RESEARCH LETTER
Is Tel Hashomer Camptodactyly a Distinct Clinical Entity? A. Mochizuki,1 J. Hyland,2 T. Brown,3* and T. P. Slavin1,4 1
University of Hawaii, Department of Pediatrics, Honolulu, Hawaii
2
Connective Tissue Gene Tests, Allentown, Pennsylvania
3
Chiropractic Sports Medicine, Newport Beach, California Kapiolani Medical Specialists, Honolulu, Hawaii
4
Manuscript Received: 29 July 2014; Manuscript Accepted: 19 September 2014
TO THE EDITOR In 1972, Goodman et al. described two siblings aged 13 and 17 years old with camptodactyly; in 1976, Goodman et al. discussed two sisters with similar features and termed the disorder Tel Hashomer camptodactyly (THC, OMIM #211960). Since then, a handful of articles regarding 21 patients have been published about THC. Melegh et al. [2005] described a boy with noticeable muscle hypoplasia by 21 months of age and rigid camptodactyly by 29 months. By age 12, the patient had continued short stature, worsened contractures of the fingers, and knees, hypotrophic and hypotonic muscles, and shuffling gait. A 2011 paper by Smolkin et al., reported on twins with intrauterine growth restriction, camptodactyly, and long bone shortening revealed by prenatal ultrasound. At birth, they were noted to have the hallmark features of THC: camptodactyly, high palate, hypertelorism, brachycephaly, and dermatoglyphic abnormalities. Their group summarized the clinical findings of THC as a rare, autosomal recessive disorder with major features of camptodactyly, high arched palate, hypertelorism, brachycephaly, and palmar dermatoglyphic abnormalities with no known genetic locus. As recently as 2013, Shah et al. presented a 25year-old individual with camptodactyly, clubfeet, dental crowding, and mitral valve prolapse (MVP) who presented with symptomatic weakness. They noted that there were many overlapping features of a connective tissue disorder and concluded that his clinical picture fit best with that of THC. Here, we suggest that at least some cases of THC may be Ehlers-Danlos syndrome (EDS), musculocontractural subtype, and recommend that individuals diagnosed with THC be evaluated for this condition. In a brief clinical report previously published in this journal, Toriello et al. [1990] presented two siblings with a generalized connective tissue disorder with features of bilateral ptosis, downslanting palpebral fissures, clubfeet, hypertelorism, high palate, winged scapulae, hypoplastic interphalangeal creases, and MVP. The authors attributed the patients’ condition to THC, describing MVP as a previously undescribed manifestation of the syndrome. The male proband from Toriello et al. [1990] is now 41 years of age (Fig. 1). Since the article’s publication in 1990, he has had multiple arthroscopic joint surgeries, significant joint pain, and innumerable large and small joint dislocations (multiple times a
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Mochizuki A, Hyland J, Brown T, Slavin TP. 2015. Is tel hashomer camptodactyly a distinct clinical entity?. Am J Med Genet Part A 167A:255–258.
week, starting when he was just 3 or 4 years old), which he averts to the best of his ability with daily taping and bracing (Fig. 2). Around the age of 30, the patient had an intestinal rupture secondary to volvulus. He continues to have severe joint laxity, bruising, tearing of skin, surgical wound dehiscence, and tympanic membrane perforations. His MVP has been stable with no aortic root dilatation. In addition, he has been afflicted by moderate hearing loss. He has had worsening vision since childhood secondary to a cataract in his left eye with retinal abnormalities including nodular nerve fibers and an unusual vascular pattern; his right eye is normal. The patient was referred by his rheumatologist to our genetics clinic for consultation in September 2012. After evaluation, it was believed his diagnosis fit better with EDS musculocontractural subtype (formerly type VIB, OMIM #601776). Blood DNA testing was performed which revealed a homozygous c.784G>A (p.Glu262Lys) transition in exon 1 of the carbohydrate sulfotransferase 14 (CHST14) gene (Fig 2). Protein modeling utilizing SIFT shows the Glu262Lys substitution to be deleterious [Ng and Henikoff, 2001]. Glutamate at position 262 is highly conserved in 26 of 29 species. Subsequently his 36 year-old sister, the female from Toriello et al. [1990] had point mutation analysis showing the same homozygous Conflict of interest: None. Correspondence to: Aaron Mochizuki, Los Angeles County þ University of Southern California Department of Pediatrics, 2020 Zonal Ave, IRD 112, Los Angeles, CA 90033. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 27 October 2014 DOI 10.1002/ajmg.a.36826
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FIG. 1. Male proband from Toriello et al. (1990); facial and hand features. Note the down-slanting palpebral fissures, narrow face, and camptodactyly.
mutation. She has a milder phenotype with features of MVP with occasional palpitations, weak eye muscles, difficulty hearing, dental crowding, excess skin, hand contractures (Fig. 3), and hyperflexibility. She has had up to 10 major joint dislocations in her life, though does not need daily bracing. CHST14 encodes dermatan-4-sulfotransferase I. It was first found to be involved in EDS VIB by Miyake et al. in 2010. Musculocontractural Ehlers-Danlos syndrome caused by mutations in CHST14 is now a rare, but recognized, autosomal recessive
FIG. 2. Chromogram of the CHTS14 mutation,c.784G>A (p. Glu262Lys).
