Short stature in a mother and daughter caused by familial der(X)t(X;X)(p22.1-3;q26)

Deletions of the terminal Xp regions, including the short-stature homeobox (SHOX) gene, were described in families with hereditary Turner syndrome and Léri-Weill syndrome. We report on a 10-2/12-year-old girl and her 37-year-old mother with short stature and no other phenotypic symptoms. In the daugther, additional chromosome material was detected in the pseudoautosomal region of one X chromosome (46,X,add(Xp.22.3)) by chromosome banding analysis. The elongation of the X chromosome consisted of Giemsa dark and bright bands with a length one-fifth of the size of Xp. The karyotype of the mother demonstrated chromosome mosaicism with three cell lines (46,X,add(X)(p22.3) [89]; 45,X [8]; and 47,X,add(X)(p22.3), add(X)(p22.3) [2]). In both daughter and mother, fluorescence in situ hybridization (FISH), together with data from G banding, identified the breakpoints in Xp22.1-3 and Xq26, resulting in a partial trisomy of the terminal region of Xq (Xq26-qter) and a monosomy of the pseudoautosomal region (Xp22.3) with the SHOX gene and the proximal region Xp22.1-3, including the steroidsulfatase gene (STS) and the Kallmann syndrome region. The derivative X chromosome was defined as ish.der(X)t(X;X)(p22.1-3;q26)(yWXD2540-, F20cos-, STS-, 60C10-, 959D10-, 2771+, cos9++). In daughter and mother, the monosomy of region Xp22.1-3 is compatible with fertility and does not cause any other somatic stigmata of the Turner syndrome or Léri-Weill syndrome, except for short stature due to monosomy of the SHOX gene.     

Mother and daughter with 45,X/46,X,r(X)(p22.3q28) and mental retardation: Analysis of the x‐inactivation patterns

We report on a mother and daughter both with a 45,X/46,X,r(X)(p22.3q28) karyotype and mental retardation. Fluorescence in situ hybridization (FISH) and microsatellite analyses for 14 loci/region at Xp22.3 and seven loci/region at Xq28 indicated that the ring X chromosome was missing a roughly 12‐Mb region from Xp22.3 with the breakpoint between DXS85 and DXS9972, and another region of less than 100 kb from Xq28 with the breakpoint distal to the region defined by the FISH probe c8.2/1. X‐inactivation analysis, using the methylation status of the AR gene (exon 1) as an indicator, showed that the normal and ring X chromosomes in the X,r(X)(p22.3q28) cell lineage were randomly inactivated. The Xp22.3 deleted region partially overlaps with the regional intervals of MRX19, MRX21, MRX24, MRX37, MRX43, and MRX49 associated with heterozygote manifestation. Therefore, it is likely that one or more of these MRX genes, subject to X‐inactivation, are lost from the ring X chromosome, and that reduced expression of the MRX gene(s) caused by random X‐inactivation has resulted in mental retardation in the mother and daughter. Am. J. Med. Genet. 91:267–272, 2000. © 2000 Wiley‐Liss, Inc.     

A familial Xp+ chromosome, dup (Xq26.3-->qter).

A maternally transmitted Xp+ chromosome was associated with an abnormal phenotype, including developmental delay and short stature, in two male cousins and their 12 year old aunt. The respective mothers were not mentally impaired but had short stature. The G banding pattern identified the extra chromosome segment as a repeat of Xq26.3-->qter attached to an apparently intact Xp22.3 sub-band, so the Xp+ chromosome may be described as rea(X)(Xqter-->p22.3::Xq26.3-->Xqter). The rearranged chromosome was late replicating in 97 to 100% of the metaphases in the mothers but it was early replicating in 43% of the lymphocytes in the mentally defective female (n = 100 cells/subject). Fluorescence in situ hybridisation using X and Y chromosome paints, as well as cosmids A and 1A1 specific for loci within Xq28, confirmed both the identity of the extra segment and the entirety of the Xp pseudoautosomal region. Therefore, the phenotypic consequences in this family can be related to the Xq26.3-->qter functional disomy allowing for the effects of X inactivation in the female carriers.     

