Chromosome deletions in 13q33-34: report of four patients and review of the literature

Deletions of chromosome bands 13q33-34 are rare. Patients with such deletions have mental retardation, microcephaly, and distinct facial features. Male patients frequently also have genital malformations. We report on four patients with three overlapping deletions of 13q33-34 that have been characterized by tiling-path array-CGH. Patient 1 had mental retardation and microcephaly with an interstitial 4.7 Mb deletion and a translocation t(12;13)(q13.3;q32.3). His mother (Patient 2), who also had mental retardation and microcephaly, carried the identical chromosome aberration. Patient 3 was a girl with a de novo insertion ins(7;13)(p15.1;q22q31) and interstitial 4.5 Mb deletion in 13q33-34. She had mental retardation and microcephaly. Patient 4 was a newborn boy with severe genital malformation (penoscrotal transposition and hypospadias) and microcephaly. He had a de novo ring chromosome 13 lacking the terminal 9.3 Mb of 13q. Karyotype-phenotype comparisons of these and eight previously published del13q33-34 patients suggest EFNB2 as a candidate gene for genital malformations in males. Molecular cytogenetic definition of a common deleted region in all patients suggests ARHGEF7 as a candidate gene for mental retardation and microcephaly.     

Report of two brothers with short stature,microcephaly, mental retardation,and retinoschisis—A new mental retardation syndrome?

Involvement of genes on the X-chromosome as a cause of mental retardation has been recognized for a long time. X-linked phenotypes of mental retardation have been divided into non-syndromic and syndromic based on associated manifestations. At present, more than 140 syndromic X-linked mental retardation (XLMR) conditions have been reported and a causative gene mutation has been identified in almost half of these. Here, we report on two brothers with short stature, microcephaly, severe mental retardation, and retinoschisis. Results of karyotype analysis, fragile-X and neuroimaging studies were normal. Fundus examination showed bilateral retinoschisis at variable stages in both sibs. X-linked retinoschisis is a retinal dystrophy caused by mutations in the RS1 gene at Xp22.1, which lead to splitting of the neural retina and reduced visual acuity in affected men. However, as yet there have been no reports of mental retardation in X-linked retinoschisis although genetic loci for XLMR and short stature have been mapped to Xp22.1. Sequencing and microarray analysis failed to find any alteration of RS1 gene or copy number alteration in the region. In addition, genotype analysis of Xp22.1 provided evidence against linkage to this region. The associated findings of retinoschisis and mental retardation in two brothers suggest a new mental retardation syndrome likely to be an X linked trait.     

Filippi syndrome: report of three additional cases.

Filippi syndrome is an autosomal recessive condition characterized by variable soft tissue syndactyly of the fingers and toes, microcephaly, pre- and postnatal growth retardation, mildly abnormal craniofacial appearance, and mental retardation. We report on three unrelated individuals with Filippi syndrome. All have microcephaly, minor facial anomalies, variable syndactyly of digits, growth impairment, and developmental delay. One patient also has polydactyly, which has not been reported previously in the Filippi syndrome.     

On the nosology of the "primary true microcephaly, chorioretinal dysplasia, lymphoedema" association

We describe a male child with prenatal growth retardation, true microcephaly, pedal lymphoedema and characteristic ocular anomalies. Ophthalmological examination revealed remnants of the posterior hyaloidea, more pronounced in the right eye where a retinal fold extended from the papilla into the vitreum, chorioretinal dysplasia with narrow retinal vessels, multiple large round areas of chorioretinal atroph and atrophic papillae. The associations "Microcephaly-chorioretinal dysplasia", "Microcephaly-retinal folds" and "Microcephaly-lymphoedema" have been reported as separate autosomal dominant conditions. The findings in the present child suggest that these associations could be variable expressions of the same autosomal dominant condition.     

Filippi syndrome: Report of three additional cases

Filippi syndrome is an autosomal recessive condition characterized by variable soft tissue syndactyly of the fingers and toes, microcephaly, pre- and postnatal growth retardation, mildly abnormal craniofacial appearance, and mental retardation. We report on three unrelated individuals with Filippi syndrome. All have microcephaly, minor facial anomalies, variable syndactyly of digits, growth impairment, and developmental delay. One patient also has polydactyly, which has not been reported previously in the Filippi syndrome. Am. J. Med. Genet. 87:128–133, 1999. © 1999 Wiley-Liss, Inc.     

Deletion of 16q with prolonged survival and unusual radiographic manifestations

Deletion of 16q is characterized by mental retardation, microcephaly, a characteristic combination of minor facial anomalies, and broad halluces. Various break points have been described. This patient's phenotype is typical of this syndrome, but in addition, unusual radiographic findings were present. This chromosome abnormality is compatible with survival into adulthood. Expression of this phenotype does not appear to be correlated with specific break points.     

