Miller syndrome, also known as Genée–Wiedemann syndrome, Wildervanck–Smith syndrome or postaxial acrofacial dystosis, is an extremely rare genetic condition that manifests as craniofacial, limb and eye deformities. It is caused by a mutation in the '' DHODH'' gene. The incidence of the condition is not known, and nothing is known of its pathogenesis.

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. Additional features of the syndrome include downward-slanting palpebral fissures,

malar hypoplasia Malar may refer to: Places Tamil Nadu, India * Malarajamkuppam, Kandamangalam block, Viluppuram Taluk, Viluppuram District * Malarasankuppam, Gingee Taluk, Viluppuram District * Thirumalarajapuram, Poonamallee Taluk, Thiruvallur District * T ...

, malformed ears, and a broad nasal ridge. Other features include supernumerary vertebrae and other vertebral segmentation and

rib In vertebrate anatomy, ribs ( la, costae) are the long curved bones which form the rib cage, part of the axial skeleton. In most tetrapods, ribs surround the chest, enabling the lungs to expand and thus facilitate breathing by expanding the ches ...

defects, heart defects ( patent ductus arteriosus, ventricular septal defect and ostium primum atrial septal defect),

lung The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...

disease from chronic infection, single umbilical artery, absence of the hemidiaphragm, hypoplasia of the femora, ossification defects of the

ischium The ischium () form ...

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 Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The other ...

biosynthesis. The protein is normally located on the outer surface of the inner

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

l 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 Oogenesis, ovogenesis, or oögenesis is the differentiation of the ovum (egg cell) into a cell competent to further develop when fertilized. It is developed from the primary oocyte by maturation. Oogenesis is initiated in the embryonic stage. O ...

, and malformed posterior legs. In humans Miller syndrome is due to 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.

Treatment

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 Hans-Rudolf Wiedemann (February 16, 1915 - August 4, 2006) was a German pediatrician, University teacher, and autograph collector. __TOC__ Life Wiedemann was born in Bremen. His father was a medical practitioner. His mother came from a medical fa ...

(1915–2006).

References

External links

{{Inborn errors of purine-pyrimidine metabolism Inborn errors of purine-pyrimidine metabolism Syndromes affecting the eye Syndromes with cleft lip and/or palate Rare syndromes