ABSTRACT
INTRODUCTION: Acute paraquat (PQ) poisoning continues to be a major public health concern in many developing countries. This study was designed to evaluate the data on cases of acute PQ poisoning and compare the different variables between survivors and non-survivors. METHODS: All patients of PQ poisoning who were admitted to the poisoning emergency department during the past five years were retrospectively evaluated. The different variables that were compared between survivors and non-survivors included age and gender, the time from ingestion of PQ to hospital admission, the amount of PQ ingested, occurrence of vomiting after ingestion, the time from hospital admission to initiation of haemodialysis, the length of hospital stay and the outcomes. RESULTS: A total of 29 patients were evaluated. The in-hospital fatality rate was 55.2 percent. No significant differences were observed between survivors and non-survivors with regard to the patient characteristics. Most of the patients who died had ingested more than 40 mg/kg of 20 percent PQ (62.5 percent). There was a correlation between the outcome of patients and vomiting (p-value is 0.05; correlation coefficient is 0.45) and age (p-value is 0.013; correlation coefficient is 0.56). CONCLUSION: A large amount of ingested PQ, vomiting and age may be important variables to consider in association with the high fatality rate of PQ poisoning.
Subject(s)
Paraquat/poisoning , Poisoning/mortality , Acute Disease , Adolescent , Adult , Age Factors , Developing Countries , Emergency Service, Hospital , Female , Hospitalization , Humans , Iran , Length of Stay , Male , Retrospective Studies , Suicide, Attempted , Treatment OutcomeABSTRACT
Mosaicism for tandem duplications is rare. Most patients reported had abnormal phenotypes of varying severity, depending on the chromosomal imbalance involved and the level of mosaicism. Post-zygotic unequal sister-chromatid exchange has been proposed as the main mechanism for tandem duplication mosaicism. However, previous molecular analyses have implicated both meiotic and post-zygotic origins for the duplication. We describe a newborn male who was originally diagnosed in utero with arrhythmia and tetralogy of Fallot. He had multiple dysmorphic features including telecanthus, blepharophimosis, high broad nasal bridge with a square-shaped nose, flat philtrum, thin upper lip, down-turned corners of the mouth, high-arched palate, micrognathia, asymmetric ears, and long, thin fingers and toes. Karyotyping of peripheral blood lymphocytes showed mosaicism for a tandem duplication of part of the long arm of one chromosome 5: mos46,XY,dup(5)(q13q33)[6]/46,XY[45]. Fibroblast cultures had the same mosaic karyotype with a higher frequency of the dup(5) clone: mos46,XY,dup(5)(q13q33)[9]/46,XY[21]. Fluorescence in situ hybridization analysis with a wcp5 confirmed the chromosome 5 origin of the additional material. Parental karyotypes were normal indicating a de novo origin of the dup(5) in the proband. Molecular analyses of chromosome 5 sequence-tagged-site (STS) markers in our family were consistent with a post-zygotic origin for the duplication. Therefore, mosaicism for tandem duplications can arise both through meiotic or mitotic errors, as a result of unequal crossing over or unequal sister-chromatid exchange, respectively. Our review indicates that mosaicism for tandem duplications is likely under-ascertained and that parental karyotyping of probands with non-mosaic tandem duplications should be performed.