Autosomal dominant microcephaly with mental retardation

A 3-year-old girl, her mother, and maternal uncle had microcephaly and mental retardation. Their facial appearance is characterized by deep-set eyes, short philtrums, and a "beaked" nose. The mother and uncle live in an adult foster care facility because of mental retardation. The 3-year-old girl has a developmental quotient of 55. Mother has normal phenylalanine level and the child's chromosomes are normal. This appears to be a first report of a autosomal dominant form of microcephaly associated with mild to moderate mental retardation in contrast to absent or mild mental retardation described in earlier reports.     

Retinoblastoma and mental retardation microdeletion syndrome: clinical characterization and molecular dissection using array CGH

We describe three patients with retinoblastoma, dysmorphic features and developmental delay. Patients 1 and 2 have high and broad forehead, deeply grooved philtrum, thick anteverted lobes and thick helix. Patient 1 also has dolicocephaly, sacral pit/dimple and toe crowding; patient 2 shows intrauterine growth retardation and short fifth toe. Both patients have partial agenesis of corpus callosum. Patient 3 has growth retardation, microcephaly, thick lower lip and micrognathia. Using array-comparative genomic hybridization (CGH), we identified a 13q14 de novo deletion in patients 1 and 2, while patient 3 had a 7q11.21 maternally inherited deletion, probably not related to the disease. Our results confirm that a distinct facial phenotype is related to a 13q14 deletion. Patients with retinoblastoma and malformations without a peculiar facial phenotype may have a different deletion syndrome or a casual association of mental retardation and retinoblastoma. Using array-CGH, we defined a critical region for mental retardation and dysmorphic features. We compared this deletion with a smaller one in a patient with retinoblastoma (case 4) and identified two distinct critical regions, containing 30 genes. Four genes appear to be good functional candidates for the neurological phenotype: NUFIP1 (nuclear fragile X mental retardation protein 1), HTR2A (serotonin receptor 2A), PCDH8 (prothocaderin 8) and PCDH17 (prothocaderin 17).     

Asymmetric crying facies with microcephaly and mental retardation. An autosomal dominant syndrome with variable expressivity

An infant boy with asymmetric crying facies, microcephaly, developmental retardation and failure to thrive is reported. His two siblings died in the newborn period because of complex congenital heart defects. The mother and the maternal grandmother have asymmetric crying facies, microcephaly and normal intelligence. A maternal aunt has severe physical and mental retardation, facial asymmetry, microcephaly, and cleft palate. This family allows an expansion of the spectrum of malformations associated with asymmetric crying facies and suggests autosomal dominant inheritance with variable expressivity.     

A 3 Mb deletion in 14q12 causes severe mental retardation, mild facial dysmorphisms and Rett-like features

The present report describes a 7-year-old girl with a de novo 3 Mb interstitial deletion of chromosome 14q12, identified by oligo array-CGH. The region is gene poor and contains only five genes two of them, FOXG1B and PRKD1 being deleted also in a previously reported case with a very similar phenotype. Both patients present prominent metopic suture, epicanthic folds, bulbous nasal tip, tented upper lip, everted lower lip and large ears and a clinical course like Rett syndrome, including normal perinatal period, postnatal microcephaly, seizures, and severe mental retardation. FOXG1B (forkhead box G1B) is a very intriguing candidate gene since it is known to promote neuronal progenitor proliferation and to suppress premature neurogenesis and its disruption is reported in a patient with postnatal microcephaly, corpus callosum agenesis, seizures, and severe mental retardation.     

Microcephaly with or without chorioretinopathy,lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations

Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR) (MIM No.152950) is a rare autosomal dominant condition for which a causative gene has recently been identified. Mutations in the kinesin family member 11 (KIF11) gene have now been described in 16 families worldwide. This is a review of the condition based on the clinical features of 37 individuals from 22 families. This report includes nine previously unreported families and additional information for some of those reported previously. The condition arose de novo in 8/20 families (40%). The parental results were not available for two probands. The mutations were varied and include missense, nonsense, frameshift, and splice site and are distributed evenly throughout the KIF11 gene. In our cohort, 86% had microcephaly, 78% had an ocular abnormality consistent with the diagnosis, 46% had lymphoedema, 73% had mild-moderate learning difficulties, 8% had epilepsy, and 8% had a cardiac anomaly. We identified three individuals with KIF11 mutations but no clinical features of MCLMR demonstrating reduced penetrance. The variable expression of the phenotype and the presence of mildly affected individuals indicates that the prevalence may be higher than expected, and we would therefore recommend a low threshold for genetic testing.     

Homozygous deletions of a copy number change detected by array CGH: a new cause for mental retardation?

