Nance-Horan syndrome (NHS) is a rare X-linked condition comprising congenital cataract with microcornea, distinctive dental, and evocative facial anomalies. Intellectual handicap was mentioned in seven published NHS patients. We performed a clinical study focused on psychomotor development, intellectual abilities, and behavior in 13 affected males in four NHS families, and present the results of a neuropsychological evaluation in 7 of them. Our study confirms that mental retardation (MR) can be a major component of the NHS. Combining our data with those from the literature leads to a frequency of MR in NHS of around 30%. In most cases, MR is mild or moderate (80%) and not associated with motor delay. Conversely, a profound mental handicap associated with autistic traits may be observed. MR has intra- and inter-familial variability but does not appear to be expressed in carriers. Awareness of MR in NHS may be of importance in the management of the patients, especially in terms of education. Cloning and characterization of the gene and analysis of mutations will be an important step towards understanding the molecular basis of mental deficiency in NHS, and in delineation from the other XLMR conditions at Xp22.

Linkage analysis was performed in a family with non‐specific X‐linked mental retardation (MRX 15). Hypotonia in infancy was the most remarkable physical manifestation. The severity of mental deficiency was variable among the patients, but all of them had poor or absent speech. Significant lod scores at a recombination fraction of zero were detected with the marker loci DXS1126, DXS255, and DXS573 (Zmax = 2.01) and recombination was observed with the two flanking loci DXS164 (Xp21.1) and DXS988 (Xp11.22), identifying a 17 cM interval. This result suggests a new gene localization in the proximal Xp region. In numerous families with non‐specific X‐linked mental retardation (MRX), the corresponding gene has been localized to the paracentromeric region in which a low recombination rate impairs the precision of mapping. © 1996 Wiley‐Liss, Inc.

X-linked mental retardation (XLMR) includes distinct entities in which mental deficiency is either associated with specific abnormalities (syndromal) or not (nonsyndromal). We report on the clinical, neuropsychological, and laboratory findings and linkage analysis in one family with XLMR and isolated growth hormone deficiency (IGHD). Mental retardation was associated in 3 males and 5 females with short stature, microcephaly, and particular facial traits, i.e., high curved forehead, midface hypoplasia, and concave nasal bridge with nasal end of normal size and broad traits. Significant lod scores (Zmax >2) at a recombination fraction of theta = 0 were detected for 6 marker loci between DXS178 (Xq22.1) and DXS292 (Xq27.2). This mapping region overlaps that of XLMR with IGHD, recently reported by Hamel et al. [1996: Am J Med Genet 64:35-41] (Xq24-q27.3), and that of agammaglobulinemia with IGHD (Xq21.33-q22.2). This observation may confirm the suspicion of a gene involved in growth hormone regulation being localized in Xq.

The TM4SF2 gene (localized at Xp11.4 between the loci DXS564 and DXS556) has been found to be mutated in one MRX family. In order to define the corresponding behavioral phenotype, global IQ and specific cognitive skills were assessed in seven males and three females of this family, independent of subject status. Mental retardation (MR) was mild in three patients and moderate in three others. Despite the broad variability of severity of MR, a cognitive profile specific to the MR in this family was documented. It was characterized by language disorder that was more marked in the articulatory component and spatial/verbal short-term memory dissociation with larger mnemonic span for spatial than for verbal cues. Linkage analysis was then performed on the basis of the cognitively determined status. Recombinations were observed with the loci DXS556 at Xp11.4 and DXS441 at Xq13.2 (maximum LOD score = 2.23 at theta = 0 for ALAS2). This localization region does not include the TM4SF2 gene that has been found mutated in both patients with MR and in one non-MR male subject of this family. The present results suggest two main hypotheses. First, TM4SF2 gene mutation could be involved in MR in this family, therefore representing accentuated intra familial phenotypic variability. Second, the structural particularity detected in the TM4SF2 gene might reflect a rare polymorphism rather than a pathogenic mutation, with the gene responsible for MR in this family being therefore more likely to be searched for in the pericentromeric region of the X chromosome.