distribution of resources in the community. Deprived groups have a limited access to preventive services. The reasons being poor location of the service, inadequate presentation by general practitioners and specialists and a reluctance to use preventive services because of certain psychological constructs. This may result in a higher prevalence of retardation caused by inadequate immunization, inappropriate nutrition and poor contraceptive, antenatal and obstetric care.
Prenatal
A healthy mother can give birth to a healthy child. The first and foremost step in this direction is education and awareness, especially amongst adolescent girls. The social and environmental factors which influence human reproduction are a legion viz. age at marriage and child bearing, child spacing, family size, fertility patterns, level of education, economic status, customs and beliefs, role of women in society, etc. A safe motherhood to all women of reproductive age group including adequate nutrition, iron and folic acid supplementation, and prenatal screening of common diseases would go a long way in the prevention of developmental disabilities. For e.g. it is now proven that supplementation of 0.4mg folate daily during the periconceptional period reduces the risk of neural tube defect by 70%. Also important are avoidance of consanguinity, routine immunization, especially MMR and TT, and good perinatal care. Other risk factors like infections, most common being the TORCH group, or metabolic states like diabetes mellitus (hypo or hyperglycemia), hypothyroidism, and iodine deficiency, or drugs e.g. antiepileptics like phenytoin and valproate, alcohol, lead, tetracyclines or radiation are modifiable risk-factors.
Perinatal Factors
The perinatal period is a very critical time zone when the neonate adjusts itself from a thermo-neutral aquatic environment to the dry ex-utero environment. Supply of important nutrients including oxygen and glucose has to shift from a trans-placental maternal uninterrupted source to a pulmonary gas exchange and an intermittent feeding schedule. This period in the infant's life is thus most prone to brain injury, with very important long term outcomes affecting the rest of the individual's life. The common causes for perinatal brain injury include hypoxic ischemic encephalopathy, intaventricular hemorrhage, bilirubin encephalopathy, hypoglycemia and brain injury and neonatal meningitis.
1. Prevention of hypoxic ischemic encephalopathy: Proper neonatal resuscitation is one of the most rewarding steps in the prevention of developmental disabilities. All nurses, dais and resident doctors should have a thorough knowledge and practice of this important step. Also important are proper fetal monitoring and early decisions for caesarean section. Babies born premature and those with apgar score 0-3 at 15 minutes, or seizures in the immediate neonatal period tend to have poorer prognosis for neuromotor development.
2. Prevention of hyperbilirubinemia: With the reduction in the number of cases of rhesus hemolytic disease, hyperbilirubinemia reaching potentially toxic levels have become less frequent. However, serum bilirubin above 25 mg% in full term and even lower levels in preterm neonates increases the risk of high tone deafness and athetoid cerebral palsy. Therefore, management of hyperbilirubinemia including early exchange transfusion vs. phototherapy as well as treating the underlying cause, if possible, are important.
3. Neonatal meningitis: Hristeva and colleagues[3] (1993) reported that the rate of bacterial meningitis over a seven-year-period was 2.5/10,000. Group B Streptococcus was the most common cause of early onset meningitis, and gram negative organism accounted for the majority of late onset meningitis. 27% of the infants had neurological sequel. Bacterial meningitis in the neonatal period is currently stated to be the leading cause of acquired deafness in childhood. This emphasizes the need for barrier nursing, hand-washing and other precautions for sepsis control as well as the '5-cleans' for a safe and clean delivery.
4. Intra-ventricular hemorrhage: Hemorrhage into the germinal matrix tissues , with or without extension into the ventricular system and parenchyma of the developing brain, has been shown to be a serious neonatal morbidity of premature infants born at less than 32 weeks gestation (Volpe)[4]. Studies published prior to the 1980's reported incidence rates of IVH to be 40-45%. Many centres are now reporting a decreasing incidence with rates between 12-30%. Treatment advances, including prenatal administration of steroids, surfactant therapy and prophylactic indomethacin, have contributed to the decline in the incidence of IVH. Saliba[5] et al . prospectively followed a cohort of low birth babies born at less than 35 weeks gestation with serial cranial ultrasonograms at weekly intervals during hospitalization and at 2, 4, 6, 9, and 19 months. Ventricular growth velocities were significantly higher in infants with a history of ventricular dilatation or periventricular leukomalacia and were associated with the poorest outcome at 18-24 months of age.
