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We describe two siblings with asymmetric limb reduction malformations. Such anomalies are usually considered to result from sporadic events, but the recurrence in siblings without any identifiable teratogenic insult suggests a genetic etiology. This finding becomes important when parents are counseled about future pregnancies. The use of prenatal diagnostic techniques during subsequent pregnancies should be considered.

Most reported microdeletions of the CREB-binding protein (CBP) gene in the Rubinstein-Taybi syndrome (RTS) were detected by fluorescence in situ hybridization (FISH) with a single cosmid probe specific to the 3' region of the gene. In order to test the hypothesis that the rate of microdeletion-positive cases would be greater if the entire gene was evaluated, we performed FISH on 66 patients with an established diagnosis of RTS, using a panel of five cosmids that span the CBP gene. Five of 66 patients had deletions by FISH (9%), consistent with those rates reported in various series that ranged between 3-25%. Among our cases, different deletions were observed; one was deleted for the 5' but not the 3' region of the CBP gene (case 055). Other deletions included a total CBP deletion extending from the 5' through the 3' region (case 017), a deletion of all but the 5' region (cases 006 and 060), and an interstitial deletion in the 3' region (case 028). Fine breakpoint mapping with additional cosmid and yeast artificial chromosome (YAC) constructs was performed on these patients. The findings of a partial 5' deletion and of interstitial deletions of the CBP gene add to the known spectrum of mutations of this gene in RTS and demonstrate the need for evaluation of the entire CBP gene region for deletions rather than only the 3' region in RTS patients. These results further suggest that the true rate of microdeletion across the CBP gene detectable by FISH has yet to be established firmly. No phenotypic differences between partial deletion, complete deletion, and nondeletion patients were observed, supporting a haploinsufficiency model for RSTS.

Toriello-Carey syndrome is characterized by agenesis of the corpus callosum, telecanthus, short palpebral fissures, Robin sequence, abnormal ears, cardiac anomalies, and hypotonia. We describe two patients with Toriello-Carey syndrome and call attention to an unbalanced sex ratio. The first patient, a male, was born at term by Cesarean section and manifests micrognathia, cleft soft palate, hypoplastic right ear, anotia on the left side, cerebellar vermis hypoplasia, hydrocephalus, agenesis of the corpus callosum, and hypoplastic left heart. He died 2 days after birth. The second patient is the male sib of a patient reported previously [Am J Med Genet 42: 374-376; 1992]. He had large fontanelles, telecanthus, a short nose, small and malformed ears, micrognathia, a large ventricular septal defect, and pulmonary stenosis. At age 8 months he has growth retardation and developmental delay. A sister is unaffected. Review documented eight other patients with Toriello-Carey syndrome, six of whom were male. The two female patients are less severely affected and are still alive. Of the other male patients, all are deceased except one who is still alive at age 5 years; he has severe growth retardation (-3 SD), mental retardation (DQ44), severe speech delay, and characteristic anomalies. The predominance of affected males and the milder phenotype in the female patients suggests an X-linked gene or sex influenced gene.

The severe phenotype of human females whose karyotype includes tiny ring X chromosomes has been attributed to the inability of the small ring X chromosome to inactivate. The XIST locus is expressed only from the inactive X chromosome, resides at the putative X inactivation center, and is considered a prime player in the initiation of mammalian X dosage compensation. Using PCR, Southern blot analysis, and in situ hybridization, we have looked for the presence of the XIST locus in tiny ring X chromosomes from eight females who have multiple congenital malformations and severe mental retardation. Our studies reveal heterogeneity within this group; some rings lack the XIST locus, while others have sequences homologous to probes for XIST. However, in the latter, the locus is either not expressed or negligibly expressed, based on reverse transcription-PCR analysis. Therefore, what these tiny ring chromosomes have in common is a level of XIST transcription comparable to an active X. As XIST transcription is an indicator of X chromosome inactivity, the absence of XIST transcription strongly suggests that tiny ring X chromosomes in females with severe phenotypes are mutants in the X chromosome inactivation pathway and that the inability of these rings to inactivate is responsible for the severe phenotypes.

