64.1 Clinical Features
and Laboratory Investigations Oculodentodigital dysplasia (ODDD) is an inherited disorder that affects the development of the face, eyes, limbs, and teeth. The disorder has an autosomal dom- inant mode of inheritance. It displays a high pene- trance but variable expression. There is also intrafa- milial variation of the clinical characteristics. Isolated patients, related to de novo mutations, are frequently observed.
Affected patients have a narrow nose with thin, an- teverted nostrils and a prominent columnella. Char- acteristic eye manifestations include short palpebral fissures, epicanthal folds, hyper- or hypotelorism, mi- crophthalmia, and bilateral microcornea, often with abnormalities of the iris. Some patients develop glau- coma or optic atrophy. Bilateral complete syndactyly of the fourth and fifth fingers is the characteristic dig- ital malformation (type III syndactyly). The third fin- ger may also be involved. Syndactyly of the third and fourth toes may be present. Midphalangeal hypopla- sia, distal phalangeal hypoplasia, or aplasia of one or more digits or toes may be present. Associated camp- todactyly or clinodactyly of the fifth fingers is a com- mon finding. The teeth are small and there is general- ized hypoplasia of the enamel. Partial anodontia may be present. Caries and premature loss of teeth may oc- cur. Less common features include dry, thin, slow- growing, and sparse hair (hypotrichosis), cleft lip and palate, conductive hearing loss, cranial and mandibu- lar hyperostosis, and microcephaly.
Neurological symptoms are frequent in ODDD.
Slowly progressive spastic paraparesis of the legs has been reported most often. Other reported problems include ataxia, dysarthria, ptosis, nystagmus, gaze palsy, strabismus, visual impairment, neurogenic bladder dysfunction, bowel disturbance, seizures, and mild mental retardation. However, the clinical expres- sion of neurological features often varies widely among affected individuals within and between ODDD kindreds. The onset of the neurological prob- lems is variable. It is usually evident by the second decade of life, but may be much later.
64.2 Pathology
No autopsy studies of ODDD are available.
64.3 Pathogenetic Considerations
ODDD is related to dominant mutations in the con- nexin 43 gene, GJA1, at chromosome 6q22–23. A high rate of de novo mutations is observed.
Connexin 43, like other connexin proteins, is a transmembrane protein with an intracellular N-ter- minus, four transmembrane domains, two extracellu- lar loops, one cytoplasmic loop, and an intracellular C-terminus. Six connexins can form a hemichannel or connexon, a specialized intracellular structure sur- rounding a pore. Two connexons in apposing cell membranes can align to form an intercellular gap junction. These channels provide a direct low-resis- tance intracellular pathway for the passage of ions and small molecules. Gaps junctions have been found in most tissues. Most tissues express more than one type of connexin. Multiple types of connexins can assemble to form gap junctions between cells, with the diversity of combinations influencing the nature of the cell-to-cell communication.
Almost all GJA1 mutations in ODDD are missense mutations. The lack of mutations resulting in the in- troduction of a stop codon into the protein suggests that the mechanism underlying ODDD is not a loss of connexin 43 function. This hypothesis is reinforced by the finding that the mouse knock-out does not have an ODDD-like phenotype. There is a strong cor- relation between the sites of GJA1 expression during mouse embryonic development and the ODDD phe- notype, suggesting that connexin 43 plays a key role in normal facial and limb development. The patho- physiology of the disease in ODDD has still to be elu- cidated.
ODDD and Hallermann–Streiff syndrome share several clinical characteristics. Some patients with Hallermann–Streiff syndrome have two mutations in the GJA1 gene, whereas their parents are carri- ers. However, in other typical Hallermann–Streiff syndrome patients no mutation in GJA1 can be found.
64.4 Therapy
At present, only symptomatic therapy is available for patients with ODDD.
Oculodentodigital Dysplasia
Chapter 64
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64.5 Magnetic Resonance Imaging
In some patients with ODDD, MRI does not reveal ab- normalities. Patients with ODDD and progressive neurological problems have white matter abnormali- ties on MRI (Fig. 64.1). The cerebral white matter is somewhat reduced in volume. A zone of mildly ab- normal signal surrounds the lateral ventricles, rela-
tively sparing the U fibers. The signal abnormalities extend downwards into the posterior limb of the in- ternal capsule and the corticospinal tracts in the brain stem. Low signal intensity on T2-weighted im- ages has been reported in the pericentral cortex, globus pallidus, and substantia nigra. The imaging abnormalities in ODDD may not be very specific, but they are consistent among patients.
Chapter 64 Oculodentodigital Dysplasia 480
Fig. 64.1. A 5.5-year-old girl with ODDD. The T2-weighted im- ages (first and second row) show ill-defined, mild periventricu- lar signal abnormalities, extending downwards into the poste- rior limb of the internal capsule. The inversion recovery (third
row, left) and FLAIR images (third row, middle and right) show that the subcortical white matter is better preserved. Courtesy of Dr. B. Tinselboer and Dr. F. Beemer, Department of Clinical Genetics, University Medical Center Utrecht, The Netherlands 064_Valk_Oculodentodigital 08.04.2005 16:22 Uhr Seite 480