Post-natal Factors
1. This includes early diagnosis and treatment of treatable illnesses like hypothyroidism, galactosemia and phenylketonuria
2. Adequate nutrition has an important role in the fostering of normal brain development. It is the protein fraction which is the most important in brain growth, but certain specific deficiencies, particularly in vitamins A and B, may interfere with brain development.
3. Repeated infections have an adverse effect on the developing brain. Factors which promote high infectivity rates include poor housing and overcrowding, inadequate sanitation and the pollution of water supplies.
4. Battering in babies commonly results in multiple fractures, including skull fractures and internal injuries. Most of the severely injured children may have some degree of brain damage; many also become blind or deaf. Intensive psychotherapy and the provision of the appropriate social benefits helps many cases and case work should be actively undertaken because inadequate care only intensifies the psychological difficulties of the parents and results in further battering. It may be necessary in some cases to remove the child and find another home.[6]
Genetic Disorders
Over 750 known genetic causes of mental retardation have now been identified. These can be single gene disorders, polygenic, chromosomal, and mitochondrial or dysmorphic. Prevention of childhood neurological diseases with a genetic basis involves various steps. The first and foremost involves making the 'correct diagnosis', using available resources. This is the most important step as rest of the things follow this essential step. The next, taking a proper family history- a three generation family tree helps in determining the mode of inheritance and thus the risk of recurrence. The third step is to explain the risk, the prognosis and the possibility of treatment to the prospective parents. Also important is the possibility of prenatal diagnosis in future pregnancies. Though the list of genetic disorders affecting mental status of a child is enormous, some of the common genetic disorders and their prevention is being discussed below.
Chromosomal disorders leading to mental retardation include Downs syndrome, trisomy 13 and 18, Fragile X, Kleinfelter, Prader-willi etc. Of all chromosomal disorders, trisomy 21 or the Down syndrome is the most common 'inherited' cause of mental retardation, with a frequency of 1 in 800 to 1000 newborns,[7] and the risk increases with increasing maternal age. It can be due to trisomy 21 (94%) or translocation (4%) or mosaicism (1%). If Down's syndrome is suspected in a child, then a karyotype analysis should be done. The recurrence risk in next pregnancy is described in Figure1.
Ideally, screening for Downs syndrome by triple test including alpha-fetoprotein (ˉ), HCG (), and unconjugated estriol (ˉ) should be done in all women >35 years and\or having a previous child with Down syndrome. Confirmation can be done with the help of direct fetal karyotype, by chorionic villus sampling (10-12 weeks) or amniocentesis(16-18 weeks).
Fragile X syndrome: It occurs due to amplification of a triple nucleotide on the X chromosome. It is characterized by anticipation i.e. greater or earlier involvement in subsequent generations, and Sherman paradox i.e. the disease is transmitted from the grandfather through a 'normal appearing' daughter to the grandson.[8] Indications for screening of fragile X syndrome include all males/ females with MR and suggestive phenotype or with familial MR and all males with idiopathic MR. The prenatal diagnosis is now available by DNA analysis.
There are a variety of other genetic diseases leading to MR. These can also be transmitted by single genes, polygenic inheritance or mitochondrial inheritance. The single gene disorders are usually mutations inherited in autosomal dominant or recessive patterns, the recurrence of which reflects specific statistical probabilities. Polygenic or multifactorial inheritance includes additive or quantitative traits, such as behaviour, cognition and intelligence, and reflects complex characteristics along a measurable continuum that does not conform to mendelian probabilities. However, mitochondrial disorders are inherited from the mother, as all mitochondria inherited by the baby are derived from the ovum. But, because of heteroplasmy, not all the children in a family are affected.
