Genitourinary anomalies are a component manifestation in the ectodermal dysplasia, ectrodactyly, cleft lip/palate (EEC) syndrome.

Here we report on 13 individuals with the EEC syndrome from a single craniofacial clinic population. Eight of 13 underwent genitourinary (GU) evaluation; all had abnormal findings. Seven had anomalies of the urinary tract, and 3 had genital anomalies. To our knowledge, this is the first report of GU evaluation of the majority of EEC patients from a single clinic population. Results support the suggestion that GU anomalies are a major component of the EEC syndrome. Genitourinary evaluation of all EEC patients and their first degree relatives seems indicated. The abnormal findings observed to date suggest variable expression of an autosomal dominant gene.

Familial congenital funnel chest.

We observed three Chinese families in which congenital isolated funnel chest was segregating. This report confirms that funnel chest (pectus excavatum) can be transmitted as an autosomal dominant trait.

Linear disruption of umbilical cord: a rare anomaly of the cord associated with acute fetal distress and perinatal death/profound psychomotor retardation.

We report on a non-malformed child with severe microcephaly and profound psychomotor delay. Review of the delivery/birth records documented descriptions consistent with linear disruption of the umbilical cord. This rare anomaly typically leads to acute fetal distress and perinatal death. Severe microcephaly and psychomotor delay without other anomalies should prompt a careful review of the delivery/birth records to search for umbilical cord descriptions consistent with this diagnosis.

New syndrome characterized by sparse hair, prominent nose, small mouth, micrognathia, cleft palate, crumpled upper helices, digit anomaly, and mild developmental delay.

A brother and a sister show very similar clinical features, including sparse hair in the first year of life, prominent nose, small mouth, micrognathia, high arched palate or cleft palate, crumpled upper helices, flexion limitation of the distal interphalangeal joint of the fingers, and mild developmental delay. Their clinical appearance suggests a premature aging phenotype, but is not really compatible with the hitherto known syndromes of that group. The mode of inheritance is likely autosomal recessive.

3C (cranio-cerebello-cardiac) syndrome: a recently delineated and easily recognizable congenital malformation syndrome.

We report on two cases of 3C (cranio-cerebello-cardiac) syndrome. At least five previous cases are known. This recently delineated malformation syndrome is characterized by congenital anomalies of the skull, hindbrain, and heart. The anomalies include a high and prominent forehead, a hypoplastic vermis and posterior fossa cyst with or without hydrocephalus, and an atrial or atrio-ventricular septal defect with or without other heart anomalies. Most patients show a postnatal growth retardation, as well as a mild to moderate psychomotor retardation. Early death is usually in association with severe congenital heart defect. Aside from two affected sisters, the other reported cases (four girls and one boy) are sporadic cases; thus, a possible genetic nature and inheritance mode remain uncertain. Nonetheless, the possibility of an autosomal recessive mode of inheritance should be considered in the genetic counselling.

Identification, counselling, and outcome of two cases of prenatally diagnosed supernumerary small ring chromosomes.

De novo supernumerary small ring chromosomes have mainly been reported in pediatric patients with clinical abnormalities, thus, there may be bias of ascertainment. Reports on prenatally diagnosed cases with postnatal follow-up are rare. With the availability of chromosome specific alpha-satellite centromeric probes, the interest in these previously unidentifiable supernumerary small ring chromosomes has been rekindled [Callen et al.: J Med Genet 27: 155-159, 1990; Callen et al.: Am J Hum Genet 48:769-782, 1991; Callen et al.: Am J Med Genet 43:709-715, 1992]. We report on 2 prenatal diagnosis cases, where a ring was noted in 25 and 60% of the amniocytes, respectively. The initial G- and C-banding in Case 1 allowed an assumption of a chromosome 1 origin of the extra chromosome. This was confirmed by fluorescence in situ hybridization (FISH) studies using the appropriate probes. No similar initial assumption could be made in Case 2; thus, random trials with multiple probes were performed. A chromosome 19 origin in Case 2 was eventually concluded. The large amount of C-band positive material on the extra chromosome and the normal level 2 fetal ultrasound examination suggested a favorable outcome in both cases, but the possibility of mental retardation could not be ruled out. An empiric risk figure with regard to prenatally diagnosed de novo supernumerary small ring chromosomes is not available. Although the decision making processes of the parents were different, they both decided to continue the pregnancy. At age 9 months and 1 1/2 years both children, a girl and a boy, showed normal growth and development.

Oculocerebrocutaneous (Delleman) syndrome: a pleiotropic disorder affecting ectodermal tissues with unilateral predominance.

We present a patient with oculocerebrocutaneous syndrome. The boy shows only mild psychomotor delay in spite of rather severe appearing anomalies of the central nervous system. A primarily unilateral involvement of this syndrome is emphasized. A postzygotic/somatic mutation resulting in a mosaic state might account for the primarily ectodermal involvement, the unilateral predominance, and the sporadic nature of this syndrome. An alternative hypothesis of an environmental factor might also explain the clinical manifestations of the syndrome.

