[Bissonette et al., 1993; Cabrera et al., 2004; Milligan M. Lacarbonara*, A.P. Cazzolla**, et al., 1989; Ogata et al., 1981; Pedersen et al., 1983; V.A. Lacarbonara**, D. Di Venere**, Powell et al., 1974]. M. Capogreco*, G. Marzo* Prolidase is a ubiquitous cytosolic with a major role in the recycling of released during *Department of Life, Health and Environmental Sciences, the degradation of and dietary proteins: Dental Clinic; University of L'Aquila, Italy actually it hydrolyses dipeptides with carboxy-terminal **Department of Dentistry and Surgery, University of Bari, Italy proline or [Endo et al., 1989; Palka et al., 1996; Phang et al., 1995]. Therefore, PD causes an e-mail: [email protected] accumulation of dipeptides, then secreted in urines and definable by capillary electrophoresis. The prolidase (PEPD) has been localised to chromosome 19q12-q13.2 and currently 17 causative Prolidase deficiency: have been reported. Moreover, marked phenotypic variability, including intrafamilial, has been documented. dento-facial aspects Considering both the amount of molecular defects and the highly variable phenotype, we could expect a wide in a paediatric patient clinical spectrum of PD [Falik-Zaccai et al., 2009]. The clinical manifestations of PD include developmental delay, mental retardation, facial dysmorphism, splenomegaly, recurrent pulmonary abstract infections and skin lesions [Falik-Zaccai et al., 2009; Freij and Der Kaloustian, 1986]. Accessory signs are Background Prolidase Deficiency (PD) is a rare vasculitis and hepatitis-like symptoms. Typical features hereditary disease consisting in developmental delay, of systemic lupus erythematosus (SLE) and hyper-IgE mental retardation, facial dysmorphism, splenomegaly, syndrome have also been documented [Shrinat et recurrent pulmonary infections and skin lesions. al., 1997]. Affected patients could even apparently Case report The present study reports a case of PD remain asymptomatic. Hyperiminodipeptiduria is treated in the Paediatric Section of the Department of the characteristic biochemical abnormality. Reduced Dentistry and Surgery at the University of Bari. A special prolidase activity in leukocytes, erythrocytes, cultured diagnostic and clinical approach to the patient was fibroblasts, or amniocytes confirms the diagnosis [Falik- useful to improve his quality of life and identify some Zaccai et al., 2009]. new aspects of this systemic disease. In particular, clinical We report a case of PD treated in the Paediatric features never described before are reported: low hair Section of the Department of Dentistry and Surgery at line, decreased osteotendinous reflexes, long upper lip, the University of Bari. microrhinia, dentoskeletal Class III, dental age (Proffit) older than chronological age, fusion of 2nd and 3rd cervical vertebrae, incomplete atlanto-occipital fusion. Case report

The patient CS, a 10-year-old male, was admitted Keywords Hyperiminodipeptiduria; ; to our Department in January 2000 with a diagnosis Prolidase deficiency; Skin lesions. of PD. The consent was obtained from the patient’s parent for publication of the case and related images. Anamnesis resulted negative for any hereditary diseases. Deficiencies of language and learning, Introduction pharyngotonsillitis, ulcerated scab lesions of feet and glutes during the first years of life were reported [Aysin Prolidase Deficiency (PD), first described in 1968, K et al., 2002; Monafo et al., 2000]. is a rare autosomal recessive disease that belongs to At the age of 9 years, the patient had been addressed monogenic human inborn errors of metabolism of to the Department of Dermatology at the University of L-proline along with hyperprolinemia type I (HPI),4 Bari because the lesions had worsened. The presence of HPII, D1-pyrroline-5-carboxylic acid (P5C) synthetase chronic ulcers on upper and lower limbs during infancy deficiency, ornithine aminotransferase (OAT) deficiency, aroused the suspicion of a metabolic disease (Fig. 1). Then, hydroxyprolinemia, and [Mitsubuchi et on the basis of prolidase dosage in erythrocytes and the al., 2008; Shrinat et al., 1997]. PD prevalence rate is presence of hyperiminodipeptiduria, Prolidase Deficiency lower than 1:1,000,000: about 100 cases have been was diagnosed. Extra-oral examination showed good deiagnosed all over the world, of which 10 in Italy facial proportions, , depressed nasal saddle,