Prevention of genetic disorders include carrier screening e.g., high level of enzyme creatine phosphokinase (CPK) in female carriers of pseudohypertrophic muscular dystrophy. Female carriers of glucose-6-phosphate dehydrogenase deficiency can be detected by demonstrating low levels of enzyme in erythrocytes. Prenatal diagnosis of various inborn errors of metabolism and single gene disorders is now possible by biochemical techniques and DNA analysis respectively. These include disorders like cystic fibrosis, Lesch-nyan syndrome, Tay-Sachs disease More Details and phenylketonuria etc.
The cells for prenatal diagnosis can be obtained by chorionic villus sampling (10-12 weeks) or amniocentesis (16-18 weeks), carrying a 2-4% and 0.5-1% risk of fetal loss, respectively. A pre-requisite of prenatal diagnosis is that there should be certainty of diagnosis of disease in the affected sibling, and the DNA of the affected child should be available for future studies. For disorders where the DNA mutations are uniformly present in most patients deletions in spinal muscular atrophy, prenatal diagnosis is possible even if the affected child is not available. This is because one can directly determine the gene deletion in the parents or the fetus. However, in non-deletion cases prenatal diagnosis becomes difficult or complicated, and has to be carried out by linkage studies. This applies to diseases like DMD, where 30% of affected subjects do not have deletions. It is therefore emphasized that whenever a child has a genetic disease, it is better to preserve the blood/DNA of the affected child.
Prevention of developmental disabilities is very important to reduce childhood neuromorbidity.
References
1. Developmental disabilities assistance and bill of rights act, 42 USCA, Section 6000 seq, West Supp 1993.
2. Kohler L, Jakobsson G. Children's health and well being in the Nordic countries. Clinics in Developmental Medicine 1987; 98.
3. Hristeva L, Booy R et al. Prospective survillence of neonatal meningitis. Arch Dis Child 1993; 69: 14-18.
4. Volpe JJ. Intraventricular hemmorage in the premature infant: current concepts. Part 1. Ann Neurol 1989; 25(1): 3-11.
5. Saliba E, Betrand P et al. Area of lateral ventricles measured on cranial ultrasound in preterm infants: association with outcome. Arch Dis Child 1990; 65: 1033-1037.
6. Kempe CH, Silverman FN, Steel BF et al. The battered baby syndrome. JAMA 1962; 181: 17-24.
7. Ghai OP, Kabra M. Genetics and disease. In Chai OP, Gupta P, Paul VK, eds. Essential Pediatrics . 5th edn. New Delhi; Mehta Publishers 200; 478-479.
8. Elango R, Verma IC. Fragile X syndrome among children with mental retardation. India J Pediatr 1996; 63(94): 553-558.(Gulati Sheffali, Wasir Va)
Abstract
People with developmental disabilities have problems with major life activities such as language, mobility, learning, self-help, and independent living. Developmental disabilities begin anytime during development upto 22 years of age and usually last throughout a person's lifetime. It reflects the person's need for a combination and sequence of special interdisciplinary or generic care, treatment or other services that are of life-long or extended duration and that are individually planned and coordinated. They currently represent a large proportion of the childhood illnesses and disorders. The causes can be environmental, genetic or multifactorial. Prevention is important to reduce the neuromorbidity in the society. Strategies for prevention are discussed which take into account the possible causal associations.
Keywords: Developmental disabilities; Prevention; Prenatal, Post natal
Developmental disabilities are a diverse group of severe chronic conditions caused due to mental and/or physical impairments. People with developmental disabilities have problems with major life activities such as language, mobility, learning, self-help, and independent living. They begin anytime during development upto 22 years of age and usually last throughout a person's lifetime.[1] It also indicates a person who has a diagnosed physical or mental condition with a high probability of resulting into developmental delay. It reflects the person's need for a combination and sequence of special interdisciplinary or generic care, treatment or other services that are of life- long or extended duration and that are individually planned and coordinated.
