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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.

We report on two mentally retarded adults with an unbalanced karyotype resulting from a familial balanced translocation between chromosomes 8 and 21, t(8;21)(p21.1;q22.3). This translocation has not been reported before. Both patients had partial trisomy 8p and partial monosomy 21q. Fluorescence in situ hybridisation (FISH) was used to determine the chromosomal breakpoints more precisely. The first patient showed mild mental retardation and facial dysmorphism, slightly resembling the earlier described trisomy 8p phenotype. He did not resemble his affected niece, who was more severely retarded, had serious epilepsy, but lacked the facial dysmorphism. Comparing the data of both patients with published reports of trisomy 8p, marked differences were found between patients with an inversion duplication (inv dup) 8p, patients with partial trisomy 8p caused by an unbalanced translocation, and our patients. Inv dup(8p) causes a recognisable phenotype, whereas the phenotype of trisomy 8p resulting from a translocation is much more variable, probably because of the accompanying monosomies. However, even the same abnormal karyotype can cause different phenotypes, as our patients show. Counselling carriers of the balanced translocation in this family, a 20-25% recurrence risk for unbalanced offspring and a 25% risk for miscarriages seem appropriate.

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The 48,XXYY syndrome is a form of sex chromosome aneuploidy presenting in 1:18,000 males. Tremor has been previously reported in 47,XXY and 47,XYY syndromes, but has not been well described in 48,XXYY syndrome. Ten males with 48,XXYY syndrome had a standardized neurological examination and videotaping, which included the Clinical Rating Scale for Tremor and the International Cooperative Ataxia Rating Scale. All 10 cases had postural and kinetic tremor on physical examination. Other findings included mild gait ataxia, dysarthria, and nystagmus. Three cases are reviewed. Tremor is a common finding in children and young adults with 48,XXYY syndrome. Dosage alteration of genes on the sex chromosomes may be involved in the pathogenesis of this tremor. Karyotyping should be considered in individuals presenting with tremor and a history of developmental delay, learning disabilities, tall stature, or micro-orchidism.

High resolution comparative genomic hybridisation (HR-CGH) is a diagnostic tool in our clinical cytogenetics laboratory. The present survey reports the results of 253 clinical cases in which 47 abnormalities were detected. Among 144 dysmorphic and mentally retarded subjects with a normal conventional karyotype, 15 (10%) had small deletions or duplications, of which 11 were interstitial. In addition, a case of mosaic trisomy 9 was detected. Among 25 dysmorphic and mentally retarded subjects carrying apparently balanced de novo translocations, four had deletions at translocation breakpoints and two had deletions elsewhere in the genome. Seventeen of 19 complex rearrangements were clarified by HR-CGH. A small supernumerary marker chromosome occurring with low frequency and the breakpoint of a mosaic r(18) case could not be clarified. Three of 19 other abnormalities could not be confirmed by HR-CGH. One was a Williams syndrome deletion and two were DiGeorge syndrome deletions, which were apparently below the resolution of HR-CGH. However, we were able to confirm Angelman and Prader-Willi syndrome deletions, which are about 3-5 Mb. We conclude that HR-CGH should be used for the evaluation of (1) dysmorphic and mentally retarded subjects where normal karyotyping has failed to show abnormalities, (2) dysmorphic and mentally retarded subjects carrying apparently balanced de novo translocations, (3) apparently balanced de novo translocations detected prenatally, and (4) for clarification of complex structural rearrangements.


Keywords: comparative genomic hybridisation; chromosome analysis; chromosome aberrations; dysmorphism

A genetic study of children attending ESN(M) schools in Coventry has shown a recurrence risk of idiopathic mental retardation in sibs lying between 1 in 4 and 1 in 5. There was also a prevalence of mental retardation in other relatives that was greater than the population prevalence, and was less for second degree relatives than for first degree, and less still for third degree relatives. Recurrence in sibs was greater if more than one first degree relative was affected. There was no suggestion of a contribution by X linked genes, once the fragile X syndrome had been excluded. The presence of perinatal and other environmental factors in the index children did not alter the recurrence risk for sibs except for very low birth weight. There was a low recurrence rate of mental retardation in Asian families, suggesting that they had a different distribution of intelligence from non-Asian families.

