Re: R: Re: Alpha Thalassemia OT
From: art fougner, md (evsono@pipeline.com)
Tue Jan 16 06:53:55 2001
today - with the ban on DDT we are witnessing a resurgence in malaria as
a world killer - parasite vs pesticide - pay now or pay later - and so
it goes.
art
At Tue, 16 Jan 2001, Andrea Corda wrote:
>
>You're right!
>I live in Sardinia and we have to face daily these problems .We had endemic
>malaria until the end of the WWII when the US came and wipe it out with DDT.
>We also tried recently to put donor bone marrow cells via cordocentesis to
>an affected fetus but the results were somewhat confusing-maybe an
>incomplete graft versus host reaction with both blood cells on the blood of
>the newborn.
>Andrea Corda.
>>----- Original Message -----
>From: James S. Smeltzer, MD <gaperina@mindspring.com>
>To: Multiple recipients of list ULTRASOUND
><ultrasound@mail.medispecialty.com>
>Sent: Tuesday, January 16, 2001 6:35 AM
>Subject: Re: Alpha Thalassemia
>
>>Terry,
>>
>>The VMax is EGA dependent. I have a chart of the MoM curves used in that
>>analysis. The exact formula is in the NEJM article - which is at work. Josh
>>should have this, since he is an author. This is the "Holy Grail" that
>>Peter Grannum was looking for for so long - a non-invasive test to replace
>>amniocentesis for fetal anemia. He went through a lot of them with initial
>>case reports that did not bear further scrutiny.
>>
>>This has sort-of worked for me in 1/1 case, though I would have liked to
>>have been able to transfuse this baby before hydrops - which has now
>>resolved except for a small pericardial effusion and placentosis. (MCA VMax
>>of 24 today). I stopped the amniocenteses for delta OD450, after Labcorp
>>messed up two consecutive specimens - both through freezing them. Once the
>>tube cracked. The other time I'm not sure what happened. I figured that
>>weekly checks for VMax and hydrops could be just as good as no result for
>>less risk. Jim
>>
>>At 25 weeks the limit for think of cordocentesis and IUT was around 45. I
>>calculate that the VMax of 74 cm/sec was about 5 SD or at the 99.99999
>>centile of a normal population........ or was it the 99.99999999? If you
>>see a VMax at 20-odd weeks of over 52, you had better find the AVM or the
>>anemia..
>>
>>At some point in time, we are going to be able to just pop some stem cells
>>in the cord and forget about hemoglobinopathies, if we can make the
>>diagnosis of a fetus at risk. IMHO. The thalassemias are fascinating
>>problems, and arose independently at multiple locations around the globe -
>>just like sickle cell - because the trait gives a large selection advantage
>>from clearing the intraerythrocytic stage of malaria parasites, or so I am
>>told.
>>
>>;^) Jim
>>
>>>----- Original Message -----
>>From: "Terry J DuBose" <tjdubose@juno.com>
>>To: "Multiple recipients of list ULTRASOUND"
>><ultrasound@mail.medispecialty.com>
>>Sent: Monday, January 15, 2001 11:30 PM
>>Subject: Re: Re: Alpha Thalassemia
>>
>>> Dr. Smeltzer, this is very interesting and exciting... what a wonderful
>>> thing for you to be able to share your literature search with someone
>>> with an on going case in Taiwan.
>>>
>>> Now, you say the VMax is 74... I did not see the numbers in the abstract,
>>> but do you know if that is the upper 95% confidence in the normal
>>> population? I assume this is due to the reduced viscosity with anemia.
>>>
>>> Thanks for this... good job.
>>>
>>> Peace, Terry J DuBose, M.S., RDMS
>>> Little Rock, ARkansas USA
>>>
>>> On Mon, 15 Jan 2001 22:18:02 -0600 "James S. Smeltzer, MD"
>>> <gaperina@mindspring.com> writes:
>>> > Hi,
>>> >
>>> > Regarding testing for fetal anemia, Mari has shown that the MCA
>>> > maximum
>>> > velocity is strongly predictive of hematocrit. Weekly testing may be
>>> > required, though. Last week I transfused a fetus with early
>>> > hydrops, an MCA
>>> > VMax of 74 (high) and a hemoglobin of 3 at 25 weeks, one week after
>>> > there
>>> > were no signs of hydrops and the MCA VMax was 42 (upper normal).
>>> >
>>> > Here is his reference:
>>> > Title
>>> > Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due
>>> > to
>>> > maternal red-cell alloimmunization. Collaborative Group for Doppler
>>> > Assessment of the Blood Velocity in Anemic Fetuses [see comments]
>>> > Author
>>> > Mari G; Deter RL; Carpenter RL; Rahman F; Zimmerman R; Moise KJ Jr;
>>> > Dorman
>>> > KF; Ludomirsky A; Gonzalez R; Gomez R; Oz U; Detti L; Copel JA;
>>> > Bahado-Singh
>>> > R; Berry S; Martinez-Poyer J; Blackwell SC
>>> > Address
>>> > Department of Obstetrics and Gynecology, Yale University School of
>>> > Medicine,
>>> > New Haven, Conn 06520-8063, USA. giancarlo.mari@yale.edu
>>> > Source
>>> > N Engl J Med, 342(1):9-14 2000 Jan 6
>>> > Abstract
>>> > BACKGROUND: Invasive techniques such as amniocentesis and
>>> > cordocentesis are
>>> > used for diagnosis and treatment in fetuses at risk for anemia due to
>>> > maternal red-cell alloimmunization. The purpose of our study was to
>>> > determine the value of noninvasive measurements of the velocity of
>>> > blood
>>> > flow in the fetal middle cerebral artery for the diagnosis of fetal
>>> > anemia.
>>> > METHODS: We measured the hemoglobin concentration in blood obtained
>>> > by
>>> > cordocentesis and also the peak velocity of systolic blood flow in
>>> > the
>>> > middle cerebral artery in 111 fetuses at risk for anemia due to
>>> > maternal
>>> > red-cell alloimmunization. Peak systolic velocity was measured by
>>> > Doppler
>>> > velocimetry. To identify the fetuses with anemia, the hemoglobin
>>> > values of
>>> > those at risk were compared with the values in 265 normal fetuses.
>>> > RESULTS:
>>> > Fetal hemoglobin concentrations increased with increasing
>>> > gestational age in
>>> > the 265 normal fetuses. Among the 111 fetuses at risk for anemia, 41
>>> > fetuses
>>> > did not have anemia; 35 had mild anemia; 4 had moderate anemia; and
>>> > 31,
>>> > including 12 with hydrops, had severe anemia. The sensitivity of an
>>> > increased peak velocity of systolic blood flow in the middle
>>> > cerebral artery
>>> > for the prediction of moderate or severe anemia was 100 percent
>>> > either in
>>> > the presence or in the absence of hydrops (95 percent confidence
>>> > interval,
>>> > 86 to 100 percent for the 23 fetuses without hydrops), with a false
>>> > positive
>>> > rate of 12 percent. CONCLUSIONS: In fetuses without hydrops that are
>>> > at risk
>>> > because of maternal red-cell alloimmunization, moderate and severe
>>> > anemia
>>> > can be detected noninvasively by Doppler ultrasonography on the
>>> > basis of an
>>> > increase in the peak velocity of systolic blood flow in the middle
>>> > cerebral
>>> > artery.
