Skeletal dysplasia

 Short femur : What ar the possible diagnosis?? What may be outcome?? ABC of Skeletal dysplasias:- To insist on   anomaly scan  by  fetal medicine consultant after initial diagnosis of short femur is mentioned by a sonologist .
There are some criteria to level as skeleton dysplasia.. Only FL is on or below 5 th Centile is not sufficient.. There is femur foot ratio, femur AC ratio, shape of thorax, bone density, bone shape, mineralization, and so many things. Which are possible to measure by Fetal Medicine expert. This has a relevance on future pregancy as skeletal dysplasia may be of genetic Cause or syndrome.. So there is chance of recurrence in subsequent pregnancies . Prevalence of skeletal dysplasia  is  estimated  as 2.4/10,000  births . How  informative is USG in picking up skeletal malformations??  Ans;-Sonography is the primary   imaging   modality used   for detection  of  an affected fetus. The prevalence   of skeletal   dysplasias   identified   by ultrasound   examination during the second and third trimesters of pregnancy is about 7.5/ 10,000  pregnancies. In early  pregnancy  the most frequently diagnosed skeletal  dysplasias are  thanatophoric  dysplasia and achondrogenesis. However   despite ultrasound   findings highly suggestive for skeletal dysplasia the definitive diagnosis   should only be determined by molecular  testing and confirmation of  the ultrasound findings later in preganncy  summarizes the sensitivity  of 2D   sonography  for the prenatal  diagnosis   of skeletal   dysplasias.

 Classification of skeletal dysplasia:-The four   most common kinds of skeletal   dysplasias were    A) thanatophoric dysplasia   B) achondroplasia   C) osteogenesis imperfecta and D) achondrogenesis. Thanatophoric dysplasia    and achondrogenesis account  for 62%  of all   lethal  skeletal  dysplasias and  the most common  nonlethal skeletal dysplasia is achondroplasia.

  Can we diagnose     diagnosis of skeletal   dysplasias before 24 weeks of gestation accurately??    If there is F/H/O skeletal dysplasia then an early USG isa must so that the gestational age is known with certainty and growth trend can be compared. For lethal skeletal dysplasias the accuracy of sonographic findings   should be around  99%  . An When there is a family   history of skeletal dysplasias the following should be carefully evaluated on ultrasound imaging complex biometry including the 1) biparietal diameter 2) head  and 3) abdominal   circumferences 4) lengths of all long   bones   5) femur /foot ratio and 6) measurements   of the   mandible 7) clavicle   8) scapula 9) skull 10)  chest and 11) spine Other   ultrasound parameters  that  might also be helpful   in differentiating skeletal  dysplasias  include  the 12)  fetal facial profile  13) presence  and shape of  vertebral  bodies  14) appearance of the  hands and 15)  feet and fetal thorax to assess the risk for lethality.

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 If there is F/H/O  skeletal dysplasia then serial Long bone  biometry is a must :   Serial long bone  growth trend have been  used extensively for the prediction   of gestational age. But this measurements are also used for diagnosis of skeletal dysplasia . Nomograms for this    purpose    display the distribution of bone   lengths   in relation to gestational    weeks. For the proper use of   these   nomograms  the clinician  must know  the accurate   gestational age   of the fetus. Therefore    patients   at risk for skeletal dysplasias are advised   to seek prenatal   care at an early gestational   age in order to   assess all clinical   estimators    of gestational age. Present    nomograms of the measurement   of limb biometry   for the upper   and lower   extremities respectively. Comparisons between the   limb dimensions   and head circumference can be   used for patients   presenting   with uncertain   gestational age.

 Dilemmea :  Should we use the cut off value at  1 st    percentile   of limb growth    for  diagnois of dysplasia  or else  should  we use  5 per centile ??  The nomograms and figures    provide the sonographers & clinicians the mean   3rd  and the 97^th  percentiles  of limb biometric parameters .The clinicians should be aware that  approximately   6%   of the general  population   will fall   outside  these boundaries  . Ideally a more stringent      criterion     such as the 1 st    percentile   of limb growth    for gestational    age should be used for diagnosis. Unfortunately none of  the currently   available nomogram has  been based   on a sufficient  number of patients   to provide an  accurate    discrimination   between the 3rd  and the   1^st  percentiles   . However   most skeletal dysplasias diagnosed in utero or   at birth are associated   with dramatic long bone   shortening and under these circumstances   the precise   boundary used    is not critical. An    exception    to this is   achondroplasia   in which limb biometry  is only mildly   affected until the   third trimester    , when abnormal growth  can be detected by examining the slope  of growth  of the femur length .

 FL shortening may herald  followings:-- The degree   of femur   length shortening can be   used as the initial  step   in distinguishing   among  the five   most common   disorders     1) thanatophoric   dysplasia. 2) OI (osteogenesis imperrfecta) --type   ll   3) achondrogenesis  4) achondroplasia   and 5) hypochonodroplasia   The early  diagnosis   of skeletal dysplasias in  women with previous pregnancies    affected   with skeletal dysplasia is possible  to note  recurrent   cases were identified   during   the first trimester  by the 1) femur   length/ crown rump length ratio  and  2) the femur    length / biparietal diameter ratio. So , early  evaluation of fetal   structures might    be helpful  in the diagnosis   of severe   skeletal dysplasias. Nomograms  for long   bone with CRL is available too:--Measurements  according to crown   rump length    in a large    population   of normal   fetuses   examined    between 11 and  14  weeks of  gestation   have been published   but still  their   role in the early   assessment    of pregnancies  at risk   for skeletal   dysplasias   remains   to be determined.