Subject(s)
Arrhythmias, Cardiac/genetics , Chromosomes, Human, Pair 5/genetics , Gene Duplication , Mosaicism/genetics , Tetralogy of Fallot/genetics , Adult , Arrhythmias, Cardiac/congenital , Arrhythmias, Cardiac/diagnosis , Female , Humans , Infant, Newborn , Male , Mosaicism/physiopathology , Pregnancy , Prenatal Diagnosis , Tandem Repeat Sequences , Tetralogy of Fallot/diagnosisABSTRACT
Hypohidrotic ectodermal dysplasia (HED), a congenital disorder of teeth, hair, and eccrine sweat glands, is usually inherited as an X-linked recessive trait, although rarer autosomal dominant and recessive forms exist. We have studied males from four families with HED and immunodeficiency (HED-ID), in which the disorder segregates as an X-linked recessive trait. Affected males manifest dysgammaglobulinemia and, despite therapy, have significant morbidity and mortality from recurrent infections. Recently, mutations in IKK-gamma (NEMO) have been shown to cause familial incontinentia pigmenti (IP). Unlike HED-ID, IP affects females and, with few exceptions, causes male prenatal lethality. IKK-gamma is required for the activation of the transcription factor known as "nuclear factor kappa B" and plays an important role in T and B cell function. We hypothesize that "milder" mutations at this locus may cause HED-ID. In all four families, sequence analysis reveals exon 10 mutations affecting the carboxy-terminal end of the IKK-gamma protein, a domain believed to connect the IKK signalsome complex to upstream activators. The findings define a new X-linked recessive immunodeficiency syndrome, distinct from other types of HED and immunodeficiency syndromes. The data provide further evidence that the development of ectodermal appendages is mediated through a tumor necrosis factor/tumor necrosis factor receptor-like signaling pathway, with the IKK signalsome complex playing a significant role.
Subject(s)
Alleles , Ectodermal Dysplasia/genetics , Immunologic Deficiency Syndromes/genetics , Incontinentia Pigmenti/genetics , Mutation/genetics , Protein Serine-Threonine Kinases/genetics , X Chromosome/genetics , Adolescent , Base Sequence , Child , Child, Preschool , DNA Mutational Analysis , Ectodermal Dysplasia/complications , Exons/genetics , Female , Genes, Recessive/genetics , Genetic Linkage/genetics , Humans , I-kappa B Kinase , Immunologic Deficiency Syndromes/complications , Infant , Infant, Newborn , Male , NF-kappa B/physiology , Pedigree , Protein Serine-Threonine Kinases/chemistry , Protein Structure, TertiaryABSTRACT
We report on a 19-month-old girl who presented with the phenotype of cardio-faciocutaneous (CFC) syndrome including characteristic minor facial anomalies, cardiac defect, ectodermal anomalies, and developmental delay. Cytogenetic analysis showed the presence of an interstitial deletion of one chromosome 12, del(12)(q21.2q22), confirmed by fluorescence in situ hybridization with chromosome band specific probes. Controversy exists as to whether CFC and Noonan syndrome (NS) are distinct disorders, a contiguous gene syndrome, or allelic variants. The identification of the del(12) in this patient, in a region distinct from the putative NS locus, supports the view that CFC is a genetically distinct condition from NS. In addition, this implicates the region 12q21.2-->4q22 as a candidate region for the gene(s) causing CFC syndrome.
Subject(s)
Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Chromosome Deletion , Chromosomes, Human, Pair 12 , Phenotype , Alleles , Chromosome Banding , Developmental Disabilities/genetics , Facies , Female , Heart Defects, Congenital/genetics , Humans , In Situ Hybridization, Fluorescence , Infant , Models, Genetic , Noonan Syndrome/diagnosis , Noonan Syndrome/genetics , Skin Abnormalities/geneticsABSTRACT
Maternal diabetes is known to have teratogenic effects. Malformations including neural tube defects, caudal dysgenesis, vertebral defects, congenital heart defects, femoral hypoplasia, and renal anomalies are described in infants of diabetic mothers. However, craniofacial anomalies have rarely been reported in such infants. Here we document craniofacial anomalies of patients born to diabetic mothers. We describe two patient populations: individuals evaluated through our genetics services for multiple malformations and individuals identified through a database search in our craniofacial clinic. The first group consists of 14 individuals evaluated in our genetics clinics who were born to diabetic mothers and had craniofacial anomalies. The second group consists of seven individuals who were identified from a craniofacial database search of patients with hemifacial microsomia and who were born to diabetic mothers. Thus, both groups were born to diabetic mothers and had hemifacial microsomia (67%), microtia (52%), hearing loss (43%), epibulbar dermoids (24%), and fused cervical vertebrae (24%). Therefore, the teratogenic effects of maternal diabetes probably include such craniofacial malformations as the oculoauriculovertebral/Goldenhar complex. Infants of diabetic mothers should be evaluated for craniofacial anomalies. Conversely, mothers of infants with craniofacial anomalies should be evaluated for diabetes to aid in counseling concerning cause and recurrence risks.
