RESEARCH ARTICLE
Mutations in LONP1, a Mitochondrial Matrix Protease, Cause CODAS Syndrome Esra Dikoglu,1 Ali Alfaiz,2,3 Maria Gorna,4 Deborah Bertola,5 Jong Hee Chae,6 Tae-Joon Cho,6 Murat Derbent,7 Yasemin Alanay,8 Tulay Guran,9 Ok-Hwa Kim,10 Juan C. Llerenar Jr.,11 Guillerme Yamamoto,5 Giulio Superti-Furga,4 Alexandre Reymond,2 Ioannis Xenarios,3 Brian Stevenson,3 Belinda Campos-Xavier,1 Luisa Bonafe,1 Andrea Superti-Furga,12 and Sheila Unger13* 1
Centre des Maladies Moleculaires CHUV, University of Lausanne, Switzerland Center for Integrative Genomics (CIG), University of Lausanne, Lausanne, Switzerland
2 3
Swiss Institute of Bioinformatics, Lausanne, Switzerland
4
Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria Genetics Unit, Instituto da CrianSc a, HC/FMUSP, Sao Paulo, Brazil
5 6
Department of Orthopaedic Surgery, Seoul National Univ Children’s Hospital, Seoul, South Korea
7
Pediatric Genetics Unit, Department of Pediatrics, BaSs kent University Faculty of Medicine, Ankara, Turkey Pediatric Genetics, Department of Pediatrics, Acibadem University School of Medicine, Istanbul, Turkey
8 9
Division of Pediatric Endocrinology, Department of Pediatrics, Marmara University Hospital, Istanbul, Turkey
10
Radiology, Woorisoa Children’s Hospital, Seoul, Korea Centro de Genetica Medica, Instituto Fernandes Fugueira/Fiocruz, Rio de Janeiro, Brazil
11 12
Department of Pediatrics, CHUV, University of Lausanne, Switzerland
13
Medical Genetics Service, CHUV, University of Lausanne, Switzerland
Manuscript Received: 18 December 2014; Manuscript Accepted: 7 February 2015
Cerebral, ocular, dental, auricular, skeletal anomalies (CODAS) syndrome (MIM 600373) was first described and named by Shehib et al, in 1991 in a single patient. The anomalies referred to in the acronym are as follows: cerebral-developmental delay, ocular-cataracts, dental-aberrant cusp morphology and delayed eruption, auricular-malformations of the external ear, and skeletal-spondyloepiphyseal dysplasia. This distinctive constellation of anatomical findings should allow easy recognition but despite this only four apparently sporadic patients have been reported in the last 20 years indicating that the full phenotype is indeed very rare with perhaps milder or a typical presentations that are allelic but without sufficient phenotypic resemblance to permit clinical diagnosis. We performed exome sequencing in three patients (an isolated case and a brother and sister sib pair) with classical features of CODAS. Sanger sequencing was used to confirm results as well as for mutation discovery in a further four unrelated patients ascertained via their skeletal features. Compound heterozygous or homozygous mutations in LONP1 were found in all (8 separate mutations; 6 missense, 1 nonsense, 1 small in-frame deletion) thus establishing the genetic basis of CODAS and the pattern of inheritance (autosomal recessive). LONP1 encodes an enzyme of bacterial ancestry that participates in protein turnover within the mitochondrial matrix. The mutations cluster at the ATP-binding and proteolytic domains of the
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Dikoglu E, Alfaiz A, Gorna M, Bertola D, Chae JH, Cho T-J, Derbent M, Alanay Y, Guran T, Kim O-H, Llerenar Jr. JC, Yamamoto G, Superti-Furga G, Reymond A, Xenarios I, Stevenson B, CamposXavier B, Bonafe L, Superti-Furga A, Unger S. 2015. Mutations in LONP1, a mitochondrial matrix protease, cause CODAS syndrome. Am J Med Genet Part A 167A:1501–1509.
