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Case report A novel mutation in TPRS1 gene caused tricho-rhino-phalangeal syndrome in a Chinese patient with severe osteoporosis SHAO Cong, TIAN Jun, SHI Dong-hong, YU Chun-xiao, XU Chao, WANG Lai-cheng, GAO Ling and ZHAO Jia-jun Keywords: osteoporosis; tricho-rhino-phalangeal syndrome; TRPS1 gene Tricho-rhino-phalangeal syndrome (TRPS) was first reported in 1966. Although mutation of TRPS1 gene is considered to be responsible for the syndromes in 2000, investigation of bone metabolism and changes of serum insulin-like growth factor (IGF)-1 level in this kind of patients is rare. Here, we report a patient with TRPS I (MIM 190350) presenting a novel mutation (1096insA) and abnormal changes of severe osteoporosis as well as low serum IGF-I level. Chin Med J 2011;124(10):1583-1585
T
richo-rhino-phalangeal syndrome (TRPS) is an autosomal dominant disorder characterized by craniofacial dysmorphism and bone deformities.1,2 Three subtypes have been described: TRPS I (MIM 190350), TRPS II (MIM 150230) and TRPS III (MIM 190351). Several studies reported that mutations in the TRPS1 gene can lead to this syndrome.1-3 However, investigation of bone metabolism and quality and changes of serum insulin-like growth factor (IGF)-1 level in this kind of patients is rare. So far, there is no mutation analysis of tricho-rhino-phalangeal syndrome reported in Mainland of China. In this study, we performed mutation analysis by direct sequencing and identified a novel mutation in TRPS1 gene in a Chinese patient suffered from TRPS I. The protocol was authorized by Ethical Committee of Provincial Hospital affiliated to Shandong University. CASE REPORT The patient, a 17-year-old boy, from a nonconsanguineous family, was referred to Department of Endocrinology and Metabolism, Provincial Hospital affiliated to Shandong University because of short stature, 154 cm. He presented with cephalus quadratus, thin and sparse hair, receded frontotemporal hairline and the medial part of the occipital hairline, rarefaction of lateral eyebrows, and ptosis. Further physical examination was remarkable for a bulbous nose, elongated philtrum, thin upper lip, high palatine arch, protruding ears and a funnel chest (Figure 1A and 1B). He showed normal development of secondary sex characteristics and brachydactyly of both hands and big toes with short and broad nails (Figure 1C and 1D). The radiograph showed brachydactyly of both hands and big toes, brachymetatarsia of both first metatarsal bones, cone-shaped epiphyses of the second to fourth middle phalanges and second to third proximal phalanges of both hands (Figure 1E and 1F). Bone age was normal. According to clinical and radiographic findings, TRPS I was diagnosed.
Bone mineral density (BMD) was determined using a Dual-Energy X-ray Absorptiometry (EXA-3000, Osteosys, Korea). The patient showed severe osteoporosis (bone mineral density: 0.345 g/cm2; T-score: –3.94) according to the standard of World Health Organization (WHO). Blood routine, liver function and serum biochemical determining did not reveal any abnormalities. The levels of serum free triiodothyronine (FT 3 ), free thyroxine (FT 4 ), thyroid-stimulating hormone (TSH), prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), testosterone (T), progesterone (P) and cortisol were also normal. Growth hormone (GH) provocation test with L-dopa showed a low response (GH: 0 minute: 1.5 µg/L; 60 minutes: 1.5 µg/L; 90 minutes: 1.9 µg/L, using radioimmunoassay). Plasmatic concentration of IGF-1 of the patient was low (56.5 µg/L) relative to the normal population matched to his age and sex (normal reference range: 140.3–220.7 µg/L, using the hIGF-1 radioimmunoassay kit, Diagnostic System Laboratories, DOI: 10.3760/cma.j.issn.0366-6999.2011.10.028 Department of Endocrinology and Metabolism, Provincial Hospital Affiliated to Shandong University, Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China (Shao C, Yu CX and Zhao JJ) Shandong Medical Imaging Research Institute, Jinan, Shandong 250021, China (Tian J) Chromosome Biology Laboratory, Department of Gynaecology and Obstetrics (Shi DH), Department of Scientific Center (Wang LC and Gao L), Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China Department of Endocrinology and Metabolism, Weihai Hospital, Medical College of Qingdao University, Weihai, Shandong 264200, China (Xu C) Correspondence to: Dr. GAO Ling, Department of Scientific Center, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China (Email:
[email protected]); Dr. ZHAO Jia-jun, Department of Endocrinology and Metabolism, Provincial Hospital Affiliated to Shandong University, Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China (Tel: 86-531-87065127 & 86-53185186149. Fax: 86-531-87067758. Email:
[email protected]) This study was supported by a grant from the National Natural Science Foundation of China (No. 81000039).
