ARTICLE
A 28-year-old mentally retarded, institutionalised woman was referred
to us for evaluation of multiple plantar warts and ingrown nails of both
great toes. The patient was born to unrelated parents of North African
origin and had one brother and three half-brothers, all of whom were healthy.
Physical examination revealed short stature, slight obesity, facial abnormalities
(Fig. 1), short and broad thumbs and big toes (Figs. 2 and
3). A keloid was found on the right forearm, that had developed
after surgical correction of a fracture (Fig. 4). Ill-defined hyperpigmented
macules were observed on the trunk. The patient also presented pruritic
eczematous lesions of the limbs and the back that had been present for
some years and were recurrent despite treatment with emollients and local
steroids. Androgenetic-type alopecia of moderate severity was seen on
the vertex of the scalp. Past medical history included polydactylism of
the feet and clinodactyly of the thumbs (both corrected surgically), respiratory
tract infections, Wolf-Parkinson-White syndrome and refractive errors
necessitating glasses.
Rubinstein-Taybi syndrome (RTS-OMIM 180849) is a congenital, multimalformative
condition first recognised in 1963 [1]. It is due to mutations in the
gene encoding the cyclic AMP-response element binding (CREB) protein (CBP),
caused by chromosomal rearrangements (translocations and inversions of
the chromosome band 16p13.3). CBP is a large nuclear protein with histone
acetyltransferase activity, participating as a transcriptional coactivator
in cyclic AMP-regulated gene expression and involved in transcription
regulation, chromatin remodelling and the integration of several signal
transduction pathways [2-5]. Its role in cAMP-regulated cell immortalization
has been considered as a possible explanation for the unusual incidence
of neoplasms and the propensity to form keloids. Rare familial cases of
RTS have been reported, involving identical twins [6] and exceptionally
parents and their offspring, and therefore a dominant inheritance pattern
has been suggested [7]; however, the great majority of cases are sporadic.
The recurrence risk figure for sibs is in the order of 0.1%, but the recurrence
risk for offspring of affected persons may be as high as 50% [8]. The
estimated incidence of RTS in the general population and in institutionalised
persons with mental retardation over age 5 years is 1:300,000 and 1:300-500,
respectively. Men and women are equally affected. The syndrome has been
diagnosed in Caucasian (European and American) and Japanese patients.
The main clinical manifestations of RTS include:
- mental deficiency (mean IQ: 51),
- growth retardation and short stature,
- facial abnormalities, including microcrania, a small, beaked
nose, prominent and wide nasal bridge, retro- or micrognathia, short upper
lip and pouting lower lip,
- broad thumbs and halluxes, clinodactyly of thumbs, polydactylism
of the feet,
- ophthalmologic abnormalities, including prominent and highly
arched eyebrows, downward slanting lids, blepharoptosis, long and prominent
eyelashes, strabismus, microphthalmia, cataracts and glaucoma,
- recurrent ear and upper respiratory tract infections,
- oral problems (small mouth, high-arched palate, crowded teeth,
cavities, talon cusps),
- neural and developmental tumours (oligondendroglioma, medulloblastoma,
neuroblastoma, meningioma, phaeochromocytoma, seminoma, leiomyosarcoma,
nasopharyngeal rhabdomyosarcoma, embryonal carcinoma, odontoma and choristoma)
[9],
- cardiac defects (33%), including atrial or ventricular septal
defect, patent ductus arteriosus, coarctation of the aorta, pulmonic stenosis,
or bicuspid aortic valve,
- cryptorchidism, constipation, patellar dislocation and joint
laxity.
Although rarely reported in the dermatological literature, RTS syndrome
comprises several cutaneous features with which the dermatologist can
be faced. They include spontaneous multiple scars and keloids (22% of
patients in the Netherlands) [10-15], hypertrichosis on the back and shoulders,
ingrowing nails/paronychia, multiple pilomatricomas [16, 17], supernumerary
or hypertrophic nipples [18], simian crease, keratosis pilaris, ulerythema
ophryogenes [19], capillary hemangiomas of the forehead, nape and lumbar
region, dermatoglyphic abnormalities [20], atopic and seborrheic dermatitis,
piebaldism [21], hyperpigmented spots on the trunk, dermoid cysts [9]
and epidermal nevus [22]. Treatment is purely symptomatic. Hypertrichosis
can be treated by depilation. Ingrowing nails and paronychia are dealt
with local antibiotics and, if refractory, by surgery. Pilomatricomas
may be excised surgically. Hemangiomas can be treated with pulsed dye
lasers and keloids with classical methods (intralesional steroids or interferon,
alone or in combination with surgical or laser excision).
Article accepted on 27/6/01
|
|
|
|
Figure 1. Facial
abnormalities: prominent, beaked nose with broad bridge, down-slanting
of eyes, prominent eyebrows. |
|
|
|
|
|
Figure 2. Short,
broad thumbs. |
|
|
|
|
|
Figure 3. Short,
broad hallux. |
|
|
|
|
|
Figure 4.