The ring nature of a tiny supernumerary chromosome fragment.

We report a 5 1/2-year-old girl with a tiny supernumerary chromosome fragment found in mosaic. The ring nature of the tiny fragment was demonstrated by the detection of the characteristic products of a ring chromosome. The clinical consequence of a ring chromosome and the impact of finding a supernumerary chromosome fragment, especially in the practice of prenatal chromosome diagnosis, are discussed.

Mapping of a gene (MRXS9) for X-linked mental retardation, microcephaly, and variably short stature to Xq12-q21.31.

Three boys from two families were identified as having a syndrome of X-linked mental retardation (XLMR) with microcephaly and short stature, clinically resembling Renpenning syndrome but with normal size of testicles in affected men. When the effort to map the gene for the above condition was initiated, it was realized that the two families were actually related to each other. Over 50 polymorphic markers of known locations along the X chromosome were scored in this family in a study to map the disease gene. Nine affected and four unaffected males were genotyped to produce a maximum LOD score of 4.42 at zero recombination with markers in proximal Xq. The results indicate that the gene responsible for this disorder is located in the cytogenetic Xq12 to Xq21.31 interval of the X chromosome within a section of chromosome of about 17 cM between the AR and DXS1217 loci over some 25 mb. Since the gene for the X-linked mental retardation from the original Saskatchewan family described by Renpenning [Renpenning et al., 1962: Can Med Assoc J 87:954-956; Fox and Gerrard, 1980: Am J Med Genet 7:491-495] was recently mapped to a different nonoverlapping region [Stevenson et al., 1998: Am J Hum Genet 62:1092-1101] this would appear to be a separate disorder.

Origin of 46,XY/46,XY,r(19) mosaicism.

We report on a case of 46,XY/46,XY,r(19) mosaicism. The patient shows minimal clinical abnormality and the terminal deletions prerequisite for the ring formation are not microscopically discernible. The origin of the mosaicism is discussed. Firstly, the mosaicism may represent chimerism with a prezygotic origin of the ring chromosome; secondly, the ring chromosome could have arisen postzygotically; and thirdly, the ring could have been of a prezygotic origin with the apparently normal cells actually containing reopened rings. The consequences of these hypothesis on genetic counselling are discussed.

Four new cases of inverted terminal duplication: a modified hypothesis of mechanism of origin.

We present 4 recently diagnosed cases of inverted tandem duplication with involvement of the respective terminal band. Based on these 4 cases and review of the literature, the term "inverted terminal duplication" is proposed to designate specifically the type of inverted tandem duplication which involves the terminal band. A modification of the previous hypothesis of mechanism of origin is advanced. It is speculated further that a telomeric deletion of a meiotic chromosome followed by a U-type reunion of the chromatids, considered to be the first steps of the proposed mechanism of origin, may not be a rare gonadal event.

Congenital central hypoventilation syndrome: inheritance and relation to sudden infant death syndrome.

We evaluated the families of 50 children with idiopathic congenital central hypoventilation syndrome (CCHS) to 1) test genetic hypotheses, 2) explore the relationship to Hirschsprung disease (HD), and 3) examine other clinical findings including sudden infant death syndrome (SIDS) in relatives of CCHS patients. A questionnaire was administered to parents of each proband to determine a detailed pedigree and medical history for 3 generations including 1,482 relatives. The data were analyzed under the unified mixed model method (assumes individual genotype composed of multifactorial [MF] and major locus [ML] components). Analysis was made of the Total dataset and on subdivided data sets: HIR1 = families of probands with HD (n = 8) vs. HIR2 = families of probands without HD; then under a premise that severe, chronic constipation may be a milder form of HD (i.e., ganglion cells present but dysfunctional), CON1 = families of probands with HD or constipation (n = 13) vs. CON2 = families of probands without HD or constipation. By statistical genetic analysis of the Total, HIR1, and CON1 datasets, the MF and ML hypotheses were about equally likely, with the MF model slightly more parsimonious. Although HIR2 and CON2 datasets indicated no familiality, statistical evidence of heterogeneity between the results of HIR1 and HIR2, or between CON1 and CON2 was lacking. A SIDS incidence of 11.2/1,000 was documented among the relatives of CON1 vs. 1.8/1,000 among relatives of CON2. Our results are consistent with familiality by either MF or ML models. Recurrence risk is likely < 5%. The relationship of CCHS to the high familial incidence of SIDS is intriguing and demands further investigation.

Tentative assignment of gene for oto-palato-digital syndrome to distal Xq (Xq26-q28).

