Case - Rhizomelic chondrodysplasia punctata
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This case presentation describes two siblings who presented with rhizomelic shortening of the limbs, flat nasal bridge, vision impairment, developmental delay, and congenital heart disease. Radiographic findings included punctate calcifications. The differential diagnosis included disorders of peroxisomal function and cholesterol metabolism. Genetic testing confirmed a diagnosis of Rhizomelic Chondrodysplasia Punctata type 1, a rare autosomal recessive disorder caused by a defect in peroxisomal protein import.
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Case - Rhizomelic chondrodysplasia punctata
- 1. CASE PRESENTATION By Kanika Singh DNB Student Medical Genetics SGRH
- 2. 15 months 3 months Presenting Complaints :
- 3. 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.
- 4. • 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
- 5. • Expired at 15 months of age • Terminal event – fever ?sepsis • Weight at death 2.5 kg (Failure to thrive)
- 6. 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 ?
- 8. 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
- 9. 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
- 10. Differential Diagnosis Rhizomelic Skeletal dysplasias: • Achondroplasia • Hypochondroplasia • Kyphomelic dysplasia • Spondylo epiphyseal dysplasia congenita • Rhizomelic Chondro dysplasia Punctata • Osteogenesis imperfecta type IV
- 11. Xray Findings : •Punctate calcification •Metaphyseal splaying • Thoracic Vertebral segmentation defect •Normal ribs scapulae clavicle •Normal mineralization
- 13. Revised Differential Diagnosis : Rhizomelic shortening + flat nasal bridge + punctate epiphysis • Genetic defects in 1. Peroxisomal metabolism 2. Cholesterol metabolism 3. Vitamin K metabolism • Acquired embryopathies 1. Maternal malabsorption of Vit K 2. Drugs –Warfarin 3. Maternal SLE
- 14. Rhizomelic Chondrodysplasia Punctata • Disorder of peroxismal import • Clinical Features : Flat nasal bridge Rhizomelic shortening (humerus > femur) Postnatal growth deficiency Cataracts Severe intellectual disability Seizures
- 15. Punctate calcification usually disappearing after 1-3 yr of age Epiphyseal and metaphyseal abnormalities Vertebral coronal clefts Others – cleft of the soft palate Congenital heart disease UPJ obstruction Brain MRI – cerebral and cerebellar atrophy with enlargement of ventricles Brain MRS – delayed myelination, decreased choline to creatinine ratios Death in infancy
- 17. Xray from published literature Our Case
- 18. 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
- 19. Matrix Protein Import in Peroxisomes
- 20. Enzymatic pathways in Peroxisomes
- 21. 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
- 22. Diagnosis & Testing of RCDP Biochemical 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
- 23. 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
- 24. • 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
- 25. Group 1a – Peroxisomal disorders Disorder Clinical Features Skeletal anomalies Site of stippling Our case Zellweger syndrome Hypotonia, hypertelorism high forehead Flat nasal bridge retinopathy cataract deafness Devp delay seizures Metatarsus adductus Patella thyroid pelvis Flat nasal bridge, vision, devp delay RCDP Flat nasal bridge Microcephaly SNHL seizures B/Lcataracts jt contracture Symmetric shortening of limbs Vertebral coronal clefts generalized Flat nasal bridge, vision, contractures, shortening, generalized stippling
- 26. Group 1b – Cholesterol biosynthesis defects Disorder Clinical Features Skeletal anomalies Site of stippling Our case Greenberg Dysplasia Polyamnios Hydrops Omphalocele Cystic hygroma Postaxial polydactyl Lethal 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,scapulae scoliosis epiphysis Epiphyseal stippling
- 27. Group 2 - Disruption of Vit K metabolism Disorder Clinical features Skeletal 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 phalanges Craniosynostosis Vertebral 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
- 28. 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
- 29. THANK YOU