224 European Journal of Paediatric Dentistry Clinical Supplement to vol. 15/2-2014 unreported Dentofacial features in prolidase deficiency

fiG. 1 fiG. 2 Skin Front lesions. view and profile of the patient.

fiG. 3 Intraoral view: palatal transverse diameter and cross-bite.

fiG. 4 Rx examinations: OPT, A.P, Telex L.L.. microrhinia, long upper lip with a low smile line, short fiG. 5 Giannì’s and Delaire’s neck, low hair line (Fig. 2). At the intraoral examination, latero-lateral cephalometry. the permanent dentition was found in initial phase of completion, poor oral hygiene with several caries, the palatal transverse diameter was narrow with both upper lateral incisors in crossbite (Fig. 3). A complete radiographic assessment was made (otthopantomography, latero-lateral, antero-posterior and axial teleradiography, wrist radiography X-rays) in order to perform the orthodontic evaluation (Fig. 4). Both cephalometric analysis according to Giannì and Delaire were considered (Fig. 5). Giannì’s cephalometric analysis revealed a dentoskeletal Class III in a hyperdivergent subject with upper jaw anteinclination and a lower jaw postrotation, Delaire’s cephalometric analysis showed that line C2 skeletal open bite, further vertical growth could be (height of the cranial vault) was not tangent to the expected. The linear dimensions of the cranial base, posterior edge of the condylus but it was anterior; the upper and lower jaw revealed: long anterior cranial anterior crus CF1 (front line of the craniofacial balance) base, lower jaw dimensions below average, long was set at the back of apex of the incisor and the mandibular ramus. The cranial base angle was reduced posterior crus CF3 (rear line of the craniofacial balance) with an anterior and lower position of glenoid fossa. showed an anteroposition of the lower jaw ramus Therefore, the dentoskeletal Class III was not caused [Delaire, 1978]. At the wrist X-ray the skeletal age was by a dimensional imbalance between the jaws but by a less than the chronological one (growth period II, phase positional one (Table 1). III of skeletal growth according to Giannì’s auxological

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v.n. v.n. SNA 82°±2° 83,5° SNA 82±2 81 SNB 80°±2° 84° SNB 80±2 86 ANB 2°±2° -0,5° ANB 2±2 -5 SNP^GoGn 20°±5° 26° SNP^GoGn 20±5 26 SN^SNP 10°±3° 3° SN^SNP 10±3 0,5 SN^GoGn 32°±5° 29° SN^GoGn 32 ±5 26 Sor-SNA 57 Sor-SNA 61 SNA-Me 61,2 63,5 SNA-Me 66,6 67 Ist-Go/Sor-Me% 62% 57,44% Ist-Go/Sor-Me% 62% 60% S-Pc/Pc-Go % 66% 76,19% S-Pc/Pc-Go 66% 76% NSPc 122°±5° 109° NSPc 122±5 106 SPcGo 143°±6° 151° SPcGo 143±6 152 PcGoGn 120°±5° 132° fig. 6 Wrist Rx (Giannì's 2nd PcGoGn 120±5 130 PcGoN 50°±2° 57° period, 3rd phase). PcGoN 50±2 47 NGoGn 70°±3° 75° NGoGn 70±3 83 NSBa 129°±5° 120° NSBa 129±5 119 S-N 73 S-N 76 Go-Me 64 61 Go-Me 76 62 SNP-A 44 44 SNP-A 46 44 SN^1¯ 103°±2° 111° SN^1¯ 103±2 109 Go-Me^1- 90°±5° 84° Go-Me^1- 90±5 86

