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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 9 3396-3401
Copyright © 2000 by The Endocrine Society

Original Studies

Anisomastia Associated with Interstitial Duplication of Chromosome 16, Mental Retardation, Obesity, Dysmorphic Facies, and Digital Anomalies: Molecular Mapping of a New Syndrome by Fluorescent in Situ Hybridization and Microsatellites to 16q13 (D16S419-D16S503)1

Constantine A. Stratakis, Antony Lafferty, Susan E. Taymans, Rachel I. Gafni, Jeanne M. Meck and Jan Blancato

Unit on Genetics and Endocrinology (C.A.S., A.L., S.E.T., R.I.G.) and Unit on Growth and Development (R.I.G.), Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1862; and Institute of Molecular and Human Genetics, Georgetown University Medical Center (J.M.M., J.B.), Washington, D.C. 20007-2197

Address all correspondence and requests for reprints to: Constantine A. Stratakis, M.D., Unit on Genetics and Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive, MSC1862, Bethesda, Maryland 20892-1862. E-mail: stratakc{at}cc1.nichd.nih.gov


   Abstract
Top
 Abstract
Introduction
 Subject and Methods
 Results
 Discussion
 References
 
Anisomastia is a common problem among developing adolescent girls. We recently evaluated a 22-yr-old female patient who had severe anisomastia (which had been repaired by surgery), associated with moderate to severe mental retardation, a stocky body habitus with mild obesity, dysmorphic facies (prominent, upslanting palpebral fissures, beaked nose, and a prominent philtrum), webbed neck, low hairline, and severe bilateral clinodactyly of the third, fourth, and fifth fingers with acral (but not large joint) flexion contractures. A peripheral blood high resolution karyotype revealed additional chromosomal material within the long arm of chromosome 16. Densitometric analysis of amplified polymorphic sequence-tagged sites (STS) mapping to 16q suggested that the duplication is defined by the noninvolved markers D16S419 [16q12-cen, 66 centimorgan (cM) from 16p terminus] and D16S421 (16q13-q21, 84.4 cM), encompassing a maximum of 18.4 cM of genetic distance. The STS analysis showed that the duplication was on the maternally derived chromosome 16, resulting in two maternal (and one paternal) copies of that region of chromosome 16. The location was further confirmed by bacterial artificial chromosomes (BACs) that were obtained from a commercially available library, labeled, and used for fluorescence in situ hybridization. The BACs containing STSs D16S408, D16S3137, and D16S3032 (markers that correspond to 16q13) showed two regions of hybridization, indicating that these sites were duplicated, whereas a BAC containing the STS D16S512 (which corresponds to 16q21-q22) revealed one hybridization signal per 16q, indicating that the corresponding region was not involved in the duplication. The distance between the probe signals suggested a tandem duplication. We conclude that even though trisomy 16 is the most common autosomal trisomy in spontaneous abortions, few patients with unbalanced chromosome 16 abnormalities survive to adulthood; in this report we describe one such patient with an interstitial chromosome 16 duplication (at 16q13), who had a specific phenotype associated with abnormal breast size. There are clinical similarities between this patient and patients with other 16q abnormalities, although the breast findings were unique. Molecular cytogenetics, including fluorescence in situ hybridization and densitometric analysis of amplified STSs, provided useful tools for the precise mapping of the syndrome to 16q13, where the gene(s) responsible for this phenotype might be localized.


   Introduction
Top
 Abstract
 Introduction
Subject and Methods
 Results
 Discussion
 References
 
ANISOMASTIA IS a common problem among developing adolescents (1). Rarely, however, is anisomastia so severe as to require surgical treatment (2, 3). In 1 surgical center, among 500 mammoplasties only 5.2% were performed on patients with asymmetry of the breast (3). Like amastia (4, 5) or polymastia (6), anisomastia may be of genetic origin (7). We recently encountered a patient with severe anisomastia that required surgical treatment; we saw her 7 yr after her surgery, and for the first time, we identified her genetic defect: she had partial trisomy for the long arm of chromosome 16.

