First known microdeletion within the Wolf‐Hirschhorn syndrome critical region refines genotype–phenotype correlation

Deletions within HSA band 4p16.3 cause Wolf‐Hirschhorn syndrome (WHS), which comprises mental retardation and developmental defects. A WHS critical region (WHSCR) of approximately 165 kb has been defined on the basis of 2 atypical interstitial deletions; however, genotype–phenotype correlation remains controversial, due to the large size of deletion usually involving several megabases. We report on the first known patient with a small de novo interstitial deletion restricted to the WHSCR who presented with a partial WHS phenotype consisting only of low body weight for height, speech delay, and minor facial anomalies; shortness of stature, microcephaly, seizures and mental retardation were absent. The deletion was initially demonstrated by FISH analysis, and breakpoints were narrowed with a “mini‐FISH” technique using 3–5 kb amplicons. A breakpoint‐spanning PCR assay defined the distal breakpoint as disrupting the WHSC1 gene within intron 5, exactly after an AluJb repeat. The proximal breakpoint was not found to be associated with a repeated sequence or a known gene. The deletion encompasses 191.5 kb and includes WHSC2, but not LETM1. Thus, manifestations attributable to this deletion are reduced weight for height, minor facial anomalies, ADHD and some learning and fine motor deficiencies, while seizures may be associated with deletions of LETM1. © 2001 Wiley‐Liss, Inc.     

Deletions involving genes WHSC1 and LETM1 may be necessary,but are not sufficient to cause Wolf–Hirschhorn Syndrome

Wolf–Hirschhorn syndrome (WHS) is a complex genetic disorder caused by the loss of genomic material from the short arm of chromosome 4. Genotype–phenotype correlation studies indicated that the loss of genes within 4p16.3 is necessary for expression of the core features of the phenotype. Within this region, haploinsufficiency of the genes WHSC1 and LETM1 is thought to be a major contributor to the pathogenesis of WHS. We present clinical findings for three patients with relatively small (<400 kb) de novo interstitial deletions that overlap WHSC1 and LETM1. 3D facial analysis was performed for two of these patients. Based on our findings, we propose that hemizygosity of WHSC1 and LETM1 is associated with a clinical phenotype characterized by growth deficiency, feeding difficulties, and motor and speech delays. The deletion of additional genes nearby WHSC1 and LETM1 does not result in a marked increase in the severity of clinical features, arguing against their haploinsufficiency. The absence of seizures and typical WHS craniofacial findings in our cohort suggest that deletion of distinct or additional 4p16.3 genes is necessary for expression of these features. Altogether, these results show that although loss-of-function for WHSC1 and/or LETM1 contributes to some of the features of WHS, deletion of additional genes is required for the full expression of the phenotype, providing further support that WHS is a contiguous gene deletion disorder.     

Mouse models for the Wolf-Hirschhorn deletion syndrome

Wolf-Hirschhorn syndrome (WHS) is a deletion syndrome caused by segmental haploidy of chromosome 4p16.3. Its hallmark features include a 'Greek warrior helmet' facial appearance, mental retardation, various midline defects and seizures. The WHS critical region (WHSCR) lies between the Huntington's disease gene, HD, and FGFR3. In mice, the homologs of these genes map to chromosome 5 in a region of conserved synteny with human 4p16.3. To derive mouse models of WHS and map genes responsible for subphenotypes of the syndrome, five mouse lines bearing radiation-induced deletions spanning the WHSCR syntenic region were generated and characterized. Similar to WHS patients, these animals were growth-retarded, were susceptible to seizures and showed midline (palate closure, tail kinks), craniofacial and ocular anomalies (colobomas, corneal opacities). Other phenotypes included cerebellar hypoplasia and a shortened cerebral cortex. Expression of WHS-like traits was variable and influenced by strain background and deletion size. These mice represent the first animal models for WHS. This collection of nested chromosomal deletions will be useful for mapping and identifying loci responsible for the various subphenotypes of WHS, and provides a paradigm for the dissection of other deletion syndromes using the mouse.     

