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fathers

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									     Editor's comment: This interesting report describesanother           treatment in PWS. The lack of a response to provocative
                              in
     clinical syndrome,PWS, which GHD        plays a major role. The      stimuli and subsequent increases during rhGH therapy
     children in the study were well characterized  both by clinical      underscorethe importanceof evaluatingthese children when
     and laboratorycriteria.These investigators havemadea worthy          seenin the clinical situation.
     retrospective analysisof a potential etiologyof GHD and rhGH                                             WilliamL. Clarke,MD



     Growth Hormone Treatment of Children With Prader-Willi Syndrome Affects Linear Growth
     and Body Composition Favorably
     Lindgrenet al studied 29 prepubertal childrenwith Prader-Willi       in fat-free masswereobserved.  Fastinginsulin levelsincreased
     syndrome (PWS),all of whom had a paternaldeletion or a                            in
                                                                          significantly the treatedgroup,butfastingglucoseand glyco-
     maternaldisomy of chromosomal    region15q11-13,hypotonia,           sylated  hemoglobin levelswereunchanged             the
                                                                                                                   throughout study.
      hypogonadism, hyperphagia, obesity,
                                        short stature,
                                                     psychomotor          Theauthors                       demonstrate the majority
                                                                                       statethatthesestudies            that
                 behavioral
      retardation,                        and
                            abnormalities, dysmorphic     features.       of thesepatients                 and
                                                                                           wereGHdeficient thatGHdeficiency part  is
     In addition,10 control healthyobeseprepubertal  childrenwere         of the hypothalamic dysfunction         in
                                                                                                         observed this disorder.
     studied.Growthhormone(GH)wassampledevery30 minutes
     for 24 hours and plasmainsulin-likegrowth factor 1 (IGF-1),                 A,                 1998:87:28-31.
                                                                          Lindgren etal. ActaPaediatr
                              and
     glycosylatedhemoglobin, fasting insulinand glucosewere
     determined.Bodymassand body massindexwere calculated.                Editor'scomment: This descriptionof the beneficialeffectsof
     Fat-free                     by
             masswasdetermined bioelectrical     impedance by
                                                            and           GHin childrenwith PWS  supports                et
                                                                                                         thoseof Thacker al recorded
     dual energyX-rayabsorptiometry.         of
                                     Fifteen the 29 childrenwith          in the previous abstract.Thechildrenin the current study did
     PWS   weretreatedwith GHata doseof 0.1IU/k/d(0.23mg/kg/wk)           not undergostimulation tests,and thus their findings are not
     SCfor 1 year.The othersservedasa second    controlgroup.             entirely biochemicallycomparableto those of Thackeret al.
                                                                          However,the growth responsesof both groups were similar,
     The obesecontrol childrenwere tall and had normalincreased           and the additional finding of increased fat-free mass and
                                  the
     serum IGF-1levels,whereas PWSchildrenwere short with                 decreasedfat mass in the current study (Lindgren)demon-
     normalor low IGF-1levels.However,   24-hourGHsecretionwas            stratesan additionalimportantbenefitof GHin thesechildren.
     low in both PWSandobese    controlchildren.Duringthe 1 yearof
     treatment,                     in
                significantincreases heightvelocitywereobserved.                                                                     MD
                                                                                                                     WilliamL. Clarke,
     Serum IGF-1 levels increased as well. Body mass index
               and
     decreased a 25% reductionin fat massand a 30% increase               Thacker M, et al. Hormone Res 1998;49:216-220.




     Fathers and FGFR3 Mutations
                     is
     Achondroplasia the prototypeof short-limb dwarfismand is             The authorsdiscussdifferences  betweenspermatogenesis  and
      byfar the mostcommonform of dwarfismin humans.It results            oogenesis,                                     to
                                                                                     notingthat meioticerrorscanaccumulate a much
     from activating mutations of the gene encoding fibroblast            greater extent in the former becausemale germ cells divide
                                        The
     growth factor receptor3 (FGFR3). vast majority of cases              much more often than do female germ cells. However,   they
      resultfrom newmutations,  which in all casesinvolvenucleotide                    that
                                                                          acknowledge the reasonswhy mutation of this particular
     1138 in exon 10 of this gene.This nucleotideis thus one of the       nucleotideis so much more commonduring spermatogenesis
                               in
     most mutablenucleotides the entire humangenome.                      are unknown.

     The association of sporadic cases of achondroplasiawith              Wilkin DJ. et al. Am J Hum Genet. 1998;63:711-716.
     advanced          age
              paternal hasbeenrecognized years,for       suggesting
                                             occur during spermato-
     that mutationsat this site preferentially
            The                                      this
     genesis. Wilkingroup hasnowdemonstrated to betrue.

     Wilkin etal studied97 familiesin whicha childwith achondropla-
     sia had beenbornto parentsof normalstature.Theyfirst identi-
     fied a DNApolymorphism     nearthe mutationsite in the FGFR3
     gene.Thisenabled   them to potentially          if
                                           determine a mutationin
     a given case had occurredon the maternalor paternalFGFR3
     allele.The analysiswas informativein 40 of the 97 families,
              that
     revealing the mutation             on
                               occurred the paternal    allelein all 40
     cases.In otherwords,the mutationhadvirtuallyalways      occurred
     in the FGFR3  geneinheritedfrom the father.



