A case-control study of nonsyndromic oral clefts in Maryland.

PURPOSE: Isolated, nonsyndromic oral clefts cases (n = 171) and unaffected controls (n = 182) were used to identify both genetic and environmental risk factors. METHODS: Infants born in Maryland between 1992 to 1998 with an isolated, nonsyndromic oral cleft [cleft lip (CL), cleft lip and palate (CLP), or cleft palate (CP)] were recruited and exposure plus family history data were collected. Controls were unaffected infants. DNA was collected from all cases and their parents, plus controls. RESULTS: No statistically significant association was found between any of the following: maternal smoking, vitamin use, urinary tract infection, or recreational drug use in either univariate analysis or after adjusting for maternal age and education. More control mothers reported alcohol use during the critical time period of pregnancy (one month before conception through the first trimester) as compared to case mothers. There was a 10-fold increase in risk to siblings of cases as compared to siblings of controls. Markers at four candidate genes were examined: transforming growth factor alpha (TGF alpha), transforming growth factor beta 3 (TGF beta 3), MSX1, and BCL3. Only MSX1 showed significant differences in allele frequencies between CP cases and controls. MSX1 also showed significant evidence of linkage disequilibrium with a susceptibility gene controlling risk for CP. CONCLUSION: Most environmental risk factors examined here gave little evidence of association with risk to isolated, nonsyndromic oral clefts, although any alcohol consumption seemed protective. MSX1 showed evidence of linkage disequilibrium in both case-control and case-parent trio analysis.

Rokitansky sequence in association with the facio-auriculo-vertebral sequence: part of a mesodermal malformation spectrum?

We report on a 4-year-old first-born monozygotic twin girl with a hypoplastic left face, mandible and zygoma, left microtia without an external auditory canal, a U-shaped cleft palate, right ectopic-fused kidneys, a blindly ending vaginal pouch, and absent uterus. We review 3 other cases with the manifestations of the Rokitansky and the facio-auriculo-vertebral sequence. The anomalies in these disorders can be thought of as deriving from an early defect or disruption in fetal mesoderm or its progenitor tissue at the time of primitive streak formation. They are frequently associated with other mesodermally derived defects or sequences and may together represent an extended polytopic field defect. While such speculation on how these spatially separated anomalies develop is probably simplistic, the concept of a mesodermal "malformation" spectrum is helpful in reminding the clinician to look for other mesodermal defects when one mesodermally derived defect or sequence is detected.

"Holoprosencephaly-polydactyly" (pseudotrisomy 13) syndrome: expansion of the phenotypic spectrum.

Analysis of familial cases of the so called "holoprosencephaly-polydactyly" ("pseudotrisomy 13") syndrome shows that neither holoprosencephaly, nor polydactyly are obligatory manifestations of this condition. This review of previous case reports shows that each of these anomalies is only found in approximately 60% of affected sibs, and therefore these sentinel abnormalities are not required for diagnosis. We propose a widening of the phenotypic spectrum of this syndrome and consideration of the use of an eponomic name, such as the Cohen-Gorlin syndrome, or clear recognition that the sentinel findings of holoprosencephaly and polydactyly are not essential for diagnosis. We propose the following diagnostic criteria for the syndrome. The diagnostic criteria for sporadic cases would include a normal karyotype and either (1) a combination of holoprosencephaly and post-axial polydactyly with or without other characteristics, or (2) a combination of holoprosencephaly with other characteristics but without polydactyly, or (3) a combination of postaxial polydactyly, brain defects (microcephaly, hydrocephaly, agenesis of corpus callosum) and other characteristics. The diagnostic criteria for the familial cases would be the same, except that, as long as the other sibs have no abnormalities contradicting the diagnosis, a normal karyotype would be required in only one affected sib.

Chondrodysplasia punctata: a boy with X-linked recessive chondrodysplasia punctata due to an inherited X-Y translocation with a current classification of these disorders.

Chondrodysplasia punctata (CDP) is a heterogeneous group of rare bone dysplasias characterized by punctate calcification of cartilage. The punctate calcifications are non-specific and have been seen in a wide variety of disorders including the Zellweger syndrome, warfarin, dilantin, alcohol and rubella embryopathies, vitamin-K-epoxide-reductase deficiency, chromosome trisomies 18 and 21, the Smith-Lemli-Opitz syndrome, prenatal infectious chondritis, hypothyroidism, and other rare disorders. We report on a boy with short stature, developmental delay, nasal hypoplasia, telebrachydactyly, hypoplastic genitalia, CDP, ichthyosis, hypoplastic genitalia, and a 46-X,+der(X),t(X;Y)(p22.31;q11.21), Y karyotype. Genomic DNA probe analysis was interpreted as showing that the translocation breakpoint was within the X-linked Kallmann syndrome gene. We review a current classification of these disorders that includes 3 well-defined single gene disorders. These include an autosomal recessive rhizomelic type with early lethality, an X-linked dominant type with presumed male lethality, and an X-linked recessive type that has only been described as part of a contiguous gene deletion syndrome.