Brachytelephalangic dwarfism due to the loss of ARSE and SHOX genes resulting from an X;Y translocation

Here we report an 8-year-old male patient who had mesomelic shortening of forearms and legs, brachytelephalangia and ichthyotic skin lesions. Chromosomal analysis showed an X;Y translocation involving the short arm of the X chromosome (Xp). Fluorescence in situ hybridization (FISH) and molecular studies localized the breakpoints on Xp22.3 in the immediate vicinity of the KAL gene demonstrating deletions of steroid sulfatase (STS), arylsulfatase E (ARSE), and short stature homeo box (SHOX) genes. It was suspected that the patient was suffering from chondrodysplasia punctata because of a loss of the arylsulfatase E (ARSE) gene. However, no stippled epiphyses were to be seen in the neonatal radiograph. Interestingly, this patient is the first case with a proven loss of the ARSE gene without chondrodysplasia punctata, assuming that chondrodysplasia punctata is not an obligatory sign of ARSE gene loss. Brachytelephalangia was the only result of ARSE gene deletion in this case. The patient's mother also had dwarfism and showed Madelung deformity of the forearms. She was detected as a carrier of the same aberrant X chromosome. The male patient did not show Madelung deformity, demonstrating that Lerri-Weill syndrome phenotype may be still incomplete in children with SHOX gene deletion. The wide clinical spectrum in the male and the Leri-Weill phenotype in his mother are the results of both a deletion involving several sulfatase genes in Xp22.3 and the SHOX gene located in the pseudoautosomal region. Nevertheless, there is no explanation for the absence of chondrodysplasia punctata despite the total loss of the ARSE gene. Further studies are necessary to investigate genotype/phenotype correlation in cases with translocations or microdeletions on Xp22.3, including the ARSE and the SHOX gene loci.     

Isochromosome consisting of terminal short arm and proximal long arm X in a girl with short stature

A 16-year-old girl with short stature, short neck, shield chest, and cubitus valgus was studied. FISH analyses of her structurally altered X chromosome showed a der(X)- (wcpX+,TelXp/Yp++,SHOX++,STS++,KAL-, 37A12-,DXZ1+,XIST++,97L7++,300O13-,404F- 18-,417G15-,404F18-,140A-,TelXq/Yq-). These results, together with the high-resolution banding analysis, indicated her karyotype to be 46,X,der(X)(Xpter-->Xp22.3::Xq22.3--> cen-->Xq22.3::Xp22.3-->Xpter). The der(X) was an isochromosome, consisting of duplicated terminal short arms and duplicated proximal long arms. This in turn suggested that the chromosome was formed through pericentric inversion of an X chromosome, followed by isochromosome formation through sister chromatid exchange at Xp, close to the centromere. Replication R-banding analysis showed that the abnormal X chromosome was late replicating. Analysis of digestion patterns with a methylation-sensitive restriction endonuclease of the phosphoglycerate kinase 1 gene, located in Xq13.3, indicated that its inactivation patterns were completely skewed.     

Brachymesomelic dysplasia with Peters anomaly of the eye results from disruptions of the X chromosome near the SHOX and SOX3 genes