>>> >
>>> > Regarding the etiology, given the name of the author (and it's Asian
>>> > origin), I agree that alpha-thalassemia is the most likely
>>> > diagnosis, as the
>>> > fetus is unable to make any normal hemoglobin tetrameres of any type:
>>> > embryonic, fetal or adult.
>>> >
>>> > It is quite common in Asian populations:
>>> > Title
>>> > Frequency of alpha-thalassemia-1 of the Southeast Asian-type among
>>> > pregnant
>>> > women in northern Thailand determined by PCR technique.
>>> > Author
>>> > Kitsirisakul B; Steger HF; Sanguansermsri T
>>> > Address
>>> > Human Genetics Unit, Faculty of Medicine, Chiang Mai University,
>>> > Thailand.
>>> > Source
>>> > Southeast Asian J Trop Med Public Health, 27(2):362-3 1996 Jun
>>> > Abstract
>>> > Five hundred pregnant women were analyzed for the presence of
>>> > alpha-thalassemia-1 of the Southeast Asian (SEA)-type by polymerase
>>> > chain
>>> > reaction (PCR) technique at the Maharaj Nakhon Chiang Mai University
>>> > Hospital in Chiang Mai during the period from April to June 1995.
>>> > Forty-four
>>> > of them (8.8%) were recognized as carriers, corresponding to a
>>> > frequency of
>>> > 0.044. Homozygous alpha-thalassemia-1 of the SEA-type, the fatal
>>> > condition
>>> > of hemoglobin Bart's hydrops fetalis, has an expected frequency of
>>> > 0.00194,
>>> > or about 2 hydrops fetalis cases per 1,000 births in this population.
>>> >
>>> > If this is the case, both parents will be microcytic and not
>>> > necessarily
>>> > very anemic. If this is the case, the risk for any particular future
>>> > child
>>> > to have this problem is 1/4. I believe that DNA testing is available
>>> > and
>>> > likely to be informative.
>>> >
>>> > Prenatal identification is important because this disease is
>>> > potentially
>>> > cureable by a stem cell transplant into the fetus, on an
>>> > investigational
>>> > compassionate need basis. Abortion is not really a factor because the
>>> > disease is universally fatal in its homozygous severe form (the one
>>> > seen in
>>> > the fetal hydrops deaths).
>>> >
>>> > Theoretically another alternative would be serial intrauterine
>>> > transfusions
>>> > like for Rh, and an ultimate curative bone marrow transplant, which
>>> > is now
>>> > done for beta thalassemia:
>>> >
>>> > Berloni Foundation
>>> > against thalassemia
>>> > THE BONE MARROW TRANSPLANTATION CENTER OF PESARO
>>> > All founds assigned to the Berloni Foundation are directed towards
>>> > the Bone
>>> > Marrow Transplantation Center, Pesaro - Haematology Division of the
>>> > Hospital
>>> > San Salvatore - which occupies a position of international
>>> > leadership in the
>>> > fight of Thalassemia due to the development of the Center's Clinical
>>> > and
>>> > Scientific Research programmes.
>>> > Thalassemia, in its homozigote form, is the most widespreaded genetic
>>> > disease in the world. In the Mediterranean and Middle East only,
>>> > there are
>>> > over 200,000 thalassemic children. In Italy there are 8,000 and
>>> > 250,000 are
>>> > born every year. Their survival depens on the possibulity of
>>> > transfusion
>>> > from age of 3 to 6 months, every 15 days and receiving subcutaneous
>>> > injections of desferrioxamine every day - continuosly - for serious
>>> > anaemia
>>> > and to remove part of the iron contained in the trasfusions. During
>>> > the
>>> > first 10 years the mortality rate in 5%, in the next ten years
>>> > between 5%
>>> > and 10% and after the age of twenty it reaches 50%.
>>> >
>>> > Up until december 1981 thalassemic children and their families were
>>> > left
>>> > completely in the dark when it came the possibility of a cure. Since
>>> > then,
>>> > however, against all odds, criticism and biological barriers
>>> > considered
>>> > insurmountable, the Bone Marrow Transplantation Center, after
>>> > surviving the
>>> > initial mortalities has performed hundreds and hundreds transplants,
>>> > 65% of
>>> > them in thalassemic children. Today the 80% of those children are at
>>> > home
>>> > cured of the disease.
>>> >
>>> > Apart from childrem Sardinia, Sicily, Calabria, Lombardia, Piemonte
>>> > and alla
>>> > other regions in Italy, transplants have been performed on children
>>> > from
>>> > Iran, India, Palestine, Arab Countries and many other nations
>>> > including USA,
>>> > Russia, Romania, Argentina, South Africa, Tobago. Due to the
>>> > requests for
>>> > transplants arriving from all over the world the current waiting
>>> > list at the
>>> > Bone Marrow Transplantation Center of Pesaro has reached 14 months.
>>> >
>>> > The impact of this discovery in Italy on the international scientific
>>> > community has been of enormous proportions, but still more important
>>> > has
>>> > been the light of hope instilled in hearts of the families with
>>> > thalassemic
>>> > children.
>>> > All results obtained at the Bone Marrow Transplantation Center are
>>> > passed on
>>> > to University Clinics an Italian and foreign Hospitals who are
>>> > committed to
>>> > curing Thalassemia by way of transplant protocol which is today
>>> > known as
>>> > "The Pesaro Protocol". Due to the increase od doctors' request for
>>> > clinical-scientific training at the Pesaro Center, exchanges on an
>>> > international basis are expected. To this end, scientific and
>>> > didactic
>>> > collaboration programmes have been established, in according whit the
>>> > Ministery of foreign Countries, with various countries including
>>> > Iran,
>>> > Russia, Romania and India. It is the hope that one day, in these
>>> > countries,
>>> > autonomous Bone Marrow Transplantation Centers will be in operation,
>>> > like
>>> > the one already realized at Minsk in Belarousse with the finances of
>>> > the
>>> > Berloni Foundation.
>>> >
>>> > Prof. Guido Lucarelli
>>> > Scientific Programme Chief
>>> > Bone Marrow Transplantation Center
>>> > Chief Physician
>>> > Haematology Department
>>> > San Salvatore Hospital, Pesaro
>>> >
>>> > The following from OMIM may be helpful:
>>> >
>>> > http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?141800
>>> >
>>> > TEXT
>>> > The alpha and beta loci determine the structure of the 2 types of
>>> > polypeptide chains in the tetrameric adult hemoglobin, Hb A,
>>> > alpha-2/beta-2.
>>> > The alpha locus also determines a polypeptide chain, the alpha
>>> > chain, in
>>> > fetal hemoglobin (alpha-2/gamma-2), in hemoglobin
>>> > A2(alpha-2/delta-2), and
>>> > in embryonic hemoglobin (alpha-2/epsilon-2). The number of normal
>>> > alpha
>>> > genes (3, 2, 1 or none) in Asian cases of alpha-thalassemia results
>>> > in 4
>>> > different alpha-thalassemia syndromes (Kan et al., 1976). Three
>>> > normal alpha
>>> > genes gives a silent carrier state. Two normal alpha genes results in
>>> > microcytosis (so-called heterozygous alpha-thalassemia). One normal
>>> > alpha
>>> > gene results in microcytosis and hemolysis (so-called Hb H disease).