Subject(s)
Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 2/complications , Ear/abnormalities , Eye Abnormalities/complications , Pregnancy in Diabetics/complications , Spine/abnormalities , Abnormalities, Multiple/etiology , Adult , Female , Humans , Infant, Newborn , Male , PregnancyABSTRACT
The mitochondrial respiratory chain and the fatty acid oxidation cycle are theoretically interdependent on each other for normal function. We describe a patient with complex I deficiency who had clinical and biochemical features of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency including liver failure, cardiomyopathy, and consistent urine organic acid pattern. Patients with features of either a respiratory chain or fatty acid oxidation disorder should have the defect characterized biochemically because of the implications with respect to potential therapy and genetic counseling.
Subject(s)
3-Hydroxyacyl CoA Dehydrogenases/deficiency , NADH, NADPH Oxidoreductases/deficiency , Electron Transport , Fatty Acids/metabolism , Humans , Infant , MaleABSTRACT
Cyclophosphamide (CP) is an alkylating agent widely used in treating cancer and autoimmune disease. CP is classified as a pregnancy risk factor D drug and is teratogenic in animals, but population studies have not conclusively demonstrated teratogenicity in humans. Six isolated reports of prenatally exposed infants with various congenital anomalies exist, but to date no specific phenotype has been delineated. The purpose of this report is to document a new case of in utero CP exposure with multiple congenital anomalies and to establish an apparent CP embryopathy phenotype. The mother had systemic lupus erythematosus and cyclophosphamide exposure in the first trimester. She also took nifedipine, atenolol, clonidine, prednisone, aspirin, and potassium chloride throughout pregnancy. The infant had growth retardation and multiple anomalies including microbrachycephaly, coronal craniosynostosis, hypotelorism, shallow orbits, proptosis, blepharophimosis, small, abnormal ears, unilateral preauricular pit, broad, flat nasal bridge, microstomia, high-arched palate, micrognathia, preaxial upper limb and postaxial lower limb defects consisting of hypoplastic thumbs, and bilateral absence of the 4th and 5th toes. Chromosomes were apparently normal. The reported cases of in utero exposure to cyclosposphamide shared the following manifestations with our patient: growth deficiency, developmental delay, craniosynostosis, blepharophimosis, flat nasal bridge, abnormal ears, and distal limb defects including hypoplastic thumbs and oligodactyly. We conclude that (a) cyclophosphamide is a human teratogen, (b) a distinct phenotype exists, and (c) the safety of CP in pregnancy is in serious question.
Subject(s)
Abnormalities, Multiple/chemically induced , Cyclophosphamide/adverse effects , Abnormalities, Multiple/pathology , Adult , Animals , Blepharophimosis/chemically induced , Craniosynostoses/chemically induced , Developmental Disabilities/chemically induced , Ear, External/abnormalities , Female , Growth Disorders/chemically induced , Humans , Infant, Newborn , Limb Deformities, Congenital/chemically induced , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/drug therapy , Maternal-Fetal Exchange , Phenotype , Pregnancy , Pregnancy Complications/drug therapy , Teratogens/toxicityABSTRACT
Kabuki syndrome (KS) is a rare multiple malformation disorder characterized by developmental delay, distinct facial anomalies, congenital heart defects, limb and skeletal anomalies, and short stature. Renal anomalies have been reported in a few cases of KS, but to our knowledge, hepatic anomalies have not. Here, we document two cases of KS requiring liver or kidney transplantation: one with severe hepatic and renal anomalies and one with severe renal anomalies. Both cases had the characteristic facial appearance of children with KS, postnatal growth deficiency, and developmental delay. At birth, case 1 presented with hypoglycemia, ileal perforation, right hydroureter, and hydronephrosis. The patient subsequently developed hyperbilirubinemia, hepatic abscess, and cholangitis. At age 8 months, he underwent a liver transplant. Hepatic pathology diagnosed neonatal sclerosing cholangitis. Case 2 presented with renal failure at age 6 years. Renal ultrasound study showed markedly dysplastic kidneys requiring transplantation. In addition to characteristic findings of KS, she had coronal synostosis and was shown to have immune deficiency and an autoimmune disorder manifesting as Hashimoto thyroiditis and vitiligo. We conclude: 1) severe hepatic and renal anomalies leading to organ failure can occur in KS; 2) patients with neonatal sclerosing cholangitis should be examined closely for features of KS; 3) coronal synostosis may occur in KS; and 4) immune deficiency and autoimmune disorder can be associated with KS.
