Lujan et al. (1984) described 4 mentally retarded males in a large kindred with marfanoid habitus and similar craniofacial changes: long, narrow face, small mandible, high-arched palate, and hypernasal voice. Fryns and Buttiens (1987) described 2 pairs of ... Lujan et al. (1984) described 4 mentally retarded males in a large kindred with marfanoid habitus and similar craniofacial changes: long, narrow face, small mandible, high-arched palate, and hypernasal voice. Fryns and Buttiens (1987) described 2 pairs of mildly to moderately mentally retarded brothers with these same features. Lalatta et al. (1991) reported 4 sporadic cases and suggested that psychotic behavior may be a manifestation. Fryns (1991) gave a brief report of 2 affected brothers and 2 sporadic males with this disorder, varying in age from 14 to 24 years. All were referred to the genetics clinic with the diagnosis of Marfan syndrome (154700). Gurrieri and Neri (1991) observed the syndrome in brother and sister. They thought that the affected sister was a manifesting heterozygote. They suggested that the Lujan-Fryns syndrome is an X-linked dominant condition with higher penetrance and greater expressivity in males. Rivera et al. (1992) reported a case, raising to 19 (18M:1F) the total reported. Rivera et al. (1992) stated that 7 of the 19 cases were isolated (i.e., nonfamilial). Fryns (1993) found 18 cases of this disorder among 682 cases of syndromic mental retardation; the fragile X syndrome (300624), the Aarskog syndrome (305400), and the Coffin-Lowry syndrome (303600) represented 560, 60, and 20 cases, respectively. Leroy et al. (1993) reviewed the disorder in 8 young adults, including 2 pairs of brothers and 1 set of 3 sibs. Lacombe et al. (1993) reported 3 additional cases with useful photographs. Wittine et al. (1999) reported a male patient and his maternal uncle, both of whom had features consistent with the diagnosis of Lujan-Fryns syndrome. Both patients also had a ventricular septal defect and aortic root dilation, neither of which had been described previously in Lujan-Fryns syndrome. The authors suggested that the similarity of Lujan-Fryns syndrome to Marfan syndrome and the presence of aortic root dilation in their patients may implicate a mutation in a structural connective tissue gene in the etiology of this condition. Williams (2006) provided a detailed neuropsychologic evaluation of the patient reported by Wittine et al. (1999). His speech and language development was delayed by 1 year at age 3 years. He subsequently had severe learning disabilities and trouble with short-term memory despite normal IQ measurements. He had attention-deficit hyperactivity disorder (ADHD; see 143465), oppositional defiant disorder, poor impulse control, obsessive compulsive disorder (see 164230), and low frustration tolerance. He was shy and seldom socialized with peers. Williams (2006) emphasized that the patient would not be classified as having mental retardation because of his normal IQ, although he had severe social and cognitive impairment. Williams (2006) noted that the patient was exposed to prenatal alcohol, but did not have physical characteristics of fetal alcohol syndrome. Stathopulu et al. (2003) described a 16-year-old male with phenotypic features of Lujan-Fryns syndrome and terminal deletion of chromosome 5p. He had the behavior of an autistic spectrum disorder. Symmetrical intrauterine growth retardation was evident upon delivery at 37 weeks' gestation. In the early neonatal period he had a 'shrill, cat-like cry' and micrognathia, resulting in feeding difficulties severe enough to require tube feeding. He had hypotonia during the first year and significant feeding difficulties. At the age of 16 years he was tall (height in the 75th centile) and slim (weight in the 50th centile). He had a very nasal voice which the authors thought was different from the voice of teenagers with velopharyngeal incompetence. The uvula and soft palate did not reach the back wall of the pharynx during speech, suggesting the presence of a submucous cleft palate, which was treated by surgical pharynoplasty. Lerma-Carrillo et al. (2006) reported a 23-year-old man with Lujan-Fryns syndrome admitted to a psychiatric hospital by judicial order for behavioral misconduct and aggressive behavior, including pyromania. He had a marfanoid habitus with long narrow face, hypernasal speech, high-arched palate, low-set ears, pectus excavatum, and long thin fingers and toes. He had a borderline IQ, a long history of hyperactivity and behavioral disorders, and complete agenesis of the corpus callosum on MRI. Psychiatric evaluation showed low insight and concrete thought pattern. A maternal uncle was similarly affected and also had ascending aortic aneurysm and a double row of teeth; a sister was diagnosed with anorexia nervosa (see 606788). A review of 32 published cases of Lujan-Fryns syndrome indicated a high frequency of psychopathology, most commonly an autistic-like disorder.
In affected members of the family reported by Lujan et al. (1984), Schwartz et al. (2007) identified a mutation in the MED12 gene (N1007S; 300188.0002). Schwartz et al. (2007) noted that 1 of the family members originally thought ... In affected members of the family reported by Lujan et al. (1984), Schwartz et al. (2007) identified a mutation in the MED12 gene (N1007S; 300188.0002). Schwartz et al. (2007) noted that 1 of the family members originally thought to be affected was later found not to be affected with the same disorder and did not carry the MED12 mutation. Schwartz et al. (2007) identified the N1007S mutation in affected members of an unrelated family. The findings indicated that Lujan-Fryns syndrome and Opitz-Kaveggia syndrome are allelic disorders. Clinically, Lujan-Fryns syndrome could be distinguished by tall stature, hypernasal voice, hyperextensible digits, and high nasal root. Schwartz et al. (2007) suggested that the Lujan-Fryns syndrome designation be used only for those cases with a compatible clinical phenotype and mutations in the MED12 gene.