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Testicular cancer in a patient with Primrose syndrome
European Journal of Medical Genetics 49 (2006) 127–133 www.elsevier.com/locate/ejmg
Original article
Testicular cancer in a patient with Primrose syndrome Inge B. Mathijssen a,*, Jos van Hasselt-van der Velde a,b, Raoul C.M. Hennekam c,d a
Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, The Netherlands b Institute for the Mentally Disabled “’s Heerenloo Midden Nederland”, Ermelo, The Netherlands c Department of Paediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands d Institute of Child Health, Great Ormond Street Hospital for Sick Children, London, UK Available online 23 June 2005
Abstract A mentally retarded, adult man was found to have joint contractures, sparse body hair, hearing loss, dysmorphic facial features, large calcified pinnae and a huge torus palatinus. All features are similar to those earlier described in patients with Primrose syndrome. In addition he developed a germ cell tumour of his right testicle at age 27 years. A comparison is provided between the main findings in the four previously reported cases with Primrose syndrome and the current patient. Calcification of the pinnae is an infrequent symptom in the general population, and a torus palatinus of limited size is commonly found but a torus of the size reported here is extremely unusual. Both symptoms are excellent handles for diagnosing this entity. It remains as yet uncertain whether an increased risk to malignancies forms part of this syndrome or is only a consequence of cryptorchidism in this patient. © 2005 Elsevier SAS. All rights reserved. Keywords: Primrose syndrome; Calcified pinnae; Torus palatinus; Camptodactyly; Hearing loss; Mental retardation; Germ cell tumour; Cancer risk
* Corresponding author. Tel.: +31 20 566 5281; fax: +31 20 691 8626. E-mail address: [email protected] (I.B. Mathijssen). 1769-7212/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.ejmg.2005.06.001
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1. Introduction In 1982 the Scottish physician Primrose described an adult male with large calcified pinnae, hearing loss, progressive distal muscle wasting, and mental retardation, and suggested this to be a hitherto unreported entity [15]. Since then three other cases with a similar combination of symptoms have been described [3,6,11]. It has been suggested [6] to name the entity after the first author ‘Primrose syndrome’. Here we report on another patient with these features, who developed cancer at a young age, and compare his findings to those from literature.
2. Clinical report The proband was born as the second of two boys from non-consanguineous (five generations) parents. His mother and father were 32 and 36 years old at his birth, respectively. They had one spontaneous miscarriage. Father was known with late onset diabetes mellitus, otherwise parents and the brother were healthy, and family history was unremarkable. During early pregnancy mother used “hormones” to prevent a miscarriage. The proband was born at term after an uncomplicated delivery, birth weight being 3250 g (50th centile). Length and head circumference were not noted. He was noted to have a small umbilical hernia and bilateral cryptorchidism. Developmental milestones were delayed from early on. He was able to crawl at 1 year and walked without support at 2 years. He never started talking. Repeated hearing studies at that time gave normal results. At 1 year of age it was reported that he had become macrocephalic. At 3 years he was admitted for evaluation of his developmental delay. Investigations included routine haematology and chemistry (including calcium and phosphate), metabolic screen in blood, urine, and spinal fluid, EEG and X-rays (skull, wrist, and chest). Pneumencephalography showed a callosal body agenesis. It was concluded that the cause of his delay remained hidden. In retrospect mother noted his pinnae to become more firm than usual from about that age on. There were no major health problems in the ensuing years. Gradually doubts arose about his hearing. At 7 years hearing studies proved a severe hearing loss (80 dB) bilaterally. From early puberty on he suffered from recurrent otitis. This urged for unilateral radical mastoidectomy, but recurrent otitis remained present ever since. At the age of 8 years behavioural problems, mainly aggression and restlessness, became more prominent and antipsychotic medications were started. He was admitted at an institute for the