High resolution characterization of an interstitial deletion of less than 1.9 Mb at 4p16.3 associated with Wolf-Hirschhorn syndrome

Wolf-Hirschhorn syndrome (WHS) caused by 4p16.3 deletions comprises growth and mental retardation, distinct facial appearance and seizures. This study characterized a subtle interstitial deletion of 4p16.3 in a girl with mild retardation and possessing facial traits characteristic of WHS. The patient had generalized seizures in conjunction with fever at 3 and 5 years of age. Fluorescence in situ hybridization (FISH) with a series of markers in the 4p16.3 region showed that the interstitial deletion in this patient was between the probes D4S96 and D4S182, enabling the size of the deletion to be estimated as less than 1.9 Mb. This is the smallest interstitial deletion of 4p16.3 which has been reported. The patient contributes to a refinement of the phenotypic map of the WHS region in 4p16.3. The critical region for the characteristic facial changes of WHS, failure to thrive and developmental delay is now localized to a region of less than 700 kb. The mental retardation of this patient was mild suggesting that small interstitial deletion may have less severe phenotypic consequences. Am. J. Med. Genet. 71:453–457, 1997. © 1997 Wiley-Liss, Inc.     

Duplication of the Wolf-Hirschhorn syndrome critical region causes neurodevelopmental delay

Wolf-Hirschhorn Syndrome (WHS) is caused by deletions on chromosome 4p and is clinically well defined. Genotype-phenotype correlations of patients with WHS point to a critical locus to be responsible for the main characteristics of this disorder. Submicroscopic duplications of this region, however, are not known. Here we report a patient with an interstitial 560 kb duplication overlapping this critical locus. The present case shows that not only deletions but also duplications of the Wolf-Hirshhorn critical region cause mental retardation and multiple congenital anomalies. Interestingly, the duplication phenotype overlaps partially with the deletion phenotype. However, his facial phenotype differs from the typical WHS gestalt.     

A microdeletion proximal of the critical deletion region is associated with mild Wolf-Hirschhorn syndrome

It is generally accepted that the facial phenotype of Wolf-Hirschhorn syndrome is caused by deletions of either Wolf-Hirschhorn critical regions 1 or 2 (WHSCR 1-2). Here, we identify a 432?kb deletion located 600?kb proximal to both WHSCR1-2 in a patient with a WHS facial phenotype. Seven genes are underlying this deletion region including FAM193a, ADD1, NOP14, GRK4, MFSD10, SH3BP2, TNIP2. The clinical diagnosis of WHS facial phenotype was confirmed by 3D facial analysis using dense surface modeling. Our results suggest that the WHSCR1-2 flanking sequence contributes directly or indirectly to the severity of WHS. Sequencing the Wolf-Hirschhorn syndrome candidate 1 and 2 genes did not reveal any mutations. Long range position effects of the deletion that could influence gene expression within the WHSCR were excluded in EBV cell lines derived from patient lymphoblasts. We hypothesize that either (1) this locus harbors regulatory sequences which affect gene expression in the WHSCR1-2 in a defined temporal and spatial developmental window or (2) that this locus is additive to deletions of WHSCR1-2 increasing the phenotypic expression.     

Interstitial deletion of 5q33.3q35.1 in a girl with mild mental retardation

Constitutional interstitial deletions of 5q are uncommon. The corresponding phenotype is not well defined. But severe mental retardation seems to be a consistent manifestation. We describe a 4-year-old girl with a de novo deletion of 5q33.3q35.1 presenting only with mild psychomotor delay, minor facial anomalies, and seizures.     

Preliminary phenotypic map of chromosome 4p16 based on 4p deletions

We have collected and analyzed clinical information from 11 patients with chromosome 4p deletions or rearrangements characterized by various molecular techniques. Comparing the extent of these patients' deletions with their respective clinical presentations led to the proposal of a preliminary phenotypic map of chromosome 4p. This map consists of regions which, when deleted, are associated with specific clinical manifestations. Nonspecific changes such as mental and growth retardation are not localized, and probably result from the deletion of more than one gene or region. The region associated with most of the facial traits considered typical in Wolf-Hirschhorn syndrome (WHS) patients coincides with the currently proposed WHS critical region (WHSCR), but some anomalies commonly seen in WHS appear to map outside of the WHSCR. The observation of clinodactyly in 2 patients with nonoverlapping deletions allows assignment of these defects to at least 2 separate regions in 4p16. These initial observations and attempts at genotype/phenotype correlation lay the groundwork for identifying the genetic basis of these malformations, a common objective of gene mapping efforts and chromosome deletion studies. © 1995 Wiley-Liss, Inc.     

