Eur J Pediatr DOI 10.1007/s00431-015-2514-8
CASE REPORT
Stickler syndrome associated with epilepsy: report of three cases Salvatore Savasta & Vincenzo Salpietro & Maria Valentina Spartà & Thomas Foiadelli & Daniela Laino & Lucio Lobefalo & Gian Luigi Marseglia & Alberto Verrotti
Received: 13 November 2014 / Revised: 20 February 2015 / Accepted: 3 March 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Stickler syndrome is a genetically heterogeneous collagenopathy characterized by auditory, ocular, musculoskeletal, and orofacial abnormalities. Stickler syndrome type 1 typically presents ophthalmologic involvement and is due to heterozygous defects of the COL2A1 gene, that have been also identified as the molecular cause of a continuous spectrum of different disorders mainly affecting the cartilage and bone (i.e., Kniest
Communicated by Beat Steinmann Revisions received: 03 January 2015 / 23 January 2015 S. Savasta : M. V. Spartà : T. Foiadelli : G. L. Marseglia Department of Pediatrics, IRCSS Policlinico BSan Matteo^, University of Pavia, Pavia, Italy S. Savasta e-mail: [email protected]
dysplasia, achondrogenesis type II, Legg-Calvè-Perthes disease). We report three Caucasian children with: (a) ocular, oral, facial, auditory, and musculoskeletal manifestations of Stickler syndrome type 1; (b) history of generalized and/or partial seizures coupled with abnormal electroencephalographic records; and (c) pathogenic heterozygous mutations of the COL2A1 gene. Epilepsy has been never reported so far in literature as a possible feature of Stickler syndrome, although neurological presentations, including epilepsy and brain abnormalities, have been occasionally described in other COL2A1related phenotypes (e.g., Legg-Calvè-Perthes disease). Conclusions: This report raises the possibility of a potential occurrence of seizures among the clinical manifestations of Stickler syndrome type 1, suggesting the presence of a continuous neurological spectrum in some individuals harboring heterozygous mutations in COL2A1.
M. V. Spartà e-mail: [email protected] T. Foiadelli e-mail: [email protected] G. L. Marseglia e-mail: [email protected] V. Salpietro Department of Pediatrics, University of Messina, Messina, Italy e-mail: [email protected] D. Laino : A. Verrotti (*) Department of Pediatrics, University of Perugia, Perugia, Italy e-mail: [email protected]
What is Known: • Stickler syndrome is a genetically heterogeneous collagenopathy characterized by auditory, ocular, musculoskeletal, and orofacial anomalies. What is New: • Involvement of the nervous central system is not a typical feature of Stickler syndrome and the association with epilepsy has not been reported so far. • This report raises the possibility of a potential occurrence of seizures among the clinical manifestations of Stickler syndrome type 1, suggesting a continuous neurological spectrum in some individuals affected by heterozygous mutations of COL2A1.
D. Laino e-mail: [email protected] L. Lobefalo Department of Experimental and Clinical Sciences-Section of Ophthalmology, University of Chieti, Chieti, Italy e-mail: [email protected]
Keywords Stickler syndrome . COL2A1 . Neurological symptoms . Epilepsy . Central nervous system . Legg-Calvè-Perthes disease
Eur J Pediatr
Abbreviations CNS Central nervous system EEG Electroencephalogram GTCS Generalized tonic-clonic seizures LCPD Legg-Calvè-Perthes disease MRI Magnetic resonance image STL Stickler syndrome STL1 Stickler syndrome type 1 VEP Visual-evoked potentials AEP Auditive-evoked potentials PCR Polymerase chain reaction VPA Valproic acid SEDC Spondyloepiphyseal dysplasia congenital KD Kniest dysplasia.