FIG. 3. Hands and feet from the female described originally in Toriello et al (1990). Note the camptodactyly and limited distal interphalangeal joint creasing.
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FIG. 4. The male proband from Toriello et al (1990) and his daily taping and bracing routine. IntelliskinTM, a proprietary sensorimotor stimulating (similar to kinesio taping) support system created by Dr. Tim Brown, is featured in the last 6 pictures, is used to increase tone and improve joint stability by improving movement and muscle imbalances to enhance proprioception and posture.
disorder of glycosaminoglycan synthesis; it consistently presents with large fontanels, downward slanting palpebral fissures, significant skin hyperextensibility, atrophic scar development, camptodactyly, multiple joint contractures, recurrent joint dislocations, cardiac valve abnormalities, and normal intelligence [MendozaLondono et al., 2012]. In summary, we have changed the diagnosis for the siblings described originally in Toriello et al. [1990] from THC to musculocontractural EDS. The female’s milder phenotype may be due to protective modifier genes that her brother did not inherit. We also provide updated clinical information on this sibling pair and show the unique and novel IntelliskinTM approach to treatment of this condition, used daily by the male proband (Fig. 4). Since no punitive genetic locus has been found to molecularly distinguish THC, the differential diagnosis should include musculocontractual EDS. In terms of musculocontractual EDS, the severity of the joint dislocations, the cardiac valve abnormalities, and other connective tissue features may not become apparent until late child or early adulthood. We recommend CHST14 gene testing for any THC patient that has phenotypic features of musculocontractual EDS.
ACKNOWLEDGMENTS We would like to acknowledge the male proband’s ophthalmologists Dr. Carlton Yuen and Dr. Byron Wong, cardiologist Dr. Samuel Dacanay, and rheumatologist Dr. Scott Kawamoto. Dr. Tim Brown is creator of PostureCue technology and founder of Intelliskin. Drs. Slavin, Hyland, and Mochizuki have no conflicts of interest to disclose.
REFERENCES Goodman RM, Katznelson MB, Manor E. 1972. Camptodactyly: Occurence in two new genetic syndromes and its relationship to other syndromes. J Med Genet 9:203–212. Goodman RM, Katznelson MB, Hertz M, Katznelson A. 1976. Camptodactyly, with muscular hypoplasia, skeletal dysplasia, and abnormal palmar creases: Tel Hashomer camptodactyly syndrome. J Med Genet 13:136–141. Melegh B, Hollo´dy K, Aszmann M, Me´hes K. 2005. Tel Hashomer camptodactyly syndrome: 12-year follow-up of a Hungarian patient and review. Am J Med Genet A 135:320–323. Mendoza-Londono R, Chitayat D, Kahr WH, Hinek A, Blaser S, Dupuis L, Goh E, Badilla-Porras R, Howard A, Mittaz L, Superti-Furga A, Unger S,
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Nishimura G, Bonafe L. 2012. Extracellular matrix and platelet function in patients with musculocontractural Ehlers-Danlos syndrome caused by mutations in the CHST14 gene. Am J Med Genet A 158A:1344–1354.
Shah K, Sreekanth R, Thomas B, Danda S. 2013. Tel Hashomer camptodactyly syndrome: A case report. West Indian Med J 62: 81–83.
Miyake N, Kosho T, Mizumoto S, Furuichi T, Hatamochi A, Nagashima Y, Arai E, Takahashi K, Kawamura R, Wakui K, et al. 2010. Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome. Hum Mutat 31:966–974.
Smolkin T, Blazer S, Gershoni-Baruch R, Makhoul IR. 2011. Tel Hashomer camptodactyly syndrome in identical twin infants. Clin Dysmorphol 20:214–216.
Ng PC, Henikoff S. 2001. Predicting deleterious amino acid substitutions. Genome Res 11:863–874.
Toriello HV, Higgins JV, Malvitz T, Waterman DF. 1990. Two siblings with Tel Hashomer camptodactyly and mitral valve prolapse. Am J Med Genet 36:398–403.
