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1.  Clinical studies on submicroscopic subtelomeric rearrangements: a checklist 
Journal of Medical Genetics  2001;38(3):145-150.
BACKGROUND—Submicroscopic subtelomeric chromosome defects have been found in 7.4% of children with moderate to severe mental retardation and in 0.5% of children with mild retardation. Effective clinical preselection is essential because of the technical complexities and cost of screening for subtelomere deletions.
METHODS—We studied 29 patients with a known subtelomeric defect and assessed clinical variables concerning birth history, facial dysmorphism, congenital malformations, and family history. Controls were 110 children with mental retardation of unknown aetiology with normal G banded karyotype and no detectable submicroscopic subtelomeric abnormalities.
RESULTS—Prenatal onset of growth retardation was found in 37% compared to 9% of the controls (p<0.0005). A higher percentage of positive family history for mental retardation was reported in the study group than the controls (50% v 21%, p=0.002). Miscarriage(s) were observed in only 8% of the mothers of subtelomeric cases compared to 30% of controls (p=0.028) which was, however, not significant after a Bonferroni correction. Common features (>30%) among subtelomeric deletion cases were microcephaly, short stature, hypertelorism, nasal and ear anomalies, hand anomalies, and cryptorchidism. Two or more facial dysmorphic features were observed in 83% of the subtelomere patients. None of these features was significantly different from the controls. Using the results, a five item checklist was developed which allowed exclusion from further testing in 20% of the mentally retarded children (95% CI 13-28%) in our study without missing any subtelomere cases. As our control group was selected for the "chromosomal phenotype", the specificity of the checklist is likely to be higher in an unselected group of mentally retarded subjects.
CONCLUSIONS—Our results suggest that good indicators for subtelomeric defects are prenatal onset of growth retardation and a positive family history for mental retardation. These clinical criteria, in addition to features suggestive of a chromosomal phenotype, resulted in the development of a five item checklist which will improve the diagnostic pick up rate of subtelomeric defects among mentally retarded subjects.


Keywords: submicroscopic subtelomeric rearrangements; clinical preselection; checklist; chromosome deletion.
doi:10.1136/jmg.38.3.145
PMCID: PMC1734836  PMID: 11238680
2.  Skeletal Age in Subjects with Mental Retardation 
Canadian Medical Association Journal  1963;89(20):1038-1039.
Delayed skeletal maturation has been long accepted as a correlate of mental retardation. Three hundred mentally retarded children were examined for skeletal age and failed to show any overall delay of bone age as compared to chronological age. Further, birth weight was found to be unrelated to bone age maturity. Children with severe levels of retardation displayed significant delay in bone development only when profound physical disability was also present. In eight diagnostic categories of mental retardation, only those with metabolic syndromes showed any significant delay in skeletal system maturation. Conversely, mongoloid children showed a larger-than-chance percentage of advanced bone maturation. Skeletal measures therefore are perhaps more reflective of etiological states than of diagnostic classifications in mental retardation.
PMCID: PMC1922104  PMID: 14081791
3.  Agreement between clinicians' and care givers' assessment of intelligence in Nigerian children with intellectual disability: 'ratio IQ' as a viable option in the absence of standardized 'deviance IQ' tests in sub-Saharan Africa 
Background
There may be need to assess intelligent quotient (IQ) scores in sub-Saharan African children with intellectual disability, either for the purpose of educational needs assessment or research. However, modern intelligence scales developed in the western parts of the world suffer limitation of widespread use because of the influence of socio-cultural variations across the world. This study examined the agreement between IQ scores estimation among Nigerian children with intellectual disability using clinicians' judgment based on International Classification of Diseases, tenth Edition
(ICD - 10) criteria for mental retardation and caregivers judgment based on 'ratio IQ' scores calculated from estimated mental age in the context of socio-cultural milieu of the children. It proposed a viable option of IQ score assessment among sub-Saharan African children with intellectual disability, using a ratio of culture-specific estimated mental age and chronological age of the child in the absence of standardized alternatives, borne out of great diversity in socio-cultural context of sub-Saharan Africa.
Methods
Clinicians and care-givers independently assessed the children in relation to their socio-cultural background. Clinicians assessed the IQ scores of the children based on the ICD - 10 diagnostic criteria for mental retardation. 'Ratio IQ' scores were calculated from the ratio of estimated mental age and chronological age of each child. The IQ scores as assessed by the clinicians were then compared with the 'ratio IQ' scores using correlation statistics.
Results
A total of forty-four (44) children with intellectual disability were assessed. There was a significant correlation between clinicians' assessed IQ scores and the 'ratio IQ' scores employing zero order correlation without controlling for the chronological age of the children (r = 0.47, df = 42, p = 0.001). First order correlation controlling for the chronological age of the children showed higher correlation score between clinicians' assessed IQ scores and 'ratio IQ' scores (r = 0.75, df = 41, p = 0.000).