Esra Dikoglu and Ali Alfaiz contributed equally to this work. Conflicts of interest: None. Grant sponsor: Brazil-Switzerland Joint Research Program CoSMO-B; Grant sponsor: Swiss National Foundation; Grant sponsor: University of Lausanne (Fonds de Developpement de la Recherche en Pediatrie); Grant sponsor: Leenaards Foundation in Lausanne (www.leenaards.ch). Correspondence to: Sheila Unger, Service of Medical Genetics, UniL - Univ. of Lausanne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 21 March 2015 DOI 10.1002/ajmg.a.37029
1501
1502 enzyme. Biallelic inheritance and clustering of mutations confirm dysfunction of LONP1 activity as the molecular basis of CODAS but the pathogenesis remains to be explored. Ó 2015 Wiley Periodicals, Inc.
Key words: CODAS; cataract; skeletal dysplasia; mitochondrial protease
INTRODUCTION Cerebral, ocular, dental, auricular, skeletal anomalies (CODAS) syndrome was originally described in a single case report [Shebib et al., 1991]. The authors sought to give a name to the disorder of their patient so that similar cases could be recognized and diagnosed. However, over the next 20 years only three further cases were reported [Cabral de Almeida et al., 1995; Innes et al., 2001; Marlin et al., 2010]. Of the possible explanations, two stand out as most plausible: either the syndrome is vanishingly rare or other cases did not share enough of the distinctive features to enable diagnosis. All the authors had commented on the ‘‘unique’’ or ‘‘highly distinctive’’ constellation of features [Cabral de Almeida et al., 1995; Innes et al., 2001; Marlin et al., 2010; Shebib et al., 1991]. The components of the CODAS acronym are as follows: cerebralhypotonia and developmental delay, ocular-early onset cataract, dental-abnormal cusps and delayed eruption of teeth, auricularmalformed outer ears, skeletal-severely delayed epiphyseal ossification, coronal clefts, and short stature. However, with such a small sample of patients it is impossible to ascertain the frequency of an individual feature and also which features should be considered classic for the disorder. For example, neurosensory hearing loss was described in the first case but not in the three subsequent. Should this then be considered a cardinal feature of CODAS, an infrequent complication or a chance association? We report on mutations (homozygous and compound heterozygous) in LONP1, a mitochondrial protease, in seven patients including one of the previously described cases [Cabral de Almeida et al., 1995]. There is a wide range in severity of symptoms of these cases ranging from a form of CODAS plus visceral malformations to prototypical to a milder skeletal-ocular only form. Currently there is no clear genotype–phenotype correlation but we propose that CODAS is a new skeletal dysplasia family with at least three distinctive clinical presentations.
PATIENTS Our cohort includes seven patients variously ascertained by geneticists, orthopaedic surgeons, and radiologists from three different countries (Brazil, Korea, and Turkey). Five of seven cases are sporadic and there is one sister–brother sib-pair. All patients had a clinical diagnosis of CODAS syndrome and had early onset cataracts and skeletal dysplasia. Other features were variably present among this cohort. The main clinical and radiographic findings are summarized in Table I. Patient 1: This girl is the first child of healthy non-consanguineous Korean parents. She was noted to have a flat face, grooved nasal tip, and crumpled ears with forward facing lobes at birth. At the age
AMERICAN JOURNAL OF MEDICAL GENETICS PART A of 2 months, she was diagnosed with bilateral cataracts that were promptly surgically corrected. She had no dental anomalies, either in shape or timing of eruption. She had a developmental delay especially important in motor milestones exacerbated by cerebellar ataxia. At 5 years of age, she is still unable to ambulate independently but can stand with assistance. Radiographic examination revealed a generalized severe epiphyseal disorder with almost absent ossification of the capital femoral epiphyses and micro-epiphyses of the long bones. There were no coronal clefts (Fig. 1). MRI of the