TabLE 1 TabLE 2

fiG. 7 Intraoral photos at two years.

fiG. 8 Post-treatment OPT, Telex L.L., Gianni’s L.L. cephalometry. analysis) (Fig. 6). relationships (Fig. 7), though the skeletal Class III was The patient was enrolled in periodontal therapy unchanged (Fig. 8, Table 2). sessions consisting in scaling and fluoroprophylaxis, to promote oral hygiene. In addition, a restorative dental treatment and interceptive orthodontics were Discussion performed: a rapid palatal expander was fabricated and bonded to the first upper molars to increase the PD is a rare autosomal recessive disorder. Although palatal transverse diameter. there is considerable knowledge concerning the putative At the two-year follow-up the patient showed a roles of the prolidase enzyme, the pathophysiology of stable correction of transverse dentoskeletal maxillary PD is still unknown.

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in literature in this patient CUTANEOUS - cutaneous atrophy YES - serious ulcerations (at lower limbs YES and gluteus) not responding to topic or YES system ic therapies NO - hyperconvex nails NO - - low hair line - teleangiectasia - alopecia OPHTALMOLOGICAL - myopia NO OTORHINOLARYNGOLOGICAL - ear anomalies and loss of hearing NO NEUROLOGICAL - mental delay from slight to moderate YES forms with deficiencies of language and - osteo learning - tendinous reflexes on lower limbs hardly evoked ORTHOPEDICAL - arachnodactyly YES - hip dislocation NO - genu valgum YES - flat feet YES - short neck; kyphoscoliosis FACIO-CRANIAL - hypertelorism YES - depressed nasal saddle YES - ogival palate YES - long upper lip - microrhinia - III dento-skeletal Class - deformities of atlanto-occipital hinge (incomplete occipito-atlantoid fusion, fusion of 2nd and 3rd cervical vertebra) DENTAL - multiple caries YES - dental age (by Proffit) superior to personal age OTHER SIGNS - anaemia NO - splenomegalia NO - frequent infections YES (pharyngotonsillitis) - skeletal age (wrist rx) less than chronological age

TabLE 3

It is a multisystem disorder in which skin ulcerations are occipital hinge (uncomplete atlanto-occipital fusion). the most prominent findings. Other common features This deformity could be the reason of the low cranial include characteristic facies, mental retardation, base angle width and skeletal Class III relationship splenomegaly, and susceptibility to infections. Skin (according to Giannì’s cephalometric analysis). ulcers are usually long standing and difficult to heal. Delaire’s cephalometric analysis revealed the presence Scarring and pitting are common. Eczematous lesions, of an architectural imbalance of the cranial structures telangiectasia, and purpura are other dermatological with a predominance of rachidial portion compared to features. Pruritus, photosensitivity, and hyperkeratosis cranial one. According to Delaire [1978], the mandibular have also been described. Other reported clinical position is influenced both by the relationship with findings include a high arched palate, simian creases, the maxilla and the cervical posture; therefore, in this wasting of the small muscles of the hand, joint laxity, patient the shortening of the cervico-occipital hinge short stature, osteoporosis, talipes equinovarus, and forward displacement of the odontoid process deafness, and ocular keratitis [Shrinat et al., 1997]. are the factors causing the counterclockwise rotation The present study reports the case of a 10-year of the occiput with fulcrum on the spheno-occipital old male child affected by PD, without any history of synchondrosis, forward displacement of the mandible hereditary diseases in his family. and Class III maloclussion. The patient presented some clinical features never described before (Table 3), such as low hair line, osteotendinous reflexes on lower limbs hardly evoked, Conclusion long upper lip, microrhinia, dentoskeletal Class III, dental age (according to Proffit) older than chronological This report confirms the importance of cooperation age, a pathological fusion of the 2nd and 3rd cervical among specialists, such as dermatologists and dentists, vertebrae, pathological malformation of the cervico- especially when treating rare syndromes.