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Figure 1. Features of the patient. A: Note bulbous distal nose, elongated philtrum, thin upper lip. B: Alopecia of the frontotemporal region in the patient, protruding ears. C, D: Brachydactyly and deviation of limbs with short and broad nails. E, F: X-ray of the hands and feet with cone-shape epiphyses.
USA). Chromosomal studies on peripheral lymphocyte culture showed a 46, XY normal male karyotype. For further study, all the members of the family were recruited (Figure 2). After obtaining informed consent, genomic DNA of all members was extracted from peripheral blood leukocytes using the DNA isolation kit (TIANGEN, Beijing). Exons 2–7 of TRPS1 gene were entirely amplified using primers selected with the program PRIMER5 (GenBank accession number: NT 008046.15). Mutations of exons and the flanking intronic sequences in TRPS1 gene were screened in the polymerase chain reaction (PCR) products by direct sequencing using an ABI Prism 3100-Avant Genetic Analyzer (Applied Biosystems, USA). A novel insertion of an adenine at nucleotide position 1096 on exon 4 (Figure 3) was identified in the patient, but not present in other members. This base insertion, with a consequent frameshift from amino acid 366, resulted in a premature stop codon at amino acid 383. Occuring prior to the nuclear localization signals (NLS), this mutation (1096insA) is predicted to result in a truncated, nonfunctional TRPS1 protein absent of NLS. Incorrect protein localization may be responsible for the loss of function. DISCUSSION Here we describe a patient suffered from tricho-rhinophalangeal syndrome type I. In addition to typical features of TRPS, he also showed severe osteoporosis which has not been reported before. Through mutation analysis, a novel insertion mutation (1096insA) in TPRS1 gene was identified which is predicted to result in a truncated, nonfunctional TRPS1 protein absent of NLS. Thus, a novel mutation (1096insA) in TPRS1 gene caused a novel phenotype of TPRS with severe osteoporosis in a Chinese patient. TRPS is a rare genetic disorder, characterized by typical craniofacial and skeletal abnormalities. Patients affected by TRPS show sparse scalp hair, bulbous nose, long flat
Figure 2. Pedigree of the family. The given arabic numbers 1–11 denote the serial numbers of individuals in the family available for analysis. The number of the patient (propositus) is 10.
Figure 3. Mutation analysis. The upper two lines show the mutant sequence in the patient (first line in the 5′→3′ direction; second line in the 3′→5′ direction) and the lower two lines show the sequence in the normal (third line in the 5′→3′ direction; fourth line in the 3′→5′ direction).