brain at 3 years of age showed prominent cerebellar folae, shrunken vermis, and dilated cisterns surrounding the cerebellum indicative of marked cerebellar atrophy. Patients 2 and 3: Patient 2 is the first child of healthy nonconsanguineous Korean parents. He was diagnosed with bilateral cataract and strabismus at six months of age. He had normal dentition. He had a grooved nasal tip. He has some developmental delay, particularly in the domain of motor skills. A developmental assessment at age 2 years was consistent with a child of 7 to 8 months. He began walking at 18 months of age but developed progressive genu valgum and patellar dislocation and has limited ambulation. Surgery was only partially corrective. Thyroid function testing and ultrasound examinations of the heart and abdomen were normal. A brain MRI at 3 years of age showed cerebellar atrophy. Radiographic examination showed generalized epiphyseal dysplasia with ossification of the capital femoral epiphyses at age 4 and very small distal femoral and proximal tibial epiphyses. The distal femoral metaphyses have a chevron deformity (inverted V shape defect) and there was bilateral severe genu valgum deformity (Fig. 1). There was mild platyspondyly but no evidence of coronal clefts (Fig. 1). His height and weight were both at the 50th centile. Given the diagnosis in the older brother, radiographs were taken of his younger sister (Patient 3) at age 4 months. Prior to these exams, the parents had not suspected that the second child might have the same disorder as her brother. However, on radiographic examination, there was a generalized epiphyseal dysplasia (no platyspondyly or coronal clefts) (Fig. 1). She had a somewhat flat face but this was consistent with her ethnic origin and the ears were mildly cupped but not clearly dysmorphic. An eye examination performed at 4 months of age showed no cataracts but a repeat exam at 7 months of age detected bilateral lens opacities with the left side requiring surgical correction. She had delayed motor milestones (standing at 26 months, ability to take one or two steps independently at 3.5 years) and delayed speech. Cerebral MRIs at 7 months and at 2 years were normal. Patient 4: This boy was the second child of healthy consanguineous Turkish parents. The prenatal history was unremarkable but congenital cataracts were noted at birth. At the time of last examination (3 years), the growth parameters were normal: height 99 cm (25th centile), weight 14 kg (10th–25th centile) and head circumference 48.5 cm (3rd–10th centile). The only dysmorphic feature was forward facing ear lobes and no dental anomalies were noted. There was bilateral genu valgum (Fig. 1). Intelligence was normal. Abdominal and heart ultrasounds were normal. Patient 5: This child was the first born of a healthy consanguineous Turkish couple. The perinatal period was unremarkable and the growth parameters at birth were normal (length 49 cm, weight 2.8 kg, head circumference 35 cm). Cataracts and glaucoma were
no þ þ þ no no þ no no no þ no þ þ þ
þ
þ no no þ no no no þ no þ þ þ
þ
Patient 2 Korean M no E476A; P749S
no þ þ
Patient 1 Korean F no P749S; G767E
no
þ no
no no
no þ þ
no
no
no no
þ
no þ þ
Patient 3 Korean F no E476A; P749S
þ no
no þ
no no þ
no
no
no no
þ
no no no
Patient 4 Turkish M yes A670V; I927del
PFO
þ no
no þ
no no þ
no
no
no
þ
no
no
Patient 5 Turkish M yes R672C; R672C
þ þ þ þ
þ þ
þ
þ
þ þ þ
þ þ
þ þ
þ
no
þ þ
þ
þ þ
þ
þ no þ
no
þ þ þ þ
þ
þ þ
þ
þ þ þ
Innes et al. Canadian M no
þ
þ þ
þ þ þ
þ
þ þ þ
Shehib et al. Canadian F no
þ
þ þ þ
Patient 7 Brazilian F no W464*; R679H
no
þ
no
þ
no þ no
Patient 6 Brazilian F no A670V; A670V
þ þ
þ þ
þ þ
þ þ þ
no
þ
þ þ
þ
þ
Marlin et al French M yes
The main clinical features of our patients and those already published are listed. Our Patient 7 has previously been published as ‘‘the second case of CODAS’’ [Cabral de Alameida et al., 1995]. The category ‘‘other’’ lists malformations not reported in the original patient and thus not part of the CODAS acronym. Laryngomalacia and congenital heart defect have been reported in the most recent CODAS publication [Marlin et al., 2010] but the asterisk (*) marks previously unreported malformations.
