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 Dihydroorotate dehydrogenase (DHODH) is an enzyme that in humans is encoded by the ''DHODH'' gene on chromosome 16. The protein encoded by this gene catalyzes the fourth enzymatic step, the ubiquinone-mediated oxidation of dihydroorotate to ...

'' gene. The incidence of the condition is not known, and nothing is known of its pathogenesis.

Presentation

The syndrome consists of severe

micrognathia Micrognathism is a condition where the jaw is undersized. It is also sometimes called mandibular hypoplasia. It is common in infants, but is usually self-corrected during growth, due to the jaws' increasing in size. It may be a cause of abnorm ...

, cleft lip and/or palate, hypoplasia or aplasia of the postaxial elements of the limbs, coloboma of the eyelids and

supernumerary nipples A supernumerary nipple is an additional instance of nipple occurring in mammals, including humans. They are often mistaken for moles. Studies variously report the prevalence of supernumerary nipples as approximately 1 in 18 and 1 in 40. https:/ ...

. 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

vertebra The spinal column, a defining synapomorphy shared by nearly all vertebrates,Hagfish are believed to have secondarily lost their spinal column is a moderately flexible series of vertebrae (singular vertebra), each constituting a characteristic ...

e 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 The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...

defects (

patent ductus arteriosus ''Patent ductus arteriosus'' (PDA) is a medical condition in which the ''ductus arteriosus'' fails to close after birth: this allows a portion of oxygenated blood from the left heart to flow back to the lungs by flowing from the aorta, which has ...

, ventricular septal defect and

ostium primum atrial septal defect The ostium primum atrial septal defect is a defect in the atrial septum at the level of the tricuspid and mitral valves. This is sometimes known as an endocardial cushion defect because it often involves the endocardial cushion, which is the port ...

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 An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

, single umbilical

artery An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pul ...

, absence of the hemidiaphragm, hypoplasia of the femora, ossification defects of the

ischium The ischium () form ...

and pubis, bilobed

tongue The tongue is a muscular organ (anatomy), organ in the mouth of a typical tetrapod. It manipulates food for mastication and swallowing as part of the digestive system, digestive process, and is the primary organ of taste. The tongue's upper surfa ...

, lung hypoplasia, and

renal reflux The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...

Cause

The gene responsible for this disorder is ''

'' located at chromosome 16q22. This gene encodes an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

– 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 ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly" or "pomace fly". Starting with Ch ...

''. 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 ''

'' gene.

Diagnosis

Differential diagnosis

The differential diagnosis includes

Treacher Collins syndrome Treacher Collins syndrome (TCS) is a genetic disorder characterized by deformities of the ears, eyes, cheekbones, and chin. The degree to which a person is affected, however, may vary from mild to severe. Complications may include breathing prob ...

, 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

(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