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The NR5A1 gene encodes for steroidogenic factor 1, a nuclear receptor that regulates proper adrenal and gonadal development and function. Mutations identified by NR5A1 sequencing have been associated with disorders of sex development (DSD), ranging from sex reversal to severe hypospadias in 46,XY patients and premature ovarian failure (POF) in 46,XX patients. Previous reports have identified four families with a history of both 46,XY DSD and 46,XX POF carrying segregating NR5A1 sequence mutations. Recently, three 46,XY DSD sporadic cases with NR5A1 microdeletions have been reported. Here, we identify the first NR5A1 microdeletion transmitted in a pedigree with both 46,XY DSD and 46,XX POF. A 46,XY individual with DSD due to gonadal dysgenesis was born to a young mother who developed POF. Array CGH analysis revealed a maternally inherited 0.23 Mb microdeletion of chromosome 9q33.3, including the NR5A1 gene. Based on this finding, we screened patients with unexplained 46,XY DSD (n = 11), proximal hypospadias (n = 21) and 46,XX POF (n = 36) for possible NR5A1 copy-number variations (CNVs) via multiplex ligation-dependent probe amplification (MLPA), but did not identify any additional CNVs involving NR5A1. These data suggest that NR5A1 CNVs are an infrequent cause of these disorders but that array CGH and MLPA are useful genomic screening tools to uncover the genetic basis of such unexplained cases. This case is the first report of a familial NR5A1 CNV transmitting in a pedigree, causing both the male and female phenotypes associated with NR5A1 mutations, and the first report of a NR5A1 CNV associated with POF., (Copyright © 2013 Wiley Periodicals, Inc.)

We describe three patients with a comparable deletion encompassing SLC25A43, SLC25A5, CXorf56, UBE2A, NKRF, and two non-coding RNA genes, U1 and LOC100303728. Moderate to severe intellectual disability (ID), psychomotor retardation, severely impaired/absent speech, seizures, and urogenital anomalies were present in all three patients. Facial dysmorphisms include ocular hypertelorism, synophrys, and a depressed nasal bridge. These clinical features overlap with those described in two patients from a family with a similar deletion at Xq24 that also includes UBE2A, and in several patients of Brazilian and Polish families with point mutations in UBE2A. Notably, all five patients with an Xq24 deletion have ventricular septal defects that are not present in patients with a point mutation, which might be attributed to the deletion of SLC25A5. Taken together, the UBE2A deficiency syndrome in male patients with a mutation in or a deletion of UBE2A is characterized by ID, absent speech, seizures, urogenital anomalies, frequently including a small penis, and skin abnormalities, which include generalized hirsutism, low posterior hairline, myxedematous appearance, widely spaced nipples, and hair whorls. Facial dysmorphisms include a wide face, a depressed nasal bridge, a large mouth with downturned corners, thin vermilion, and a short, broad neck., (© 2010 Wiley-Liss, Inc.)

The goal of this study was to expand the description of the cognitive development phenotype in boys with Klinefelter syndrome (47,XXY). We tested neuropsychological measures of memory, attention, visual-spatial abilities, visual-motor skills, and language. We examined the influence of age, handedness, genetic aspects (parental origin of the extra X chromosome, CAG(n) repeat length, and pattern of X inactivation), and previous testosterone treatment on cognition. We studied 50 boys with KS (4.1-17.8 years). There was a significant increase in left-handedness (P = 0.002). Specific language, academic, attentional, and motor abilities tended to be impaired. In the language domain, there was relative sparing of vocabulary and meaningful language understanding abilities but impairment of higher level linguistic competence. KS boys demonstrated an array of motor difficulties, especially in strength and running speed. Deficits in the ability to sustain attention without impulsivity were present in the younger boys. Neither genetic factors examined nor previous testosterone treatment accounted for variation in the cognitive phenotype in KS. The cognitive results from this large KS cohort may be related to atypical brain lateralization and have important diagnostic and psychoeducational implications. The difficulty in complex language processing, impaired attention and motor function in boys with KS may be missed. It is critical that boys with KS are provided with appropriate educational support that targets their learning challenges in school in addition to modifications that address their particular learning style. These findings would also be an important component of counseling clinicians and families about this disorder., ((c) 2008 Wiley-Liss, Inc.)

We present the clinical and molecular characteristics of a multi-generation family in which the proband presented with clinical features of Langer mesomelic dysplasia (LMD) whilst different family members had a diagnosis of Léri-Weill dyschondrosteosis (LWD) and/or pseudoachondroplasia (PSACH). In the LMD proband two different deletions were identified in the pseudoautosomal 1 region (PAR1) of the X and Y chromosomes: a SHOX-encompassing deletion inherited from his father and a downstream PAR1 deletion, which did not include SHOX, inherited from his mother. The individuals with PSACH features presented the previously described G719D mutation in the C-terminal globular domain of the cartilage oligomeric matrix protein gene (COMP). The LMD proband described here represents the first LMD case due to compound heterozygosity for deletions of the two different PAR1 regions, SHOX-encompassing and downstream from SHOX, that have been shown to be implicated in the pathogenesis of LWD and LMD.

We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had achondroplasia and the other had hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and hypochondroplasia to a N540K mutation in the same gene. The patient with hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with achondroplasia. The phenotypes of combined LWD and achondroplasia or hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development., (Copyright 2002 Wiley-Liss, Inc.)