>>> > No
>>> > normal alpha gene results in 'homozygous alpha-thalassemia'
>>> > manifested as
>>> > fatal hydrops fetalis.
>>> > By studies of somatic cell hybrids, Deisseroth et al. (1976) showed
>>> > that the
>>> > alpha and beta loci are on different chromosomes. Gandini et al.
>>> > (1977)
>>> > concluded, incorrectly as it turned out, that the alpha loci are on
>>> > the long
>>> > arm of chromosome 4 (4q28-q34). The conclusion was based on a
>>> > finding of
>>> > excessive synthesis of alpha chains in patients with duplication of
>>> > this
>>> > region. Deisseroth et al. (1977) combined the methods of somatic cell
>>> > hybridization and DNA-cDNA hybridization to establish assignment of
>>> > the
>>> > alpha-globin locus to chromosome 16. This represents an extension of
>>> > the
>>> > cell hybridization method permitting mapping of genes that are not
>>> > functional in the cultured cell. Weitkamp et al. (1977) presented
>>> > data
>>> > concerning linkage of the alpha and beta loci to 34 marker loci.
>>> > Data on
>>> > alpha-thalassemia, combined with those on the Hopkins-2 variant,
>>> > excluded
>>> > linkage of alpha and haptoglobin at a recombination fraction less
>>> > than 0.15.
>>> > Deisseroth and Hendrick (1978) confirmed the assignment of the alpha
>>> > locus
>>> > to chromosome 16 by means of cotransfer of this gene with the human
>>> > APRT
>>> > gene, known to be on 16 (see 102600), into mouse erythroleukemia
>>> > cells. (The
>>> > APRT gene is on the long arm of chromosome 16.) On the basis of
>>> > findings in
>>> > a case of partial trisomy 16, Wainscoat et al. (1981) concluded that
>>> > the
>>> > alpha-globin genes are on segment 16p12-pter. By combining somatic
>>> > cell
>>> > hybridization with a cDNA probe in the study of a cell line with
>>> > reciprocal
>>> > translocation between 16q and 11q, Koeffler et al. (1981) showed
>>> > that the
>>> > alpha-globin genes are on the short arm of 16. Gerhard et al. (1981)
>>> > used an
>>> > improved method of in situ hybridization to confirm the assignment
>>> > of the
>>> > alpha-globin cluster to chromosome 16p. The evidence on the precise
>>> > location
>>> > of HBAC is conflicting, with assignments from 16p13.33 to 16p13.11
>>> > (Reeders,
>>> > 1986). The fact that adult polycystic kidney disease (APKD; 173900)
>>> > is
>>> > proximal to HBAC and is on the 5-prime side of HBAC appears to
>>> > indicate that
>>> > the order is 16cen--APKD--5-prime HBZ1--HBA1--3-prime HVR--pter.
>>> > (3-prime
>>> > HVR is the hypervariable region used in mapping APKD to 16p.) On the
>>> > basis
>>> > of the findings in a fetus with an unbalanced translocation
>>> > involving 16p,
>>> > Breuning et al. (1987) concluded that the HBA cluster is distal to
>>> > PGP. By a
>>> > combination of in situ hybridization, Southern blot analysis, and
>>> > linkage
>>> > analysis using the fragile site 16p12.3 and translocation
>>> > breakpoints within
>>> > band 16p13.1, Simmers et al. (1987) mapped the alpha-globin gene
>>> > complex to
>>> > 16pter-p13.2. Buckle et al. (1988) described a child in whom
>>> > cytogenetic
>>> > analysis indicated monosomy for 16pter-p13.3. DNA studies showed
>>> > that the
>>> > patient had not inherited either maternal alpha-globin allele. The
>>> > child had
>>> > the alpha-thalassemia trait as well as moderate mental retardation
>>> > and
>>> > dysmorphic features. They determined that the gene is located in the
>>> > 16pter-p13.3 segment. After reviewing earlier data placing the
>>> > alpha-globin
>>> > cluster slightly more proximal, they concluded that the findings in
>>> > this
>>> > child may be more reliable.
>>> >
>>> > Orkin (1978) identified alpha-globin gene fragments in restriction
>>> > endonuclease digests of total DNA after electrophoresis by
>>> > hybridization
>>> > with P32-labeled cDNA probes. The data indicated that the alpha
>>> > genes occur
>>> > in duplicate and that the 2 copies lie close together. Thus direct
>>> > physical
>>> > evidence is provided for the duplication deduced from the findings
>>> > with
>>> > mutant alpha chains and with the alpha-thalassemias and the kinetics
>>> > of
>>> > hybridization in solution. The 2 alpha chains lie about 3.7
>>> > kilobases apart.
>>> > Leder et al. (1978) presented evidence that the alpha and beta genes
>>> > of all
>>> > adult mammalian hemoglobins have 2 intervening sequences at analogous
>>> > positions. Wilson et al. (1977) described a possible nucleotide
>>> > polymorphism
>>> > in the untranslated 3-prime region of the alpha-globin gene and
>>> > suggested
>>> > that the heterogeneity is related to the existence of 2 alpha gene
>>> > loci.
>>> > Musumeci et al. (1978) pointed out that the combination of
>>> > alpha-thalassemia
>>> > and beta-thalassemia leads to less severe clinical expression of
>>> > homozygous
>>> > beta-thalassemia. The rarity of a chromosome 16 with both alpha loci
>>> > deleted
>>> > (as demonstrated by the restriction endonuclease mapping technique of
>>> > Southern) explains the rarity of severe forms of alpha-thalassemia in
>>> > Africans, e.g., Hb H disease which requires loss of 3 alpha loci and
>>> > homozygous alpha-thalassemia which requires loss of 4 alpha loci
>>> > (Dozy et
>>> > al., 1979). By restriction endonuclease mapping, Goossens et al.
>>> > (1980)
>>> > identified 12 persons heterozygous for a chromosome carrying 3 alpha
>>> > genes.
>>> > There were no hematologic abnormalities. The frequency was 0.0036 in
>>> > American Blacks and 0.05 in Greek Cypriots. They had previously
>>> > shown a
>>> > frequency of 0.16 for the single alpha-globin locus in black
>>> > Americans. The
>>> > single locus had a frequency of 0.18 in Sardinians, but none of 125
>>> > Sardinians had a triple alpha locus, suggesting that the former had a
>>> > selective advantage. Greek Cypriots have a frequency of 0.07 for the
>>> > single
>>> > alpha locus. Among 645 Japanese subjects studied, Nakashima et al.
>>> > (1990)
>>> > found 10 persons heterozygous for a chromosome with the triplicated
>>> > alpha-globin locus. Thus, the frequency of the triplicate alpha
>>> > locus was
>>> > 0.008 in this population, while that of the single alpha-locus,
>>> > i.e., the
>>> > alpha-thalassemia-2 gene, may be lower than 0.0008. Analysis of
>>> > haplotypes
>>> > suggested that the triple alpha loci may have had multiple origins.
>>> > Nakashima et al. (1990) commented on the fact that in Melanesia the
>>> > frequency of the triplicated genotype is about the same (Flint et
>>> > al., 1986)
>>> > as in Japan, whereas the frequency of the single alpha gene is much
>>> > higher,
>>> > compatible with a selective advantage vis-a-vis malaria. Liebhaber
>>> > et al.
