Codas Syndrome

A number sign (#) is used with this entry because of evidence that CODAS syndrome is caused by homozygous or compound heterozygous mutation in the LONP1 gene (605490) on chromosome 19p13.

Description

CODAS is an acronym for cerebral, ocular, dental, auricular, and skeletal anomalies. CODAS syndrome is a rare disorder characterized by a distinctive constellation of features that includes developmental delay, craniofacial anomalies, cataracts, ptosis, median nasal groove, delayed tooth eruption, hearing loss, short stature, delayed epiphyseal ossification, metaphyseal hip dysplasia, and vertebral coronal clefts (summary by Strauss et al., 2015).

Clinical Features

In a 3-year-old girl of Mennonite German background, Shebib et al. (1991) described a newly recognized multiple congenital anomalies syndrome characterized by cerebral, ocular, dental, auricular, and skeletal abnormalities and designated by the acronym CODAS syndrome. The unaffected parents were nonconsanguineous, and there were 3 healthy older sibs. At birth, the proband was noted to have borderline microcephaly, double hair-whorl pattern, flat nasal bridge with prominent vertical groove on nasal tip, left ptosis, epicanthal folds, low-set malformed ears with 'crumpled' hypoplastic upper helices, bilateral hip dislocation, proximally placed thumbs, hypermobility of all joints, and mild generalized hypotonia. At age 1 month, fundi were normal and refraction showed slight hyperopia; by 4 months of age, cataracts had developed, which were removed. X-rays at 3 months showed no ossification of the odontoid and incomplete ossification of the bodies of the third through sixth cervical vertebrae. There were coronal clefts involving all vertebrae from T11 to S2. At 2 years of age, she had visual acuity that was less than 20/200 in both eyes. Mild lumbar scoliosis was apparent, as well as genu valgum and pes valgus. Coronal clefts were still present at 3 years of age, at which time markedly delayed epiphyseal ossification and moderate thoracic and lumbar scoliosis were also noted. In addition, the acetabular roofs were flatter and the lateral margins of the iliac wings more vertical than normal. At 3 years of age, she was functioning at a 2-year-old level, was just beginning to walk without support, and had a limited vocabulary. All growth parameters were slightly below the fifth percentile. She remained hypotonic with mild generalized weakness and a hypotonic face. She had delayed tooth eruption and an unusual tooth shape, with pointed extension of tooth structure at the cusp tips of the maxillary and mandibular deciduous canine, first molar, and second molar teeth, with 'dished-out' occlusal surfaces. Brainstem auditory-evoked potentials were abnormal bilaterally, affecting both peripheral and central brainstem auditory pathways.

De Almeida et al. (1995) reported a patient, followed for 5 years, with a strikingly similar phenotype: psychomotor delay, cataracts, abnormally shaped teeth, malformed ears, and radiologic findings of spondyloepiphyseal dysplasia. Both of the reported cases were sporadic and were female. Parental consanguinity was absent in both cases. De Almeida et al. (1995) suggested autosomal recessive inheritance, a fresh mutation of an autosomal dominant disorder, or an X-linked dominant mutation with lethality in males.

Innes et al. (2001) described a third case of particular significance because it involved a male infant who, like the patient reported by Shebib et al. (1991), was of Mennonite ancestry. The child, 2 years old at the time of report, exhibited ptosis, cataracts, overfolded ears, grooved nasal tip, dental projections, developmental delay, and characteristic skeletal anomalies (delayed epiphyseal ossification in the upper and lower extremities, vertebral coronal clefts with deformed vertebral bodies, and abnormally shaped iliac bones). Innes et al. (2001) suggested the possibility of autosomal recessive inheritance in this disorder; however, there had not been a familial recurrence to the time of this study.