Autosomal dominant tetramelic postaxial oligodactyly.

Postaxial limb deficiencies are most frequently unilateral and sporadic with deficiencies of the ulnar ray about one-third as common as those affecting the radial ray. Postaxial deficiency occurs in a number of genetic and sporadic syndromes, but isolated inherited tetramelic, postaxial oligodactyly has to our knowledge not been described. We report an affected mother and her 3 affected children from a 4-generation family with apparent autosomal dominant, non-syndromic, tetramelic, postaxial oligodactyly. The affected individuals manifest a very uniform pattern of postaxial deficiency ranging from complete absence of the 5th metacarpals, metatarsals, and phalanges to complete absence of the 5th metacarpals and metatarsals, but with some residual distal 5th phalanges. Limb buds may be considered a single developmental field with development proceeding rostral to caudal. Digit formation is apparently controlled by the zone of polarizing activity which releases a diffusible morphogen specifying positional information along the anterior/posterior axis. Recent investigations using chick and mouse embryo models suggest that 5' members of the Hox-4 gene cluster are responsible for interpreting this positional information to effect digit formation. The present family may represent a defect in Hox-4 gene patterning of hand and foot formation, an abnormality in morphogen gradient formation or alternately an inability of the most ulnar rays to respond to morphogen (receptor defect).

Vertebral hypersegmentation in a case of the VATER association.

Associations are statistical clusterings of malformations not known to be polytopic field defects, sequences, or syndromes. The VATER association is a nonrandom association of malformations including vertebral, anal, cardiovascular, tracheoesophageal, genitourinary, and limb defects. The caudal "dysplasia" sequence of lumbosacral vertebral defects, genitourinary abnormalities, and imperforate anus overlaps the VATER association. The cloacal membrane agenesis sequence is a pattern of malformations resulting in the absence of anal, genital, and urinary orifices with associated malformations in surrounding structures. We report on a 37-week gestation liveborn male with oligohydramnios deformations, tetralogy of Fallot, "H-type" tracheoesophageal fistula, duodenal atresia, imperforate anus, urethral atresia, undescended testes, absent right kidney with a small dysplastic left kidney, a "cloacal-like" abnormality of the bladder and distal bowel, and thoracic and lumbar vertebral hypersegmentation. This patient has manifestations of the VATER association, the caudal dysplasia sequence, and the cloacal membrane agenesis sequence. We propose that some of his defects may represent a malformation sequence secondary to excessive embryonic flexion resulting from vertebral hypersegmentation.

Third Prader-Willi syndrome phenotype due to maternal uniparental disomy 15 with mosaic trisomy 15.

We report on a boy with mosaicism for trisomy 15 and Prader-Willi syndrome (PWS) due to maternal isodisomy for chromosome 15. His phenotype is consistent with PWS and trisomy 15 mosaicism. Although our patient is unusual in having maternal isodisomy rather than the more common maternal heterodisomy, we think that his more severe PWS phenotype is due to his trisomy 15 mosaicism rather than to homozygosity for deleterious chromosome 15 genes. We propose that individuals with PWS have one of three similar but distinctive phenotypes depending on the cause of their condition. Patients with paternal deletions have the typical PWS phenotype, patients with maternal UPD have a slightly milder phenotype with better cognitive function, and those with maternal UPD and mosaic trisomy 15 have the most severe phenotype with a high incidence of congenital heart disease. These phenotype-genotype differences are useful to guide the work-up of patients with suspected PWS and to provide prognostic counseling for families.

A 15 leads to 1 translocation in a patient mosaic for presence or absence of an isodic(15p)(q11).

We report a patient with a 15 leads to 1 translocation who was mosaic for presence or absence of an isodic(15p)(q11). Her phenotype is similar to that of patients with deletions of proximal 15q or isodic(15p). Several phenotypes, including the Prader-Labhart-Willi syndrome, have been described with abnormalities of proximal 15q and have in common severe hypotonia, developmental delay, and lack of major congenital anomalies. Our patient is the first to be described with an isodic (15p)(q11) associated with a nonreciprocal translocation. We think her isodic(15p)(q11) arose as a result of a sister chromatid fusion rather than nonsister chromatid exchange as has been proposed in most other cases. Because of the various phenotypes described with proximal 15q abnormalities, we recommend caution in the assignment of specific phenotypes to small chromosome changes in this area.

