Re: True agonadism: report of a case analyzed with Y-specific DNA probes.
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Adult↗
Biomedical subjects
R A Pagon
Publications and source records attributed to R A Pagon.
Okihiro syndrome.
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Abnormalities, Multiple↗
Hypomelanosis of Ito in a girl with plexus papilloma and translocation (X;17)
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Female↗
The 8993 mtDNA mutation: heteroplasmy and clinical presentation in three families.
The point mutation at bp 8993 of human mtDNA in the ATPase 6 gene is associated with neurogenic weakness, ataxia and retinitis pigmentosa, and with subacute necrotizing encephalomyelopathy (Leigh disease) when present at high copy number. In this study we describe three new multiplex families with the ATPase 8993 mtDNA mutation and demonstrate a correlation between the percentage heteroplasmy of this mutation and the clinical phenotype. By combining this study with previous data we produce a graph of age of onset of symptoms versus percentage heteroplasmy of the mutation. Finally, we determine that ATP synthesis with NAD-linked substrates in cultured lymphoblast mitochondria from three patients with Leigh disease who had a high percentage heteroplasmy was on average 66% of the rate seen in control lymphoblast mitochondria. Similar rates are observed in lymphoblast mitochondria isolated from patients with Leigh disease due to complex I deficiency. This percentage appears to be independent of the rate of electron transport in mitochondria from patient cell lines with the mtDNA 8993 mutation.
Adenosine Triphosphatases↗
A contiguous gene deletion syndrome at 7q21-q22 and implications for a relationship between isolated ectrodactyly and syndromic ectrodactyly.
Ectrodactyly is a genetically heterogeneous human limb developmental malformation with an autosomal locus at 7q21 designated SHFD1. We report a patient with ectrodactyly and a small interstitial deletion of 7q21, detected by high resolution karyotype, which provides additional evidence for the existence of an ectrodactyly gene in this region and further restricts the size of the critical region containing SHFD1. A review of previously published patients with ectrodactyly and similar deletions suggests a contiguous gene deletion syndrome at 7q21-q22 which consists of ectrodactyly, growth retardation, developmental delay, hypertelorism, ear malformation, components of the Robin sequence, and GU abnormalities. Moreover, the clinical, genetic, and cytogenetic similarities of a number of multiple congenital anomaly syndromes which include ectrodactyly as just one component lead us to propose that a common genetic basis may underlie many of these syndromes. Thus, evaluation for related physical anomalies and high resolution cytogenetic studies are indicated in patients with ectrodactyly.
Abnormalities, Multiple↗
Phenotypic variability in X-linked ocular albinism: relationship to linkage genotypes.
One hundred nineteen individuals from 11 families with X-linked ocular albinism (OA1) were studied with respect to both their clinical phenotypes and their linkage genotypes. In a four-generation Australian family, two affected males and an obligatory carrier lacked cutaneous melanin macroglobules (MMGs); ocular features were identical to those of Nettleship-Falls OA1. Four other families had more unusual phenotypic features in addition to OA1. All OA1 families were genotyped at DXS16, DXS85, DXS143, STS, and DXS452 and for a CA-repeat polymorphism at the Kallmann syndrome locus (KAL). Separate two-point linkage analyses were performed for the following: group A, six families with biopsy-proved MMGs in at least one affected male; group B, four families whose biopsy status was not known; and group C, OA-9 only (16 samples), the family without MMGs. At the set of loci closest to OA1, there is no clear evidence in our data set for locus heterogeneity between groups A and C or among the four other families with complex phenotypes. Combined multipoint analysis (LINKMAP) in the 11 families and analysis of individual recombination events confirms that the major locus for OA1 resides within the DXS85-DXS143 interval. We suggest that more detailed clinical evaluations of OA1 individuals and families should be performed for future correlation with specific mutations in candidate OA1 genes.
Albinism, Ocular↗
Fine mapping of the autosomal dominant split hand/split foot locus on chromosome 7, band q21.3-q22.1.