mentally retarded at that same age. At present, his cognitive level is that of a child of 1 1/2 years of age. Growth and growth spurt at puberty were normal. In early puberty it was noted that the tuberositas tibiae were bilaterally more prominent than usual. He started to develop progressive loss of mobility of his joints over the years. At 18 years of age a torus palatinus was first noted. His pinnae were noted to become exceptionally firm at palpation. At 27 years he developed a swelling of his right groin. Surgical exploration showed this to be an enlarged testicle urging orchidectomy. Histological exams proved this to be a germ cell tumour (teratocarcinoma). Multiple retroperitoneal lymph nodes were found to be
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enlarged, allowing a diagnosis of a testis carcinoma stage 2A. He received chemotherapy in a modified regimen to ensure compliance. A 4-year follow-up showed good results. Radiographic studies showed pseudocystes in both femurs, at that time thought to be secondary to chemotherapy. At physical examination at 31 years his height was 190 cm (80th centile), weight 93.4 kg (90th centile), and head circumference 61.5 cm (> 98th centile). He was severely mentally retarded and showed a remarkably shy behaviour. He had a brachyturricephaly, bossed and asymmetric forehead, deeply set eyes, bilateral ptosis, downward slanted palpebral fissures, and high nasal bridge (Fig. 1a). Inspection of his oral cavity showed dental malalignment and a huge torus palatinus (estimated 2 × 2 × 4 cm) (Fig. 1b). He had a firm and somewhat square lower jaw. His ears were large, dysplastic, highly set, and immobile and firm as bone (Fig. 1c). Facial hair and body hair were sparse. He had an unusual build: truncal obesity with pseudomammae, but thin limbs, especially distally. The physiologic thoracic kyphosis was diminished, there was no scoliosis. Mobility of all larger joints was limited, most pronounced in elbows, hips, and knees. In addition there was camptodactyly. Both tuberositas tibiae were enlarged. He had bilateral mild hallux valgus with hypoplastic nails. Laboratory investigations revealed normal serum levels of calcium, phosphate and parathyroid hormone. Serum testosterone level was low and LH and FSH were raised. Chromosomal analysis showed a normal male karyotype (550 bands). Fluorescence in situ hybridisation (FISH) of the subtelomeric regions, metabolic screen of both blood (amino acids, acylcarnitine analysis, very long chain fatty acids, biliary acids, phytanic acid, transferrine IEF) and urine samples (including oligosaccharides, mucopolysaccharides, organic acids, phenol acids, guanidinoacetate, sialic acid, purines, pyrimidines), and DNA analysis of the MGP-gene for Keutel syndrome and PTEN-gene for Cowden syndrome, revealed no abnormalities. As testicular germ cell tumours have been reported to occur together with deletions of chromosome region 12q22, FISH studies for this region were performed, which yielded normal results. Cardiologic examination was normal (especially no pulmonary stenosis or cardiomyopathy was present). Neurological examination showed mild gait disturbances and low APR but otherwise normal tendon reflexes. It was not possible to perform an electromyography. Ophthalmologic examination showed no obvious abnormalities.
3. Discussion The present patient is the fifth literature case reported with Primrose syndrome. The main findings of the four previously reported cases and the current patient are compared in Table 1. Primrose syndrome is mainly characterised by mental retardation, unusual facial morphology, and several symptoms with a progressive course which include muscle wasting, joint contractures, cystic bone lesions, hearing loss, cataract, sparse body hair, and a torus palatinus. The facial features are small, deeply set eyes with downslanting palpebral fissures and ptosis, and large and superiorly displaced ears. The most unusual facial symptom, however, is the calcification of the pinnae. Calcification of the pinnae is an infrequent physical finding [7,11,12]. It can be caused by environmental factors (e.g. ear trauma, frostbite, radiation therapy), conditions associ-
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Fig. 1. Facial appearance of the proband. a. Note the brachyturricephaly, bossed and asymmetric forehead, deeply set eyes, bilateral ptosis, downward slanted palpebral fissures and high nasal bridge. b. Torus palatinus. c. Ears: large, dysplastic, highly set, immobile and firm as bone.