Two unique patients with novel microdeletions in 4p16.3 that exclude the WHS critical regions: implications for critical region designation

Wolf-Hirschhorn syndrome (WHS) is characterized by growth delay, developmental delay, hypotonia, seizures, feeding difficulties, and characteristic facial features. Deletion of either of two critical regions (WHSCR and WHSCR-2) within chromosome band 4p16.3 has been proposed as necessary for the minimal clinical manifestations of WHS and controversy remains regarding their designation. We describe two patients with novel terminal microdeletions in 4p16.3 who lack the characteristic facial features but do show some of the more nonspecific manifestations of WHS. The first patient had a ring chromosome 4 with an intact 4q subtelomere and a terminal 4p microdeletion of approximately 1.27-1.46 Mb. This deletion was distal to both proposed critical regions. The second patient had a normal karyotype with a terminal 4p microdeletion of approximately 1.78 Mb. This deletion was distal to WHSCR and the breakpoint was near or within the known distal boundary for WHSCR-2. Both patients showed significant postnatal growth delay, mild developmental delays and feeding difficulties. Their facial features were not typical for WHS. The phenotype of the first patient may have been influenced by the presence of a ring chromosome. Seizures were absent in the first patient whereas the second patient had a complex seizure disorder. Characterization of these patients supports the hypothesis that a gene in WHSCR-2, LETM1, plays a direct role in seizure development, and demonstrates that components of the WHS phenotype can be seen with deletions distal to the known boundaries of the two proposed critical regions. These patients also emphasize the difficulty of mapping clinical manifestations common to many aneusomy syndromes.     

The new Wolf-Hirschhorn syndrome critical region (WHSCR-2): a description of a second case

The Wolf-Hirschhorn syndrome (WHS), is a well known contiguous gene syndrome characterized by microcephaly, hypertelorism, prominent glabella, epicanthal folds, cleft lip or palate, cardiac defects, growth and mental retardation and seizures. The currently accepted WHS critical region (WHSCR) is localized between the loci D4S166 and D4S3327, where a deletion seems to generate all the clinical manifestations of the syndrome. Here we present a patient with a subtelomeric deletion of 4p16.3 showing growth and psychomotor delay with a typical WHS facial appearance and two episodes of seizures in conjunction with fever. The high-resolution G-banded karyotype was normal. Fluorescence in situ hybridization (FISH) with a set of cosmids from 4p16.3, showed that the deletion in this patient was from the D4S3327 to the telomere, enabling the size of the deletion to be estimated as 1.9 Mb, excluding the accepted WHSCR deletion. This patient supports the recent proposal by Zollino et al. [2003] that the critical region for WHS is located distally to the WHSCR between the loci D4S3327 and D4S98-D4S16, and it is called "WHSCR-2" [Zollino et al., 2003].     

On the nosology and pathogenesis of Wolf-Hirschhorn syndrome: genotype-phenotype correlation analysis of 80 patients and literature review

Based on genotype-phenotype correlation analysis of 80 Wolf-Hirschhorn syndrome (WHS) patients, as well as on review of relevant literature, we add further insights to the following aspects of WHS: (1) clinical delineation and phenotypic categories; (2) characterization of the basic genomic defect, mechanisms of origin and familiarity; (3) identification of prognostic factors for mental retardation; (4) chromosome mapping of the distinctive clinical signs, in an effort to identify pathogenic genes. Clinically, we consider that minimal diagnostic criteria for WHS, defining a "core" phenotype, are typical facial appearance, mental retardation, growth delay and seizures (or EEG anomalies). Three different categories of the WHS phenotype were defined, generally correlating with the extent of the 4p deletion. The first one comprises a small deletion not exceeding 3.5 Mb, that is usually associated with a mild phenotype, lacking major malformations. This category is likely under-diagnosed. The second and by far the more frequent category is identified by large deletions, averaging between 5 and 18 Mb, and causes the widely recognizable WHS phenotype. The third clinical category results from a very large deletion exceeding 22-25 Mb causing a severe phenotype, that can hardly be defined as typical WHS. Genetically, de novo chromosome abnormalities in WHS include pure deletions but also complex rearrangements, mainly unbalanced translocations. With the exception of t(4p;8p), WHS-associated chromosome abnormalities are neither mediated by segmental duplications, nor associated with a parental inversion polymorphism on 4p16.3. Factors involved in prediction of prognosis include the extent of the deletion, the occurrence of complex chromosome anomalies, and the severity of seizures. We found that the core phenotype maps within the terminal 1.9 Mb region of chromosome 4p. Therefore, WHSCR-2 should be considered the critical region for this condition. We also confirmed that the pathogenesis of WHS is multigenic. Specific and independent chromosome regions were characterized for growth delay and seizures, as well as for the additional clinical signs that characterize this condition. With the exception of parental balanced translocations, familial recurrence is uncommon.     