Cerebral Hypotonia Delay in motor milestones Intellectual disability/ developmental delay Ocular Cataracts Dental Delayed tooth eruption Abnormal cusp extension Auricular Scapha and helix dysplasia (‘‘crumpled‘‘ ears) Conductive/Sensorineural hearing loss Skeletal Short stature Subluxation of hips Epiphyseal hypoplasia and delayed ossification Vertebral coronal clefts Genu valgus Facies Flat Grooved nasal tip Other Laryngomalacia Congenital heart defect Tibial hemimelia* Umbilical hernia* Cerebellar hypoplasia*
Ethnicity Gender Parental consanguinity LONP1 mutation
TABLE I. Clinical Characteristics of CODAS Cohort
DIKOGLU ET AL. 1503
1504
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
FIG. 1. The radiographic appearance of CODAS. The top left panel shows radiographs of the lateral spine from Patient 6 at 2 months, Patient 1 at 1 year, and Patient 3 at 4 years of age. Patient 6 has coronal clefts through the entire lumbar spine. The other two lateral spine films are slightly immature but without frank abnormalities. The upper right panel shows radiographs of the left hand of Patient 3 at 4 months and patient 1 at 30 months. There is a clear epiphyseal delay but without morphological anomalies. The middle panel shows pelvic radiographs of Patient 3 at 8 months, Patient 2 at 4 years, Patient 4 at 4 years, and Patient 2 at 5years. There is marked delay in ossification of the capital femoral epiphyses and they have an irregular contour when they do ossify and are flat. The femoral necks are short and poorly modelled. The bottom panel show radiographs of the knees taken in AP of Patient 1 at 30 months, Patient 2 at 4 years, and Patient 4 at 4 years. Similar to the situation at the hips, the epiphyses are small, flat, and irregular in contour. There is a steep central chevron deformity of the distal femoral metaphysis.
detected at 2 months of age. On examination at 3.5 years, his growth remained normal (height 107.2 cm, weight 18.6 kg and head circumference 50.8 cm). He was non-dysmorphic and had no dental anomalies. He had bilateral genu valgum. Intelligence and hearing tests were normal. Cardiac ultrasound revealed only a patent foramen ovale. The most recent height measurement at age 8 years, 3 months was 120.8 cm (10th centile). Radiographic features were consistent with CODAS syndrome. There was no platyspondyly but there was a suggestion of a resolved coronal cleft in L3
(indentation). There was a generalized epiphyseal problem most evident at the hips and knees. At the hips, the capital femoral epiphyses were small, flat, and fragmented. The femoral necks were short and broad. The distal femoral metaphyses had a small but acute chevron deformity and small epiphyses. Patient 6: This girl was the first child of healthy apparently nonconsanguineous Brazilian parents. Prenatal ultrasound revealed club foot and congenital heart defect. She was born at term with a weight of 2.8 kg and length of 44 cm. She had a flat midface, grooved
DIKOGLU ET AL. nasal tip, and crumpled ears (Fig. 2A). Cardiac ultrasound showed that the congenital heart defect consisted of atrial and ventricular septal defects. Congenital bilateral cataracts were detected at day 2 of age. The left leg was shorter than the right as a consequence of hip dysplasia/luxation and tibial hemi-melia (left tibia was truncated at the midshaft level) (Fig. 2B). Abdominal ultrasound, audiological evaluation, and karyotype were all normal. Tracheostomy was performed at one month of age because of laryngomalacia and gastrostomy because of gastroesophageal reflux. An umbilical hernia was corrected at 2.5 years of age and the gastrostomy tube was removed at that time. Her motor development was delayed but intelligence was within normal limits. At age 2 years and 3 months, her growth parameters were weight 8.8 kg ( C p.E476A c.2009C > T p.A670V c.2014C > T p.R672C c.2036G > A p.R679H c.2245C > T p.P749S c.2300G > A p.G767E c.2779 2781delATC p.I927del
Patient 7 2, 3 4, 6 2, 3, 5 7 1 1 4