Subject(s)
Abnormalities, Multiple/pathology , Craniofacial Abnormalities/pathology , Kidney Transplantation , Liver Transplantation , Adult , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Intellectual Disability/pathology , Male , SyndromeABSTRACT
Congenital diaphragmatic defects (CDDs) may occur in malformation syndromes of varied causes. Syndromic cases of CDDs due to chromosomal defects, autosomal recessive, autosomal dominant, or X-linked inheritance have been described. In order to determine the frequency and nature of syndromes, malformations, and chromosome abnormalities associated with CDDs, we reviewed the records of all patients with CDDs evaluated over a 4-year period. During the 4-year interval, a total of 60 patients was evaluated. Of these, 29 had a therapeutic or spontaneous abortion, and 31 received postnatal care. On prenatal ultrasonography, 20 of 60 (33%) of patients with CDDs had additional anomalies. Additional anomalies, besides CDDs, were present in 15 of 31 (48%) of liveborn patients on newborn evaluation. In total, 16 patients with multiple anomalies were evaluated. Of these, 12 of 16 (75%) had additional abnormalities detected by prenatal ultrasonography. The 4 of 16 (25%) without additional anomalies on prenatal sonography had multiple anomalies found neonatally, lethal multiple pterygium syndrome being diagnosed in one case. Prenatal chromosome analysis was performed in 7 of 16 patients, and all had postnatal karyotypes. All initial karyotypes were normal. Tetrasomy 12p was documented on postnatal fibroblast analysis in one case who had percutaneous umbilical blood sampling (PUBS). Syndromes diagnosed postnatally in 7 of 16 patients (44%) include: Fryns syndrome (2), Simpson-Golabi-Behmel syndrome (2), tetrasomy 12p (1), Brachmann-de Lange syndrome (1), and lethal multiple pterygium syndrome (1). We were unable to make a specific diagnosis in 9 of 16 patients (56%) with multiple malformations. In patients with CDDs, a normal prenatal karyotype, especially if obtained by PUBS, and absence of other detected abnormalities by fetal ultrasonography, do not exclude the presence of other major anomalies, including chromosome abnormalities and severe multiple malformation syndromes.
Subject(s)
Chromosome Aberrations/genetics , Diaphragm/abnormalities , Chromosome Aberrations/diagnosis , Chromosome Disorders , Female , Humans , Infant, Newborn , Infant, Newborn, Diseases/genetics , Pregnancy , Prenatal Diagnosis , Retrospective Studies , Syndrome , Ultrasonography, PrenatalABSTRACT
We describe 8 patients affected with Costello syndrome including an affected sib pair and review the literature on 29 previously reported cases. We emphasize an association with advanced parental age, which is consistent with autosomal dominant inheritance with germline mosaicism. The pathogenesis appears to involve metabolic dysfunction, with growth disturbance, storage disorder appearance, acanthosis nigricans, hypertrophic cardiomyopathy, and occasional abnormalities of glucose metabolism. Although the cause is currently unknown, Costello syndrome is interesting because of a potential genetic-metabolic etiology.
