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 ].…”

Community‐based recruitment and exome sequencing indicates high diagnostic yield in adults with intellectual disability

“…As a consequence, most adults with ID who have had access to genetic testing as children have likely had the less comprehensive older tests, for example, karyotype, microarray, or single‐gene analysis and are lacking a more comprehensive genetic evaluation. An illustrative case study of a 55‐year‐old adult recently diagnosed with Xia‐Gibbs syndrome, previously only described in pediatric patients, shows how exome sequencing can bring new knowledge to families, aiding both the diagnosed adult and younger individuals who can then develop more informed prognoses (Murdock et al, 2019). Recently studies of adults with epilepsy and comorbid ID reported the yield of diagnostic exome testing in the range of 25%–27% (Benson et al, 2020; Snoeijen‐Schouwenaars et al, 2019).…”