Dysmorphology Dysmorphology Guy Besley Guy Besley Willink - - PowerPoint PPT Presentation

Dysmorphology Dysmorphology

Guy Besley Guy Besley

Willink Biochemical Genetics Unit, Willink Biochemical Genetics Unit, Manchester Children Manchester Children’ ’s Hospital s Hospital

Dysmorphic Dysmorphic presentation presentation

• 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 Congenital dysmorphology dysmorphology – – 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 Postnatal dysmorphology dysmorphology – – 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 Disorders of the fetus fetus Peroxisomal Peroxisomal disorders disorders

• 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
• xidation

defects defects

• Especially

Especially bifunctional bifunctional protein defect protein defect

Peroxisomal Peroxisomal biogenesis disorder biogenesis disorder

• Zellweger

Zellweger syndrome syndrome

• Typical facial

Typical facial dysmorphism dysmorphism: high forehead, : high forehead, large anterior large anterior fontanelle fontanelle, , hypoplastic hypoplastic supraorbital supraorbital ridges, epicanthic folds ridges, epicanthic folds

• 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 Biogenesis and beta-

• oxidation
• xidation

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

• Phytanate/Pristanate

Phytanate/Pristanate

• Bile acids

Bile acids

• Pipecholic

Pipecholic acid acid Peroxisome Peroxisome biogenesis biogenesis disorder disorder Bile acids Bile acids Pristanate Pristanate Oxidase Oxidase def def Bifunctional Bifunctional Enz

• Enz. def.

. def.

normal normal

Peroxisome Peroxisome β β-

• oxidation
• xidation

defect defect VLCFAs VLCFAs

normal normal increased increased

Check for Check for

• ther disorders
• ther disorders

normal normal

Plasmalogens Plasmalogens DHAP DHAP-

• AT

AT

deficient deficient high high

Calcified ( Calcified (punctate punctate) stippling ) stippling and and rhizomelia rhizomelia

Zellweger RCDP

Clinical suspicion Clinical suspicion

Flow chart for RCDP Flow chart for RCDP

Atypical bone Atypical bone dysplasia dysplasia, , cataracts, mental retardation cataracts, mental retardation Classical RCDP Classical RCDP plasmalogens plasmalogens DHAP DHAP-

• AT

AT phytanate phytanate Excludes RCDP Excludes RCDP Types 1, 2 and 3 Types 1, 2 and 3 Check for other Check for other types of types of chondrodysplasia chondrodysplasia eg eg sterol analyses sterol analyses Type 2 RCDP Type 2 RCDP Type 3 RCDP Type 3 RCDP Classical type 1 RCDP Classical type 1 RCDP

deficient deficient normal normal normal normal deficient deficient normal normal raised raised

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 Mevalonic aciduria aciduria -

• mevalonate

mevalonate kinase kinase deficiency deficiency

• Psychomotor retardation, failure to thrive,

Psychomotor retardation, failure to thrive, and and hypotonia hypotonia are common are common

• Severely affected patients have

Severely affected patients have microcephaly microcephaly, short stature , short stature dolichocephaly dolichocephaly, , wide wide fontanele fontanele, low set ears, blue , low set ears, blue sclerae sclerae and and cataracts.

• cataracts. Cerebellar

Cerebellar hypoplasia hypoplasia. .

• Febrile crises, hepatosplenomegaly, lymph

Febrile crises, hepatosplenomegaly, lymph-

• adenopathy

adenopathy, diarrhoea and rashes may be , diarrhoea and rashes may be present present

• Diagnosis by urine organic acids

Diagnosis by urine organic acids – – increased increased mevalonic mevalonic acid and acid and lactone lactone

Smith Smith-

• Lemli

Lemli-

• Opitz

Opitz

7-dehydrocholesterol → cholesterol

7-DHC reductase deficiency

Smith Smith-

• Lemli

Lemli-

• Opitz

Opitz syndrome syndrome

• Severe type II presentation

Severe type II presentation

• Stillborn or neonatal presentation with major

Stillborn or neonatal presentation with major malformations: malformations: polydactyly 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 retrognathea etc), etc),

• 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 unreliable since dehydrocholesterols dehydrocholesterols also react in the also react in the oxidase

• xidase assay

assay

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 rhizomelic limb shortening, facial limb shortening, facial dysmorphism dysmorphism, ambiguous genitalia etc) , ambiguous genitalia etc)

• 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 desmosterol – – plasma sterols plasma sterols

Lathosterolosis Lathosterolosis

Lathosterol 7-dehydrocholesterol

Lathosterol 5-desaturase deficiency

• Mental retardation,

Mental retardation, polydactyly polydactyly, vertebral , vertebral abnormalities, liver abnormalities, liver disease disease

• Plasma sterols show high

Plasma sterols show high lathosterol lathosterol

Conradi Conradi-

• H

Hü ünermann nermann syndrome syndrome

8(9)-cholestanol lathosterol

• X

X-

• linked dominant

linked dominant

• Ichthyosis

Ichthyosis, cataracts, short stature, , cataracts, short stature, punctate punctate calcifications and asymmetric limb shortening calcifications and asymmetric limb shortening