In a description of 8 girls who had Ullrich-Turner syndrome (UTS) with a small r(X), mental retardation, and other unusual findings, it was hypothesized that the distinctive phenotype was associated with the loss of the X inactivation center from the r(X) and lack of genetic inactivation of the ring [Van Dyke et al., 1992]. Here, we present a 17-year-old young woman with 45,X/46,X,r(X)(?p11q13) mosaicism, Ullrich-Turner syndrome, and normal intelligence. In situ hybridization with the X-centromere DNA probe DXZ1 (Oncor, Inc., Gaithersburg, MD) was performed on previously G-banded slides, and the probe hybridized to the centromere regions of the normal X and the ring. The r(X) appears to be inactivated since a buccal smear demonstrated 5% Barr bodies. Furthermore, DAPI stain and FISH analysis with the X-centromere DNA probe DXZ1 was employed to distinguish the inactive X from the active X, and verified the presence of a sex chromatin mass in fibroblasts. These observations are consistent with the active-ring-X-and-mental-retardation hypothesis since the ring in this patient, although very small, appears to be normally inactivated and she has normal intelligence.

We evaluated 10 patients with an inverted tandem duplication of 8p. Inverted duplications of chromosome 8 have been reported infrequently, and no syndrome has been previously identified. All 8 patients on whom birth histories were available were hypotonic at birth, and had feeding difficulties in the neonatal period. All patients have significant developmental delay. Manifestations present in 5 or more patients were prominent forehead, high arched palate, large mouth with a thin upper lip, malformed and/or apparently low-set ears, broad nasal bridge, dental and skeletal abnormalities, and joint laxity or hyperextensibility. Variation in the phenotype may, in part, be explained by the different breakpoints. Recurrence risks of de novo rearrangements are probably very low, but for the recombinants the risk may be significant. The duplication appeared to be de novo in 6 patients (both parental karyotypes were normal); maternal karyotypes were normal in 2 patients, and both parents of 1 patient were not available. One propositus had a monocentric recombinant of a paracentric inv(8) (p12p23.3) carried by the mother, and is one of only 6 known cases of duplication associated with a balanced paracentric inversion in a parent. The carrier parent was the mother in 5 of those 6 cases. Each case involved a different chromosome, and each probably was created by an unusual meiotic recombination event. Inverted duplication 8p is one of the most common duplications observed in our laboratories, and ranks in frequency with the classical deletions, such as Wolf-Hirschhorn and cri-du-chat syndromes and duplication or secondary trisomy 15q1.(ABSTRACT TRUNCATED AT 250 WORDS)

Since some patients with Ullrich-Turner syndrome (UTS) have mental retardation, we reviewed our experience to look for a high-risk subgroup. Among 190 UTS and gonadal dysgenesis patients with X chromosome abnormalities, 12 had mental retardation. All of the six (100%) with a small ring X were educable (EMI) or trainable mentally impaired (TMI) with more severe delay than expected in UTS. Among the 184 with other X abnormalities, only 6 had similar delays (2 from postnatal catastrophes), for a frequency of 3.3% mental retardation among those without a small ring X; only 2.2% of these had unexplained mental retardation. Polymerase chain reaction studies showed no Y-derived material in the 2 patients who were evaluated, and in situ hybridization confirmed X origin of the ring in the 6 subjects who were evaluated. We describe the phenotype of the 6 individuals with a small ring X, and an additional 2 patients with a small ring X who were identified outside the survey. The subjects with a small ring X comprised a clinically distinct subgroup which had EMI/TMI and shorter stature than expected in UTS. Seizures and a head circumference less than 10th centile were observed in half of the patients with a small ring X, and strabismus, epicanthus, and single palmar creases were present in more than half. A "triangular" face in childhood, pigmentary dysplasia, sacral dimple, and heart defects were also common. Neck webbing appeared to be less frequent than in 45,X. We hypothesize that the high risk of mental retardation in this form of the UTS results from lack of lyonization of the ring X due to loss of the X inactivation center. Excluding those with a small ring X, mental retardation is not significantly increased in patients with UTS.

We cytogenetically studied four cases of adenocarcinoma of the prostate. All tumors were moderately differentiated or well-differentiated, with different degrees of invasion. One tumor with microscopic seminal vesicle invasion and lymph node metastasis (tumor 4) had trisomy 7 as a sole clonal abnormality, suggesting that this is a primary change in some prostatic tumors. Although only normal karyotypes were observed in the other three tumors, several nonclonal changes were evident. Monosomy 9 or deletion of the long arm of 9 was observed in at least one cell in the three tumors without trisomy 7. Furthermore, in one of these tumors (tumor 3, moderately differentiated), several rearrangements (five of 26 cells) were observed, two of which had a common breakpoint at 15q11. Although complex chromosome changes including del(10q) and del(7q) have been described in prostatic tumors, they were not observed in the four tumors studied. This is the first report of a prostate tumor with trisomy 7 as a single clonal chromosome abnormality.

