Lujan-Fryns综合症

Lujan-Fryns综合症（Lujan–Fryns syndrome、LFS）是一种X染色体伴性遗传障碍，会导致轻度至中度智能障碍和类似于马凡氏症候群的特征。特征包括高瘦身材和修长四肢。
综合症与精神病理学和人类行为异常有关。综合症还表现出许多如大脑心脏畸形的影响。
归因于MED12基因的错义突变，该疾病以X连锁显性遗传方式遗传。目前还没有针对潜在的MED12功能障碍的治疗或疗法，并且该疾病的确切原因仍不清楚。
体征和症状.
智力障碍通常从轻度到中度不等，但也有严重病例的报导。
相对常见的大脑异常，综合症的是，因胚胎发育错误导致不存在连接左右两个大脑半球的胼胝体。缺乏胼胝体会发现许多不良神经学影响，智力障碍的发生率约73%。然而，尚未有综合症胼胝体发育不全与智力障碍之间的相关性研究。
精神病学.
诊断该病症可能要考虑该症通常出现的精神病理学和相关行为异常。
综合症最常见的是自闭症样谱系障碍，该综合症被认为是与自闭症相关的遗传障碍之一。
Additional alterations of psychopathology with behavioral manifestations that have been observed in LFS include: psychotic behavior, schizophrenia, hyperactivity and attention-deficit hyperactivity disorder, aggression, oppositional defiant disorder, obsessive compulsive disorder, extreme shyness, learning disability, cognitive impairment, short-term memory deficit, low frustration tolerance, social dysfunction, lack of impulse control, eating disorder and associated malnutrition, attributed to psychogenic loss of appetite; and pyromania.
While psychiatric conditions like these are to be expected with LFS, there have also been cases of the disorder with some preservation of mental and behavioral abilities, such as problem solving, reasoning and normal intelligence.
The psychopathology of LFS usually exhibits schizophrenia. When schizophrenia is diagnosed in an individual known to be affected by intellectual disability, LFS may be considered in the differential diagnosis of schizophrenia, with confirmation of cause through appropriate psychiatric and genetic evaluation methods.
LFS is clinically distinguished from other X-linked forms of intellectual disability by the accompanying presence of marfanoid habitus. Marfanoid habitus describes a group of physical features common to Marfan syndrome. Including Marfan syndrome and LFS, marfanoid features of this type have also been observed with several other disorders, one of which is multiple endocrine neoplasia type 2.
In LFS, specific features identified as marfanoid include: a long, narrow face; tall, thin stature; long, slender limbs, fingers and toes (not unlike arachnodactyly) with joint hyperextensibility, shortened halluces (the big toes) and long second toes.
诊断经常被延迟，因为与之相关的许多身体特征和特征通常直到青春期才明显。
头脸.
Craniofacial and other features of LFS include: maxillary hypoplasia (underdevelopment of the upper jaw bone), a small mandible (lower jaw bone) and receding chin, a high-arched palate (the roof of the mouth), with crowding and misalignment of the upper teeth; macrocephaly (enlarged skull) with a prominent forehead, hypernasal speech (voice), a long nose with a high, narrow nasal bridge; a deep, short philtrum (the indentation in the upper lip, beneath the nose), low-set ears with some apparent retroversion, hypotonia (decreased muscle tone), pectus excavatum (a malformity of the chest), slightly enlarged to normal testicular size in males, and seizures.
Hypernasal speech, or "hypernasality", is primarily the result of velopharyngeal insufficiency, a sometimes congenital aberration in which the velopharyngeal sphincter allows too much air into the nasal cavity during speech. In LFS, hypernasality may also be caused by failure of the soft palate and uvula to reach the back wall of the pharynx (the interior cavity of the throat where swallowing generally occurs) during speech, a condition that can be associated with a submucosal cleft palate.
心脏.
A number of features involving the heart have been noted in several LFS cases, the most significant being dilation of the aortic root, a section of the ascending aorta. Aortic root dilation (enlargement) is associated with a greatly increased risk of dissection of the aortic wall, resulting in aortic aneurysm. As this presents a possible life-threatening consequence of LFS, routine cardiac evaluation methods such as echocardiogram are implemented when the disorder is first diagnosed, along with MRI scans of the brain to screen for suspected agenesis of the corpus callosum. Additional effects on the heart that have been reported with LFS are ventricular and atrial septal defect.
原因.
A missense mutation in the "MED12" gene, located on the human X chromosome, has been established as the cause of LFS. Missense mutations are genetic point mutations in which a single nucleotide in the genetic sequence is exchanged with another one. This leads to an erroneously substitution of a particular amino acid in the protein sequence during translation. The missense mutation in the "MED12" gene, that causes LFS, is identified as p.N1007S. This indicates that the amino acid asparagine, normally located at position 1007 along the "MED12" sequence, has been mistakenly replaced by serine. This mutation in "MED12" causes incorrect expression and activity of the protein it encodes, resulting in the disorder.
病理生理学.
MED12, or "mediator of RNA polymerase II transcription, subunit 12 homolog of S. cerevisiae", is one of several subunits in the mammalian mediator complex, which regulates RNA polymerase II during mRNA transcription.
The Mediator complex is required for polymerase II transcription and acts as a bridge between the polymerase II enzyme and different gene-specific transcription factors. Mediator can contain up to 30 subunits, but some of the subunits are only required for regulation of transcription in particular tissues or cells. Currently, the exact mechanism by which dysfunction of "MED12" results in LFS and its associated neuropsychopathic and physical characteristics is unclear. Marfanoid habitus, a highly arched palate and several other features of LFS can be found with Marfan syndrome, a connective tissue disorder. The finding of aortic root dilation in both disorders suggests that a mutation in an unspecified connective tissue regulating gene may contribute to the etiology of LFS. 