SIFT – 0 (deleterious) 0 (deleterious) 0 (deleterious) 0.05 (tolerated) 0.01 (deleterious) 0 (deleterious) –
PolyPhen-2 – 0.968 (probably damaging) 0.935 (probably damaging) 0.485 (possibly damaging) 0.014 (benign) 0.983 (probably damaging) 1 (probably damaging) –
The patients with whom the mutations are associated are listed in the second column. None of the mutations were present in the ExAC browser. The missense mutations were evaluated by SIFT and PolyPhen2. Note that SIFT scores range from 0 to 1 with scores
Mutations in LONP1, a Mitochondrial Matrix Protease, Cause CODAS Syndrome Esra Dikoglu,1 Ali Alfaiz,2,3 Maria Gorna,4 Deborah Bertola,5 Jong Hee Chae,6 Tae-Joon Cho,6 Murat Derbent,7 Yasemin Alanay,8 Tulay Guran,9 Ok-Hwa Kim,10 Juan C. Llerenar Jr.,11 Guillerme Yamamoto,5 Giulio Superti-Furga,4 Alexandre Reymond,2 Ioannis Xenarios,3 Brian Stevenson,3 Belinda Campos-Xavier,1 Luisa Bonafe,1 Andrea Superti-Furga,12 and Sheila Unger13* 1
Centre des Maladies Moleculaires CHUV, University of Lausanne, Switzerland Center for Integrative Genomics (CIG), University of Lausanne, Lausanne, Switzerland
2 3
Swiss Institute of Bioinformatics, Lausanne, Switzerland
4
Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria Genetics Unit, Instituto da CrianSc a, HC/FMUSP, Sao Paulo, Brazil
5 6
Department of Orthopaedic Surgery, Seoul National Univ Children’s Hospital, Seoul, South Korea
7
Pediatric Genetics Unit, Department of Pediatrics, BaSs kent University Faculty of Medicine, Ankara, Turkey Pediatric Genetics, Department of Pediatrics, Acibadem University School of Medicine, Istanbul, Turkey
8 9
Division of Pediatric Endocrinology, Department of Pediatrics, Marmara University Hospital, Istanbul, Turkey
10
Radiology, Woorisoa Children’s Hospital, Seoul, Korea Centro de Genetica Medica, Instituto Fernandes Fugueira/Fiocruz, Rio de Janeiro, Brazil
11 12
Department of Pediatrics, CHUV, University of Lausanne, Switzerland
13
Medical Genetics Service, CHUV, University of Lausanne, Switzerland
Manuscript Received: 18 December 2014; Manuscript Accepted: 7 February 2015
Cerebral, ocular, dental, auricular, skeletal anomalies (CODAS) syndrome (MIM 600373) was first described and named by Shehib et al, in 1991 in a single patient. The anomalies referred to in the acronym are as follows: cerebral-developmental delay, ocular-cataracts, dental-aberrant cusp morphology and delayed eruption, auricular-malformations of the external ear, and skeletal-spondyloepiphyseal dysplasia. This distinctive constellation of anatomical findings should allow easy recognition but despite this only four apparently sporadic patients have been reported in the last 20 years indicating that the full phenotype is indeed very rare with perhaps milder or a typical presentations that are allelic but without sufficient phenotypic resemblance to permit clinical diagnosis. We performed exome sequencing in three patients (an isolated case and a brother and sister sib pair) with classical features of CODAS. Sanger sequencing was used to confirm results as well as for mutation discovery in a further four unrelated patients ascertained via their skeletal features. Compound heterozygous or homozygous mutations in LONP1 were found in all (8 separate mutations; 6 missense, 1 nonsense, 1 small in-frame deletion) thus establishing the genetic basis of CODAS and the pattern of inheritance (autosomal recessive). LONP1 encodes an enzyme of bacterial ancestry that participates in protein turnover within the mitochondrial matrix. The mutations cluster at the ATP-binding and proteolytic domains of the
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Dikoglu E, Alfaiz A, Gorna M, Bertola D, Chae JH, Cho T-J, Derbent M, Alanay Y, Guran T, Kim O-H, Llerenar Jr. JC, Yamamoto G, Superti-Furga G, Reymond A, Xenarios I, Stevenson B, CamposXavier B, Bonafe L, Superti-Furga A, Unger S. 2015. Mutations in LONP1, a mitochondrial matrix protease, cause CODAS syndrome. Am J Med Genet Part A 167A:1501–1509.