Familial DiGeorge/velocardiofacial syndrome with deletions of chromosome area 22q11.2: report of five families with a review of the literature.

The DiGeorge (DG), velocardiofacial (VCF), and conotruncal anomaly-face (CTAF) syndromes were originally described as distinct disorders, although overlapping phenotypes have been recognized. It is now clear that all three syndromes result from apparently similar or identical 22q11.2 deletions, suggesting that they represent phenotypic variability of a single genetic syndrome. We report on 12 individuals in five families with del(22)(q11.2) by fluorescent in situ hybridization, and define the frequency of phenotypic abnormalities in those cases and in 70 individuals from 27 del(22)(q11.2) families from the literature. Common manifestations include mental impairment (97%), abnormal face (93%), cardiac malformations (68%), thymic (64%) and parathyroid (63%) abnormalities, and cleft palate or velopharyngeal insufficiency (48%). Familial DG, VCF, and CTAF syndromes due to del(22) (q11.2) show significant inter- and intrafamilial clinical variability consistent with the hypothesis that a single gene or group of tightly linked genes is the common cause of these syndromes. Up to 25% of 22q deletions are inherited, indicating that parents of affected children warrant molecular cytogenetic evaluation. We propose use of the compound term "DiGeorge/velocardiofacial (DG/VCF) syndrome" in referring to this condition, as it calls attention to the phenotypic spectrum using historically familiar names.

Confirmation of the Catania brachydactylous type of acrofacial dysostosis: report of a second family.

The acrofacial dysostoses (AFD) are a heterogeneous group of disorders combining varying severities of mandibulofacial dysostosis (MFD) with pre- and/or postaxial limb abnormalities. In 1993, Opitz et al. [Am J Med Genet 47:660-678] described a new AFD with mental retardation in a Sicilian mother and her four sons characterized by intrauterine growth retardation (IUGR), postnatal short stature, microcephaly, widow's peak, MFD without cleft palate, mild pre- and postaxial limb hypoplasia with brachydactyly, mild interdigital webbing, and cryptorchidism and hypospadias in males. We report a mother and daughter with this same phenotype, confirming this new type of AFD and expanding the clinical phenotype to include frequent dental caries. Analysis of cephalometric and metacarpophalangeal profiles in this family showed no distinctive diagnostic abnormalities. This family confirms the Catania brachydactylous type of AFD and supports an autosomal dominant mode of inheritance, although male-to-male transmission has not been demonstrated.

Acrofacial dysostosis with ambiguous genitalia.

We report on a 46,XY infant with mandibulofacial dysostosis, preaxial and postaxial limb anomalies, urethral stenosis with left hydronephrosis, and ambiguous genitalia with phallic/scrotal transposition. This infant with atypical pre/postaxial acrofacial dysostosis (AFD) is the first to be reported with ambiguous genitalia. The acrofacial dysostoses are a heterogenous group of disorders characterized by varying degrees of mandibulofacial dysostosis with acral limb defects and may represent a polytopic field defect. These disorders have generally been separated on the basis of their limb anomalies into preaxial, postaxial, lethal, and atypical types. Most cases are sporadic, but various causes have been postulated including autosomal dominant and recessive inheritance, a chromosome 2q duplication, and a possible case of diabetic embryopathy. We review the nonfacial/limb anomalies in other cases of AFD and compare them to those of our case, thereby expanding the spectrum of anomalies in these disorders.

Chromosome 10qter deletion syndrome: a review and report of three new cases.

We report on three patients with terminal deletions of chromosome 10q and compare them to 15 previously reported patients. A similar facial appearance with a prominent beaked nose, large and/or malformed ears, and a pattern of major abnormalities including severe mental retardation, cardiac anomalies, and anogenital anomalies are reviewed. We feel the manifestations of del 10qter are sufficiently distinct to suggest this diagnosis on clinical examination.

OEIS complex (omphalocele-exstrophy-imperforate anus-spinal defects) in monozygotic twins.

The omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex is a consistent and recognizable pattern of midline abdominal and pelvic defects. It is rare, affecting 1 in 200,000 to 400,000 pregnancies and is even rarer in twin gestations. This is an autopsy study of OEIS complex in monozygotic twins after pregnancy termination at 20 weeks of gestation. Unremarkable family history but concordance of monozygotic twins for the defects may support the theory that early malformation complexes, e.g., OEIS, and monozygotic twinning are manifestations of the same disturbance of early blastogenesis.