Although trisomy 16 accounts for 15% of all chromosomally abnormal abortuses and for 29% of all autosomal trisomies (8), whole or partial trisomy 16 is rarely observed in liveborn or older children and adults (9, 10, 11, 12). Duplication of the heterochromatic region 16q11-q12 is probably without clinical significance, but duplication of large regions of the long arm of chromosome 16 (from 16q13 to qter) result in severe malformations and early lethality (9, 10, 11, 12, 13). Partial trisomy 16q21-qter may be associated with a nonlethal phenotype in some cases (13), but not in all (10, 12). In almost all patients reported with variable phenotypes, the extent of the 16q anomaly has not been precisely delineated. In several patients, other defects are present in addition to the partial trisomy 16 (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21). It has been suggested that the length of the 16q duplication correlates with clinical phenotype and survival (22); nevertheless, accurate phenotype prediction can only be achieved after precise description of the cytogenetic defect in the affected patients and its correlation with existing genetic and physical maps of chromosome 16. Accordingly, patients with relatively smaller defects involving chromosome 16 duplications are useful in defining chromosomal regions associated with particular phenotypes.

Proximal duplication of 16q has only been reported in four patients, involving various intervals from 16q12 to 16q13 (23, 24); in only one of these patients, however, was fluorescent in situ hybridization (FISH) used for confirmation and mapping of the anomaly (24). There has been no precise molecular genetic mapping of proximal 16q duplications, and only one study confirmed a 16q22-qter duplication by both FISH and polymorphic markers (22).

The patient described in this report, a 22-yr-old female, had a distinct phenotype, with only a few findings in common with those of other patients with 16q anomalies (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25). Her anisomastia was reminiscent of that of patients with ulnar-mammary syndrome (UMS), a condition that, in addition, affects normal development of the upper extremities (26); however, our patient had no other findings from that syndrome. The abnormality was confirmed by FISH, using as probes clones from available genomic area contigs, and was defined by flanking genetic markers to be not longer than 15.8 centimorgans (cM).


   Subject and Methods
Top
 Abstract
 Introduction
 Subject and Methods
Results
 Discussion
 References
 
Patient report

The patient was a 22-yr-old female (Fig. 1Go) with mild to moderate developmental delay who was referred to our clinic with the diagnosis of possible Williams-Beuren syndrome (WBS), commonly referred to as Williams syndrome or infantile hypercalcemia with elfin facies (Mendelian inheritance in man catalog no. 194050) (27). Her past medical history included a normal birth and early infancy with developmental delay becoming evident after the first year of life. At about the same time, several developmental defects were recognized for the first time, too. These included dysmorphic facies, dental hypoplasia with small teeth and large interdental spaces, an enlarged left atrium without any other heart defects and normal heart function (by echocardiography), an intensely hoarse voice due to vocal cord soft tissue nodules (without vocal cord paralysis), a growing umbilical hernia (which was eventually surgically repaired at the age of 5 yr), gastroesophageal reflux (which was medically treated), clinodactyly, contractions of the small joints (fingers and toes), and hyperextensibility of large joints. The patient had a normal adrenarche (7 yr of age) and menarche (at age 11 yr), with normal menses thereafter. Breast development was asymmetric, which led to left breast surgical reduction at age 15 yr. Other chronic problems included attention deficit disorder (treated medically), recurrent urinary tract infections (with normal urinary tract anatomy by imaging studies), constipation, and severe hyperopia requiring bifocal lenses.



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  		Figure 1. Clinical findings in a patient with interstitial duplication of chromosome 16: a beaked nose, anteverted nares, and other minor facial dysmorphic features (A); a stocky body habitus (B and C) with a short neck with a low posterior hairline and a mild dorsocervical fat pad (D); anisomastia (E; even after surgical reduction of the left breast); bilateral clinodactyly and contractures of third, fourth, and fifth fingers (F); and small and widely spaced teeth (G).

 
Both parents and a 24-yr-old sister were essentially healthy, although the father died of complications of liver cirrhosis due to chronic alcoholism just before the completion of this study.