Esra Dikoglu and Ali Alfaiz contributed equally to this work. Conflicts of interest: None. Grant sponsor: Brazil-Switzerland Joint Research Program CoSMO-B; Grant sponsor: Swiss National Foundation; Grant sponsor: University of Lausanne (Fonds de Developpement de la Recherche en Pediatrie); Grant sponsor: Leenaards Foundation in Lausanne (www.leenaards.ch). Correspondence to: Sheila Unger, Service of Medical Genetics, UniL - Univ. of Lausanne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 21 March 2015 DOI 10.1002/ajmg.a.37029
1501
1502 enzyme. Biallelic inheritance and clustering of mutations confirm dysfunction of LONP1 activity as the molecular basis of CODAS but the pathogenesis remains to be explored. Ó 2015 Wiley Periodicals, Inc.
Key words: CODAS; cataract; skeletal dysplasia; mitochondrial protease
INTRODUCTION Cerebral, ocular, dental, auricular, skeletal anomalies (CODAS) syndrome was originally described in a single case report [Shebib et al., 1991]. The authors sought to give a name to the disorder of their patient so that similar cases could be recognized and diagnosed. However, over the next 20 years only three further cases were reported [Cabral de Almeida et al., 1995; Innes et al., 2001; Marlin et al., 2010]. Of the possible explanations, two stand out as most plausible: either the syndrome is vanishingly rare or other cases did not share enough of the distinctive features to enable diagnosis. All the authors had commented on the ‘‘unique’’ or ‘‘highly distinctive’’ constellation of features [Cabral de Almeida et al., 1995; Innes et al., 2001; Marlin et al., 2010; Shebib et al., 1991]. The components of the CODAS acronym are as follows: cerebralhypotonia and developmental delay, ocular-early onset cataract, dental-abnormal cusps and delayed eruption of teeth, auricularmalformed outer ears, skeletal-severely delayed epiphyseal ossification, coronal clefts, and short stature. However, with such a small sample of patients it is impossible to ascertain the frequency of an individual feature and also which features should be considered classic for the disorder. For example, neurosensory hearing loss was described in the first case but not in the three subsequent. Should this then be considered a cardinal feature of CODAS, an infrequent complication or a chance association? We report on mutations (homozygous and compound heterozygous) in LONP1, a mitochondrial protease, in seven patients including one of the previously described cases [Cabral de Almeida et al., 1995]. There is a wide range in severity of symptoms of these cases ranging from a form of CODAS plus visceral malformations to prototypical to a milder skeletal-ocular only form. Currently there is no clear genotype–phenotype correlation but we propose that CODAS is a new skeletal dysplasia family with at least three distinctive clinical presentations.
PATIENTS Our cohort includes seven patients variously ascertained by geneticists, orthopaedic surgeons, and radiologists from three different countries (Brazil, Korea, and Turkey). Five of seven cases are sporadic and there is one sister–brother sib-pair. All patients had a clinical diagnosis of CODAS syndrome and had early onset cataracts and skeletal dysplasia. Other features were variably present among this cohort. The main clinical and radiographic findings are summarized in Table I. Patient 1: This girl is the first child of healthy non-consanguineous Korean parents. She was noted to have a flat face, grooved nasal tip, and crumpled ears with forward facing lobes at birth. At the age
AMERICAN JOURNAL OF MEDICAL GENETICS PART A of 2 months, she was diagnosed with bilateral cataracts that were promptly surgically corrected. She had no dental anomalies, either in shape or timing of eruption. She had a developmental delay especially important in motor milestones exacerbated by cerebellar ataxia. At 5 years of age, she is still unable to ambulate independently but can stand with assistance. Radiographic examination revealed a generalized severe epiphyseal disorder with almost absent ossification of the capital femoral epiphyses and micro-epiphyses of the long bones. There were no coronal clefts (Fig. 1). MRI of the