Microcephaly/Trigonocephaly, Intellectual Disability, Autism Spectrum Disorder, and Atypical Dysmorphic Features in a Boy with Xp22.31 Duplication

Abstract

The Xp22.31 segment of the short arm of the human X chromosome is a region of high instability with frequent rearrangement. The duplication of this region has been found in healthy people as well as in individuals with varying degrees of neurological impairment. The incidence has been reported in a range of 0.4-0.44% of the patients with neurological impairment. Moreover, there is evidence that Xp22.31 duplication may cause a common phenotype including developmental delay, intellectual disability, feeding difficulty, autistic spectrum disorders, hypotonia, seizures, and talipes. We report on a patient with microcephaly and trigonocephaly, moderate intellectual disability, speech and language delay, and poor social interaction in addition to minor but atypical dysmorphic features. This report provides further insight into the pathogenicity of the Xp22.31 duplication by extending knowledge of its clinical features. This case, in association with those reported in the literature, indicates that the Xp22.31 duplication may contribute to cause pathological phenotypes with minor facial dysmorphisms, microcephaly, and intellectual disability as main features.

Poland Syndrome with Atypical Malformations Associated to a de novo 1.5 Mb Xp22.31 Duplication

“…The common, yet nonspecific, clinical modalities of presentation in individuals with Xp22.31 duplication might be explained by variable expressivity, decreased penetrance, and skewed X-inactivation in female. 15,18 All of these hypotheses need to be further confirmed. Additionally, the duplication might act not directly but rather predispose the patients to the action of other factors that cause the clinical features.…”

“…14 Our research group published a case report of a child affected by microcephaly, autism spectrum disorder, and intellectual disability, in which a Xp22.31 duplication was also detected. 15 The most frequently reported neurological involvement in patients carrying Xp22.31 rearrangements consists of autism spectrum disorder (ASD) and DD/ID. In this view, three large cohorts of patients with Xp22.31 duplication have been reported in this decade.…”

“…Additionally, the duplication might act not directly but rather predispose the patients to the action of other factors that cause the clinical features. 15 The region duplicated in our patient at the Xp22.31 subband encompasses the following loci: PUDP, PNPLA4, VCX, and the microRNA MIR4767 whose protein biological functions are poorly understood, and have not yet been linked to the human nosology, plus the steroid sulfatase (STS) gene encoding for a STS which serves for a membrane-bound microsomal enzyme that hydrolyzes several 3-β-hydroxysteroid sulfates serving as metabolic precursors for estrogens, androgens, and cholesterol. To date, only the last one was annotated in OMIM (308100) as responsible for an X-linked ichthyosis form.…”

Relevance of Copy Number Variation at Chromosome X in Male Fetuses Inherited from the Mother May Be Ascertained by Including Male Relatives from the Maternal Lineage in Addition to Trio Analyses

“…In Family 2, the duplicated segment included the STS and HDHD1/PUDP genes. Chromosome Xp22.31 duplication including STS has been recognized as a pathogenic CNV by multiple authors [ 8 , 16 ]. In Family 3, the size of the duplicated region was larger and harbored more genes; it consisted of HDHD1/PUDP , STS , VCX , PNPLA4 , and MIR651 .…”

Medical and neurobehavioural phenotypes in male and female carriers of Xp22.31 duplications in the UK Biobank

“…Whilst the phenotypes associated with XLI-associated deletions are reasonably well-characterised, the phenotypes associated with the reciprocal duplications have yet to be investigated systematically in large or adult samples. Case series/studies documenting predominantly young, clinically-ascertained, individuals with Xp22.31 duplications report a number of neurological features including intellectual disability/cognitive impairment (40%), autism or autistic behaviours (10–20%), global developmental delay (10%), delayed speech and language (10%) and seizures (10%), as well as other less common clinical manifestations including microcephaly (5–10%), muscular hypotonia (5–10%) and clinodactyly or shortness of the fifth finger (5%) ( 10–20 ), and ( Supplementary Material, Table 1 ). Whether the Xp22.31 duplication is pathogenic (particularly with regard to its role in brain function and head/facial dysmorphism), or whether it is benign but tends to occur in combination with other pathogenic mechanisms, has been a matter for debate ( 21–23 ).…”