Conclusion
Agreement between clinicians' assessed IQ scores and 'ratio IQ' scores was good. 'Ratio IQ' test would provide a viable option of assessing IQ scores in sub-Saharan African children with intellectual disability in the absence of culture-appropriate standardized intelligence scales, which is often the case because of great diversity in socio-cultural structures of sub-Saharan Africa.
doi:10.1186/1744-9081-5-39
PMCID: PMC2752456  PMID: 19754953
4.  Children with Usher syndrome: mental and behavioral disorders 
Background
Mental and behavioral disorders among adults with Usher syndrome have been discussed and reported in some case studies but no research has been reported on children with Usher syndrome.
Methods
This article investigates the prevalence and characteristics of mental and behavioral disorders among 26 children, 3-17 years of age, with Usher syndrome.
Results
Six of the 26 children were diagnosed with a mental or behavioral disorder (1 with schizophrenia and mild mental retardation, 1 with atypical autism and severe mental retardation, 1 with atypical autism and mild mental retardation, 1 with mild mental retardation, and 2 with conduct disorder). Another 3 children had had a mental or behavioral disorder previously in their childhood.
Conclusion
Even though vision impairment first manifests in late childhood, some children with Usher syndrome seem to develop mental and behavioral disorders during childhood. The aetiology and treatment of mental and behavioral disorders among children with Usher syndrome are discussed. Children with Usher syndrome and their parents may need clinical support during early childhood to prevent development of mental and behavioral disorders.
doi:10.1186/1744-9081-8-16
PMCID: PMC3337277  PMID: 22449032
Deafblindness; Dual sensory loss; Mental and behavioral disorders; Usher syndrome; Psychiatry
5.  Syndromic diarrhea/Tricho-hepato-enteric syndrome 
Abstract
Syndromic diarrhea/Tricho-hepato-enteric syndrome (SD/THE) is a rare and severe bowel disorder caused by mutation in SKIV2L or in TTC37, 2 genes encoding subunits of the putative human SKI complex. The estimated prevalence is 1/1,000,000 births and the transmission is autosomal recessive. The classical form is characterized by 5 clinical signs: intractable diarrhea of infancy beginning in the first month of life, usually leading to failure to thrive and requiring parenteral nutrition; facial dysmorphism characterised by prominent forehead and cheeks, broad nasal root and hypertelorism; hair abnormalities described as woolly and easily removable; immune disorders resulting from defective antibody production; intrauterine growth restriction. The aetiology is a defect in TTC37, a TPR containing protein, or in the RNA helicase SKIV2L, both constituting the putative human ski complex. The ski complex is a heterotetrameric cofactor of the cytoplasmic RNA exosome which ensures aberrants mRNAs decay. The diagnosis SD/THE is initially based on clinical findings and confirmed by direct sequencing of TTC37 and SKIV2L. Differential diagnosis with the other causes of intractable diarrhea is easily performed by pathologic investigations. During their clinical course, most of the children require parenteral nutrition and often immunoglobulin supplementation. With time, some of them can be weaned off parenteral nutrition and immunoglobulin supplementation. The prognosis depends on the management and is largely related to the occurrence of parenteral nutrition complications or infections. Even with optimal management, most of the children seem to experience failure to thrive and final short stature. Mild mental retardation is observed in half of the cases.
Abstract in French
Les diarrhées syndromiques ou syndrome tricho-hepato-enterique (SD/THE) sont un syndrome rare et sévère dont l’incidence est estimée à 1 cas pour 1 million de naissances et la transmission autosomique récessive. La forme typique associe 5 signes cliniques: une diarrhée grave rebelle nécessitant dans la majorité des cas une nutrition parentérale du fait de la malnutrition, une dysmorphie avec un front large et bombé, une racine du nez large et un hypertélorisme, des anomalies des cheveux qui sont fragiles, cassants, incoiffables et qualifiés de « laineux », un retard de croissance intra utérine et des anomalies de l’immunité à type de déficit en immunoglobuline ou d’absence de réponse aux antigènes vaccinaux. Des anomalies de deux protéines peuvent être à l’origine du syndrome SD/THE: TTC37, une protéine à motif TPR et SKIV2L, une hélicase à ARN, toutes 2 étant des constituants du complexe SKI humain. Le complexe SKI est un co-facteur de l’exosome cytoplasmique qui assure la dégradation des ARN aberrants ou exogènes. Le diagnostic est d’abord clinique puis confirmé par le séquençage des gènes TTC37 et SKIV2L. Le diagnostic différentiel avec les autres formes de diarrhées intraitables est fait grâce aux analyses anatomopathologiques qui montrent dans les autres formes, des lésions spécifiques. La prise en charge clinique repose sur la nutrition parentérale et la supplémentation en immunoglobuline si nécessaire. Un certain nombre d’enfants peuvent être sevrés de la nutrition parentérale et des supplémentations en immunoglobulines. En cas d’atteinte hépatique, celle-ci peut être sévère et conduire au décès. Même avec une prise en charge optimale, les enfants présentent une petite taille et, dans la moitié des cas, un retard mental modéré.