brain at 3 years of age showed prominent cerebellar folae, shrunken vermis, and dilated cisterns surrounding the cerebellum indicative of marked cerebellar atrophy. Patients 2 and 3: Patient 2 is the first child of healthy nonconsanguineous Korean parents. He was diagnosed with bilateral cataract and strabismus at six months of age. He had normal dentition. He had a grooved nasal tip. He has some developmental delay, particularly in the domain of motor skills. A developmental assessment at age 2 years was consistent with a child of 7 to 8 months. He began walking at 18 months of age but developed progressive genu valgum and patellar dislocation and has limited ambulation. Surgery was only partially corrective. Thyroid function testing and ultrasound examinations of the heart and abdomen were normal. A brain MRI at 3 years of age showed cerebellar atrophy. Radiographic examination showed generalized epiphyseal dysplasia with ossification of the capital femoral epiphyses at age 4 and very small distal femoral and proximal tibial epiphyses. The distal femoral metaphyses have a chevron deformity (inverted V shape defect) and there was bilateral severe genu valgum deformity (Fig. 1). There was mild platyspondyly but no evidence of coronal clefts (Fig. 1). His height and weight were both at the 50th centile. Given the diagnosis in the older brother, radiographs were taken of his younger sister (Patient 3) at age 4 months. Prior to these exams, the parents had not suspected that the second child might have the same disorder as her brother. However, on radiographic examination, there was a generalized epiphyseal dysplasia (no platyspondyly or coronal clefts) (Fig. 1). She had a somewhat flat face but this was consistent with her ethnic origin and the ears were mildly cupped but not clearly dysmorphic. An eye examination performed at 4 months of age showed no cataracts but a repeat exam at 7 months of age detected bilateral lens opacities with the left side requiring surgical correction. She had delayed motor milestones (standing at 26 months, ability to take one or two steps independently at 3.5 years) and delayed speech. Cerebral MRIs at 7 months and at 2 years were normal. Patient 4: This boy was the second child of healthy consanguineous Turkish parents. The prenatal history was unremarkable but congenital cataracts were noted at birth. At the time of last examination (3 years), the growth parameters were normal: height 99 cm (25th centile), weight 14 kg (10th–25th centile) and head circumference 48.5 cm (3rd–10th centile). The only dysmorphic feature was forward facing ear lobes and no dental anomalies were noted. There was bilateral genu valgum (Fig. 1). Intelligence was normal. Abdominal and heart ultrasounds were normal. Patient 5: This child was the first born of a healthy consanguineous Turkish couple. The perinatal period was unremarkable and the growth parameters at birth were normal (length 49 cm, weight 2.8 kg, head circumference 35 cm). Cataracts and glaucoma were
no þ þ þ no no þ no no no þ no þ þ þ
þ
þ no no þ no no no þ no þ þ þ
þ
Patient 2 Korean M no E476A; P749S
no þ þ
Patient 1 Korean F no P749S; G767E
no
þ no
no no
no þ þ
no
no
no no
þ
no þ þ
Patient 3 Korean F no E476A; P749S
þ no
no þ
no no þ
no
no
no no
þ
no no no
Patient 4 Turkish M yes A670V; I927del
PFO
þ no
no þ
no no þ
no
no
no
þ
no
no
Patient 5 Turkish M yes R672C; R672C
þ þ þ þ
þ þ
þ
þ
þ þ þ
þ þ
þ þ
þ
no
þ þ
þ
þ þ
þ
þ no þ
no
þ þ þ þ
þ
þ þ
þ
þ þ þ
Innes et al. Canadian M no
þ
þ þ
þ þ þ
þ
þ þ þ
Shehib et al. Canadian F no
þ
þ þ þ
Patient 7 Brazilian F no W464*; R679H
no
þ
no
þ
no þ no
Patient 6 Brazilian F no A670V; A670V
þ þ
þ þ
þ þ
þ þ þ
no
þ
þ þ
þ
þ
Marlin et al French M yes
The main clinical features of our patients and those already published are listed. Our Patient 7 has previously been published as ‘‘the second case of CODAS’’ [Cabral de Alameida et al., 1995]. The category ‘‘other’’ lists malformations not reported in the original patient and thus not part of the CODAS acronym. Laryngomalacia and congenital heart defect have been reported in the most recent CODAS publication [Marlin et al., 2010] but the asterisk (*) marks previously unreported malformations.
