47,XYY Syndrome: Clinical Phenotype and Timing of Ascertainment

Abstract

Objective To describe auxologic, physical, and behavioral features in a large cohort of males with 47,XYY (XYY), ages newborn to young adult. Study design This is a cross-sectional descriptive study of male subjects with XYY who were evaluated at 1 of 2 specialized academic sites. Subjects underwent a history, physical examination, laboratory testing, and cognitive/behavioral evaluation. Results In 90 males with XYY (mean age 9.6 ± 5.3 years [range 0.5-36.5]), mean height SD was above average (1.0 ± 1.2 SD). Macrocephaly (head circumference >2 SD) was noted in 28/84 (33%), hypotonia in 57/90 (63%), clinodactyly in 47/90 (52%), and hypertelorism in 53/90 (59%). There was testicular enlargement for age (>2 SD) in 41/82 (50%), but no increase in genital anomalies. No physical phenotypic differences were seen in boys diagnosed prenatally vs postnatally. Testosterone, luteinizing hormone, and follicle stimulating hormone levels were in the normal range in most boys. There was an increased incidence of asthma, seizures, tremor, and autistic spectrum disorder (ASD) compared with the general population rates. Prenatally diagnosed boys scored significantly better on cognitive testing and were less likely to be diagnosed with ASD (P < .01). Conclusions The XYY phenotype commonly includes tall stature, macrocephaly, macroorchidism, hypotonia, hypertelorism, and tremor. Physical phenotypic features were similar in boys diagnosed prenatally vs postnatally. Prenatal diagnosis was associated with higher cognitive function and less likelihood of an ASD diagnosis.

Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics

“…microcephaly and pontocerebellar hypoplasia). Likewise individual BA2492 has a constellation of symptoms (sleep disturbance, DD, cognitive impairment, brachydactyly) compatible with only the most severe 47,XYY sex chromosome aneuploidy cases [76]. Consistent with the hypothesis of expanded phenotypes, the phenotypic variability of White-Sutton syndrome associated with variants in POGZ keeps extending with clinical features including ASD, DD, ID, schizophrenia, and microcephaly [57, 71, 77–83].…”

A non-mosaic isodicentric Y chromosome resulting from breakage and fusion at the Yq pseudo-autosomal region in a fetus

“…This case actually represents a unique type of 47, XYY. The phenotypes of 47,XYY individuals commonly include tall stature, macrocephaly, macroorchidism, hypotonia, hypertelorism, and tremor, but they are usually presented with normal fertility [16]. Significant raised mortality has been observed for disease of various organ systems (nervous system, circulatory system, respiratory system, genitourinary system, and congenital anomalies) in men with an extra Y chromosome.…”

Behavioral phenotypes in males with XYY and possible role of increased NLGN4Y expression in autism features

“…The male sex chromosome aneuploidy disorder 47,XYY (XYY syndrome) is associated with an increased risk for neurodevelopmental phenotypes, including developmental delays, attention‐deficit hyperactivity disorder (ADHD), learning disabilities, social‐emotional difficulties and autism spectrum disorders (ASDs) (Bardsley et al ; Bishop & Scerif ; Cordeiro et al ; Geerts et al ; Margari et al ; Robinson et al ; Ross et al , ; Tartaglia et al ). Additional neurocognitive phenotypes in XYY include increased difficulties with language and an increased frequency of seizure disorders (present in 13%) (Bardsley et al ). Consecutive newborn screening series show that XYY occurs in 1 in 1000 males, but it is diagnosed much less frequently, most likely because associated features such as tall stature or developmental delays are not distinctive (Robinson et al ).…”