                                                                                                                    Vol.
                                                                                                                 GGH 15,No.1-March 1999

11
Editor'scomment:Thispaperconfirmswhathasbeensuspected             offspring.It is interestingthat recurrentmutationsresponsible
for years-that achondroplasiamutations of FGFR3occur              for thanatophoricdysplasiaoccur in FGFR3      nucleotidesthat
primarily;if not exclusively;
                            during spermatogenesis. Unfortu-      neighbor nucleotide1138. This suggests that the underlying
nately;the mechanismfor the high rate of mutation in male         mechanism             not
                                                                               operates just on theonenucleotidebut also on
germ cells remains obscure.The authors point out that the         the surroundingarea,making it a very hot spot for mutation.
mutation occurs in the contextof CpG dinucleotide,  which is
thought to predisposeto mutationbecause methylation
                                          of            and                                                   WilliamA. Horton,MD
deaminationof the G nucleotide.Other possibilities include
defectiverepair of base mismatchesthat occur at this nu-                                                           Dr.
                                                                  2nd Editor's comment: In GGH 1997;13(4):49-54, Horton
cleotideduring DNAreplication,  whichfor somereasonoccurs         wrotean enlighteningleadarticle entitled,"MolecularGenetics
                                                                  of HumanChondrodysplasias,  ffwhich can profitablybe readin
only during spermatogenesis.   Another idea, which is pure
speculation, that suchmutationsadversely
             is                            affectthe survival         conjunctionwith the abstractand editor'scommentsabove.
of femalegermcells so that onlymalegerm cellsharboringthe
mutationsurvivegametogenesis contributethe mutationsto
                                to                                                                                            MD
                                                                                                             RobertM. Blizzard,



Celiac Disease and Turner Syndrome
The authors initially observed 2 of 26 patientswith Turner        The authorsconcludethat the results of the study indicatethat
syndrome (TS) who did not experience      increasedgrowth as      gluten sensitivity may be an associated characteristic
expectedwhen given recombinanthuman growth hormone                                       with EMA
                                                                  in TS,and that screening        togetherwith other autoanti-
(rhGH).Thesetwo GH-resistant     patientswere then diagnosed                         in
                                                                  bodiesis advisable TS at leastbeforestartingrhGHtreatment.
                                         a             of
as havingceliacdisease(CD)antibodies, characteristic CD.
Both patientshad subtotalvillus atrophyin the gastrointestinal    Bonamico M, et al. J Pediatr Gastroenterol Nutr 1998:26;496-499.
tract,which confirmedthe diagnosis.  Thesefindingsstimulated
screeningof 35 TS girls, includingthe 26 receivingrhGH.Four                    comment: The association of autoimmune diseases,
of the patients,including the first 2, were anti-endomysium           particularly thyroid autoimmune disease, has long been
                                   14
antibody(EMA)positive. However, of the 35 patientswere                recognized. This is the first account known to me of the
positivefor antigliadinantibodies,suggestingan immunologic            possible association of CDand TSand should be explored furthel:
phenomenonseen in CD. The authors confirmed the high
            of
coincidence TS and autoimmune       thyroid diseasein 6 of the
35 patientsand overt hypothyroidism 4.in                                                                                      MD
                                                                                                             RobertM. Blizzard,



 SHOX Mutations in Dyschondrosteosis
The SHOX    story beganabouta year ago with the identification        Two independent     groups,Belin et al and Shearset ai, carried
of a geneencodinga homeobox-containing   transcriptionfactor          out very similar studies. Starting with several large families
that maps to the pseudoautosomal region of the                        exhibiting dominanttransmission of DCS,both groups first
X chromosome. The detection of a missense mutation                    establishedlinkage of DCSto gene markersnear the SHOX
predicted truncatethe proteinin a short child suggested
          to                                             that         locus. Belin et al also linkedDCSto a markerwithin the SHOX
it or, more appropriately, absencemayplaya role in the short
                         its                                          gene.Next,both groupsdetected     deletionsof the SHOX   genein
stature of Turner syndrome(TS). The story has taken a new             DCSpatients;  Belinand colleagues                   in
                                                                                                         found deletions 7 families
turn with the finding of SHOXmutationsand deletionsin pa-                         and              had
                                                                      and Shears colleagues detecteddeletions 5 families.in
tientswith dyschondrosteosis (DCS).                                   Finally,point mutations   werefound in 2 familiesthat segregated
                                                                      with the DCSclinical phenotype.Both groups concludedthat
DCS,or Leri-Weill syndrome, is a relatively mild dwarfing             the DCS phenotype results from haploinsufficiency the    for
condition that mainly involves the middle segments of the              SHOX  transcriptionfactor since patientswere either missing
limbs. The major features are shortening of the lower legs            1 SHOXallele or had mutations predicted to make the
and bowing of the radius associated with the Madelung                 transcriptionfactor nonfunctional.
deformity of the wrist. DCS occurs in both males and
females and is usually more severe in females. Its                    Both groups also provided evidencethat Langer mesomelic
inheritancehas been consideredautosomal dominant based                dysplasiaresultsfrom the homozygous   loss of SHOXfunction.
on severalexamplesof male-to-maletransmission. In fact, it            Langermesomelic            had
                                                                                        dysplasia beensuspected      clinicallyin an
has long been suspected that the much more severe                     infant with 45,XO TS in 1 of the studies by Belin's group.
condition, Langer mesomelic dysplasia, results from                   Molecular studiesshowedthat this patienthadno SHOX    alleles;
 homozygosityfor DCS.                                                 she inherited an X chromosomeharboringa SHOX         deletion


 GGH 15,
   Vol. No.1-March
                 1999                                            12
Editor's

								
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