Disease name/synonyms – Syndromic diarrhea – Phenotypic diarrhea – Tricho-hepato-enteric syndrome – Intractable diarrhea of infancy with facial dysmorphism – Trichorrhexis nodosa and cirrhosis – Neonatal hemochromatosis phenotype with intractable diarrhea and hair abnormalities – Intractable infant diarrhea associated with phenotypic abnormalities and immune deficiency- Syndromatic diarrhea. [ORPHA84064 MIM 222470 and MIM614602]. Possibly chronic diarrhea and skin hyperpigmentation.
doi:10.1186/1750-1172-8-5
PMCID: PMC3560276  PMID: 23302111
SKI COMPLEX; SKIV2L; TTC37; WDR61; SKI3; SKI2; SKI8; Intractable diarrhea; Syndromic diarrhea; Tricho-hepato-enteric syndrome; Woolly hair
6.  The first unprovoked, untreated seizure in childhood: a hospital based study of the accuracy of the diagnosis, rate of recurrence, and long term outcome after recurrence. Dutch study of epilepsy in childhood 
OBJECTIVE—To assess the accuracy of the diagnosis of a first unprovoked seizure in childhood, the recurrence rate within two years, the risk factors for recurrence, and the long term outcome two years after recurrence.
METHODS— One hundred and fifty six children aged 1 month to 16 years after a first seizure, and 51 children with a single disputable event were followed up. The diagnosis of a seizure was confirmed by a panel of three child neurologists on the basis of predescribed diagnostic criteria. None of the children was treated after the first episode.
RESULTS—Five children with a disputable event developed epileptic seizures during follow up. The diagnosis did not have to be revised in any of the 156 children with a first seizure. The overall recurrence rate after two years was 54%. Significant risk factors were an epileptiform EEG (recurrence rate 71%) and remote symptomatic aetiology and/or mental retardation (recurrence rate 74%). For the 85 children with one or more recurrences, terminal remission irrespective of treatment two years after the first recurrence was >12 months in 50 (59%),
PMCID: PMC2170103  PMID: 9598673
Archives of Disease in Childhood  1990;65(10):1133-1136.
A diagnostic survey was undertaken of children aged 11 to 19 years in Tameside with severe learning difficulties (intelligence quotient less than or equal to 50). Eighty-two children were identified and their medical records reviewed. A specific diagnosis for the retardation was documented in 25 (30%) of the children, 18 of whom had Down's syndrome. A probable aetiology or a disorder of unknown aetiology had been identified in a further 21 (26%) children. To confirm the existing diagnosis, identify new diagnoses, and offer genetic counselling, the parents of 63 children were offered detailed reassessment of their child. Fifty three children were reviewed, and a specific disorder identified in 25 out of 31 previously undiagnosed children. The most frequent diagnoses made were fragile X syndrome and Rett's syndrome. On completion of the survey, 61 of the 82 children (74%) had a specific diagnosis or probable aetiology identified, 12 (15%) had associated disorders such as cerebral palsy, and in only nine of the 82 children (11%) were there no clues at all to the cause of their retardation.
PMCID: PMC1792345  PMID: 2248505
Indian Journal of Psychiatry  2002;44(4):372-374.
Pica is an interesting psychiatric entity that merits special clinical attention. This report describes three cases of pica and calls for its separate nosological placement in clinical psychiatry. In the Diagnostic and statistical manual of mental disorders fourth edition (DSM-IV), pica is described as persistent eating of nonutritive substances for a period of at least 1 month which is inappropriate to the developmental level and not part of a culturally sanctioned practice (American Psychiatric Association, 1994). On the other hand, impulse-control disorders not elsewhere classified is defined as failure to resist an impulse, drive or temptation to perform an act that is harmful to the person or to others, feeling of an increasing sense of tension or arousal before committing the act and pleasure, gratification or relief at the time of committing the act or shortly thereafter (American Psychiatric Association, 1994). Regarding the aetiologies of Pica most contemporary literatures have cited various causative factors, e.g. normal exploratory orality of children, pregnancy, stress and conflicts, cultural beliefs, mental retardation, psychotic disorders and even nutritional deficiencies (Chatoor, 2000; Popper & West, 2001). Here, we report 3 atypical cases of Pica, attending outpatient department of the Institute of Psychiatry, Calcutta. These reported cases are unique in their time of onset, phenomenological progression and therapeutic responsiveness.
