RESUMO
Purpose The L216R mutation, seen in individuals of Polynesian descent, is considered one of the most severe mutations associated with holocarboxylase synthetase (HLCS) deficiency and is regarded as being unresponsive to biotin. This report describes the presentation and outcome in two surviving siblings, homozygous for this highly lethal mutation. Methods and results Both cases had perinatal head imaging findings of brain hemorrhage and subependymal cysts. Both had metabolic decompensation within 24 h after birth consisting of metabolic acidosis, lactic acidosis, and thrombocytopenia. Biochemical profiles were consistent with HLCS deficiency, and genetic analysis confirmed homozygosity for the L216R mutation. After resolution of neonatal metabolic crisis, dosing of biotin was titrated on an outpatient basis to primarily control dermatitis. The eldest is currently on 1.2 g of oral biotin daily, well above any dose previously reported to treat HLCS deficiency. To date, neither patient has required hospital readmission for acute metabolic decompensation. At the age of 7, the eldest child is, to our knowledge, the oldest patient ever described in the literature who is homozygous for the L216R mutation. She has mild intellectual disability. Conclusion This report contrasts previous reports of poor outcomes and neonatal deaths in homozygous L216R patients. We also provide data on the potential upper tolerable limit of biotin. These cases suggest that the outcome of HCLS deficiency due to a homozygous L216R mutation, when diagnosed and treated early with high-level neonatal care and biotin, may not be as severe as previously reported.
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Monozygotic twins with discordant karyotypes are rare. We report a case of monozygotic twins discordant for trisomy 13 by amniocyte karyotypes. Ultrasound revealed multiple congenital anomalies in Twin A (47,XY,+13), none in Twin B (46,XY), and monochorionic-diamniotic placentation. Zygosity testing performed both prenatally and after birth supported monozygosity. Twin A died in the neontal period. Twin B survived and had normal physical examination, but peripheral blood karyotype revealed 20% mosaicism for trisomy 13. Monochorionic-diamniontic placentation with vascular anastomoses was confirmed by pathological examination. In this paper, we discuss the various mechanisms by which monozygotic twins may have discordant karyotypes. The surviving twin, structurally and developmentally normal at 6 months of age, will be monitored for potential complications of uniparental disomy of chromosome 13 and trisomy 13 mosaicism.
Assuntos
Transtornos Cromossômicos/genética , Doenças em Gêmeos/genética , Trissomia/genética , Gêmeos Monozigóticos , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adulto , Quimerismo , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 13/genética , Evolução Fatal , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Cariotipagem , Masculino , Mosaicismo , Gravidez , Primeiro Trimestre da Gravidez , Trissomia/diagnóstico , Síndrome da Trissomia do Cromossomo 13 , Ultrassonografia Pré-Natal , Dissomia UniparentalRESUMO
X-linked adrenal hypoplasia congenita (AHC) is caused by mutations in the NR0B1 gene. This gene encodes an orphan member of the nuclear receptor superfamily, DAX1. Ongoing efforts in our laboratory have identified nine novel NR0B1 mutations in X-linked AHC patients (Y81X, 343delG, 457delT, 629delG, L295P, 926-927delTG, 1130delA, 1141-1155del15, and E428X). Two additional families segregate previously identified NR0B1 mutations (501delA and R425T). Sequence analysis of the mitochondrial D-loop indicates that the 501delA family is unrelated through matrilineal descent to our previously analyzed 501delA family.