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The early diagnosis of a rare pathology as PD in this of human prolidase. J Biol Chem 1989: 264-4476-81. › Falik-Zaccai TC, Khayat M, Luder A, Frenke LP, Magen D, Brik R, young patient meaningfully improved his quality of life. Gershoni-Baruch R, Mandel H. A broad spectrum of developmental delay Above all, this work points out some dental features in a large cohort of prolidase deficiency patients demonstrates marked not described before, except for multiple caries, and it interfamilial and intrafamilial phenotipic variability. Am J Med Genet B shows that patients with rare diseases and craniofacial Neuropsychiatr Genet 2009 Mar;23. deformities exhibit an alteration of the normal growth › Freij BJ, Der Kaloustian VM. Prolidase deficiency. A metabolic disorder presenting with dermatologic signs. Int J Dermatol. 1986:25(7):431-3. pattern. Consequently, for these patients not only › Milligan A, Graham-Brown RAC, Burns DA, Anderson I. Prolidase conventional analysis referring to statistical averages deficiency: a case report and literature review. Br J Derm 1989; 121: should be used, but also cephalometric analysis on 405-409. craniofacial balance and individual proportions. › Mitsubuchi H, Nakamura K, Matsumoto S, Endo F. Inborn errors of proline metabolism. J Nutr 2008 Oct;138(10):2016S-2020S. › Monafo V, Marseglia GL, Maghnie M, Dyne KM, Cetta G. Transient beneficial effect of GH replacement therapy and topical GH application References on skin ulcers in a boy with prolidase deficiency. Pediatr Dermatol 2000 May-Jun; 17(3): 227-30. › Aysin K, Tamer IK, Guliz I, Aynur K. Prolidase deficiency. Int J Dermatol › Ogata A, Tanaka S, Tomoda T, et al. Autosomal recessive prolidase 2002:41(1). deficiency. Arch Dermatol 1981;117:689-694. › Bissonette R, Friedmann D, Giroux JM, Dolenza M, Hechtman P, Der › Palka JA. The role of prolidasy as an anzyme participating in the Kaloustian VM, Dubuc R. Prolidase deficiency: a multisystemic hereditary metabolism of collagen. Roc Akad Med Bial-miyst 1996: 41: 149-60. disorder. J Am Acad Dermatol 1993;29(5 Pt 2): 818-21. › Pedersen PS, Christensen E, Brandt NJ. Prolidase deficiency. Acta › Cabrera HN, Della Giovanna P, Bozzini NF, Forlino A. Prolidase Paediatr Scand 1983; 72(5):785-8. deficiency:case reports of two Argentinian brothers. Int J Dermatol › Phang JM, Yeh GC, Scriver CR. Disorders of praline and hydroxiproline 2004; 43(9):684-686. metabolism. In: Scriver CR, Beaudet al., Sly WS, Valle D, eds. The › Cantatore FP, Papadia F, Giannico G, Simonetti S, Carrozzo M. Chronic Metabolic and Molecular Bases of Inherited Disease. New York: McGraw leg ulcerations resembling vasculitis in two siblings with prolidase Hill; 1995. 1125-46. deficiency. Clin Rheumatol,1993 Sep;12(3): 410-4. › Powell GF, Rasco MA, Maniscalco RM. A prolidase deficiency in man › Delaire J. L’analyse architecturale et sructurale cranio-faciale (de profil). with iminopeptiduria. Metabolism 1974, 23: 505-513. Pricipes thèoriques. Quelques exemples d’emploi en chirurgie maxillo- › Shrinat M, Waltewr JH, Haeney M, Couriel J.M., Lewis MA, Herrick AL. faciale. Revue de Stomatologie,1978; (1): 1-33. Prolidase deficiency and systemic lupus erythematosus Arch Dis Child, › Endo F, Tanoue A, Nakai H, et al. Primary structure and gene localization 1997;76: 441-444.

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