>>> > (1981) found identity of the alpha-1-globin genes from an Asian and a
>>> > Caucasian. Furthermore, the alpha-1 and alpha-2 genes have a much
>>> > higher
>>> > degree of homology than would be predicted from the timing of the
>>> > duplication before the bird-mammal divergence (about 300 Myr ago).
>>> > Liebhaber
>>> > et al. (1981) presented this as evidence for the existence of
>>> > mechanisms for
>>> > suppression of allelic polymorphisms and for exchange of genetic
>>> > information
>>> > within the alpha-globin gene complex. See 142200 for a discussion of
>>> > gene
>>> > conversion in relation to a comparably surprising homology of the 2
>>> > gamma-globin genes.
>>> >
>>> > Lehmann and Carrell (1984) suggested the use of the following
>>> > nomenclature
>>> > for alpha-thalassemias based on the number of alpha-globin genes
>>> > that are
>>> > missing or abnormal: 1-alpha-thalassemia (silent type);
>>> > 2-alpha-thalassemia,
>>> > trans or cis (thalassemia trait); 3-alpha-thalassemia (Hb H
>>> > disease); and
>>> > 4-alpha-thalassemia (Hb Bart's hydrops fetalis). In this scheme,
>>> > homozygous
>>> > Hb Constant Spring is a 2-alpha-thalassemia which, if combined with
>>> > a cis
>>> > 2-alpha-thalassemia heterozygous Hb Constant Spring, gives a
>>> > 3-alpha-thalassemia and results in Hb H disease. Lehmann and Carrell
>>> > (1984)
>>> > also proposed that the 2 alpha-globin genes be designated as 5-prime
>>> > (now
>>> > alpha-2) and 3-prime (now alpha-1). Liebhaber and Cash (1985)
>>> > described a
>>> > method for identifying whether the alpha-1 or alpha-2 locus is the
>>> > site of
>>> > particular alpha-globin mutations. Rubin and Kan (1985) described a
>>> > sensitive method for determining how many alpha-globin genes are
>>> > present. It
>>> > had the advantages of not requiring restriction enzyme digestion and
>>> > gel
>>> > electrophoresis and using the much more stable isotope (35)S rather
>>> > than
>>> > 32(P) for labeling. Only a small sample of DNA is needed.
>>> > Application of the
>>> > approach to diagnosis of Down syndrome was proposed. Assum et al.
>>> > (1985)
>>> > added a fourth restriction site polymorphism in the alpha-globin gene
>>> > cluster. Compared to the beta-globin cluster, the alpha-globin
>>> > cluster
>>> > seemed to show a poverty of DNA polymorphism; however, Higgs et al.
>>> > (1986)
>>> > demonstrated a remarkable degree of DNA polymorphism in the
>>> > alpha-globin
>>> > gene cluster. In addition, the RFLP haplotype is associated with
>>> > hypervariable regions of DNA.
>>> >
>>> > Pseudo-alpha-1 (HBAP1), a pseudogene, is defective in several
>>> > respects,
>>> > including splice junction mutations and premature termination codons.
>>> > Hardison et al. (1986) identified a previously undetected pseudogene
>>> > in the
>>> > alpha-globin cluster. It was not detected by hybridization studies
>>> > but was
>>> > found only on sequence analysis. Hardison et al. (1986) suggested
>>> > that
>>> > 'divergent copies of a large number of genes may comprise a
>>> > substantial
>>> > fraction of the slowly renaturing DNA of mammalian genomes.' The
>>> > newly
>>> > detected pseudogene, which will be symbolized HBAP2, is only 65 bp
>>> > 3-prime
>>> > to the polyadenylation site of zeta-1 (HBZP). The sequence is:
>>> > 5-prime--HBZ--HBZP--HBAP2--HBA2--HBA1--3-prime. (The functional Hba
>>> > gene of
>>> > the mouse is on chromosome 11, but pseudogenes are dispersed to other
>>> > chromosomes (e.g., Hba-ps3 to mouse chromosome 15) (Popp et al.,
>>> > 1981; Leder
>>> > et al., 1981; Eicher and Lee, 1991).)
>>> >
>>> > Vandenplas et al. (1987) described a new form of alpha-0 thalassemia
>>> > in a
>>> > South African family ascertained through a case of Hb H disease. A
>>> > novel
>>> > deletion of 22.8-22.7 kb of DNA removed 3 pseudogenes as well as the
>>> > alpha-2
>>> > and alpha-1 genes. Since the alpha-2-globin gene encodes the
>>> > majority of
>>> > alpha-globin, a thalassemic mutation of the alpha-1-globin gene
>>> > would be
>>> > expected to result in a less severe loss of alpha-chain synthesis.
>>> > Moi et
>>> > al. (1987) described an initiation codon mutation, AUG-to-GUG, in the
>>> > alpha-1-globin gene. As predicted, the degree of interference with
>>> > alpha-globin synthesis was less in this mutation than in the
>>> > mutation in the
>>> > initiation codon of the alpha-2-globin gene (see 141850). Hill et
>>> > al. (1987)
>>> > described a unique nondeletion form of Hb H disease in Papua New
>>> > Guinea: all
>>> > 4 alpha genes were intact. Hill et al. (1987) commented on the
>>> > striking
>>> > difference in the hemoglobinopathies that occur in Southeast Asia
>>> > and in
>>> > Melanesia. In the former area, Hb E, Hb Constant Spring, and the
>>> > Southeast
>>> > Asian form of deletion alpha-0-thalassemia are all common, whereas
>>> > these
>>> > forms have never been found in Melanesians or Polynesians. Jarman
>>> > and Higgs
>>> > (1988) identified a highly polymorphic region approximately 100 kb
>>> > upstream
>>> > of the alpha-globin genes and referred to it as 5-prime HVR. This is
>>> > a
>>> > valuable genetic marker for 16p. Higgs et al. (1989) gave a
>>> > comprehensive
>>> > review of the molecular genetics of the alpha-globin gene cluster,
>>> > including
>>> > its diseases.
>>> >
>>> > Hatton et al. (1990) presented evidence for the existence of an
>>> > alpha-locus
>>> > activating region (LAR), called alpha-dominant control region
>>> > (alpha-DCR) or
>>> > locus control region, alpha (LCRA; 152422), located 5-prime to the
>>> > alpha-globin gene cluster. (This is comparable to the beta-DCR, or
>>> > beta-LAR,
>>> > which controls expression of the beta-like genes; see 152424.)
>>> > Hatton et al.
>>> > (1990) studied an English patient with alpha-thalassemia in which
>>> > the basis
>>> > appeared to be a deletion of 62 kb from a region upstream of the
>>> > alpha-globin genes. Romao et al. (1992) likewise described
>>> > alpha-thalassemia
>>> > in a person with truncation of 16p, which they referred to as the
>>> > locus
>>> > control region (LCR), with resulting inactivation of the adjacent
>>> > intact
>>> > alpha-globin genes.
>>> >
>>> > Hemoglobinopathies of alpha-globin can result from missense
>>> > mutations at
>>> > either of the 2 alpha-globin loci, HBA1 or HBA2. Since the normal
>>> > HBA1 and
>>> > HBA2 genes encode an identical alpha globin, these mutants cannot be
>>> > assigned to their specific loci on the basis of protein structural
>>> > analysis.