Our physical examination revealed a patient with a pleasant, "party-like" personality (which is frequently found in patients with WBS), with a stocky body habitus, slightly overweight (95%), and with a height appropriate for her genetic (midparental) height (10–25%). Findings included mildly upslanting palpebral fissures and stellate iris pattern bilaterally; narrow and tortuous ear canals; a beaked nose and anteverted nares; hypoplastic philtrum and a small mouth; a high arched palate and small, widely spaced teeth; a short neck with a low posterior hairline and a mild dorsocervical fat pad; anisomastia (despite the previous surgery) with widely spaced nipples; thin upper and lower extremities with bilateral clinodactyly and contractures of third, fourth, and fifth fingers; anteverted finger- and toenails; hyperextensibility of metacarpal joints; and several skin lentigines and fewer nevi throughout the body. Imaging studies were normal, including sonograms of the heart, kidneys, and pelvis; magnetic resonance imaging of the brain, chest, and abdomen were also normal. Biochemical studies excluded Cushing syndrome and thyroid and gonadal dysfunction; other routine laboratory studies were also normal.

The patient, her mother, and her sister consented to cytogenetic and DNA studies and use of the proband’s photographs for the purposes of medical education and publication.

Karyotype

High resolution karyotype analysis was obtained by standard methods from the patient, her mother, and her sister. Targeted FISH, using chromosome bands 16q12, 13, 14, 21, 22, 23, and 24 DNAs as probes, was then performed as previously reported (28).

DNA extraction, polymorphic marker analysis and mapping, and karyotype

DNA was extracted from peripheral blood, as previously described (29). Polymorphic markers of chromosome 16 were tested by PCR after end labeling with [{gamma}-32P]ATP of the reverse primer for each marker, as previously described (29). The sequences and genomic order of these primers are available in the genome database on line (HYPERLINK "http://gdbwww.gdb.org/" http://gdbwww.gdb.org/and HYPERLINK "http://www-genome.wi.mit.edu/" http://www-genome.wi.mit.edu) as well as in maps that have been published previously (30, 31, 32, 33, 34, 35).

For polymorphic marker analysis, equal amounts of DNA from the patient, her mother, and her sister were amplified along with control samples; the specimens were then run on 6% acrylamide gels (Promega Corp., Madison, WI), which were dried and exposed to X-OMAT films (Eastman Kodak Co., Rochester, NY). The autoradiography films were scanned, and the optical density (OD) of the bands was calculated using the NIH 1.611 program, as previously described (36). An increase in OD in patient’s allelic bands compared to the corresponding alleles in the patient’s mother and sister and control samples (adjusted for homozygosity or heterozygosity at the given locus) was considered evidence of inclusion of the marker’s physical locus in the duplicated segment.

Radiation hybrid mapping of the markers that were found to be included in the duplicated segment (Table 1Go) and were not included in the on-line or published maps was obtained by standard methods (37) to determine their most likely order on 16q13.


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  		Table 1. Analysis of polymorphic microsatellite markers from chromosome 16

 
Probe selection and FISH

FISH was performed with three bacterial artificial chromosomes (BACs) as probes, in a process that was recently outlined by our laboratory (38, 39) (Fig. 2Go). The BAC addresses were 7-G-2 (which contains polymorphic marker D16S3117), 571-E-20 (marker D16S3137), 137-F-4 (marker D16S3032), 110-D-9 (marker D16S408), and 277-I-4 (marker D16S512) in chromosomal order cen-D16S3117-D16S3137-D16S3032-D16S408-D16S512-tel. All clones were obtained from a commercially available library (Research Genetics, Inc., Huntsville, AL) after screening for these two markers by PCR (38, 39). Location, primers, and PCR conditions for these markers are available on line (see above) or have been published previously (30, 31, 32, 33, 34, 35).



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  		Figure 2. Genetic identification of the 16q13 duplication: FISH with BAC 137-F-4 (A; containing marker D16S3032) and BAC 110-D-9 (B; containing marker D16S408) on metaphase spreads from the patient; duplicate signals are indicated by the arrows on both occasions on one of the chromosomes 16, indicating that these BACs are contained in the interstitial duplication, which appears to be tandem. C, The chromosome 16 pair of the patient as it appeared upon G banding; the long arm of the chromosome 16 on the right contains additional chromosomal material in the area shown by the arrow.