A 45-year-old male was referred for diabetes mellitus. Clinical examination found a family history of multiple precocious deaths, strong consanguinity, personal history of seizures during childhood, small testicles, small penis, sparse body hair, long arms and legs, dysmorphic features, mental retardation, dysarthria, tremor, and mild gait ataxia. Investigations found pigmentary retinitis, metabolic syndrome, unilateral renal aplasia, and hypergonadotropic hypogonadism, and ruled out mitochondrial cytopathy and leucodystrophy. Karyotype study showed a 48XXYY chromosomal type. Renal aplasia and pigmentary retinitis have not been described in 48XXYY patients. They may be related to the chromosomal sex aneuploidy, or caused by other genetic aberrations in light of the high consanguinity rate in the patient's family.

Background

Autosomal monosomies in human are generally suggested to be incompatible with life; however, there is quite a number of cytogenetic reports describing full monosomy of one chromosome 21 in live born children. Here, we report a cytogenetically similar case associated with congenital malformation including mental retardation, motor development delay, craniofacial dysmorphism and skeletal abnormalities.

Results

Initially, a full monosomy of chromosome 21 was suspected as only 45 chromosomes were present. However, molecular cytogenetics revealed a de novo unbalanced translocation with a der(7)t(7;21). It turned out that the translocated part of chromosome 21 produced GTG-banding patterns similar to original ones of chromosome 7. The final karyotype was described as 45,XX,der(7)t(7;21)(q34;q22.13),-21. As a meta analysis revealed that clusters of the olfactory receptor gene family (ORF) are located in these breakpoint regions, an involvement of OFR in the rearrangement formation is discussed here.

Conclusion

The described clinical phenotype is comparable to previously described cases with ring chromosome 21, and a number of cases with del(7)(q34). Thus, at least a certain percentage, if not all full monosomy of chromosome 21 in live-borns are cases of unbalanced translocations involving chromosome 21.

We report an unbalanced translocation involving chromosome 2 and 7 due to a balanced reciprocal translocation 2;7 in the father. The female fetus had a partial trisomy of the long arm of chromosome 2 with a partial monosomy of distal 7q. Ultrasound at the first trimester had indicated normal fetal anatomy, including normal intracranial structures. Parental karyotypes showed a paternal balanced translocation: 46,XY,t(2;7)(q37.3;-->q34). The unbalanced translocation in the fetus resulted in trisomy for 2q37.3 qter and monosomy for 7q34-->qter. Postnatal examination showed that the female abortus had a cleft lip and palate, and mild dysmorphic features. The clinical phenotype was in agreement with previous descriptions and allowed us to propose a fetal phenotype for this chromosomal abnormality.

Background

Carriers of apparently balanced translocations are usually phenotypically normal; however in about 6% of de novo cases, an abnormal phenotype is present. In the current study we investigated 12 patients, six de novo and six familial, with apparently balanced translocations and mental retardation and/or congenital malformations by applying 1 Mb resolution array-CGH. In all de novo cases, only the patient was a carrier of the translocation and had abnormal phenotype. In five out of the six familial cases, the phenotype of the patient was abnormal, although the karyotype appeared identical to other phenotypically normal carriers of the family. In the sixth familial case, all carriers of the translocations had an abnormal phenotype.