• Maybe similar to CHILD syndrome (congenital

Maybe similar to CHILD syndrome (congenital hemidysplasia hemidysplasia, , ichthyosis ichthyosis and limb defects) and limb defects)

• Plasma sterol analysis

Plasma sterol analysis

ü

Sterol-∆8-isomerase deficiency

Disorders of energy metabolism Disorders of energy metabolism

• Pyruvate

Pyruvate dehydrogenase dehydrogenase deficiency deficiency

• Cerebral malformations, agenesis of corpus

Cerebral malformations, agenesis of corpus callosum callosum, facial , facial dysmorphism dysmorphism, metabolic acidosis , metabolic acidosis

• Blood and CSF lactate, fibroblast PDH assay and

Blood and CSF lactate, fibroblast PDH assay and mutations mutations

• Mitochondrial respiratory chain defect

Mitochondrial respiratory chain defect

• Muscle respiratory chain assays, mutation analyses

Muscle respiratory chain assays, mutation analyses

• GAII

GAII

• Dysmorphic

Dysmorphic, renal cysts, characteristic smell , renal cysts, characteristic smell

• Defective ETF or ETF

Defective ETF or ETF-

• DH

DH

• Test organic acids and

Test organic acids and acylcarnitines acylcarnitines

Congenital disorders of Congenital disorders of glycosylation glycosylation -

• CDG syndromes

CDG syndromes

• Protein

Protein glycosylation glycosylation is is either through either through asparagine asparagine (N) or (N) or serine/ serine/threonine threonine (O) (O)

• There are some 18

There are some 18 different disorders of different disorders of glycosylation glycosylation

• CDGI are N

CDGI are N-

• linked (12)

linked (12)

• CDGII are O

CDGII are O-

• linked (6)

linked (6)

• Diagnosis by

Diagnosis by transferrin transferrin isoelectric isoelectric focussing focussing

CDG syndrome CDG syndrome

Transferrin isoelectric focussing

Molybdenum cofactor/Sulphite Molybdenum cofactor/Sulphite

• xidase
• xidase deficiency

deficiency

• Diagnosis

Diagnosis

• Low uric acid

Low uric acid

• Positive urine sulphite test

Positive urine sulphite test

• Increased

Increased sulphocysteine sulphocysteine in urine and in urine and plasma, low plasma plasma, low plasma cystine cystine

Postnatal Postnatal dysmorphic dysmorphic disorders disorders

• Remodelling of bone and soft tissue

Remodelling of bone and soft tissue

• lysosomal storage disorders

lysosomal storage disorders

• MPSI

MPSI – – MPS VII MPS VII

• Mucolipidosis

Mucolipidosis II II

• GM1

GM1-

• gangliosidosis

gangliosidosis

• alpha

alpha mannosidosis mannosidosis

• galactosialidosis

galactosialidosis

• multiple

multiple sulphatase sulphatase deficiency deficiency

• Connective tissue effects

Connective tissue effects

• Homocystinuria

Homocystinuria

• Menkes disease

Menkes disease

Lysosomal storage disorders Lysosomal storage disorders

• Usually presents in

Usually presents in the first months the first months

• But may present

But may present with with fetal fetal hydrops hydrops

• Especially MPSVII

Especially MPSVII

• Or as

Or as colloiden colloiden baby baby ( (Gaucher Gaucher disease) disease)

Lysosomal disorders Lysosomal disorders – – diagnostic diagnostic tests tests

• MPS disorders:

MPS disorders:

• Urinary MPS analysis

Urinary MPS analysis

• Specific enzyme assays

Specific enzyme assays

• Other lysosomal disorders:

Other lysosomal disorders:

• Specific enzyme assays

Specific enzyme assays

• Sialic

Sialic acid analysis acid analysis

Urinary MPS electrophoresis

Homocystinuria Homocystinuria

• Marfanoid

Marfanoid features features

• Skeletal abnormalities

Skeletal abnormalities

• Osteoporosis

Osteoporosis

• Dislocated lenses

Dislocated lenses

• Mental retardation, thrombosis, seizures

Mental retardation, thrombosis, seizures

• Diagnosis

Diagnosis

• Increased

Increased homocystine homocystine in plasma and urine, in plasma and urine, increased plasma increased plasma methionine methionine

Menkes Menkes

• X

X-

• linked disorder of

linked disorder of copper transport copper transport

• Low plasma Cu

Low plasma Cu++

++ and

and ceruloplasmin ceruloplasmin

• Fibroblast copper

Fibroblast copper uptake studies/DNA uptake studies/DNA

Metabolic disease and Metabolic disease and Dysmorphology Dysmorphology

• Maternal PKU

Maternal PKU

• Peroxisomal

Peroxisomal disorders disorders

• Disorders of sterol metabolism

Disorders of sterol metabolism

• Disorders of energy metabolism

Disorders of energy metabolism – – PDH PDH

• Congenital disorders of

Congenital disorders of glycosylation glycosylation

• Molybdenum cofactor/Menkes disease

Molybdenum cofactor/Menkes disease

• Lysosomal

Lysosomal disorders disorders