Introduction Stickler syndrome (STL), also called hereditary progressive arthroophtalmopathy, was described in 1965 by Stickler [16]. The phenotype of STL is clinically heterogeneous, and most patients have various ophthalmological findings, including high myopia, vitreoretinal degeneration, retinal detachment, and cataracts [2–4]. Additional features include hearing loss, midline defects (e.g., cleft palate, bifid uvula, flattened mid face), Pierre Robin sequence, early-onset osteoarthritis, and mild spondyloepiphyseal dysplasia [1, 3, 4]. The autosomal dominant form of STL is classified into three different types (types I, II, III), on the basis of clinical features and specific molecular defects [3, 4]. The most frequent form is STL type I (MIM 108300; SLT1), caused by abnormalities in the COL2A1 gene and characterized by congenital vitreous abnormalities [2, 7]. The COL2A1 gene encodes type II collagen, a component of the extracellular cartilage matrix which plays a role for endochondral bone ossification. Collagen type II is present also in the vitreous humor and the inner ear, explaining the frequent visual and hearing impairment in STL1 [3]. Central nervous system (CNS) involvement is not a typical feature of STL. A thorough research in the published literature (PubMed and the Cochrane Library) was performed using the following keywords: BStickler epilepsy^, BStickler seizures^, BCOL2A1^, and B(stickler) NOT stickler [Author], Bepilepsy^, Bseizures^, Bcentral nervous system^: all retrieved abstracts were screened for an association between STL and CNS abnormalities and epilepsy. Thus, the association between STL and epilepsy has not been reported so far. We describe three children affected by STL1, followed up at our institutions for 6 years, who developed seizures, with abnormal electroencephalogram (EEG) patterns. We speculate on the possible underlying pathophysiology of epilepsy and neurological
manifestations within the spectrum of STL1- and COL2A1related disorders.
Case report Patient 1 This male patient was delivered after 32 weeks of gestation by cesarean section because of chorioamnionitis. His weight was 2050 g, his length was 45 cm, and his head circumference was 33 cm. He did not present neonatal seizures. At birth, cleft palate, retrognathia, and split uvula were noticed. Since the first year of life, psychomotor delay, mild to moderate sensorineural hearing loss, and strabismus were evident. He also had peculiar facies, characterized by midfacial hypoplasia, flattened nasal bridge, micro-retrognathia, associated with joint hypermobility, and severe myopia; mild scoliosis and bilateral tibial epiphyseal dysplasia were present. Visualevoked potentials (VEP) showed bilateral conductive retardation with morphological abnormalities and reduced amplitudes, and acoustic-evoked potentials (AEP) confirmed the presence of a mild sensorineural hearing loss. At 14 months of age, he presented two brief episodes of generalized tonic-clonic seizures (GTCS). At the age of 3 years, the child presented another GTCS with perioral cyanosis, which spontaneously remitted after a few minutes. Sleep EEG showed symmetrical theta-delta activity of high amplitude, with sharp-waves of medium voltage predominantly on the right fronto-temporal regions. No ph oto pa ro xys mal res pon se was ob ser ved d urin g photostimulation (Fig. 1). Genetic analysis of genomic DNA for STL1 was performed from extracted blood using standard method. The entire coding regions of COL2A1 (Gen Bank accession number: NM_001844.3) with flanking intronic regions were examined by High-Resolution Melt (HRM) analysis after polymerase chain reaction (PCR) amplification. A heterozygous nonsense mutation was identified in the exon 30 (c.1957C > T; p.Arg653X) of the COL2A1 gene, confirming the diagnosis of STL1. The same mutation was identified in his mother, and grandmother; they presented only ocular alterations (i.e., myopia and strabismus, respectively) and cleft palate. Two months, later he presented a new episode of GTCS associated with automatic oral movements, which were interrupted after the administration of intrarectal diazepam. EEG showed the same abnormalities of the previous one. Brain magnetic resonance imaging (MRI) was normal. Extensive diagnostic workup excluded any underlying metabolic disorder. The boy was treated with sodium valproate (VPA) and achieved full resolution of seizures within 2 months; he continued to be seizurefree at last follow-up evaluation (after 5.9 years from the onset).