PMCID: PMC2955310  PMID: 21206603
Pica; Impulse-control disorder; Atypical obsession
Background:
The study was carried out with the aim of determining the factors affecting and to evaluate anxiety situations and self-esteem of children with and without mentally retarded siblings.
Materials and Methods:
The sampling included 227 healthy children: 108 of them have mental retarded sibling and 119 of them do not have mental retarded sibling. The context of this study consisted of 15-18 year of age healthy children with mentally retarded siblings and 15-18 year of aged healthy children having at least one sibling between the dates February 15st and June 26st 2010. Personal Information Form, Rosenberg Self-Esteem Scale and Trait Anxiety Scale were used.
Results:
It was found out that trait anxiety of 17-18 aged of children with mental retarded sibling (47.04 ± 7.3) was higher than that of the children without mental retarded siblings (44.05 ± 11.23) (P < 0.05). It was observed that self-esteem of children with mentally retarded sibling was not affected from the handicap of their siblings (P > 0.05). Trait anxiety score averages of children with mentally retarded sibling and experience some difficulties due to his or her siblings's handicap (47.00 ± 7.76) were found higher than those of those of the children without any problem with the environment (42.61 ± 7.48) (P < 0.05).
Conclusion:
Although the average score of trait anxiety and self-esteem in both groups were not significant different, score of trait anxiety for children with mentally disabled siblings was higher in comparison. It was concluded that anxiety of children with and without mentally retarded siblings increased as self-esteem of these children decreased.
PMCID: PMC3906787  PMID: 24523782
Mental retardation; self-esteem; sibling; trait anxiety
Paediatrics & Child Health  2003;8(6):345-356.
Mental Retardation (MR) is a problem encountered in almost all paediatric clinical settings. The assessment of a child with MR is a common diagnostic and management dilemma for paediatricians. The field of MR research is currently in a state of flux regarding not just our understanding of the condition, but also in the language and the processes we use in naming, defining and describing MR. This article will provide a better understanding and a rational approach toward MR. Prevalence rates for MR are variable in the literature and may be attributable to the variation in major classification systems and the diversity in study operation definitions and methodologies. Etiologies of MR are diverse and include many different influences. MR most often presents during infancy or preschool years as developmental delay. There is no universally accepted approach to the etiological work-up of mental retardation. The number of medical conditions associated with MR that are completely treatable by medical means remains small. The paediatrician plays a key role establishing short and long term treatment goals, as well as providing support to families who have children with MR.
PMCID: PMC2795455  PMID: 20052328
Children; Developmental delay; Mental retardation
The American psychologist  2011;66(2):95-106.
As the infant mental health field has turned its focus to the presentation, course and treatment of clinically significant mental health disorders, the need for reliable and valid criteria for identifying and assessing mental health symptoms and disorders in early childhood has become urgent. In this paper, we offer a critical perspective on diagnostic classification of mental health disorders in young children. We place the issue of early childhood diagnosis within the context of classification of psychopathology at other ages and describe, in some detail, diagnostic classifications that have been developed specifically for young children included DC:0-3, a diagnostic classification for mental health symptoms and disorders in infant, toddlers, and preschoolers. We will briefly outline the role of diagnostic classification in clinical assessment and treatment planning. Lastly, we will review the limitations of current approaches to the diagnostic classification of mental health disorders in young children.
doi:10.1037/a0021026
PMCID: PMC3064438  PMID: 21142337
psychopathology; diagnosis; infant mental health; nosology; DC:0-3R
Indian Journal of Psychiatry  2013;55(2):170-172.
Background:
Ocular problems are common in mentally retarded children. Due to population growth these problems are increasing. Prevalence rate is variable from region to region. Data on ocular problems in mentally retarded school children is lacking in this region.
Aim:
The aim of the present study was to identify the ocular disorders in children with mental retardation attending special schools in a district and to study their relationship with the degree of retardation.
Materials and Methods:
A total of 241 mentally retarded school children in the age group of 6-16 years attending special schools for the mentally retarded children in a district in central India were examined by a team of ophthalmologist, psychiatrist, and a resident in ophthalmology department of a medical college. Complete ocular examination was done. Ocular problems were identified and categorized according to the intelligent quotient.
Results:
One hundred and twenty four children (51.45%) had ocular problems. Strabismus (10.37%) and refractive error (20.75%) were the common ocular problems seen in this study. An association was found between the severity of mental retardation and ocular problems (P<0.005). However, no association was seen between the severity of mental retardation and strabismus and refractive error.
