RESUMO
History has preserved a beautiful 16th century woodcut print, which depicts an infant with several malformations. The German inscription describes the infant's hypotonia and ectopic growths, and the image itself shows a child with an ectopic accessory third lower limb, a large papilla, and an omphalocele-like growth. The 'case' bears striking similarity to reported human cases of the disorganization (Ds) syndrome. This article describes the woodcut, describes Ds, and then explains how the image may represent the earliest depiction of Ds in history.
Assuntos
Anormalidades Múltiplas/história , Pinturas/história , Animais , História do Século XVI , Humanos , Lactente , Masculino , Camundongos Mutantes , SíndromeRESUMO
Microdeletions of chromosomal region 2q23.1 that disrupt MBD5 (methyl-CpG-binding domain protein 5) contribute to a spectrum of neurodevelopmental phenotypes; however, the impact of this locus on human psychopathology has not been fully explored. To characterize the structural variation landscape of MBD5 disruptions and the associated human psychopathology, 22 individuals with genomic disruption of MBD5 (translocation, point mutation and deletion) were identified through whole-genome sequencing or cytogenomic microarray at 11 molecular diagnostic centers. The genomic impact ranged from a single base pair to 5.4 Mb. Parents were available for 11 cases, all of which confirmed that the rearrangement arose de novo. Phenotypes were largely indistinguishable between patients with full-segment 2q23.1 deletions and those with intragenic MBD5 rearrangements, including alterations confined entirely to the 5'-untranslated region, confirming the critical impact of non-coding sequence at this locus. We identified heterogeneous, multisystem pathogenic effects of MBD5 disruption and characterized the associated spectrum of psychopathology, including the novel finding of anxiety and bipolar disorder in multiple patients. Importantly, one of the unique features of the oldest known patient was behavioral regression. Analyses also revealed phenotypes that distinguish MBD5 disruptions from seven well-established syndromes with significant diagnostic overlap. This study demonstrates that haploinsufficiency of MBD5 causes diverse phenotypes, yields insight into the spectrum of resulting neurodevelopmental and behavioral psychopathology and provides clinical context for interpretation of MBD5 structural variations. Empirical evidence also indicates that disruption of non-coding MBD5 regulatory regions is sufficient for clinical manifestation, highlighting the limitations of exon-focused assessments. These results suggest an ongoing perturbation of neurological function throughout the lifespan, including risks for neurobehavioral regression.
Assuntos
Ansiedade/genética , Transtorno Bipolar/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , MutaçãoRESUMO
Ahi-1 (Abelson helper integration site 1) is a novel gene frequently activated by provirus insertional mutagenesis in murine leukemias and lymphomas. Its involvement in human leukemogenesis is demonstrated by gross perturbations in its expression in human leukemia cells, particularly in cutaneous T-cell lymphoma cell lines where increases in AHI-1 transcripts of 40-fold are seen. To test directly whether deregulated expression of AHI-1 contributes to their transformed properties, knockdown of AHI-1 expression in Hut78 cells, a cell line derived from a patient with Sezary syndrome (SS), was performed using retroviral-mediated RNA interference. Retroviral-mediated suppression specifically inhibited expression of AHI-1 and its isoforms in transduced cells by 80% and also reduced autocrine production of interleukin (IL)-2, IL-4 and tumor necrosis factor-alpha (TNFalpha) by up to 85%. It further significantly reduced their growth factor independence in vitro and the ability to produce tumors in immunodeficient mice. Interestingly, aberrant expression of AHI-1, particularly truncated isoforms, was present in CD4+CD7- Sezary cells from some patients with SS. Elevated expression of IL-2 and TNFalpha was also found in these cells. These findings provide strong evidence of the oncogenic activity of AHI-1 in human leukemogenesis and demonstrate that its deregulation may contribute to the development of SS.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Linfoma de Células T/fisiopatologia , Síndrome de Sézary/fisiopatologia , Neoplasias Cutâneas/fisiopatologia , Proteínas Adaptadoras de Transporte Vesicular , Animais , Sequência de Bases , Western Blotting , Linhagem Celular , Citocinas/biossíntese , Primers do DNA , Vetores Genéticos , Humanos , Linfoma de Células T/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Interferência de RNA , Retroviridae/genética , Neoplasias Cutâneas/patologiaRESUMO