Eur J Pediatr
Fig. 1 Sleep EEG showing sharp-waves of medium voltage predominantly on the right fronto-temporal regions (highlighted by landmarks)
Patient 2 This female patient was born at term after natural delivery. Her weight was 3300 g, her length was 52 cm, and her head circumference was 32 cm. At birth, considering the peculiar facies (cleft palate, split uvula, micrognathia, and glossoptosis), a Pierre-Robin sequence was strongly suspected. She underwent several ultrasound investigations (e.g., cerebral, renal, cardiac) that were normal. Since the age of 1.5 year, a psychomotor delay was noticed, associated with ophthalmological alterations (i.e., severe bilateral myopia, convergent strabismus); AEP showed sensorineural hearing loss (i.e., moderate bilateral high-frequency). Skeletal survey yielded bone generalized rarefaction, shortening of the fifth metacarpal bone, and marked hypoplasia of the distal phalanx in the right foot. Echocardiography showed mitral valve prolapse not associated with regurgitation. At 6.3 years of age, the girl presented a self-limiting episode of GTCS that lasted 4 min and was characterized by eye rolling and loss of sphincter control. EEG showed symmetrical alpha-theta activity, with sporadic sharp-waves of medium voltage mainly localized in the left temporo-occipital regions. No photoparoxysmal response was observed during photostimulation (Fig. 2). We suspected STL1, and genetic testing of COL2A1 gene as in Patient 1 revealed a heterozygous nonsense mutation (c.3106C>T; p.Arg1036X) in exon 44 of the COL2A1 gene. The patient’s father was heterozygous for this
mutation, but he was not affected by the disease. At 7.2 years of age, the girl presented another GTCS associated to eye rolling that spontaneously remitted. EEG revealed paroxysmal discharges from the left temporo-occipital regions. Brain MRI was normal. An extensive metabolic diagnostic work-up was performed and did not identify any significant alteration. She was treated with VPA with a good clinical response (EEG pattern normalization in the follow-up controls, complete remission of seizures) in a 6-month period. The child was seizure-free during the last 3 years. Patient 3 This male patient was born at term by cesarean delivery because of maternal gestational diabetes treated with insulin; at birth, blood glucose levels were normal and he did not present neonatal seizures. His weight was 3800 g, his length was 53 cm, and his head circumference was 33 cm. At 2 years of age, cleft palate, myopia, and mild combined (i.e., conductive and sensorineural) hearing loss at AEP were noticed, leading us to suspect STL1. Genetic testing as in Patient 1 showed a heterozygous pathogenic mutation (c.3508G>A; p.G1170S) within exon 50, confirming the diagnosis of STL1. The same mutation was found in his mother, who only presented cleft palate. At 4.4 years of age, the child presented two brief episodes of partial seizures characterized by left deviation of the head, right deviation of the mouth, and movements of the left side of the body. After
Eur J Pediatr
Fig. 2 Paroxysmal discharges from the left temporo-occipital regions (highlighted by landmarks)
5 months, he presented another longer episode of partial seizure, interrupted after 6 min by intrarectal diazepam administration and followed by a transient postictal hemiparesis. Interictal EEG recordings during wakefulness were characterized by normal background activity with temporal intermittent spike-wave discharges in the left hemisphere. No photoparoxysmal response was seen during photostimulation. Brain MRI did not show any abnormality. Extensive metabolic tests were fully reported as normal, and other common causes of epilepsy were excluded. After the third epileptic episode, anticonvulsant treatment with VPA was initiated, with complete disappearance of seizures in the following 5 weeks. At last follow-up, the child was still seizure-free (after 4.2 years).
Discussion We report three children with (a) ocular, oral, facial, auditory, and musculoskeletal manifestations of STL1; (b) history of generalized or partial seizures with abnormal EEG records; and (c) pathogenic heterozygous mutations of the COL2A1 gene, confirming the diagnosis of STL1. In previous large cohort studies, seizures and any other CNS-related manifestations have never been reported in patients with STL [7]. Our cases suggest that the occurrence of epilepsy may not be coincidental in this genetic condition and that an underlying etiological relationship is conceivable.
