Dysmorphology Dysmorphology Guy Besley Guy Besley Willink Biochemical Genetics Unit, Willink Biochemical Genetics Unit, Manchester Children’ ’s Hospital s Hospital Manchester Children
Dysmorphic presentation presentation Dysmorphic � Congenital malformation Congenital malformation � � Disorder of embryogenesis Disorder of embryogenesis � � Intrauterine insult Intrauterine insult – – infection; infection; � chromosomal/genetic or metabolic chromosomal/genetic or metabolic � Postnatal Postnatal � � Normal at birth but later remodelling Normal at birth but later remodelling � � Accumulation of toxic metabolites Accumulation of toxic metabolites �
Congenital dysmorphology dysmorphology – – Congenital disorders of embryogenesis disorders of embryogenesis � Disorder due to maternal IEM Disorder due to maternal IEM � � Maternal PKU Maternal PKU � � Disorders due to Disorders due to fetal fetal IEM IEM � � Peroxisomal Peroxisomal disorders disorders � � Disorders sterol metabolism Disorders sterol metabolism � � Disorders of energy metabolism Disorders of energy metabolism � � Congenital disorders of Congenital disorders of glycosylation glycosylation � � Others Others �
Postnatal dysmorphology dysmorphology – – Postnatal remodelling remodelling � Lysosomal disorders, especially Lysosomal disorders, especially � MPS MPS � Amino acid disorders Amino acid disorders � � Trace metal disorders Trace metal disorders � � Many others Many others �
Disorder of embryogenesis – – Disorder of embryogenesis Maternal PKU Maternal PKU � 90% infants born to mothers with 90% infants born to mothers with phe phe � >1200umol/L have congenital abnormalities >1200umol/L have congenital abnormalities � Metabolic Metabolic teratogenesis teratogenesis resembling resembling fetal fetal � alcohol syndrome alcohol syndrome � Microcephaly Microcephaly, IUGR and facial , IUGR and facial dysmorphism dysmorphism, , � severe learning difficulties, congenital heart severe learning difficulties, congenital heart disease and other malformations disease and other malformations � Has mother been screened for PKU? Has mother been screened for PKU? �
Disorders of the fetus fetus Disorders of the Peroxisomal disorders disorders Peroxisomal � Peroxisome Peroxisome biogenesis disorders biogenesis disorders � � Zellweger Zellweger/NALD/IRD /NALD/IRD � � Rhizomelic Rhizomelic chondrodysplasia chondrodysplasia punctata punctata � � Single or multiple enzyme defects Single or multiple enzyme defects � � Single Single peroxisomal peroxisomal beta beta- -oxidation oxidation � defects defects � Especially Especially bifunctional bifunctional protein defect protein defect �
Peroxisomal biogenesis disorder biogenesis disorder Peroxisomal -Zellweger Zellweger syndrome syndrome - � Typical facial Typical facial dysmorphism dysmorphism: high forehead, : high forehead, � large anterior fontanelle fontanelle, , hypoplastic hypoplastic large anterior supraorbital ridges, epicanthic folds ridges, epicanthic folds supraorbital � Profound Profound hypotonia hypotonia and seizures and seizures � � Retinopathy, cataracts, hearing loss Retinopathy, cataracts, hearing loss � � Enlarged liver Enlarged liver � � Renal cysts Renal cysts � � Punctate Punctate stippling esp. patella and epiphyses stippling esp. patella and epiphyses �
Biogenesis and beta- -oxidation oxidation Biogenesis and beta disorders biochemical tests disorders biochemical tests � Plasma VLCFA Plasma VLCFA � � Plasma Plasma phytanate/pristanate phytanate/pristanate � � Plasma bile acid intermediates Plasma bile acid intermediates � � Red cell Red cell plasmalogens plasmalogens � � Platelet/fibroblast DHAP Platelet/fibroblast DHAP- -AT assay AT assay �
Diagnostic flow chart Diagnostic flow chart Clinical suspicion Clinical suspicion normal normal VLCFAs VLCFAs increased increased Check for Peroxisome Check for normal normal Peroxisome Plasmalogens Plasmalogens other disorders -oxidation oxidation other disorders β - β DHAP- -AT AT DHAP defect defect deficient deficient Bile acids Bile acids Peroxisome biogenesis biogenesis Peroxisome Pristanate Pristanate disorder disorder normal normal high high •Phytanate/Pristanate Phytanate/Pristanate • •Bile acids Bile acids • Bifunctional Bifunctional Oxidase def def Oxidase •Pipecholic Pipecholic acid acid • Enz. def. . def. Enz