ated with hypercalcaemia (e.g. hyperparathyroidism, sarcoidosis), systemic diseases (e.g. Addison disease, diabetes mellitus, acromegaly) and several genetically determined syndromes (Keutel syndrome (MIM 245150) [10]; Nance–Sweeney syndrome (MIM 215150) [14]; diastrophic dysplasia (MIM 222600) [19]; alkaptonuria (MIM 203500) [1]; familial
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Table 1 Findings in the present patient compared to those from literature Primrose (1982)
Collacott et al. (1986)
Lindor et al. (1996) 43 M 95 – (P80) Learning problems Schizophrenia (+) + + + + (–) – – + + + – + + + + ?
Battisti et al. (2002) 49 F ? ? Severe MR ? ? (–) + + + + ? ? ? + + ? + ? + + NR
Age (years) Gender Height (percentile) OFC ≥ P98 Cognition
33 M 70 “Hydrocephaly” Severe MR
39 M <3 + Severe MR
Psychiatric problems Frontal bossing Downslanting palpebral fissures Ptosis Deeply set eyes Cataract Large jaw Torus palatinus Large ears Superiorly displaced ears Calcified pinnae Hearing loss Recurrent otitis media (Distal) muscle wasting Joint contractures Gait ataxia Sparse body/facial hair Low serum testosterone
? (–) (+) (+) (+) + (+) + + (+) + + + + + ? + +
Diminished bone density Cystic bone lesions
? +
? ? + (+) (+) + (+) + + ? + + + + + ? + – (LH/FSH raised) + +
Present patient 31 M 80 + Severe MR Autism + + + + – + + + + + + + + + – + +
+ –
+ ?
– +
+, Present; – absent; () symptoms derived from reevaluation of published photos are indicated between brackets; ?, unknown; NR, not relevant.
cold hypersensitivity (MIM 120100) [12]). The current patient does not fit into any of these syndromes because of the absence of (rhizomelic) shortening of limbs, absence of facial features of each of these syndromes, and the presence of mental retardation. As Keutel syndrome can show a remarkable variable phenotype we searched for a mutation in the MGP gene, with a negative result. In three of the five patients with Primrose syndrome, a torus palatinus is described. A torus palatinus is a benign osseous elevation usually located on the midline of the hard palate. It is classified according to size into small, medium and large [21]. The small type (elevation < 3 mm, width < 10 mm, length < 15 mm) is the most frequent, the large type (elevation > 5 mm, width> 15 mm, length > 25 mm) the least frequent. Comparison of studies on the prevalence of torus palatinus is hampered by differences in definitions, and also seem to vary widely between different ethnic groups, ranging from 0.4% in Chileans
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[20], 13.5% in Germans [16], to 66% in Eskimos [21]. The prevalence of idiopathic torus palatinus is higher in females compared to males. A positive correlation has been described between the size of the torus palatinus and bone mineral density in postmenopausal, Caucasian women [4]. Both autosomal dominant transmission [2,9], multi-factorial inheritance [17], and exogenous causes [17] have been suggested in isolated occurrence. Torus palatinus is described as part of entities with increased bone density (e.g. autosomal dominant high bone mass [MIM 601884]; autosomal dominant hyperostosis corticalis generalisata [MIM 144750]). In both conditions mutations in the gene for low density lipoprotein receptor-related protein 5 (LRP5) have been detected [5,18]. We suggest the torus to be part of Primrose syndrome, because of the unusual size in this entity and because of the simultaneous occurrence with calcification of the ears, cerebral calcification in one other Primrose patient [3], more prominent formation of the tuberositas tibiae in the present patient, and general osteopenia/osteoporosis in several patients. This suggests an underlying disturbance in calcium metabolism. It is recognised that increased vulnerability to malignancies can be part of a growing number of multiple congenital abnormalities/mental retardation syndromes [13]. The current patient developed a germ cell