>>> > A clue to the encoding locus, HBA1 versus HBA2, is provided by the
>>> > relative
>>> > concentration of the alpha-globin mutant in the erythrocyte based on
>>> > the 2-
>>> > to 3-fold higher level of expression of the HBA2 gene (Liebhaber et
>>> > al.,
>>> > 1986). However, since variables such as protein stability,
>>> > efficiency of
>>> > hemoglobin tetramer formation, and other factors can affect the
>>> > steady-state
>>> > levels of globin mutants, a definitive locus assignment must be
>>> > directly
>>> > determined. Cash et al. (1989) quantitated the expression of 2
>>> > alpha-globin
>>> > structural mutants found in the Caribbean basin, Fort de France and
>>> > Spanish
>>> > Town, and showed that they are HBA1 and HBA2 mutants, respectively,
>>> > on the
>>> > basis of low or high expression. Liebhaber et al. (1990) identified
>>> > an
>>> > individual with alpha-thalassemia in whom structurally normal
>>> > alpha-globin
>>> > genes were inactivated in cis by a discrete de novo 35-kb deletion
>>> > located
>>> > about 30 kb 5-prime to the alpha-globin gene cluster. They concluded
>>> > that
>>> > the deletion inactivates expression of the alpha-globin genes by
>>> > removing
>>> > one or more of the previously identified upstream regulatory
>>> > sequences that
>>> > are critical to expression of the alpha-globin genes.
>>> >
>>> > Wilkie et al. (1991) described major polymorphic length variation in
>>> > the
>>> > terminal region of 16p (16p13.3) by physically linking the
>>> > alpha-globin
>>> > locus with probes to telomere-associated repeats. They found 3
>>> > alleles in
>>> > which the alpha-globin genes lie 170 kb, 350 kb, or 430 kb from the
>>> > telomere. The 2 most common alleles were found to contain different
>>> > terminal
>>> > segments, starting 145 kb distal to the alpha-globin genes. Beyond
>>> > this
>>> > boundary these alleles are nonhomologous, yet each contains sequences
>>> > related to other, different chromosome termini. This chromosome-size
>>> > polymorphism probably arose by occasional exchanges between the
>>> > subtelomeric
>>> > regions of nonhomologous chromosomes. Wilkie et al. (1991) raised the
>>> > possibility that the high frequency of trisomy 16 may be related to
>>> > this
>>> > nonhomology of the 2 common 16pter alleles in their subtelomeric
>>> > region.
>>> >
>>> > Huisman et al. (1996) found that of the 141 codons of the
>>> > alpha-globin genes
>>> > (there are no sequence differences between the coding regions of the
>>> > alpha-2
>>> > and alpha-1 genes), as many as 99 have been found to be mutated; for
>>> > several, 3 or 4 mutations have been discovered, while 5 mutations
>>> > are known
>>> > for codons 23, 75, and 94, and 6 for codon 141. The mutations appear
>>> > to
>>> > occur at random; thus, either one of the 3 bases are replaced in the
>>> > 199
>>> > known alpha-globin gene mutants.
>>> >
>>> > The suggestion that alpha(+)-thalassemia has achieved a high
>>> > frequency in
>>> > some populations as a result of selection by malaria is based on a
>>> > number of
>>> > epidemiologic studies. In the southwest Pacific region, there is a
>>> > striking
>>> > geographic correlation between the frequency of alpha(+)-thalassemia
>>> > and the
>>> > endemicity of Plasmodium falciparum. Allen et al. (1997) undertook a
>>> > prospective case-control study of children with severe malaria on
>>> > the north
>>> > coast of Papua New Guinea, where malaria transmission is intense and
>>> > alpha(+)-thalassemia affects more than 90% of the population
>>> > (homozygotes
>>> > comprise approximately 55% and heterozygotes 37% of the population).
>>> > Compared with normal children, the risk of having severe malaria was
>>> > 0.40 in
>>> > alpha(+)-thalassemia homozygotes and 0.66 in heterozygotes.
>>> > Unexpectedly,
>>> > the risk of hospital admission with infections other than malaria
>>> > also was
>>> > reduced to a similar degree in homozygotes (0.36) and heterozygotes
>>> > (0.63).
>>> > This clinical study demonstrated that a malaria resistance gene
>>> > protects
>>> > against disease caused by infections other than malaria. A reduction
>>> > in
>>> > mortality greater than that attributable directly to malaria had been
>>> > observed after the prevention of malaria by insecticides,
>>> > chemoprophylaxis,
>>> > and insecticide-impregnated bed nets. Previous observations that
>>> > direct
>>> > malaria mortality cannot account for observed hemoglobin S gene
>>> > frequencies
>>> > suggest that the findings of this study may apply equally to other
>>> > malaria
>>> > resistance genes.
>>> >
>>> > Fung et al. (1999) reported 3 cases of homozygous alpha-thalassemia
>>> > who
>>> > survived beyond the newborn period, all with hypospadias. Review of
>>> > the
>>> > literature identified 2 additional cases. Fung et al. (1999)
>>> > suggested that
>>> > the hypospadias may have been secondary to the in utero edema
>>> > leading to
>>> > failure of fusion of urogenital folds or due to defect or deletion of
>>> > another gene at 16p13.3.
>>> >
>>> > For a review of hydrops fetalis caused by alpha-thalassemia, see
>>> > Chui and
>>> > Waye (1998).
>>> >
>>> > >From work on the mouse model of alpha-thalassemia, Leder et al.
>>> > (1999)
>>> > demonstrated that a normal beta-globin allele can act as a modifying
>>> > gene
>>> > ameliorating the severity of alpha-thalassemia. They found that the
>>> > phenotype of alpha-thalassemia was strongly influenced by the genetic
>>> > background in which the mutation resided; when both mutant genes
>>> > were on a
>>> > chromosome derived from strain 129, the phenotype was severe,
>>> > whereas it was
>>> > mild when the gene was on a 129 chromosome and a C57BL/6 chromosome.
>>> > Linkage
>>> > mapping indicated that the modifying gene is very tightly linked to
>>> > the
>>> > beta-globin locus (lod score = 13.3). Furthermore, the severity of
>>> > the
>>> > phenotype correlated with the size of beta-globin-containing
>>> > inclusion
>>> > bodies, which accumulate in red blood cells and likely accelerate
>>> > their
>>> > destruction. The beta-major globin chains encoded by the 2 strains
>>> > differed
>>> > by 3 amino acids, one of which is a glycine-to-cysteine substitution
>>> > at
>>> > position 13. The cys13 should be available for interchain disulfide
>>> > bridging
>>> > and consequent aggregation between excess beta chains. This normal
>>> > polymorphic variation between murine beta-globin chains could
>>> > account for
>>> > the modifying action of the unlinked beta-globin locus. Here, the
>>> > variation
>>> > in severity of the phenotype would not depend on a change in the
>>> > ratio
>>> > between alpha and beta chains but on the chemical nature of the
>>> > normal beta
>>> > chain, which is in excess. This work also indicated that modifying
>>> > genes can
>>> > be normal variants that, absent an apparent physiologic rationale,
>>> > may be
>>> > difficult to identify on the basis of structure alone.