Conclusion:
A high prevalence of ocular problems was seen in mentally retarded school children. Children with mental retardation should undergo annual ophthalmological check up. Early detection and correction of ocular problems will prevent visual impairment in future.
doi:10.4103/0019-5545.111457
PMCID: PMC3696242  PMID: 23825853
Children; mental retardation; ocular disorder; refractive error; strabismus
BioMed Research International  2013;2013:158746.
Psychomotor retardation is a central feature of depression which includes motor and cognitive impairments. Effective management may be useful to improve the classification of depressive subtypes and treatment selection, as well as prediction of outcome in patients with depression. The aim of this paper was to review the current status of knowledge regarding psychomotor retardation in depression, in order to clarify its role in the diagnostic management of mood disorders. Retardation modifies all the actions of the individual, including motility, mental activity, and speech. Objective assessments can highlight the diagnostic importance of psychomotor retardation, especially in melancholic and bipolar depression. Psychomotor retardation is also related to depression severity and therapeutic change and could be considered a good criterion for the prediction of therapeutic effect. The neurobiological process underlying the inhibition of activity includes functional deficits in the prefrontal cortex and abnormalities in dopamine neurotransmission. Future investigations of psychomotor retardation should help improve the understanding of the pathophysiological mechanisms underlying mood disorders and contribute to improving their therapeutic management.
doi:10.1155/2013/158746
PMCID: PMC3830759  PMID: 24286073
The diagnosis of childhood psychosis raises a host of unresolved problems, despite the Diagnostic and Statistical Manual Of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) giving identical symptoms and definitions for children, adolescents, and adults. The fantasy lives of children, and issues of developing language and cognition (including retardation), all impair diagnostic accuracy, particularly when differentiating between childhood-onset schizophrenia (COS) (≤12 years), bipolar affective disorder, major depressive disorder, and even obsessive-compulsive disorder and attention-deficit/hyperactivity disorder: the catch-all classification, psychosis not otherwise specified (PNOS), is always available for conundra that prove unsolvable. Typical if nonpathognomonic features include neurocognitive difficulties. Multiple screening instruments and specialized versions of semistructured diagnostic interviews are available. Although smooth-pursuit eye-tracking movements may prove a genetic marker for COS, etiologies are likely to be oligogenetic rather than related to a single gene. No specific biological markers or neuroimages have been identified. As such, psychoses may be indicative of a more general pattern of brain dysfunction. Drug treatments are largely based on the adult literature because of a dearth of controlled data below age 18. There are still no rigorous studies of psychosocial treatments and psychotherapy specific to childhood psychosis.
PMCID: PMC3181648  PMID: 22033588
childhood-onset schizophrenia; diagnosis; psychosis in children; psychopharrnacological treatment; psychosocial treatment
Background:
Growth of mentally retarded children differs from that of normal children. However, the adolescent growth and development of Indian mentally retarded children has not been studied.
Aim:
This study was conducted to evaluate the physical growth and sexual development of adolescent mentally retarded girls in North Indian population and to compare it with that of normal girls of same age group.
Materials and Methods:
One hundred mentally retarded (intelligence quotient (IQ) less than 70) and 100 normal girls between 10 and 20 years of age were categorized into 1-year age groups. Their height was measured and the sexual development was assessed based on breast development (BD) and pubic hair growth (PH) stages 1-5 on the basis of Tanner scale. The data was then compared between the two groups using Student's t-test. The mean age of menarche was calculated by applying Probit analysis.
Results:
The mean height of mentally retarded girls was significantly retarded as compared to normal girls at all ages; however, the mean height gain during 11-20 years was same in both the groups. The mentally retarded girls also showed significant retardation in PH growth at 15-17 years and in BD at 15-16 years of age.
Conclusions:
The physical growth and sexual development of adolescent mentally retarded girls was retarded as compared to the normal girls. The physical growth retardation occurred during early childhood (before 11 years), however the retardation in sexual maturity occurred during middle adolescence, between 15-17 years of age.