tumour of his right testicle at 27 years. None of the other known patients with Primrose syndrome developed a malignancy (ID Young and NM Lindor, personal communications, 2003). Clinical studies show that germ cell tumours occur more frequently in undescended testes compared to intra-scrotal testes: the relative risk of malignant transformation in a cryptorchid testes was estimated to be 9.7-fold that of a normal testis [8]. It may be that the increased risk of development of germ cell testis tumours in patients with Primrose syndrome is caused by the cryptorchidism only. However, the small number of reported patients does not allow exclusion of another relation between cancer and this syndrome. The cause of Primrose syndrome is as yet not known. No familial occurrence or parental consanguinity has been reported. The diagnosis of Primrose syndrome in a woman [3] makes X-linked recessive inheritance less probable. The mean reported parental ages seem somewhat high (maternal age: 31.7 years [37, 26, and 32 years, respectively]; paternal age: 31.5 years [27 and 36 years, respectively]), but the number of data are too small to allow any conclusions. In four of the patients the karyotype was reported to be normal. Also the progressive course of the entity makes a chromosomal cause less likely. In no patient a clue for a metabolic cause was identified. Because of the combination of calcified pinnae, torus palatinus, cerebral calcification, enlarged tuberositas tibiae, and general osteopenia, a mutation in a gene that is also influencing the calcium homeostasis may play a role. This should be considered in any further studies.
Acknowledgements We would like to thank Dr. Marianne Vink (De Weerklank, Amsterdam) for initial referral of the patient and Dr. Hans Waterham (AMC, Amsterdam) for performing mutation analysis of the MGP-gene, and I.D. Young and N.M. Lindor for providing us further information about their patients.
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S.E. Albers, S.J. Brozena, L.F. Glass, N.A. Fenske, Alkaptonuria and ochronosis: case report and review, J. Am. Acad. Dermatol. 27 (4) (1992) 609–614. G. Barbujani, M. Rolo, I. Barrai, J. Pinto-Cisternas, Torus palatinus: a segregation analysis, Hum. Hered. 36 (5) (1986) 317–325. C. Battisti, M.T. Dotti, A. Cerase, A. Rufa, F. Sicurelli, C. Scarpini, A. Federico, The Primrose syndrome with progressive neurological involvement and cerebral calcification, J. Neurol. 249 (10) (2002) 1466– 1468. J.L. Belsky, J.S. Hamer, J.E. Hubert, K. Insogna, W. Johns, Torus palatinus: a new anatomical correlation with bone density in postmenopausal women, J. Clin. Endocrinol. Metab. 88 (5) (2003) 2081–2086. L.M. Boyden, J. Mao, J. Belsky, L. Mitzner, A. Farhi, M.A. Mitnick, D. Wu, K. Insogna, R.P. Lifton, High bone density due to a mutation in LDL-receptor-related protein 5, N. Engl. J. Med. 346 (20) (2002) 1513–1521. R.A. Collacott, B.P. O’Malley, I.D. Young, The syndrome of mental handicap, cataracts, muscle wasting and skeletal abnormalities: report of a second case, J. Ment. Defic. Res. 30 (1986) 301–308. J.R. DiBartolomeo, The petrified auricle: comments on ossification, calcification and exostoses of the external ear, Laryngoscope 95 (5) (1985) 566–576. J.H. Farrer, A.H. Walker, J. Rajfer, Management of the postpubertal cryptorchid testis: a statistical review, J. Urol. 134 (6) (1985) 1071–1076. M. Gorsky, A. Bukai, M. Shohat, Genetic influence on the prevalence of torus palatinus, Am. J. Med. Genet. 75 (2) (1998) 138–140. J. Keutel, G. Jorgensen, P. Gabriel, A new autosomal-recessive hereditary syndrome. Multiple peripheral pulmonary stenosis, brachytelephalangia, inner-ear deafness, ossification or calcification of cartilages, Dtsch. Med. Wochenschr. 96 (43) (1971) 1676–1681. N.M. Lindor, A.D. Hoffman, D.A. Primrose, A neuropsychiatric disorder associated with dense calcification of the external ears and distal muscle wasting: ‘Primrose syndrome’, Clin. Dysmorphol. 