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A Shanske

Publications and source records attributed to A Shanske.

18 recordsLinked to original sources
PubMed2001

Hirschsprung disease in an infant with a contiguous gene syndrome of chromosome 13.

Hirschsprung disease is a developmental disorder resulting from the arrest of the craniocaudal migration of enteric neurons from the neural crest along gastrointestinal segments of variable length; see Behrman [Nelson textbook of pediatrics, 1992:954-956]. It is a heterogeneous disorder in which familial cases map to at least three loci whose function is necessary for normal neural crest-derived cell development. Homozygous mutations in the endothelin-B receptor gene (EDNRB) on 13q22 have been identified in humans and mice with Hirschsprung disease type 2 (HSCR2). The auditory pigmentary disorder, Waardenburg-Shah syndrome, comprises Waardenburg syndrome and Hirschsprung disease and has also been mapped to the EDNRB locus. Hirschsprung disease, malrotation, isochromia, a profound sensorineural hearing loss, and several other anomalies were found in an infant with an interstitial deletion of 13q, suggesting the existence of a contiguous gene syndrome involving developmental genes necessary for the normal growth of the neural crest derivatives of the eye, inner ear, and colon. We report on an additional patient with a deletion in 13q and Hirschsprung disease. Congenital anomalies associated with deletions of the distal long arm of chromosome 13 are sufficiently consistent to suggest a clinical syndrome.

Chromosome Banding↗
PubMed2001

Subtle radiographic findings of achondroplasia in patients with Crouzon syndrome with acanthosis nigricans due to an Ala391Glu substitution in FGFR3.

A unique type of craniofacial dysostosis, Crouzon syndrome with acanthosis nigricans (CAN), has been attributed to a specific substitution (Ala391Glu) in the fibroblast growth factor receptor 3 (FGFR3) gene. At birth, individuals with this disorder have craniosynostosis, ocular proptosis, midface hypoplasia, choanal atresia, hydrocephalus, and they experience the onset of acanthosis nigricans during childhood. We report three cases and compare the clinical characteristics of our cases with the previously reported cases of this disorder. Since the Ala391Glu substitution in FGFR3 is close to the substitutions in the transmembrane domain that result in achondroplasia, we carefully reviewed the skeletal findings in six patients. We identified subtle radiographic findings of achondroplasia in all six cases including narrow sacrosciatic notches, short vertebral bodies, lack of the normal increase in interpediculate distance from the upper lumbar vertebrae caudally, and broad, short metacarpals and phalanges. Even before acanthosis nigricans appears, the presence of choanal atresia and hydrocephalus in an individual with features of Crouzon syndrome should suggest the diagnosis of CAN, and subtle skeletal findings can lend further support to this diagnosis.

Acanthosis Nigricans↗
PubMed2000

AT-rich palindromes mediate the constitutional t(11;22) translocation.

The constitutional t(11;22) translocation is the only known recurrent non-Robertsonian translocation in humans. Offspring are susceptible to der(22) syndrome, a severe congenital anomaly disorder caused by 3&rcolon;1 meiotic nondisjunction events. We previously localized the t(11;22) translocation breakpoint to a region on 22q11 within a low-copy repeat termed "LCR22" and within an AT-rich repeat on 11q23. The LCR22s are implicated in mediating different rearrangements on 22q11, leading to velocardiofacial syndrome/DiGeorge syndrome and cat-eye syndrome by homologous recombination mechanisms. The LCR22s contain AT-rich repetitive sequences, suggesting that such repeats may mediate the t(11;22) translocation. To determine the molecular basis of the translocation, we cloned and sequenced the t(11;22) breakpoint in the derivative 11 and 22 chromosomes in 13 unrelated carriers, including two de novo cases and der(22) syndrome offspring. We found that, in all cases examined, the reciprocal exchange occurred between similar AT-rich repeats on both chromosomes 11q23 and 22q11. To understand the mechanism, we examined the sequence of the breakpoint intervals in the derivative chromosomes and compared this with the deduced normal chromosomal sequence. A palindromic AT-rich sequence with a near-perfect hairpin could form, by intrastrand base-pairing, on the parental chromosomes. The sequence of the breakpoint junction in both derivatives indicates that the exchange events occurred at the center of symmetry of the palindromes, and this resulted in small, overlapping staggered deletions in this region among the different carriers. On the basis of previous studies performed in diverse organisms, we hypothesize that double-strand breaks may occur in the center of the palindrome, the tip of the putative hairpin, leading to illegitimate recombination events between similar AT-rich sequences on chromosomes 11 and 22, resulting in deletions and loss of the palindrome, which then could stabilize the DNA structure.

AT Rich Sequence↗
PubMed1999

Deletion of the pseudoautosomal region in a male with a unique Y;13 translocation and short stature.