Deletion of a 760 kb region at 4p16 determines the prenatal and postnatal growth retardation characteristic of Wolf-Hirschhorn syndrome

Background

Recently the genotype/phenotype map of Wolf‐Hirschhorn syndrome (WHS) has been refined, using small 4p deletions covering or flanking the critical region in patients showing only some of the WHS malformations. Accordingly, prenatal‐onset growth retardation and failure to thrive have been found to result from haploinsufficiency for a 4p gene located between 0.4 and 1.3 Mb, whereas microcephaly results from haploinsufficiency of at least two different 4p regions, one of 2.2–2.38 Mb and a second one of 1.9–1.28 Mb.

Methods and Results

We defined the deletion size of a ring chromosome (r(4)) in a girl with prenatal onset growth retardation, severe failure to thrive and true microcephaly but without the WHS facial gestalt and mental retardation. A high‐resolution comparative genome hybridisation array revealed a 760 kb 4p terminal deletion.

Conclusions

This case, together with a familial 4p deletion involving the distal 400 kb reported in normal women, may narrow the critical region for short stature on 4p to 360–760 kb. This region is also likely to contain a gene for microcephaly. “In silico” analysis of all genes within the critical region failed to reveal any strikingly suggestive expression pattern; all genes remain candidates for short stature and microcephaly.Attempts are ongoing to better correlate specific symptoms or malformations in patients with 4p deletions to specific genes or, at least, molecularly defined regions. The most recent genotype–phenotype map¹ confirmed that WHSC1 hemizygosity is essential to the development of the Wolf‐Hirschhorn syndrome (WHS) facial gestalt with the typical “Greek helmet” profile whereas the other key features (growth retardation, microcephaly, cleft palate, mental retardation and epilepsy) result from haploinsufficiency of more than one gene in that region. Particularly, the presence of a dose‐sensitive gene at 4p15–p16, involved in linear growth, was suggested several years ago because of the finding of prenatal and postnatal harmonic short stature in most patients with WHS.² Patients with the typical WHS facial gestalt but normal stature and interstitial rather than terminal 4p deletions confirmed the presence on 4p of at least two genes with complete penetrance, one for linear growth and the other, more proximal, for distinctive facial features.We have detected a 760 Kb terminal deletion of the short arm of chromosome 4 due to a ring chromosome in a 34‐month‐old girl examined for growth retardation with microcephaly and normal psychomotor development. Comparison of this case to other critical 4p cases seems to define a 360 kb region containing a gene(s) for which haploinsufficiency correlates with short stature and microcephaly.     

Mild phenotype in two unrelated patients with a partial deletion of 21q22.2-q22.3 defined by FISH and molecular studies

We describe two unrelated patients with cytogenetically visible deletions of 21q22.2-q22.3 and mild phenotypes. Both patients presented minor dysmorphic features including thin marfanoid build, facial asymmetry, downward-slanting palpebral fissures, depressed nasal bridge, small nose with bulbous tip, and mild mental retardation (MR). FISH and molecular studies indicated common deleted areas but different breakpoints. In patient 1, the breakpoint was fine mapped to a 5.2 kb interval between exon 5 and exon 8 of the ETS2 gene. The subtelomeric FISH probe was absent on one homologue 21 indicating a terminal deletion spanning approximately 7.9 Mb in size. In patient 2, the proximal breakpoint was determined to be 300-700 kb distal to ETS2, and the distal breakpoint 2.5-0.3 Mb from the 21q telomere, indicating an interstitial deletion sized approximately 4.7-7.3 Mb. The 21q- syndrome is rare and typically associated with a severe phenotype, but different outcomes depending on the size and location of the deleted area have been reported. Our data show that monosomy 21q of the area distal to the ETS2 gene, representing the terminal 7.9 Mb of 21q, may result in mild phenotypes comprising facial anomalies, thin marfanoid build, and mild MR, with or without signs of holoprosencephaly.     