We report on a mother and son affected with an unusual skeletal dysplasia and anterior segment eye abnormalities. Their skeletal phenotype overlaps with the SHOX-related skeletal dysplasias and is intermediate between Leri-Weill dyschondrosteosis (LWD) and Langer Mesomelic dysplasia (LMD). The mother has bilateral Peters anomaly of the eye and was reported as having a new syndrome; the son had severe bilateral sclerocornea. Chromosome analysis showed that the mother has a pericentric inversion of the X chromosome [46,X,inv(X)(p22.3q27)] and the son, a resultant recombinant X chromosome [46,Y,rec(X)dup(Xq)inv(X)(p22.3q27)]. The observed skeletal and ophthalmologic abnormalities in both patients were similar in severity. The additional features of developmental delay, growth retardation, agenesis of the corpus callosum, cryptorchidism and hypoplastic scrotum in the son are consistent with Xq28 duplication. Analysis of the son's recombinant X chromosome showed that the Xp22.33 breakpoint lies 30-68 kb 5' of the SHOX gene. This finding suggests that the skeletal dysplasia in both mother and son is allelic with LWD and LMD and results from a novel misexpression of SHOX. Analysis of the Xq27.1 breakpoint localized it to a 90 kb interval 3' of the SOX3 gene, supporting a novel role of SOX3 misexpression in the development of Peters anomaly of the eye.     

FISH analysis for apparently simple terminal deletions of the X chromosome: Identification of hidden structural abnormalities

We report on fluorescence in situ hybridization (FISH) analysis in 30 mosaic or nonmosaic females diagnosed as having apparently simple terminal X deletions by standard G‐banding analysis. FISH studies for DXZ1, the Xp and Xq telomere regions, and the whole X chromosome painting were carried out for the 30 females, indicating rearranged X chromosomes with signal patterns discordant with terminal deletions in 6 cases: one dic(X)(DXZ1++) chromosome, two der(X)(qtel++) chromosomes, one Xq? (qtel+) chromosome, and two der(X)(ptel++) chromosomes. Additional FISH studies were performed for the 6 cases using probes defining 12 loci on the X chromosome, showing large Xp deletion and small Xp duplication in the dic(X)(DXZ1++) chromosome, partial Xp deletions and partial Xq duplications in the two der(X)(qtel++) chromosomes, an interstitial Xq deletion in the Xq? (qtel+) chromosome, and partial Xq deletions and partial Xp duplications in the two der(X)(ptel++) chromosomes. Clinical assessment of the 6 cases revealed tall and normal stature in the two mosaic cases with the der(X)(ptel++) chromosomes that were shown to be associated with SHOX duplication. The results suggest that unusual X chromosome rearrangements are often misinterpreted as simple terminal X deletions, and that FISH analysis is useful for precise structural determination and better genotype‐phenotype correlation of the X chromosome aberrations. © 2001 Wiley‐Liss, Inc.     

Mother and daughter with 45,X/46,X,r(X)(p22.3q28) and mental retardation: analysis of the X-inactivation patterns

We report on a mother and daughter both with a 45,X/46,X,r(X)(p22. 3q28) karyotype and mental retardation. Fluorescence in situ hybridization (FISH) and microsatellite analyses for 14 loci/region at Xp22.3 and seven loci/region at Xq28 indicated that the ring X chromosome was missing a roughly 12-Mb region from Xp22.3 with the breakpoint between DXS85 and DXS9972, and another region of less than 100 kb from Xq28 with the breakpoint distal to the region defined by the FISH probe c8.2/1. X-inactivation analysis, using the methylation status of the AR gene (exon 1) as an indicator, showed that the normal and ring X chromosomes in the X,r(X)(p22.3q28) cell lineage were randomly inactivated. The Xp22.3 deleted region partially overlaps with the regional intervals of MRX19, MRX21, MRX24, MRX37, MRX43, and MRX49 associated with heterozygote manifestation. Therefore, it is likely that one or more of these MRX genes, subject to X-inactivation, are lost from the ring X chromosome, and that reduced expression of the MRX gene(s) caused by random X-inactivation has resulted in mental retardation in the mother and daughter.     

