Paula and Bobby
Parents of Lillie
What is Lujan-Fryns syndrome?
Lujan syndrome is a rare genetic disease which occurs mainly in males. Its defining facial features are similar to those of Marfan syndrome, including a tall and thin stature.
The other main symptoms of the syndrome include intellectual disability and behavioral issues.
Lujan-Fryns syndrome Mental Retardation, X-linked, With Marfanoid Habitus X-linked mental retardation - marfanoid habitus
What gene change causes Lujan-Fryns syndrome?
As an X-linked disorder, mainly males are affected by the syndrome.
Mutations in the MED12 gene are responsible for the syndrome.
Syndromes inherited in an X-linked recessive pattern generally only affect males. Males only have one X chromosome, and so one copy of a gene mutation on it causes the syndrome. Females, with two X chromosomes, only one of which will be mutated, are not likely to be affected.
With syndromes inherited in an X-linked dominant pattern, a mutation in just one of the copies of the gene, causes the syndrome. This can be in one of the female X chromosomes, and in the one X chromosomes males have. Males tend to have more severe symptoms than females.
what are the main symptoms of Lujan-Fryns syndrome?
Mild to moderate intellectual disability is a major symptom of the syndrome. Behavioral issues related to the syndrome include hyperactivity, aggression, extreme shyness and social anxiety as well as extreme attention-seeking behaviors. Some affected individuals may also be diagnosed as on the autism spectrum, and issues with communication and interacting with others are common with the syndrome. In severe cases delusions and hallucinations may also be potential symptoms.
Unique facial and physical features of the syndrome are a tall stature, large head, a long face, prominent top of the nose, short philtrum (the space between the nose and upper lip), and a narrow palate, crowded teeth and a small chin.
Low muscle tone is also a common symptom associated with the syndrome.
Other possible symptoms include speech delay, seizures, hyperextensibility of the joints and brain abnormalities.
Possible clinical traits/features:
Flexion contracture, Emotional lability, Dental crowding, Deep philtrum, Agenesis of corpus callosum, Disproportionate tall stature, Intellectual disability, Narrow face, Low frustration tolerance, Low-set ears, Long face, Long nose, Narrow nasal bridge, Joint laxity, Micrognathia, Pectus excavatum, X-linked recessive inheritance, Ventricular septal defect, Frontal bossing, Prominent forehead, Short philtrum, Thin upper lip vermilion, Macrocephaly, Impaired social interactions, High palate, Hyperactivity, Prominent nasal bridge, Nasal speech, Generalized hypotonia, Abnormality of the genitourinary system, Hypoplasia of the maxilla, Seizure, Psychosis, Obsessive-compulsive behavior, Open mouth, Autism, Atrial septal defect, Broad thumb, Arachnodactyly, Dilatation of ascending aorta, Aggressive behavior, Abnormality of the rib cage, Abnormally folded helix
How does someone get tested for Lujan-Fryns syndrome?
The initial testing for Lujan-Fryns syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Lujan-Fryns syndrome
Lujan (1984) studied four males, the offspring of three sisters, with mental retardation, a marfanoid habitus, a long narrow face, a large head, a high-arched palate, micrognathia, abnormal speech with a hypernasal voice, joint laxity and borderline large testes. The halluces can be short. Mental retardation ranged from mild to severe. There may be significant behavioural problems (extreme shyness, autistic features, poor attention or frank psychotic features (De Hert et al., 1996; Alonso et al., 2006, Lerma-Carrillo et al., 2006, Williams, 2006). One case had an ASD and one had agenesis of the corpus callosum. Fragile X chromosomes were not detected. There are some similarities to FG syndrome. Fryns and Van den Berghe (1992) point out that the diagnosis might be difficult before puberty, when the marfanoid habitus becomes more obvious. They also suggest that overall height might not be excessive. De Hert et al., (1996) reported a 22-year-old male with schizophrenia and features of the condition. Wittine et al., (1999) reported a 19 year old male and his maternal aunt with features of the condition. They both had a sub-aortic VSD and aortic root dilatation. The uncle also had mild pulmonary stenosis. The authors review other reports of cardiac anomalies in the condition including ASD, mitral valve prolapse and innocent systolic murmurs.
Stathopulu et al., (2003) reported a male with features suggestive of Lujan-Fryns syndrome and with an autistic spectrum disorder, who had a subtle terminal deletion of the short arm of chromosome 5.
Lacombe et al., (1993) reported three further cases and provided a good review. Donders et al., (2002) reported a 19-year-old male with features of the condition. However, he did not demonstrate any of the psychiatric features that have been reported with the syndrome, and showed intact concrete problem-solving skills under structured, interactive conditions.
Two families reported by Raymond et al., (2007) mapped to Xq26 and had mutations in ZDHHC9 which encodes a palmitoyltransferase of NRASand HRAS. No pictures of the affected males were shown.
Interestingly, the original Lujan family has been found to have a MED12 mutation (Schwartz et al., 2007). Mutations in the same gene is responsible for the FG syndrome (see elsewhere). These 2 syndromes are thus allelic.
See also under 'X-linked mental retardation - mapping to Xq24 - UPF3 mutations', as these patients might have the Lujan-Fryns phenotype. Hackmann et al., (2016) looked for MED12, ZDHHC9 and UPF3 mutations in a cohort of patients with a tentative diagnosis of Lujan-Fryns syndrome. No mutations were found andWES examination found one (out of 28) with a 16p11.2 microduplication and one with a 12p13.31 duplication. These authors suggest that the clinical diagnosis needs pedigree evidence of X-linkage, a marfanoid phenotype, specific facial features and a nasal speech.
Khan et al. (2016) described a 17-year old boy with Lujan-Fryns syndrome and a missense de novo mutation p.N1007S in MED12. He was diagnosed with acute onset dysphagia, hypernasal speech and nasal regurgitation of liquids. No cognitive delay or psychiatric abnormalities were reported. The boy was described as tall and thin, with increased ratio of arm span to height, and reduced ratio of upper limbs to lower limbs. He also had pes cavus and pectus excavatum. Dysmorphic features included a low-set, small ears, micrognathia, short mandible, relatively flat nasal bridge, maxillary hypoplasia, high-arched palate, thin long fingers and digits, sandal gap, hyper-flexible joints, relative hypotonia, and positive wrist and thumb signs. An echocardiogram showed a mild aortic regurgitation and minimal mitral valve prolapse.
* This information is courtesy of the L M D.
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