Primary developmental field III: Clinical and epidemiological study of blastogenetic anomalies and their relationship to different MCA patterns

Opitz [1993: BD:OAS XXIX (1):3–37] suggested that during blastogenesis the entire embryo constitutes a developmental field, i.e., the primary developmental field. Based on this principle, he postulated that a single “hit,” that during late morphogenesis would cause a monotopic malformation, during blastogenesis would produce a polytopic malformation or an association. Lubinsky [1986: Am J Med Genet [Supp1]2:6–16] had stated previously that “since the embryo develops in an integrated manner, organized and differentiating spatially, temporally, and in an epimorphically hierarchical manner, disturbances result in nonrandom patterns of anomalies.” He then concluded that “associations are derivatives of causally nonspecific disruptive events acting on developmental fields.” These concepts, confirmed by our epidemiological observations [Martínez-Frías, 1994: Am J Med Genet 49:45–51], imply that some associations are, by definition, abnormalities of blastogenesis that is, that their component congenital anomalies are produced by events occurring during the first 4 weeks of development. We present an analysis of the characteristics of blastogenetic anomalies and their relationship with midline abnormalities, as well as with the schisis and VACTERL associations. Am. J. Med. Genet. 70:11–15, 1997. © 1997 Wiley-Liss, Inc.     

Recurrence of diaphragmatic agenesis associated with multiple midline defects: Evidence for an autosomal gene regulating the midline

We report the familial occurrence of diaphragmatic agenesis in association with other midline anomalies in a brother and sister. Opitz and Gilbert [Am J Med Genet 1982, 12:443–455] introduced the concept of the midline as a developmental field, and there have been reports of pedigrees compatible with the hypothesis of an X-linked gene regulating the development of the mid-line. This family suggests that an autosomal gene also contributes to the morphogenesis of midline structures. © 1994 Wiley-Liss, Inc.     

X-linked midline defects

Opitz and Gilbert [Am J Med Genet 12:443–455, 1982] have postulated that the midline may be a kind of developmental field. Although developmental field defects (primary malformations) usually occur sporadically, in some instances they can be caused by a single gene mutation. We report on a family in which the occurrence of midline defects was consistent with X-linked inheritance. Anomalies present in the family include hydrocephalus, anencephaly, cleft lip, congenital heart defect, renal agenesis, and hypospadias.     

Anophthalmia,intracerebral cysts,and cleft lip/palate: Expansion of the phenotype in oculocerebrocutaneous syndrome?

We report on a patient with multiple congenital anomalies including anophthalmia, cleft lip and palate, and central nervous system anomalies similar to the case reported by Leichtman et al. [1994: Am J Med Genet 50:39–41] and to oculocerebrocutaneous (Delleman) syndrome. Although the two cases and those with oculocerobrocutaneous syndrome may represent separate but overlapping entities, our patient and the case described by Leichtman et al. [1994: Am J Med Genet 50:39–41] may represent a more severe form of oculocerebrocutaneous syndrome. Am. J. Med. Genet. 68:39–42, 1997 © 1997 Wiley-Liss, Inc.     

X-linked midline defects

Opitz and Gilbert [Am J Med Genet 12:443-455, 1982] have postulated that the midline may be a kind of developmental field. Although developmental field defects (primary malformations) usually occur sporadically, in some instances they can be caused by a single gene mutation. We report on a family in which the occurrence of midline defects was consistent with X-linked inheritance. Anomalies present in the family include hydrocephalus, anencephaly, cleft lip, congenital heart defect, renal agenesis, and hypospadias.     

Distinctive autosomal or X-linked dominant syndrome of microcephaly,mild developmental delay,short stature,and distinctive face

We report on a mother and two sons with a syndrome of microcephaly, short stature, a distinctive face, broad thumbs and great toes, and mild developmental delay. There are similarities to the patients reported by Bawle and Horton [Am J Med Genet 33:382–384, 1989] and Evans [Clin Genet 39:178–180, 1991] but it is not certain whether the patients have the same condition. Inheritance could either be autosomal or X-linked dominant. © 1993 Wiley-Liss, Inc.     

Stratton-Parker syndrome: Confirmation of a new entity

Recently, Stratton and Parker [Am J Med Genet 32:169–173, 1989] reported on a child with a previously undescribed combination of growth hormone deficiency, wormian bones, dextrocardia, brachycamptodactyly, and other midline defects. We report on another patient with similar clinical signs. © 1994 Wiley-Liss, Inc.     