Cerebral Hypotonia Delay in motor milestones Intellectual disability/ developmental delay Ocular Cataracts Dental Delayed tooth eruption Abnormal cusp extension Auricular Scapha and helix dysplasia (‘‘crumpled‘‘ ears) Conductive/Sensorineural hearing loss Skeletal Short stature Subluxation of hips Epiphyseal hypoplasia and delayed ossification Vertebral coronal clefts Genu valgus Facies Flat Grooved nasal tip Other Laryngomalacia Congenital heart defect Tibial hemimelia* Umbilical hernia* Cerebellar hypoplasia*
Ethnicity Gender Parental consanguinity LONP1 mutation
TABLE I. Clinical Characteristics of CODAS Cohort
DIKOGLU ET AL. 1503
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A
FIG. 1. The radiographic appearance of CODAS. The top left panel shows radiographs of the lateral spine from Patient 6 at 2 months, Patient 1 at 1 year, and Patient 3 at 4 years of age. Patient 6 has coronal clefts through the entire lumbar spine. The other two lateral spine films are slightly immature but without frank abnormalities. The upper right panel shows radiographs of the left hand of Patient 3 at 4 months and patient 1 at 30 months. There is a clear epiphyseal delay but without morphological anomalies. The middle panel shows pelvic radiographs of Patient 3 at 8 months, Patient 2 at 4 years, Patient 4 at 4 years, and Patient 2 at 5years. There is marked delay in ossification of the capital femoral epiphyses and they have an irregular contour when they do ossify and are flat. The femoral necks are short and poorly modelled. The bottom panel show radiographs of the knees taken in AP of Patient 1 at 30 months, Patient 2 at 4 years, and Patient 4 at 4 years. Similar to the situation at the hips, the epiphyses are small, flat, and irregular in contour. There is a steep central chevron deformity of the distal femoral metaphysis.
detected at 2 months of age. On examination at 3.5 years, his growth remained normal (height 107.2 cm, weight 18.6 kg and head circumference 50.8 cm). He was non-dysmorphic and had no dental anomalies. He had bilateral genu valgum. Intelligence and hearing tests were normal. Cardiac ultrasound revealed only a patent foramen ovale. The most recent height measurement at age 8 years, 3 months was 120.8 cm (10th centile). Radiographic features were consistent with CODAS syndrome. There was no platyspondyly but there was a suggestion of a resolved coronal cleft in L3
(indentation). There was a generalized epiphyseal problem most evident at the hips and knees. At the hips, the capital femoral epiphyses were small, flat, and fragmented. The femoral necks were short and broad. The distal femoral metaphyses had a small but acute chevron deformity and small epiphyses. Patient 6: This girl was the first child of healthy apparently nonconsanguineous Brazilian parents. Prenatal ultrasound revealed club foot and congenital heart defect. She was born at term with a weight of 2.8 kg and length of 44 cm. She had a flat midface, grooved
DIKOGLU ET AL. nasal tip, and crumpled ears (Fig. 2A). Cardiac ultrasound showed that the congenital heart defect consisted of atrial and ventricular septal defects. Congenital bilateral cataracts were detected at day 2 of age. The left leg was shorter than the right as a consequence of hip dysplasia/luxation and tibial hemi-melia (left tibia was truncated at the midshaft level) (Fig. 2B). Abdominal ultrasound, audiological evaluation, and karyotype were all normal. Tracheostomy was performed at one month of age because of laryngomalacia and gastrostomy because of gastroesophageal reflux. An umbilical hernia was corrected at 2.5 years of age and the gastrostomy tube was removed at that time. Her motor development was delayed but intelligence was within normal limits. At age 2 years and 3 months, her growth parameters were weight 8.8 kg ( C p.E476A c.2009C > T p.A670V c.2014C > T p.R672C c.2036G > A p.R679H c.2245C > T p.P749S c.2300G > A p.G767E c.2779 2781delATC p.I927del
Patient 7 2, 3 4, 6 2, 3, 5 7 1 1 4
SIFT – 0 (deleterious) 0 (deleterious) 0 (deleterious) 0.05 (tolerated) 0.01 (deleterious) 0 (deleterious) –
PolyPhen-2 – 0.968 (probably damaging) 0.935 (probably damaging) 0.485 (possibly damaging) 0.014 (benign) 0.983 (probably damaging) 1 (probably damaging) –
The patients with whom the mutations are associated are listed in the second column. None of the mutations were present in the ExAC browser. The missense mutations were evaluated by SIFT and PolyPhen2. Note that SIFT scores range from 0 to 1 with scores