>>> >
>>> > N.B.: Alpha-globin variants for which it is unknown whether HBA1 or
>>> > HBA2 is
>>> > involved have arbitrarily been included in this entry. Carver and
>>> > Kutlar
>>> > (1995) listed 191 alpha-globin variants as of January 1995. The
>>> > syllabus by
>>> > Huisman et al. (1996) listed 199 alpha-chain hemoglobin variants as
>>> > of
>>> > January 1996. These included single-base mutations in the alpha-2 and
>>> > alpha-1 genes as well as 2-base mutations. Not included in their
>>> > syllabus
>>> > were deletions in mutations that result in alpha-thalassemia, even
>>> > if such a
>>> > change (point mutation or frameshift) occurred in one of the coding
>>> > regions
>>> > of the gene. Information about the alpha-thalassemias was provided
>>> > by Higgs
>>> > et al. (1989).
>>> >
>>> > Also, Activation of the other components such as epsulon may be
>>> > possible to
>>> > replace missing alpha subunits:
>>> >
>>> > WESTPORT, Nov 10 (Reuters Health) - US researchers believe that
>>> > reactivation
>>> > of embryonic zeta- or epsilon-globin genes might be used to treat
>>> > individuals with alpha or beta-thalassemia.That is based on
>>> > experiments
>>> > showing that expression of human embryonic globin genes can rescue
>>> > mice with
>>> > inactivated alpha- and beta-globin genes.
>>> > Dr. J. Eric Russell and Stephen A. Liebhaber, writing in the
>>> > November 1st
>>> > issue of Blood, point out that patients with thalassemia have intact
>>> > embryonic globin genes, but these are silenced during development.The
>>> > researchers, from the University of Pennsylvania School of Medicine,
>>> > Philadelphia, speculated that reactivating the "back-up" embryonic
>>> > globin
>>> > genes could be a potential therapeutic approach for human
>>> > thalassemia.
>>> >
>>> > The researchers generated two strains of mice, one that expressed
>>> > human
>>> > embryonic zeta-globin genes in adulthood and another that expressed
>>> > human
>>> > embryonic epsilon-globin.They mated the mice with the zeta gene with
>>> > mice
>>> > that carried a mutation in the alpha-globin genes.Mice with the
>>> > epsilon gene
>>> > were mated with others carrying mutations in the beta-globin genes.
>>> >
>>> > The blood cell morphology of the offspring from the breeding was
>>> > examined
>>> > for signs of thalassemia.
>>> >
>>> > The group found erythrocyte morphology alterations similar to those
>>> > seen in
>>> > human alpha-thalassemia in the offspring that carried the
>>> > alpha-globin
>>> > mutation but did not express zeta-globin.In contrast, those
>>> > offspring that
>>> > had inherited the human zeta-globin genes had normal erythrocytes.
>>> >
>>> > Similarly, offspring with beta-globin mutations that inherited the
>>> > epsilon-globin gene had normal erythrocytes and those that did not
>>> > displayed
>>> > characteristics seen in severe human beta-thalassemia.
>>> >
>>> > "This report demonstrates that embryonic [zeta]- and
>>> > [epsilon]-globins can
>>> > functionally substitute for their adult [alpha]- and [beta]-globin
>>> > homologues in adult erythroid cells," the researchers write. "These
>>> > results
>>> > illustrate the potential therapeutic utility of embryonic globins as
>>> > substitutes for deficient adult globins in thalassemic individuals."
>>> >
>>> > Blood 1998;92:3057-3063.
>>> >
>>> > Of course, this has not been shown in humans. The cooperativity of
>>> > the alpha
>>> > and beta chains appears to be important:
>>> >
>>> > Thalassemia
>>> > So let's move on to a discussion of thalassemia. Thalassemia is
>>> > essentially
>>> > the absence of one of the chains of hemoglobin.
>>> >
>>> > In the case of a thalassemia, that means that the a chains are
>>> > missing or
>>> > not functioning properly.
>>> >
>>> > Lacking a chains is the basic cause of a thalassemia. The basic
>>> > symptom is
>>> > an anemia.
>>> > When the a chains are missing, the b chains are still synthesized
>>> > and they
>>> > can aggregate to form tetramers, b chain tetramers.
>>> > These are known as hemoglobin H, they're (b)4forms of hemoglobin.
>>> > The b
>>> > chains are quite normal so in theory, at least, they could bind
>>> > oxygen and
>>> > carry out the oxygen transport function.
>>> >
>>> > But if you think about it, the cooperativity is essential for the
>>> > proper
>>> > function. If you only have one kind of chain in hemoglobin, the
>>> > cooperativity is lost. The (b)4 tetramer has no cooperativity of
>>> > oxygen
>>> > binding.
>>> > This means that the oxygen binding can't be used to properly deliver
>>> > oxygen
>>> > to the tissues because the lack of cooperativity means that this
>>> > hemoglobin
>>> > will bind oxygen but it won't release it at the right oxygen
>>> > concentration.
>>> > So a thalassemia is characterized by the presence of these b chain
>>> > tetramers.
>>> > You also find g chain tetramers, particularly of course, in the
>>> > fetus and
>>> > this is known as hemoglobin Barts. It has the same problem as b chain
>>> > tetramers, it has no cooperativity and so no possibility of
>>> > transporting
>>> > oxygen.
>>> > No cooperativity is the basic problem and
>>> > the oxygen affinity is much too high so oxygen is taken up in the
>>> > lungs but
>>> > not released in the tissues.
>>> > In b thalassemia much of the situation is kind of similar,
>>> > this time we're lacking b chains.
>>> > The a chains are present, and so we get a chain tetramers formed.
>>> > Again,
>>> > they don't work.
>>> > There's no cooperativity and
>>> > the oxygen affinity is too high. So, basically, we get an anemia
>>> > because of
>>> > the inability of the remaining hemoglobin subunits to correctly
>>> > transport
>>> > oxygen in the body. So thalassemias are the absence of one of the
>>> > side
>>> > chains
>>> >
>>> > Also:
>>> >
>>> > Silent alpha thalassemia carrier state and hemoglobin
>>> > Constant-Spring can
>>> > only be detected with alpha globin DNA mutation analysis. This is a
>>> > method
>>> > of examining the alpha globin gene for changes that prevent the gene
>>> > from
>>> > functioning properly. DNA testing is performed at specialty labs,
>>> > and again,
>>> > involves having a single blood sample taken. A doctor or genetic
>>> > counselor
>>> > can arrange the DNA testing if it is indicated.
>>> >
>>> > Also:
>>> >
>>> > Title
>>> > Alpha-thalassemia carrier identification by DNA analysis in the
>>> > screening
>>> > for thalassemia.
>>> > Author
>>> > Galanello R; Sollaino C; Paglietti E; Barella S; Perra C; Doneddu I;
>>> > Pirroni
>>> > MG; Maccioni L; Cao A
>>> > Address
>>> > Istituto di Clinica e Biologia dell'Et`a Evolutiva Universit`a degli
>>> > Studi
>>> > di Cagliari, Ospedale Regionale Microcitemie, Cagliari, Italy.