Subject(s)
Dwarfism/pathology , Facies , Intellectual Disability/pathology , Acanthosis Nigricans/pathology , Acanthosis Nigricans/physiopathology , Adolescent , Adult , Age Factors , Carbohydrate Metabolism, Inborn Errors/pathology , Carbohydrate Metabolism, Inborn Errors/physiopathology , Cardiomyopathy, Hypertrophic/pathology , Cardiomyopathy, Hypertrophic/physiopathology , Child , Child, Preschool , Diagnosis, Differential , Dwarfism/diagnosis , Dwarfism/etiology , Dwarfism/genetics , Dwarfism/physiopathology , Female , Genes, Dominant/genetics , Germ-Line Mutation/genetics , Glucose/metabolism , Humans , Intellectual Disability/diagnosis , Intellectual Disability/etiology , Intellectual Disability/genetics , Intellectual Disability/physiopathology , Male , Metabolic Diseases/pathology , Metabolic Diseases/physiopathology , Mosaicism/genetics , Nose Neoplasms/diagnosis , Nose Neoplasms/etiology , Nose Neoplasms/genetics , Nose Neoplasms/pathology , Nose Neoplasms/physiopathology , Papilloma/diagnosis , Papilloma/etiology , Papilloma/genetics , Papilloma/pathology , Papilloma/physiopathology , Parents , Phenotype , SyndromeABSTRACT
OBJECTIVE: This study aimed to describe the clinical and histopathologic findings in four patients with complex limbal choristomas associated with linear nevus sebaceous syndrome (LNSS), a rare disorder including nevus sebaceous, seizures, and mental retardation, and often accompanied by ocular anomalies. DESIGN: Small observational case series. METHODS: A retrospective review of the clinical and histopathologic records of four patients. RESULTS: Each of four patients had complex limbal choristomas in the setting of clinical and histopathologic LNSS. The limbal choristomas were multiple in three patients and bilateral in two patients. Most choristomas involved the superotemporal limbus (6 of 10), although nasal (3 of 10) and inferior (1 of 10) limbal tumors also were present. Three patients had significant corneal astigmatism or involvement of the central cornea requiring surgical removal of their choristomas, one accompanied by a lamellar keratoplasty and another accompanied by two consecutive penetrating keratoplasties. Each graft eventually vascularized, reducing vision. One patient's vision was limited by amblyopia and another by occipital cortical dysgenesis with visual impairment. Histopathologic examination of the excised choristomas showed foci of lacrimal gland (3 of 4 patients), adipose tissue (3 of 4), neural tissue (1 of 4), cartilage (1 of 4), lymphoid follicles (1 of 4), skin adnexal tissue (1 of 4), and smooth muscle (1 of 4). Other associated ocular findings included an eyelid mass (1 of 4), colobomas of the eyelid (3 of 4), colobomas of the choroid and retina (2 of 4), nonparalytic strabismus (2 of 4), scleral ectasia (1 of 4), partial oculomotor palsy with ptosis and anisocoria (1 of 4), microphthalmia (1 of 4), hypertelorism (1 of 4), and cortical visual impairment (1 of 4). CONCLUSIONS: Complex limbal choristomas, although rare, can occur in the setting of LNSS and can be associated with multiple ocular and systemic abnormalities. Visual prognosis appears poor in most cases despite aggressive management.
