American Journal of Medical GeneticsVolume 111, Issue 3 p. 324-327 Research Letter TCOF1 mutations excluded from a role in other first and second branchial arch-related disorders Alessandra Splendore, Alessandra Splendore Centro de Estudos do Genoma Humano, Departamento de Biologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilSearch for more papers by this authorMaria Rita Passos-Bueno, Corresponding Author Maria Rita Passos-Bueno passos@ib.usp.br Centro de Estudos do Genoma Humano, Departamento de Biologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilDepartamento de Genética—Instituto de Biociências, Universidade de São Paulo, Rua do Matão, 277, CEP 05508-900, Cidade Universitária, São Paulo, SP, Brazil.Search for more papers by this authorEthylin Wang Jabs, Ethylin Wang Jabs Institute of Genetic Medicine, Center for Craniofacial Development and Disorders, Department of Pediatrics, Medicine, and Plastic Surgery, Johns Hopkins University School of Medicine Baltimore, MarylandSearch for more papers by this authorLionel Van Maldergem, Lionel Van Maldergem Centre de Génétique Humaine, Loverval, BelgiumSearch for more papers by this authorEric A. Wulfsberg, Eric A. Wulfsberg Department of Pediatrics, University of Maryland, College Park, MarylandSearch for more papers by this author Alessandra Splendore, Alessandra Splendore Centro de Estudos do Genoma Humano, Departamento de Biologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilSearch for more papers by this authorMaria Rita Passos-Bueno, Corresponding Author Maria Rita Passos-Bueno passos@ib.usp.br Centro de Estudos do Genoma Humano, Departamento de Biologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilDepartamento de Genética—Instituto de Biociências, Universidade de São Paulo, Rua do Matão, 277, CEP 05508-900, Cidade Universitária, São Paulo, SP, Brazil.Search for more papers by this authorEthylin Wang Jabs, Ethylin Wang Jabs Institute of Genetic Medicine, Center for Craniofacial Development and Disorders, Department of Pediatrics, Medicine, and Plastic Surgery, Johns Hopkins University School of Medicine Baltimore, MarylandSearch for more papers by this authorLionel Van Maldergem, Lionel Van Maldergem Centre de Génétique Humaine, Loverval, BelgiumSearch for more papers by this authorEric A. Wulfsberg, Eric A. Wulfsberg Department of Pediatrics, University of Maryland, College Park, MarylandSearch for more papers by this author First published: 11 June 2002 https://doi.org/10.1002/ajmg.10567Citations: 14Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume111, Issue315 August 2002Pages 324-327 RelatedInformation

In this study, we extend our examination of the function of the Prrx1 (a.k.a Mhox, Prx1, K-2, and Pmx1) as well as Prrx2 (a.k.a. S8 and Prx2) genes by characterizing the expression of the human orthologs and their potential for causing specific human malformations. The expression pattern of PRRX2 and its close relative, PRRX1, were analyzed in human tissue by RT-PCR. Although the expression of these human genes is similar to their mouse orthologs, there are notable differences in expression. PRRX2 was detected in the human kidney and lung, whereas in mice and chickens neither of these tissues has been reported to express Prrx2. For PRRX1 the expression pattern was quite similar to other vertebrates, but the ratio of the two isoforms was reversed. To begin the search for the gene-disease connection, both genes were mapped to human chromosomes by FISH. The PRRX1 locus maps to 1q23, whereas the PRRX2 locus maps to 9q34.1. This localization, along with the recently described phenotypes of the gene-targeted Prrx1, Prrx2 and double mutant mice, enabled us to search the human disease databases for similar malformations. This examination suggested that mutations at the PRRX1 and/or PRRX2 loci could result in Nager Acrofacial Dysostosis (NAFD) syndrome. We obtained DNA samples from eight patients with NAFD, as well as two patients with Miller syndrome, and analyzed them for mutations in the PRRX1 and PRRX2 genes. The data excludes mutations in the presumed coding sequences of these genes from causing NAFD.