>>> > rgalanel@mcweb.unica.it
>>> > Source
>>> > Am J Hematol, 59(4):273-8 1998 Dec
>>> > Abstract
>>> > Differentiation between heterozygous alpha-thalassemia and several
>>> > phenotypically resembling alleles at the beta-globin gene cluster
>>> > such as
>>> > coinherited delta- and beta-thalassemia or gammadelta
>>> > beta-thalassemia is a
>>> > critical step in genetic counseling. In this paper we report our
>>> > experience
>>> > in the identification of the alpha-thalassemia carrier state using
>>> > polymerase chain reaction (PCR)-based methods, and the feasibility
>>> > and
>>> > simplification of screening for thalassemia using this approach.
>>> > Alpha-globin genotype was determined by PCR-based method in 526 adult
>>> > subjects with reduced mean corpuscular volume (MCV) and mean
>>> > corpuscular
>>> > hemoglobin (MCH), normal hemoglobin A2 and F, and normal serum iron.
>>> > To
>>> > verify the reliability of the protocol used, in 68 of these subjects
>>> > we
>>> > performed globin chain synthesis analysis and in 101 we determined
>>> > alpha-globin genotype by Southern blot analysis. Five hundred
>>> > twenty-one
>>> > (99%) of 526 subjects examined were identified as carriers of one or
>>> > two
>>> > alpha-thalassemia alleles. The identification of the
>>> > alpha-thalassemia
>>> > carrier state may be fast and accurate by PCR-based method, avoiding
>>> > other
>>> > cumbersome and expensive methods such as globin chain synthesis and
>>> > Southern
>>> > blot analysis.
>>> >
>>> > Obviously a lot is going on in this area.
>>> >
>>> > Other possibilities are many:
>>> > Title
>>> > Alpha-thalassemia carrier identification by DNA analysis in the
>>> > screening
>>> > for thalassemia.
>>> > Author
>>> > Galanello R; Sollaino C; Paglietti E; Barella S; Perra C; Doneddu I;
>>> > Pirroni
>>> > MG; Maccioni L; Cao A
>>> > Address
>>> > Istituto di Clinica e Biologia dell'Et`a Evolutiva Universit`a degli
>>> > Studi
>>> > di Cagliari, Ospedale Regionale Microcitemie, Cagliari, Italy.
>>> > rgalanel@mcweb.unica.it
>>> > Source
>>> > Am J Hematol, 59(4):273-8 1998 Dec
>>> > Abstract
>>> > Differentiation between heterozygous alpha-thalassemia and several
>>> > phenotypically resembling alleles at the beta-globin gene cluster
>>> > such as
>>> > coinherited delta- and beta-thalassemia or gammadelta
>>> > beta-thalassemia is a
>>> > critical step in genetic counseling. In this paper we report our
>>> > experience
>>> > in the identification of the alpha-thalassemia carrier state using
>>> > polymerase chain reaction (PCR)-based methods, and the feasibility
>>> > and
>>> > simplification of screening for thalassemia using this approach.
>>> > Alpha-globin genotype was determined by PCR-based method in 526 adult
>>> > subjects with reduced mean corpuscular volume (MCV) and mean
>>> > corpuscular
>>> > hemoglobin (MCH), normal hemoglobin A2 and F, and normal serum iron.
>>> > To
>>> > verify the reliability of the protocol used, in 68 of these subjects
>>> > we
>>> > performed globin chain synthesis analysis and in 101 we determined
>>> > alpha-globin genotype by Southern blot analysis. Five hundred
>>> > twenty-one
>>> > (99%) of 526 subjects examined were identified as carriers of one or
>>> > two
>>> > alpha-thalassemia alleles. The identification of the
>>> > alpha-thalassemia
>>> > carrier state may be fast and accurate by PCR-based method, avoiding
>>> > other
>>> > cumbersome and expensive methods such as globin chain synthesis and
>>> > Southern
>>> > blot analysis.
>>> >
>>> > Title
>>> > Mucopolysaccharidosis type VII associated with hydrops fetalis:
>>> > histopathological and ultrastructural features with genetic
>>> > implications.
>>> > Author
>>> > Molyneux AJ; Blair E; Coleman N; Daish P
>>> > Address
>>> > Department of Cellular Pathology, Northampton General Hospital NHS
>>> > Trust.
>>> > Source
>>> > J Clin Pathol, 50(3):252-4 1997 Mar
>>> > Abstract
>>> > A case of mucopolysaccharidosis type VII (MPS VII, beta glucuronidase
>>> > deficiency) causing fatal hydrops fetalis in the third trimester is
>>> > presented. The diagnosis was suspected on histopathological
>>> > examination by
>>> > the presence of foam cells in many of the viscera and foamy change
>>> > in the
>>> > placental Hofbauer cells. Electron microscopy showed empty
>>> > cytoplasmic
>>> > inclusion bodies within macrophages and in the Hofbauer cells.
>>> > Enzyme assay
>>> > of cultured fibroblasts showed markedly deficient beta glucuronidase
>>> > activity, thus confirming the diagnosis. A detailed and thorough
>>> > histopathological examination of hydrops fetalis cases is important
>>> > to
>>> > detect subtle features of inherited metabolic disorders. Use of a
>>> > structured
>>> > necropsy protocol is recommended for cases of non-immune hydrops.
>>> > Electron
>>> > microscopy is a useful adjunct to light microscopy in cases where an
>>> > inherited metabolic disorder is suspected. Precise necropsy
>>> > diagnosis is
>>> > important as there are implications for genetic counselling and
>>> > possible
>>> > prenatal diagnosis in subsequent pregnancies.
>>> >
>>> > Title
>>> > Recurrent nonimmune hydrops fetalis: a rare presentation of sialic
>>> > acid
>>> > storage disease.
>>> > Author
>>> > Lefebvre G; Wehbe G; Heron D; Vautjoer Brouzes D; Choukroun JB;
>>> > Darbois Y
>>> > Address
>>> > Department of Obstetrics and Gynecology, PitiŽe-SalpŽetri`ere
>>> > University
>>> > Hospital, Paris, France.
>>> > Source
>>> > Genet Couns, 10(3):277-84 1999
>>> > Abstract
>>> > A case of recurrent hydrops fetalis, diagnosed on second trimester's
>>> > ultrasonography, has led to the diagnosis of sialic acid storage
>>> > disease. No
>>> > classic etiology was found after the first accident. The recurrence
>>> > in
>>> > subsequent pregnancy raised the possibility of a storage disease
>>> > that was
>>> > confirmed by amniocentesis. The diagnosis of Salla's disease was
>>> > based on
>>> > high levels of free sialic acid in amniotic fluid and fetal cells
>>> > culture
>>> > and by specific histologic features on fetopathologic examination.
>>> > Diagnosis
>>> > of inherited diseases is important because it implies a high risk of
>>> > recurrence which makes mandatory genetic counseling and prenatal
>>> > care in
>>> > subsequent pregnancies.
>>> >
>>> > Title
>>> > Osteopenia, abnormal dentition, hydrops fetalis and communicating
>>> > hydrocephalus: unusual early clinical signs in Coffin-Lowry syndrome
>>> > [letter; comment]
>>> > Author
>>> > Fryns JP
>>> > Source
>>> > Clin Genet, 50(2):112 1996 Aug
>>> >
>>> > Title
>>> > Investigation of nonimmune hydrops fetalis: multidisciplinary
>>> > studies are
>>> > necessary for diagnosis--review of 94 cases.