Results

Chromosomal and FISH analyses suggested that the rearrangements were "truly balanced" in all patients. However, array-CGH, revealed cryptic imbalances in three cases (3/12, 25%), two de novo (2/12, 33.3%) and one familial (1/12, 16.6%). The nature and type of abnormalities differed among the cases. In the first case, what was identified as a de novo t(9;15)(q31;q26.1), a complex rearrangement was revealed involving a ~6.1 Mb duplication on the long arm of chromosome 9, an ~10 Mb deletion and an inversion both on the long arm of chromosome 15. These imbalances were located near the translocation breakpoints. In the second case of a de novo t(4;9)(q25;q21.2), an ~6.6 Mb deletion was identified on the short arm of chromosome 7 which is unrelated to the translocation. In the third case, of a familial, t(4;7)(q13.3;p15.3), two deletions of ~4.3 Mb and ~2.3 Mb were found, each at one of the two translocation breakpoints. In the remaining cases the translocations appeared balanced at 1 Mb resolution.

Conclusion

This study investigated both de novo and familial apparently balanced translocations unlike other relatively large studies which are mainly focused on de novo cases. This study provides additional evidence that cryptic genomic imbalances are common in patients with abnormal phenotype and "apparently balanced" translocations not only in de novo but can also occur in familial cases. The use of microarrays with higher resolution such as oligo-arrays may reveal that the frequency of cryptic genomic imbalances among these patients is higher.

A structurally abnormal X chromosome was found in a nine year old girl with mild mental retardation and dysmorphic features. Subsequent clinical examination at 18 years of age showed tall stature and gonadal dysgenesis. Re-examination of her karyotype using a variety of banding techniques on prometaphase chromosomes allowed the identification of the abnormal chromosome as a duplication/deficient X chromosome, 46,Xder X(pter----q28::p11.2----pter). The clinical features are discussed in terms of karyotype/phenotype correlation.

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Seventy-six children had computerized tomography scans as part of an investigation of mental subnormality; most of them are severely retarded and all those over age 5 years attend special schools. Seventy-two per cent of the children had normal scans. Twenty per cent showed cerebral atrophy and in only 8% was there a specific abnormality (agenesis of corpus callosum, arachnoid cyst, communicating hydrocephalus). None of these findings had any positive prognostic implication. Sedation or general anaesthesia was required for all except one child. Injection pethidine compound was used for children under age 5 years or less than 30 kg in weight, and trimeprazine orally was used for older children. The radiation exposure was high--5.6 rad per scan, which is 100 times greater than that from a posteroanterior and lateral chest x-ray film. For these reasons computerised tomography scans cannot be recommended as a routine part of the investigation of children with non-specific mental subnormality.

Background

Subtelomeric deletions of the long arm of chromosome 20 are rare, with only 11 described in the literature. Clinical features of individuals with these microdeletions include severe limb malformations, skeletal abnormalities, growth retardation, developmental and speech delay, mental retardation, seizures and mild, non-specific dysmorphic features.

Methodology/Principal Findings

We characterized microdeletions at 20q13.33 in six individuals referred for genetic evaluation of developmental delay, mental retardation, and/or congenital anomalies. A comparison to previously reported cases of 20q13.33 microdeletion shows phenotypic overlap, with clinical features that include mental retardation, developmental delay, speech and language deficits, seizures, and behavior problems such as autistic spectrum disorder. There does not appear to be a clinically recognizable constellation of dysmorphic features among individuals with subtelomeric 20q microdeletions.

Conclusions/Significance

Based on genotype-phenotype correlation among individuals in this and previous studies, we discuss several possible candidate genes for specific clinical features, including ARFGAP1, CHRNA4 and KCNQ2 and neurodevelopmental deficits. Deletion of this region may play an important role in cognitive development.

