Pseudoautosomal inheritance of Léri-Weill syndrome: what does it mean?

Mammalian male meiosis requires homologous recombination between the X and Y chromosomes. In humans, such recombination occurs exclusively in the short arm pseudoautosomal region (PAR1) of 2.699 Mb in size. Although it is known that complete deletion of PAR1 causes spermatogenic arrest, no studies have addressed to what extent male meiosis tolerates PAR1 size reduction. Here, we report two families in which PAR1 partial deletions were transmitted from fathers to their offspring. Cytogenetic analyses revealed that a ∼400-kb segment at the centromeric end of PAR1, which accounts for only 14.8% of normal PAR1 and 0.26% and 0.68% of the X and Y chromosomes, respectively, is sufficient to mediate sex chromosomal recombination during spermatogenesis. These results highlight the extreme recombinogenic activity of human PAR1. Our data, in conjunction with previous findings from animal studies, indicate that the minimal size requirement of mammalian PARs to maintain male fertility is fairly small.

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“…1992 ), 2) the estimated genetic size of PAR1 in normal males is ∼50 cM ( Flaquer et al. 2009 ; Evers et al. 2011 ; Otto et al.…”

Section: Resultscontrasting

confidence: 61%

Human Spermatogenesis Tolerates Massive Size Reduction of the Pseudoautosomal Region

Fukami

Fujisawa

Ono

et al. 2020

Genome Biology and Evolution

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“…However, most reports discussed recombination events in the PAR1 in the context of a Y-located SHOX deletion transmitted from father to daughter or included pedigrees that did not differentiate between Y- and X- chromosomal SHOX mutations [5-8]. Indeed, to our knowledge, the transfer of an originally X-located SHOX deletion to the Y chromosome after transmission from father to son has only been documented by FISH in two patients in the literature to date, and not in an apparently phenotypically normal male child [9,10].…”

Section: Case Presentationmentioning

confidence: 99%

Rare inheritance of Leri-Weill Syndrome due to crossover of short stature Homeobox Gene (SHOX) Deletions between X and Y Chromosomes: a case report

Censani

Anyane‐Yeboa

Wapner

et al. 2013

Int J Pediatr Endocrinol

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BackgroundLeri-Weill syndrome (LWS) is a genetic disorder caused by deletions or mutations in the SHOX gene or by deletions downstream of the gene and is classically characterized by short stature, mesomelic shortening of forearms and legs, and Madelung deformity. Correct identification of short stature homeobox-containing gene (SHOX) deficiency in children with growth problems is vital for appropriate initiation of growth hormone therapy.MethodWe report a phenotypically normal 23 day old male infant born to a father diagnosed with Leri-Weill syndrome at age 12 years with a documented SHOX deletion on his X chromosome. The patient’s fetal long bones had been found to be about three weeks delayed in growth on prenatal ultrasound during the second trimester.ResultsThe infant underwent genetic evaluation at 23 days of life and was found to have a SHOX deletion on Yp11.32 identified using single nucleotide polymorphism microarray (SNP) analysis and confirmed by FISH using a SHOX gene probe.ConclusionWe report the case of a male infant diagnosed with Leri-Weill syndrome with an unusual documented inheritance between father and son due to crossover between X and Y chromosomes during paternal meiosis. Our case is the youngest patient in literature documented by FISH analysis to have an X to Y chromosome transfer and the first of these patients diagnosed prior to onset of short stature or Madelung deformity. Our patient was identified prior to growth failure and can now be monitored for growth abnormalities with the ability to implement growth augmentation therapy without delay. Our case highlights the importance of advising affected SHOX patients of risks to future offspring and supports screening off-spring of parents carrying SHOX abnormalities regardless of sex.

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“…Recent studies have shown that deletions in the downstream enhancer region of SHOX, and (less frequently) in the upstream enhancer region (SHOX enhancer deletions (SEDs)), can result in a clinical picture similar to that of SHI (5,6,7,8,9,10). In about two-thirds of cases LWD is caused by intragenic point mutations or deletions of the complete coding sequence of SHOX, and in one-third of cases by deletions in the enhancer sequences in the 3 0 -or 5 0 -flanking region of SHOX, leaving the gene itself intact (11).…”

Section: Introductionmentioning

confidence: 99%

The growth response to GH treatment is greater in patients with SHOX enhancer deletions compared to SHOX defects

Donze¹,

Meijer²,

Kant³

et al. 2015

European Journal of Endocrinology

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Objective: Short stature caused by point mutations or deletions of the short stature homeobox (SHOX) gene (SHOX haploinsufficiency (SHI)) is a registered indication for GH treatment. Patients with a SHOX enhancer deletion (SED) have a similar phenotype, but their response to GH is unknown. It is uncertain if duplications of SHOX or its enhancer (SDUP) cause short stature. This study aimed to describe the clinical characteristics and growth response to GH treatment in patients with aberrations of SHOX and its enhancers. Design: In this retrospective multi-center study (2002( -March 2014 clinical information was available from 130 patients (72 SHI, 44 SED, and 14 SDUP) of whom 52 patients were treated with GH. We evaluated height, sitting height (SH), arm span, dysmorphic features and indicators of the growth response to GH (delta height SDS, height velocity, and index of responsiveness). Results: Patients with SEDs showed similar HtSDS to patients with SHI (K2.3 and K2.6, respectively, PZ0.2), but they were less disproportionate (SH/height ratio SDS 2.0 vs 3.1 (P!0.01) and extremities/trunk ratio 2.57 vs 2.43 (PZ0.03)). The 1st year growth response to GH treatment was significantly greater in prepubertal patients with SEDs than SHI. None of the patients with an SDUP was disproportionate and SDUP cosegregated poorly with short stature; their growth response to GH treatment (nZ3) was similar to the other groups. Conclusions: Patients with SEDs are equally short, but less disproportionate than patients with SHI, and show a greater response to GH.

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Pseudoautosomal inheritance of Léri-Weill syndrome: what does it mean?

Cited by 10 publications

References 26 publications

Human Spermatogenesis Tolerates Massive Size Reduction of the Pseudoautosomal Region

Human Spermatogenesis Tolerates Massive Size Reduction of the Pseudoautosomal Region

Rare inheritance of Leri-Weill Syndrome due to crossover of short stature Homeobox Gene (SHOX) Deletions between X and Y Chromosomes: a case report

The growth response to GH treatment is greater in patients with SHOX enhancer deletions compared to SHOX defects

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