Of note, COL2A1 mutations give rise to a continuous spectrum of phenotypes affecting the cartilage and bone, ranging from severe disorders that are perinatally lethal (i.e., thanatophoric dysplasia Torrance variant; MIM 151210) to milder conditions recognized in the postnatal period and childhood, (i.e., spondyloepiphyseal dysplasia congenita (SEDC; MIM 183900), Kniest dysplasia (KD; MIM 156550), ac hon drog ene sis typ e II ( ACG2; MI M 200 610 ), spondyloperipheral dysplasia (SPD; MIM 271700), and Legg-Calvè-Perthes disease (LCPD; MIM 150600)) [3, 8]. Despite the description of few specific genotype–phenotype relationships within the COL2A1 spectrum, the majority of mutations reported so far do not predict with certainty the phenotype [8, 10, 13]. STL1 is predominantly caused by loss-of-function mutations in the COL2A1 gene. Most frequent mutations result in nonsense-mediated decay, such as those identified in two patients of our series (i.e., Patient 1, 2), both previously reported as pathogenic mutations, because they cause a premature stop codon in the COL2A1 gene [7]. Missense mutations of COL2A1 account only for 10 % of the genetic alterations of STL1 [7]. Missense mutation found in Patient 3 (p.G1170S) leads to a glycine substitution that hampers proper triple helix formation of the collagen trimer; the insertion of this serine residue may generate aberrant disulfide bonds between mutant procollagen chains, likely impairing proper chain alignment and trimer formation [7, 11, 12]. Therefore, the mutation may
Eur J Pediatr
exert a loss-of-function effect on the protein, resulting in STL1. Of note, glycine substitutions have been more frequently identified as the molecular cause of other COL2A1-related phenotypes, such as SEDC, KD, and LCPD [7]. Interestingly, there are reports of patients harboring COL2A1 mutations due to glycine substitutions, who were exclusively affected by femoral head disease, whereas their children, harboring the same mutation, presented the typical (ocular, musculoskeletal, facial) STL1 features [13]. These reports support the notion that discordant phenotypes may arise by the same COL2A1 defect [8, 10]. Moreover, the p.G1170S mutation identified in one child with STL1 of our series (Patient 3) has been previously reported in some families with classic LCPD [11, 12]. Previous reports have described children affected by LCPD with neurological manifestations, including cognitive and motor impairment, epilepsy, and brain abnormalities (e.g., thickening of the temporal cortex, partial agenesis of the corpus callosum, cerebral hemiatrophy) [5, 6, 14, 15]. Although the diagnosis of each different COL2A1-related condition is addressed by the presence of peculiar specific manifestations, overlapping features among the distinct phenotypes may occur, and a recognizable continuous clinical spectrum in individuals with type II collagen defects has been proposed [8, 9]. Therefore, we suggest that epilepsy observed in our children could be considered a possible feature in the context of STL1. In the three children with STL1 and epilepsy, the long-term prognosis was excellent, with rapid response to anticonvulsant therapies and persistent remission after follow-up. Epilepsy in STL1 seems to be easily controlled by monotherapy (e.g., VPA). Probably, the absence of CNS abnormalities can explain the good response to anticonvulsant therapy. In conclusion, this report suggests the possible occurrence of epilepsy in STL1 as in other COL2A1-related disorders (e.g., LCPD), further expanding the CNS involvement in some dominantly inherited collagenopathies.
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12. Compliance with ethical standards All the authors declare that they have no conflict of interest. Author’s contributions SS and AV wrote the article, critically reviewed the article, and contributed to data collection. MVS, TF, DL, and GM contributed to study design and analysed and interpreted the data, and takes responsibility for the study as a whole. LL and VS contributed to data collection.
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References 15. 1. Acke FR, Dhooge IJ, Malfait F, De Leenheer EM (2012) Hearing impairment in Stickler syndrome: a systematic review. Orphanet J Rare Dis 7:84 2. Ahmad NN, Ala-Kokko L, Knowlton RG, Jimenez SA, Weaver EJ, Maguire JI, Tasman W, Prockop DJ (1991) Stop codon in the
16.