Short stature is a common finding in patients with Ullrich-Turner syndrome. Structural abnormalities involving the terminal short arms of the X and Y chromosomes have been shown to lead to short stature. A putative locus affecting height called PHOG/SHOX has been localized to a 170-kb critical region within the pseudoautosomal region (PAR). It contains a homeodomain and functions as a transcription factor. We have studied a 10-year-old boy with idiopathic short stature who was found to have a unique Y;13 translocation. Southern blot analysis using cDNA probes indicated that most of the PAR, including PHOG/SHOX, was lost as a result of this translocation. We conclude that haploinsufficiency for this gene is responsible for the growth failure in our patient. Treatment with recombinant growth hormone has resulted in greatly improved growth velocity.

Body Height↗
PubMed1999

Der(22) syndrome and velo-cardio-facial syndrome/DiGeorge syndrome share a 1.5-Mb region of overlap on chromosome 22q11.

Derivative 22 (der[22]) syndrome is a rare disorder associated with multiple congenital anomalies, including profound mental retardation, preauricular skin tags or pits, and conotruncal heart defects. It can occur in offspring of carriers of the constitutional t(11;22)(q23;q11) translocation, owing to a 3:1 meiotic malsegregation event resulting in partial trisomy of chromosomes 11 and 22. The trisomic region on chromosome 22 overlaps the region hemizygously deleted in another congenital anomaly disorder, velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS). Most patients with VCFS/DGS have a similar 3-Mb deletion, whereas some have a nested distal deletion endpoint resulting in a 1.5-Mb deletion, and a few rare patients have unique deletions. To define the interval on 22q11 containing the t(11;22) breakpoint, haplotype analysis and FISH mapping were performed for five patients with der(22) syndrome. Analysis of all the patients was consistent with 3:1 meiotic malsegregation in the t(11;22) carrier parent. FISH-mapping studies showed that the t(11;22) breakpoint occurred in the same interval as the 1.5-Mb distal deletion breakpoint for VCFS. The deletion breakpoint of one VCFS patient with an unbalanced t(18;22) translocation also occurred in the same region. Hamster-human somatic hybrid cell lines from a patient with der(22) syndrome and a patient with VCFS showed that the breakpoints occurred in an interval containing low-copy repeats, distal to RANBP1 and proximal to ZNF74. The presence of low-copy repetitive sequences may confer susceptibility to chromosome rearrangements. A 1.5-Mb region of overlap on 22q11 in both syndromes suggests the presence of dosage-dependent genes in this interval.

Adolescent↗
PubMed1999

Joubert syndrome: monozygotic twins with discordant phenotypes.

We describe three sisters with Joubert syndrome, two of whom are monozygotic twins with highly discordant phenotypes. The twins were born at 34 weeks' gestation with discordant birthweights. Their anatomic, neurologic, and developmental status differs greatly: Twin B is able to walk, run, and is verbal, unlike Twin A who is wheelchair-bound, severely retarded, nonverbal, and autistic. Abnormal eye movements and retinal dysplasia are striking features in all three girls, but none has renal cysts seen by ultrasonography. Magnetic resonance images show the "molar tooth sign," the radiologic hallmark of Joubert syndrome, although only one twin, the most severely handicapped, has severe hypoplasia of the cerebellar hemispheres. Phenotypic differences between the twins could be attributable to postzygotic unequal division of the inner cell mass, unequal sharing of the venous return from a monochorionic placenta, mosaicism, or a mutation of a modifying gene.

Cerebellum↗
PubMed1998

An adult with 49,XYYYY karyotype: case report and endocrine studies.

Sex chromosome abnormalities, such as 47,XXX, 47,XXY, 47,XYY, and 45,X, are relatively common and occur in approximately 1 of 400 births. Sex chromosome tetrasomy and pentasomy are much rarer events. The somatic and developmental consequences of supernumerary sex chromosomes have not been studied adequately. This is especially true of individuals with only supernumerary Y chromosomes. Based on available case reports, the effects of extra Y chromosomes appear not as severe as those of supernumerary X chromosomes. Only two case reports of nonmosaic tetrasomy of the Y chromosome have been published. We evaluated a 30-year-old man with a 49,XYYYY karyotype and assessed his severe physical and mental handicaps (particularly the endocrine abnormalities) and attempted to clarify the effects of extra Y chromosomes on growth, development, and behavior.

Adult↗
PubMed1998

Normal adaptive function with learning disability in duplication 8p including band p22.

Duplication 8p usually results in a syndrome characterized by profound mental retardation, mild facial anomalies, and malformations of hand, heart, and brain. We report on a large kindred segregating a Y;8 translocation in whom several individuals have duplication 8p22-->8pter. These individuals have normal adaptive function despite their unbalanced karyotype. The family was studied with G-banding and fluorescent in situ hybridization (FISH) using probes to chromosomes 8 and Y. Comparison of this family with other reported cases defines a mild clinical outcome for trisomy 8p22-->8pter in contrast to the severe findings when the duplication involves a longer, more proximal segment.

Adaptation, Physiological↗
PubMed1997

Central nervous system anomalies in Seckel syndrome: report of a new family and review of the literature.