Split hand/split foot (SHFD) is a human developmental defect characterized by missing digits, fusion of remaining digits, and a deep median cleft in the hands and feet. Cytogenetic studies of deletions and translocations associated with this disorder have indicated that an autosomal dominant split hand/split foot locus (gene SHFD1) maps to 7q21-q22. To characterize the SHFD1 locus, somatic cell hybrid lines were constructed from cytogenetically abnormal individuals with SHFD. Molecular analysis resulted in the localization of 93 DNA markers to one of 10 intervals surrounding the SHFD1 locus. The translocation breakpoints in four SHFD patients were encompassed by the smallest region of overlap among the SHfD-associated deletions. The order of DNA markers in the SHFD1 critical region has been defined as PON-D7S812-SHFD1-D7S811-ASNS. One DNA marker, D7S811, detected altered restriction enzyme fragments in three patients with translocations when examined by pulsed-field gel electrophoresis (PFGE). These data map SHFD1, a gene that is crucial for human limb differentiation, to a small interval in the q21.3-q22.1 region of human chromosome 7.
Adult↗
Mosaic isochromosome 8p.
Findings in a patient with mosaic isochromosome 8p are compared with those of previously reported cases. There were no distinguishing findings on physical examination; all had cognitive delays, especially in speech and language development.
Abnormalities, Multiple↗
Mapping of the distal boundary of the X-inactivation center in a rearranged X chromosome from a female expressing XIST.
A female patient with primary amenorrhea, immature secondary sexual characteristics, and tall stature was found to have a normal X chromosome and a rearranged X [rea(X)] chromosome that resembled an 'isochromosome' Xp, but retained the proximal portion of Xq. The rea(X) was interpreted as rec(X)dup p,inv(X)(p11.4q13). Replication studies demonstrated that the rea(X) was always the late-replicating and, therefore, presumably inactive X chromosome, which must contain the X-inactivation center. Consistent with this interpretation, fluorescence in situ hybridization demonstrated that the rea(X) retained the XIST gene, and reverse transcription polymerase chain reaction analysis showed that XIST was expressed in the patient's cells. By fluorescence in situ hybridization with previously mapped probes, the breakpoint of the rea(X) was located within an approximately 500-kb region located approximately 200 to 700 kb distal to the XIST locus. This is the closest breakpoint distal to XIST in an inactivated X chromosome and, therefore, defines a new distal boundary for the X-inactivation center in humans.
Adolescent↗
Phenotypic correlations of ocular coloboma without known cause.
Ocular coloboma can occur as an autosomal dominant condition or as part of a known syndrome or chromosomal abnormality. We have designated those patients with ocular coloboma who do not fit into any of these three groups as having coloboma without known cause. We completed a retrospective review of 58 patients from our clinics with coloboma without known cause to determine the frequency of other co-existing congenital malformations and mental retardation. Mental retardation was present in 14 of the 42 patients (33%) who were more than 1 year of age. However, only 14% of the children who had no other malformations had mental retardation, whereas 57% of those with other malformations were mentally retarded. We found that the severity of the colobomatous malformation did not correlate with intellect.
Adolescent↗
Familial hydrocephalus with a low-insertion umbilicus.
Two brothers, age 16 months and 3 years, had a seemingly unique combination of hydrocephalus of the lateral ventricles and a low-insertion umbilicus. Both had similar mildly unusual facies and inguinal hernias; one had unilateral cryptorchidism. The older brother had tetralogy of Fallot, and the younger had mildly enlarged, echogenic kidneys with vesicoureteral reflux. Neither boy had adducted thumbs, pyramidal tract signs, or significant developmental delay. A review of the literature on familial hydrocephalus found no similar cases. A low-set umbilicus is not a frequently noted anomaly; its embryology and associated syndromes are discussed. The association of hydrocephalus and a low-set umbilicus appears to be the manifestation of a monogenic disorder in this family, and could be inherited in either an autosomal recessive or X-linked recessive manner.
Child, Preschool↗
Preferential mutation of the neurofibromatosis type 1 gene in paternally derived chromosomes.
An interesting feature of neurofibromatosis type 1 (NF1) is its high mutation rate of 1 x 10(-4) per gamete per generation. The molecular basis for frequent NF1 mutation in unknown; the gene is not deletion prone. We have found that in all ten families examined, the apparent new NF1 mutation occurred on the paternally-derived chromosome. The probability of observing this result by chance is less than 0.001 assuming an equal frequency of mutation of paternal and maternal NF1 genes. We hypothesize a role for genomic imprinting that may either enhance mutation of the paternal NF1 gene or confer protection from mutation to the maternal NF1 gene.
Chromosomes, Human↗
Deletion mapping of H-Y antigen to the long arm of the human Y chromosome.