procollagen II gene (COL2A1) in a family with the Stickler syndrome (arthro-ophthalmopathy). Proc Natl Acad Sci 88:6624–6627 Bateman JF, Lamande SR, Ramshaw JAM (1996) Collagen superfamily. In: Comper WE (ed) Extracellular matrix, vol 2. Harwood Academic Publishers, Amsterdam Couchouron T, Masson C (2011) Early-onset progressive osteoarthritis with hereditary progressive ophtalmopathy or Stickler syndrome. Joint Bone Spine 78:45–49 Czeizel A, Lowry RB (1990) Syndrome of cataract, mild microcephaly, mental retardation and Perthes-like changes in sibs. Acta Paediatr Hung 30:343–349 Hall DJ, Harrison MH, Burwell RG (1979) Congenital abnormalities and Perthes’ disease. Clinical evidence that children with Perthes’ disease may have a major congenital defect. J Bone Joint Surg Br 61:18–25 Hoornaert KP, Vereecke I, Dewinter C, Rosenberg T, Beemer FA, Leroy JG, Bendix L, Björck E, Bonduelle M, Boute O, CormierDaire V, De Die-Smulders C, Dieux-Coeslier A, Dollfus H, Elting M, Green A, Guerci VI, Hennekam RC, Hilhorts-Hofstee Y, Holder M, Hoyng C, Jones KJ, Josifova D, Kaitila I, Kjaergaard S, Kroes YH, Lagerstedt K, Lees M, Lemerrer M, Magnani C, Marcelis C, Martorell L, Mathieu M, McEntagart M, Mendicino A, Morton J, Orazio G, Paquis V, Reish O, Simola KO, Smithson SF, Temple KI, Van Aken E, Van Bever Y, van den Ende J, Van Hagen JM, Zelante L, Zordania R, De Paepe A, Leroy BP, De Buyzere M, Coucke PJ, Mortier GR (2010) Stickler syndrome caused by COL2A1 mutations: genotypephenotype correlation in a series of 100 patients. Eur J Hum Genet 18: 872–880, Note: Erratum: Europ. J. Hum. Genet. 18:881 Kannu P, Bateman J, Savarirayan R (2012) Clinical phenotypes associated with type II collagen mutations. J Paediatr Child Health 48: 38–43 Kannu P, Irving M, Aftimos S, Savarirayan R (2011) Two novel COL2A1 mutations associated with a Legg-Calvé-Perthes diseaselike presentation. Clin Orthop Relat Res 469:1785–1790 Liberfarb RM, Levy HP, Rose PS, Wilkin DJ, Davis J, Balog JZ, Griffith AJ, Szymko-Bennett YM, Johnston JJ, Francomano CA, Tsilou E, Rubin BI (2003) The Stickler syndrome: genotype/ phenotype correlation in 10 families with Stickler syndrome resulting from seven mutations in the type II collagen gene locus COL2A1. Genet Med 5(1):21–7 Liu YF, Chen WM, Lin YF, Yang RC, Lin MW, Li LH, Chang YH, Jou YS, Lin PY, Su JS, Huang SF, Hsiao KJ, Fann CS, Hwang HW, Chen YT, Tsai SF (2005) Type II collagen gene variants and inherited osteonecrosis of the femoral head. N Engl J Med 352:2294–2301 Miyamoto Y, Matsuda T, Kitoh H, Haga N, Ohashi H, Nishimura G, Ikegawa S (2007) A recurrent mutation in type II collagen gene causes Legg-Calvé-Perthes disease in a Japanese family. Hum Genet 121:625–629 Richards AJ, Laidlaw M, Meredith SP, Shankar P, Poulson AV, Scott JD, Snead MP (2007) Missense and silent mutations in COL2A1 result in Stickler syndrome but via different molecular mechanisms. Hum Mutat 28(6):639 Ruggieri M, Milone P, Pavone P, Falsaperla R, Polizzi A, Caltabiano R, Fichera M, Gabriele AL, Distefano A, De Pasquale R, Salpietro V, Micali G, Pavone L (2012) Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke-Davidoff-Masson type in two patients. Am J Med Genet A 158:2870–2880 Savasta S, Ruggieri M, Pavone P, Praticò AD, Polizzi A, Beluffi G, Pavone V (2012) Microcephaly associated with Legg-Calvè-Perthes disease in two siblings. Neurol Sci 33:1401–1405 Stickler GB, Belau PG, Farrell FJ, Jones JD, Pugh DG, Steinberg AG, Ward LE (1965) Hereditary progressive arthro-ophthalmopathy. Mayo Clin Proc 40:433–455
CASE REPORT
Stickler syndrome associated with epilepsy: report of three cases Salvatore Savasta & Vincenzo Salpietro & Maria Valentina Spartà & Thomas Foiadelli & Daniela Laino & Lucio Lobefalo & Gian Luigi Marseglia & Alberto Verrotti
Received: 13 November 2014 / Revised: 20 February 2015 / Accepted: 3 March 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Stickler syndrome is a genetically heterogeneous collagenopathy characterized by auditory, ocular, musculoskeletal, and orofacial abnormalities. Stickler syndrome type 1 typically presents ophthalmologic involvement and is due to heterozygous defects of the COL2A1 gene, that have been also identified as the molecular cause of a continuous spectrum of different disorders mainly affecting the cartilage and bone (i.e., Kniest
Communicated by Beat Steinmann Revisions received: 03 January 2015 / 23 January 2015 S. Savasta : M. V. Spartà : T. Foiadelli : G. L. Marseglia Department of Pediatrics, IRCSS Policlinico BSan Matteo^, University of Pavia, Pavia, Italy S. Savasta e-mail: [email protected]
dysplasia, achondrogenesis type II, Legg-Calvè-Perthes disease). We report three Caucasian children with: (a) ocular, oral, facial, auditory, and musculoskeletal manifestations of Stickler syndrome type 1; (b) history of generalized and/or partial seizures coupled with abnormal electroencephalographic records; and (c) pathogenic heterozygous mutations of the COL2A1 gene. Epilepsy has been never reported so far in literature as a possible feature of Stickler syndrome, although neurological presentations, including epilepsy and brain abnormalities, have been occasionally described in other COL2A1related phenotypes (e.g., Legg-Calvè-Perthes disease). Conclusions: This report raises the possibility of a potential occurrence of seizures among the clinical manifestations of Stickler syndrome type 1, suggesting the presence of a continuous neurological spectrum in some individuals harboring heterozygous mutations in COL2A1.