Subject(s)
Choristoma/complications , Corneal Diseases/complications , Eye Neoplasms/complications , Intellectual Disability/complications , Neoplasms, Complex and Mixed/complications , Nevus, Pigmented/complications , Sebaceous Gland Neoplasms/complications , Seizures/complications , Child, Preschool , Choristoma/pathology , Choristoma/surgery , Corneal Diseases/pathology , Corneal Diseases/surgery , Eye Abnormalities/complications , Eye Abnormalities/pathology , Eye Neoplasms/pathology , Eye Neoplasms/surgery , Female , Humans , Infant , Infant, Newborn , Intellectual Disability/pathology , Keratoplasty, Penetrating , Limbus Corneae/pathology , Male , Neoplasms, Complex and Mixed/pathology , Neoplasms, Complex and Mixed/surgery , Neoplasms, Multiple Primary/complications , Neoplasms, Multiple Primary/pathology , Nevus, Pigmented/pathology , Retrospective Studies , Sebaceous Gland Neoplasms/pathology , Seizures/pathology , SyndromeABSTRACT
Among 58,000 amniocenteses completed, our laboratories found one case of true cytogenetic trisomy 2 mosaicism in a fetus with multiple abnormalities. In contrast, 11 fetuses phenotypically normal at birth were found to have true trisomy 2 mosaicism in their chorionic villus cells among the 10,500 fetuses tested by chorionic villus sampling (CVS). In our single abnormal case, amniocentesis performed at 19 weeks after finding an elevated maternal serum AFP found two independent cultures with trisomy 2 karyotypes in 8 of 25 and 7 of 31 amniocytes, respectively. Although oligohydramnios was noted by ultrasound, the mother elected to continue the pregnancy. At 26 weeks the fetus had intrauterine growth retardation (IUGR), hydronephrosis, and cardiac abnormalities. When delivered by Cesarean section at 30 weeks, the infant had multiple anomalies and developed necrotizing enterocolitis and severe cholestasis. At 5 months coronal magnetic resonance imaging (MRI) displayed delayed myelination and abnormal brain morphology. The patient also exhibited significant growth failure and developmental delay. Although chromosomes were normal in blood, skin fibroblasts, and ascites fluid cells, 4 of 100 hepatic biopsy fibroblasts were 47,XY,+2. Molecular analysis excluded uniparental disomy (UPD) of chromosome 2 in the 46,XY cell line. This and other reports of rare phenotypically abnormal trisomy 2 mosaic fetuses identified by karyotyping amniocytes emphasizes the substantially higher fetal risk of abnormal development than when trisomy 2 is found only in chorionic villus cells.
Subject(s)
Abnormalities, Multiple/genetics , Amnion/pathology , Chromosomes, Human, Pair 2 , Liver/abnormalities , Mosaicism/genetics , Trisomy , Adult , Alleles , Female , Humans , Male , Mosaicism/pathology , PregnancyABSTRACT
A review of clinical findings in 12 children with Kabuki syndrome revealed a high prevalence of otolaryngologic problems, including dysmorphic pinnae (100%), ear disease (92%), hearing loss (82%) and airway problems (58%). The high prevalence of ear disease and hearing loss was not explained solely on the basis of prevalence of cleft palate. Patients with Kabuki syndrome require the diagnostic and treatment expertise of otolaryngologists on an ongoing basis.
Subject(s)
Abnormalities, Multiple/diagnosis , Airway Obstruction/diagnosis , Face/abnormalities , Otorhinolaryngologic Diseases/diagnosis , Abnormalities, Multiple/genetics , Cleft Palate/diagnosis , Ear, External/abnormalities , Female , Humans , Male , Otorhinolaryngologic Diseases/genetics , SyndromeABSTRACT
Velocardiofacial syndrome (VCFS) and the DiGeorge sequence (DGS) are caused by 22q11.2 deletions. Fluorescence in situ hybridization (FISH) using the DiGeorge chromosome region (DGCR) probe (Oncor) was used to detect 31 deletions in 100 patients with possible VCFS. Retrospective FISH analysis of archived slides from 14 patients originally studied only by high-resolution G banding detected 6 patients with a DGCR deletion, and only 2 of these 6 had a microscopically visible chromosome deletion. The 4 familial deletions found exhibited a wide range of clinical presentations within each family. Comparison of clinical characteristics of patients with and without the DGCR deletion determined findings predictive of the deletion: abundant or unruly scalp hair; narrow palpebral fissures; a laterally "built-up" nose; velopharyngeal inadequacy; thymic hypoplasia; and congenital heart defects, specifically tetralogy of Fallot, ventriculoseptal defect, and interrupted aortic arch.