Seckel syndrome (SS) is a rare, heterogeneous form of primordial dwarfism. The clinical delineation of this disorder has been inconsistent, using even Seckel's original criteria. As a result, probably fewer than one-third of reported cases are truly affected with SS. Among these, there have been only six familial cases, all of whom were born to normal parents, and in only one case has a detailed description of the central nervous system (CNS) anomalies been given. We describe a family in which three of eight children were affected with SS. CNS anomalies seen in our patients included agenesis of the corpus callosum, a dysgenetic cerebral cortex, a large dorsal cerebral cyst, and pachygyria, suggesting an underlying neuronal migration disorder. The parents are first cousins, representing only the second instance of consanguinity, supporting an autosomal recessive mode of inheritance.

Brain↗
PubMed1993

Craniofacial, limb, and abdominal anomalies in a distinct syndrome: relation to the spectrum of Pfeiffer syndrome type 3.

Presented are 2 patients with abnormal craniofacial region, limbs, and abdomen, features that may be consistent with Pfeiffer syndrome, type 3. Both patients had bicoronal and bisphenoidal synostosis, extreme exophthalmic midface hypoplasia, and hydrocephalus. The limbs had a fixed flexion deformity of the elbows with broad thumbs which were radiopalmarly deviated; the toes were broad with a varus deformity and syndactyly toes 2-5. Both patients developed bowel obstruction secondary to midgut malrotation, and one of the patients had prune belly syndrome. Review of the literature disclosed an additional patient who, in retrospect, had Pfeiffer syndrome type 3 and midgut malrotation. These patients suggest that intestinal malrotation with or without prune belly syndrome may be a common component of this entity.

Abdomen↗
PubMed1992

Proposed guidelines for diagnosis of chromosome mosaicism in amniocytes based on data derived from chromosome mosaicism and pseudomosaicism studies.

Currently, accepted protocol which has been developed at the Prenatal Diagnosis Laboratory of New York City (PDL) requires that when a chromosome abnormality is found in one or more cells in one flask, another 20-40 cells must be examined from one or two additional flasks. Chromosome mosaicism is diagnosed only when an identical abnormality is detected in cells from two or more flasks. In a recent PDL series of 12,000 cases studied according to this protocol, we diagnosed 801 cases (6.68 per cent) of single-cell pseudomosaicism (SCPM), 126 cases (1.05 per cent) of multiple-cell pseudomosaicism (MCPM), and 24 cases (0.2 per cent) of true mosaicism. Pseudomosaicism (PM) involving a structural abnormality was a frequent finding (2/3 of SCPM and 3/5 of MCPM), with an unbalanced structural abnormality in 55 per cent of SCPM and 24 per cent of MCPM. We also reviewed all true mosaic cases (a total of 50) diagnosed in the first 22,000 PDL cases. Of these 50 cases, 23 were sex chromosome mosaics and 27 had autosomal mosaicism; 48 cases had numerical abnormalities and two had structural abnormalities. Twenty-five cases of mosaicism were diagnosed in the first 20 cells from two flasks, i.e., without additional work-up, whereas the other 25 cases required extensive work-up to establish a diagnosis (12 needed additional cell counts from the initial two culture flasks; 13 required harvesting a third flask for cell analysis). Our data plus review of other available data led us to conclude that rigorous efforts to diagnose true mosaicism have little impact in many instances, and therefore are not cost-effective. On the basis of all available data, a work-up for potential mosaicism involving a sex chromosome aneuploidy or structural abnormality should have less priority than a work-up for a common viable autosomal trisomy. We recommend revised guidelines for dealing with (1) a numerical versus a structural abnormality and (2) an autosomal versus a sex chromosome numerical aneuploidy. Emphasis should be placed on autosomes known to be associated with phenotypic abnormalities. These new guidelines, which cover both flask and in situ methods, should result in more effective prenatal cytogenetic diagnosis and reduced patient anxiety.

Amniocentesis↗
PubMed1985

Dominantly inherited ureteropelvic junction obstruction.

We report on siblings from two families with unilateral ureteropelvic junction obstruction. HLA studies were undertaken and found to be a useful marker between affected members. We believe that incomplete penetrance with variable expression is the most probable mode of transmission of this disorder.

Adolescent↗
PubMed1969

Multiplicity of hepatic excretory mechanisms for organic anions.

Previous studies based upon competition between different organic anions for biliary excretion in vivo have suggested that all organic anions share a common hepatic secretory mechanism. Corriedale sheep with an inherited defect in organic anion excretion by the liver were used to study this problem directly without the need for competition studies, the results of which are difficult to analyze. Maximal biliary excretion of sulfobromphthalein (BSP) in mutant Corriedale sheep was less than 7% of that observed in normal sheep whereas maximal biliary excretion of taurocholate, the major organic anion in sheep bile, was not different in mutant and normal sheep. Taurocholate infusion enhanced maximal hepatic excretion of BSP in normal but not in mutant sheep. These studies of an inheritable disorder which appears to be identical to the Dubin-Johnson syndrome in man, demonstrate that taurocholate excretion requires at least one step in biliary excretion which is not required by other organic anions such as bile pigment, porphyrins, drugs, and dyes.

Animals↗