Developmental field defects and associations: Epidemiological evidence of their relationship

Lubinsky [1986: Am J Med Genet 2:9–16] has defined associations as derivatives of causally nonspecific disruptive events acting on developmental fields. Opitz [1992: Second International Workshop on Fetal Genetic Pathology] considers developmental fields as the basic biologic units of individual development and of evolution, and has stated that associations represent the idiopathic occurrence of multiple congenital anomalies during blastogenesis. These concepts imply that associations represent the concurrence of a greater number of developmental field defects (DFDs) than other patterns of multiple anomalies. The coding system for children with multiple congenital anomalies, developed in the Spanish Collaborative Study of Congenital Malformations (ECEMC), permits analysis of DFDs as morphogenetic units. Thus, we can study their presence in any type of MCA pattern, regardless of its etiology. Here we present the analysis of a selected group of DFDs of blastogenic origin. Specifically, we have studied how the groups of defects, usually comprised in those specifics DFDs, are observed in children who present different clinical entities such as associations, embryopathies, syndromes of known etiology, and others. The results of our analysis show a greater concurrence of the selected DFDs in associations than in other MCA pattern, and support the concept of Lubinsky [1985: Am J Med Genet 21:35–38; 1986] and Opitz [1992]. © 1994 Wiley-Liss, Inc.     

Anomalous inferior and superior venae cavae with oculoauriculovertebral defect: Review of Goldenhar complex and malformations of left-right asymmetry

We observed a girl with an interrupted, left inferior vena cava with hemiazygous continuation, bilateral superior venae cavae, heart defects, and sacral agenesis. She had macrostomia and bilateral ear tags and pits, as in oculoauriculovertebral defect. Maternal diabetes was present. The combination, which we call OAV-heterotaxia complex, supports the view that some cases of oculoauriculovertebral defect may be part of a midline field defect of blastogenesis. Am. J. Med. Genet. 75:88–94, 1998. © 1998 Wiley-Liss, Inc.     

An MCA/MR syndrome with hypocholesterolemia due to familial hypobetalipoproteinemia: report of a second patient with Nguyen syndrome

[Nguyen et al. (2003); Am J Med Genet 121A: 109-112] reported a boy with severe hypocholesterolemia due to autosomal dominant hypobetalipoproteinemia (ADBHL) associated with severe growth retardation, mental deficiency, epicanthal folds, a short nose with low nasal bridge and anteverted nares and bilateral partial cutaneous syndactyly of toes 2 and 3. Many of these manifestations resembled those in a mild form of Smith-Lemli-Opitz syndrome (SLOS). We report on a 13-year-old boy with ADHBL, who manifested a SLOS-like phenotype, including mental retardation and a characteristic face, similar to that of a patient reported by [Nguyen et al. (2003); Am J Med Genet 121A: 109-112]. Our patient supports the hypothesis by [Nguyen et al. (2003); Am J Med Genet 121A: 109-112] that ADHBL induced cholesterol deficiency has a significant effect on morphogenesis during embryogenesis, although additional genetic or environmental factors may be required to develop an SLOS-like phenotype in individuals with ADHLB. This is a second case of Nguyen syndrome.     

Choanal stenosis,hypothelia, deafness,recurrent dacryocystitis,neck fistulas,short stature,and microcephaly: report of a case

We report on a 11-year-old girl with bilateral choanal stenosis, hypothelia, hearing loss, recurrent dacryocystitis, neck fistulas, short stature, and microcephaly. Only three individuals with choanal atresia from a consanguineous family have been reported. One of the patients also had hypoplastic nipples, hypotonia, and delay in speech development. Similar clinical features were seen in two children reported by Greenberg [1987: Am J Med Genet 28:931-934] and Wilson et al. [1998: Am J Med Genet 75:220-222]. They were prenatally exposed to methimazole because of maternal Graves disease. Neck fistulas and microcephaly noted in our patient were not previously reported as features of the syndrome or in the patients prenataly exposed to methimazole. Our patient and those reported by Qazi et al. [1982: Am J Med Genet 13:413-416] most probably have a rare syndrome characterized by this distinctive combination of symptoms. Prenatal exposure to methimazole can cause a phenocopy of the syndrome, which was probably the case in the patients reported by Greenberg and Wilson et al.     

