Editor's comment: This interesting report describesanother treatment in PWS. The lack of a response to provocative
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
hypogonadism, hyperphagia, obesity,
psychomotor Theauthors demonstrate the majority
abnormalities, dysmorphic features. of thesepatients and
wereGHdeficient thatGHdeficiency part is
In addition,10 control healthyobeseprepubertal childrenwere of the hypothalamic dysfunction in
observed this disorder.
for 24 hours and plasmainsulin-likegrowth factor 1 (IGF-1), A, 1998:87:28-31.
Lindgren etal. ActaPaediatr
glycosylatedhemoglobin, fasting insulinand glucosewere
determined.Bodymassand body massindexwere calculated. Editor'scomment: This descriptionof the beneficialeffectsof
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
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
significantincreases heightvelocitywereobserved. MD
Serum IGF-1 levels increased as well. Body mass index
decreased a 25% reductionin fat massand a 30% increase Thacker M, et al. Hormone Res 1998;49:216-220.
Fathers and FGFR3 Mutations
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
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
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.
paternal hasbeenrecognized years,for suggesting
occur during spermato-
that mutationsat this site preferentially
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,
revealing the mutation on
occurred the paternal allelein all 40
cases.In otherwords,the mutationhadvirtuallyalways occurred
in the FGFR3 geneinheritedfrom the father.
GGH 15,No.1-March 1999
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
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.
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
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
coincidence TS and autoimmune thyroid diseasein 6 of the
35 patientsand overt hypothyroidism 4.in MD
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