The autosomal dominant progeroid form of cutis laxa is a recently identified multiple congenital anomaly disorder characterized by thin, wrinkled skin, a progeroid appearance, intra-uterine growth retardation, postnatal growth restriction, psychomotor developmental delay, microcephaly, cataract, hypotonia and contractures. De novo heterozygous mutations in ALDH18A1 have been described in this condition. We present neuroimaging abnormalities in three patients. One patient had intracranial arterial and venous tortuosity, widened ventricular and extra-axial cerebrospinal fluid (CSF) spaces, wide perivascular spaces and increased T2 signal intensity in the cerebral white matter over time. The second patient had vascular tortuosity. The third patient had prominent ventricular and extra-axial cerebrospinal fluid (CSF) spaces on CT. We propose an embryological mechanism for the development of intracranial vascular tortuosity and discuss the anatomical basis of wide perivascular spaces in relation to this syndrome. Although we do not know the clinical implications of these cerebral vascular anomalies, we suggest inclusion of neuroimaging in the baseline evaluation of these patients.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Cútis Laxa/diagnóstico por imagem , Cútis Laxa/patologia , Aldeído Desidrogenase/genética , Cútis Laxa/genética , Feminino , Humanos , Lactente , Masculino , Mutação , Neuroimagem/métodos , SíndromeRESUMO
Six patients with univentricular heart and one patient with d-transposition of the great arteries had transection of the main pulmonary artery with an end to side anastomosis of the main pulmonary artery to the ascending aorta to relieve subaortic obstruction. Two operations were performed as a palliative procedure within the first 6 months of life and five were performed as part of a definitive repair (four modified Fontan procedures and one repair of transposition of the great arteries with ventricular septal defect). There was one surgical death (14%) occurring 1 day postoperatively from low cardiac output. The remaining six patients are doing well 1 to 19 months postoperatively (mean 11.4 months). The proximal pulmonary artery to ascending aorta end to side anastomosis is an effective means of bypassing subaortic obstruction associated with complex congenital heart disease.
Assuntos
Aorta/cirurgia , Estenose Aórtica Subvalvar/cirurgia , Cardiomiopatia Hipertrófica/cirurgia , Cardiopatias Congênitas/cirurgia , Artéria Pulmonar/cirurgia , Estenose Aórtica Subvalvar/congênito , Feminino , Comunicação Interventricular/cirurgia , Ventrículos do Coração/anormalidades , Ventrículos do Coração/cirurgia , Humanos , Lactente , Recém-Nascido , Masculino , Complicações Pós-Operatórias , Transposição dos Grandes Vasos/cirurgiaRESUMO
Upper limb malformations occur in patients with congenital heart disease as multifactorial, chromosomal or teratogenic combinations, and can be predictable (nonrandom) or sporadic (random) associations. The cardiac and limb defects represent either essential features of a syndrome or less common or less significant components. A practical classification is proposed based on the frequency and relative consistency of upper limb and cardiac associations. Recognition of upper limb malformations helps to identify accompanying cardiac disease and aids in the choice of diagnostic and therapeutic interventions in determination of prognosis and in genetic counseling. Upper limb malformations are the commonest skeletal abnormalities in patients with congenital heart disease, but it is also important to know with which limb defects concordance is low.