Marlin et al. (2010) reported a 5-year-old boy, born of first-cousin parents of Moroccan origin, who presented features consistent with CODAS syndrome. He had short stature and facial dysmorphism including a broad forehead with prominent metopic suture, thin eyebrows, bilateral ptosis, small nose with grooved nasal tip, anteverted nares, flat nasal bridge, short philtrum, small chin, low-set ears with 'crumpled' upper hypoplastic helices, and a flat facial profile. He had moderate mental retardation with a normal neurologic exam and did not have hearing impairment or speech delay. Dental examination revealed delayed tooth eruption, small teeth, protrusion of the maxillary and mandibular central incisors, and pointed extensions at cusp tips. Enamel dysplasia was noted, and he had several decayed teeth. Skeletal survey demonstrated delayed bone age, coronal clefts of the lumbar vertebrae, and squared iliac bones with flat acetabular margins and dislocated hips. Epiphyseal ossification was severely delayed with absent or reduced epiphyses of both long bones and short tubular bones. He did not have hypotonia as noted in the previous 3 patients but did have significant hypermobility. In addition, this patient presented 4 features previously unreported in CODAS syndrome: ventricular septal defect with pulmonary hypertension, extrahepatic bile duct atresia, dilation of the left ureter, and bilateral laryngeal palsy. Karyotype and metabolic screening were normal, and array CGH analysis did not detect any copy number loss or gain in the patient. Royer-Bertrand et al. (2015) noted similarities between the features of the Moroccan boy described by Marlin et al. (2010) and those of EVEN-plus syndrome (EVPLS; 616854).

Strauss et al. (2015) studied 8 children with CODAS syndrome from 6 sibships in the Old Order Amish community of Pennsylvania who were homozygous for a missense mutation in the LONP1 gene (see MOLECULAR GENETICS). Three affected children had died of laryngeal obstruction in the first days of life, and another, who had received a tracheostomy, died of pneumonia in early infancy. The 4 remaining children required tracheostomies to survive infancy; 3 underwent laryngoscopic evaluation, which showed paretic and atrophic vocal cords, glottic narrowing, chronic sialorrhea, and swallowing dysfunction. Two patients had marked hemiatrophy of the tongue, and 3 were nourished exclusively by gastrostomy tube. All exhibited the characteristic features of CODAS syndrome, with broad skull and flattened midface, helix hypoplasia, ptosis, grooved nasal tip, anteverted nares, and with advancing age, short stature, scoliosis, genu valgum, and pes valgus. Teeth erupted late, with cusp-tip extensions. Dense bilateral nuclear cataracts developed rapidly between 2 and 6 months of age. Audiologic testing showed impaired tympanic membrane mobility (type B pattern) and low-frequency conductive hearing loss, with the 2 oldest patients exhibiting a mixed pattern involving mild to moderate sensory hearing loss in the 2- to 4-kHz range. All affected children had hypotonia, developmental delay, and variable intellectual disability, some of which was remediable. The oldest patient died at age 14 years of accidental trauma. Neuroimaging of 1 patient at 4 years of age showed prominent cortical sulci, symmetric ventriculomegaly, subcortical hypomyelination, and thin corpus callosum. Skeletal radiographs showed metaphyseal dysplasia, and both hypoplasia and delayed ossification of epiphyses. Cervical radiographs in 2 children showed dens hypoplasia and, in 1 case, synostosis between the odontoid and C2. Coronal clefts could be observed at various levels of the vertebral column. Other features present in the Amish children included omphalocele, imperforate anus, rectovaginal fistula, and cryptorchidism. In addition, features observed on prenatal ultrasound of a stillborn female infant with CODAS included polyhydramnios, 2-vessel umbilical cord, balanced atrioventricular canal, and absence of left lower long bones, with a relatively well-formed foot attached directly to the hip.

Molecular Genetics

By exome sequencing in 2 Old Order Amish children with CODAS syndrome, Strauss et al. (2015) identified a homozygous missense mutation in the mitochondrial peptidase gene LONP1 (R721G; 605490.0001) that segregated with disease in the respective families. In total, 8 affected Amish children from 6 sibships were homozygous for R721G. Analysis of LONP1 in the original CODAS patient, a Mennonite girl from Manitoba, Canada who was reported by Shebib et al. (1991), revealed homozygosity for a different missense mutation (P676S; 605490.0002). Another Canadian patient with CODAS who was of mixed European ancestry was compound heterozygous for missense mutations in LONP1 (S631Y, 605490.0003 and A724V, 605490.0004). Transmission electron microscopy of Amish patient lymphoblast cell lines (LCLs) showed enlarged mitochondria with swollen intra- or intercristal compartments, uniform vesicular structures, and electron-dense intramitochondrial inclusions, suggestive of abnormal inner-membrane topology. In contrast, parental LCLs showed typical mitochondrial morphology with well-organized cristae and only occasional swollen cristal spaces.