We describe two unrelated patients with mental retardation and normal karyotypes found to have relatively large homozygous deletions (>150 kb) of different regions detected by array comparative genomic hybridization (aCGH). Patient 1 showed a 157-214 kb deletion at 8q24.2, containing BAC clone RP11-17M8. This patient was born to phenotypically normal parents and has microcephaly, distinctive craniofacial features, brachymetacarpia, brachymetatarsia and severe mental retardation. This BAC clone is listed as a copy number variant on the Database of Genomic Variants (http://projects.tcag.ca/variation/). Heterozygosity for the deletion was found in the mother (father is deceased) and uniparental disomy of chromosome 8 was excluded. Patient 2 showed a 812-902 kb deletion at 12q21.1, containing BAC clone RP11-89P15. This region was not listed in any public database as a known variant. This patient has mild craniofacial dysmorphic features, bifid uvula, peripheral pulmonic stenosis and developmental delay. Heterozygosity for this deletion was confirmed in the phenotypically normal parents and two normal siblings, but surprisingly, homozygosity for the deletion in an apparently normal younger sibling brings into question whether this large homozygous copy number change (CNC) is causal. Homozygous deletions of CNCs have not previously been reported in association with a phenotype or mental retardation. These cases represent homozygosity for presumably benign CNCs, and while causality for the phenotypes cannot be confirmed, similar deletions are bound to be identified more frequently as aCGH is used with increasing regularity. Such homozygous deletions should be viewed as potentially clinically relevant.     

Clinical delineation of Giuffrè-Tsukahara syndrome: another case with microcephaly and radio-ulnar synostosis with apparent X-linked semi-dominant inheritance

Two families and three sporadic cases have been described so far with the combination of radio-ulnar synostosis and microcephaly as main features. Some authors have discussed whether the first family reported by Giuffrè et al. [1994] and the second family described by Tsukahara et al. [1995] had the same syndrome. Although there is phenotypic variability among the described cases (especially with respect to facial dysmorphisms and mental retardation), the clinical patterns do not seem to be clearly distinguishable from each other. We describe another family with apparent X-linked semi-dominant inheritance with milder features in the female patient due to skewed X-inactivation. From a clinical synopsis, we consider the Giuffrè-Tsukahara syndrome as one genetic entity, which is characterized by the association of microcephaly and radio-ulnar synostosis, mental retardation in male patients and variable minor features. Patients with the Giuffrè-Tsukahara syndrome do not present with a characteristic pattern of facial features.     

Deletion of the short arm of chromosome 3: a case report with necropsy findings.

A male infant with partial deletion of the short arm of chromosome 3 is described. The features this patient shares with six previously reported cases include microcephaly, dolichocephaly, micrognathia, epicanthic folds, ptosis, low set or malformed ears, postaxial polydactyly, and growth or mental retardation or both. In addition, visceral anomalies not previously reported in association with this chromosomal abnormality are described. These characteristics may constitute a recognisable clinical syndrome.     

Chorio-retinal dysplasia, microcephaly and mental retardation. An autosomal dominant syndrome

A condition is described which is characterized by chorio-retinal dysplasia, microcephaly and mental retardation, transmitted in an autosomal dominant fashion with variable expressivity. It is suggested that this condition is a distinct autosomal dominant syndrome.     

Familial complex 3q;10q rearrangement unraveled by subtelomeric FISH analysis

In recent years, subtelomeric rearrangements have been identified as a major cause of multiple congenital anomalies/mental retardation syndromes. Currently, more than 2,500 individuals with mental retardation have been tested and reported in whom subtelomeric rearrangements were detected ranging from 2% to 29%. Therefore, subtelomeric FISH analysis is indicated as a second tier test after high-resolution G-banding analysis in patients with otherwise unexplained developmental delay/mental retardation and/or multiple congenital anomalies. We describe a patient and her three maternal female cousins, all showing an undiagnosed MCA/MR syndrome, associated with the same complex subtelomeric rearrangement. Subtelomeric FISH testing performed between 3(1/2) and 18 years after the initial karyotype showed, in all four patients, distal trisomy 3q and distal monosomy 10q as follows: 46,XX,ish der(10)t(3;10)(q29;q26.3)mat(D10S2488+,D10S2490-, D3S1272+,D10Z1+). Parental subtelomeric FISH analysis showed that the proposita's mother and three of four brothers and one of two sisters had a cryptic balanced 3:10 telomere translocation. The three brothers with the balanced translocation were father to one each of the three proband's cousins. All four affected girls showed a similar phenotype with pre/postnatal growth retardation, microcephaly, severe developmental delay/mental retardation, poor/absent speech, and a distinct pattern of malformation. On examination there were coarsening of facial features with low fronto-temporal hairline; thick eyebrows; bilateral epicanthal folds; hypertelorism; prominent nose with squared nasal root and narrow alar base; low-set posteriorly rotated large ears with a prominent anthelix; high arched palate; prominent chin; hands/feet brachydactyly; bilateral squint; hypotonia; and muscle hypotrophy. A slow overall improvement was seen in all patients over time. To our knowledge, this complex subtelomeric rearrangement in our patients has never been reported so far. Monosomy 10q has recently been described either isolated or as part of a complex rearrangement involving telomeres other than the 3q. Trisomy 3q29 has not yet been reported, but our patients resembled cases with 3q26 trisomy suggesting that the critical region of duplication for this phenotype is in 3q29.     