M. V. Spartà e-mail: [email protected] T. Foiadelli e-mail: [email protected] G. L. Marseglia e-mail: [email protected] V. Salpietro Department of Pediatrics, University of Messina, Messina, Italy e-mail: [email protected] D. Laino : A. Verrotti (*) Department of Pediatrics, University of Perugia, Perugia, Italy e-mail: [email protected]
What is Known: • Stickler syndrome is a genetically heterogeneous collagenopathy characterized by auditory, ocular, musculoskeletal, and orofacial anomalies. What is New: • Involvement of the nervous central system is not a typical feature of Stickler syndrome and the association with epilepsy has not been reported so far. • This report raises the possibility of a potential occurrence of seizures among the clinical manifestations of Stickler syndrome type 1, suggesting a continuous neurological spectrum in some individuals affected by heterozygous mutations of COL2A1.
D. Laino e-mail: [email protected] L. Lobefalo Department of Experimental and Clinical Sciences-Section of Ophthalmology, University of Chieti, Chieti, Italy e-mail: [email protected]
Keywords Stickler syndrome . COL2A1 . Neurological symptoms . Epilepsy . Central nervous system . Legg-Calvè-Perthes disease
Eur J Pediatr
Abbreviations CNS Central nervous system EEG Electroencephalogram GTCS Generalized tonic-clonic seizures LCPD Legg-Calvè-Perthes disease MRI Magnetic resonance image STL Stickler syndrome STL1 Stickler syndrome type 1 VEP Visual-evoked potentials AEP Auditive-evoked potentials PCR Polymerase chain reaction VPA Valproic acid SEDC Spondyloepiphyseal dysplasia congenital KD Kniest dysplasia.
Introduction Stickler syndrome (STL), also called hereditary progressive arthroophtalmopathy, was described in 1965 by Stickler [16]. The phenotype of STL is clinically heterogeneous, and most patients have various ophthalmological findings, including high myopia, vitreoretinal degeneration, retinal detachment, and cataracts [2–4]. Additional features include hearing loss, midline defects (e.g., cleft palate, bifid uvula, flattened mid face), Pierre Robin sequence, early-onset osteoarthritis, and mild spondyloepiphyseal dysplasia [1, 3, 4]. The autosomal dominant form of STL is classified into three different types (types I, II, III), on the basis of clinical features and specific molecular defects [3, 4]. The most frequent form is STL type I (MIM 108300; SLT1), caused by abnormalities in the COL2A1 gene and characterized by congenital vitreous abnormalities [2, 7]. The COL2A1 gene encodes type II collagen, a component of the extracellular cartilage matrix which plays a role for endochondral bone ossification. Collagen type II is present also in the vitreous humor and the inner ear, explaining the frequent visual and hearing impairment in STL1 [3]. Central nervous system (CNS) involvement is not a typical feature of STL. A thorough research in the published literature (PubMed and the Cochrane Library) was performed using the following keywords: BStickler epilepsy^, BStickler seizures^, BCOL2A1^, and B(stickler) NOT stickler [Author], Bepilepsy^, Bseizures^, Bcentral nervous system^: all retrieved abstracts were screened for an association between STL and CNS abnormalities and epilepsy. Thus, the association between STL and epilepsy has not been reported so far. We describe three children affected by STL1, followed up at our institutions for 6 years, who developed seizures, with abnormal electroencephalogram (EEG) patterns. We speculate on the possible underlying pathophysiology of epilepsy and neurological
manifestations within the spectrum of STL1- and COL2A1related disorders.