Assuntos
Insuficiência Adrenal/genética , Proteínas de Ligação a DNA/genética , Receptores do Ácido Retinoico/genética , Proteínas Repressoras , Fatores de Transcrição/genética , Insuficiência Adrenal/congênito , Códon sem Sentido , Receptor Nuclear Órfão DAX-1 , DNA/química , DNA/genética , Análise Mutacional de DNA , Mutação da Fase de Leitura , Humanos , Mutação , Mutação de Sentido Incorreto , Deleção de SequênciaRESUMO
Lymphedema-distichiasis (LD) is an autosomal dominant disorder that classically presents as lymphedema of the limbs, with variable age at onset, and double rows of eyelashes (distichiasis). Other complications may include cardiac defects, cleft palate, extradural cysts, and photophobia, suggesting a defect in a gene with pleiotrophic effects acting during development. We previously reported neonatal lymphedema, similar to that in Turner syndrome, associated with a t(Y;16)(q12;q24.3) translocation. A candidate gene was not found on the Y chromosome, and we directed our efforts toward the chromosome 16 breakpoint. Subsequently, a gene for LD was mapped, by linkage studies, to a 16-cM region at 16q24.3. By FISH, we determined that the translocation breakpoint was within this critical region and further narrowed the breakpoint to a 20-kb interval. Because the translocation did not appear to interrupt a gene, we considered candidate genes in the immediate region that might be inactivated by position effect. In two additional unrelated families with LD, we identified inactivating mutations-a nonsense mutation and a frameshift mutation-in the FOXC2 (MFH-1) gene. FOXC2 is a member of the forkhead/winged-helix family of transcription factors, whose members are involved in diverse developmental pathways. FOXC2 knockout mice display cardiovascular, craniofacial, and vertebral abnormalities similar to those seen in LD syndrome. Our findings show that FOXC2 haploinsufficiency results in LD. FOXC2 represents the second known gene to result in hereditary lymphedema, and LD is only the second hereditary disorder known to be caused by a mutation in a forkhead-family gene.
Assuntos
Proteínas de Ligação a DNA/genética , Ligação Genética/genética , Linfedema/genética , Mutação/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Sequência de Bases , Criança , Cromossomos Humanos Par 16/genética , Fissura Palatina/genética , Análise Mutacional de DNA , Edema/genética , Feminino , Fatores de Transcrição Forkhead , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Fotofobia/genética , Mapeamento Físico do Cromossomo , SíndromeRESUMO
OBJECTIVES: To conduct surveillance for neural tube defects (NTDs) in a high-risk region of the United States and to prevent occurrence and recurrence of NTDs through the periconceptional use of folic acid supplements. DESIGN: Active and passive methods were used for surveillance of NTD-affected pregnancies and births during a 6-year period (October 1992-September 1998). Individual genetic counseling was used to prevent NTD recurrences and a public awareness campaign was used to reduce NTD occurrences. SETTING: State of South Carolina. PATIENTS: All cases of spina bifida, anencephaly, and encephalocele identified among 278 122 live births and fetal deaths to South Carolina residents during 1992-1998 were included. MAIN OUTCOME MEASURE: Changes in occurrence and recurrence rates during a 6-year period. RESULTS: Over the 6 years of surveillance, the prevalence rates for NTDs decreased from 1.89 to.95 cases per 1000 live births and fetal deaths. The prevalence decrease is explained primarily by a decrease in cases of spina bifida. Isolated NTDs accounted for 297/360 (82%) NTDs and 63/360 (18%) had at least 1 other structural anomaly. Females predominated among isolated NTDs but the sex distribution was equal among NTD cases with other anomalies. Prevalence rates for whites (1.48 cases per 1000 live births and fetal deaths) were higher than rates for blacks (.87 cases per 1000 live births and fetal deaths). There were no NTD recurrences in 113 subsequent pregnancies to mothers of infants with isolated NTDs who took periconceptional folic acid. The rate of periconceptional folic acid use among women of childbearing years increased from 8% to 35% during the 6-year project period. CONCLUSION: The prevalence of NTDs in a high-risk region has declined coincident with the increased periconceptional use of folic acid supplements among women of childbearing age.neural tube defects, high-risk region, birth defects, folic acid, spina bifida, anencephaly, encephalocele.