doi:10.4103/2229-516X.125691
PMCID: PMC3931213  PMID: 24600577
Growth; mentally retarded; sexual maturity
Mefford, Heather C. | Sharp, Andrew J. | Baker, Carl | Itsara, Andy | Jiang, Zhaoshi | Buysse, Karen | Huang, Shuwen | Maloney, Viv K. | Crolla, John A. | Baralle, Diana | Collins, Amanda | Mercer, Catherine | Norga, Koen | de Ravel, Thomy | Devriendt, Koen | Bongers, Ernie M.H.F. | de Leeuw, Nicole | Reardon, William | Gimelli, Stefania | Bena, Frederique | Hennekam, Raoul C. | Male, Alison | Gaunt, Lorraine | Clayton-Smith, Jill | Simonic, Ingrid | Park, Soo Mi | Mehta, Sarju G. | Nik-Zainal, Serena | Woods, C. Geoffrey | Firth, Helen V. | Parkin, Georgina | Fichera, Marco | Reitano, Santina | Giudice, Mariangela Lo | Li, Kelly E. | Casuga, Iris | Broomer, Adam | Conrad, Bernard | Schwerzmann, Markus | Räber, Lorenz | Gallati, Sabina | Striano, Pasquale | Coppola, Antonietta | Tolmie, John L. | Tobias, Edward S. | Lilley, Chris | Armengol, Lluis | Spysschaert, Yves | Verloo, Patrick | De Coene, Anja | Goossens, Linde | Mortier, Geert | Speleman, Frank | van Binsbergen, Ellen | Nelen, Marcel R. | Hochstenbach, Ron | Poot, Martin | Gallagher, Louise | Gill, Michael | McClellan, Jon | King, Mary-Claire | Regan, Regina | Skinner, Cindy | Stevenson, Roger E. | Antonarakis, Stylianos E. | Chen, Caifu | Estivill, Xavier | Menten, Björn | Gimelli, Giorgio | Gribble, Susan | Schwartz, Stuart | Sutcliffe, James S. | Walsh, Tom | Knight, Samantha J.L. | Sebat, Jonathan | Romano, Corrado | Schwartz, Charles E. | Veltman, Joris A. | de Vries, Bert B.A. | Vermeesch, Joris R. | Barber, John C.K. | Willatt, Lionel | Tassabehji, May | Eichler, Evan E.
The New England journal of medicine  2008;359(16):1685-1699.
BACKGROUND
Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients.
METHODS
We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons.
RESULTS
We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P = 1.1×10−7). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in the nine children with mental retardation or autism spectrum disorder and other variable features (P = 0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies.
CONCLUSIONS
We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.
doi:10.1056/NEJMoa0805384
PMCID: PMC2703742  PMID: 18784092
Neurology  2009;73(11):887-897.
Objective:
To make evidence-based recommendations concerning the evaluation of the child with microcephaly.
Methods:
Relevant literature was reviewed, abstracted, and classified. Recommendations were based on a 4-tiered scheme of evidence classification.
Results:
Microcephaly is an important neurologic sign but there is nonuniformity in its definition and evaluation. Microcephaly may result from any insult that disturbs early brain growth and can be seen in association with hundreds of genetic syndromes. Annually, approximately 25,000 infants in the United States will be diagnosed with microcephaly (head circumference <−2 SD). Few data are available to inform evidence-based recommendations regarding diagnostic testing. The yield of neuroimaging ranges from 43% to 80%. Genetic etiologies have been reported in 15.5% to 53.3%. The prevalence of metabolic disorders is unknown but is estimated to be 1%. Children with severe microcephaly (head circumference <−3 SD) are more likely (∼80%) to have imaging abnormalities and more severe developmental impairments than those with milder microcephaly (−2 to −3 SD; ∼40%). Coexistent conditions include epilepsy (∼40%), cerebral palsy (∼20%), mental retardation (∼50%), and ophthalmologic disorders (∼20% to ∼50%).
Recommendations:
Neuroimaging may be considered useful in identifying structural causes in the evaluation of the child with microcephaly (Level C). Targeted and specific genetic testing may be considered in the evaluation of the child with microcephaly who has clinical or imaging abnormalities that suggest a specific diagnosis or who shows no evidence of an acquired or environmental etiology (Level C). Screening for coexistent conditions such as cerebral palsy, epilepsy, and sensory deficits may also be considered (Level C). Further study is needed regarding the yield of diagnostic testing in children with microcephaly.
GLOSSARY
= cerebral palsy;
= global developmental delay;
= head circumference;
= medically refractory epilepsy;
= Online Mendelian Inheritance in Man.
doi:10.1212/WNL.0b013e3181b783f7
PMCID: PMC2744281  PMID: 19752457
Indian Journal of Psychiatry  1997;39(4):304-308.
Most of the autistic disorder patients are also mentally retarded and many mentally retarded persons exhibit autistic symptoms. By using a standard instrument (Ritvo-Freeman Real Life Rating Scale) the autistic features of the mentally retarded children were studied. The study also examined the influence of age, sex and level of mental retardation on the occurrence of autistic symptoms. Children who came for consultation to child psychiatric unit were compared with those at a school for children with mental retardation receiving stimulation. Male children from child psychiatric unit had significantly higher scores than those from the school. Social and language impairment could be reliably identified and grouped. It was possible to diagnose the syndrome of autism in children with mental retardation in a significant number (9.6%)as compared to that was possible only clinically (1.9%). More number of children with severe/ profound mental retardation could be diagnosed as autistic. The autistic syndrome in children with mental retardation can be picked up more effectively by the use of structured instrument.
PMCID: PMC2967163  PMID: 21584097
Autism; mental retardation
Journal of medical genetics  2009;46(6):382-388.