Is Tel Hashomer Camptodactyly a Distinct Clinical Entity? A. Mochizuki,1 J. Hyland,2 T. Brown,3* and T. P. Slavin1,4 1
University of Hawaii, Department of Pediatrics, Honolulu, Hawaii
2
Connective Tissue Gene Tests, Allentown, Pennsylvania
3
Chiropractic Sports Medicine, Newport Beach, California Kapiolani Medical Specialists, Honolulu, Hawaii
4
Manuscript Received: 29 July 2014; Manuscript Accepted: 19 September 2014
TO THE EDITOR In 1972, Goodman et al. described two siblings aged 13 and 17 years old with camptodactyly; in 1976, Goodman et al. discussed two sisters with similar features and termed the disorder Tel Hashomer camptodactyly (THC, OMIM #211960). Since then, a handful of articles regarding 21 patients have been published about THC. Melegh et al. [2005] described a boy with noticeable muscle hypoplasia by 21 months of age and rigid camptodactyly by 29 months. By age 12, the patient had continued short stature, worsened contractures of the fingers, and knees, hypotrophic and hypotonic muscles, and shuffling gait. A 2011 paper by Smolkin et al., reported on twins with intrauterine growth restriction, camptodactyly, and long bone shortening revealed by prenatal ultrasound. At birth, they were noted to have the hallmark features of THC: camptodactyly, high palate, hypertelorism, brachycephaly, and dermatoglyphic abnormalities. Their group summarized the clinical findings of THC as a rare, autosomal recessive disorder with major features of camptodactyly, high arched palate, hypertelorism, brachycephaly, and palmar dermatoglyphic abnormalities with no known genetic locus. As recently as 2013, Shah et al. presented a 25year-old individual with camptodactyly, clubfeet, dental crowding, and mitral valve prolapse (MVP) who presented with symptomatic weakness. They noted that there were many overlapping features of a connective tissue disorder and concluded that his clinical picture fit best with that of THC. Here, we suggest that at least some cases of THC may be Ehlers-Danlos syndrome (EDS), musculocontractural subtype, and recommend that individuals diagnosed with THC be evaluated for this condition. In a brief clinical report previously published in this journal, Toriello et al. [1990] presented two siblings with a generalized connective tissue disorder with features of bilateral ptosis, downslanting palpebral fissures, clubfeet, hypertelorism, high palate, winged scapulae, hypoplastic interphalangeal creases, and MVP. The authors attributed the patients’ condition to THC, describing MVP as a previously undescribed manifestation of the syndrome. The male proband from Toriello et al. [1990] is now 41 years of age (Fig. 1). Since the article’s publication in 1990, he has had multiple arthroscopic joint surgeries, significant joint pain, and innumerable large and small joint dislocations (multiple times a
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Mochizuki A, Hyland J, Brown T, Slavin TP. 2015. Is tel hashomer camptodactyly a distinct clinical entity?. Am J Med Genet Part A 167A:255–258.
week, starting when he was just 3 or 4 years old), which he averts to the best of his ability with daily taping and bracing (Fig. 2). Around the age of 30, the patient had an intestinal rupture secondary to volvulus. He continues to have severe joint laxity, bruising, tearing of skin, surgical wound dehiscence, and tympanic membrane perforations. His MVP has been stable with no aortic root dilatation. In addition, he has been afflicted by moderate hearing loss. He has had worsening vision since childhood secondary to a cataract in his left eye with retinal abnormalities including nodular nerve fibers and an unusual vascular pattern; his right eye is normal. The patient was referred by his rheumatologist to our genetics clinic for consultation in September 2012. After evaluation, it was believed his diagnosis fit better with EDS musculocontractural subtype (formerly type VIB, OMIM #601776). Blood DNA testing was performed which revealed a homozygous c.784G>A (p.Glu262Lys) transition in exon 1 of the carbohydrate sulfotransferase 14 (CHST14) gene (Fig 2). Protein modeling utilizing SIFT shows the Glu262Lys substitution to be deleterious [Ng and Henikoff, 2001]. Glutamate at position 262 is highly conserved in 26 of 29 species. Subsequently his 36 year-old sister, the female from Toriello et al. [1990] had point mutation analysis showing the same homozygous Conflict of interest: None. Correspondence to: Aaron Mochizuki, Los Angeles County þ University of Southern California Department of Pediatrics, 2020 Zonal Ave, IRD 112, Los Angeles, CA 90033. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 27 October 2014 DOI 10.1002/ajmg.a.36826
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A
256
FIG. 1. Male proband from Toriello et al. (1990); facial and hand features. Note the down-slanting palpebral fissures, narrow face, and camptodactyly.
mutation. She has a milder phenotype with features of MVP with occasional palpitations, weak eye muscles, difficulty hearing, dental crowding, excess skin, hand contractures (Fig. 3), and hyperflexibility. She has had up to 10 major joint dislocations in her life, though does not need daily bracing. CHST14 encodes dermatan-4-sulfotransferase I. It was first found to be involved in EDS VIB by Miyake et al. in 2010. Musculocontractural Ehlers-Danlos syndrome caused by mutations in CHST14 is now a rare, but recognized, autosomal recessive
FIG. 2. Chromogram of the CHTS14 mutation,c.784G>A (p. Glu262Lys).
