Table 3.

Disorders and Genes of Interest in the Differential Diagnosis of Chondrodysplasia Punctata 2, X-Linked

Differential Diagnosis DisorderGene(s)MOIFeatures of the Differential Diagnosis Disorder
Overlapping w/CDPX2Distinguishing from CDPX2
Skeletal dysplasia w/radiographic evidence of CDP 1
Chondrodysplasia punctata 1, X-linked (CDPX1)ARSL
(ARSE) 2		XL

Affected males have short stature & short limbs

  • Cataracts & cutaneous features are rare.
  • Brachytelephalangy & nasomaxillary hypoplasia are characteristic.
  • Delayed cognitive development has been reported.
  • CDP is usually symmetric.
CHILD syndrome (congenital hemidysplasia, ichthyosis, limb defects) (See NSDHL Disorders.)NSDHL 3XL
  • Asymmetric skeletal abnormalities incl CDP, rhizomelia, polydactyly, vertebral anomalies, scoliosis/kyphoscoliosis
  • Pathognomonic abnormalities in plasma or tissue sterol levels 4
  • Male lethal
  • Normal intelligence
  • Strict midline demarcation & striking unilaterality of skin findings that persist rather than improve over time.
  • More severe limb reduction defects that are usually ipsilateral to skin findings
  • Ipsilateral organ abnormalities
  • No cataracts
Keutel syndrome (OMIM 245150) MGP ARCDP in addition to brachytelephalangyPeripheral pulmonary stenosis, brachytelephalangia, & hearing impairment are key features of Keutel syndrome.
Greenberg dysplasia (OMIM 215140) LBR ARSkeletal abnormalities incl CDP, rhizomelia, polydactyly, & vertebral anomalies
  • Prenatally lethal & more severe skeletal abnormalities
  • CDP has a characteristic "moth-eaten" appearance.
Rhizomelic chondrodysplasia punctata type 1 (RCDP1) PEX7 AR
  • Rhizomelic shortening of limbs, punctate calcifications in cartilage w/epiphyseal & metaphyseal abnormalities (CDP), vertebral abnormalities (notching but not commonly CDP)
  • Cataracts (usually present at birth or appear in 1st few months of life)
  • Birth size often in lower range of normal, but postnatal growth deficiency is profound, ID severe, & seizures common.
  • Skeletal findings in RCDP are more symmetric & less widespread than in CDPX2.
  • There are few calcifications in the spine in RCDP.
  • Cataracts are more symmetric.
  • Most children w/RCDP do not survive 1st decade of life & a substantial % die in neonatal period.
  • RCDP1 is most common.
RCDP2 (OMIM 222765) GNPAT AR
RCDP3 (OMIM 600121) AGPS AR
RCDP5 (OMIM 616716) PEX5 AR
Disorders of post-squalene cholesterol biosynthesis
Smith-Lemli-Opitz syndrome DHCR7 ARSkeletal abnormalities incl rhizomelia & polydactyly
  • Significant phenotypic overlap w/MEND syndrome 5 incl ID, facial dysmorphism, multiple congenital abnormalities & genital abnormalities
  • No CDP
Antley-Bixler syndrome (See Cytochrome P450 Oxidoreductase Deficiency.) POR ARSkeletal abnormalities incl rhizomelia & scoliosis
  • No CDP or skeletal asymmetry
  • Other features incl craniosynostosis, midface hypoplasia, joint contractures, & DD
Desmosterolosis (OMIM 602398) DHCR24 ARSkeletal abnormalities incl rhizomelia, joint contractures, & poor growth
  • No CDP or skeletal asymmetry
  • ID
  • Brain & visceral anomalies
Lathosterolosis SC5D ARSkeletal abnormalities incl rhizomelia, postaxial polydactyly & spinal abnormalitiesNo CDP or skeletal asymmetry
CK (See NSDHL Disorders.) NSDHL XLMild skeletal abnormalities incl scoliosis/kyphosis
  • ID & neuronal migration abnormalities
  • Allelic to CHILD syndrome, but no overlapping features
Sterol-C4-methyloxidase-like deficiency (OMIM 616834)MSMO1
(SC4MOL)		ARShort stature, generalized ichthyosiform dermatitis, & cataracts reportedBroader phenotype incl ID, immune dysfunction, & failure to thrive
Peroxisome biogenesis disorders
Zellweger spectrum disorder PEX1
PEX2
PEX3
PEX5
PEX6
PEX10
PEX11B
PEX12
PEX13
PEX14
PEX16
PEX19
PEX26 		ARCDP of the patella & long bonesBroader phenotype incl congenital malformations, seizures, & liver disease of variable severity

AR = autosomal recessive; CDP = chondrodysplasia punctata; CDPX2 = chondrodysplasia punctata 2, X-linked; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked

1.

Classification of differential diagnoses is presented according to the most recent Nosology and Classification of Skeletal Disorders [Mortier et al 2019].

2.

Contiguous gene deletions involving ARSL and other genes in this region result in more complex phenotypes, including, variously, additional findings of ichthyosis, anosmia, hypogonadism, short stature, and corneal opacities.

3.

CHILD syndrome is caused by pathogenic variants in NSDHL, which encodes a cholesterol biosynthetic 4-methylsterol dehydrogenase [König et al 2000]. The enzyme, part of a 4-methylsterol demethylase complex, occurs one step proximal to the EBP sterol isomerase.

4.

Individuals with CHILD syndrome have increased levels of 4-methyl- and carboxysterols in cultured lymphoblasts, but only occasionally in plasma, whereas those with CDPX2 have increased levels of 8(9)-cholestenol and 8-dehydrocholeterol. In cultured lymphoblasts, both disorders manifest a paradoxic increase in the distal sterol metabolite lathosterol, including hemizygous males with an EBP pathogenic variant. The embryologic cause of the CHILD phenotype, common in NSDHL deficiency and rare in EBP deficiency, is unknown. Interestingly, fibroblasts cultured from normal skin from both the hemidysplastic and normal sides of the body can manifest the classic abnormal sterol profile.

5.

From: Chondrodysplasia Punctata 2, X-Linked

Cover of GeneReviews®
GeneReviews® [Internet].
Adam MP, Feldman J, Mirzaa GM, et al., editors.
Seattle (WA): University of Washington, Seattle; 1993-2024.
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.