 
In addition, the WSCR probe was used for the diagnosis of WBS, as previously described (40). All probes were nick translated and hybridized on metaphase chromosomes that were prepared from peripheral lymphocytes, as previously described (38, 39, 40, 41). Ten metaphases were scored for every probe examined. Chromosome identification was accomplished through cohybridization of a chromosome 16-specific {alpha} satellite probe labeled with digoxigenin (Oncor, Inc., Gaithersburg, MD) and detected with fluorescein. Images were obtained with a Carl Zeiss Axiophot microscope (New York, NY), equipped with a Cytovision imaging system (Applied Imaging, Pittsburgh, PA), as previously described (42).


   Results
Top
 Abstract
 Introduction
 Subject and Methods
 Results
Discussion
 References
 
Comparison of the proband with other patients with chromosome 16 duplications

The patient’s most important findings are shown in Fig. 1Go. There have been more than 20 patients with partial trisomy of chromosome 16 reported (21); 4 patients had duplications of the proximal 16q area (23, 24). Failure to thrive, various degrees of lipoatrophy, hypotonia, and other neurological abnormalities were present in all patients with partial trisomy 16, but not in our patient and the others with proximal 16q duplication. Anisomastia or other breast abnormalities were not present in any other patient with chromosome 16 anomalies. Specific facial dysmorphic changes, such as high arched palate, hypoplastic philtrum, and/or thin upper lip, were common in all patients with partial trisomy 16, including the patient of this report. Other clinical manifestations (anorectal and other intestinal anomalies, congenital heart and genital defects, and choanal atresia) that have been reported in most patients with partial trisomy 16 were not present in our patient. On the other hand, flexion and other anomalies of the fingers that were not found in 1 patient with distal 16q duplications (23) are present in our patient (Fig. 1Go) and have been described in most patients with partial trisomy for the entire, proximal, and middle 16q.

Karyotype, FISH, and analysis of chromosome 16 molecular markers

A peripheral blood high resolution karyotype of the patient revealed additional chromosomal material in the middle of the long arm of chromosome 16. Chromosome 16q band-specific probes prepared using microdissection were initially used as FISH probes to delineate the duplicated region (Fig. 2Go), whereas the WSCR probe showed the expected two signals (data not shown), making the molecular diagnosis of WBS unlikely (40). The chromosome 16 anomaly was not present in the karyotype of the patient’s mother or that of her sister (data not shown); thus, it was most likely a de novo defect.

A total of 21 polymorphic STSs that map along chromosome 16 were then used in the patient’s DNA and that of her mother and sister (Table 1Go). Densitometric analysis showed that D16S400, a marker located at 81.8 cM from the top of chromosome 16, was likely to be involved in the duplication. Seven markers proximal to D16S400 by radiation hybrid mapping were tested in the same panel of DNA samples. Markers D16S3137 (67 cM from the top of chromosome 16), D16S3032 (71 cM), D16S408 (73 cM), and D16S400 (81.8 cM) were included in the duplication, whereas the two flanking markers (with normal OD) were D16S419 (66 cM) and D16S421 (84.4 cM), centromeric and telomeric of the duplication, respectively. Markers D16S415 and D16S503 were uninformative (Table 1Go).

The location of the duplication was further confirmed and precisely mapped by BACs, which were obtained from a commercially available library, labeled, and used for FISH (Fig. 2Go). The BACs containing STSs D16S408, D16S3137, and D16S3032, markers that correspond to 16q13, revealed the duplication (Fig. 2Go), whereas a BAC containing D16S512, which corresponds to 16q21-q22, revealed normal chromosome 16 material (data not shown). The distance between the probe signals suggested a tandem duplication. The allele analysis of the polymorphic STSs showed that the duplication was present on the maternally derived chromosome 16.


   Discussion
Top
 Abstract
 Introduction
 Subject and Methods
 Results
 Discussion
References
 
A number of genes have been mapped to the 16q13 region (27, 43). The patient described in this report had several findings that were similar to those of other patients with partial trisomy 16, but she also had some unique manifestations. The most characteristic among the latter was anisomastia, which was so profound that it required surgical treatment. This symptom has only been described to be familial in two kindreds from West Africa (7) and is genetic in patients with a condition called UMS (26). Our patient, although she had hand anomalies, did not have the defects that have been described in patients with UMS. These include postaxial polydactyly and oligodactyly, absent ulna, and shoulder hypoplasia. Ipsilateral breast abnormalities are common in these patients (44).