A man who inherited his SRY gene and Leri‐Weill dyschondrosteosis from his mother and neurofibromatosis type 1 from his father

We report on a man with neurofibromatosis type 1 (NF1) and Leri‐Weill dyschondrosteosis (LWD). His father had NF1. His mother had LWD plus additional findings of Turner syndrome (TS): high arched palate, bicuspid aortic valve, aortic stenosis, and premature ovarian failure. The proband's karyotype was 46,X,dic(X;Y)(p22.3;p11.32). Despite having almost the same genetic constitution as 47,XXY Klinefelter syndrome, he was normally virilized, although slight elevation of serum gonadotropins indicated gonadal dysfunction. His mother's karyotype was mosaic 45,X[17 cells]/46,X,dic(X;Y)(p22.3;p11.32)[3 cells].ish dic(X;Y)(DXZ1 + ,DYZ1 + ). The dic(X;Y) chromosome was also positive for Y markers PABY, SRY, and DYZ5, but negative for SHOX. The dic(X;Y) chromosome was also positive for X markers DXZ1 and a sequence < 300 kb from PABX, suggesting that the deletion encompassed only pseudoautosomal sequences. Replication studies indicated that the normal X and the dic(X;Y) were randomly inactivated in the proband's lymphocytes. LWD in the proband and his mother was explained by SHOX haploinsufficiency. The mother's female phenotype was most likely due to 45,X mosaicism. This family segregating Mendelian and chromosomal disorders illustrates extreme sex chromosome variation compatible with normal male and female sexual differentiation. The case also highlights the importance of karyotyping for differentiating LWD and TS, especially in patients with findings such as premature ovarian failure or aortic abnormalities not associated with isolated SHOX haploinsufficiency. © 2001 Wiley‐Liss, Inc.     

Chromosomal localisation of a pseudoautosomal growth gene(s).

Although recent molecular studies in patients with sex chromosome aberrations are consistent with a growth gene(s) being present in the pseudoautosomal region (PAR), the precise location has not been determined. In this report, we describe a Japanese boy and his mother with an interstitial deletion in Xp22.3 and review the correlation between genotype and stature in six cases of partial monosomy of the PAR. The results indicate that the region from DXYS20 to DXYS15 is the critical region for the putative growth gene(s).     

Xp pseudoautosomal gene haploinsufficiency and linear growth deficiency in three girls with chromosome Xp22;Yq11 translocation.

Colony stimulating factor-2 receptor alpha (CSF2RA) and interleukin-3 receptor alpha (IL3RA), two genes from the chromosome Xp and Yp pseudoautosomal region (PAR), have been suggested as candidate genes for short stature in Turner syndrome. We report three girls with X;Y translocation (46,X,der(X)t(X;Y)(p22;q11) initially detected by amniocentesis. The terminal portion of the X chromosome distal to the translocation breakpoint at Xp22 was deleted on the derivative X chromosome in all three patients. Each had normal stature at birth, with greater than expected deceleration of growth velocity by the second year. Using fluorescence in situ hybridisation (FISH), we have shown deletion of the CSF2RA and IL3RA loci on the derivative X chromosomes of all three patients. The role of CSF2RA and IL3RA haploinsufficiency in linear growth and final adult stature is discussed. Additional studies, particularly of molecular deletions within the PAR, are needed to improve our understanding of the role of these and other PAR loci in the genetic control of adult stature.     

Léri-Weill syndrome as part of a contiguous gene syndrome at Xp22.3

We report on a mother and her 5-year old son, both with a terminal deletion of the short arm of the X chromosome. By molecular genetic analysis the breakpoint was located distal to steroid sulfatase gene. The boy manifested, due to nullisomy of this region, short stature (SHOX), chondrodysplasia punctata (ARSE), and mental retardation (putative mental retardation gene MRX 49). Short stature is present in mother and son, but both also had bilateral Madelung deformity, a key finding in the Léri-Weill syndrome.We discuss the phenotype in relationship to hitherto published cases with chromosomal aberrations and contiguous gene syndromes of Xp22.3.     