Calcified (punctate punctate) stippling ) stippling Calcified ( and rhizomelia rhizomelia and Zellweger RCDP
Flow chart for RCDP Clinical suspicion Flow chart for RCDP Clinical suspicion Atypical bone dysplasia dysplasia, , Atypical bone Classical RCDP Classical RCDP cataracts, mental retardation cataracts, mental retardation plasmalogens plasmalogens normal normal deficient deficient normal normal DHAP- DHAP -AT AT Type 3 RCDP Type 3 RCDP Excludes RCDP Excludes RCDP deficient deficient Types 1, 2 and 3 Types 1, 2 and 3 normal normal phytanate Type 2 RCDP phytanate Type 2 RCDP raised raised Classical type 1 RCDP Classical type 1 RCDP Check for other Check for other types of chondrodysplasia chondrodysplasia types of eg sterol analyses sterol analyses eg
Sterol disorders Sterol disorders � Mevalonic Mevalonic aciduria aciduria � � Smith Smith- -Lemli Lemli- -Opitz Opitz � syndrome syndrome � Desmosterolosis Desmosterolosis � � Lathosterolosis Lathosterolosis � � Conradi Conradi- -Hunermann Hunermann � syndrome syndrome � CHILD syndrome CHILD syndrome �
Mevalonic aciduria aciduria - - Mevalonic mevalonate kinase kinase deficiency deficiency mevalonate � Psychomotor retardation, failure to thrive, Psychomotor retardation, failure to thrive, � and hypotonia hypotonia are common are common and � Severely affected patients have Severely affected patients have � microcephaly, short stature , short stature dolichocephaly dolichocephaly, , microcephaly wide fontanele fontanele, low set ears, blue , low set ears, blue sclerae sclerae and and wide cataracts. Cerebellar Cerebellar hypoplasia hypoplasia. . cataracts. � Febrile crises, hepatosplenomegaly, lymph Febrile crises, hepatosplenomegaly, lymph- - � adenopathy, diarrhoea and rashes may be , diarrhoea and rashes may be adenopathy present present � Diagnosis by urine organic acids Diagnosis by urine organic acids – – increased increased � mevalonic acid and acid and lactone lactone mevalonic
Smith- -Lemli Lemli- -Opitz Opitz Smith 7-dehydrocholesterol → cholesterol 7-DHC reductase deficiency
Smith- -Lemli Lemli- -Opitz Opitz syndrome syndrome Smith � Severe type II presentation Severe type II presentation � � Stillborn or neonatal presentation with major Stillborn or neonatal presentation with major � malformations: polydactyly malformations: polydactyly, cleft palate, structural , cleft palate, structural abnormalities in brain, heart and kidneys abnormalities in brain, heart and kidneys � Type I presentation Type I presentation � � craniocial craniocial ( (microcephaly microcephaly, , ptosis ptosis, , anteverted anteverted nares nares, , � retrognathea etc), etc), retrognathea � skeletal ( skeletal (syndactyly syndactyly), ), � � genital ( genital (hypospadias hypospadias, , cryptorchidism cryptorchidism), ), � � develpoment develpoment (growth and mental retardation, (growth and mental retardation, � feeding problems) feeding problems)
SLO diagnosis SLO diagnosis � Diagnosis by sterol analysis of plasma or Diagnosis by sterol analysis of plasma or � tissues tissues � GC GC- -MS analysis of 7 MS analysis of 7- -DHC and isomer (8 DHC and isomer (8- - � DHC) usually reliable although levels in DHC) usually reliable although levels in milder patients may only be slightly high milder patients may only be slightly high � Free cholesterol is usually reduced in Free cholesterol is usually reduced in � plasma but routine analyses are usually plasma but routine analyses are usually unreliable since dehydrocholesterols dehydrocholesterols unreliable since also react in the oxidase oxidase assay assay also react in the
Desmosterolosis Desmosterolosis Desmosterol Cholesterol Desmosterol reductase deficiency � Few cases reported, first case in Few cases reported, first case in fetus fetus with with � multiple malformations (growth deficient, multiple malformations (growth deficient, rhizomelic limb shortening, facial limb shortening, facial rhizomelic dysmorphism, ambiguous genitalia etc) , ambiguous genitalia etc) dysmorphism � Two subsequent cases milder with severe dev Two subsequent cases milder with severe dev � delay, cleft palate, small mandible) delay, cleft palate, small mandible) � Diagnosis as for SLO but looking for Diagnosis as for SLO but looking for � desmosterol – – plasma sterols plasma sterols desmosterol
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