Chromosomal aberrations are a common cause of multiple anomaly syndromes that include growth and developmental delay and dysmorphism. Novel high resolution, whole genome technologies, such as array based comparative genomic hybridisation (array-CGH), improve the detection rate of submicroscopic chromosomal abnormalities allowing re-investigation of cases where conventional cytogenetic techniques, Spectral karyotyping (SKY), and FISH failed to detect abnormalities. We performed a high resolution genome-wide screening for submicroscopic chromosomal rearrangements using array-CGH on 41 children with idiopathic mental retardation (MR) and dysmorphic features. The commercially available microarray from Spectral Genomics contained 2600 BAC clones spaced at approximately 1 Mb intervals across the genome. Standard chromosome analysis (>450 bands per haploid genome) revealed no chromosomal rearrangements. In addition, multi-subtelomeric FISH screening in 30 cases and SKY in 11 patients did not detect any abnormality. Using array-CGH we detected chromosomal imbalances in four patients (9.8%) ranging in size from 2 to 14 Mb. Large scale copy number variations were frequently observed. Array-CGH has become an important tool for the detection of chromosome aberrations and has the potential to identify genes involved in developmental delay and dysmorphism. Moreover, the detection of genomic imbalances of clinical significance will increase knowledge of the human genome by performing genotype-phenotype correlation.

A 3 1/2-year-old boy was referred for chromosomal evaluation because of mental and developmental retardation, peculiar facies, and abnormalities of the extremities. Karyotype analysis disclosed the presence of 46 and 47 chromosome cell lines. The 46 chromosome line contained 4 normal G group chromosomes and an abnormally small Y identified by G banding. Further investigation with Q and C band techniques revealed that the missing segment of the Y, the distal long arm, had been translocated to the end of the long arm of a number 6 chromosome. This de novo rearrangement appeared to be balanced and was found in all cells examined. The 47 chromosome line, which had a frequency of 10% in the patient's leucocytes, was identical to the 46 line except for the presence of an additional copy of the small chromosome. The morphology and banding patterns of the two small acrocentrics in the aneuploid line were found to correspond to those of the der (derivative) Y in the euploid line. The cytogenetic findings suggest that the translocation was followed by non-disjunction of one of its products resulting in mosaicism. Possible causes for the clinical and karyotypic abnormalities are discussed.

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The clinical manifestations and cytogenetic details of five patients with a de novo deletion of the short arm of chromosome 8, del(8)(p23), are described. Of the four surviving children all had mild mental retardation and subtle facial anomalies; three of the five had cardiac abnormalities. The clinical features seen in these patients are compared with those of three previous single case reports with del(8)(p23), and with patients described as having the '8p-' syndrome associated with del(8)(p21). The findings in these patients suggest that major congenital anomalies, especially congenital heart defects, are frequent even in small distal 8p deletions, but facial dysmorphism may be subtle and mental retardation less severe than in those with deletions associated with more proximal breakpoints. The five patients were detected within a four year period, suggesting that this deletion syndrome is relatively frequent. The possible mechanisms for the formation of terminal deletions are discussed.

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Partial trisomy 3p results from either unbalanced translocation or de novo duplication. Common clinical features consist of dysmorphic facial features, congenital heart defects, psychomotor and mental retardation, abnormal muscle tone, and hypoplastic genitalia. In this paper, we report a case of partial trisomy 3p with rare clinical manifestations. A full-term, female newborn was transferred to our clinic. She had cleft lip-plate, dysgenesis of the corpus callosum, patent ductus arteriosus, pulmonary hypertension, and severe right-sided hydronephrosis, associated with ureteropelvic junction obstruction. Cytogenetic investigation revealed partial trisomy 3p; 46,XX,der(4)t(3;4) (p21.1;p16). The karyotype of her father showed a balanced translocation, t(3;4)(p21.1;p16). Therefore, the size of duplication can be an important factor.

Background

Cryptic structural abnormalities within the subtelomeric regions of chromosomes have been the focus of much recent research because of their discovery in a percentage of people with mental retardation (UK terminology: learning disability). These studies focused on subjects (largely children) with various severities of intellectual impairment with or without additional physical clinical features such as dysmorphisms. However it is well established that prevalence of schizophrenia is around three times greater in those with mild mental retardation. The rates of bipolar disorder and major depressive disorder have also been reported as increased in people with mental retardation. We describe here a screen for telomeric abnormalities in a cohort of 69 patients in which mental retardation co-exists with severe psychiatric illness.