Assuntos
Anormalidades Múltiplas/etiologia , Braço/anormalidades , Cardiopatias Congênitas/complicações , Anormalidades Múltiplas/classificação , Aberrações Cromossômicas , Cardiopatias Congênitas/classificação , Humanos , SíndromeRESUMO
Two-dimensional echocardiography (2-D echo) was used as an imaging device for the performance of balloon atrial septostomy (n = 25) and blade atrial septostomy (n = 3). Biplane fluoroscopy with 2-D echo or 2-D echo alone were used in the cardiac catheterization laboratory to place the balloon or blade septostomy catheter in the left atrium. Echocardiography confirmed the position of the septostomy catheter before pullback. Balloon inflation and balloon or blade pullback to the right atrium was performed with 2-D echocardiographic visualization. In 8 critically ill newborn infants, balloon atrial septostomy was done in the neonatal intensive care unit without flouroscopy. The safety and efficacy of 2-D echo to assist balloon or blade atrial septostomy in the catheterization laboratory or as the sole imaging device in the neonatal intensive care unit are confirmed. Use of the subcostal 4-chamber and sagittal views to image cardiac anatomy and catheter position during the procedure are emphasized. Two-dimensional echo is particularly helpful in cases of cardiac malposition and during transseptal puncture of the atrial septum before blade septostomy, and lowers radiation dose when used in conjunction with fluoroscopy.
Assuntos
Ecocardiografia/métodos , Cardiopatias Congênitas/cirurgia , Cuidados Paliativos/métodos , Transposição dos Grandes Vasos/cirurgia , Cateterismo Cardíaco/métodos , Pré-Escolar , Átrios do Coração/cirurgia , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Cuidados Intraoperatórios/métodosRESUMO
We report on a mother and daughter with the Brachmann-de Lange syndrome which supports the view that in some families this disorder is due to autosomal dominant inheritance. A review of the literature concerning autosomal and recessive inheritance of this syndrome is presented.
Assuntos
Síndrome de Cornélia de Lange/genética , Genes Dominantes , Adulto , Criança , Face/anormalidades , Feminino , Transtornos do Crescimento/genética , Deformidades Congênitas da Mão/genética , Humanos , Deficiência Intelectual/genéticaRESUMO
We report on monozygotic twins with Turner syndrome (45,X) with discordant phenotypes. One twin had severe neck webbing and extremity edema and died of severe coarctation of the aorta. The other twin had fewer craniofacial anomalies and no congenital heart defect, suggesting a pathogenetic relationship between cardiac abnormality and phenotype severity.
Assuntos
Doenças em Gêmeos , Cardiopatias Congênitas/genética , Síndrome de Turner/genética , Gêmeos Monozigóticos , Gêmeos , Feminino , Humanos , Recém-Nascido , Cariotipagem , Linfócitos/citologia , FenótipoRESUMO
Sotos syndrome is characterized by somatic overgrowth, i.e., macrocephaly and tall stature. Because the cause and pathogenesis of Sotos syndrome remain unknown, we selected nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) as possible genes mutated in Sotos syndrome. In seven patients with the classic phenotype, we excluded mutations in these growth factor genes. It is possible that these three genes are not involved in the cause of Sotos syndrome, or alternatively, mutations could not be identified in the small number of patients studied.
Assuntos
Gigantismo/etiologia , Fatores de Crescimento Neural/genética , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Criança , Pré-Escolar , Feminino , Testes Genéticos , Gigantismo/genética , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/genética , Humanos , Lactente , Masculino , Mutação , Neurotrofina 3/genética , Polimorfismo Conformacional de Fita Simples , SíndromeRESUMO
Formation of the atrioventricular canal (AVC) results from complex interactions of components of the extracellular matrix. In response to signaling molecules, endothelial/mesenchymal transformations are crucial to normal development of the AVC. Atrioventricular septal defects (AVSDs) can result from arrest or interruption of normal endocardial cushion development. The presence of AVSDs has been associated with chromosome abnormalities, laterality or left-right axis abnormalities, and a variety of syndromes. An AVSD susceptibility gene has been identified in a large kindred with many affected members. Studies of transcription factors and signaling molecules in heart development over the past decade are paving the way for our understanding of the heterogeneous mechanisms of causation of AVSDs.
