CASE PRESENTATION

By Kanika SinghDNB Student Medical GeneticsSGRH

15 months 3 months

Presenting Complaints :

First child•Antenatal history – uneventful, no h/o

oligo/polyhydramnios, fetal movements ?

•Birth history – Term/NVD/Cried after birth/ Bwt – 3kg. No immediate perinatal complications

•After birth noted to have short limbs and contractures. B/L knees and elbows in flexion and restriction of movement at shoulder joints.

•H/o global developmental delay present – no neck holding, social smile, did not grasp objects

•Vision impairment - Unable to fix gaze on an object or parents noticed at 3 months of age

•Acyanotic heart disease detected at 6 months of age

•Not gaining weight

•Expired at 15 months of age

•Terminal event – fever ?sepsis

•Weight at death 2.5 kg (Failure to thrive)

Second Child

•Antenatal history - ? Polyhydramnios

•Term born/3.5kgs/Respiratory distress at birth

Nicu stay x 20 days. Echo – small ASD

•Short limbs and contractures

•Feeding – Normal

•Vision - ? Parents unsure

•Expired at 3 months of age. Cause ?

Physical Findings• Frontal bossing

• ?sparse hair

• Depressed nasal bridge

• Broad nose

• Shortening of limbs (predominantly proximal or rhizomelic)

• Flexion at elbow and knees ( ?contractures)

• Hands and feet – could not be seen

• Spine – could not be seen

Summary•Consanguinous family

•Two siblings affected, both boy and girl

•Flat nasal bridge + rhizomelic shortening + contractures + failure to thrive + developmental delay + congenital heart disease + Vision involvement

Differential Diagnosis Rhizomelic Skeletal dysplasias:•Achondroplasia•Hypochondroplasia•Kyphomelic dysplasia•Spondylo epiphyseal dysplasia congenita•Rhizomelic Chondro dysplasia Punctata

•Osteogenesis imperfecta type IV

Xray Findings :•Punctate calcification•Metaphyseal splaying• Thoracic Vertebral segmentation defect•Normal ribs scapulae clavicle•Normal mineralization

Revised Differential Diagnosis :Rhizomelic shortening + flat nasal bridge + punctate epiphysis

•Genetic defects in 1. Peroxisomal metabolism2. Cholesterol metabolism3. Vitamin K metabolism

• Acquired embryopathies1. Maternal malabsorption of Vit K2. Drugs –Warfarin3. Maternal SLE

Rhizomelic Chondrodysplasia Punctata•Disorder of peroxismal import

•Clinical Features :Flat nasal bridgeRhizomelic shortening (humerus > femur)Postnatal growth deficiencyCataractsSevere intellectual disabilitySeizures

Punctate calcification usually disappearing after 1-3 yr of age

Epiphyseal and metaphyseal abnormalitiesVertebral coronal cleftsOthers – cleft of the soft palateCongenital heart diseaseUPJ obstructionBrain MRI – cerebral and cerebellar

atrophy with enlargement of ventriclesBrain MRS – delayed myelination,

decreased choline to creatinine ratiosDeath in infancy

Reported Cases

Our case

Xray from published literature

Our Case

Vertebral Coronal Clefts

•Failure of fusion of anterior and posterior ossification centers•Best seen on lateral Xray films•Radiolucent band running through the vertebral bodies

Matrix Protein Import in Peroxisomes

Enzymatic pathways in Peroxisomes

Classification•Multiple enzyme deficiencies:Peroxisomal

Biogenesis Disorders (PBD) ▫Zellweger spectrum disorder▫Rhizomelic chondrodysplasia punctata

spectrum (RCDP)▫Neonatal ALD▫Infantile Refsum disease

•Single enzyme deficiencies▫X-linked adrenoleukodystrophy (X-ALD)▫Acyl-CoA oxidase deficiency▫Adult Refsum disease▫Hyperoxaluria Type I

Diagnosis & Testing of RCDPBiochemical tests:

