(TODPD): Follow-Up of the First Reported Family,
Characterization of the Radiological Phenotype, and
Refinement of the Linkage Region
Nicola Brunetti-Pierri,1Ralph Lachman,2Kwanghyuk Lee,1Suzanne M. Leal,1Pasquale Piccolo,1
Ignatia B. Van den Veyver,3and Carlos A. Bacino1*
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
2Medical Genetics Institute, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California
3Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
Received 12 February 2010; Accepted 1 April 2010
pigmentary skin defects. We have previously described this
syndrome in several females from a large, four-generation pedi-
tary 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
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 ofthe gene responsible for this rarecondition will
shed light on the molecular pathways leading to the various
congenital anomalies of TODPD and will allow a more accurate
Key words: skeletal dysplasia; X-linked dominant; terminal
osseous dysplasia with pigmentary defects
Terminal osseous dysplasia with pigmentary defects (TODPD;
OMIM 300244) is a disorder characterized by pigmentary anoma-
lies of the skin, skeletal abnormalities, mainly involving the limbs,
1998; Bacino et al., 2000; Breuning et al., 2000; Drut et al., 2005;
Baroncini et al., 2007; Kokitsu-Nakata et al., 2008]. The X-linked
dominant pattern of inheritance is supported by the description of
only female affected patients, paucity of males, recurrent early
miscarriages, and X-inactivation studies showing a skewed pattern
follow-up and the radiological characterization of the original
TODPD family [Bacino et al., 2000]. Moreover, we have refined
the critical linkage region on Xq28 and we have excluded some
candidate genes mapping in this critical region.
Carlos A. Bacino, M.D., Department of Molecular and Human Genetics,
Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX
77030. E-mail: firstname.lastname@example.org
Published online 23 June 2010 in Wiley InterScience
How to Cite this Article:
Terminal osseous dysplasia with pigmentary
defects (TODPD): Follow-up of the first
reported family, characterization of the
Am J Med Genet Part A 152A:1825–1831.
? 2010 Wiley-Liss, Inc.
CLINICAL AND RADIOLOGICAL FINDINGS
The detailed clinical findings of the affected patients were previ-
ously reported [Bacino etal., 2000].Inthisarticle we characterized
more in depth the radiological phenotypes of some of the affected
The proposita was first evaluated at the age of 4 months for short
stature, dysmorphic features, pigmentary abnormalities, alopecia,
multiple digital fibromas, patent foramen ovale, and atrial septal
defect [Bacino et al., 2000]. At age 11 years, she was noted to have
hand contractures (Fig. 1). The oral exam at this age, showed
at the previous evaluation at 4 months of age. She attended regular
school and had normal cognitive functions like the other affected
members of the family.
The skull X-rays in the proposita, as well as other family
members, showed thick diploe which can also be observed as a
normal variant. Hand X-rays at the age of 11 years showed
symmetrical shortening of the bones and amorphous ossification.
Metacarpal bones of I, II, III, IV digits were hypoplastic and
abnormally ossified (amorphous). Middle phalanges of the II, III,
and IV digits were either shortened or absent. Digital phalanges of
the level of the II digit of the left hand. The carpal bones were
(between II and III digits) and bridging synostosis between the
an amorphous architecture and shortened bones. The great toes
were bilaterally disproportionally enlarged. Metatarsal, proximal
IV digits of the right foot were short. Fusions of tarsal bones, tarsal
The long bones showed humeral bowing and unusual bony
architecture, which was more severe on the left side (Fig. 4). Ulnar
bowing was also present with radial head dislocations. The radial
diaphyses also had an unusual architecture. The distal radii were
bilaterally shortened with large lucent defects containing sclerotic
borders.The femurs showed longitudinal striation,andboth tibias
were S-shaped (Fig. 4).
FIG. 2. Proposita’s hand and wrist radiographs: bilateral, fairly
symmetrical involvement with shortening of the bones,
hypoplastic. II, III, IV metacarpals are short and abnormally
ossified. The distal radii have lytic (cystic-like) lesions.
FIG. 1. Propositaattheageof11years:notethehypertelorism,hyperpigmentedpunchedoutlesionsoverfaceandforehead,pectusexcavatum,and
multiple hand contractures.