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Ácido Fólico/uso terapêutico , Defeitos do Tubo Neural/epidemiologia , Adolescente , Adulto , Causalidade , Uso de Medicamentos/estatística & dados numéricos , Uso de Medicamentos/tendências , Feminino , Humanos , Recém-Nascido , Pessoa de Meia-Idade , Defeitos do Tubo Neural/etnologia , Defeitos do Tubo Neural/prevenção & controle , Vigilância da População , Gravidez , Resultado da Gravidez , Prevalência , Grupos Raciais , Distribuição por Sexo , South Carolina/epidemiologiaRESUMO
Spondylocarpotarsal synostosis syndrome is a recently delineated autosomal recessive condition comprising short stature with short trunk, failure of normal spine segmentation resulting in block vertebrae and fusion of posterior elements, carpal and/or tarsal coalition, scoliosis, lordosis, pes planus, dental enamel hypoplasia, decreased range of motion or dislocation of the elbow, renal anomalies, and hearing loss. The vertebral segmentation defects may involve noncontiguous areas of the cervical, thoracic, and lumbar spine. Odontoid hypoplasia was noted in two cases. We report on a sporadic case of spondylocarpotarsal synostosis in a 5-year-old girl with hypoplasia of C1 and odontoid and subluxation of C2 upon C3. This brings the number of well-documented cases of spondylocar- potarsal synostosis to 19, and is the first documenting cervical spine instability. Careful evaluation for this complication should be considered in other cases.
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Anormalidades Múltiplas , Coluna Vertebral/anormalidades , Sinostose , Anormalidades Múltiplas/diagnóstico por imagem , Ossos do Carpo/anormalidades , Ossos do Carpo/diagnóstico por imagem , Vértebras Cervicais/anormalidades , Vértebras Cervicais/diagnóstico por imagem , Pré-Escolar , Feminino , Humanos , Radiografia , Coluna Vertebral/diagnóstico por imagem , Síndrome , Sinostose/diagnóstico por imagem , Ossos do Tarso/anormalidades , Ossos do Tarso/diagnóstico por imagemRESUMO
Hemihyperplasia is characterized by asymmetric growth of cranium, face, trunk, limbs, and/or digits, with or without visceral involvement. It may be an isolated finding in an otherwise normal individual, or it may occur in several syndromes. Although isolated hemihyperplasia (IHH) is of unknown cause, it may represent one end of the clinical spectrum of the Wiedemann-Beckwith syndrome (WBS). Uniparental paternal disomy of 11p15.5 or altered expression of insulin-like growth factor 2 (IGF2) from the normally silent maternal allele have been implicated as causes of some cases of WBS. IHH and other mild manifestations of WBS may represent patchy overexpression of the IGF2 gene following defective imprinting in a mosaic fashion. The natural history of IHH varies markedly. An association among many overgrowth syndromes and a predisposition to neoplasia is well recognized. Heretofore the risk for tumor development in children with IHH was unknown. We report on the results of a prospective multicenter clinical study of the incidence and nature of neoplasia in children evaluated because of IHH. One hundred sixty-eight patients were ascertained. A total of 10 tumors developed in nine patients, for an overall incidence of 5.9%. Tumors were of embryonal origin (similar to those noted in other overgrowth disorders), including Wilms tumor, hepatoblastoma, adrenal cell carcinoma, and leiomyosarcoma of the small bowel in one case. These data support a tumor surveillance protocol for children with IHH similar to that performed in other syndromes associated with overgrowth.
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Hipertrofia/epidemiologia , Neoplasias/epidemiologia , Humanos , Estudos ProspectivosRESUMO
An unusual family with Waardenburg syndrome type 1 (WSI), cleft lip (palate), and Hirschsprung disease is not linked to the PAX 3 gene since there is an obligate crossover which has occurred between PAX 3 DNA markers and the disorder in this family. This family may also have anticipation of the WSI traits as the proband's grandmother is nonpenetrant, his mother has dystopia canthorum, and severe cleft lip (palate), while the proband has dystopia canthorum, severe cleft lip (palate), and Hirschsprung disease. Thus, a locus other than PAX 3 is implicated in this Waardenburg-like syndrome with Hirschsprung disease and cleft lip (palate).
