Lujan syndrome and FG syndrome are among the XLMR syndromes that have posed the greatest diagnostic challenges for clinicians.9,14,15,16,17,18
Individuals with Lujan syndrome have tall stature with asthenic build, macrocephaly, a tall narrow face, maxillary hypoplasia, a high narrow palate with dental crowding, a small or receding chin, long hands with hyperextensible digits, hypernasal speech, hypotonia, mild‐to‐moderate mental retardation, behavioural abnormalities (hyperactivity, emotional lability, shyness, aggressiveness, autistic mannerisms and/or psychoses) and agenesis/dysgenesis of the corpus callosum. In FG syndrome, the major findings are agenesis of the corpus callosum, relative macrocephaly, facial dysmorphism (frontal hair upsweep, a high prominent forehead, hypertelorism, downslanting palpebrae, small cupped ears, a thin upper lip and a full lower lip), short hands with broad thumbs, broad big toes, anal anomalies/constipation, hypotonia, variable mental retardation and behavioural disturbances. Anal anomalies or constipation, which occur commonly in FG syndrome, have not been reported in Lujan syndrome. Tall stature, long hands and fingers, and hypernasal speech are to be expected in Lujan syndrome, but are absent or less notable in FG syndrome.
Certain findings—macrocephaly/relative macrocephaly, tall forehead, tall narrow palate with dental crowding, hypotonia, mental retardation, behavioural disturbances and dysgenesis of the corpus callosum—are shared by both syndromes (table 2). Apart from these similarities, neither of the syndromes has been considered in the differential diagnosis of the other.19,20
None of the somatic findings is obligatory in either syndrome and some seem to be common among people with mental retardation.
Fryns and van den Berghe16
have commented that the muscle hypotrophy, hypotonia, developmental delay and shyness were more notable in individuals with Lujan syndrome before puberty, whereas the Marfanoid habitus, more specifically the excess of span over height, became obvious only after puberty. Unfortunately, we do not have span measurements at various ages in the original family (K8295) to support this observation. Span centiles were less than height centiles in all the three adult males in whom measurements were available (table 1). In K9359, measurements during the teenage years showed that the span exceeded the height by only 1 cm in the two affected brothers.
A spectrum of behavioural disturbances, ranging from shyness to frank psychosis, has been noted among individuals with Lujan syndrome.15,16,21
Some individuals, however, seem to be friendly, jovial and outgoing, without overt signs of behavioural disturbances.22
In K8295, emotional lability, excessive talkativeness, attention seeking and anxiety were evident in two individuals (IV‐12, V‐9), whereas two others were more passive and cooperative, at least in adult life. In K9359, the males were hyperactive and prone to outbursts of aggression and tantrums.
The occurrence of mental retardation of apparently unrelated cause in the original family with Lujan syndrome reported here may be unsettling. Yet, the prevalence of mental retardation among males in the population (~3%) makes it probable that at least 1 out of 30 kindreds with XLMR will contain a minimum of one male with mental retardation of a different cause than other affected males in the kindred. An additional ascertainment bias may be seen among kindreds with multiple males with mental retardation.
The highly conserved MED12 protein, also known as HOPA and TRAP230, is the largest component of the mediator complex, which has an essential role in regulating RNA polymerase II activity.23,24
The mediator complex contains a large number of subunits, some core elements and others like MED12, that serve as transcriptional facilitators for specific pathways. A number of studies highlight the importance of MED12 in model organisms where it seems to be essential for normal development.25,26,27
Other studies have also implicated MED12 in specific developmental pathways. Boyer and colleagues have reported two specific findings that link MED12 to the Wnt/B‐catenin pathway and to the sonic hedgehog pathway through direct interaction with Gli3.28,29
Another report by Lehner et al30
has also featured MED12 (dpy‐22
in Caenorhabditis elegans
) as a highly connected “hub” gene with the potential to enhance phenotypic consequences of many different forms of genetic variation. The current data, along with other substantial functional studies, suggest that MED12 and the entire mediator complex are involved in a broad range of developmental processes.
The p.N1007S alteration found in Lujan syndrome seems to significantly affect predicted protein folding domains within the MED12 protein. The presence of a serine at position 1007 removes a coiled region while also reducing the length of a β‐pleated sheet based on Protean analysis (DNA Star package, Lasergene, Madison, Wisconsin, USA). Additionally, PolyPhen (http://tux.embl‐heidelberg.de/ramensky/
) analysis predicts the p.N1007S substitution to be possibly deleterious.
The evidence that Lujan syndrome is caused by the p.N1007S alteration in MED12 rests with (1) identification of the alteration in the original family with Lujan syndrome, (2) identification of the same alteration in a second family with compatible clinical findings, (3) an earlier report of another missense variant in MED12 in FG syndrome, an XLMR syndrome with clinical findings overlapping those of Lujan syndrome, (4) absence of the missense variation in over 1400 control X chromosomes, and (5) computer protein modelling, which indicates that the alteration is probably pathogenic.
- A novel missense mutation (p.N1007S) in the MED12 gene is present in the original family with Lujan syndrome and in a second family with compatible findings.
- Lujan syndrome is thus allelic to Opitz–Kaveggia (FG) syndrome, another X‐linked mental retardation syndrome previously found to have mutations in the MED12 gene.
- Lujan syndrome and FG syndrome share certain clinical findings (dysgenesis of the corpus callosum, macrocephaly, a tall forehead, a high palate, hypotonia, mental retardation and behavioural disturbances). Anal anomalies/constipation are common in FG syndrome, and tall stature, long hands and fingers, and hypernasal speech are common in families with Lujan syndrome.
A certain deference should be accorded kindred 8295, which is the prototype for Lujan syndrome.9
Only those kindreds/cases with a compatible clinical phenotype and mutations in the MED12
gene should retain the diagnosis of Lujan syndrome. Consideration should be given to reclassification for those kindreds/cases reported subsequent to K8295 that do not have mutations in the MED12
gene. With this approach, the phenotypic boundaries of Lujan syndrome (ie, those cases with mutations in the MED12
gene) may be determined.