Xia–Gibbs syndrome in adulthood: a case report with insight into the natural history of the condition

Abstract

A 55-yr-old male with severe intellectual disability, behavioral problems, kyphoscoliosis, and dysmorphic features was referred for a genetic evaluation. Chromosomal microarray, RASopathy gene panel, mitochondrial sequencing, and fragile X testing were all negative. Subsequent whole-exome sequencing revealed a heterozygous, truncating variant in the AHDC1 gene, consistent with a diagnosis of Xia–Gibbs syndrome (XGS). Review of his clinical history showed many classic dysmorphic and clinical features of XGS, but no major health issues in adulthood other than intellectual disability. This individual is the oldest published XGS case to date, demonstrates the wide phenotypic spectrum of the disorder, and provides information on the condition's natural history. As more adults undergo genomic studies, we will continue to learn about the adult phenotypes of genetic conditions typically diagnosed in the pediatric setting.

Xia-Gibbs Syndrome: A Review of Literature

“…The eldest patient reported was a 55-year-old male. Unlike 90% of cases described earlier, Murdock et al (2019) documented that this adult did not have low tone but he displayed remarkable disturbance in coordination and balance as evidenced by ataxia and frequent falls [ 31 ]. The frequent finding of sleep apnea was also missing though disruption of sleep was recorded.…”

“…It is noteworthy that genetic defects that disrupt DNA repair pose an increased risk of cancer. Though the exact role of AHDC1 in humans is still a matter of debate, it is recommended that patients diagnosed with XGS should be referred to specialists for cancer screening while keeping the suspicion high [ 31 ].…”

“…In more than half of the patients, brain abnormalities like corpus callosum hypoplasia or dysgenesis, delayed myelination or hypomyelination, leukomalacia, dysmorphic sulci-gyri, and cystic lesion, have been observed as magnetic resonance imaging (MRI) findings [ 1 - 3 , 12 , 13 , 30 , 33 - 35 ]. Movement disorders including ataxia, tremors, and bradykinesia are frequently associated with XGS [ 2 , 4 , 31 ]. It needs further investigation to include movement disorders in classical features of XGS.…”

“…The frequent finding of sleep apnea was also missing though disruption of sleep was recorded. Surprisingly, he had prominent macrocephaly which was novel for XGS, though it is sometimes associated with a craniosynostosis condition known as Muenke syndrome [ 21 , 31 ]. Scoliosis was reported in one-fifth of the surveyed patients with XGS, which is a much higher prevalence than the general population [ 12 ].…”

“…Scoliosis was reported in one-fifth of the surveyed patients with XGS, which is a much higher prevalence than the general population [ 12 ]. Scoliosis can be attributed to connective tissue abnormalities as the 55-year-old male also carried loose and soft skin texture [ 31 ]. Additionally, another cohort study found that almost half of the cases with XGS had an abnormality in the skin and in other connective tissues [ 30 , 37 ].…”