Detailed physical mapping of oto-palato-digital (OPD) syndrome gene on the X-chromosome was attempted on a family of 3 generations with 2 affected men. Although the result remains statistically non-significant, it indicates that the OPD-I gene might be located on the distal Xq.

Chromosome 6q deletions: a report of two additional cases and a review of the literature.

Here we report on two additional cases of distal 6q deletions with one case showing a terminal deletion of chromosome 6 (46,XY, del(6)(pter----q26:)) and one case showing an interstitial deletion of chromosome 6 (46,XY, del(6)(pter----q23::q25----qter)). The association of retinal abnormalities in 6q deletions is supported, and the additional manifestations of skin hyperextensibility, sacral abnormality, and imperforate anus are described.

Syndrome of short stature, widow's peak, ptosis, posteriorly angulated ears, and joint problems: exclusion of the Aarskog (FGD1) gene as a candidate gene.

A syndrome encompassing postnatal onset of short stature, widow's peak, ptosis, posteriorly angulated ears, and limitation of forearm supination is reported in a boy and his mother. The boy has not yet experienced dislocation of patella or other joint anomaly except for limitation of supination of the forearms. On the other hand, the mother has a milder limitation of supination only on the left arm and is devoid of ptosis. Their condition is reminiscent of that described in the family reported by Kapur et al. [1989: Am. J. Med. Genet. 33: 357-363.], which showed an X-linked dominant mode of inheritance. DNA study on our family using an intragenic polymorphism of the Aarskog syndrome (FGD1) gene and four other adjacent markers convincingly excludes the possibility that their condition could be caused by a mutation of the FGD1 gene. Our family and the family reported by Kapur et al. may suggest segregation of a novel X-linked dominant condition.

Autosomal dominant transmission of familial laterality defects.

Heterotaxy results from failure to establish normal left-right asymmetry during embryonic development. Most familial cases are thought to be autosomal recessive. We have identified a family in which 4 individuals from 3 generations manifest laterality defects. Twenty-five family members have been examined. Two have complete reversal of normal laterality (situs inversus) while 2 others have asplenia, midline liver, and complex cardiac malformations (situs ambiguus). Two additional obligate gene carriers are anatomically normal (situs solitus). Male-to-male transmission confirms autosomal inheritance. Identification of this family establishes an autosomal dominant form of laterality defect, suggesting that a portion of sporadic cases may be new-mutation dominant or unrecognized familial cases. The finding of all forms of laterality (solitus, ambiguus, and inversus) among obligate disease gene carriers within a single family may be relevant to genetic evaluation and counseling in apparently isolated patients with laterality disturbance.

Determining the origins and the structural aberrations of small marker chromosomes in two cases of 45,X/46,X, + mar by use of chromosome-specific DNA probes.

A 17-year-old girl (S.M.) and a 13-year-old girl (C.L.) both with Ullrich-Turner syndrome (UTS) were found to have 45,X/46,X, + mar mosaicism. The marker chromosomes in both patients were very small in size. In S.M. the marker chromosome was present in 80% of phytohemagglutinin-stimulated lymphocytes, 28% of skin fibroblasts, and 11-20% of gonadal fibroblasts. In C.L., the small marker chromosome was found in 50% of stimulated lymphocytes. S.M. is of normal height, but C.L. is short. Molecular hybridization with a number of Y-specific DNA probes demonstrated their presence in S.M. but absence in C.L. In situ hybridization with Y-specific and X-centromere-specific DNA probes confirmed the Y origin of the marker chromosome in S.M. and the X origin of the minute chromosome in C.L. Biotinylated centromere and telomere probes were also used for in situ hybridization to show the presence of centromeric and telomeric sequences in the Y-marker chromosome, suggesting that the deletion of this marker chromosome is interstitial.

Double supernumerary isochromosome 9p in myeloproliferative syndrome.

The presence of supernumerary isochromosome 9p in duplicate in about 50% of bone marrow cells of an elderly female patient with myeloproliferative syndrome is reported.

Confirmation of centromeric fusion in 7p/1q translocation associated with myelodysplastic syndrome.

Fluorescence in situ hybridization (FISH) using chromosome 1- and chromosome 7-specific centromeric alpha-satellite probes was performed on the bone marrow (BM) cells of a patient with myelodysplastic syndrome (MDS) who had been treated for lymphoma and whose BM karyotype was initially considered to be 46,XY,-7,+der(1)t(1;7)(p11;p11). FISH results suggested the presence of both chromosome 1 and chromosome 7 centromeres in the rearranged chromosome. Thus, the correct karyotype should be written as 46,XY,-7,+der(1;7)(q10;p10).

Two cases of variant Philadelphia chromosome resulting from translocation (21;22) and (3;19;22).

Two further cases of variant Philadelphia chromosome are presented. The possible presence of a specific oncogene on the long arm of chromosome #22 is discussed.