Léri-Weill syndrome as part of a contiguous gene syndrome at Xp22.3

We report on a mother and her 5-year old son, both with a terminal deletion of the short arm of the X chromosome. By molecular genetic analysis the breakpoint was located distal to steroid sulfatase gene. The boy manifested, due to nullisomy of this region, short stature (SHOX), chondrodysplasia punctata (ARSE), and mental retardation (putative mental retardation gene MRX 49). Short stature is present in mother and son, but both also had bilateral Madelung deformity, a key finding in the Léri-Weill syndrome.We discuss the phenotype in relationship to hitherto published cases with chromosomal aberrations and contiguous gene syndromes of Xp22.3. Am. J. Med. Genet. 83:367–371, 1999. © 1999 Wiley-Liss, Inc.     

Schizophrenia susceptibility gene locus at Xp22.3

Multiple genetic loci have been implicated in the search for schizophrenia susceptibility genes, none having been proven as causal. Genetic heterogeneity is probable in the polygenic etiology of schizophrenia. We report on two unrelated Caucasian women with paranoid schizophrenia (meeting Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria) who have an Xp22.3 overlapping deletion characterized by fluorescence in situ hybridization (FISH). Patient 1 was previously reported by us (Wyandt HE, Bugeau-Michaud L, Skare JC, Milunsky A. Partial duplication of Xp: a case report and review of previously reported cases. Amer J Med Genet 1991: 40: 280-283) to have a de novo partial duplication of Xp. At that time, she was a 24-year-old woman with short stature, irregular menses, other abnormalities suggestive of Turner syndrome, and paranoid schizophrenia. Recently, FISH analysis demonstrated that she has an inverted duplication (X)(p22.1p11.2) and a microscopic deletion (X)(p22.2p22.3) between DXS1233 and DXS7108 spanning approximately 16-18 cM. Patient 2 is a 14-year-old girl with short stature, learning disabilities, and paranoid schizophrenia. High-resolution chromosome analysis revealed a de novo deletion involving Xp22. FISH analysis showed that the deletion (X)(p22.2p22.3) spanned 10-12 cM between AFMB290XG5 and DXS1060. Given that deletions of Xp22 are not common events, the occurrence of two unrelated schizophrenia patients with an overlapping deletion of this region would be extraordinarily rare. Hence, the deletion within Xp22.3 almost certainly contains a gene involved in the pathogenesis of paranoid schizophrenia.     

A familial contiguous gene deletion syndrome at Xp22.3 characterized by severe learning disabilities and ADHD

We describe a mother and two sons with a 6-Mb terminal deletion of the short arm of the X chromosome. The breakpoint was localized to a region between DXS6837 and sAJ243947 in Xp22.33. The two boys were shown to be deleted for the SHOX and ARSE genes on their X chromosome. Both sons were short in stature and showed mild to moderate skeletal abnormalities. The most significant findings in the younger son were severe learning disabilities and attention deficit hyperactivity disorder (ADHD). The older son tested in the mild mental retardation range and was also affected by ADHD. The VCX-A gene, implicated recently in X-linked nonspecific mental retardation, was found to be present in both boys. The mother's stature was greater than one standard deviation below her target height and she had only subtle radiographic evidence of Madelung deformity. Our findings indicate that loss of the Xp22.3 region is not always associated with the classic presentations of Léri-Weill syndrome, or chondrodysplasia punctata, and that one or more genes involved in learning and attention may reside in Xp22.3.     

Hypospadias in ring X syndrome

Ring X is a chromosomal anomaly mainly seen in females with turner syndrome and usually present in mosaic form with 45,X cells (45,X/46,X,r(X)) because of their mitotic instability. In males it is an extremely rare finding because large nullisomy for X chromosome material is likely not compatible with survival. Only two cases of male with ring chromosome X were previously reported. We report here a four-year-old male with ring chromosome X characterized using Karyotype, FISH and array CGH and presenting short stature, microcephaly and hypospadias. Molecular investigations showed 923 Kb terminal deletion on the pseudoautosomal region 1 (PAR1) including SHOX gene followed by a duplication of 2.4 Mb. The absence of functional nullisomy because of a second copy of deleted genes was present in chromosome Y PAR1 region may explain the compatibility with survival in our case of male with ring X. Short stature common with the two previously reported cases is likely related to SHOX gene deletion but also to the effect of “ring syndrome”. However, hypospadias was not reported in the previous cases and can be due to the associated duplication outside PAR1 region including in particular PRKX gene coding for a protein involved in urogenital system morphogenesis.     