Background
Microdeletions within chromosome 15q13.3 are associated both with a recently recognised syndrome of mental retardation, seizures, and dysmorphic features, and with schizophrenia.
Methods and results
Based on routine diagnostic testing of ~8200 samples using array comparative genomic hybridisation, we identified 20 individuals (14 children and six parents in 12 families) with microdeletions of 15q13.3. Phenotypes in the children included developmental delay, mental retardation, or borderline IQ in most and autistic spectrum disorder (6/14), speech delay, aggressiveness, attention deficit hyperactivity disorder, and other behavioural problems. Both parents were available in seven families, and the deletion was de novo in one, inherited from an apparently normal parent in four, and inherited from a parent with learning disability and bipolar disorder in two families. Of the 14 children, six in five families were adopted, and DNA was available for only one of these 10 biological parents; the deletion was very likely inherited for one of these families with two affected children. Among the unavailable parents, two mothers were described as having mental retardation, another mother as having “mental illness”, and one father as having schizophrenia. We hypothesise that some of the unavailable parents have the deletion.
Conclusions
The occurrence of increased adoption, frequent autism, bipolar disorder, and lack of penetrance are noteworthy findings in individuals with deletion 15q13.3. A high rate of adoption may be related to the presence of the deletion in biological parents.
Unconfirmed histories of antisocial behaviours in unavailable biological parents raise the concern that future research may show that deletion 15q13.3 is associated with such behaviours.
doi:10.1136/jmg.2008.064378
PMCID: PMC2776649  PMID: 19289393
Background & objectives:
The aetiology of mental retardation is varied and difficult to establish. Reports from India on the spectrum of underlying causative conditions are lacking. This retrospective study was conducted to establish the various aetiologies of mental retardation (MR) and developmental delay (DD) in patients attending a medical genetics centre in north India and to assess the contribution of genetic disorders.
Methods:
This retrospective study was conducted at a tertiary care centre in north India. All patients attending the centre with MR or DD from January 2007 to December 2009 were included. The aetiology of MR/DD was ascertained after clinical assessment and targeted laboratory evaluation. The spectrum of causative conditions and contribution of genetic disorders was established.
Results:
A total of 338 patients were included in the study, of whom definite diagnosis was established in 253 (74.8%). The various aetiological categories were: chromosomal disorders in 112 (33.1%), non chromosomal syndromes in 32 (9.5%), neurometabolic disorders in 34 (10.1%), central nervous system structural defects in 25 (7.4%), cerebral palsy in 43 (12.7%) and environmental insults in 7 (2%). Eighty five patients (25.2%) had idiopathic mental retardation. A total of 196 (58%) patients had a genetic disorder as the cause of MR/DD.
Interpretation & conclusions:
The aetiology of MR/DD is varied and difficult to establish in a significant proportion of patients. Chromosomal and various monogenic disorders contribute to a large number of MR/DD cases and hence a genetic work up is essential for all such patients.
PMCID: PMC3510890  PMID: 23041737
Aetiology; developmental delay; genetic diseases; India; mental retardation
Journal of Medical Genetics  2002;39(8):546-553.
Objective: The frequency of subtelomeric rearrangements in patients with unexplained mental retardation (MR) is uncertain, as most studies have been retrospective and case retrieval may have been biased towards cases more likely to have a chromosome anomaly. To ascertain the frequency of cytogenetic anomalies, including subtelomeric rearrangements, we prospectively screened a consecutive cohort of cases with unexplained MR in an academic tertiary centre.
Methods: Inclusion criteria were: age <18 years at referral, IQ<85, no aetiological diagnosis after complete examination, which included karyotyping with high resolution banding (HRB).
Results: In 266 karyotyped children, anomalies were detected in 20 (7.5%, seven numerical, 13 structural); 39 cases were analysed by FISH for specific interstitial microdeletions, and anomalies were found in nine (23%). FISH analyses for subtelomeric microdeletions were performed in 184 children (44% moderate-profound MR, 51% familial MR), and one rearrangement (0.5%) was identified in a non-familial MR female with mild MR (de novo deletion 12q24.33-qter). The number of probable polymorphisms was considerable: 2qter (n=7), Xpter (n=3), and Ypter (n=1). A significantly higher total number of malformations and minor anomalies was present in the cytogenetic anomaly group compared to the group without cytogenetic anomalies.
Conclusions: The total frequency of cytogenetic anomalies in this prospective study was high (1:10), but the frequency of subtelomeric rearrangements was low. The most likely explanations are the high quality of HRB cytogenetic studies and the lack of clinical selection bias. Conventional cytogenetic analyses, combined with targeted microdeletion testing, remain the single most effective way of additional investigation in mentally retarded children, also in a tertiary centre.
doi:10.1136/jmg.39.8.546
PMCID: PMC1735204  PMID: 12161591
Archives of Disease in Childhood  1986;61(3):223-226.
