Renpenning Syndrome 1

A number sign (#) is used with this entry because Renpenning syndrome is caused by mutation in the PQBP1 gene (300463) on chromosome Xp11.

Description

Renpenning syndrome is an X-linked mental retardation syndrome with clinically recognizable features. Affected individuals have microcephaly, short stature, small testes, and dysmorphic facies, including tall narrow face, upslanting palpebral fissures, abnormal nasal configuration, cupped ears, and short philtrum. The nose may appear long or bulbous, with overhanging columella. Less consistent manifestations include ocular colobomas, cardiac malformations, cleft palate, and anal anomalies. Stevenson et al. (2005) proposed that the various X-linked mental retardation syndromes due to PQBP1 mutations be combined under the name of Renpenning syndrome.

Clinical Features

Renpenning et al. (1962) reported a Dutch Mennonite pedigree from Alberta and Saskatchewan in which X-linked mental retardation was associated with short stature, moderate microcephaly, unremarkable facies, and no other neurologic abnormalities. This pedigree was reexamined by Fox et al. (1980) who found a mean IQ of 30, with one man having an IQ of 70. None of the affected males in this pedigree had the marXq28 (Fox et al., 1980; Jacobs et al., 1980).

Martinez-Garay et al. (2007) described 2 male cousins, aged 29 years and 4 years, respectively, who had right microphthalmia and left choroid coloboma, microcephaly, mental retardation, and spastic diplegia; the older cousin also displayed camptodactyly and arachnodactyly, whereas the younger cousin had seizures and a hypoplastic and malpositioned left kidney. The older cousin had a long narrow face, large anteverted ears, bulbous nose, maxillary hypoplasia, and prognathism; the younger cousin had large, low-set, simple protruding ears and a bulbous nose, but a rounded face, with micrognathia, long philtrum, and prominent metopic suture.

Sutherland et al. (1987, 1988) described a family in which 7 males had a syndrome of mental retardation, short stature, microcephaly, brachycephaly, spastic diplegia, small testes, and possibly intrauterine growth retardation; an eighth male was possibly affected. Obligate carriers were normal. Sutherland et al. (1988) felt certain that this was not the Juberg-Marsidi syndrome (309580) and called the disorder MRX2.

Hamel et al. (1994) reported a family in which 2 brothers and their 2 maternal uncles had a syndromic form of X-linked severe mental retardation. Other features included short stature, severe congenital heart defects, and craniofacial abnormalities consisting of cleft or highly arched palate, microcephaly, abnormal ears, bulbous nose, broad nasal bridge, malar hypoplasia, small mouth, and micrognathia. Spasticity was also present. Three of the 4 patients died at an early age.

Deqaqi et al. (1998) reported a family with a nonspecific X-linked mental retardation, which they termed MRX55.

Stevenson et al. (1998) conducted clinical and molecular studies on the Mennonite family with X-linked mental retardation reported by Renpenning et al. (1962). The clinical phenotype included severe mental retardation, microcephaly, up-slanting palpebral fissures, small testes, and stature shorter than that of unaffected males. Major malformations, neuromuscular abnormalities, and behavioral disturbances were not seen. Longevity was not impaired. Carrier females showed no heterozygote manifestations. Stevenson et al. (1998) pointed out that Renpenning syndrome has been referred to as MRXS8. They noted that the phenotypic features were similar to those of several other X-linked mental retardation syndromes.

Fichera et al. (2002) reported a family in which 5 males were affected with an X-linked mental retardation syndrome similar to Sutherland-Haan syndrome. Affected males showed mild mental retardation, microcephaly, hyperreflexia or spastic diplegia, and a similar facial appearance, including a triangular face, prognathism, and open mandibular angle.

Kalscheuer et al. (2003) reported 2 affected families. One had a similar phenotype as the family described by Sutherland et al. (1988), but did not have spastic paraplegia or small testes. Another family had mental retardation, microcephaly, anal atresia, and complete situs inversus.

Kleefstra et al. (2004) reported detailed clinical features of the families reported by Kalscheuer et al. (2003) and a family reported by Hamel et al. (1994). Affected patients had a characteristic phenotype, including microcephaly, lean body habitus, short stature, long and narrow facies, malar hypoplasia, and high-arched palate. Other features, such as anal atresia, small testes, and iris coloboma, were variable. Some obligate female carriers had decreased head circumference without impaired intelligence, and one had an atrial septal defect, indicating that heterozygotes may have some mild disease manifestations.

Germanaud et al. (2011) reviewed the features of 13 French patients with Renpenning syndrome from 7 unrelated families. All patients had mental retardation varying from mild to moderate severity, microcephaly, leanness, and mild short stature. Most had language delay, several had autistic features, and many had anxiety manifest as fear of separation, panic attacks, or phobias. There were specific facial dysmorphic features, including long triangular face, large ridged nose, half-depilated eyebrows, dysplastic or protruding ears, and rough slightly sparse hair. An aged appearance was noticed in older patients. Novel features included progressive muscular atrophy affecting the upper back, metacarpophalangeal ankylosis of the thumb, and velar dysfunction, resulting in nasal voice and perhaps contributing to poor feeding and failure to thrive in infancy.

Mapping

In a family with mental retardation, microcephaly, and spastic diplegia, Sutherland et al. (1988) found a suggestion of linkage of the disorder near the centromere of the X chromosome (maximum lod score = 2.10 at theta = 0.11 for DXYS1).

