Presymptomatic screening for MEN-2A
Transcript of Presymptomatic screening for MEN-2A
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time of four minutes at 61°C, were done before the normal cyclingreaction. 25 pl of amplified product were removed and directlydigested with Nco I or Sty I according to the manufacturer’s (LifeTechnology Ltd) directions, without further purification. Ourresults were:
Mutation No
G985 heterozygotes 6
A985 homozygotes 404
G985 homozygotes 0Total newborn babies 410
These results show a carrier frequency for the G985 mutation in thegeneral population of 1 in 68. This suggests that the G985
homozygote, corresponding to the MCAD deficient phenotype, hasa frequency of about 1 in 18 500 births.
Other workers have discussed heterogeneity of the MCADmutation.’"’ Since the frequency of mutant MCAD alleles otherthan G985 in the population amounts to some 15% of total mutantMCAD alleles, the total carrier frequency would be 1 in 58, with atotal population risk for MCAD deficiency of 1 in 13 400. In
calculating these data we have assumed no increased in-uteromortality for any MCAD mutation. This estimate lies well withinthe population frequency discussed by others.1,5The estimated frequency of MCAD deficiency, based on our
figures obtained from the newborn population, suggests thatneonatal screening might be worthwhile. However, a clearer
understanding of the natural history of this disease, in particular ofthe population of homozygous G985 children who remain
symptom free, is needed before undertaking such a venture.
A. 1. F. B. is funded by the Wellcome Trust.
Subdepartment of Human Genetics,University of Sheffield, Sheffield
School of Biological Sciences,University of Leicester
Neonatal Screening Unit,Children’s Hospital, Sheffield
Department of Molecular Biologyand Biotechnology,
University of Sheffield
Institute of Human Genetics,University of Aarhus, Denmark
Laboratory of Molecular Genetics,Skejby Sygehus, Aarhus
Subdepartment of Human Genetics,University of Sheffield,Sheffield S10 5DN, UK
ALEXANDRA I. F. BLAKEMORE
HELEN SINGLETON
RODNEY J. POLLITT
PAUL C. ENGEL
STEEN KOLVRAA
NIELS GREGERSEN
DIANA CURTIS
1. Bennett MJ, Allison F, Pollitt RJ, Variend S. Fatty acid oxidation defects as causes ofunexpected death in infancy. In: Tanaka K, Coates PM, eds. Fatty acid oxidation:clinical, biochemical and molecular aspects. New York: Alan R. Liss, 1990:349-64.
2. Matsubara Y, Narisawa K, Miyabayashi S, Tada K, Coates PM. Molecular lesion inpatients with medium chain acyl-CoA dehydrogenase deficiency. Lancet 1990; 335:1589.
3 Yokota I, Tanaka K, Coates PM, Ugarte M. Mutations is medium chain acyl-CoAdehydroxgenase deficiency. Lancet 1990; 336: 748.
4. Din J-H, Roe CR, Chen Y-T, Matsubara Y, Nansawa K. Mutations in medium chainacyl-CoA dehydrogenase deficiency. Lancet 1990; 336: 748-49.
5. Gregersen N, Andresen BS, Bross P, et al. Molecular characterisation of mediumchain acyl-CoA dehydrogenase (MCAD) deficiency: identification of a lys 329-glumutation in the MCAD gene and expression of inactive mutant protein in E coli.Hum Genet (in press).