1826 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
The spine wasremarkable for severe scoliosisandmild vertebral
coxa vara on the right.
The DXA studies in the proposita showed normal whole body
localized osteoporosis was detected at the femoral neck (BMD
The proposita’s mother was the least affected in the family. The
hand X-rays showed a normal left hand and on the right hand a
normal thumb, shortening of the IV metacarpal, of the III and IV
middle phalanges, and of III and IV distal phalanges. The carpal
bones appeared to be normal (Fig. 5). The X-rays of her feet were
normal. The DXA studies in the mother did not reveal reduced
bone density and showed a whole body BMC z-score of ?0.7,
BMD T-score of ?0.9, lumbar spine T-score of ?0.4, BMCz-score
of ?0.4, left hip BMD z-score of ?0.9, and left hip BMC z-score
Proposita’s Maternal Aunt
Radiological evaluation of the proposita’s maternal aunt showed
the presence of mild pectus carinatum, scoliosis, and mild spinal
stenosis with interpedunculate narrowing at L5-S1. The hand X-
rays showed shortening of the IV and V metacarpals, IV and V
proximal phalanges,IIandVmiddlephalanges, andabsence ofthe
normal (Fig. 6).
FIG. 4. Proposita’slongboneradiographs:dysplasticchangesincludinghumeralbowing,unusualbonyarchitecturemoresevereontheleftside,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. 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.
BRUNETTI-PIERRI ET AL.
shortened bones. II and III metatarsal bone were shortened. II and
III proximal, middle, and distal phalanges were also shortened. IV
and V middle phalanges were absent, whereas IV and V proximal
remainder of the skeletal radiographs did not show significant
Proposita’s First Cousin
The right-hand X-rays showed shortening of the II and III meta-
carpals which are irregularly shaped with bone fusion at the base.
Carpal–metacarpal fusions were also noted. The proximal phalan-
ges appeared normal but there was shortening of the II, III, and V
middle phalanges. The proximal interphalangeal joints had angu-
severe with shortening of the III metacarpal, normal proximal
phalanges except for mild shortening of the V middle phalanges,
shortening of the II and V middle phalanges, angulation of
proximal–distal interphalangeal joints of the V digit, and normal
distal phalanges (Fig. 8).
The left foot showed shortening of the III and V metatarsals,
shortening of the II and IV middle phalanges, absence of the
III and V middle phalanges, and shortening of the III and V distal
phalanges. The right foot showed similar findings although the
III and IV digits were less affected (Fig. 9).
bones revealed abnormal structure in the intratrochanteric region
and S-shaped tibiae with abnormal cystic bone texture in the
proximal portions (Fig. 10). Bone density studies showed normal
bone mass (whole body BMC z-score þ0.4; whole body BMD
T-score þ0.2; left hip BMD T-score ?0.7; left hip BMC z-score
?0.7; lumbar spine BMD z-score ?0.6; lumbar spine BMC
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
FIG. 8. Proposita’s first cousin hand radiographs. Asymmetric
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. 6. Proposita’s maternal aunt hand radiographs: relatively
symmetrical involvement with shortening of the IV and V
1828AMERICAN JOURNAL OF MEDICAL GENETICS PART A
MATERIALS AND METHODS
The family members were genotyped using the Illumina linkage
panel 12, which contains 6,090 SNP marker loci. To identify the
possible genotyping errors, PedCheck [O’Connell and Weeks,
1998] was used to find Mendelian inconsistencies, while Merlin
was utilized to detect double-recombinants [Abecasis et al., 2002].
The multi-point linkage analysis was carried out using Allegro1.2c
nant model with reduced penetrance and a disease allele frequency
database. Genetic map distances were derived directly or through
interpolation from the Rutgers combined linkage-physical map of
the human genome. Physical positions of the marker loci were
based on the build 36 human genome from the genome browser.
The haplotype analysis was performed via Simwalk2 program
[Sobel and Lange, 1996].
Intron–exon junctions and exons of filamin A (FLNA) and
FAM58A were directly sequenced. Primer sequences are available
We have further refined the critical region within the Xq28 region
between rs1860929 (147,693,062bp) and qter (154,913,754bp).