>>> > Author
>>> > Lallemand AV; Doco-Fenzy M; Gaillard DA
>>> > Address
>>> > Laboratoire Pol Bouin, Department of Developmental Biology, CHU
>>> > Reims,
>>> > H^opital Maison Blanche, 45 Rue Cognacq-Jay, F-51100 Reims, France.
>>> > Source
>>> > Pediatr Dev Pathol, 2(5):432-9 1999 Sep-Oct
>>> > Abstract
>>> > This review of 94 cases of nonimmune hydrops fetalis (NIHF) over a
>>> > 10-year
>>> > period was undertaken to evaluate the frequency of this pathology
>>> > among
>>> > fetal and infant deaths and to determine the most common likely
>>> > etiologies
>>> > in a northeastern region of France. NIHF represented 6% of the fetal
>>> > deaths
>>> > examined in our laboratory. The combination of findings from
>>> > morphologic
>>> > examination of the placenta and fetus with the results of
>>> > microbiological
>>> > and cytogenetic investigations (conventional cytogenetic study,
>>> > fluorescent
>>> > in situ hybridization [FISH], or DNA ploidy image analysis) led to an
>>> > etiologic diagnosis for NIHF in two-thirds of the cases and
>>> > suggested a
>>> > diagnosis in an additional 23% of cases. The most common causes of
>>> > NIHF were
>>> > chromosome abnormalities (33%), infections (16%), and cardiac
>>> > pathology
>>> > (13.8%). The detection of a cause for NIHF is important for genetic
>>> > counseling and management of subsequent pregnancies. Our experience
>>> > suggests
>>> > that a diagnosis is possible in a large majority of NIHF when
>>> > obstetricians
>>> > and pathologists carefully coordinate the management of prenatal and
>>> > postnatal investigations and when new techniques, such as molecular
>>> > biology
>>> > and DNA quantification, are used.
>>> >
>>> > Title
>>> > Investigation of nonimmune hydrops fetalis: multidisciplinary
>>> > studies are
>>> > necessary for diagnosis--review of 94 cases.
>>> > Author
>>> > Lallemand AV; Doco-Fenzy M; Gaillard DA
>>> > Address
>>> > Laboratoire Pol Bouin, Department of Developmental Biology, CHU
>>> > Reims,
>>> > H^opital Maison Blanche, 45 Rue Cognacq-Jay, F-51100 Reims, France.
>>> > Source
>>> > Pediatr Dev Pathol, 2(5):432-9 1999 Sep-Oct
>>> > Abstract
>>> > This review of 94 cases of nonimmune hydrops fetalis (NIHF) over a
>>> > 10-year
>>> > period was undertaken to evaluate the frequency of this pathology
>>> > among
>>> > fetal and infant deaths and to determine the most common likely
>>> > etiologies
>>> > in a northeastern region of France. NIHF represented 6% of the fetal
>>> > deaths
>>> > examined in our laboratory. The combination of findings from
>>> > morphologic
>>> > examination of the placenta and fetus with the results of
>>> > microbiological
>>> > and cytogenetic investigations (conventional cytogenetic study,
>>> > fluorescent
>>> > in situ hybridization [FISH], or DNA ploidy image analysis) led to an
>>> > etiologic diagnosis for NIHF in two-thirds of the cases and
>>> > suggested a
>>> > diagnosis in an additional 23% of cases. The most common causes of
>>> > NIHF were
>>> > chromosome abnormalities (33%), infections (16%), and cardiac
>>> > pathology
>>> > (13.8%). The detection of a cause for NIHF is important for genetic
>>> > counseling and management of subsequent pregnancies. Our experience
>>> > suggests
>>> > that a diagnosis is possible in a large majority of NIHF when
>>> > obstetricians
>>> > and pathologists carefully coordinate the management of prenatal and
>>> > postnatal investigations and when new techniques, such as molecular
>>> > biology
>>> > and DNA quantification, are used.
>>> >
>>> > An excellent case! Please let us know how it turns out!
>>> >
>>> > Jim Smeltzer James.Smeltzer@wellstar.org
>>> >
>>>> > ----- Original Message -----
>>> > From: "The-Hung Bui" <The-Hung.Bui@ks.se>
>>> > To: "Multiple recipients of list ULTRASOUND"
>>> > <ultrasound@mail.medispecialty.com>
>>> > Sent: Monday, January 15, 2001 7:43 AM
>>> > Subject: Re:
>>> >
>>> > > At 11:29 2001-01-13 -0600, you wrote:
>>> > > >Dear netters,
>>> > > >
>>> > > >I saw a fetus last Friday. Second trimester SGA. The mother was
>>> > sure
>>> > about
>>> > > >her
>>> > > >LMP and the gestational age was confirmed ealier by a dating scan
>>> > at
>>> > another
>>> > > >hospital. The gestational age was 21+ weeks, but the fetal size
>>> > was
>>> > > >equivalent
>>> > > >to 18-weeks. The anatomical screening was normal, and no
>>> > chromosomal
>>> > markers
>>> > > >were found except mild dolichocephaly. The placental morphology
>>> > was
>>> > normal.
>>> > > >There was only a small and unilateral notch on the uterine artery
>>> > Doppler
>>> > > >waveform, with normal PI. Liquor volume was around 3rd
>>> > percentile. No
>>> > PPROM.
>>> > > >
>>> > > >Placental insufficiency?
>>> > > >
>>> > > >The mother had a previous IUFD around 28 weeks because of hydrops
>>> > fetalis.
>>> > > >The
>>> > > >previous fetus was also growth retarded. An FBS before fetal death
>>> > revealed
>>> > > >severe fetal anemia. No infection or anomaly was identified. This
>>> > is all
>>> > the
>>> > > >information I have for the previous pregnancy.
>>> > > >
>>> > > >Well, my friends. First, what will you do next? Second, what will
>>> > you
>>> > > >recommand
>>> > > >to scan for fetal anemia?
>>> > > >
>>> > > >Tung-yao Chang, MD
>>> > > >Dept. of obstetric and Gynecology,
>>> > > >Mackay Memorial Hospital,
>>> > > >Taipei, Taiwan.
>>> > >
>>> > > In addition to what has been already proposed (workup for IUGR
>>> > including
>>> > > fetal infection and karyotype), you should screen both parents for
>>> > alpha
>>> > > (in particular but also beta)-thalassemia (because some fetuses
>>> > from Asia
>>> > > may have both disorder) in view of previous obstetric history and
>>> > patient
>>> > > from Taiwan.
>>> > >
>>> > > *****************************************************************
>>> > > The-Hung Bui, M.D.
>>> > > *****************************************************************
>>> > > Senior Consultant
>>> > > Director, Fetal Diagnosis Programme
>>> > > Department of Molecular Medicine
>>> > > Clinical Genetics Unit
>>> > > Karolinska Hospital
>>> > > S-171 76 Stockholm, Sweden
>>> > >
>>> > > phone: +46 8 517 74989 or 517 72472 (secretary)
>>> > > fax: +46 8 32 77 34
>>> > > E-mail: The-Hung.Bui@ks.se
>>> > > ******************************************************************
>>> > >
>>> > > ******************************************************************
>>> >
>>>
>>
--
art fougner, md
A series of 1000 cases begins with but a single anecdote.