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Fenda Labial/genética , Proteínas de Ligação a DNA/genética , Ligação Genética , Doença de Hirschsprung/genética , Fatores de Transcrição , Síndrome de Waardenburg/genética , Sequência de Bases , Fissura Palatina/genética , Feminino , Heterogeneidade Genética , Ligação Genética/genética , Marcadores Genéticos/genética , Haplótipos/genética , Humanos , Recém-Nascido , Masculino , Dados de Sequência Molecular , Fator de Transcrição PAX3 , Fatores de Transcrição Box Pareados , Linhagem , Sequências Repetitivas de Ácido Nucleico/genética , Síndrome de Waardenburg/classificaçãoRESUMO
A blind study was designed to test the hypothesis that some persons with a relatively rare cardiac malformation, pulmonary atresia with ventriculoseptal defect (PA/VSD), have a recognisable phenotype. Fourteen patients with cyanotic congenital heart lesions were examined by dysmorphologists blinded to the type of cardiac malformation. Six children were judged to have a similar craniofacial appearance; all had PA/VSD. These children were not originally considered to fall within the classic phenotypes of the DiGeorge sequence or the velocardiofacial syndrome, both of which have been shown to be associated with deletions of 22q11. More recently, 22q11 deletions have been documented in the conotruncal anomaly face syndrome and apparently isolated conotruncal heart defects. A new acronym, CATCH 22 syndrome (Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, and Hypocalcaemia) has been suggested to encompass this very broad phenotypic spectrum. A preliminary molecular study was conducted using the dinucleotide repeat D22S264 located on chromosome 22q11.2. All cases tested with the subtle but recognisable phenotype had deletions, all lacking the maternal contribution at this locus, suggesting there may be a parent of origin effect.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22 , Face/anormalidades , Comunicação Interventricular/genética , Atresia Pulmonar/genética , Sequência de Bases , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Fenótipo , Reação em Cadeia da Polimerase , Método Simples-Cego , SíndromeRESUMO
46,XX female pseudohermaphrodites have been previously described with nearly complete masculinization of the external genitalia and no apparent source of testosterone. Multiple malformations of internal genital, urinary, and gastrointestinal tracts are associated. We have evaluated four such infants with female pseudohermaphroditism and multiple caudal anomalies. Three cases had apparently normal chromosomes (46,XX); one had a 46,XX,del(10)(q25.3-->qter) chromosome constitution. The chromosome breakpoint is in the region of PAX2, a developmentally important paired box gene which is expressed in urogenital tissue. Using the polymerase chain reaction, we screened for the presence of multiple Y specific sequences, including SRY (sex determining region, Y chromosome), that could explain masculinization of the external genitalia. All were negative for Y centromeric sequences, ZFY (Zinc finger Y), and SRY. Furthermore, there was no evidence for adrenal or other sources of testosterone. We suggest that the masculinization in these cases is the result of abnormal expression of genes which would normally be regulated by testosterone.
Assuntos
Anormalidades Múltiplas/genética , Transtornos do Desenvolvimento Sexual/genética , Genes Homeobox , Glândulas Suprarrenais/anormalidades , Anus Imperfurado/genética , Sequência de Bases , Deleção Cromossômica , Cromossomos Humanos Par 10 , Primers do DNA , Feminino , Genitália/anormalidades , Humanos , Recém-Nascido , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Sistema Urinário/anormalidades , Cromossomo YRESUMO
OBJECTIVE: To determine if maternal toluene abuse produces any structural or developmental disabilities in the developing fetus, a cohort of toluene-exposed infants was ascertained and examined. METHODOLOGY: Eighteen infants with a history of in utero toluene exposure were examined at birth. Nine of these infants were reexamined 3 to 36 months after their initial evaluations. The clinical findings in these patients were compared with those of similarly exposed children from the literature and with patients who had the fetal alcohol syndrome. RESULTS: Thirty-nine percent of all toluene-exposed infants described in this and other studies were born prematurely, and 9% died during the perinatal period. Fifty-four percent were small for gestational age, and 52% exhibited continued postnatal growth deficiency. A 33% incidence of prenatal microcephaly, a 67% incidence of postnatal microcephaly, and an 80% incidence of developmental delay were observed. Eighty-three percent of the patients had craniofacial features similar to the fetal alcohol syndrome, and 89% of these children had other minor anomalies. CONCLUSIONS: Data from the patients herein described and the available scientific literature suggest that the mechanism of alcohol craniofacial teratogenesis may be nonspecific, with a variety of teratogens, including toluene, giving rise to phenotypic facial abnormalities similar to those of the fetal alcohol syndrome. We propose a common mechanism of craniofacial teratogenesis for toluene and alcohol, namely a deficiency of craniofacial neuroepithelium and mesodermal components due to increased embryonic cell death.