Case report Patient 1 This male patient was delivered after 32 weeks of gestation by cesarean section because of chorioamnionitis. His weight was 2050 g, his length was 45 cm, and his head circumference was 33 cm. He did not present neonatal seizures. At birth, cleft palate, retrognathia, and split uvula were noticed. Since the first year of life, psychomotor delay, mild to moderate sensorineural hearing loss, and strabismus were evident. He also had peculiar facies, characterized by midfacial hypoplasia, flattened nasal bridge, micro-retrognathia, associated with joint hypermobility, and severe myopia; mild scoliosis and bilateral tibial epiphyseal dysplasia were present. Visualevoked potentials (VEP) showed bilateral conductive retardation with morphological abnormalities and reduced amplitudes, and acoustic-evoked potentials (AEP) confirmed the presence of a mild sensorineural hearing loss. At 14 months of age, he presented two brief episodes of generalized tonic-clonic seizures (GTCS). At the age of 3 years, the child presented another GTCS with perioral cyanosis, which spontaneously remitted after a few minutes. Sleep EEG showed symmetrical theta-delta activity of high amplitude, with sharp-waves of medium voltage predominantly on the right fronto-temporal regions. No ph oto pa ro xys mal res pon se was ob ser ved d urin g photostimulation (Fig. 1). Genetic analysis of genomic DNA for STL1 was performed from extracted blood using standard method. The entire coding regions of COL2A1 (Gen Bank accession number: NM_001844.3) with flanking intronic regions were examined by High-Resolution Melt (HRM) analysis after polymerase chain reaction (PCR) amplification. A heterozygous nonsense mutation was identified in the exon 30 (c.1957C > T; p.Arg653X) of the COL2A1 gene, confirming the diagnosis of STL1. The same mutation was identified in his mother, and grandmother; they presented only ocular alterations (i.e., myopia and strabismus, respectively) and cleft palate. Two months, later he presented a new episode of GTCS associated with automatic oral movements, which were interrupted after the administration of intrarectal diazepam. EEG showed the same abnormalities of the previous one. Brain magnetic resonance imaging (MRI) was normal. Extensive diagnostic workup excluded any underlying metabolic disorder. The boy was treated with sodium valproate (VPA) and achieved full resolution of seizures within 2 months; he continued to be seizurefree at last follow-up evaluation (after 5.9 years from the onset).
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Fig. 1 Sleep EEG showing sharp-waves of medium voltage predominantly on the right fronto-temporal regions (highlighted by landmarks)
Patient 2 This female patient was born at term after natural delivery. Her weight was 3300 g, her length was 52 cm, and her head circumference was 32 cm. At birth, considering the peculiar facies (cleft palate, split uvula, micrognathia, and glossoptosis), a Pierre-Robin sequence was strongly suspected. She underwent several ultrasound investigations (e.g., cerebral, renal, cardiac) that were normal. Since the age of 1.5 year, a psychomotor delay was noticed, associated with ophthalmological alterations (i.e., severe bilateral myopia, convergent strabismus); AEP showed sensorineural hearing loss (i.e., moderate bilateral high-frequency). Skeletal survey yielded bone generalized rarefaction, shortening of the fifth metacarpal bone, and marked hypoplasia of the distal phalanx in the right foot. Echocardiography showed mitral valve prolapse not associated with regurgitation. At 6.3 years of age, the girl presented a self-limiting episode of GTCS that lasted 4 min and was characterized by eye rolling and loss of sphincter control. EEG showed symmetrical alpha-theta activity, with sporadic sharp-waves of medium voltage mainly localized in the left temporo-occipital regions. No photoparoxysmal response was observed during photostimulation (Fig. 2). We suspected STL1, and genetic testing of COL2A1 gene as in Patient 1 revealed a heterozygous nonsense mutation (c.3106C>T; p.Arg1036X) in exon 44 of the COL2A1 gene. The patient’s father was heterozygous for this
mutation, but he was not affected by the disease. At 7.2 years of age, the girl presented another GTCS associated to eye rolling that spontaneously remitted. EEG revealed paroxysmal discharges from the left temporo-occipital regions. Brain MRI was normal. An extensive metabolic diagnostic work-up was performed and did not identify any significant alteration. She was treated with VPA with a good clinical response (EEG pattern normalization in the follow-up controls, complete remission of seizures) in a 6-month period. The child was seizure-free during the last 3 years. Patient 3 This male patient was born at term by cesarean delivery because of maternal gestational diabetes treated with insulin; at birth, blood glucose levels were normal and he did not present neonatal seizures. His weight was 3800 g, his length was 53 cm, and his head circumference was 33 cm. At 2 years of age, cleft palate, myopia, and mild combined (i.e., conductive and sensorineural) hearing loss at AEP were noticed, leading us to suspect STL1. Genetic testing as in Patient 1 showed a heterozygous pathogenic mutation (c.3508G>A; p.G1170S) within exon 50, confirming the diagnosis of STL1. The same mutation was found in his mother, who only presented cleft palate. At 4.4 years of age, the child presented two brief episodes of partial seizures characterized by left deviation of the head, right deviation of the mouth, and movements of the left side of the body. After
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Fig. 2 Paroxysmal discharges from the left temporo-occipital regions (highlighted by landmarks)
5 months, he presented another longer episode of partial seizure, interrupted after 6 min by intrarectal diazepam administration and followed by a transient postictal hemiparesis. Interictal EEG recordings during wakefulness were characterized by normal background activity with temporal intermittent spike-wave discharges in the left hemisphere. No photoparoxysmal response was seen during photostimulation. Brain MRI did not show any abnormality. Extensive metabolic tests were fully reported as normal, and other common causes of epilepsy were excluded. After the third epileptic episode, anticonvulsant treatment with VPA was initiated, with complete disappearance of seizures in the following 5 weeks. At last follow-up, the child was still seizure-free (after 4.2 years).