5 (1) (1996) 27–34. V.A. McKusick, R.M. Goodman, Pinnal calcification, J. Am. Med. Assoc. 179 (1962) 230–232. J.H. Merks, H.N. Caron, R.C. Hennekam, High incidence of malformation syndromes in a series of 1073 children with cancer, Am. J. Med. Genet. 134 (2) (2005) 132–143. W.E. Nance, A. Sweeney, A recessively inherited chondrodystrophy, Birth Defects Orig. Artic. Ser. 6 (4) (1970) 25–27. D.A. Primrose, A slowly progressive degenerative condition characterized by mental deficiency, wasting of limb musculature and bone abnormalities, including ossification of the pinnae, J. Ment. Defic. Res. 26 (1982) 101–106. P.A. Reichart, F. Neuhaus, M. Sookasem, Prevalence of torus palatinus and torus mandibularis in Germans and Thai, Community Dent. Oral Epidemiol. 16 (1) (1988) 61–64. Y.H. Seah, Torus palatinus and torus mandibularis: a review of the literature, Aust. Dent. J. 40 (5) (1995) 318–321. L. Van Wesenbeeck, E. Cleiren, J. Gram, R.K. Beals, O. Benichou, D. Scopelliti, L. Key, T. Renton, C. Bartels, Y. Gong, M.L. Warman, M.C. De Vernejoul, J. Bollerslev, W. Van Hul, Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density, Am. J. Hum. Genet. 72 (3) (2003) 763–771. B.A. Walker, C.I. Scott, J.G. Hall, J.L. Murdoch, V.A. McKusick, Diastrophic dwarfism, Medicine (Baltimore) 51 (1) (1972) 41–59. C.J. Witkop Jr., L. Barros, Oral and genetic studies of Chileans, 1960. I. Oral anomalies, Am. J. Phys. Anthropol. 21 (1963) 15–24. J.K. Woo, Torus palatinus, Am. J. Phys. Anthropol. 8 (1) (1950) 81–111.
Original article
Testicular cancer in a patient with Primrose syndrome Inge B. Mathijssen a,*, Jos van Hasselt-van der Velde a,b, Raoul C.M. Hennekam c,d a
Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, The Netherlands b Institute for the Mentally Disabled “’s Heerenloo Midden Nederland”, Ermelo, The Netherlands c Department of Paediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands d Institute of Child Health, Great Ormond Street Hospital for Sick Children, London, UK Available online 23 June 2005
Abstract A mentally retarded, adult man was found to have joint contractures, sparse body hair, hearing loss, dysmorphic facial features, large calcified pinnae and a huge torus palatinus. All features are similar to those earlier described in patients with Primrose syndrome. In addition he developed a germ cell tumour of his right testicle at age 27 years. A comparison is provided between the main findings in the four previously reported cases with Primrose syndrome and the current patient. Calcification of the pinnae is an infrequent symptom in the general population, and a torus palatinus of limited size is commonly found but a torus of the size reported here is extremely unusual. Both symptoms are excellent handles for diagnosing this entity. It remains as yet uncertain whether an increased risk to malignancies forms part of this syndrome or is only a consequence of cryptorchidism in this patient. © 2005 Elsevier SAS. All rights reserved. Keywords: Primrose syndrome; Calcified pinnae; Torus palatinus; Camptodactyly; Hearing loss; Mental retardation; Germ cell tumour; Cancer risk
* Corresponding author. Tel.: +31 20 566 5281; fax: +31 20 691 8626. E-mail address: [email protected] (I.B. Mathijssen). 1769-7212/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.ejmg.2005.06.001
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1. Introduction In 1982 the Scottish physician Primrose described an adult male with large calcified pinnae, hearing loss, progressive distal muscle wasting, and mental retardation, and suggested this to be a hitherto unreported entity [15]. Since then three other cases with a similar combination of symptoms have been described [3,6,11]. It has been suggested [6] to name the entity after the first author ‘Primrose syndrome’. Here we report on another patient with these features, who developed cancer at a young age, and compare his findings to those from literature.