One hundred and sixty six children attending educationally subnormal/mild (ESN/M) schools were karyotyped as part of a project investigating the aetiology of mild mental retardation. Nine had significant chromosome abnormalities. Five of six children identified during the survey had no dysmorphic features--47,XXY (two), 48,XXYY, 46,XX 15q-, and 46,XX,t(X;19). One dysmorphic boy had a balanced translocation--46,XY,t(3;15). Three were already known--47,XX+21 (two) and 46,XY, 14q+. We suggest that routine karyotyping of children with mild mental retardation be considered.
PMCID: PMC1777694  PMID: 2421647
Archives of Disease in Childhood  1985;60(10):946-952.
Risk factors for mental retardation were studied prospectively in 12 000 children born in northern Finland in 1966 and followed to the age of 14 years. The number of untraced children was less than 2 per 1000. Altogether 326 children had an IQ less than 86, and the incidence of severe retardation (IQ less than 50) was especially high. An incidence figure for children with mental retardation, a separate figure for healthy children, and also the death rate were calculated for each disease. Only in the cases of Down's syndrome and some hereditary diseases were all the exposed children mentally retarded; in other diseases some children did not seem to suffer any sequelae. A risk factor could be found for 50.6% of the total number of children with mental retardation, the percentage decreasing from the severest to the mildest form (86.7%, 45.4%, and 30.9%). Some 9.4% of the healthy children and 77.7% of those who died had had one or more of these conditions. Prenatal conditions were most often associated with severe mental retardation (64%), and perinatal conditions with mild retardation, (IQ 50 to 70; 27%) and mental subnormality (IQ 71 to 85; 18%). Cases with no known risk factor were more common among boys than girls.
PMCID: PMC1777517  PMID: 3840671
Background & objectives:
Developmental delay (DD)/mental retardation also described as intellectual disability (ID), is seen in 1-3 per cent of general population. Diagnosis continues to be a challenge at clinical level. With the advancement of new molecular cytogenetic techniques such as cytogenetic microarray (CMA), multiplex ligation-dependent probe amplification (MLPA) techniques, many microdeletion/microduplication syndromes with DD/ID are now delineated. MLPA technique can probe 40-50 genomic regions in a single reaction and is being used for evaluation of cases with DD/ID. In this study we evaluated the clinical utility of MLPA techniques with different probe sets to identify the aetiology of unexplained mental retardation in patients with ID/DD.
Methods:
A total of 203 randomly selected DD/ID cases with/without malformations were studied. MLPA probe sets for subtelomeric regions (P070/P036) and common microdeletions/microduplications (P245-A2) and X-chromosome (P106) were used. Positive cases with MLPA technique were confirmed using either fluorescence in situ hybridization (FISH) or follow up confirmatory MLPA probe sets.
Results:
The overall detection rate was found to be 9.3 per cent (19 out of 203). The detection rates were 6.9 and 7.4 per cent for common microdeletion/microduplication and subtelomeric probe sets, respectively. No abnormality was detected with probe set for X-linked ID. The subtelomeric abnormalities detected included deletions of 1p36.33, 4p, 5p, 9p, 9q, 13q telomeric regions and duplication of 9pter. The deletions/duplications detected in non telomeric regions include regions for Prader Willi/Angelman regions, Williams syndrome, Smith Magenis syndrome and Velocardiofacial syndrome.
Interpretation & conclusions:
Our results show that the use of P245-A2 and P070/P036-E1 probes gives good diagnostic yield. Though MLPA cannot probe the whole genome like cytogenetic microarray, due to its ease and relative low cost it is an important technique for evaluation of cases with DD/ID.
PMCID: PMC3994742  PMID: 24604040
Common microdeletion/microduplication syndromes; developmental delay; intellectual disability; India; MLPA; subtelomeric abnormalities
Archives of Disease in Childhood  1987;62(10):1035-1040.
A register of children with cerebral palsy born to mothers resident in the Mersey region from 1966 to 1977 was compiled from health service records. Frequency distributions and prevalences of birth weight and gestational age differed for those with hemiplegia, diplegia, and quadriplegia. In particular, the children with diplegia showed a bimodal frequency distribution. Children of normal birth weight with diplegia had a higher prevalence of severe mental retardation than those of low birth weight. These differences may be due to survival bias and may not be of aetiological importance. Furthermore, the mothers of diplegic infants had a significantly higher proportion of spontaneous abortions, stillbirths, and low birthweight infants in their obstetric history. This suggests that prenatal factors predominate in the aetiology of diplegia.
PMCID: PMC1778677  PMID: 3674922

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