Mild Wolf-Hirschhorn phenotype and partial GH deficiency in a patient with a 4p terminal deletion

Wolf-Hirschhorn syndrome (WHS) is caused by a variably-sized deletion of chromosome 4 involving band 4p16 whose typical craniofacial features are "Greek warrior helmet appearance" of the nose, microcephaly, and prominent glabella. Almost all patients show mental retardation and pre- and post-natal growth delay. Patient was born at term, after a pregnancy characterized by intra-uterine growth retardation (IUGR). Delivery was uneventful. Developmental delay was evident since the first months of life. At 2 years, he developed generalized tonic-clonic seizures. Because of short stature, low growth velocity and delayed bone age, at 4 years he underwent growth hormone (GH) evaluation. Peak GH after two provocative tests revealed a partial GH deficiency. Clinical observation at 7 years disclosed a distinctive facial appearance, with microcephaly, prominent eyes, and beaked nose. Brain MRI showed left temporal mesial sclerosis. GTG banded karyotype was normal. Because of mental retardation, subtelomeric fluorescence in situ hybridization (FISH) analysis was performed, disclosing a relatively large deletion involving 4p16.2 --> pter (about 4.5 Mb), in the proband, not present in the parents. The smallest deletion detected in a WHS patient thus far includes two candidate genes, WHSC1 and WHSC2. Interestingly, that patient did not show shortness of stature, and that could be due to the haploinsufficiency of other genes localized in the flanking regions. Contribution of GH alterations and possible GH therapy should be further considered in WHS patients.     

Mother to son amplification of a small subtelomeric deletion: a new mechanism of familial recurrence in microdeletion syndromes

A 2.8-Mb 4p16.3 terminal deletion, with proximal breakpoint at locus D4S182, was diagnosed by FISH in a 16-year-old boy who presented with a typical Wolf-Hirschhorn syndrome (WHS) phenotype. The deletion, which was maternally derived, was isolated, and a balanced translocation was ruled out in both parents by FISH with probe 33c6 (locus D4S43) falling within the patient's deletion interval, at a distance of about 2.3 Mb from the telomere. His older brother, who died from pneumonia at the age of 18 years, also presented with clinical signs consistent with WHS, including typical facial appearance and major malformations, but the genetic test was not performed. A smaller 4p deletion, spanning the 1.5 Mb region from locus D4S96 to the telomere was detected in the healthy mother. When critically analyzed, after the FISH results, she was noted to present with partial WHS facial "gestalt," borderline mental delay, a few episodes of seizures as a child, normal weight and head circumference, and height at the lower limit of normal range. This report highlights a previously undescribed mechanism of familial recurrence of a microdeletion syndrome. Potential meiotic amplification is to be considered for different subtelomeric deletions that are currently interpreted as population polymorphisms. At the same time, the present report adds new insights to mapping some peculiar WHS clinical signs, such as seizures and severe growth delay.     

A novel 4p16.3 microduplication distal to WHSC1 and WHSC2 characterized by oligonucleotide array with new phenotypic features

Larger imbalances on chromosome 4p in the form of deletions associated with Wolf-Hirschhorn syndrome (WHS) and duplications of chromosome 4p have a defined clinical phenotype. The critical region for both these clinical disorders has been narrowed based on the genotype-phenotype correlations. However, cryptic rearrangements in this region have been reported infrequently. We report on a male patient with a microduplication of chromosome 4p, who presents with findings of macrocephaly, irregular iris pigmentation-heterochromia, and preserved linear growth in addition to overlapping features of trisomy 4p such as seizures, delayed psychomotor development, and dysmorphic features including prominent glabella, low-set ears, and short neck. Using a high-density oligonucleotide microarray, we have identified a novel submicroscopic duplication involving dosage sensitive genes TACC3, FGFR3, and LETM1. The microduplication did not involve WHSC1 and WHSC2 which are considered in the critical region for WHS and trisomy 4p. This patient's presentation and genomic findings help further delineate clinical significance of re-arrangements in the 4p16 region without the involvement of WHS critical region.     