Keloid of the forearm. |
|
References
1. Rubinstein J, Taybi H. Broad thumbs and toes and facial abnormalities.
Am J Dis Child 1963; 105: 588-608.
2. Petrij F, Giles R, Dauwerse H, Saris J, Hennekam R, Masuno
M, Tommerup N, van Ommen GJ, Goodman R, Peters D, Breuning M. Rubinstein-Taybi
syndrome caused by mutations in the transcriptional co-activator CBP.
Nature 1995; 376: 348-51.
3. Petrij F, Dauwerse H, Blough R, Giles R, van den Smagt J,
Wallerstein R, Maaswinkel-Mooy P, van Karnebeek C, van Ommen G, van Haeringen
A, Rubinstein J, Saal H, Hennekam R, Peters D, Breuning M. Diagnostic
analysis of the Rubinstein-Taybi syndrome: five cosmids should be used
for microdeletion detection and low number of protein truncating mutations.
J Med Genet 2000; 37: 168-76.
4. Bartsch O, Hinkel G, Krebs P, Stumm M, Schmalenberger B, Bohm
S, Balci S, Majewski F. FISH studies in 45 patients with Rubinstein-Taybi
syndrome: deletions associated with polysplenia, hypoplastic left heart
and death in infancy. Eur J Hum Genet 1999; 7: 748-56.
5. Murata T, Kurokawa R, Krones A, et al. Defect of histone
acetyltransferase activity of the nuclear transcriptional coactivator
CBP in Rubinstein-Taybi syndrome. Hum Mol Genet 2001; 10: 1071-6.
6. Preis S, Majewski F. Monozygotic twins concordant for Rubinstein-Taybi
syndrome: changing phenotype during infancy. Clin Genet 1995; 48:
72-5.
7. Marion R, Garcia D, Karasik J. Apparent dominant transmission
of the Rubinstein-Taybi syndrome. Am J Med Genet 1993; 46: 284-7.
8. Hennekam R, Stevens C, van de Kamp J. Etiology and recurrence
risk in Rubinstein-Taybi syndrome. Am J Med Genet 1990; 6 (suppl.):
56-64.
9. Miller R, Rubinstein J. Tumors in Rubinstein-Taybi syndrome.
Am J Med Genet 1995; 56: 112-5.
10. Goodfellow A, Emmerson R, Calvert H. Rubinstein-Taybi syndrome
and spontaneous keloids. Clin Exp Dermatol 1980; 5: 369-70.
11. Kurwa A. Rubinstein-Taybi syndrome and spontaneous keloids.
Clin Exp Dermatol 1979; 4: 251-4.
12. Sammartino A, Cerbella R, Lembo G, Federico A, Loffredo L.
Syndrome de Rubinstein-Taybi avec chéloïdes multiples. J
Fr Ophtalmol 1986; 9: 725-9.
13. Siraganian P, Rubinstein J, Miller R. Keloids and neoplasms
in the Rubinstein-Taybi syndrome. Med Pediatr Oncol 1989; 17: 485-91.
14. Selmanowitz V, Stiller M. Rubinstein-Taybi syndrome. Cutaneous
manifestations and colossal keloids. Arch Dermatol 1981; 117: 504-6.
15. Hendrix JD, Greer KE. Rubinstein-Taybi syndrome with multiple
flamboyant keloids. Cutis 1996; 57: 346-8.
16. Cambiaghi S, Ermacora E, Brusasco A, Canzi L, Caputo R. Multiple
pilomatricomas in Rubinstein-Taybi syndrome. Pediatr Dermatol 1994;
11: 21-5.
17. Masuno M, Imaizumi K, Ishii T, Kuroki Y, Baba N, Tamaka Y.
Pilomatrixomas in Rubinstein-Taybi syndrome. Am J Med Genet 1998;
77: 81-2.
18. Rousseau MC, Tachji K. Syndrome de Rubinstein-Taybi : hypertrophie
mamelonnaire. Rev Neurol 2000; 156: 1161.
19. Gomez Centeno P, Roson E, Mercedes Pereiro M, Toribio J.
Rubinstein-Taybi syndrome and ulerythema ophryogenes in a 9-year-old boy.
Pediatr Dermatol 1999; 16: 134-6.
20. Giroux J, Miller JR. Dermatoglyphics of the broad thumb and
great toe syndrome. Am J Dis Child 1967; 113: 207-9.
21. Herranz P, Borbujo J, Martinez W, Vidaurrazaga C, Diaz R,
Casado M. Rubinstein-Taybi syndrome with piebaldism. Clin Exp Dermatol
1994; 19: 170-2.
22. Schepi C, Grego D, Siragusa M, Batolo D, Romano C. Rubinstein-Taybi
syndrome with epidermal nevus: a case report. Pediatr Dermatol
2001; 18: 34-7.
|
Version imprimable