2. Clinical report The proband was born as the second of two boys from non-consanguineous (five generations) parents. His mother and father were 32 and 36 years old at his birth, respectively. They had one spontaneous miscarriage. Father was known with late onset diabetes mellitus, otherwise parents and the brother were healthy, and family history was unremarkable. During early pregnancy mother used “hormones” to prevent a miscarriage. The proband was born at term after an uncomplicated delivery, birth weight being 3250 g (50th centile). Length and head circumference were not noted. He was noted to have a small umbilical hernia and bilateral cryptorchidism. Developmental milestones were delayed from early on. He was able to crawl at 1 year and walked without support at 2 years. He never started talking. Repeated hearing studies at that time gave normal results. At 1 year of age it was reported that he had become macrocephalic. At 3 years he was admitted for evaluation of his developmental delay. Investigations included routine haematology and chemistry (including calcium and phosphate), metabolic screen in blood, urine, and spinal fluid, EEG and X-rays (skull, wrist, and chest). Pneumencephalography showed a callosal body agenesis. It was concluded that the cause of his delay remained hidden. In retrospect mother noted his pinnae to become more firm than usual from about that age on. There were no major health problems in the ensuing years. Gradually doubts arose about his hearing. At 7 years hearing studies proved a severe hearing loss (80 dB) bilaterally. From early puberty on he suffered from recurrent otitis. This urged for unilateral radical mastoidectomy, but recurrent otitis remained present ever since. At the age of 8 years behavioural problems, mainly aggression and restlessness, became more prominent and antipsychotic medications were started. He was admitted at an institute for the mentally retarded at that same age. At present, his cognitive level is that of a child of 1 1/2 years of age. Growth and growth spurt at puberty were normal. In early puberty it was noted that the tuberositas tibiae were bilaterally more prominent than usual. He started to develop progressive loss of mobility of his joints over the years. At 18 years of age a torus palatinus was first noted. His pinnae were noted to become exceptionally firm at palpation. At 27 years he developed a swelling of his right groin. Surgical exploration showed this to be an enlarged testicle urging orchidectomy. Histological exams proved this to be a germ cell tumour (teratocarcinoma). Multiple retroperitoneal lymph nodes were found to be
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enlarged, allowing a diagnosis of a testis carcinoma stage 2A. He received chemotherapy in a modified regimen to ensure compliance. A 4-year follow-up showed good results. Radiographic studies showed pseudocystes in both femurs, at that time thought to be secondary to chemotherapy. At physical examination at 31 years his height was 190 cm (80th centile), weight 93.4 kg (90th centile), and head circumference 61.5 cm (> 98th centile). He was severely mentally retarded and showed a remarkably shy behaviour. He had a brachyturricephaly, bossed and asymmetric forehead, deeply set eyes, bilateral ptosis, downward slanted palpebral fissures, and high nasal bridge (Fig. 1a). Inspection of his oral cavity showed dental malalignment and a huge torus palatinus (estimated 2 × 2 × 4 cm) (Fig. 1b). He had a firm and somewhat square lower jaw. His ears were large, dysplastic, highly set, and immobile and firm as bone (Fig. 1c). Facial hair and body hair were sparse. He had an unusual build: truncal obesity with pseudomammae, but thin limbs, especially distally. The physiologic thoracic kyphosis was diminished, there was no scoliosis. Mobility of all larger joints was limited, most pronounced in elbows, hips, and knees. In