Macrocephaly, defined as a frontooccipital head circumference above the 97th percentile, can have a variety of causes. It can be differentiated into asymptomatic familial forms (so-called benign macrocephaly) and secondary forms resulting from hydrocephalus or other space-occupying intracranial processes such as tumors, hygroma or hematomas. Isolated thickening of the calvarium is rare. In most other cases megalencephaly of varying degree may be the cause, which in turn may also have various causes. After exclusion of the above-mentioned secondary causes, rare genetic diseases can be considered, such as lysosomal storage diseases; leukodystrophies, such as Alexander's disease; metabolic disorders of organic or amino acids, such as glutaraciduria or Canavan disease; as well as other syndromic diseases, such as large growth syndromes. If the usual imaging procedures and/or metabolic examinations do not reveal a cause, a genetic examination using next generation sequencing (gene panel diagnostics) can help clarification, especially in the presence of a developmental disorder.
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Patients with Lujan-Fryns syndrome (LFS), also known as X-linked intellectual disability (XLMR) with marfanoid habitus or X-lined syndromic intellectual developmental disorder (MRXSLF), present with marfanoid habitus, certain craniofacial features, generalized muscle hypotonia, developmental delay, behavioral problems, and nasal speech. Thus, there is clinical overlap with other connective tissue disorders such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS). Inheritance is X-linked recessive, resulting in predominantly male patients, while female carriers are usually clinically inconspicuous.
Hemizygous variants in the MED12 gene, which encodes mediator complex subunit 12, are the genetic cause. Allelic disorders with MED12 variants include FG syndrome type 1 (FGS1) and X‑linked Ohdo syndrome (XLOS). Subsequently, variants in the UPF3B and ZDHHC9 genes have also been described in patients with intellectual disability and marfanoid habitus. However, these patients only partially exhibited the characteristic facial abnormalities of LFS, such as a long narrow face, prominent forehead, broad nasal root, short philtrum, micrognathia, and high palate.
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Robinow syndrome is a rare genetic syndrome, the main symptoms of which are characteristic craniofacial features (prominent forehead and flat midface, short nose with everted nasal floor, wide interocular distance), diminutive growth with mesomelic shortening especially of the upper extremities, brachydactyly-clinodactyly V and hypoplastic genitals, especially in males. Cognitive abilities are normal for 80 to 90% of cases. In 10 to 20% a developmental disorder is described.
The first report by Meinhard Robinow et al. (1969) of a family with affected persons in six generations suggested an autosomal dominant pattern of inheritance. Affected siblings with healthy parents, especially with consanguinity, showed that there is also an autosomal recessive inherited form. Pathogenic variants in the ROR2 gene (Afzal et al., Bokhoven et al.), which codes for a tyrosine kinase, were found to be the cause of this form; its pathogenic variants also cause an autosomal dominant form of brachydactyly type B. Person et al. (2010) found pathogenic variants in the WNT5A gene to be the genetic cause of the autosomal dominantly inherited form in the originally described family, and in 2015 pathogenic changes in the genes DVL1 and DVL3 were found to be a further cause (White et al.). Thus, three forms are genetically distinguished at this time. Clinically, the dominant forms are similar, while the recessive form seems to be associated with more pronounced short stature and additional skeletal malformations in the area of the ribs and vertebrae.
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SOTOS AND WEAVER SYNDROME
Sotos syndrome is an overgrowth syndrome of childhood that is characterized by macrocephaly, distinctive craniofacial features, mild intellectual disability (IQ average 76), advanced bone age, and normal height in adulthood. The head is narrow and long (dolichocephalic), the forehead high and broad with a laterally receding frontal hairline, and the is chin accentuated and pointed. The distance between the eyes seems widened, and the eyelids slope downwards. The palate is pointed and high. Hands and feet are large and the joints are often hyperextensible. Feeding problems are common in infancy. About 50% of the children have seizures, and about half of them occur with fever. Congenital malformations such as heart defects are rare. A slightly increased tumor rate has been reported involving various tissues. Increased anxiety, hyperactivity and aggressiveness are often described.
In 75-90% of cases, Sotos syndrome is caused by nucleotide alterations or deletions in the NSD1 gene (nuclear receptor-binding SET domain-containing protein 1) in 5q35. In Central Europe and the USA, 60-80% of patients carry nucleotide changes and about 10% carry deletions, while in Japanese patients, microdeletions are causal in over 50%. The frequency of Sotos syndrome is estimated at 1:10,000 to 1:50,000. The recurrence risk for siblings is low because the nucleotide changes or deletions are mostly new.
Weaver syndrome (WVS; OMIM 277590), a rare autosomal dominant disorder characterized by tall stature, variable intellectual disability and characteristic facial dysmorphia, offers a potential differential diagnosis. Pathogenic variants in the EZH2 gene (enhancer of zeste, Drosophila, homolog 2; OMIM 601573) have been found to be causative for a large number of Weaver syndrome cases. However, genetic heterogeneity cannot be excluded.
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