• Deficiency of plasmalogens in RBC’s

• Elevated plasma concentration of phytanic acid

• Normal plasma VLCFA

Done in limited no. Of laboratories worldwide

Assays in cultured skin fibroblasts

• Possible to demonstrate defective plasmalogen biosynthesis,

defective phytanic acid oxidation and normal VLCFA oxidation

Genetic Testing• Autosomal Recessive

• Three types of RCDP – same clinical phenotype

• Type 1 – Mutations in PEX7 gene encodes for peroxisomal type 2 targeting signal receptor. Located at 6q22-q24

• Type 2 – deficiency of the peroxisomal enzyme dihydroxyacetone phosphate acyltransferase, encoded by GNPAT

• Type 3 - deficiency of the alkyl-dihydroxyacetone phosphate synthase, encoded by AGPS

• Diagnosis is by sequencing of the genes

• Correlations between the predicted severity

of PEX7 pathogenic variants and phenotype 

• Homozygosity for the p.Leu292Ter pathogenic variant

have classic RCDP1.

• Phenotype of Compound heterozygotes

for p.Leu292Ter and another pathogenic

variant,depends on the other allele.

Several PEX7 alleles that are associated with a milder

RCDP phenotype, adult Refsum disease,

or isolated congenital cataracts have been identified

Group 1a – Peroxisomal disordersDisorder Clinical

FeaturesSkeletal anomalies

Site of stippling

Our case

Zellweger syndrome

Hypotonia, hypertelorismhigh foreheadFlat nasal bridge retinopathy cataract deafnessDevp delay seizures

Metatarsus adductus

Patella thyroid pelvis

Flat nasal bridge, vision, devp delay

RCDP Flat nasal bridge MicrocephalySNHL seizures B/Lcataracts jt contracture

Symmetric shortening of limbsVertebral coronal clefts

generalized Flat nasal bridge, vision, contractures, shortening, generalized stippling

Group 1b – Cholesterol biosynthesis defectsDisorder Clinical

FeaturesSkeletal anomalies

Site of stippling

Our case

Greenberg Dysplasia

PolyamniosHydropsOmphaloceleCystic hygromaPostaxial polydactylLethal

Moth eaten appearance scapulae pelvis, short thorax

Trachea ribs sternum pelvis platyspondyly

nil

CDP X-linked Dominant

SNHL icthyosis sparse hair cataract (U/L) dandy walker

Assymetric shortening vertebral body defects

generalized Shortening vision sparse hair

CHILD MMC ichthyosis

Hypoplastic /absent limbs ,ribs,scapulaescoliosis

epiphysis Epiphyseal stippling

Group 2 - Disruption of Vit K metabolismDisorder Clinical

featuresSkeletal anomalies

Site of stippling

Fetal warfarin syndrome

flat nasal bridge,cataract cardiac defects, upper airway obst

Shortening of limbs, short broad phalanges & metacarpals

Generalized

Fetal phenytoin Hypoplastic nails, distal phalanges, cleft lip/palate cardiac

Short terminal phalangesCraniosynostosisVertebral saggital clefts

Thyroid, sacrococcyx, periarticular

Combined def of vit K dep clotting factors

Nasal hypoplasia, bleeding manif

Short terminal phalanges

generalized

CDP X linked Recessive

Hypotonia Short terminal phalanges & metacarpal

Carpal, metacarpal

Others• Chromosomal - Trisomy 21 & 18 – stippling in

sacrococcyx / calcaneo talus

• Maternal SLE – hypoplastic nails, hypoplasia of facial bones, short distal phalanges, vertebral clefts Stippling in trachea/vertebra/periarticular

• Dappled diaphysial dysplasia – hydrops, shortening of limbs, platyspondyly, stippling pelvis,tracha,ribs

• Pacman dysplasia – cystic hygroma, cloudy cornea, shortening of limbs, vertebral clefts, generalized stippling

THANK YOU