Subject(s)
Chromosome Aberrations/genetics , Chromosome Deletion , Chromosomes, Human, Pair 22/genetics , Craniofacial Abnormalities/genetics , DiGeorge Syndrome/genetics , Adolescent , Adult , Child , Child, Preschool , Chromosome Aberrations/diagnosis , Chromosome Disorders , Craniofacial Abnormalities/diagnosis , DNA Probes , Female , Heart Defects, Congenital/genetics , Humans , In Situ Hybridization, Fluorescence/methods , Infant , Infant, Newborn , Karyotyping , Male , Pedigree , Phenotype , Retrospective Studies , SyndromeABSTRACT
Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth disorder recently shown to be caused by mutations in the heparan sulfate proteoglycan GPC3 [Pilia et al., Nat Genet; 12:241-247 1996]. We have used Southern blot analysis and polymerase chain reaction amplification of intra-exonic sequences to identify four new GPC3 mutations and further characterize three previously reported SGBS mutations. De novo GPC3 mutations were identified in 2 families. In general, the mutations were unique deletions ranging from less than 0.1 kb to more than 300 kb in length with no evidence of a mutational hot spot discerned. The lack of correlation between the phenotype of 18 affected males from these 7 families and the location and size of the GPC3 gene mutations suggest that SGBS is caused by a nonfunctional GPC3 protein.
Subject(s)
Chromosome Deletion , Heparitin Sulfate/genetics , Mutation , Proteoglycans/genetics , Abnormalities, Multiple/genetics , Autoradiography , Blotting, Southern , DNA Probes , Genotype , Heparan Sulfate Proteoglycans , Humans , Male , Pedigree , Phenotype , Polymerase Chain Reaction , X Chromosome/geneticsABSTRACT
Beare-Stevenson cutis gyrata syndrome (MIM 123790) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death. Many of these features are characteristic of some of the autosomal dominant craniosynostotic syndromes. Mutations in Crouzon, Jackson-Weiss, Pfeiffer and Apert syndromes have been reported in the FGFR2 extracellular domain. In Crouzon syndrome patients with acanthosis nigricans, a recurrent mutation occurs in the transmembrane domain of FGFR3. We now describe the detection of FGFR2 mutations in the Beare-Stevenson cutis gyrata syndrome. In three sporatic cases, a novel missense mutation was found causing an amino acid to be replaced by a cysteine; two had the identical Ty375Cys mutation in the transmembrane domain and one had a Ser372Cys mutation in the carboxyl-terminal end of the linker region between the immunoglobulin III-like (Iglll) and transmembrane domains. In two patients, neither of these mutations were found suggesting further genetic heterogeneity.
Subject(s)
Abnormalities, Multiple/genetics , Receptor Protein-Tyrosine Kinases/genetics , Receptors, Fibroblast Growth Factor/genetics , Skin Abnormalities , Acanthosis Nigricans/genetics , Amino Acid Sequence , Base Sequence , Craniosynostoses/genetics , DNA Primers/chemistry , Exons , Female , Genes, Dominant , Humans , Male , Membrane Glycoproteins/genetics , Molecular Sequence Data , Pedigree , Point Mutation , Receptor, Fibroblast Growth Factor, Type 2 , SyndromeABSTRACT
Trichothiodystrophy (TTD), an autosomal recessive disorder characterized by sulfur-deficient brittle hair, identifies a group of genetic disorders with an altered synthesis of high-sulfur matrix proteins and a defect in excision repair of ultraviolet damage in fibroblasts of most TTD patients. In contrast to patients with xeroderma pigmentosum (XP), TTD patients do not have an increased frequency of skin cancers. TTD patients may be grouped into four categories: 1) those without photosensitivity and without a defect in excision repair of UV damage; 2) those without photosensitivity and with an excision-repair defect in the same gene as in XP-D (complementation group D); 3) those with photosensitivity and with the XP-D repair defect; 4) those with photosensitivity and with a repair defect distinct from that in XP-D. We present a brother and sister in the third category of TTD. Clinically, the patients have brittle hair, short stature, ichthyosis, photosensitivity, nail and dental dysplasias, cataracts, mental retardation, and pyramidal tract abnormalities. Diagnosis was made by hair mount, which shows the characteristic banding pattern with polarizing microscopy, and by hair amino acid analysis, which demonstrated decreased high-sulfur matrix proteins. Fibroblasts cultured from skin biopsies had a marked DNA excision repair defect similar to the repair defect seen in XP-D. We have documented a unique dysmyelinating disorder on magnetic resonance imaging of the brain that might explain their mental retardation, marked hyperactivity, and neurologic deficits. Following the discovery that the human excision repair cross complementing rodent ultraviolet group 2 (ERCC2) gene is able to correct the ultraviolet sensitivity of XP-D cell strains, the ERCC2 cDNA from previous TTD patients was sequenced and shows frameshifts, deletions and point mutations in the ERCC2 gene. Molecular analysis of our patients is in progress. Molecular analysis of the defects in ERCC2 in clinically distinct patients with XP,XP/Cockayne's syndrome, and TTD may provide insight into the molecular mechanisms of these genetically related but clinically distinct disorders.