We report on two patients with rare 6q duplications. The karyotype of patient 1 is 46,XY,dup(6)(q21q23.3). The karyotype of patient 2 is 46,XX,dup(6)(q21.15q23.3). These two patients have some nonspecific physical findings in common including a depressed nasal bridge, epicanthal folds, mild heart defects, and developmental delay, but each had other congenital anomalies.

We describe a patient with familial neurofibromatosis (NF1), short stature, developmental delay, and a de novo chromosome abnormality. In sity hybridization was done using chromosome specific centromere probes to characterize the karyotype as 46,XX/47, XX,+r(X) (p11q11)/47,XX,+r(17) (p11q11)/48, XX,+r(X) (p11q11),+r(17) (p11q11). The NF1 mutation, as well as each superunmerary ring chromosome, may have played a role in perturbing the normal developmenal process of this patient. © 1993 Wiley-Liss, Inc.

intestinal chloride transport in cystic fibrosis. FASEB J 1988;2:2625-9. 7. Orlando RC, Powell DW, Croom TD, et al. Colonic and esophageal transepithelial potential difference in cystic fibrosis. Gastroenterology 1989;96:1041-8. 8. Powell DW. Ion and water transport in the intestine. In: Anreoli TE, Hoffman DE, Fanestil DD, et al, eds. Physiology of membrane disorders. New York: Plenum Press, 1986;559-96. 9. Goldstein JL, Nash NT, AI-Bazzaz F, et al. Rectum has abnormal ion transport but normal cAMP-binding proteins in cystic fibrosis. Am J Physiol 1988;254:C719-24. 10. Rask-Madsen J, Schiotz PO, Bartels U, et al. Electrical polarization of rectal mucosa and excretion of tetrahydroaldosterone in patients with cystic fibrosis of pancreas and in normal subjects. Acta Paediatr Scand 1975;64:81-6. 11. Rechkemmer G, Halm D, Work J, et al. Independent regulation of potassium transport and sodium absorption by aldosterone in guinea pig distal colon [Abstract]. Fed Proc 1987;46:635A.

High resolution cytogenetics, microsatellite marker analyses, and fluorescence in situ hybridization were used to define Xq deletions encompassing the fragile X gene, FMR1, detected in individuals from two unrelated families. In Family 1, a 19-year-old male had facial features consistent with fragile X syndrome; however, his profound mental and growth retardation, small testes, and lover limb skeletal defects and contractures demonstrated a more severe phenotype, suggestive of a contiguous gene syndrome. A cytogenetic deletion including Xq26.3-q27.3 was observed in the proband, his phenotypically normal mother, and his learning-disabled non-dysmorphic sister. Methylation analyses at the FMR1 and androgen receptor loci indicated that the deleted X was inactive in95% of his mother's white blood cells and 80-85% of the sister's leukocytes. The proximal breakpoint for the deletion was approximately 10 Mb centromeric to FMR1, and the distal breakpoint mapped 1 Mb distal to FMR1. This deletion, encompassing approximately 13 Mb of DNA, is the largest deletion including FMR1 reported to date. In the second family, a slightly smaller deletion was detected. A female with moderate to severe mental retardation, seizures, and hypothyroidism, had a de novo cytogenetic deletion extending from Xq26.3 to q27.3, which removed approximately 12 Mb of DNA around the FMR1 gene. Cytogenetic, and molecular data revealed that approximately 50% of her white blood cells contained an active deleted X. These findings indicate that males with deletions including Xq26.3-q27.3 may exhibit a more severe phenotype than typical fragile X males, and females with similar deletions may have an abnormal phenotype if the deleted X remains active in a significant proportion of the cells. Thus, important genes for intellectual and neurological development, in addition to FMR1, may reside in Xq26.3-q27.3. One candidate gene in this region, SOX3, is thought to be involved in neuronal development and its loss may partly explain the more severe phenotypes of our patients.

It has recently become possible to detect female carriers of Duchenne muscular dystrophy with no affected male relative in the family. These "isolated carriers" represent about 10% of women with high serum creatine phosphokinase (CPK) levels and clinical evidence of a muscle disease. Most isolated carriers ascertained by clinical and/or CPK levels and diagnosed by dystrophin immunostaining of muscle biopsy show symptoms of a muscular dystrophy, and often carry the diagnosis of recessive "limb-girdle muscular dystrophy" prior to dystrophin analysis. It has been difficult to offer genetic counseling and prenatal diagnosis for Duchenne muscular dystrophy in the families of these isolated carriers, largely due to the difficulty in determining which of the dystrophin alleles segregating in the family harbors the mutation in the heterozygote. Here we report genetic counseling of three isolated carriers and their families. In two cases, prenatal diagnosis of at-risk pregnancies was conducted. We determined X inactivation patterns and inheritance of X chromosomes in each family, and used this information to define the at-risk dystrophin gene. In all three families, the mutation was a de novo event, two in the paternal germ-line, and one in the maternal germ-line. In each case we show that sibs of the heterozygous woman are at population risk, while pregnancies of each propositus are at high risk. Our results show that accurate genetic counseling and prenatal diagnosis can be offered to these families.