Discussion We report three children with (a) ocular, oral, facial, auditory, and musculoskeletal manifestations of STL1; (b) history of generalized or partial seizures with abnormal EEG records; and (c) pathogenic heterozygous mutations of the COL2A1 gene, confirming the diagnosis of STL1. In previous large cohort studies, seizures and any other CNS-related manifestations have never been reported in patients with STL [7]. Our cases suggest that the occurrence of epilepsy may not be coincidental in this genetic condition and that an underlying etiological relationship is conceivable.
Of note, COL2A1 mutations give rise to a continuous spectrum of phenotypes affecting the cartilage and bone, ranging from severe disorders that are perinatally lethal (i.e., thanatophoric dysplasia Torrance variant; MIM 151210) to milder conditions recognized in the postnatal period and childhood, (i.e., spondyloepiphyseal dysplasia congenita (SEDC; MIM 183900), Kniest dysplasia (KD; MIM 156550), ac hon drog ene sis typ e II ( ACG2; MI M 200 610 ), spondyloperipheral dysplasia (SPD; MIM 271700), and Legg-Calvè-Perthes disease (LCPD; MIM 150600)) [3, 8]. Despite the description of few specific genotype–phenotype relationships within the COL2A1 spectrum, the majority of mutations reported so far do not predict with certainty the phenotype [8, 10, 13]. STL1 is predominantly caused by loss-of-function mutations in the COL2A1 gene. Most frequent mutations result in nonsense-mediated decay, such as those identified in two patients of our series (i.e., Patient 1, 2), both previously reported as pathogenic mutations, because they cause a premature stop codon in the COL2A1 gene [7]. Missense mutations of COL2A1 account only for 10 % of the genetic alterations of STL1 [7]. Missense mutation found in Patient 3 (p.G1170S) leads to a glycine substitution that hampers proper triple helix formation of the collagen trimer; the insertion of this serine residue may generate aberrant disulfide bonds between mutant procollagen chains, likely impairing proper chain alignment and trimer formation [7, 11, 12]. Therefore, the mutation may
Eur J Pediatr
exert a loss-of-function effect on the protein, resulting in STL1. Of note, glycine substitutions have been more frequently identified as the molecular cause of other COL2A1-related phenotypes, such as SEDC, KD, and LCPD [7]. Interestingly, there are reports of patients harboring COL2A1 mutations due to glycine substitutions, who were exclusively affected by femoral head disease, whereas their children, harboring the same mutation, presented the typical (ocular, musculoskeletal, facial) STL1 features [13]. These reports support the notion that discordant phenotypes may arise by the same COL2A1 defect [8, 10]. Moreover, the p.G1170S mutation identified in one child with STL1 of our series (Patient 3) has been previously reported in some families with classic LCPD [11, 12]. Previous reports have described children affected by LCPD with neurological manifestations, including cognitive and motor impairment, epilepsy, and brain abnormalities (e.g., thickening of the temporal cortex, partial agenesis of the corpus callosum, cerebral hemiatrophy) [5, 6, 14, 15]. Although the diagnosis of each different COL2A1-related condition is addressed by the presence of peculiar specific manifestations, overlapping features among the distinct phenotypes may occur, and a recognizable continuous clinical spectrum in individuals with type II collagen defects has been proposed [8, 9]. Therefore, we suggest that epilepsy observed in our children could be considered a possible feature in the context of STL1. In the three children with STL1 and epilepsy, the long-term prognosis was excellent, with rapid response to anticonvulsant therapies and persistent remission after follow-up. Epilepsy in STL1 seems to be easily controlled by monotherapy (e.g., VPA). Probably, the absence of CNS abnormalities can explain the good response to anticonvulsant therapy. In conclusion, this report suggests the possible occurrence of epilepsy in STL1 as in other COL2A1-related disorders (e.g., LCPD), further expanding the CNS involvement in some dominantly inherited collagenopathies.
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12. Compliance with ethical standards All the authors declare that they have no conflict of interest. Author’s contributions SS and AV wrote the article, critically reviewed the article, and contributed to data collection. MVS, TF, DL, and GM contributed to study design and analysed and interpreted the data, and takes responsibility for the study as a whole. LL and VS contributed to data collection.
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