In a family with mental retardation and multiple congenital anomalies, Hamel et al. (1994) narrowed the locus for the responsible gene to the pericentromeric region Xp21.3-q21.3. Deqaqi et al. (1998) reported linkage of MRX55 to a 34-cM region of Xp11.

In the Mennonite family with mental retardation originally reported by Renpenning et al. (1962), Stevenson et al. (1998) mapped the RENS1 locus to Xp11.4-p11.2, with a maximum lod score of 3.21 (at theta = 0.0) between DXS1039 and DXS1068.

In a family with an X-linked mental retardation syndrome similar to the syndrome reported by Sutherland et al. (1988), Fichera et al. (2002) mapped the disorder to a 29-cM region at Xp11.2-q12.

Genetic Heterogeneity

Cui et al. (2004) reported a large 3-generation Chinese family with X-linked mental retardation, short stature, and microcephaly, resembling Renpenning syndrome. Linkage analysis identified a suggestive locus on chromosome Xq21-qter (maximum 2-point lod score of 1.81 at DXS6789 and GATA165B12).

Molecular Genetics

In 5 of 29 families with X-linked mental retardation, Kalscheuer et al. (2003) identified mutations in the PQBP1 gene (300463.0001-300463.0003). The family reported by Sutherland et al. (1988) and a family with a similar phenotype, but without spasticity or small testes, had the same 2-bp insertion (300463.0001). In the family with MRX55 reported by Deqaqi et al. (1998) and in a family with mental retardation, anal atresia, and situs inversus, Kalscheuer et al. (2003) identified a 4-bp deletion in the PQBP1 gene (300463.0002). Finally, in the family reported by Hamel et al. (1994), a 2-bp deletion was identified (300463.0003). Kalscheuer et al. (2003) noted the clinical variability in this group of patients, even in those with the same mutation, and suggested that the differences may be due to genetic background.

In the family with mental retardation originally reported by Renpenning et al. (1962), Lenski et al. (2004) identified a 1-bp insertion (300463.0004) in the PQBP1 gene.

Stevenson et al. (2005) described affected members of a family (K8600) with Renpenning syndrome who had the same 4-bp deletion (300463.0002) in the PQBP1 gene that was identified by Kalscheuer et al. (2003). In affected members and obligate carriers of a family with MRXS3, previously described by Fichera et al. (2002), Fichera et al. (2005) identified the same 4-bp deletion. The authors observed skewed X inactivation in 8 of 9 heterozygous females in this family; the inactivated X chromosome was of maternal origin.

Lubs et al. (2006) identified a mutation in the PQBP1 gene (Y65C; 300463.0007) in affected members of a family with an X-linked mental retardation syndrome originally described by Golabi et al. (1984) under the moniker 'Golabi-Ito-Hall syndrome.' Features included microcephaly, postnatal growth deficiency, and other anomalies, such as atrial septal defect, all of which are also found in the Renpenning type of X-linked mental retardation. Although Golabi-Ito-Hall syndrome is thus considered within the Renpenning spectrum (Stevenson et al., 2005), Lubs et al. (2006) did note 2 clinical differences between Golabi-Ito-Hall syndrome and other PQBP1-related disorders: growth appeared to be more severely restricted, most notably head circumference and length, and small testes were not observed in patients from the original report of Golabi et al. (1984).

In 2 half brothers and 3 unrelated boys with X-linked mental retardation associated with variable clinical features such as microcephaly, short stature, and hyperactivity, Cossee et al. (2006) identified deletions in the PQBP1 gene (300463.0005 and 300463.0006, respectively).

In 2 male cousins with microphthalmia, microcephaly, mental retardation, renal hypoplasia, and spastic paraplegia, initially thought to represent Lenz microphthalmia syndrome (MCOPS1; 309800), Martinez-Garay et al. (2007) found no mutations in the BCOR gene (300485) but identified the 2-bp deletion (300463.0003) in the PQBP1 gene previously reported by Kalscheuer et al. (2003). Noting the substantial phenotypic overlap of the 2 affected males in this family with the previously described patients with PQBP1 mutations, Martinez-Garay et al. (2007) concluded that these allelic X-linked mental retardation syndromes should be combined under the name Renpenning syndrome.

Animal Model

Ito et al. (2009) generated Pqbp1-knockdown mice using a transgene expressing double-strand RNA that is endogenously cleaved to an siRNA, which inhibited 50% of Pqbp1 expression. Pqbp1-knockdown mice possessed normal ability in ordinary memory tests including water-maze test, whereas they showed abnormal anxiety-related behavior in light/dark exploration test and open-field test, and showed obvious declines of anxiety-related cognition in the repetitive elevated plus maze or novel object recognition test. C-fos upregulation and histone H3 acetylation after behavior tests were decreased in neurons of amygdala, prefrontal cortex, and hippocampus. Administration of 4-phenylbutyric acid (PBA), an HDAC inhibitor, efficiently improved expression of these genes and rescued the abnormal phenotypes in adult Pqbp1-knockdown mice. Ito et al. (2009) suggested that Pqbp1 dysfunction in regulating gene expression may underlie the abnormal behavior and cognition of Pqbp1-knockdown mice and that recovery of expression of such PQBP1 target genes might improve the symptoms in adult patients with Renpenning syndrome and PQBP1-linked mental retardation.

History

Another pedigree (Dunn et al., 1963) reported by Renpenning (who was a medical student at the initiation of his work--see Gerrard and Renpenning, 1974) was phenotypically different from the first pedigree reported by Renpenning et al. (1962) and was found to be typically affected by marXq28 (309550) (Fox et al., 1980).