Duplication of the distal long arm of chromosome 15: report of three new patients and review of the literature

Patients with trisomies or duplications of distal 15q have rarely been reported in the literature. Previous authors [Zollino et al., 1999: Am J Med Genet 87:391-394] have described a distal 15q trisomy syndrome, including the unusual features of prenatal overgrowth, tall stature, macrocephaly, and craniosynostosis. We report three new patients with a duplication of 15q24-q26.3; features common to the two surviving patients include ptosis, small size, and developmental delay. None of these patients had craniosynostosis or overgrowth. We propose that the previously described distal 15q trisomy syndrome [Zollino et al., 1999: Am J Med Genet 87:391-394] may result from specific disruption of a gene linked to 15q25, rather than partial trisomy for the region.     

Frank-ter Haar syndrome with unusual clinical features

Frank-ter Haar syndrome first recognized by Frank et al. [Y. Frank, M. Ziprkowski, A. Romano, R. Stein, M.B. Katznelson, B. Cohen, R.M. Goodman, Megalocornea associated with multiple skeletal anomalies: a new genetic syndrome?, J. Genet. Hum. 21 (1973) 67–72.] and subsequently confirmed by ter Haar et al. [B. Ter Haar, B. Hamel, J. Hendriks, J. de Jager, Melnick–Needles syndrome: indication for an autosomal recessive form, Am. J. Med. Genet. 13 (1982) 469–477.]. The main clinical features of the syndrome are brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, macro cornea with or without glaucoma, full cheeks, small chin, bowing of the long bones, and flexion deformity of the fingers [S.M. Maas, H. Kayserili, J. Lam, M.Y. Apak, R.C. Hennekam, Further delineation of Frank-ter Haar syndrome, Am. J. Med. Genet. 131 (2004) 127–133.]. We report a child with Frank-ter Haar syndrome presenting unusual clinical features. Hypopigmented areas in hair, bilateral adducted thumb, bilateral contractures in elbows and pelvic limb, atrial septal defect have not been described previously in the literature. Our patient also had double-outlet right ventricle.     

Linkage disequilibrium, haplotype and association studies of a chromosome 4 GABA receptor gene cluster: candidate gene variants for addictions.

Strong genetic contributions to individual differences in vulnerability to addictions are well supported by classical genetic studies. Linkage and association genome scans for addiction vulnerability have provided converging evidence for several chromosomal regions which are likely to harbor allelic variants that contribute to such vulnerability. We and others have delineated a candidate addiction-associated chromosome 4p12 "rSA3" region based on convergent data from association genome scanning studies in polysubstance abusers [Uhl et al. (2001); Am J Hum Genet 69(6):1290-1300], linkage-based studies in alcoholism [Long et al. (1998); Am J Med Genet 81(3):216-221; Reich et al. (1998); Am J Med Genet 81(3):207-215] and association-based studies for alcoholism and association-based studies for individual differences in electroencephalographic (EEG) spectral power phenotypes [Porjesz et al. (2002); Proc Natl Acad Sci USA 99(6):3729-3733; Edenberg et al. (2004); Am J Hum Genet 74(4):705-714]. The rSA3 region contains interesting candidate genes that encode the alpha 2, alpha 4, beta 1, and gamma 1 receptor subunits for the principal brain inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) [Covault et al. (2004); Am J Med Genet Part B 129B:104-109; Edenberg et al. (2004); Am J Hum Genet 74(4):705-714; Lappalainen et al. (2005); Alcohol Clin Exp Res 29(4):493-498]. We now report assessment of single nucleotide polymorphism (SNP) genotypes in this region in three samples of substance abusers and controls. These results delineate the haplotypes and patterns of linkage disequilibrium in this region, focus attention of the GABRA2 gene and identify modest associations between GABRA2 genotypes and addiction phenotypes. These results are consistent with modest roles for GABRA2 variants in addiction vulnerabilities.     