A gene encoding or controlling the expression of the H-Y transplantation antigen was previously mapped to the human Y chromosome. We now report the sublocalization of this gene on the long arm of the human Y chromosome. Eight patients with Y-chromosomal abnormalities were examined with a series of existing and new DNA markers for the Y chromosome. The resulting deletion map was correlated with H-Y antigen expression. We conclude that the H-Y antigen gene maps to a portion of deletion interval 6 that is identified by specific DNA markers.
Adolescent↗
Causal heterogeneity in isolated lissencephaly.
We report clinical, cytogenetic, and molecular studies in 65 patients with isolated lissencephaly sequence (ILS). All had type I lissencephaly of varying severity and a grossly normal cerebellum. Some had additional brain abnormalities. Facial appearance was essentially normal. All had severe to profound mental retardation, seizures, hypotonia that evolved into spasticity, and feeding difficulties. Clinical and laboratory studies demonstrated etiologic heterogeneity. Molecular studies detected microdeletions in chromosome band 17p13.3 in six of 44 patients tested, confirming that deletion of all or part of this "critical region" is the cause of ILS in some cases. There were slightly larger deletions in the same region in a majority of patients with Miller-Dieker syndrome. One patient had an apparently balanced, de novo reciprocal translocation with breakpoints at Xq22 and 2p25. Four sibs from two families had a new, autosomal recessive syndrome of ILS with neonatal death. Other causes supported by clinical observations include autosomal recessive inheritance, intrauterine infection, and intrauterine perfusion failure. Those ILS probands in whom no etiology could be established had 41 sibs of whom three were affected, giving an empiric recurrence risk of 7%.
Brain↗
Autosomal dominant transmission of acrodysostosis.
A mother and daughter with acrodysostosis are described. This documented parent-to-child transmission supports the hypothesis of autosomal dominant inheritance of acrodysostosis. The daughter exhibited many features of acrodysostosis by two months of age, demonstrating that acrodysostosis may be diagnosed in infancy.
Adult↗
Twin fetuses with abnormalities that overlap with three midline malformation complexes.
Twin fetuses aborted at an estimated gestational age of 145 days were concordant for oral, facial, skeletal, and central nervous system malformations. The twins were discordant for other anomalies including cardiac defects, polydactyly, and malrotated short bowel. The combination of malformations observed overlaps with that of the oral-facial-digital syndrome, hydrolethalus syndrome, and Pallister-Hall syndrome. The problem of phenotypic overlap between these syndromes is discussed.
Abnormalities, Multiple↗
Nasal dermoid sinus cysts: association with intracranial extension and multiple malformations.
Nasal dermoid and sinus cysts (NDSC) are uncommon congenital anomalies that may have intracranial extension and can be associated with other anomalies. We identified 22 patients in a retrospective review of cases diagnosed with NDSC at our institution over the past 10 years. Nine (41 percent) had associated anomalies and ten (45 percent) had intracranial extension of the sinus. In half of the patients with intracranial extension, the sinus transversed either the cribriform plate or foramen cecum and attached to the dura; in the other half, the sinus extended to cysts within the falx or other brain structures. Of the patients with multiple anomalies, six (67 percent) had intracranial extension. Presurgical complications occurred in a total of eight patients (36 percent): two had meningitis, two had osteomyelitis, four had periorbital-nasal cellulitis, three had nasal abscess, and four had nose anomalies requiring rhinoplasty.
Abnormalities, Multiple↗
X-linked sideroblastic anemia and ataxia: linkage to phosphoglycerate kinase at Xq13.
Molecular linkage analysis was performed on a kindred with X-linked sideroblastic anemia and ataxia. Two-point analysis with a DNA probe for phosphoglycerate kinase (PGK1), which maps to Xq13, suggested linkage to the disorder by a lod score of at least 2.60 at a recombination fraction of zero. The disease in this kindred appears to be clinically and genetically distinct from that in previously reported families with X-linked hereditary ataxia or spastic paraparesis. No mapping data are available for inherited X-linked sideroblastic anemia without neurologic abnormalities. However, structural alterations of band Xq13 may be involved in the development of idiopathic acquired sideroblastic anemia. No alterations in the restriction patterns of two X-linked genes involved in erythrocyte formation-i.e., a DNA-binding protein (GF-1) and 5-aminolevulinate synthase (ALAS)-were detected in DNA from affected males, arguing against a large deletion in either of these candidate genes.
Anemia, Sideroblastic↗