Antenatal diagnosis of lethal skeletal dysplasias.

Lethal skeletal dysplasias (LSD) are a heterogeneous group of rare but important genetic disorders characterized by abnormal growth and development of bone and cartilage. We describe the diagnosis and outcome of 29 cases of lethal skeletal dysplasias evaluated between January 1989 and December 1996 at the University of Maryland Medical Center and the Ultrasound Institute of Baltimore. Two cases presented at delivery with no prenatal care while the remaining 27 cases were identified by antenatal sonography. Final diagnoses included thanatophoric dysplasia (14), osteogenesis imperfecta, type II (6), achondrogenesis (2), short rib syndromes (3), campomelic syndrome (2), atelosteogenesis (1), and no evidence of a skeletal dysplasia (1). Twenty out of 27 pregnancies were terminated with an average at detection of 21.6 weeks. The other 7 pregnancies that went on to deliver had an average age at detection of 29.2 weeks. Fetal abnormalities in the terminated pregnancies were identified at a significantly earlier gestational age (P = 0.0016) than the pregnancies that continued. While the identification of LSD by sonography was excellent (26/27), only 13/27 (48%) were given an accurate specific antenatal diagnosis. In 8/14 (57%) cases with an inaccurate or nonspecific diagnosis there was a significant or crucial change in the genetic counseling. Thus, while antenatal sonography is an excellent method for discovering LSD, clinical examination, radiographs, and autopsy are mandatory for making a specific diagnosis.

A complex chromosome rearrangement in a boy with autism.

Autism is a rare behavioral phenotype defined by a qualitative impairment in reciprocal social interaction, impairment in communication and imaginative activity, and a markedly restricted repertoire of activities and interests. It is the most severe and prototypical form of the general category of Pervasive Developmental Disorders of Childhood. Using even strict diagnostic criteria, the currently described etiologies of autism are heterogeneous, with the majority of cases continuing to be idiopathic. At present, it is not clear whether autism is merely a behaviorally defined phenotype arising from diverse etiologies or a separate category of psychological dysfunction for which some unifying etiology exists. Complex chromosome rearrangements (CCR) are rare structural abnormalities involving at least three chromosomes and three or more break-points. We report a 6.5-year-old boy with classic infantile autism and a CCR involving chromosomes 1, 7, and 21. We discuss the possible relationship of his chromosome abnormality to the etiology of his autism.

The McKusick-Kaufman syndrome: phenotypic variation observed in familial cases as a clue for the evaluation of sporadic cases.

The characteristic clinical picture of the McKusick-Kaufman syndrome was observed in a girl of Belorussian background. A supernumerary nipple was the only finding not previously described in reported familial cases of this syndrome. In general, the range of phenotypic variability should be the same in both familial and sporadic cases. For this reason we feel that some sporadic cases reported as patients with unusual variants of the McKusick-Kaufman syndrome have more likely "new" genetic syndromes or non-genetic conditions, which only resemble the syndrome. The comparison of the phenotypes of alleged sporadic cases with familial cases of single gene syndromes should be helpful in syndrome delineation, if the number of familial observations is sufficient.

Phenotypic variability of del(2) (q22-q23): report of a case with a review of the literature.

An interstitial deletion of 2q22-q23 was found in a 2.5 year old boy with multiple congenital abnormalities (including Hirschsprung's disease) and severe mental retardation. Comparison with seven additional cases of 2q deletions from the literature does not allow the delineation of a clinically recognizable syndrome. Some of the previously reported patients had features rarely observed in chromosomal syndromes (i.e., occipital encephalocele and tracheo-esophageal fistula). Possible reasons for such phenotypic variability are briefly discussed.

Duchenne muscular dystrophy in a 46 XY female.

The most common muscular dystrophy, Duchenne muscular dystrophy (DMD), is an X-linked disorder that ordinarily has full clinical expression only in males. Reports of typical clinical features in females are rare but have occurred with a phenotypically identical autosomal recessive muscular dystrophy as well as in females with X-chromosome abnormalities such as the Turner syndrome. A girl with full expression of DMD due to a 46 XY karyotype is reported, and other clinical conditions in which expression of the DMD gene occurs in females are reviewed.

The acrocallosal syndrome: expansion of the phenotypic spectrum.

A family demonstrating the acrocallosal syndrome in a female proband whose sister had anencephaly is described. Two similar cases were found in the literature (Gelman-Kohan et al., 1991; Cataltepe and Tuncbilek, 1992). Analysis of the multiplex family data suggests that anencephaly may be an extreme manifestation of the spectrum of brain anomalies associated with the acrocallosal syndrome.