Methods

We have applied two techniques, subtelomeric fluorescence in situ hybridisation (FISH) and multiplex amplifiable probe hybridisation (MAPH) to detect abnormalities in the patient group.

Results

A subtelomeric deletion was discovered involving loss of 4q in a patient with co-morbid schizoaffective disorder and mental retardation.

Conclusion

The precise region of loss has been defined allowing us to identify genes that may contribute to the clinical phenotype through hemizygosity. Interestingly, the region of 4q loss exactly matches that linked to bipolar affective disorder in a large multiply affected Australian kindred.

Background/Aims:

The objective of this study was to describe patients with chronic diarrhea and abnormal skin hyperpigmentation with distinct distribution.

Methods:

This is a retrospective review of children who presented with diarrhea and skin hyperpigmentation. The clinical presentation, laboratory investigations as well as endoscopic and histological data were reviewed.

Results:

Seven patients with chronic diarrhea had abnormal skin hyperpigmentation with distinct distribution and presented in the first two months of life. Six patients had other features such as abnormal hair and facial dysmorphism. Mental retardation was reported in one patient. Consanguinity was positive in six patients, and there was family history of consanguinity in four patients, with two patients being siblings. No significant immunodeficiency was reported. Intestinal biopsies were obtained in six patients and showed active chronic inflammation in three patients, partial villous atrophy in two patients, and eosinophilic infiltrate with mild villous atrophy in one patient. Colonic biopsies showed mild focal colitis in three patients and mild colitis with eosinophilic infiltrate in one patient. Skin biopsies showed a greater number of melanophagies with fibrosis of papillary derma in two patients but skin biopsy was normal in one patient. The hair of two patients was analyzed by electron microscopy, which showed an abnormal pattern with decreased pigmentation and diameter; however, its chemical analysis was normal. Two other patients had trichorrhexis nodosa, but no abnormalities were seen in one patient. Chromosomal number was normal in three patients. One patient died because of sepsis, and only one patient was dependent on total parenteral nutrition.

Conclusions:

We believe that this association might represent a new syndrome with an autosomal recessive inheritance that warrants further studies.

The interstitial deletion of a segment of chromosome 13, 13q21 leads to 13q22, and its inversion and insertion into the long arm of chromosome 3 at breakpoint q12, was found to segregate in 3 generations of a family. Segregation of this 3 break rearrangement gave rise to individuals monosomic, trisomic, or balanced for the involved segment. Monosomy for 13q21 leads to 13q22 was associated with mental retardation, expressive aphasia, microcephaly, hand abnormalities, and short stature. Partially trisomic individuals had normal mentality, extremely high arched palate, and mild dysmorphic features. There was no evidence for retinoblastoma in the individuals examined. The balanced carriers were normal. Comparison of monosomic individuals with one previous report of a similar deletion reveals marked phenotypic similarities.

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We report a case of an unbalanced cryptic telomeric translocation 46,XY,der(17),t(9;17)(q34.3;p13.3) in a boy with dysmorphic features and developmental delay. The proband had intrauterine growth retardation, postnatal short stature, and mild microcephaly. Magnetic resonance imaging showed incomplete myelination, but no evidence of lissencephaly. Cytogenetic analysis of the proband's peripheral blood showed an abnormal 17p. Fluorescence in situ hybridisation (FISH) with a Miller-Dieker cosmid probe did not detect a deletion for that area. Further analysis with a 17p telomere specific probe identified an unbalanced telomeric translocation. The same probe was used to determine the presence of an apparent balanced translocation t(9;17)(q34.3;p13.3) in the mother of the proband. The balanced translocation was confirmed with two cosmids that map distally on 9q34.3. Two phenotypically normal half sibs, a maternal aunt, a maternal uncle, and the maternal grandmother were found to be balanced translocation carriers as well. A subtle translocation carriers as well. A subtle translocation is one mechanism that can produce an abnormal phenotype in a patient who had a normal karyotype at lower band resolution levels.