addition there was camptodactyly. Both tuberositas tibiae were enlarged. He had bilateral mild hallux valgus with hypoplastic nails. Laboratory investigations revealed normal serum levels of calcium, phosphate and parathyroid hormone. Serum testosterone level was low and LH and FSH were raised. Chromosomal analysis showed a normal male karyotype (550 bands). Fluorescence in situ hybridisation (FISH) of the subtelomeric regions, metabolic screen of both blood (amino acids, acylcarnitine analysis, very long chain fatty acids, biliary acids, phytanic acid, transferrine IEF) and urine samples (including oligosaccharides, mucopolysaccharides, organic acids, phenol acids, guanidinoacetate, sialic acid, purines, pyrimidines), and DNA analysis of the MGP-gene for Keutel syndrome and PTEN-gene for Cowden syndrome, revealed no abnormalities. As testicular germ cell tumours have been reported to occur together with deletions of chromosome region 12q22, FISH studies for this region were performed, which yielded normal results. Cardiologic examination was normal (especially no pulmonary stenosis or cardiomyopathy was present). Neurological examination showed mild gait disturbances and low APR but otherwise normal tendon reflexes. It was not possible to perform an electromyography. Ophthalmologic examination showed no obvious abnormalities.
3. Discussion The present patient is the fifth literature case reported with Primrose syndrome. The main findings of the four previously reported cases and the current patient are compared in Table 1. Primrose syndrome is mainly characterised by mental retardation, unusual facial morphology, and several symptoms with a progressive course which include muscle wasting, joint contractures, cystic bone lesions, hearing loss, cataract, sparse body hair, and a torus palatinus. The facial features are small, deeply set eyes with downslanting palpebral fissures and ptosis, and large and superiorly displaced ears. The most unusual facial symptom, however, is the calcification of the pinnae. Calcification of the pinnae is an infrequent physical finding [7,11,12]. It can be caused by environmental factors (e.g. ear trauma, frostbite, radiation therapy), conditions associ-
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Fig. 1. Facial appearance of the proband. a. Note the brachyturricephaly, bossed and asymmetric forehead, deeply set eyes, bilateral ptosis, downward slanted palpebral fissures and high nasal bridge. b. Torus palatinus. c. Ears: large, dysplastic, highly set, immobile and firm as bone.
ated with hypercalcaemia (e.g. hyperparathyroidism, sarcoidosis), systemic diseases (e.g. Addison disease, diabetes mellitus, acromegaly) and several genetically determined syndromes (Keutel syndrome (MIM 245150) [10]; Nance–Sweeney syndrome (MIM 215150) [14]; diastrophic dysplasia (MIM 222600) [19]; alkaptonuria (MIM 203500) [1]; familial
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Table 1 Findings in the present patient compared to those from literature Primrose (1982)
Collacott et al. (1986)
Lindor et al. (1996) 43 M 95 – (P80) Learning problems Schizophrenia (+) + + + + (–) – – + + + – + + + + ?
Battisti et al. (2002) 49 F ? ? Severe MR ? ? (–) + + + + ? ? ? + + ? + ? + + NR
Age (years) Gender Height (percentile) OFC ≥ P98 Cognition
33 M 70 “Hydrocephaly” Severe MR
39 M <3 + Severe MR
Psychiatric problems Frontal bossing Downslanting palpebral fissures Ptosis Deeply set eyes Cataract Large jaw Torus palatinus Large ears Superiorly displaced ears Calcified pinnae Hearing loss Recurrent otitis media (Distal) muscle wasting Joint contractures Gait ataxia Sparse body/facial hair Low serum testosterone
? (–) (+) (+) (+) + (+) + + (+) + + + + + ? + +
Diminished bone density Cystic bone lesions
? +
? ? + (+) (+) + (+) + + ? + + + + + ? + – (LH/FSH raised) + +
Present patient 31 M 80 + Severe MR Autism + + + + – + + + + + + + + + – + +
+ –
+ ?
