Craniofacial Dysmorphism, Skeletal Anomalies, And Mental Retardation Syndrome
A number sign (#) is used with this entry because of evidence that craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome (CFSMR) is caused by homozygous mutation in the TMCO1 gene (614123) on chromosome 1q24.
Clinical FeaturesPascual-Castroviejo et al. (1975) described a multiple congenital anomaly/mental retardation syndrome in 3 unrelated children. The features included facial dysmorphism, multiple malformations of the vertebrae and ribs, and mental retardation. Cerebrofaciothoracic dysplasia was the suggested designation. In 2 of the families, the parents were consanguineous.
Philip et al. (1992) described 2 brothers, born to second-cousin parents from Morocco, who had facial dysmorphism, complex anomalies of the vertebrae and ribs, enlarged cerebral ventricles and septum pellucidum, mental retardation, and affable behavior. In the second sib reported by Philip et al. (1992), the diagnosis was suspected on ultrasound scan during pregnancy, indicating that prenatal diagnosis of this condition is possible. The costovertebral abnormalities were similar to those of spondylocostal dysplasia (277300), but mental retardation is not a feature of that condition.
Guion-Almeida et al. (1996) reported a male infant who had a large septum pellucidum, hypodensity of gray matter, hypertelorism, and costovertebral anomalies. Cleft lip/palate was also present.
Kanaka-Gantenbein et al. (2004) reported a brother and sister, born to nonconsanguineous parents, with cerebrofaciothoracic dysplasia. Both had severe intrauterine and postnatal growth failure, costovertebral abnormalities (hemivertebrae and fused ribs), and mental retardation. The sister, 20 years old at the time of report, had had repeated surgery for rectovaginal fistula. The brother, 8 years old at the time of report, had cleft palate. He, but not his sister, showed growth hormone deficiency.
Cilliers et al. (2007) reported an Asian boy and a Turkish girl, both born to consanguineous parents, with cerebrofaciothoracic dysplasia. In addition to typical features of the disorder, the boy had bilateral colobomas of the optic nerve, a left-sided divergent strabismus, ptosis, small conical teeth, severe left-sided talipes, valgus deformity of both feet, overlapping of the toes, hypermobile joints (especially in his hands), and anterior subluxation of the shoulders. He also had right-sided renal pelvic dilation and dilated right distal ureter, and his echocardiogram showed a small patent ductus arteriosus.
Xin et al. (2010) described a mental retardation syndrome in 11 patients from the Old Order Amish population of Geauga County in northeastern Ohio. Some abnormalities, such as cleft lip and palate and ventriculomegaly, could be observed from the prenatal period, although not all patients had prenatal ultrasound. Features at birth included hypotonia, poor feeding, and craniofacial dysmorphisms, including brachycephaly, flat face, low hairline, low-set ears, high-arched palate, and cleft lip and palate. Features that appeared later included highly arched bushy eyebrows, synophrys, hypertelorism, long eyelashes, wide nasal bridge, short nose with anteverted nares, microdontism, and gingival hyperplasia. Skeletal dysmorphisms tended to involve the axial skeleton, with pectus excavatum, scoliosis, vertebral fusion, and rib anomalies. Two patients had tall stature, whereas 3 had short stature. All had global developmental delay. Neurologic examination showed hyporeflexia, unsteady gait, and intention tremor in some older patients. Some had variable genitourinary anomalies, such as renal agenesis, hydronephrosis, vesicoureteral reflux, and undescended testes. First trimester spontaneous abortions occurred in 22% of pregnancies.
Caglayan et al. (2013) reported a 7-year-old Turkish boy, born of first-cousin parents, who was hypotonic at birth and had feeding difficulties, hypothyroidism, and significant neurodevelopmental delay. His family reported that he was anxious and exhibited self-mutilating behavior such as chewing his fingers. Examination at 7 years of age revealed dysmorphic features including short neck, low hairline, low-set ears, synophrys, hypertelorism, anteverted nares, high-arched palate, prognathism, hyperextensible fingers, pectus carinatum, scoliosis, and genu varus. He was awake but unable to speak, walk, or feed himself. Brain MRI showed dysgenesis of the corpus callosum and cerebellar herniation.
InheritanceParental consanguinity supports autosomal recessive inheritance of this disorder (Pascual-Castroviejo et al., 1975).
Kanaka-Gantenbein et al. (2004) noted that the sibs they reported, in addition to the 2 affected brothers reported by Philip et al. (1992), suggested autosomal recessive inheritance. In contrast, both autosomal recessive and autosomal dominant inheritance had been suggested for cerebrocostomandibular syndrome (CCMS; 117650).
The transmission pattern of CFSMR in the families reported by Xin et al. (2010) was consistent with autosomal recessive inheritance; the affected individuals were of Old Order Amish descent and genealogic analysis revealed multiple lines of common descent between all parents of affected children.
Molecular GeneticsBy genomewide homozygosity mapping followed by candidate gene sequencing, Xin et al. (2010) identified homozygosity for a 2-bp deletion in the TMCO1 gene (614123.0001) in 9 of 11 northeastern Ohio Amish patients with a mental retardation syndrome and skeletal anomalies. Two patients were deceased, and their genotype was not confirmed. Screening of ethnically matched controls from the same community showed a carrier frequency of 0.7%. Screening of Old Order Amish from southeastern Pennsylvania yielded a carrier frequency of 6.6%. Further analysis identified 6 more patients from Pennsylvania with a similar phenotype who were also homozygous for the 2-bp deletion. Two patients from Somerset County, Pennsylvania, were on the same haplotype as the Ohio Amish patients, and 3 patients from Lancaster County, Pennsylvania, were on a different haplotype. Xin et al. (2010) proposed the designation 'TMCO1 defect syndrome.'
In a 7-year-old Turkish boy with mental retardation and craniofacial and skeletal anomalies, Caglayan et al. (2013) performed homozygosity mapping followed by exome sequencing and identified homozygosity for a nonsense mutation in the TMCO1 gene (R87X; 614123.0002). The mutation was found in heterozygosity in the available parent. In contrast to patients previously described with TMCO1 deficiency, Caglayan et al. (2013) noted that this patient had more profound developmental impairment and did not show craniosynostosis or spinal fusion, which occurred in 18% and 55% of the original cases, respectively.
By exome sequencing in 3 Turkish families diagnosed with cerebrofaciothoracic dysplasia mapping to chromosome 1q24, 1 of which had previously been studied by Cilliers et al. (2007), Alanay et al. (2014) identified homozygosity for the R87X mutation in the TMC01 gene (614123.0002). The mutation was confirmed by Sanger sequencing in the 3 families; no mutation was found in TMCO1 in the proband from a fourth family that did not map to 1q24. In addition, analysis of a fifth affected Turkish family also revealed homozygosity for R87X. Alanay et al. (2014) concluded that the 'TMCO1-defect syndrome,' initially believed to represent a distinct disorder, belongs to the spectrum of cerebrofaciothoracic dysplasia, and noted that the exclusion of the entire critical region on chromosome 1q24 in 1 affected Turkish family provided evidence for genetic heterogeneity of the disorder.
MappingAlanay et al. (2014) performed homozygosity mapping in affected members from 4 consanguineous Turkish families who had been diagnosed with cerebrofaciothoracic dysplasia, including that of the Turkish girl previously studied by Cilliers et al. (2007). In 3 of the 4 families, they identified homozygous haplotypes spanning approximately 2.28 Mb, between SNPs rs3185695 and rs10918635 on chromosome 1q24. The parents were heterozygous in this region.