Assuntos
Comunicação Atrioventricular/genética , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Animais , Padronização Corporal/genética , Aberrações Cromossômicas/embriologia , Aberrações Cromossômicas/patologia , Transtornos Cromossômicos , Mapeamento Cromossômico , Cromossomos Humanos/genética , Cromossomos Humanos/ultraestrutura , Modelos Animais de Doenças , Síndrome de Down/patologia , Comunicação Atrioventricular/embriologia , Comunicação Atrioventricular/epidemiologia , Coração Fetal/patologia , Heterogeneidade Genética , Humanos , Mesoderma , Camundongos , Morfogênese/genética , Baço/anormalidades , Síndrome , TrissomiaRESUMO
We describe 2 unrelated families with male-to-male transmission of Nager syndrome. All 5 affected individuals have moderate expression of the phenotype. One affected boy also has Hirschsprung disease. Although Nager acrofacial dysostosis usually occurs sporadically, both recessive and dominant inheritance have been suggested on the basis of reported familial cases. The 2 families described here with father-to-son transmission strongly support the hypothesis that some cases of Nager acrofacial dysostosis occur in individuals who are heterozygous for dominantly expressed, autosomal mutations.
Assuntos
Anormalidades Múltiplas , Disostose Mandibulofacial/genética , Polegar/anormalidades , Genes Dominantes , Doença de Hirschsprung/complicações , Humanos , Lactente , Recém-Nascido , Masculino , Disostose Mandibulofacial/complicações , Crista Neural/anormalidades , Fenótipo , SíndromeRESUMO
Of 144 patients with the CHARGE association (literature 136, new patients 8), 47 (33%) had either a postmortem examination (30) or computerized axial tomography scan (17) of the head. Twenty-six of 47 (55%) had definite central nervous system (CNS) malformations; arhinencephaly, with or without other defects (11), holoprosencephaly (2), holoprosencephaly with arhinencephaly (1), other forebrain defects (3), hindbrain defects (3), or other defects (6). The presence of CNS malformation was most strongly associated with choanal atresia. This review demonstrates a predominance of forebrain anomalies, particularly arhinencephaly and holoprosencephaly, which may provide a clue to the mechanism of abnormal morphogenesis involved in CHARGE association.
Assuntos
Anormalidades Múltiplas , Encéfalo/anormalidades , Atresia das Cóanas , Coloboma , Surdez , Orelha/anormalidades , Feminino , Genitália/anormalidades , Transtornos do Crescimento , Cardiopatias Congênitas , Holoprosencefalia , Humanos , Deficiência Intelectual , Masculino , SíndromeRESUMO
Diverse cardiac abnormalities have been reported in patients with the Simpson-Golabi-Behmel syndrome (SGBS), and it is suspected that they are related to the apparently high incidence of early death. To clarify the incidence and significance of the various cardiac abnormalities, we reviewed 101 SGBS patients (89 from the literature, 12 new). All were male, except for one clearly affected female patient with translocation X;1 [Punnett, 1994: Am J Med Genet 50: 391-393]. Ninety-six of 99 (97%) patients had the classic phenotype of macrosomia and typical "coarse" face. Thirty-six patients (36%) had a cardiac abnormality, of whom 26 (26%) had a cardiovascular malformation (CVM). After excluding 24 patients with insufficient clinical data, these percentages among the 77 informative cases were 47% and 34%, respectively. When grouped according to a mechanistic classification, most cases (20/ 26, or 77%) were class II CVMs (attributed to altered embryonic intracardiac flow). Other cardiac abnormalities included cardiomyopathy (n = 4) and electrocardiogram (ECG) conduction or rhythm abnormalities (n = 12); three of the affected patients (25%) also had a CVM. Among 92 informative cases, there were 29 (32%) deaths, a figure that excludes seven elective terminations. Among the 25 patients younger than 3 years, death was associated with a cardiac abnormality in six (23%). GPC3 mutation analysis using Southern blot testing and polymerase chain reaction amplification was performed for 37 of 101 (37%) patients. A mutation was detected in 26 of the 37 patients tested (70%), 12 of whom (46%) had a cardiac abnormality. We conclude that cardiac abnormalities of any type are common in SGBS (almost one-half of informative cases), with CVMs seen in one-third of cases. The heterogeneous ECG abnormalities in this survey must be viewed with caution, since they may represent a genuine component of the syndrome or reporting bias. Determining the true prevalence and natural history of cardiac abnormalities in SGBS will require a larger number of patients and more consistent prospective cardiac evaluations. There are sufficient data to recommend a baseline echocardiogram and ECG in SGBS patients. Data are insufficient to define a cardiac phenotype/molecular correlation.
