Table 7.

Skeletal Dysplasias Associated with Microcephaly in the Differential Diagnosis of RNU4atac-opathy

Gene(s)DisorderMOIKey Features of Disorder
Overlapping w/RNU4atac-opathyDistinguishing from RNU4atac-opathy
CDC6
CDC45
CDT1
GMNN
ORC1
ORC4
ORC6 		Meier-Gorlin syndrome (OMIM PS224690)AR
AD 1		IUGR, extreme short stature w/microcephaly; patella hypoplasiaMicrotia; craniosynostosis; congenital lobar emphysema; typically normal intellect
COG4 Saul-Wilson syndrome ADIUGR, extreme short stature; occasional microcephaly; retinal dystrophy & hearing loss; iIntermittent neutropenia (but no known B cell defects)Relative macrocephaly; distinct facial features; megaepiphyses; lamellar cataracts; clubfoot; normal intellect
PCNT Microcephalic osteodysplastic primordial dwarfism type II ARIUGR, extreme short stature; microcephaly; neurovascular diseaseDistinct facial features; renovascular & cardiovascular disease; microdontia; insulin resistance
POLE IMAGe-I syndrome (OMIM 618336)ARIUGR, extreme short stature; often microcephalic; immune dysfunction (T, B, or NK cell lymphopenia or hypogammaglobulinemia)Adrenal insufficiency; cryptorchidism, small penis; distinct facial features (long, thin nose, small, low-set, posteriorly rotated ears); short wide neck; metaphyseal changes often absent or mild (linear striations)
RMRP Cartilage-hair hypoplasia – anauxetic dysplasia spectrum disorders ARGrowth deficiency; sparse hair; immune dysfunction (e.g., CVID, SCID); microcephaly sometimes a feature of CHH (OFC range: 4 SD below to 2 SD above the mean)Disproportionately long fibula; anemia; predisposition to malignancy; intestinal dysfunction (e.g., congenital megacolon, Hirschsprung disease); head circumference can be normal
POP1 Anauxetic dysplasia 2 (OMIM 617396)ARShort statureMetaphyseal dysplasia; no clinical symptoms of immunodeficiency
NEPRO Anauxetic dysplasia 3 (OMIM 618853)ARShort stature; hair hypoplasiaMetaphyseal dysplasia; no clinical symptoms or laboratory signs of immunodeficiency
SMARCAL1 Schimke immunoosseous dysplasia ARIUGR, extreme short stature; ± microcephaly; neurovascular disease; immune dysfunction (T cell lymphocyte deficiency rather than humoral deficiency)Disproportionately short trunk; focal segmental glomerulosclerosis / nephrotic syndrome, leading to progressive renal failure

AD = autosomal dominant; AR = autosomal recessive; CVID = combined variable immunodeficiency; IUGR = intrauterine growth restriction; MOI = mode of inheritance; SCID = severe combined immunodeficiency; SD = standard deviation(s)

1.

Meier-Gorlin syndrome is inherited in an autosomal recessive manner with the exception of GMNN-related Meier-Gorlin syndrome, which is inherited in an autosomal dominant manner.

From: RNU4atac-opathy

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