Subject(s)
Brain/pathology , Demyelinating Diseases/genetics , Hair/abnormalities , Child , Child, Preschool , DNA Repair/radiation effects , Female , Hair/pathology , Humans , Magnetic Resonance Imaging , Male , Photosensitivity Disorders/genetics , Ultraviolet RaysABSTRACT
Thirty two infants referred for in-patient genetics evaluation at the University of California at San Francisco, 1987-1992, were found to have a history of maternal cocaine use. Genetics reports and medical records were reviewed on all these infants to identify features distinctive for cocaine exposure. Among these 32 cases, 14 infants were exposed only to cocaine; 18 were exposed to alcohol and cocaine. The infants evaluated displayed a distinctive phenotype, consisting of neurologic irritability, large fontanels, prominent glabella, marked periorbital and eyelid edema, low nasal bridge with transverse crease, short nose, lateral soft tissue nasal buildup, and small toenails. Features consistent with the fetal alcohol syndrome appeared distinct and coexistent with the other described facial findings. Other severe abnormalities included cleft lip/palate, atypical facial cleft, abnormal BSER, intraventricular hemorrhages, arthrogryposes, and genitourinary abnormalities. Forty percent of the infants were born prematurely; 28% were small for gestational age; 43% showed head circumference values less than the 10th percentile. We conclude that these findings may be distinctive for a diagnosis of fetal cocaine syndrome; such findings should be further established by a future blinded prospective study of mothers and neonates.
Subject(s)
Birth Weight/drug effects , Cocaine/adverse effects , Ethanol/adverse effects , Face/abnormalities , Alcoholism , Anthropometry , Female , Gestational Age , Humans , Infant, Newborn , Male , Maternal-Fetal Exchange , Pregnancy , Pregnancy Complications , Substance-Related DisordersABSTRACT
Xp21 microdeletion syndrome is associated with variable size Xp21 deletions that usually include the glycerol kinase locus. The clinical phenotypes we studied in this chromosome region include: Xpter - Aland Island eye disease (AIED) -adrenal hypoplasia (AH) -glycerol kinase (GKD) -Duchenne muscular dystrophy (DMD) -retinitis pigmentosa (RP) -ornithine transcarbamylase (OTC) -centromere. In a compilation of 18 individuals in 14 families with the AH, GKD, and DMD loci deleted, 17 were male and all were developmentally delayed. In contrast, we report mentally retarded female carriers in two Xp21 deletion syndrome families with DMD, GKD, and AH in affected males. In the first family with normal karyotypes, a submicroscopic deletion was associated with DMD in the retarded male and with retardation in carrier females. In the second family an X chromosome with a cytogenetically deleted Xp21 distal to the OTC and RP genes segregated in the affected male and retarded female carriers. DNA analysis at the DMD locus verified the cytogenetic findings. This report of mental retardation in otherwise asymptomatic female carriers of Xp21 deletion classifies one form of mental retardation in females.