The maximum multi-point LOD score 2.9 was observed from the
marker rs1860929 to qter, and an identical haplotype was found
only in affected individuals. The reduced genetic interval was
refined to Xq28qter, a region including over 100 genes. Given the
negative for mutations. FLNA mutations were also ruled out by
first and largest reported family with TODPD, refinement of the
linkage region, and exclusion of two candidate genes.
As noted in the original description of this condition, and as
the involvement of the hands and the digital fibromas [Horii et al.,
1998; Bacino et al., 2000; Breuning et al., 2000; Drut et al., 2005;
Baroncini et al., 2007; Kokitsu-Nakata et al., 2008]. The digital
fibromas appear to be prevalent in infancy and they tend to regress
with age in many cases, making them an inconsistent feature in
adults. This is clearly exemplified by our proposita exhibiting the
fibromas only in the first years of life and not at later evaluations.
The carpal and tarsal coalitions were particularly striking in the
proposita of our family (Fig. 2). This feature was not noted in the
early report as the carpal bones were not ossified yet [Bacino et al.,
2000]. The abnormal bony texture and the localized areas of
osteoporosis also point to an unusual bone process involved in
the pathogenesis of the disorder.
Although the skeletal manifestations of TODPD mostly involve
hands and feet, a more generalized bone involvement including
bowing, mesomelic shortening, abnormal bony texture, areas of
localized osteoporosis, cytic lesions, and amorphous ossification
FIG. 10. Proposita’s first cousin thorax, pelvis, and tibia/fibula
iliac wingsandS-shapedtibias areverysimilar tothe appearance
intertrochanteric region and in the proximal tibiae.
FIG. 9. Proposita’s first cousin foot hand radiographs: shortening of
phalanges. The III and V metacarpals are absent.
BRUNETTI-PIERRI ET AL.
suggest a more generalized bone involvement and it may point to
a defect of matrix degradation, because of similarities with the
radiologic features of the osteolysis syndromes [Superti-Furga and
Unger, 2007], which may be due to defects in genes involved in
on the ulnar side is more severe.
Linkage analysis has indicated that the mutated gene in this
et al., 2000]. However, the genetic defect of TODPD remains
unknown. In the effort to identify the gene responsible for this
a high density SNP array which allowed us to restrict the linkage to
Xq28qter. Because of clinical overlap between STAR syndrome
(OMIM 300707), an X-linked dominant condition presenting
with anogenital and renal malformations, dysmorphic facial
features, normal intellect, and syndactyly of toes [Unger et al.,
2008], we sequenced the FAM58A gene, responsible for STAR
syndrome. However, no mutations were found in the exons
and intro/exon boundaries of this gene in the TODPD affected
region, is involved in signaling pathways that mediate organogen-
esis in multiple systems including the skeleton. Some of the
generalized skeletal features of our proband and the patient’s first
changes, while hand and foot changesradiographically, such as the
carpal and tarsal coalitions and flexion contractures [Robertson
et al., 2006], suggest similarity to frontometaphyseal dysplasia
result in a broad range of congenital malformations observed in
four X-linked human disorders: otopalatodigital syndrome types I
(OMIM 311300) and II (OMIM 304120), frontometaphyseal dys-
plasia, and Melnick–Needles syndrome. Given the clinical similar-
ities between some of these disorders and TODPD, we have also
considered FLNA as a candidate gene. However, direct sequencing
of this gene failed to reveal pathogenic mutations.
signaling pathways involving secreted molecules that bind to cell
surface receptors to elicit a response in the target cell. Bone
morphogenetic proteins (BMPs) are an important part of this
process. Their signaling capacity is regulated on several levels
including the extracellular space where inhibitors such as Noggin
importance of the signaling pathway for the development of joints
BMP family, and NOG in patients with symphalangism (OMIM
185800) and multiple synostosis syndrome (OMIM 186500)
[Groppe et al., 2002; Seemann et al., 2005; Dawson et al., 2006].
The presence of multiple joint fusions in TODPD may lead to the
in the pathogenesis in this disorder as well.
The identification of the responsible gene will allow more
accurate genetic counseling to the affected families and will shed
light on the molecular pathways leading to the various clinical and
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