We report on a mother and son with a 3p25-pter deletion. Both have postnatal growth retardation, mental retardation, apparently low-set or malformed ears, and telecanthus. The mother also has ptosis and multiple joint pains, while the son has a long philtrum and anteverted nares. These phenotypes are compared to those of other 3p- patients. Both patients have many manifestations previously described. The son appears to be more severely affected than the mother.

There are 23 females known with Duchenne or Becker muscular dystrophy (DMD or BMD) who have X;autosome translocations that disrupt the X chromosome within band p21. A female with a t(X;4)(p21;q35) translocation was identified prenatally at routine amniocentesis. At birth, she was found to have a raised CK level, consistent with a diagnosis of Duchenne muscular dystrophy. Her cells were fused with mouse RAG cells and the translocated chromosomes were separated from one another and from the normal X chromosome by segregation in the resulting somatic cell hybrids. Southern blot analysis of the hybrids indicated that the translocation occurred on the X chromosome between genomic probes GMGX11 and J-66, both of which lie within the DMD gene. Further localisation with a subfragment of the DMD cDNA clone placed the translocation breakpoint in an intron towards the middle of the gene, confirming that the de novo translocation disrupted the DMD gene. RFLP analysis of the patient, her parents, and the hybrid cell lines showed that the translocation originated in the paternal genome. This brings to six out of six the number of DMD gene translocations of paternal origin, a fact that may be an important clue in future studies of the mechanism by which X;autosome translocations arise.

A ring chromosome 6 has been identified by GTG-banding in a male with microcephaly, growth retardation, seizures, epicanthus, hypertelorism, micrognathia, and other congenital anomalies. Cytogenetic studies indicate the instability of the ring chromosome. The most common findings in subjects with ring 6 include: profound to moderate mental retardation, microcephaly, prenatal growth failure, retarded bone age, epicanthal folds, flat nasal bridge, short neck, ears low-set or malformed, microphthalmia, and micrognathia. Linkage studies, including HLA, are consistent with reported maps of chromosome 6.

We report on a patient with an interchromosomal duplication of 3p, from 3p21 to 3pter, which apparently arose de novo. The infant had multiple malformations including holoprosencephaly and cyclopia. It is possible that duplication 3p has a generalized effect on the holoprosencephalon or the cleavage of the embryonic forebrain. Fibroblasts from the patient are available from the NIGMS Human Genetic Mutant Cell Repository (GM 7216).

Deafness due to inner ear anomalies is rarely associated with malformations of the auricles. We describe two brothers with profound congenital sensorineural deafness, abnormal vestibular function, normal ossicles, and delayed motor development. Since the external and inner ear originate from distinctly separate structures, the embryogenesis of this malformation association is less clear than in the more common association of external and middle anomalies, where the latter two structures are derived from the first and second branchial arches. The combination of auricular and inner ear anomalies, with sparing of the middle ear structures, can be explained on the assumption that mesodermal induction is responsible for normal differentiation of both the otocyst and of the branchial arch ectoderm. A recessive mutant gene may lead to a deficiency of a mesodermal inducer substance of a target tissue receptor site. A similar mechanism may be involved in other multiple malformation syndromes, whereby a mutant gene acting during a specific period of organogenesis causes disruption of the normal induction-competence relationship.

While duplication and deletion of the short arm of chromosome 12 cause well-recognized syndromes, duplication of the long arm chromosome 12 is rarely observe. We are reporting a duplication of chromosome 12 distal to band q24.1 in a five-month-old child. His chromosome constitution is 46,XY,-4+der(4),t(4:12)(p16;q24.1)mat. The balanced translocation is also carried by his maternal grandmother and two of the mother's brothers. The malformation syndrome consisted of unusual facial appearance and anomalies of the musculoskeletal, cardiovascular, genitourinary, and central nervous systems. Four previously reported patients had similar break points on chromosome 12 with similar malformations; therefore, phenotype-karyotype correlation suggests a definitive malformation syndrome associated with duplication of chromosome region 12q24.1 leads to qter.

