Terminal osseous dysplasia with pigmentary defects (TODPD): Follow-up of the first reported family, characterization of the radiological phenotype, and refinement of the linkage region

Abstract

Terminal osseous dysplasia with pigmentary defects (TODPD) is an X-linked dominant syndrome with distal limb anomalies and pigmentary skin defects. We have previously described this syndrome in several females from a large, four-generation pedigree. The presentation in the affected patients included multiple anomalies, hypertelorism, iris colobomas, punched-out pigmentary abnormalities over the face and scalp, brachydactyly, and digital fibromatosis. The phenotype was highly variable thus suggesting that X-inactivation plays an important role in the expression of the disease. Following our initial description of this condition there have been reports of more cases supporting the initial phenotypic description of this disease. We report on the follow-up of this family at about 10 years from the first evaluation. A detailed clinical follow-up and a review of the skeletal surveys suggests that although the most striking features involves the hands and feet, the skeletal involvement is more generalized and affects many other areas. Our previous linkage analysis has demonstrated mapping to Xq27.3-Xq28. Using a 6,056 SNP array, we have further refined the critical region within the Xq28 region. We have also excluded two candidate genes (FLNA and FAM58A) mapping in the critical region. The identification of the gene responsible for this rare condition will shed light on the molecular pathways leading to the various congenital anomalies of TODPD and will allow a more accurate genetic counseling to the affected individuals.

FIG. 1

Proposita at the age of 11 years: note the hypertelorism, hyperpigmented punched out lesions over face and forehead, pectus excavatum, and multiple hand contractures.

FIG. 2

Proposita's hand and wrist radiographs: bilateral, fairly symmetrical involvement with shortening of the bones, amorphous ossification and interosseous fusions. The thumbs are hypoplastic. II, III, IV metacarpals are short and abnormally ossified. The distal radii have lytic (cystic-like) lesions.

FIG. 3

Proposita's foot radiographs: symmetrical, amorphous architecture of the shortened bones. Great toes are proportionately enlarged. Fusions between calcaneal and cuneiform bones and between metatarsal bones are evident.

FIG. 4

Proposita's long bone radiographs: dysplastic changes including humeral bowing, unusual bony architecture more severe on the left side, ulnar bowing, radial head dislocations, unusual architecture of the radial diaphyses, large lucent defects with sclerotic borders of the distal radius, longitudinal striation of the femurs, coxa valga on the left, coxa vara on the right, and S-shaped tibias (left more severe than right).

FIG. 5

Proposita's mother hand radiographs: normal left hand and shortening of the III and IV metacarpals, middle, and distal phalanges on the right. The punctate radiopacities are due to application of a nail product.

FIG. 6

Proposita's maternal aunt hand radiographs: relatively symmetrical involvement with shortening of the IV and V metacarpals and proximal phalanges; shortening of the II, IV, and V middle phalanges. The thumbs are intact and the carpal bones are normal.

FIG. 7

Proposita's maternal aunt foot radiographs: some amorphously ossified short bones. Metatarsals, proximal, middle, and distal phalanges are very short. IV and V middle phalanges are absent and proximal and middle phalanges are very short. The great toe is of normal size and proportionately enlarged (hallux valgus).

FIG. 8

Proposita's first cousin hand radiographs. Asymmetric bilateral involvement: on the right hand, shortening of the II and III metacarpals with bone fusion at the base (“picture-puzzle shape sign”). Proximal phalanges are normal while middle phalanges of the II, III, and V digits are short. Angulation deformities of the proximal interphalangeal joints. The left hand is much less severely affected, with mild shortening of III metacarpals, and shortening of the II and V middle phalanges. Angulation of the proximal–distal interphalangeal joints of the V digit.

FIG. 9

Proposita's first cousin foot hand radiographs: shortening of the III and V metatarsal, II and IV middle phalanges, III and V distal phalanges. The III and V metacarpals are absent.

FIG. 10

Proposita's first cousin thorax, pelvis, and tibia/fibula radiographs: eventration of the left diaphragm is noted. The narrow iliac wings and S-shaped tibias are very similar to the appearance of Melnick–Needles syndrome. The bone texture is abnormal in the intertrochanteric region and in the proximal tibiae.