Before this definition was developed, the following specific conditions or syndromes were considered to define developmental disabilities.
Mental retardation
Autistic spectrum disorders
Attention deficit hyperactivity disorder
Cerebral palsy
Learning disorders
Epilepsy
Hearing impairment
Vision impairment
Neuromuscular disorders
Magnitude of the Problem
The developmental disabilities currently represent a large proportion of the childhood illnesses and disorders commonly seen by the general pediatrician, the public health worker, the social service worker, and the teacher in daily practice. The World Health Organization (WHO) estimates that, worldwide, 15%-20% of children have disabilities; Kohler et al suggest a prevalence of 5%-20%.[2]
Causes of developmental disabilities
The cause of developmental disabilities can be environmental, genetic or multifactorial and are detailed in table1.
Prevention Strategies
In every age, man has recognized the special importance of the child's role in society. If children are the indicators of the general health of society, it follows that steps for primary prevention and care must logically begin in childhood, where the task is to so enhance the child's environment, that mental health is maintained and promoted and pathology is aborted at the primary source.
Environmental
It is said that the secret of national health lies in the homes of the people. Primary prevention operates on a community basis. Availability and acceptability of services are usually related to the overall distribution of resources in the community. Deprived groups have a limited access to preventive services. The reasons being poor location of the service, inadequate presentation by general practitioners and specialists and a reluctance to use preventive services because of certain psychological constructs. This may result in a higher prevalence of retardation caused by inadequate immunization, inappropriate nutrition and poor contraceptive, antenatal and obstetric care.
Prenatal
A healthy mother can give birth to a healthy child. The first and foremost step in this direction is education and awareness, especially amongst adolescent girls. The social and environmental factors which influence human reproduction are a legion viz. age at marriage and child bearing, child spacing, family size, fertility patterns, level of education, economic status, customs and beliefs, role of women in society, etc. A safe motherhood to all women of reproductive age group including adequate nutrition, iron and folic acid supplementation, and prenatal screening of common diseases would go a long way in the prevention of developmental disabilities. For e.g. it is now proven that supplementation of 0.4mg folate daily during the periconceptional period reduces the risk of neural tube defect by 70%. Also important are avoidance of consanguinity, routine immunization, especially MMR and TT, and good perinatal care. Other risk factors like infections, most common being the TORCH group, or metabolic states like diabetes mellitus (hypo or hyperglycemia), hypothyroidism, and iodine deficiency, or drugs e.g. antiepileptics like phenytoin and valproate, alcohol, lead, tetracyclines or radiation are modifiable risk-factors.
Perinatal Factors
The perinatal period is a very critical time zone when the neonate adjusts itself from a thermo-neutral aquatic environment to the dry ex-utero environment. Supply of important nutrients including oxygen and glucose has to shift from a trans-placental maternal uninterrupted source to a pulmonary gas exchange and an intermittent feeding schedule. This period in the infant's life is thus most prone to brain injury, with very important long term outcomes affecting the rest of the individual's life. The common causes for perinatal brain injury include hypoxic ischemic encephalopathy, intaventricular hemorrhage, bilirubin encephalopathy, hypoglycemia and brain injury and neonatal meningitis.
1. Prevention of hypoxic ischemic encephalopathy: Proper neonatal resuscitation is one of the most rewarding steps in the prevention of developmental disabilities. All nurses, dais and resident doctors should have a thorough knowledge and practice of this important step. Also important are proper fetal monitoring and early decisions for caesarean section. Babies born premature and those with apgar score 0-3 at 15 minutes, or seizures in the immediate neonatal period tend to have poorer prognosis for neuromotor development.
2. Prevention of hyperbilirubinemia: With the reduction in the number of cases of rhesus hemolytic disease, hyperbilirubinemia reaching potentially toxic levels have become less frequent. However, serum bilirubin above 25 mg% in full term and even lower levels in preterm neonates increases the risk of high tone deafness and athetoid cerebral palsy. Therefore, management of hyperbilirubinemia including early exchange transfusion vs. phototherapy as well as treating the underlying cause, if possible, are important.
