X-linked mental retardation and severe short stature with a novel mutation ofthe KDM5C gene

摘要

Many monogenetic disorders of short stature have autosomal recessive/dominant form ofinheritance. However, X-linked short stature has not been well recognized. Herein, wereport a case of a boy from a family with familial severe short stature and mentalretardation, who displayed an X-linked recessive trait. The boy at the age of 4 yr and 6mo presented with remarkable growth failure (height: 76.5 cm [-6.3 SD]) and mentalretardation (IQ: 30) and cerebellar volume loss and without an external anomaly ormicrocephaly to our hospital. A careful interview to determine the family historysuggested a genetic background of familial mental retardation and short stature. Hismother had mild intellectual disability with normal stature and his maternal uncle hadsevere mental retardation with remarkably short stature. Whole-exome sequencing identifieda pathogenic variant in the KDM5C gene, {"type":"entrez-nucleotide","attrs":{"text":"NM_004187","term_id":"1772790824","term_text":"NM_004187"}}NM_004187: exon 23:c.3874_3875del: (p.Ala1292Glnfs*7). He presented with a novel frameshift mutation. Hismother was a heterozygous carrier of the variant. This case suggests that a disorderassociated with the KDM5C gene should be considered when patients presentwith remarkably short stature and X-linked mental retardation.Short stature is defined as height below the 3~(rd) percentile for thechronological age or -2 SD of the corresponding mean height for a given age, sex, andpopulation. The pathogenesis is heterogeneous, including environmental exposure toinfection, drugs, chemical compounds, or genetic factors involving largely unknown geneticvariants (1). A recent genetic study identifiedseveral genes associated with monogenic disorders of short stature, including genescontributing to the proliferation of growth plate chondrocytes, such as SHOX , NPR2 , NPPC , FGFR3 , and ACAN , and genes associated with GH/IGF-1secretion and intracellular signaling, such as GH1 , GHR , GHSR , IGFALS , and STAT5B (2). Many of the monogenic disorders of short stature areinherited as autosomal recessive or dominant traits. A defect in the SHOX gene, located on Xp22.33, has an autosomal dominant mode of inheritance because it islocated within the pseudoautosomal region in the X chromosome (3). However, X-linked idiopathic short stature has not been wellrecognized.