During a study of an Amish population of Northern Indiana, 25 individuals with a syndrome of brittle hair, short stature, and intellectual impairment were found in one large kindred. Observations in 20 of these affected individuals have shown that the short stature and intellectual impairment are relatively mild except in the propositus who also has a deletion of a portion of the long arm of chromosome 14. The hair in each affected individual has an abnormal appearance by light and scanning electron microscopy with an irregular grooved surface lacking in scales. Polarization microscopy of the hair revealed an alternating birefringent pattern. Neutron activation analysis of the hair of 11 affected individuals showed the sulfur content to average 2.51% by weight (approximately one half that of controls and nine obligate heterozygotes). This condition can be differentiated from Menkes' kinky-hair syndrome by the microscopic appearance of the hair, the normal copper and ceruloplasmin levels and the mode of inheritance. The syndrome being reported has similarities to and may be identical with a condition previously reported in two siblings by Pollitt et al. in 1968 and that reported in a 4-year-old girl by Brown et al. in 1970. The number of affected individuals and their distribution in this large kindred have provided evidence for the autosomal recessive inheritance of the condition and for its decreased fertility.

A congenital sex cord-stromal tumor of the testis with morphologic features of juvenile granulosa cell tumor is reported. The tumor occurred in an abdominal testis of a newborn infant with an X/XY karyotype and ambiguous genitalia and presented as a partially cystic mass associated with ascites. Histologically the tumor was comprised of an admixture of solid, cellular, poorly differentiated lobules mimicking graafian follicles. Residual hypoplastic testicular tissue was present at the periphery. This is the 19th reported case of testicular juvenile granulosa cell tumor and the fourth with an underlying sex chromosome anomaly, further emphasizing the relationship of this uncommon neoplasm to abnormal sexual or gonadal development.

Introduction Prenatal diagnosis for an increasing variety of genetic disorders and congenital defects has been possible since about 1970. During the last decade the demand for prenatal diagnostic services has increased almost logarithmically and has become an overwhelming service load for many cytogenetic laboratories. This demand will probably continue to grow during the 1980s. Requests for chromosome studies are the most common. followed by requests to diagnose errors of morphogenesis (mostly neural tube defects), inborn errors of metabolism, and other Mendelian disorders. The most common indication for a prenatal cytogenetic study is advanced maternal age, which has an associated increased risk for trisomy 21 (Down syndrome) and other aneuploid conditions (Table 1). Prenatal diagnosis is indicated for pregnant women 35 years of age or more. The incidence of trisomy 21 is greater in amniotic fluid samples than at birth partly because about 65% of trisomy 21 fetuses abort spontane~usly,~ many after the 16th week of gestation.= Couples who have had a child with karyotype abnormality may be at increased risk in subsequent pregnancies; the recurrence risk for trisomy 21 is about 1 % . Individuals who carrv a balanced chromosome rearrangement are also at risk of having offspring or abortuses with unbalanced karyotypes. The risk of the amniocentesis procedure to the mother and fetus has been the subiect of considerable discussion. Only about 2% of women experience apparent complication such as vaginal bleeding, leakage of amniotic fluid, or abdominal cramping. The chance of miscarriage or problems associated with labor and delivery have not been shown to be significantly increased, and injury to the fetus from the needle appears very rare. A study undertaken in the United States concluded that

Maroteaux-Lamy syndrome exhibits deficient activity of the enzyme arylsulfatase-B in cultured skin fibroblasts. Prenatal diagnosis was successfully attempted in two pregnancies of a consanguineous Chaldean couple whose first child is affected with Maroteaux-Lamy syndrome. In both instances, deficient arylsulfatase-B activity was observed in amniotic fluid cell cultures, and the diagnosis was confirmed by 35S-sulfate studies and postmortem enzymology and electron microscopy. The prenatal diagnosis of Maroteaux-Lamy syndrome remains problematic. Residual activity of arylsulfatase-B in the affected homozygote can make interpretation difficult, and the behavior of many lysosomal enzymes varies greatly in response to tissue culture conditions and enzyme extraction processes.

An unusual spectrum of craniofacial and foot abnormalities has been detected within a large midwestern Amish kindred. Enlarged great toes and craniofacial abnormalities suggested Pfeiffer acrocephalosyndactyly type V; however, thumb abnormalities were not present. Eighty-eight affected individuals were observed, and another 50 were reliably reported to be affected. An autosomal dominant inheritance pattern was observed associated with variable expressivity. All affected individuals had some clinical or radiologic abnormality of the feet. The phenotypic expression was so variable that the entire spectrum of dominantly inherited craniofacial dysostoses-acrocephalosyndactylys (except the typical Apert syndrome) was seen within this kindred.