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Anormalidades Induzidas por Medicamentos , Embrião de Mamíferos/efeitos dos fármacos , Face/anormalidades , Microcefalia/induzido quimicamente , Crânio/anormalidades , Tolueno/efeitos adversos , Adolescente , Adulto , Deficiências do Desenvolvimento/induzido quimicamente , Etanol/farmacologia , Feminino , Transtornos do Espectro Alcoólico Fetal , Humanos , Recém-Nascido , Troca Materno-Fetal , Fenótipo , Gravidez , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal , Transtornos Relacionados ao Uso de Substâncias/complicações , Tolueno/farmacologiaAssuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Cardiomiopatia Dilatada/etiologia , Oxo-Ácido-Liases/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Cardiomiopatia Dilatada/enzimologia , Cardiomiopatia Dilatada/patologia , Evolução Fatal , Cromatografia Gasosa-Espectrometria de Massas , Ventrículos do Coração/patologia , Humanos , Lactente , MasculinoRESUMO
An apparently autosomal recessive syndrome of hereditary vitreoretinal degeneration (VRD) with retinal detachment, high myopia, and congenital encephalocele was described in 1971 by Knobloch and Layer [J Pediatr Ophthalmol 8:181-184]. Clinical confirmation of the presence of encephaloceles was lacking, and no neuropathologic studies were reported. We have evaluated a similarly affected family with 2 sibs with high myopia, VRD, and occipital scalp defects. Histologic examination of the scalp defects showed heterotopic neuronal tissue in both instances. The older girl has had a unilateral retinal detachment. Her other eye and both eyes of the younger sib have so far been treated successfully with prophylactic retinal cryotherapy. Both children have normal to above normal intelligence. The family reported by Knobloch and Layer [1971] and the sibship herein described appear to represent a distinct autosomal recessive trait. Analysis of the associated defects suggests an underlying defect in early cephalic neuroectodermal morphogenesis. Data from these families imply that congenital occipital scalp defects rather than true encephaloceles may, as is true in some cases of Meckel syndrome, accompany Knobloch syndrome. The presence of a congenital midline scalp defect should alert the clinician to possible underlying central nervous system and/or ocular pathology and should lead to consideration of further diagnostic evaluations and prophylactic measures.
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Oftalmopatias/genética , Degeneração Retiniana/genética , Couro Cabeludo/anormalidades , Corpo Vítreo , Criança , Pré-Escolar , Feminino , Genes Recessivos , Humanos , Masculino , Miopia/genética , Descolamento Retiniano/genética , Couro Cabeludo/patologia , SíndromeRESUMO
A range of infections, physical agents, maternal diseases and metabolic states, drugs, and chemicals have been demonstrated to be human teratogens. These agents cause structural or functional disabilities postnatally in exposed embryos and fetuses. Such disabilities are potentially totally preventable through public education and awareness. Pediatricians must be able to recognize potential teratogenic exposures, diagnose teratogenically-induced disabilities, and be knowledgeable in the natural history of these disorders so that they can support and educate those who care for these children in the home and in the community.
Assuntos
Anormalidades Induzidas por Medicamentos , Pediatria , Papel do Médico , Teratogênicos , Anormalidades Induzidas por Medicamentos/diagnóstico , Anormalidades Induzidas por Medicamentos/terapia , Criança , Humanos , América do Norte , Fatores de Risco , Teratogênicos/farmacologiaRESUMO
We report on a mother and son with a similar syndrome of hypertelorism and telecanthus, epicanthal folds, downslanting palpebral fissures, ptosis, broad nasal bridge, malar hypoplasia, thin upper lip, smooth philtrum, and apparently low-set prominent ears. The son also has a hypoplastic shawl scrotum, cryptorchidism, and genu valgum. His language development was delayed at 18 months, but subsequently improved and was normal at age 3. The mother has the additional findings of marked cubitus valgus, hyper-extensible joints, dull normal intelligence and a bleeding diathesis. This pattern of multiple congenital anomalies may represent a new syndrome.