Assuntos
Cardiopatias Congênitas/etiologia , Proteoglicanas de Heparan Sulfato , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Morte Fetal , Glipicanas , Heparitina Sulfato/genética , Humanos , Lactente , Masculino , Mutação , Proteoglicanas/genética , SíndromeRESUMO
We reviewed 215 patients (59 new, 156 from the literature) with Smith-Lemli-Opitz syndrome (SLOS), and found that 95 (44%) had a cardiovascular malformation (CVM). Classifying CVMs by disordered embryonic mechanisms, there were 5 (5.3%) class 1 (ectomesenchymal tissue migration abnormalities), 56 (58.9%) class II (abnormal intracardiac blood flow), 25 (26.3%) class IV (abnormal extracellular matrix), and 5 (5.3%) class V (abnormal targeted growth). Comparing the frequencies of individual CVMs in this series with a control group (the Baltimore-Washington Infant Study), there were 6 individual CVMs which showed a significant difference from expected values. When frequencies of CVMs in SLOS were analyzed by mechanistic class, classes IV and V were significantly more frequent, and class I significantly less frequent, than the control group. Although CVMs in SLOS display mechanistic heterogeneity, with an overall predominance of class II CVMs, the developmental error appears to favor alteration of the cardiovascular developmental mechanisms underlying atrioventricular canal and anomalous pulmonary venous return. This information should assist the clinical geneticist evaluating a patient with possible SLOS, and should suggest research direction for the mechanisms responsible for the SLOS phenotype.
Assuntos
Cardiopatias Congênitas/patologia , Síndrome de Smith-Lemli-Opitz/patologia , Feminino , Humanos , Masculino , FenótipoRESUMO
We report on an infant girl with hydrops, macrocephaly, high forehead, flat face, hypertelorism, broad nasal bridge, median cleft lip and alveolar ridge, grooved palate, accessory frenula, small tongue, milia, severe rib and limb shortness, brachydactyly, talipes equinovarus, Dandy-Walker malformation, accessory spleen, unfixed mesentery, ectopic pancreas, and renal cysts. This patient resembles seven previously reported patients with the Beemer-Langer syndrome, a distinct lethal short rib syndrome characterized by hydrops, markedly short ribs and limbs, median cleft lip with or without cleft palate, flat face, and macrocephaly. Polydactyly is usually absent. Our patient's oral anomalies suggest an orofaciodigital syndrome, but the severe rib and limb shortness distinguish it from those disorders.
Assuntos
Síndromes Orofaciodigitais/diagnóstico , Síndrome de Costela Curta e Polidactilia/diagnóstico , Adulto , Feminino , Humanos , Recém-Nascido , Síndromes Orofaciodigitais/genética , Síndromes Orofaciodigitais/patologia , Gravidez , Síndrome de Costela Curta e Polidactilia/genética , Síndrome de Costela Curta e Polidactilia/patologiaRESUMO
Three new patients with the Baller-Gerold syndrome bring the number of reported cases to 20. In addition to craniosynostosis involving various sutures and preaxial reduction defects of variable severity, affected patients may have anal, urogenital, cardiac, central nervous system, and vertebral defects. Autosomal recessive inheritance is supported by the presence of affected sibs and parental consanguinity.