3. Neonatal meningitis: Hristeva and colleagues[3] (1993) reported that the rate of bacterial meningitis over a seven-year-period was 2.5/10,000. Group B Streptococcus was the most common cause of early onset meningitis, and gram negative organism accounted for the majority of late onset meningitis. 27% of the infants had neurological sequel. Bacterial meningitis in the neonatal period is currently stated to be the leading cause of acquired deafness in childhood. This emphasizes the need for barrier nursing, hand-washing and other precautions for sepsis control as well as the '5-cleans' for a safe and clean delivery.
4. Intra-ventricular hemorrhage: Hemorrhage into the germinal matrix tissues , with or without extension into the ventricular system and parenchyma of the developing brain, has been shown to be a serious neonatal morbidity of premature infants born at less than 32 weeks gestation (Volpe)[4]. Studies published prior to the 1980's reported incidence rates of IVH to be 40-45%. Many centres are now reporting a decreasing incidence with rates between 12-30%. Treatment advances, including prenatal administration of steroids, surfactant therapy and prophylactic indomethacin, have contributed to the decline in the incidence of IVH. Saliba[5] et al . prospectively followed a cohort of low birth babies born at less than 35 weeks gestation with serial cranial ultrasonograms at weekly intervals during hospitalization and at 2, 4, 6, 9, and 19 months. Ventricular growth velocities were significantly higher in infants with a history of ventricular dilatation or periventricular leukomalacia and were associated with the poorest outcome at 18-24 months of age.
Post-natal Factors
1. This includes early diagnosis and treatment of treatable illnesses like hypothyroidism, galactosemia and phenylketonuria
2. Adequate nutrition has an important role in the fostering of normal brain development. It is the protein fraction which is the most important in brain growth, but certain specific deficiencies, particularly in vitamins A and B, may interfere with brain development.
3. Repeated infections have an adverse effect on the developing brain. Factors which promote high infectivity rates include poor housing and overcrowding, inadequate sanitation and the pollution of water supplies.
4. Battering in babies commonly results in multiple fractures, including skull fractures and internal injuries. Most of the severely injured children may have some degree of brain damage; many also become blind or deaf. Intensive psychotherapy and the provision of the appropriate social benefits helps many cases and case work should be actively undertaken because inadequate care only intensifies the psychological difficulties of the parents and results in further battering. It may be necessary in some cases to remove the child and find another home.[6]
Genetic Disorders
Over 750 known genetic causes of mental retardation have now been identified. These can be single gene disorders, polygenic, chromosomal, and mitochondrial or dysmorphic. Prevention of childhood neurological diseases with a genetic basis involves various steps. The first and foremost involves making the 'correct diagnosis', using available resources. This is the most important step as rest of the things follow this essential step. The next, taking a proper family history- a three generation family tree helps in determining the mode of inheritance and thus the risk of recurrence. The third step is to explain the risk, the prognosis and the possibility of treatment to the prospective parents. Also important is the possibility of prenatal diagnosis in future pregnancies. Though the list of genetic disorders affecting mental status of a child is enormous, some of the common genetic disorders and their prevention is being discussed below.
Chromosomal disorders leading to mental retardation include Downs syndrome, trisomy 13 and 18, Fragile X, Kleinfelter, Prader-willi etc. Of all chromosomal disorders, trisomy 21 or the Down syndrome is the most common 'inherited' cause of mental retardation, with a frequency of 1 in 800 to 1000 newborns,[7] and the risk increases with increasing maternal age. It can be due to trisomy 21 (94%) or translocation (4%) or mosaicism (1%). If Down's syndrome is suspected in a child, then a karyotype analysis should be done. The recurrence risk in next pregnancy is described in Figure1.
Ideally, screening for Downs syndrome by triple test including alpha-fetoprotein (ˉ), HCG (), and unconjugated estriol (ˉ) should be done in all women >35 years and\or having a previous child with Down syndrome. Confirmation can be done with the help of direct fetal karyotype, by chorionic villus sampling (10-12 weeks) or amniocentesis(16-18 weeks).