Failure to replicate an association between the catechol‐O‐methyltransferase polymorphism and attention deficit hyperactivity disorder in a second,independently recruited Israeli cohort

Attention deficit hyperactivity disorder (ADHD) is a developmental syndrome expressed along three domains: inattention, hyperactive‐impulsive, and combined type. Both environmental and genetic factors contribute to the etiology of this complex disease. We previously reported an association in 48 ADHD triads (both parents and proband) between the catechol‐O‐methyl‐ transferase (COMT) polymorphism (especially the high enzyme activity val allele) and the Diagnostic and Statistical Manual of Mental Disorders (DSM IV) combined category (excluding inattention) of ADHD (however, see erratum, Am. J. Med. Genet. [Neuropsychiatr. Genet.] 96:893). In the current report, we attempted to replicate this finding in an independently recruited group of 70 nuclear families using the haplotype relative risk design. In the current investigation, no evidence for association of the COMT polymorphism and ADHD (or any of the DSM IV subtypes) was observed in either the current cohort or the expanded cohort of 118 Israeli triads. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:858–860, 2000. © 2000 Wiley‐Liss, Inc.     

Syndrome of coronal craniosynostosis, Klippel-Feil anomaly, and sprengel shoulder with and without Pro250Arg mutation in the FGFR3 gene.

A unique Pro250Arg point mutation in fibroblast growth factor receptor 3 (FGFR3) was initially reported by Bellus et al. [1996: Nat Genet 14:174-176] and the phenotype subsequently by Muenke et al. [1997: Am J Hum Genet 60:555-564], Reardon et al. [1997: J Med Genet 34:632-636], and Graham et al. [1998: Am J Med Genet 77:322-329]. These authors emphasized the pleiotropic nature of this form of coronal craniosynostosis, including brachydactyly with carpal and/or tarsal coalitions, with other anomalies at lower frequency. We report on a family with autosomal dominant coronal synostosis, segmentation and fusion anomalies of the vertebra and ribs, and Sprengel shoulder due to the Pro250Arg mutation. We also report a single case with an identical phenotype without the mutation.     

Polyasplenia, caudal deficiency, and agenesis of the corpus callosum

Fullana et al. [Am J Med Genet (suppl. 2): 23-29, 1986] reported on 2 sibs with an autosomal recessive syndrome of caudal deficiency and polyasplenia anomalies. We report on a similar patient in which agenesis of the corpus callosum (ACC) was also found. Such an association has not been reported previously. This finding of ACC is to be interpreted as another midline anomaly rather than as a causally independent malformation.     

Sporadic case of trichorhinophalangeal syndrome type III in a European patient.

Trichorhinophalangeal syndrome type III (TRP III) shares common traits with TRP I and II, including sparse hair, a "pear-shaped" nose, osteodysplasia with cone-shaped epiphyses, and autosomal dominant inheritance, but is distinguished by the presence of severe brachydactyly. TRP III was first described in 1984 in Japanese patients, one sporadic case [Sugio and Kajii, 1984: Am. J. Med. Genet. 19:741-753,1984] and two families [Niikawa and Kamei, 1986: Am. J. Med. Genet. 24:759-760; Naga? et al., 1994: Am. J. Med. Genet. 49:278-280], and more recently in a Turkish family [Itin et al., 1996: Dermatology 193:349-352]. We report an additional observation in a patient of European descent, who presented with short stature, cone-shaped epiphyses, sparse hair, a pear-shaped nose, normal intelligence and severe brachydactyly. Neither parent had manifestations of TRP and there was no other reported case in the family, indicating a presumably fresh mutation. Our observation refines the clinical spectrum of TRP III in another ethnic background and may be of help in identifying the gene or genes for TRP syndromes.     

Acrocallosal syndrome in Algerian boy born to consanguineous parents: Review of the literature and further delineation of the syndrome

We present a 17-month-old boy with the acrocallosal syndrome. He was born to consanguineous parents. Abnormal findings included agenesis of the corpus callosum, a ventricular septal defect (VSD), postaxial polydactyly of fingers, cleft soft palate, intestinal malrotation, large anterior fontanelle, prominent forehead, hypertelorism, epicanthic folds, short nose and mandible and preauricular skin tags, mixed hearing loss, laryngomalacia, and growth and severe motor and mental retardation. A review of previous reports on the acrocallosal syndrome shows considerable clinical variability; minimal diagnostic criteria are proposed. A developmental field defect with disturbance of midline development is suggested. Am. J. Med. Genet. 69:17–22, 1997. © 1997 Wiley-Liss, Inc.