 How relevant is femur length:: abdominal   circumference ratio   of 0.16 or femur length below the 1^st percentile for gestational   age   ??Which one is to adopt??   .                How to detect / identify which dysplasia are lethal??Ans;- Short   Femur  length   and prediction   of lethality   in skeletal   dysplasias . Fetuses with skeletal dysplasias in which    all lethal cases were associated with a femur length   abdominal   circumference ratio   of 0.16  . Although   the test detected   lethal cases   with 100 % sensitivity   few cases   of achondroplasia   were  erroneously  identified   as lethal using this method. A different   approach   has been proposed   which mentions   lethality    in 23 out of 25 cases of skeletal dysplasias with a femur length below the 1^st percentile for gestational   age and   presence of bell shaped  thorax  or decreased  bone echogenicity.  If one cannot estimate many important diameters  necessary to confirm the diagnosis of skeletal dysplasia / due possibly to time constraints then a femur/  abdominal   circumference ratio  less than 0.16  have to be measured as a minimum. In fact  F/ AC  is the  main  discriminator  among fetuses  with lethal skeletal   dysplasias and   that this   measurement   has  still a  better  performance  than a)  femur  shortening b)  thoracic circumference and c) thoracic circumference/ abdominal circumference  ratio.

Which  gene has undergone mutation?? :-- Till date it is known that about    25%   of all bone   disorders  the mutated gene   has not been  yet identified . What is the classification of constitutional disorders of bone ?? Ans:- Skeletal dysplasias   are a heterogeneous group  of disorders affecting the development   of chondro-osseous tissues leading  to abnormalities in the size ,   mineralization  and   shape of various  segments of  the skeleton. Despite recent advances in   imaging and molecular genetics accurate   prenatal diagnosis of  skeletal   dysplasias remains a clinical   challenge. In the most recent   revision   of the International Nosology and Classification of Constitutional disorders of bones , it  is mentioned that in approximately   25%   of all bone   disorders  the mutated gene   has not been  yet identified.

What does  International  skeletal  Dysplasia   Registry tells us??  :--It is   important  to acknowledge  the contribution  of the International  skeletal  Dysplasia   Registry in the  identification   and study  of skeletal   anomalies   assisting  providers  and  patients  in the diagnosis   and clinical  management  of skeletal  disorders. This registry informs us that a-twenty three percent   of the affected infants  were stillborn  whereas 32%  died during the first  week of life. The overall   frequency  of skeletal  dysplasias among perinatal  deaths was 9.1/1000.

 c) How significant is  incidental  solo findings of “short femoral length at late trimester”  ?? Will  we be  worried?? Concern to the Obstetrician is “Am I   dealing with normal biological variant/ real pathology of bone so called –“skeltal dysplasia” ?? Ans:- Significance of short   femoral length if noticed at  mid to late  third trimester “” This is  not unusual  for the femur  to be significantly shorter than the other  measurements   used to estimate   gestational age. In many cases  the femur is approximately 2 weeks   less than   the head circumference and menstrual age. The cause of this is often uncertain   and the short femur is often   attributed to biologic variation or ethnicity.  If the bones appear normal   morphologically and no other anomalies   are seen it is likely a normal variant.

One week less is permissible. Short F L . But my dear members this even 1 week lag may rarely be due to 1)  a sign  of trisomy   21 or 2) an  early manifestation of a short    limb   skeletal   dysplasia.  :-- One should acknowledge that a fetus from white  parents of normal height   and middle   socioeconomic   status will have a standard FL which one should not compare with that of FL of Indian parents of low socioeconomic  status .  Although   the femur can be   smaller than other   measurements in the third trimester   it is not acceptable for it to be greater    than 1 week less than the other measurements in the late first   and early to mid second   trimesters. Although   this deviation  may be nothing  more than   a temporary  growth lag or  normal   variation   at this stage , it may also be  1)  a sign  of trisomy   21 or 2) an  early manifestation of a short    limb   skeletal   dysplasia. This  may be  a case  of trisomy 21 as well . One should    not take   comfort   in comparing the femur measurement to the estimated   gestational   age by ultrasound imaging   . Remember that   unless excluded the femur measurement    is included   in the sonographic estimation of   gestational  age.

Classification  of Genetic    skeletal disorders—As many as   364        genes may be involved in the etiology of skeletal dysplasia !!! :-   . Most  skeletal    anomalies  are a phenotypic  manifestation of  a   mutation in a gene   and altered  protein expression therefore they can be  grouped according  to the   affected   genes as they share    similar clinical characteristics. The International skeletal   dysplasia Society   periodically   reviews this.  But with the advent of   “sequencing   technologies    and the  increasing  availability of whole   exome sequencing”--   allowing the discovery  of more gene   related skeletal anomalies. With these technologies as many as  436   clinical conditions were classified into   42 groups involving 364    affected    genes . The classification provides the A) group/ name of the skeletal disorder B)  type of   inheritance; C) MIM number   ; D)  locus  of  the mutation in the  gene   , F) affected protein  and F) associations/ difference with other skeletal   anomalies   . International Nosology and Classification of Constitutional disorders of bones  &  International  skeletal  Dysplasia   Registry:-- Also tell us  classification includes:-Skeletal   dysplasias , metabolic bone   disorders,   dysostosis  ,  skeletal malformations and reduction  syndromes are included   in this   classification . However   the authors also   clarify that in approximately 25% of skeletal   disorders   the mutated gene has  not yet been  identified . The genetic   basis   for classification of very  rare   diseases   was done  by   family pedigree or was based   on homogeneity  or phenotype  in unrelated families. The classification aims to provide  more complete   information   for prenatal  counseling   and clinical   management  . The full   document  can be consulted   ate the ISDS website.