Characterisation of an inverted X chromosome (p11.2q21.3) associated with mental retardation using FISH.

We report on a patient with a pericentric inversion of the X chromosome, 46,Y,inv(X) (p11.2q21.3), who was referred for cytogenetic analysis because of mild mental retardation, short stature, prepubescent macro-orchidism, and submucous cleft palate. The same chromosomal abnormality was found in the proband's mother. The inverted X chromosome was late replicating in all the mother's lymphocytes studied, indicative of a likely unbalanced inversion. We show, by fluorescence in situ hybridisation (FISH) using a panel of ordered yeast artificial chromosome (YAC) clones, that the Xp breakpoint is localised in Xp11.23 between DXS146 and DXS255 and that the Xq breakpoint is assigned to the X-Y homologous region in Xq21.3. YACs crossing the Xp and Xq breakpoints have been identified. One of these two breakpoints could be linked to the mental retardation in this patient as many non-specific mental retardation (MRX) loci have previously been located in the pericentromeric region of the X chromosome. Morever, the elucidation at the molecular level of this rearrangement will also indicate if cleft palate or prepubescent macro-orchidism, or both, in this boy are related to one of the two X breakpoints.     

Structural analysis of a rare rearranged Y chromosome and its bearing on genotype–phenotype correlation

We report on a 9‐year‐old boy with a rare rearranged Y chromosome and borderline short stature (−2.0 SD). Standard metaphase chromosome analysis indicated a 46,X,i(Y)(q10) karyotype, but high resolution G‐banding showed an asymmetric band pattern for the rearranged Y chromosome. FISH and DNA studies for a total of 15 different Y chromosomal loci or regions showed that the rearranged Y chromosome was accompanied by: 1) a partial deletion of the short arm pseudoautosomal region (PAR1) involving SHOX, with the breakpoint distal to DXYS85; and 2) a partial duplication of Yq, with the breakpoint proximal to DAZ. The karyotype was determined as 46,X,?i(Y)(q10).ish der(Y)(Yqter→ Yp11.3::Yq11.2→Yqter)(DAZ++,DYZ3+,SRY+, SHOX−). The X chromosome and the autosomes were normal. The results suggest that haploinsufficiency of SHOX is primarily responsible for the borderline short stature, and that the deletion of the PAR1 may result in spermatogenic failure due to defective X‐Y pairing and recombination in the PAR1. Am. J. Med. Genet. 92:256–259, 2000. © 2000 Wiley‐Liss, Inc.     

Contiguous gene syndrome due to a maternally inherited 8.41 Mb distal deletion of chromosome band Xp22.3 in a boy with short stature, ichthyosis, epilepsy, mental retardation, cerebral cortical heterotopias and Dandy-Walker malformation

Microdeletions of Xp22.3 are associated with contiguous gene syndromes, the extent and nature of which depend on the genes encompassed by the deletion. Common symptoms include ichthyosis, mental retardation and hypogonadism. We report on a boy with short stature, ichthyosis, severe mental retardation, cortical heterotopias and Dandy-Walker malformation. The latter two abnormalities have so far not been reported in terminal Xp deletions. MLPA showed deletion of SHOX and subsequent analysis using FISH and SNP-arrays revealed that the patient had an 8.41 Mb distal deletion of chromosome region Xp22.31 --> Xpter. This interval contains several genes whose deletion can partly explain our patient's phenotype. His cortical heterotopias and DWM suggest that a gene involved in brain development may be in the deleted interval, but we found no immediately obvious candidates. Interestingly, further analysis of the family revealed that the patient had inherited his deletion from his mother, who has a mos 46,X,del(X)(p22)/45,X/46, XX karyotype.