Summary A girl, age 26 months, with profound dwarfism, mental retardation, and minor congenital abnormalities was studied. Cytogenetic analysis revealed a ring 1 chromosome in all of the cells counted. The patient is so similar clinically to the one child previously reported with a ring 1 chromosome that the two patients may represent a clinical syndrome.

SUMMARY The normal human karyotype consists of 44 autosomes and two sex chromosomes. Chromosome abnormalities can result in abortion in the first trimester of pregnancy, multiple congenital malformations, mental retardation, or abnormalities of sexual development. There are three recognizable autosomal trisomic syndromes (trisomy 13, trisomy 18, and trisomy 21). Each of these syndromes can be recognized by its clinical and radiographic characteristics and the diagnosis confirmed by chromosome analysis. Deletion of a portion of an autosome results in mental retardation and multiple congenital anomalies (e.g., cat cry syndrome, Wolf's syndrome). The somatic manifestations of sex chromosome abnormalities are not as severe as those of the autosomal abnormalities. Patients with Turner's syndrome (45,X) have short stature and primary amenorrhea and may have somatic and radiographic abnormalities. Klinefelter's syndrome (47.XXY) causes azospermia and may be the cause of moderate mental retardation. The XYY males are taller than average and have a higher than normal incidence of aberrant behavior.

The relative length and centromere index were compared in prometaphase and midmetaphase for each human chromosome from five normal men. There were very few differences between prometaphase and midmetaphase chromosomes in these two parameters. Chromosome 7 had a significantly different centromere index between prometaphase and midmetaphase, but no difference in relative length. This was accounted for by significant differences in the relative length of both 7p and 7q between prometaphase and midmetaphase; 7p became relatively less condensed and 7q relatively more condensed with progression from prometaphase to midmetaphase. For chromosome 1, the short arm was significantly longer than the long arm in both prometaphase and midmetaphase, a finding that underscores the structural similarity of this chromosome among the hominids.

The inactivated X chromosome has a site of unusually frequent folding in region Xq1, whereas a fold in Xq1 is uncommon on the active X. We investigated the pattern of X chromosome folding in high-resolution GTG- and RBG-stained preparations from four women. In early metaphase cells, slightly more than 50% of late-replicating Xs folded at Xq1----Xq21, compared with about 6% of early replicating Xs. The late-replicating X folded in about 80% of prometaphase cells; the early, in only about 14% of these cells. and the late-replicating X folded in 19 of 20 prophase cells. Occasionally, one X had an omega-shaped loop or apparent physical connection between Xq13 and Xq21.1. It is possible that a segment of Xq1 never completely uncoils and may help to provide continuity for the Barr body from one interphase to the next.

• A 10-year-old boy with mixed bilateral hearing loss and unusual facies was found to have frontometaphyseal dysplasia. He has prominent supraorbital ridges, height-span disproportion, dental abnormalities, thick clavicles, pectus excavatum, winged scapulae, joint contractures, and generalized muscular underdevelopment. Roentgenograms show supraorbital hyperostosis, antegonial notching of the mandible, flared ilia, contraction of the midpelvis, flattened vertebrae, deformities of the ribs posteriorly, flared metaphyses of the long tubular bones, and greatly widened and elongated metacarpals, metatarsals, and phalanges. His mother has prominent supraorbital ridges, distinct scoliosis, contractures of the fifth fingers, and conductive hearing loss. She also has many of the roentgenographic features of frontometaphyseal dysplasia. Frontometaphyseal dysplasia in a mother and son strongly suggests a dominant mode of inheritance. ( Am J Dis Child 130:259-261, 1976)

In humans, the X chromosome inactivation center and an X inactivation-associated metaphase fold are at the same location (bands Xq13----21) or are very closely associated. In other mammals, the location of the X inactivation center is unknown, but it has been suggested that the relationship between the inactivation center and the inactivation-associated fold may make it a useful marker for both identifying the inactivated X and locating the inactivation center in other mammalian species. If a similar metaphase fold is present in other mammals, the inactivation center would be located at the same site or very nearby. All of nine primate species did express an inactivation-associated fold. In most, the fold was located at the band homologous to human Xq13----q21. In one of two chimpanzees, band Xq23----q24 was implicated. In five other mammals an inactivation-associated fold was observed, but in two species, no fold was observed.

