American Journal of Medical Genetics 85:495–497 (1999) Brief Clinical Report Sporadic Case of Trichorhinophalangeal Syndrome Type III in a European Patient Catheline Vilain,1 Yves Sznajer,1 Françoise Rypens,2 Daniel Désir,3 and Marc J. Abramowicz1* 1 Department of Medical Genetics, Brussels University Clinics—Hôpital Erasme, Free University of Brussels (ULB), Brussels, Belgium 2 Department of Medical Imaging, Brussels University Clinics—Hôpital Erasme, Free University of Brussels (ULB), Brussels, Belgium 3 Department of Endocrinology, Brussels University Clinics—Hôpital Erasme, Free University of Brussels (ULB), Brussels, Belgium Trichorhinophalangeal syndrome type III (TRP III) shares common traits with TRP I and II, including sparse hair, a “pearshaped” nose, osteodysplasia with coneshaped epiphyses, and autosomal dominant inheritance, but is distinguished by the presence of severe brachydactyly. TRP III was first described in 1984 in Japanese patients, one sporadic case [Sugio and Kajii, 1984: Am. J. Med. Genet. 19:741–753,1984] and two families [Niikawa and Kamei, 1986: Am. J. Med. Genet. 24:759–760; Nagaı̈ et al., 1994: Am. J. Med. Genet. 49:278–280], and more recently in a Turkish family [Itin et al., 1996: Dermatology 193:349–352]. We report an additional observation in a patient of European descent, who presented with short stature, cone-shaped epiphyses, sparse hair, a pear-shaped nose, normal intelligence and severe brachydactyly. Neither parent had manifestations of TRP and there was no other reported case in the family, indicating a presumably fresh mutation. Our observation refines the clinical spectrum of TRP III in another ethnic background and may be of help in identifying the gene or genes for TRP syndromes. Am. J. Med. Genet. 85:495– 497, 1999. © 1999 Wiley-Liss, Inc. KEY WORDS: brachydactyly; alopecia; osteodysplasia; arthropathy INTRODUCTION The trichorhinophalangeal (TRP) syndromes are distinguished as type I, II, and III. TRP I is characterized C. Vilain and Y. Sznajer contributed equally to this work. *Correspondence to: Marc J. Abramowicz, M.D., Ph.D., Service de Génétique médicale, Hôpital Erasme, B-1070 Brussels, Belgium. E-mail: firstname.lastname@example.org Received 2 November 1998; Accepted 8 March 1999 © 1999 Wiley-Liss, Inc. by sparse hair, a distinctive, bulbous nose with dorsally tented nares, and mild skeletal dysplasia with coneshaped epiphyses, short stature, and shortening of the metacarpals and metatarsals [Giedion et al., 1973]. TRP II includes findings of TRP I, exostoses, mental retardation, and skin abnormalities [Hall et al., 1974]. TRP III was first described by Sugio and Kajii in 1984. It differs from TRP II by normal intelligence and absence of exostoses and from TRP I by the severe shortness of all phalanges and metacarpals. To date, a Japanese TRP III sporadic case [Niikawa and Kamei, 1986], another Japanese family with four affected individuals [Nagai et al., 1994], and a Turkish family with seven patients [Itin et al., 1996] have been reported. TRP III seems much rarer than the other types. When familial, inheritance of the TRP syndromes is autosomal dominant, with male-to-male transmission [Itin et al., 1996]. Cytogenetic observations in TRP I mapped the defect to 8q24 [Bühler and Malik, 1984] with no evidence for locus heterogeneity [Ludecke et al., 1995]. Although a TRP gene has not been cloned yet, evidence indicates that TRP type II may be caused by a contiguous gene deletion in the 8q24 region encompassing the TRP1 and EXT1 loci, defects of the latter causing dominantly inherited multiple exostoses [Ludecke et al., 1995]. We report on an additional case of TRP III, to our knowledge the first in a patient of western European descent. CLINICAL REPORT A 29-year-old man was investigated for chronic pain in multiple joints. He was short (147 cm), and had a distinctive face, with a “pear-shaped” nose and hypoplastic alae nasi (Fig. 1). The hair was sparse with baldness in rapid progression since a few months before admission. The beard was also sparse. The hands were extremely short, with a total hand length of 13.5 cm and a middle finger length of 5.7 cm, both values below the 3rd centile. The hands had a swollen appearance, and the patient was handicapped from pain limiting finger movement. The feet were short, with very 496 Vilain et al. Fig. 1. A composite of the patient. Distinctive face with pear-shaped nose and long philtrum, and sparseness of hair and beard. Short, swollen hands with severe brachydactyly. Short metacarpals and phalanges. The distal epiphysis of the second metacarpal is cone shaped. short first and fourth metatarsals. The gait was abnormal, with limping and pain in the left hip. The patient reported a subjective feeling of an accelerated aging process and was depressed. He was of normal intelligence and worked as a computer operator. He was born to healthy, nonconsanguineous Belgian parents, the father being 175 cm and the mother 157 cm tall. A younger sister was 180 cm tall and of normal appearance, and review of the family history was unremarkable. Birth weight and length had been normal (3.3 kg and 52 cm). He was first investigated at 3 years for moderately short stature. Supernumerary teeth were removed, and bilateral carpal tunnels surgically corrected. X-ray skeletal investigations showed numerous abnormalities including short metacarpals and metatarsals with cone-shaped epiphyses (Fig. 1), Legg-CalvéPerthes–like changes of the femoral epiphyses, mild scoliosis, and generalized osteopenia. There were no exostoses. A standard karyotype was normal and fluorescent in situ hybridization (FISH) analysis of 8q24 probed with Y30C3 [Ludecke et al., 1995] detected two normal signals (not shown). DISCUSSION Our patient displays marked growth retardation and severe brachydactyly along with hair, facial, and epiphyseal changes typical of TRP, with absence of mental retardation or exostoses, consistent with a diagnosis of TRP type III [Nagaı̈ et al., 1994]. To our knowledge, this is the first case of TRP III in a western European patient. It is a sporadic case, consistent with a new mutation. Severe brachydactyly is the hallmark of TRP III. However, it is not a constant finding in all affected subjects from TRP III families [Sugio and Kajii, 1984], and it has been observed in patients from TRP I families [Giedion et al., 1973]. Thus it remains possible that the TRP III brachydactyly might represent one phenotypic extreme of the clinical spectrum of TRP I. If TRP I and III should prove to be allelic disorders, our observation may help delineate genotype-phenotype correlations regarding brachydactyly. TRP III in a European Patient Although the TRP genes have not been cloned yet, evidence suggests that null mutations may cause TRP I, given that small deletions of the 8q24.12 region have been observed in TRP I patients, and larger ones encompassing the 8q24.11-8q24.13 region in TRP II patients [Bühler and Malik, 1984; Ludecke et al., 1995]. Marked growth retardation and severe brachydactyly are not cardinal manifestations of TRP II, a finding that argues against the presence of a distinct gene within the contiguous 8q24 segment responsible for severe brachydactyly, and favors the hypothesis of locus heterogeneity for TRP III. Consistent with this speculation, the 8q24 region appeared intact in our patient on FISH analysis using probe Y30C3. REFERENCES Bühler EM, Malik NJ. 1984. 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