Interstitial deletion in 3q in a patient with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and microcephaly, mild mental retardation and growth delay: clinical report and review of the literature

We present a boy with blepharophimosis, ptosis, epicanthus inversus, microcephaly, mild mental retardation, and growth delay. Chromosomal analysis revealed a male karyotype with an interstitial deletion in the long arm of chromosome 3. DNA-analysis showed that the deletion is of maternal origin and encompasses the region between markers D3S1535 and D3S1593. The deletion contains not only the FOXL2 gene, but also the gene encoding ataxia-telangiectasia and Rad3-related protein (ATR). Mutations in FOXL2 have been shown to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). ATR has been identified as a candidate gene for Seckel syndrome, an autosomal recessive syndrome that comprises growth retardation, microcephaly, and mental retardation. We hypothesize that our patient has a contiguous gene syndrome and that the non-BPES-associated abnormalities (microcephaly, mild mental retardation, and growth delay) are the result of the deletion of the maternal ATR gene. However, it has not yet been excluded that haploinsufficiency of some other gene in this region plays a role.     

De novo dup(X)(q22.3q26) in a girl with evidence that functional disomy of X material is the cause of her abnormal phenotype

The relationship between phenotype and Xq duplications in females remains unclear. Some females are normal; some have short stature; and others have features such as microcephaly, developmental delay/mental retardation, body asymmetries, and gonadal dysgenesis. There are several hypotheses proposed in the literature to explain this variability. We describe a 7-year-old girl with dup(X)(q22.3q26). The pregnancy was complicated by intrauterine growth retardation, and she was distressed during labor. During her first year she fed poorly and failed to thrive. She has microcephaly, her height is at the 10th centile, and her hands and feet are strikingly small. She is hypotonic and delayed. Asymmetries of muscle power, and of leg and foot length have been noted. She has mild unilateral ptosis. She has some features of Turner syndrome, and multiple other minor anomalies such as flat labia. These are features common to other described females. This report describes our patient in detail and compares her phenotype to those of the other females with Xq duplications, displays our laboratory investigations, and discusses ideas regarding the pathogenesis of phenotype. The duplicated X is of paternal origin. It is inactivated in all cells; however, the distal duplicated portion appears to be active. We suggest that functional disomy of the duplicated X material, due to local escape from inactivation, may be responsible for the phenotype in the affected females.     

The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype

Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized by mental retardation and congenital microcephaly with a head circumference at least 4 SD below age and sex means, in the absence of other significant malformations or neurological deficits. Truncating alterations in the MCPH1 gene have previously been shown to exhibit a distinct cellular phenotype, with a high proportion of prophase-like cells (>10%) due to premature chromosome condensation in early G2- and delayed decondensation in early G1-phase of the cell cycle. We report here the first patient with a homozygous substitution of a highly conserved threonine residue by an arginine (c.80C>G, Thr27Arg) localized in the N-terminal BRCT domain of MCPH1. The cellular and clinical phenotype of this patient is much less pronounced than that of previously described patients with truncating alterations in the MCPH1 gene. Firstly, the fraction of prophase-like cells accounts for just 3-4% of the cell population. Secondly, clinically, he has only a very mild mental retardation with predominantly delayed motor skills but normal verbal IQ attainment. Additionally, head circumference was less severely affected, being -2.4 SD at birth and -3 SD at the age of six years. This justifies reconsideration and widening of the clinical phenotype definition of MCPH1.     

De novo X;Y translocation associated with imperforate anus and retinal pigmentary abnormalities

Cytogenetically detectable translocations of Y chromosome material onto the distal short arm of an X chromosome are rare and result in a variable and poorly defined phenotype of short stature and short limbs occasionally associated with mental retardation. We report on a patient with a de novo 46,X,t(X;Y)(p22;q11) chromosome constitution who has additional features not previously described with this chromosome abnormality, including abnormal retinal pigmentation, imperforate anus, and hydronephrosis. Our patient extends the phenotype associated with X;Y translocations, raising new considerations for the clinical management and genetic counseling of such patients and their families.