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A 6-year-old boy with speech delay and mild mental retardation (IQ 82) was found to have a complex double translocation involving four chromosomes and a total of five breakpoints, two being on the same arm. This resulted in the karyotype 46,XY,t(2;4;7)(7;8)(q14;q31;q11q22;q13). As far as the authors are aware this is the first time that such a complex double translocation has been reported. Both parents had normal karyotypes.

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A patient with mental retardation and mild facial dysmorphism had a karyotype which was considered to be normal before the availability of chromosomal banding techniques. She had a history of a cat-like cry and severe feeding problems during infancy. At the age of 9, she was still found to have initial aphonia on trying to initiate sounds. Repeat chromosome analysis with G banding showed an interstitial deletion of the long arm of chromosome 7.

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The most common sex chromosome complex in sex chromatin-positive males with Klinefelter's syndrome is XXY. When the complex is XXYY or XXXY, the clinical findings do not seem to differ materially from those seen in XXY subjects, although more patients with these intersexual chromosome complements need to be studied to establish possible phenotypical expressions of the chromosomal variants.

Two male children with an XXXXY sex chromosome abnormality are described. The data obtained from the study of these cases and five others described in the literature suggest that the XXXXY patient is likely to have congenital defects not usually seen in the common form of the Klinefelter syndrome. These include a triad of (1) skeletal anomalies (including radioulnar synostosis), (2) hypogenitalism (hypoplasia of penis and scrotum, incomplete descent of testes and defective prepubertal development of seminiferous tubules), and (3) greater risk of severe mental deficiency.

That the conclusions are based on data from a small number of patients is emphasized, together with the need for a cytogenetic survey of a large control or unselected population.

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Twelve infants (six boys, six girls) with severe hypocalcaemic tetany or convulsions were seen over a three year period. Nine patients were symptomatic in the newborn period. Their hypocalcaemia was associated with hyperphosphataemia and very low concentrations of immunoreactive parathyroid hormone. None of the babies suffered from congenital cardiac disease. Cell mediated immunity, measured in five patients, was normal. There were no chromosomal abnormalities but all patients shared several dysmorphic features including deep set eyes, microcephaly, thin lips, beaked nose tip, external ear anomalies, micrognathia, and depressed nasal bridge. Mental retardation of varying degree was found in all patients. All had severe intrauterine and postnatal growth retardation. Four patients have died. The remaining eight patients are on treatments with vitamin D and calcium supplements with no change in their growth pattern. We believe that this association of congenital hypoparathyroidism with severe growth failure and dysmorphism represents a new syndrome.

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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator gene (AIRE). Terminal 4q deletion is also a rare cytogenetic abnormality that causes a variable syndrome of dysmorphic features, mental retardation, growth retardation, and heart and limb defects. We report a 12-year-old Saudi boy with mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical failure consistent with APECED. In addition, he has dysmorphic facial features, growth retardation, and severe global developmental delay. Patient had late development of chronic renal failure. The blastogenesis revealed depressed lymphocytes' response to Candida albicans at 38% when compared to control. Chromosome analysis of the patient revealed 46,XY,del(4)(q33). FISH using a 4p/4q subtelomere DNA probe assay confirmed the deletion of qter subtelomere on chromosome 4. Parental chromosomes were normal. The deleted array was further defined using array CGH. AIRE full gene sequencing revealed a homozygous mutation namely 845_846insC. Renal biopsy revealed chronic interstitial nephritis with advanced fibrosis. In addition, there was mesangial deposition of C3, C1q, and IgM. This is, to the best of our knowledge, the first paper showing evidence of autoimmune nephropathy by renal immunofluorescence in a patient with APECED and terminal 4q deletion.