FIG. 3. Hands and feet from the female described originally in Toriello et al (1990). Note the camptodactyly and limited distal interphalangeal joint creasing.
MOCHIZUKI ET AL.
257
FIG. 4. The male proband from Toriello et al (1990) and his daily taping and bracing routine. IntelliskinTM, a proprietary sensorimotor stimulating (similar to kinesio taping) support system created by Dr. Tim Brown, is featured in the last 6 pictures, is used to increase tone and improve joint stability by improving movement and muscle imbalances to enhance proprioception and posture.
disorder of glycosaminoglycan synthesis; it consistently presents with large fontanels, downward slanting palpebral fissures, significant skin hyperextensibility, atrophic scar development, camptodactyly, multiple joint contractures, recurrent joint dislocations, cardiac valve abnormalities, and normal intelligence [MendozaLondono et al., 2012]. In summary, we have changed the diagnosis for the siblings described originally in Toriello et al. [1990] from THC to musculocontractural EDS. The female’s milder phenotype may be due to protective modifier genes that her brother did not inherit. We also provide updated clinical information on this sibling pair and show the unique and novel IntelliskinTM approach to treatment of this condition, used daily by the male proband (Fig. 4). Since no punitive genetic locus has been found to molecularly distinguish THC, the differential diagnosis should include musculocontractual EDS. In terms of musculocontractual EDS, the severity of the joint dislocations, the cardiac valve abnormalities, and other connective tissue features may not become apparent until late child or early adulthood. We recommend CHST14 gene testing for any THC patient that has phenotypic features of musculocontractual EDS.
ACKNOWLEDGMENTS We would like to acknowledge the male proband’s ophthalmologists Dr. Carlton Yuen and Dr. Byron Wong, cardiologist Dr. Samuel Dacanay, and rheumatologist Dr. Scott Kawamoto. Dr. Tim Brown is creator of PostureCue technology and founder of Intelliskin. Drs. Slavin, Hyland, and Mochizuki have no conflicts of interest to disclose.
REFERENCES Goodman RM, Katznelson MB, Manor E. 1972. Camptodactyly: Occurence in two new genetic syndromes and its relationship to other syndromes. J Med Genet 9:203–212. Goodman RM, Katznelson MB, Hertz M, Katznelson A. 1976. Camptodactyly, with muscular hypoplasia, skeletal dysplasia, and abnormal palmar creases: Tel Hashomer camptodactyly syndrome. J Med Genet 13:136–141. Melegh B, Hollo´dy K, Aszmann M, Me´hes K. 2005. Tel Hashomer camptodactyly syndrome: 12-year follow-up of a Hungarian patient and review. Am J Med Genet A 135:320–323. Mendoza-Londono R, Chitayat D, Kahr WH, Hinek A, Blaser S, Dupuis L, Goh E, Badilla-Porras R, Howard A, Mittaz L, Superti-Furga A, Unger S,
258
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Nishimura G, Bonafe L. 2012. Extracellular matrix and platelet function in patients with musculocontractural Ehlers-Danlos syndrome caused by mutations in the CHST14 gene. Am J Med Genet A 158A:1344–1354.
Shah K, Sreekanth R, Thomas B, Danda S. 2013. Tel Hashomer camptodactyly syndrome: A case report. West Indian Med J 62: 81–83.
Miyake N, Kosho T, Mizumoto S, Furuichi T, Hatamochi A, Nagashima Y, Arai E, Takahashi K, Kawamura R, Wakui K, et al. 2010. Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome. Hum Mutat 31:966–974.
Smolkin T, Blazer S, Gershoni-Baruch R, Makhoul IR. 2011. Tel Hashomer camptodactyly syndrome in identical twin infants. Clin Dysmorphol 20:214–216.
Ng PC, Henikoff S. 2001. Predicting deleterious amino acid substitutions. Genome Res 11:863–874.
Toriello HV, Higgins JV, Malvitz T, Waterman DF. 1990. Two siblings with Tel Hashomer camptodactyly and mitral valve prolapse. Am J Med Genet 36:398–403.