philtrum, thin upper vermillion border, and protruding ears. The skeletal abnormalities include cone-shaped epiphyses of the phalanges, hip malformation, chest and spinal abnormalities. Short stature is another characteristic of these patients.4 Kunath and Malik et al5,6 reported GATA type zinc finger of TRPS1 is involved in regulation of bone and hair development and may be responsible for growth and skeletal abnormalities in these patients. In addition to typical features of TRPS reported before, the patient had some uncommon signs like cephalus
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quadratus, a funnel chest, a low level of plasmatic IGF-1 and a low response to L-dopa stimulation. Measurement of IGF-1 has shown comparable diagnostic performance with GH stimulation tests and are valuable for patients’ convenience and ease of performance and can be useful in the initial workup of short stature.7 IGF-I level below the mean according to age indicates high probability of GH deficiency. The L-dopa provocation test can be used as one of the methods to diagnose midgetism.8 This indicates he might have GH deficiency.9 Significantly reduced bone mass and quality with normal bone metabolism parameters (serum calcium and phosphorus levels) also attracted us. The combination of characteristics above has not been described in the patients affected by TRPS I yet. So our study expanded genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome. A further interesting characteristic of the patient was the complaint of more tears and saliva. So far, only one case with more tears has been reported in TRPS.10 There are no studies on expression of TRPS1 in glands, and the relationship between abnormal secretion of glands and TRPS needs further investigation. TRPS1 gene, encoding TRPS1 protein, has a nuclear localization signal (NLS) which is indispensable for translocation of TRPS1 protein into the nucleus and may also assist in specifying the DNA binding of the GATA zinc finger. To date, 44 mutations in the TRPS1 gene have been reported, among which 21 mutations can result in TRPS1 protein absent of NLS. The mutant protein lacking NLS theoretically can not enter the nucleus and play correct role. The phenotype of most patients with these mutations fits into the observed spectrum of TRPS I. It has been shown that TRPS I is associated with deletions and nonsense mutations of one allele of TRPS1, which is believed to cause a reduction of the TRPS1 protein concentration in the nucleus, a phenomenon called haploinsufficiency.11 Our findings are consistent with the haploinsufficiency model of TRPS I. In summary, our study shows that a Chinese patient with TRPS I presented significantly reduced bone mass and quality. A novel mutation (1096insA) in TPRS1 gene was also identified. It is recommended that mutation analysis of candidate genes, TRPS1, should be carried out in the patients suffered from TRPS. Study on the regulatory effect and functional analysis of this mutation will doubtlessly assist in understanding the mechanism of the disorder.
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Momeni P, Glöckner G, Schmidt O, von Holtum D, Albrecht B, Gillessen-Kaesbach G, et al. Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I. Nat Genet 2000; 24: 71-74. 2. Lüdecke HJ, Schaper J, Meinecke P, Momeni P, Gross S, von Holtum D, et al. Genotypic and phenotypic spectrum in trichorhinophalangeal syndrome types I and III. Am J Hum Genet 2001; 68: 81-91. 3. Matthew JH, Jacob MS, Laura G, Amber H, Ting CK, Dan EW. Analysis of novel and recurrent mutations responsible for the tricho-rhino-phalangeal syndromes. J Hum Genet 2002; 47: 103-106. 4. Naselli A, Vignolo M, Di Battista E, Papale V, Aicardi G, Becchetti S, et al. Trichorhinophalangeal syndrome type I in monozygotic twins discordant for hip pathology. Report on the morphological evolution of cone-shaped epiphyses and the unusual pattern of skeletal maturation. Pediatr Radiol 1998; 28: 851-855. 5. Kunath M, Lüdecke HJ, Vortkampa A. Expression of Trps1 during mouse embryonic development. Gene Expr Patterns 2002; 2: 119-122. 6. Malik TH, Von Stechow D, Bronson RT, Shivdasani RA. Deletion of the GATA domain of TRPS1 causes an absence of facial hair and provides new insights into the bone disorder in inherited tricho-rhino-phalangeal syndromes. Mol Cell Biol 2002; 22: 8592-8600. 7. Ali A, Hashim R, Khan FA, Sattar A, Ijaz A, Manzoor SM, et al. Evaluation of insulin-like growth factor-1 and insulinlike growth factor binding protein-3 in diagnosis of growth hormone deficiency in short-stature children. J Ayub Med Coll Abbottabad 2009; 21: 40-45. 8. Zhao GB, Chu XH, Jia L, Cong AL, Ye ZH. Value of the L-dopa provocation test in children with growth retardation. Anhui Med Pharmaceut J (Chin) 2006; 10: 349. 9. Jung CH, Lee WY, Rhee EJ, Kim SY, Oh KW, Yun EJ, et al. Serum ghrelin and leptin levels in adult growth hormone deficiency syndrome. Arch Med Res 2006; 37: 612-618. 10. Liu K, Tian J. A case report: trichorhinophalangeal syndrome. J Med Imaging (Chin) 2006; 16: 1092-1096. 11. Kaiser FJ, Brega1 P, Raff ML, Byers PH, Gallati S, Kay TT, et al. Novel missense mutations in the TRPS1 transcription factor define the nuclear localization signal. Eur J Hum Genet 2004; 12: 121-126.
(Received August 26, 2010) Edited by GUO Li-shao