Assuntos
Anormalidades Múltiplas/patologia , Craniossinostoses/patologia , Anormalidades Múltiplas/genética , Adulto , Canal Anal/anormalidades , Sistema Nervoso Central/anormalidades , Craniossinostoses/genética , Feminino , Cardiopatias Congênitas/genética , Humanos , Recém-Nascido , Gravidez , Coluna Vertebral/anormalidades , Síndrome , Polegar/anormalidades , Anormalidades UrogenitaisRESUMO
Three unrelated infants presented with radiographic punctate calcifications, nasal hypoplasia, and abnormalities of the spine. Additional anomalies included cupped ears in 2 patients and one each with Dandy-Walker malformation with hydrocephaly, congenital cataracts, and peripheral pulmonary artery stenosis. The mothers of these 3 patients had chronic conditions associated with intestinal malabsorption requiring total parenteral nutrition for varying periods of time. The underlying causes of malabsorption were celiac disease, short bowel syndrome secondary to surgical resection, and jejuno-ileal bypass, respectively. Bleeding diathesis occurred in one mother requiring vitamin K supplementation during the second and third trimesters of pregnancy. We speculate that the chondrodysplasia punctata and other abnormalities in these children were caused by an acquired maternal vitamin K deficiency manifested during early pregnancy. However, the involvement of other vitamin deficiencies cannot be excluded. Thus, vitamin K deficiency of the embryo secondary to maternal malabsorption appears to be a third vitamin K-related mechanism leading to chondrodysplasia punctata in addition to warfarin embryopathy and epoxide reductase deficiency (pseudo-warfarin embryopathy).
Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Anticoagulantes/efeitos adversos , Doenças Fetais/etiologia , Síndromes de Malabsorção/complicações , Complicações na Gravidez , Deficiência de Vitamina K/etiologia , Varfarina/efeitos adversos , Anormalidades Induzidas por Medicamentos/diagnóstico por imagem , Anormalidades Induzidas por Medicamentos/patologia , Pré-Escolar , Condrodisplasia Punctata/diagnóstico por imagem , Condrodisplasia Punctata/etiologia , Condrodisplasia Punctata/patologia , Feminino , Doenças Fetais/metabolismo , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Gravidez , Radiografia , Vitamina K/metabolismoRESUMO
We reviewed 45 patients with a deletion of the long arm of chromosome 4. Forty-one were previous reports (25 terminal deletions and 16 interstitial deletions) and 4 are new cases with terminal deletions. Of the 29 patients with terminal deletions, 18 with deletion at 4q31 and 4 at 4q32----qter had an identifiable phenotype consisting of abnormal skull shape, hypertelorism, cleft palate, apparently low-set abnormal pinnae, short nose with abnormal bridge, virtually pathognomonic pointed fifth finger and nail, congenital heart and genitourinary defects, moderate-severe mental retardation, poor postnatal growth, and hypotonia. Six patients with a deletion at 4q33 and one patient with deletion 4q34 were less severely affected. In general, patients with various interstitial deletions proximal to 4q31 had a phenotype that was less specific, although mental retardation and minor craniofacial anomalies were also present. There were 3 patients with piebaldism and one with Rieger syndrome. We conclude that terminal deletion of chromosome 4q (4q31----qter) appears to produce a distinctive malformation (MCA/MR) syndrome in which the phenotype correlates with the amount of chromosome material missing and which differs from the more variable phenotype associated with interstitial deletions of 4q.
Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 4/ultraestrutura , Fenótipo , Ossos Faciais/anormalidades , Feminino , Dedos/anormalidades , Humanos , Recém-Nascido , Deficiência Intelectual/genética , Cariotipagem , Masculino , Síndrome , Dedos do Pé/anormalidadesRESUMO
In addition to craniofacial, auricular, ophthalmologic, and oral anomalies, the distinctive phenotype of the branchio-oculo-facial (BOF) syndrome (MIM 113620) includes skin defects in the neck or infra/supra-auricular region. These unusual areas of thin, erythematous wrinkled skin differ from the discrete cervical pits, cysts, and fistulas of the branchio-oto-renal (BOR) syndrome (MIM 113650). Although the BOF and BOR syndromes are sufficiently distinctive that they should not be confused, both can be associated with nasolacrimal duct stenosis, deafness, prehelical pits, malformed pinna, and renal anomalies. Furthermore, a reported father and son [Legius et al., 1990, Clin Genet 37:347-500] had features of both conditions. It was not clear whether they had an atypical presentation of either BOR or BOF syndrome, or represented a private syndrome. In light of these issues, we selected the BOR locus (EYA1) as a possible gene mutation for the BOF syndrome. In five BOF patients, there were no mutations detected in the EYA1 gene, suggesting that it is not allelic to the BOR syndrome.