LE and tart cells were demonstrated in a black male infant whose serum contained milk-percipitating antibodies and who had pulmonary infiltrates. Immunoblasts, plasmocytoid lymphocytes, and an LE cell were found in a milk-stimulated skin window. The presence of LE cells corresponded to the presence of ENA antibody. Tart cells varied with oral milk challenge. A large Arthus type of skin reaction to injected milk was demonstrated. An oral feeding of milk resulted in a decrease in plasma C3. Lymphocyte transformation resulted from in vitro milk stimulation. ENA (extractable nuclear antigen) antibody and resulting LE cell formation possibly represented the combination of nuclear protein with milk antigen. The pulmonary infiltrates may represent a hypersensitivity pneumonitis characterized by both Arthus and cell-mediated reaction to milk.

We evaluated 22 patients with end-stage renal disease (ESRD) due to adult polycystic kidney disease (APKD) to assess their knowledge of the hereditary nature of the condition and to determine whether they received adequate genetic counseling. Patients were evaluated by means of a questionnaire and a review of their medical records. Only 5 of 22 (23%) knew their disorder was hereditary at the time of diagnosis, and in only 4 (18%) was genetic counseling suggested. In no instance had proband and spouse received genetic counseling together. Diagnostic studies of children at risk were rarely suggested. We also evaluated the children of 9 probands for APKD. Of 26 children evaluated, 17 had APKD (65%). Sixteen had no children at the time of testing. All but two of the 26 were less than 25 years old. Of the probands' children over 15 years of age, 55% knew the name of the condition in the family but only 9% knew they should be tested. Our study demonstrated inadequacy of genetic counseling and follow-up in this group of patients; we suggest that referral for counseling become a routine part of their management. Early diagnosis and effective counseling has the potential benefit for the individuals of making rational reproductive decisions appropriate for their situation. Counseling may have to be repeated during the course of the patients' disease, as their perception of risk may change with time. With advances in dialysis and transplantation, ESRD may not be as devastating in years to come as it is now.

If the mother is the fragile X gene carrier, her daughters (and sons) with the mutation are at high risk of mental retardation. If the father is the (clinically unaffected) carrier, his daughters are normal. This is strong evidence for a maternal effect. The decreased penetrance and variable expressivity in fra(X) offspring of carriers could be related, at least in part, to variabile expression or availability of some meternal factor between pregnancies. We hypothesize a maternal effect in fra(X), with variability in intelligence of heterozygotes and hemizygotes mediated mainly by the maternal uterus or placenta by virtue of different patterns of lyonization in those tissues between pregnancies. If the mother is a carrier, the matenal placenta could develop with a skewed proportion of the normal or the fra(X) genetically active. Each female or male embryo could be exposed to very different enviroments with respect to genetic activity fo the fra(X) chromosome, depending on the site of implantation within the uterus. If the father contributes the fra(X), the intrauterine enviroment is invariably normal and so are the daughters. Modifiers of the intrauterine effect could include lyonzation patterns in tissues of the carrier fetus, and preferential inactivation of the paternal X in extra-embryonic tissues. The ultimate phenotype of the developing heterozygote and hemizygote may be determined by a threshold effect and interaction between the maternal genotype, the placental genotype, and the fetal genotype. The possibility of maternal effects is testable and has implications for treatment.

• A 12-year-old boy being examined for vague chest pains was found to be suffering from acid maltase deficiency. Unlike previously reported cases in which vacuolization was most commonly noted in type I fibers, type II fibers were selectively involved in this patient and were atrophic. Type I fibers were spared, or occasionally contained one or more small globular structures consisting of large, complex aggregates of lysosomal profiles.

Of 226 consecutive papillary carcinoma patients, 14 indicated that at least one other relative was similarly affected. Pathology confirmation was obtained in 8 of the 14 families. Of the eight families with documented familial papillary carcinoma, one had five members, another had four members, and yet another had three members affected. The remaining families had two members affected. In those families with two or more persons with confirmed papillary carcinomas of the thyroid, 20 first- and second-degree relatives were examined. Of those, one had a previously unidentified papillary carcinoma and 6 had a benign thyroid disease (4 primary hypothyroidism and 2 simple goiters). High-resolution chromosome studies of four patients from four different families were normal, and there was no increase in chromosome breakage in a fifth patient from yet another family. Autosomal dominant inheritance is possible. Although there was no family history of lipomas, osteomas, or intestinal polyposis to suggest Gardner syndrome, four parents of our familial papillary carcinoma patients had colon cancer. In addition, three other relatives died of unidentified intra-abdominal cancer. The apparently high frequency of colon cancer and other abdominal cancer in relatives was an additional concern. Based on our observations, three clinical recommendations can be made: obtain a family history of all patients with papillary carcinoma of the thyroid, since between 3.5 to 6.2% will have another affected relative; when two or more persons in a family have papillary carcinoma of the thyroid, all first- and second-degree relatives should have a neck palpation by an experienced examiner; and families with two or more persons with papillary carcinoma should be observed for possible colon cancer.