– +
+, Present; – absent; () symptoms derived from reevaluation of published photos are indicated between brackets; ?, unknown; NR, not relevant.
cold hypersensitivity (MIM 120100) [12]). The current patient does not fit into any of these syndromes because of the absence of (rhizomelic) shortening of limbs, absence of facial features of each of these syndromes, and the presence of mental retardation. As Keutel syndrome can show a remarkable variable phenotype we searched for a mutation in the MGP gene, with a negative result. In three of the five patients with Primrose syndrome, a torus palatinus is described. A torus palatinus is a benign osseous elevation usually located on the midline of the hard palate. It is classified according to size into small, medium and large [21]. The small type (elevation < 3 mm, width < 10 mm, length < 15 mm) is the most frequent, the large type (elevation > 5 mm, width> 15 mm, length > 25 mm) the least frequent. Comparison of studies on the prevalence of torus palatinus is hampered by differences in definitions, and also seem to vary widely between different ethnic groups, ranging from 0.4% in Chileans
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[20], 13.5% in Germans [16], to 66% in Eskimos [21]. The prevalence of idiopathic torus palatinus is higher in females compared to males. A positive correlation has been described between the size of the torus palatinus and bone mineral density in postmenopausal, Caucasian women [4]. Both autosomal dominant transmission [2,9], multi-factorial inheritance [17], and exogenous causes [17] have been suggested in isolated occurrence. Torus palatinus is described as part of entities with increased bone density (e.g. autosomal dominant high bone mass [MIM 601884]; autosomal dominant hyperostosis corticalis generalisata [MIM 144750]). In both conditions mutations in the gene for low density lipoprotein receptor-related protein 5 (LRP5) have been detected [5,18]. We suggest the torus to be part of Primrose syndrome, because of the unusual size in this entity and because of the simultaneous occurrence with calcification of the ears, cerebral calcification in one other Primrose patient [3], more prominent formation of the tuberositas tibiae in the present patient, and general osteopenia/osteoporosis in several patients. This suggests an underlying disturbance in calcium metabolism. It is recognised that increased vulnerability to malignancies can be part of a growing number of multiple congenital abnormalities/mental retardation syndromes [13]. The current patient developed a germ cell tumour of his right testicle at 27 years. None of the other known patients with Primrose syndrome developed a malignancy (ID Young and NM Lindor, personal communications, 2003). Clinical studies show that germ cell tumours occur more frequently in undescended testes compared to intra-scrotal testes: the relative risk of malignant transformation in a cryptorchid testes was estimated to be 9.7-fold that of a normal testis [8]. It may be that the increased risk of development of germ cell testis tumours in patients with Primrose syndrome is caused by the cryptorchidism only. However, the small number of reported patients does not allow exclusion of another relation between cancer and this syndrome. The cause of Primrose syndrome is as yet not known. No familial occurrence or parental consanguinity has been reported. The diagnosis of Primrose syndrome in a woman [3] makes X-linked recessive inheritance less probable. The mean reported parental ages seem somewhat high (maternal age: 31.7 years [37, 26, and 32 years, respectively]; paternal age: 31.5 years [27 and 36 years, respectively]), but the number of data are too small to allow any conclusions. In four of the patients the karyotype was reported to be normal. Also the progressive course of the entity makes a chromosomal cause less likely. In no patient a clue for a metabolic cause was identified. Because of the combination of calcified pinnae, torus palatinus, cerebral calcification, enlarged tuberositas tibiae, and general osteopenia, a mutation in a gene that is also influencing the calcium homeostasis may play a role. This should be considered in any further studies.
Acknowledgements We would like to thank Dr. Marianne Vink (De Weerklank, Amsterdam) for initial referral of the patient and Dr. Hans Waterham (AMC, Amsterdam) for performing mutation analysis of the MGP-gene, and I.D. Young and N.M. Lindor for providing us further information about their patients.
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