Neurodevelopmental variability in three young girls with a rare chromosomal disorder, 48, XXXX

Abstract

Fourty eight, XXXX is a rare chromosomal aneuploidy associated with neurocognitive deficits, speech and language disorders and executive dysfunction but the scarcity and variability of reported cases limit our understanding of the 48, XXXX phenotype. To our knowledge, this is the first study to report on the neurodevelopmental profile of three young females with 48, XXXX. Patient 1 (age = 11.0), Patient 2 (age = 10.9), and Patient 3 (age = 6.4) were evaluated using comprehensive neurodevelopmental assessments. Parent questionnaires were completed to assess behavioral and psychosocial domains including executive function, ADHD and anxiety. Nonverbal intelligence quotients were 56, 80, and 91 for Patients 1, 2, and 3, respectively. There were significantly impaired visual motor capacities in graphomotor and perceptual domains below the 5th centile in Patients 1 and 2, and mildly impaired visual perception skills in Patient 3. All three patients had Childhood Apraxia of Speech (CAS) but of varying severity and similar executive dysfunction, externalizing problems and social difficulties. Familial learning disabilities (FLD) in Patient 1 and the co-occurrence of ADHD in Patient's 1 and 2 may contribute to their more impaired cognitive performances relative to Patient 3 who is the second reported case of 48, XXXX to have normal intellect. These distinct and overlapping characteristics expand the phenotypic profile of 48, XXXX and may be used in the counseling of families and treatment of children with 48, XXXX.

A case report of hypersomnia in tetrasomy X improved with medical therapy

“…Abnormalities of teeth and enamel, radioulnar synostosis, and joint hyperflexibility characterize the connective tissue and skeletal disorders. Neurocognitive deficits, speech and language disorders, and executive dysfunction have been described .…”

Live-Born Double Aneuploidy at the Johns Hopkins Cytogenomics Laboratory: Case Report and Review of the Literature

“…Due to the gross genomic imbalance, tetrasomy (2N + 2) with only partial chromosomal arm involvement may be compatible with life, and observation in live births is rare. The single exception being 48,XXXX or tetrasomy X which can be observed in female live-born children [4] due to X-inactivation. In the excess of the normal sex chromosomal complement, cellular processes accommodate this imbalance via inactivation of any additional X chromosomes, resulting in a highly variable phenotype as some loci are not subject to inactivation [5].…”

Impact of early diagnosis and noninvasive prenatal testing (NIPT): Knowledge, attitudes, and experiences of parents of children with sex chromosome aneuploidies (SCAs)

“…These populations typically present with severely delayed speech, language, and motor skills, as well as increased incidences of anxiety, LLDs, childhood apraxia of speech, and developmental dyspraxia . 48,XXXX was first described in 1961, and, while much remains unknown about this disorder, these girls are often tall in stature, with below average IQ . 48,XXXY has an incidence of one in 40 000 to 60 000, while 49,XXXXY is the least common SCA, with an incidence of one in every 100 000 births.…”

“…8,12,25 48,XXXX was first described in 1961, and, while much remains unknown about this disorder, these girls are often tall in stature, with below average IQ. 26,27 48,XXXY has an incidence of one in 40 000 to 60 000, while 49,XXXXY is the least common SCA, with an incidence of one in every 100 000 births. Both disorders include mild to severe dysmorphology, childhood apraxia of speech, and musculoskeletal problems that become more prevalent with age.…”