A number of interesting experimental results have been obtained by studying "MED12" mutations in the zebrafish, an animal model representing vertebrates. In zebrafish, a mutation in "MED12" was found to be responsible for the mutant "motionless" ("mot"). Zebrafish with the "mot" mutation have neuronal and cardiovascular defects, although not all types of neurons are affected. Introduction of human "MED12" mRNA into the zebrafish restores normal development. "MED12" is also a critical coactivator for the gene "SOX9", which is involved in the developmental regulation of neurons, cartilage and bone. In the zebrafish, "MED12" defects cause maldevelopment of vertebrate embryonic structures such as the neural crest, which would alter function of the autonomic and peripheral nervous systems; and they also cause malformations of cell types serving as precursors to cartilage and bone, such as osteocytes. Some features found in LFS, like agenesis of the corpus callosum and cartilage-related craniofacial anomalies, are similar to defects found in zebrafish with "MED12" and associated mutations.
遗传学.
Lujan–Fryns syndrome is inherited in an X-linked dominant manner. This means the defective gene responsible for the disorder ("MED12") is located on the X chromosome, and only one copy of the defective gene is sufficient to cause the disorder when inherited from a parent who has the disorder. Males are normally hemizygous for the X chromosome, having only one copy. As a result, X-linked dominant disorders usually show higher expressivity in males than females. This phenomenon is thought to occur with LFS.
As the X chromosome is one of the sex chromosomes (the other being the Y chromosome), X-linked
inheritance is determined by the gender of the parent carrying a specific gene and can often seem complex. This is because, typically, females have two copies of the X-chromosome, while males have only one copy. The difference between dominant and recessive inheritance patterns also plays a role in determining the chances of a child inheriting an X-linked disorder from their parentage.
In LFS, X-linked dominant inheritance was suspected, as boy and girl siblings in one family both exhibited the disorder. A scenario such as this would also be possible with X-linked recessive inheritance, but in this particular case report, the girl was believed to be a manifesting heterozygote carrying one copy of the mutated gene.
Sporadic cases of LFS, where the disorder is present in an individual with no prior family history of it, have also been reported in a small number of affected males.
与其他遗传病的相似之处.
An individual exhibiting intellectual disability and other symptoms similar to LFS was found to have a terminal deletion of the subtelomeric region in the short arm of chromosome 5. Deletion of this area of chromosome 5 is associated with intellectual disability, psychotic behavior, autism, macrocephaly and hypernasal-like speech, as well as the disorder Cri du chat syndrome. Fryns (2006) suggests a detailed examination of chromosome 5 with FISH should be performed as part of the differential diagnosis of LFS.
Mutations in the "UPF3B" gene, also found on the X chromosome, are another cause of X-linked intellectual disability. "UPF3B" is part of the nonsense-mediated mRNA decay (NMD) complex, which performs mRNA surveillance, detecting mRNA sequences that have been erroneously truncated (shortened) by the presence of nonsense mutations. Mutations in "UPF3B" alter and prevent normal function of the NMD pathway, resulting in translation and expression of truncated mRNA sequences into malfunctioning proteins that can be associated with developmental errors and intellectual disability. Individuals from two families diagnosed with LFS and one family with FGS were found to have mutations in "UPF3B", confirming that the clinical presentations of the different mutations can overlap.
诊断.
Although LFS is usually suspected when intellectual disability and marfanoid habitus are observed together in a patient, the diagnosis of LFS can be confirmed by the presence of the p.N1007S missense mutation in the "MED12" gene.
鉴别诊断.
In the differential diagnosis of LFS, another disorder that exhibits some features and symptoms of LFS and is also associated with a missense mutation of "MED12" is Opitz-Kaveggia syndrome (FGS). Common features shared by both LFS and FGS include X-linked intellectual disability, hyperactivity, macrocephaly, corpus callosum agenesis and hypotonia. Notable features of FGS that have not been reported with LFS include excessive talkativeness, consistent strength in socialization skills, imperforate anus (occlusion of the anus) and ocular hypertelorism (extremely wide-set eyes).
综合症与错义突变 p.N1007S 相关，而 FGS 与错义突变 p.R961W 相关。 As both disorders originate from an identical type of mutation in the same gene, while exhibiting similar, yet distinct characteristics; LFS and FGS are considered to be allelic. In the context of "MED12", this suggests that the phenotype of each disorder is related to the way in which their respective mutations alter the "MED12" sequence and its function.
治疗.
虽然没有针对综合症的潜在遗传原因特定治疗方法，但在治疗和管理与该疾病相关的许多颅面、骨科、精神问题时，可以考虑纠正程序、预防性干预措施和疗法。更紧迫的问题，如心脏受累或癫痫发作，应进行常规检查和监测。应给予密切关注和专门的后续护理，包括神经心理学评估方法和疗法以及特殊教育，以诊断和预防精神障碍和相关的行为问题，如精神病和攻击性爆发。
流行病学.
是一种罕见的 X 连锁显性综合征，男性多于女性。它在普通人群中的流行程度尚未确定。
历史.
综合症是以医师的 J. Enrique Lujan 和 Jean-Pierre Fryns 命名的。 The initial observation of suspected X-linked intellectual disability with Marfanoid features and craniofacial effects such as a high-arched palate was described by Lujan et al. in 1984.
In the report, four affected male members of a large kindred (consanguinous family) were noted. Additional investigations of combined X-linked intellectual disability and Marfanoid habitus in other families, including two brothers, were reported by Fryns et al., beginning in 1987. The disorder soon became known as Lujan–Fryns syndrome.