Presymptomatic screening for MEN-2ASIR,-Dr Mathew and colleagues (Jan 5, p 7) show that linkage of
DNA markers (MEN203, RBP3, MCK2, and TBQ16) to theMEN-2A gene on chromosome 10 is useful for carrier prediction ofmultiple endocrine neoplasia type 2A. In Northern Ireland we havescreened a large MEN-2A family with DNA markers with similarresults. In our large four-generation family, all the affectedmembers were symptom free and basal or stimulated calcitonin3 and
radiological screening had limitations: a normal serum calcitoninvalue does not indicate the absence of MEN-2A, and a "borderline"calcitonin value increases anxiety. Furthermore, the calcitonin levelreflects only the potential for medullary thyroid metaplasia.The benefit of DNA analysis is that it permits more accurate
estimation of carrier risks in MEN-2A. We support Mathew and
colleagues’ conclusion that DNA analysis should be introduced intothe screening of MEN-2A families. The MEN-2A gene may beexpressed not only as medullary thyroid cancer but also as
phaeochromocytoma and parathyroid adenomas or hyperplasia.Several years ago one of our patients, during an operation for anapparently isolated thyroid carcinoma, died with anaesthetic
complications due to an unsuspected phaeochromocytoma.Thyroid surgery, perhaps at an earlier age, with the knowledge thatadrenal problems may present, will prevent metastases in patientswith a positive DNA test. An equally important benefit is thatpatients with a negative DNA test can be reassured (provided thatthe carrier risk is less than 1%) and will need infrequent or noscreening, thus eliminating the need for uncomfortable pentagastrinprovocation tests or repeated serum calcitonin measurements.The availability of DNA analysis for the MEN-2A gene does
provide for the possibility of prenatal diagnosis. However, sinceprenatal tests involve a significant risk of miscarriage and sincesurgery in presymptomatic gene carriers is effective, we feel thatprenatal diagnosis is unwarranted.A further benefit, in an era of audit and budgeting, is that a
"closed case" frees the clinician to tackle more chronic anduntreated cases, and this may bring a rare smile to the unitadministrator’s face.
Department of Medical Genetics,Belfast City Hospital,Belfast BT9 7AB, UK,and Sir George E Clark Metabolic Unitand Endocrine Surgery Wards,
Royal Victoria Hospital, Belfast
P. J. MORRISONN. C. NEVINA. E. HUGHESD. R. HADDENC. F. J. RUSSELL
1 Hadden DR, O’Reilly F, Kennedy L, Russell C. Multiple endocrine neoplasia type 2a:a Northern Ireland and Australian family. Henry Ford Hosp Med J 1987; 35:107-09.
2. Morrison PJ, Hadden DR, Russell CJ, Nevin NC. MEN2A: update on the NorthernIreland and Australian family. Henry Ford Hosp Med J 1989; 37: 127-28.
3. Telemus-Berg M, Almqvist S, Berg B, et al. Screening for medullary carcinoma of thethyroid in families with Sipple syndrome evaluation of new screening tests. Eur JClin Invest 1977; 7: 7-16.
Failure of fetal karyotyping and diagnosis ofcomplete Di George syndrome
SiR,-Prenatal diagnosis of severe immunodeficiencies is
possible from chorionic villi or amniotic cells only in hereditarysyndromes with enzyme deficiencies or cytogenetic abnormalities.Prenatal diagnosis of many inherited immune disorders can bemade for the study of fetal lymphocyte subpopulations.1 The DiGeorge syndrome is caused by the congenital absence or hypoplasiaof the thymus and parathyroid glands. Primary deficiencies incellular immunity and hypoparathyroidism are often associatedwith cardiac and facial malformations.2,3 The complete Di Georgesyndrome has a severe prognosis mainly because of the deficiency incell-mediated immunity, with associated serious bacterial, viral, andfungal infections. Cardiac malformations also strongly affect theoutlook. We report a patient with Di George syndrome which wasdiscovered through an unusual prenatal diagnostic approach.A 34-year-old gravida 3, para 2 was referred for rapid fetal
karyotyping at 34 weeks after ultrasound diagnosis of double-outletright ventricle with proximal pulmonary artery restriction, shortupper limbs, and a bilateral cleft palate. There was no personal or
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family history of malformations or hereditary disease. Fetal bloodsampling was done under ultrasound guidance but karyotypingwas unsuccessful. In a second fetal blood sample karyotyping againfailed; one lymphocyte count was normal but characterisation oflymphocyte subpopulations showed a very low proportion of Tlymphocytes and an increase in B cells (table). Pregnancy wasterminated at 36 weeks’ gestational age at the couple’s request, inaccordance with French law. Necropsy confirmed facial and cardiacmalformations and agenesis of the thymus.
Prenatal diagnosis of congenital malformations byultrasonography allows a more appropriate management of themalformed fetus and newborn baby. Prenatal karyotyping is
important since chromosome abnormalities are seen in 15-4% offetuses with an isolated cardiac malformation and in 42-7% with an