UMS is caused by mutations in the TBX3 gene, which has been localized to chromosome 12q23 and is part of a large family of genes with various developmental functions (44). None of the members of the TBX protein family or their functional regulators has been mapped to the 16q11-q21 region (27, 43). Furthermore, anisomastia in patients with UMS, when present, is the result of unilateral breast aplasia or hypoplasia (26, 44); in the patient of this report, anisomastia, like that in the previously reported families (7), was the result of uneven breast growth with absence of other mammary developmental abnormalities. Nevertheless, it is possible that a gene(s) localized on chromosome 16q13 acts in a molecular pathway that involves TBX3 in regulating normal breast development.

It is interesting that none of the other four patients with duplications limited to the 16q11-q13 region had breast abnormalities (23, 24, 45, 46), including a 34-yr-old woman (24). In patients with chromosomal duplications, however, the abnormalities result not only from increased dosage of the involved genetic material, but also from the disruption of a gene(s) localized at the boundaries of the duplicated region. In that sense, each of the described patients is unique, because even though duplicated regions may overlap (which may be the reason behind some clinical similarities), the boundaries of the lesions are almost always different. Given that the size of the involved area in our patient is the smallest reported among all patients with partial trisomy 16, it is more likely that her anisomastia and perhaps most of her other findings are the result of gene(s) disruption rather than increased dosage effect.

What clinical similarities, if any, did our patient have with the other reported patients? The proband’s small joint contractures have been described in almost all patients with partial trisomy 16, with the exception of those with distal anomalies (23). This suggests the presence of a gene in the 16q13 region that is responsible for the proper formation or function of the small joints of the upper and lower extremities. Interestingly, a 3-yr-old patient has been described with cerebro-oculo-facio-skeletal syndrome and flexure contracture of the joints who had an apparently balanced translocation involving 16q13 [46,XX, t(1;16)(q23;q13)] (45). There are, however, no obvious candidate genes in the database (27, 43) for such a defect.

Some of the patient’s anomalies, especially the facial features, have been described in other patients with partial trisomy 16 (23, 24, 47) and also in cases of uniparental disomy (UPD) involving chromosome 16 (48, 49). We speculated above that in our patient, haploinsufficiency for disrupted genes could be present. However, the similarities between her and patients with UPD for chromosome 16 suggest that there might be genes on the long arm of this chromosome that are imprinted. If this is the case, gene disruption may lead not only to haploinsufficiency, but also to homozygosity for silenced genes, not unlike the case in patients with UPD for 16.

We have recently reported that familial macromastia may be associated with increased and aberrant expression of the aromatase (P450arom) gene (50). It is unlikely that P450arom or any other endocrine abnormalities are involved in the presentation of the patient of this report, who had a normal hormonal profile (data not shown) and completed a physiological puberty.

In summary, we reported a patient with partial duplication of the long arm of chromosome 16, who shared facial and other features with other patients with partial trisomy 16q, but also had the unique manifestation of pronounced anisomastia. We speculate that a gene with a role in the control of normal breast growth is located in the 16q13 area, in which our patient had a duplication. The information presented in this report may lead to the appropriate linkage or other genetic studies in families and isolated patients with similar clinical manifestations that will identify these genes.


   Acknowledgments
 
We thank Drs. Yuan Jiang and Michael Bittner (Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD) for supplying the band-specific DNA probes for the original FISH studies. We are indebted to the patient and her family; we thank in particular her mother, who has been very supportive of this work and never quit investigating the cause of her daughter’s problems!


   Footnotes
 
1 This work was presented in abstract form at the 81st Annual Meeting of The Endocrine Society, San Diego, California, June 13–15, 1999. Back

Received February 1, 2000.

Revised May 8, 2000.

Accepted May 24, 2000.


   References
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 Abstract
 Introduction
 Subject and Methods
 Results
 Discussion
 References
 

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