Nonsyndromic cleft lip with or without cleft palate is a common birth defect, affecting approximately 1 in 1,000 Caucasian newborns. Thirty-five multiplex families from the mid-Atlantic region of the United States and 22 families from central Mexico with a nonsyndromic form of cleft lip with or without cleft palate were selected for a linkage analysis. A tetranucleotide repeat marker (D2S443) located on the same yeast artificial chromosome as the transforming growth factor alpha locus was tested for linkage to a putative susceptibility Mendelian locus under varying levels of pentrance. No evidence for linkage between D2S443 and a susceptibility locus for cleft lip with or without cleft palate was found. Insight is given to explain this outcome in spite of the statistically significant associations found by other investigators.

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.

It has been reported that BCL3 on chromosome 19q, or a nearby gene, may play a role in the etiology of non-syndromic cleft lip with or without cleft palate (NSCL/P) in some families. We tested 30 USA and 11 Mexican multiplex NSCL/P families for four markers on chromosome 19q: D19S178, APOC2/AC1, APOC2/007, and BCL3. While likelihood-based linkage analysis failed to show significant evidence of linkage, the transmission disequilibrium test indicated highly significant deviation from independent assortment of allele 3 at the BCL3 marker in both data sets (USA:P = 0.001; Mexican: P = 0.018; both combined: P < 0.001) and for allele 13 of the D19S178 marker in the Mexican data set (P = 0.004). These results support an association, possibly due to linkage disequilibrium, between chromosome 19 markers and a putative NSCL/P locus.

Saethre-Chotzen, Crouzon, and Jackson-Weiss syndromes are craniosynostotic autosomal dominant conditions with a wide variability in expression. Saethre-Chotzen has been mapped to chromosome 7p by L. A. Brueton et al. (1992, J. Med. Genet. 29: 681-685), the Greig cephalopolysyndactyly gene was identified at 7p13 by A. Vortkamp et al. (1991, Nature 352: 539-540), and many cases of craniosynostosis have been associated with 7p deletions. We confirmed linkage of the Saethre-Chotzen syndrome locus to chromosome 7p. The tightest linkage was to locus D7S493 (Z = 5.04, θ = 0.00), and linkage and haplotype analyses refined the location of the gene to the region between D7S513 and D7S516. Jackson-Weiss and Crouzon syndrome loci were analyzed using markers spanning the entire 7p arm and were excluded, proving that they are nonallelic to Saethre-Chotzen, Greig cephalopolysyndactyly, and the del(7p) syndromes.

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.

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.

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.

Diploid/triploid mosaicism is an uncommon clinical syndrome with a subtle but distinctive phenotype. Characteristic features include prenatal and postnatal asymmetric growth deficiency, triangular and/or asymmetric facies, micrognathia, finger and/or toe syndactyly, clinodactyly, single transverse palmar creases, male genital anomalies, hypotonia and psychomotor retardation. This disorder is underdiagnosed because in 70% of cases the triploid cell line is only seen in fibroblasts. In cases in which a triploid cell line is found in lymphocytes, it usually occurs in less than 5% of cells. While some reports of diploid/triploid mosaicism have mentioned unusual skin pigmentary patterns, including hypomelanosis of Ito, it was only recently recognized that this is a helpful diagnostic clue in mosaic chromosome disorders. We report monozygotic twin girls with diploid/triploid mosaicism whose cutaneous pigmentary dysplasia led to their diagnosis.

Congenital heart defects (CHD) are a group of structural abnormalities that in humans have a combined incidence of approximately 1%. It is estimated that 4–5% of CHD are associated with chromosome abnormalities, 1–2% are associated with single gene syndromes, 1–2% are due to known teratogens, with the rest presumably determined multifactorially. We report on a brother and sister with tetralogy of Fallot with pulmonary atresia, and review the inheritance of familial conotruncal anomalies. We feel the small number of family clusters and the rare instances of consanguinity in non‐syndromal conotruncal defects are consistent with multifactorial determination. While it is prudent in counseling families with 2 or more individuals with conotruncal CHD to raise the possibility of single gene inheritance, we believe that current empiric recurrence risk estimates most accurately reflect their risks.

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.

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.

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.