A woman with myelofibrosis and myeloid metaplasia had a karyotype of 47,X,del(X)(q22),+del(X)(q22) in unstimulated peripheral blood and bone marrow aspirate cultures. The normal X chromosome was late replicating, and the two deleted X chromosomes always replicated early and synchronously. The karyotype from phytohemagglutin-stimulated peripheral blood cultures was uniformly 46,XX. Structurally abnormal X chromosomes are exceedingly rare in myeloproliferative disease. The abnormal karyotype very likely reflects monoclonal proliferation of an abnormal myeloid cell line. The X chromosome inactivation process, which acts upon embryonic somatic cells of all mammals, apparently does not react to postembryonic nondisjunction of the active X chromosome.

Twenty-nine patients with unilateral or bilateral cryptorchism underwent biopsies of the testis at the time of orchiopexy. Karyotype evaluation of fibroblasts obtained from tissue cultures of the biopsy specimen was completed counting a minimum of twenty-five cells. In 1 patient with multiple anomalies a 46,XY,Dq + karyotype was identified. All other karyotypes were normal suggesting cryptorchism is not associated with abnormal testicular cytogenetics.

Tandem repeats of chromosome material can arise as inverted or as direct duplications. Such duplications of the X chromosome are instructive regarding X-linked genetic determinants of phenotype. We describe a 40-year-old woman with a direct duplication Xq13.3 to Xq27.2, short stature, gonadal dysgenesis, and secondary amenorrhea. Comparison of her phenotype with that of two other women with a direct duplication of part of Xq confirms the existence of statural determinants within the region X13 to Xq21, determinants of ovarian function within X22 to X27, and the X inactivation center within or proximal to band Xq13.3. In humans, direct duplications are more frequent than inverted, but both forms are rare. The mean age of parents is normal in subjects with direct duplications, but is advanced in subjects with inverted duplications. An inverted duplication can arise from a three-break rearrangement that includes a U-type exchange; a similar origin (two breaks and a U-type exchange) and a parental age association can be postulated for dicentric inverted duplications including dicentric isochromosome X.

Curvature of the fingers is fairly common. While it is frequently seen without associated abnormality, it has been noted in conjunction with other pathological conditions often enough that its presence should alert the physician to their possibility. Since the lesion is usually asymptomatic, it is mentioned only briefly in radiologic textbooks. A book on congenital hand anomalies (2) shows crooked fingers in a variety of hand anomalies, but mentions no associated abnormalities. The purpose of this communication is to describe the various types of curved fingers and the conditions with which they are related, as well as the significant associated findings which may aid in a specific diagnosis. The study is based on a review of clinical material from the Henry Ford Hospital in Detroit and the University Hospital in Ann Arbor, as well as a review of the literature. The presence of curved fingers has been appreciated in the medical literature for many years. In an article on mongolism, Smith in 1896 (68) publ...

A 22-year-old white woman with acute myelofibrosis and agnogenic myeloid metaplasia is reported. She was found to have a consistent chromosomal aberration in her myeloblasts, interpreted as a 1-3 translocation. Bone marrow fibroblasts were successfully cultured, yielding a normal karyotype. The lymphocyte karyotype in this patient was also normal. It is proposed that these findings favor a secondary role of the fibroblastic proliferation in myelofibrosis and suggest that the primary cellular disturbance resides only in the hematopoietic cell lines.

IT HAS become standard practice to study the chromosomes of parents of children with Down's syndrome before giving genetic counseling. In some families the presence of a balanced translocation greatly increases the risk of having another similarly affected child. The chance of an unbalanced karyotype and, therefore, an affected individual can be estimated from the normal segregation ratios. Before giving counseling, however, it is important to realize that the existence in a parent of a balanced translocation can result in an abnormal child as the result of a chromosome abnormality other than an unbalanced translocation. In phenotypically normal individuals balanced translocations can at times interfere with meiosis in such a way as to cause nondisjunction.1-4The resulting offspring carry the balanced translocation and, in addition, are trisomic for another chromosome,2-4or in the case of the X chromosome, they are monosomic.1We are reporting our findings in