Fragile X syndrome: It occurs due to amplification of a triple nucleotide on the X chromosome. It is characterized by anticipation i.e. greater or earlier involvement in subsequent generations, and Sherman paradox i.e. the disease is transmitted from the grandfather through a 'normal appearing' daughter to the grandson.[8] Indications for screening of fragile X syndrome include all males/ females with MR and suggestive phenotype or with familial MR and all males with idiopathic MR. The prenatal diagnosis is now available by DNA analysis.
There are a variety of other genetic diseases leading to MR. These can also be transmitted by single genes, polygenic inheritance or mitochondrial inheritance. The single gene disorders are usually mutations inherited in autosomal dominant or recessive patterns, the recurrence of which reflects specific statistical probabilities. Polygenic or multifactorial inheritance includes additive or quantitative traits, such as behaviour, cognition and intelligence, and reflects complex characteristics along a measurable continuum that does not conform to mendelian probabilities. However, mitochondrial disorders are inherited from the mother, as all mitochondria inherited by the baby are derived from the ovum. But, because of heteroplasmy, not all the children in a family are affected.
Prevention of genetic disorders include carrier screening e.g., high level of enzyme creatine phosphokinase (CPK) in female carriers of pseudohypertrophic muscular dystrophy. Female carriers of glucose-6-phosphate dehydrogenase deficiency can be detected by demonstrating low levels of enzyme in erythrocytes. Prenatal diagnosis of various inborn errors of metabolism and single gene disorders is now possible by biochemical techniques and DNA analysis respectively. These include disorders like cystic fibrosis, Lesch-nyan syndrome, Tay-Sachs disease More Details and phenylketonuria etc.
The cells for prenatal diagnosis can be obtained by chorionic villus sampling (10-12 weeks) or amniocentesis (16-18 weeks), carrying a 2-4% and 0.5-1% risk of fetal loss, respectively. A pre-requisite of prenatal diagnosis is that there should be certainty of diagnosis of disease in the affected sibling, and the DNA of the affected child should be available for future studies. For disorders where the DNA mutations are uniformly present in most patients deletions in spinal muscular atrophy, prenatal diagnosis is possible even if the affected child is not available. This is because one can directly determine the gene deletion in the parents or the fetus. However, in non-deletion cases prenatal diagnosis becomes difficult or complicated, and has to be carried out by linkage studies. This applies to diseases like DMD, where 30% of affected subjects do not have deletions. It is therefore emphasized that whenever a child has a genetic disease, it is better to preserve the blood/DNA of the affected child.
Prevention of developmental disabilities is very important to reduce childhood neuromorbidity.
References
1. Developmental disabilities assistance and bill of rights act, 42 USCA, Section 6000 seq, West Supp 1993.
2. Kohler L, Jakobsson G. Children's health and well being in the Nordic countries. Clinics in Developmental Medicine 1987; 98.
3. Hristeva L, Booy R et al. Prospective survillence of neonatal meningitis. Arch Dis Child 1993; 69: 14-18.
4. Volpe JJ. Intraventricular hemmorage in the premature infant: current concepts. Part 1. Ann Neurol 1989; 25(1): 3-11.
5. Saliba E, Betrand P et al. Area of lateral ventricles measured on cranial ultrasound in preterm infants: association with outcome. Arch Dis Child 1990; 65: 1033-1037.
6. Kempe CH, Silverman FN, Steel BF et al. The battered baby syndrome. JAMA 1962; 181: 17-24.
7. Ghai OP, Kabra M. Genetics and disease. In Chai OP, Gupta P, Paul VK, eds. Essential Pediatrics . 5th edn. New Delhi; Mehta Publishers 200; 478-479.
8. Elango R, Verma IC. Fragile X syndrome among children with mental retardation. India J Pediatr 1996; 63(94): 553-558.(Gulati Sheffali, Wasir Va)