Miller syndrome

Presentation

The syndrome consists of severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the postaxial elements of the limbs, coloboma of the eyelids and supernumerary nipples. Other characteristics of the syndrome include palpebral fissures that slant downward, malar hypoplasia, malformed ears, and a broad nasal ridge. Other features include supernumerary vertebrae and other vertebral segmentation and rib defects, heart defects (patent ductus arteriosus, ventricular septal defect and ostium primum atrial septal defect), lung disease from chronic infection, single umbilical artery, absence of the hemidiaphragm, hypoplasia of the femora, ossification defects of the ischium and pubis, bilobed tongue, lung hypoplasia, and renal reflux.

Cause

The gene responsible for this disorder is DHODH located at chromosome 16q22. This gene encodes an enzyme, dihydroorotate dehydrogenase, which catalyses the ubiquinone-mediated oxidation of dihydroorotate to orotate, the fourth enzymatic step in de novo pyrimidine biosynthesis. The protein is normally located on the outer surface of the inner mitochondrial membrane.

Genetics

A mutation in this gene was reported by Morgan in 1910 in the fruit fly Drosophila melanogaster. In the fly, this mutation is characterized by wing anomalies, defective oogenesis, and malformed posterior legs. In humans, Miller syndrome is due to a recessive mutation in the DHODH gene.

Diagnosis

Differential diagnosis

The differential diagnosis includes Treacher Collins syndrome, Nager acrofacial dysostosis (preaxial cranial dysostosis). Other types of axial cranial dysostosis included the Kelly, Reynolds, Arens (Tel Aviv), Rodríguez (Madrid), Richieri-Costa and Patterson-Stevenson-Fontaine forms.

History

This condition was first described in 1969 by Genée, who assumed the condition to be an extreme form of Treacher Collins syndrome (dysostosis mandibulofacialis). Wiedemann in 1975 described it as a separate entity. Further cases were reported by Wildervanck in 1975 and by Miller et al in 1979 The syndrome was named the Genée-Wiedemann syndrome in 1987. A family harboring Miller syndrome was the first human family to be ever sequenced with whole-genome sequencing.

Eponym

Genée–Wiedemann syndrome is named after two German physicians: Ekkart Genée (1936–), and his mentor Hans-Rudolf Wiedemann (1915–2006).

References

References

1. (January 2010). "Exome sequencing identifies the cause of a mendelian disorder". Nature Genetics.
2. (April 2010). "Analysis of genetic inheritance in a family quartet by whole-genome sequencing". Science.
3. (July 1910). "Sex limited inheritance in ''drosophila''". Science.
4. (1969). "Une forme de dysostose mandibulo-faciale". J. De Génét. Humaine.
5. (1973). "Missbildungs-Retardierungs-Syndrom mit Fehlen des 5. Strahls an Händen und Füssen, Gaumenspalte, dysplastischen Ohren und Augenlidern und radioulnarer Synostose". Klin Padiatr.
6. (1975). "Case report 28.". Syndrome Identification.
7. (December 1979). "Postaxial acrofacial dysostosis syndrome". The Journal of Pediatrics.
8. (August 1987). "The Genée-Wiedemann syndrome, an acrofacial dysostosis--further observation". American Journal of Medical Genetics.
9. McAuliffe, Kathleen. (April 27, 2011). "#5: Family Genomics Links DNA to Disease". Discover.