FISH and cytogenetic characterization of a terminal chromosome 1q deletion: clinical case report and phenotypic implications

We report a 24-year-old woman with minor facial anomalies, mental retardation, seizures, and partial agenesis of the corpus callosum. Cytogenetic analysis showed a de novo terminal chromosome 1 long arm deletion. FISH with a panel of chromosome 1q42-qter bands-specific BAC and YAC clones located the breakpoint at the 1q42-q43 junction, with monosomy restricted to the 1q43 and 1q44 bands. The changing craniofacial phenotype of this patient with age is described as part of the del(1)(q) syndrome natural history. The patient's features are compared with those of other patients with similar deletions, and variable phenotypic findings due to different deleted chromosomal segments are discussed.     

Schizophrenia in an adult with 6p25 deletion syndrome

Chromosomal deletions at 6p25-p24 are rare findings in patients with developmental delay. There is limited information about the adult phenotype. We present a 36-year-old patient with schizophrenia, mild mental retardation, progressive hearing deficits, and characteristic facial features. Ocular (Axenfeld-Rieger anomaly) abnormalities were diagnosed in infancy; vision, however, has remained unimpaired. There were no other major congenital anomalies. Brain imaging showed only minor changes. There was no family history of intellectual deficits or psychosis. Karyotyping revealed a 6p25 deletion, and detailed fluorescence in situ hybridization (FISH) analyses using 23 probes confirmed a 6.7 Mb 6p25-pter deletion. The breakpoint is near a possible 6p25-p24 locus for schizophrenia. Psychotic illness may be part of the neurodevelopmental abnormalities and long-term outcome of patients with 6p terminal deletions. Other similarly affected patients likely remain to be diagnosed in adult populations of schizophrenia and/or mental retardation.     

Clinical phenotype and molecular characterization of 6q terminal deletion syndrome: Five new cases

Mental retardation, facial dysmorphisms, seizures, and brain abnormalities are features of 6q terminal deletions. We have ascertained five patients with 6q subtelomere deletions (four de novo, one as a result of an unbalanced translocation) and determined the size of the deletion ranging from 3 to 13 Mb. Our patients showed a recognizable phenotype including mental retardation, characteristic facial appearance, and a distinctive clinico-neuroradiological picture. Focal epilepsy with consistent electroencephalographic features and with certain brain anomalies on neuroimaging studies should suggest 6q terminal deletion. The awareness of the distinctive clinical picture will help in the diagnosis of this chromosomal abnormality.     

Karyotype-phenotype insights from 11q14.1-q23.2 interstitial deletions: FZD4 haploinsufficiency and exudative vitreoretinopathy in a patient with a complex chromosome rearrangement

We detected a unique de novo complex chromosome rearrangement (CCR) in a patient with multiple abnormalities including growth retardation, facial anomalies, exudative vitreoretinopathy (EVR), cleft palate, and minor digital anomalies. Cytogenetic analysis, fluorescent in situ hybridization, and microsatellite genotyping showed a reciprocal translocation between chromosomes 5 and 8, and a complex translocation-deletion-inversion process in the formation of derivative chromosomes 11 and 16. High-density whole-genome oligonucleotide array comparative genomic hybridization (oaCGH) defined a 35-megabase interstitial deletion of 11q14.1-q23.2 and a 1 megabase deletion of 16q22.3-q23.1. The Frizzled-4 (FZD4) gene is located within this 11q deletion. Parental studies and sequencing analysis confirmed that the patient was hemizygous for FZD4 due to the loss of a paternal allele on the derivative chromosome 11. Mutations in FZD4 are known to cause autosomal dominant exudative vitreoretinopathy (EVR1). Our patient's findings suggest that haploinsufficiency of the FZD4 gene product can also be a disease-causing mechanism for EVR1. We reviewed the clinical manifestations of 23 cases with 11q14-q23 interstitial deletions, with particular scrutiny of the present case and four reported cases characterized by molecular cytogenetics. These findings were used to construct a regional deletion map consisting of a haplosufficient segment at 11q14.3, a flanking centromeric segment at 11q14.1-q14.2, and a flanking telomeric segment at 11q21-q23.3. We propose that deletions of the FZD4 gene located within the centromeric segment cause retinal dysgenesis, while deletions within the telomeric segment account for dysmorphic craniofacial features, growth and mental retardation, and mild digital anomalies. These results provide insight into karyotype-phenotype correlations and prompt a rational analytic approach to cases with interstitial deletions of the 11q14-q23 region.