Alternative titles; symbols
ORPHA: 1515; DO: 0080803;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q21.3-q22.1 | Cranioectodermal dysplasia 1 | 218330 | Autosomal recessive | 3 | IFT122 | 606045 |
A number sign (#) is used with this entry because of evidence that cranioectodermal dysplasia-1 (CED1) is caused by homozygous or compound heterozygous mutation in the IFT122 gene (606045) on chromosome 3q21.
Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is an autosomal recessive disorder characterized by sagittal craniosynostosis and facial, ectodermal, and skeletal anomalies (summary by Gilissen et al., 2010).
Genetic Heterogeneity of Cranioectodermal Dysplasia
Also see CED2 (613610), caused by mutation in the WDR35 gene (613602) on chromosome 2p24; CED3 (614099), caused by mutation in the IFT43 gene (614068) on chromosome 14q24; and CED4 (614378), caused by mutation in the WDR19 gene (608151) on chromosome 4p14.
In a review, Lin et al. (2013) found that of 14 of 39 patients with Sensenbrenner syndrome who had a molecular diagnosis, 6 (43%) had mutations in WDR35, 4 in IFT122, 2 in WDR19, and 2 in IFT43.
Levin et al. (1977) described 5 children with dolichocephaly (with sagittal suture synostosis in 3), sparse, slow-growing, fine hair, epicanthal folds, hypodontia and/or microdontia, brachydactyly, and narrow thorax. Intelligence was normal. Two were sibs and 2 others were monozygous female twins. According to Levin (1987), 3 of the 5 patients died by age 7 years: 1 of heart failure, 1 of interstitial pneumonitis, and the third of unknown cause. An additional patient was reported in brief by Gellis and Feingold (1979). Young (1989) reported a case; Lang and Young (1991) reported a subsequently born affected sib. The report of an affected brother and sister lent further support for autosomal recessive inheritance. Each of the 2 sib pairs that have been reported have shown discordance for sagittal suture synostosis, confirming that this is an inconstant feature. The absence of any demonstrable ultrasonographic abnormality until 27 weeks' gestation indicated the difficulties in reliable prenatal diagnosis.
Eke et al. (1996) provided follow-up on the brother and sister reported by Lang and Young (1991). Both had developed a symptomatic photoreceptor dystrophy and chronic renal failure. Elevated serum creatinine was noted when the sister was 4 years of age; chronic renal failure due to tubulointerstitial nephropathy progressed to death shortly before her sixth birthday. In the third year of life the sister began to have difficulty navigating in dim illumination. The fundus examination was normal at age 4 years, but electroretinography showed gross abnormalities. The younger brother likewise had multiple chest infections and evidence of renal failure, difficulty seeing in dim light, and electroretinographic abnormalities.
Amar et al. (1997) reported the case of a 27-month-old Caucasian girl with cranioectodermal dysplasia, pre- and postnatal growth retardation, microcephaly, hypoplasia of the posterior corpus callosum, photophobia, and aberrant calcium homeostasis. They reviewed a total of 12 cases, including a set of monozygotic twins and 3 pairs of brothers. The findings present in all patients were dolichocephaly and rhizomelia. Manifestations of ectodermal dysplasia were variable. Short thorax and heart defect were also inconsistent findings. Previously unreported anomalies included growth deficiency, delayed psychomotor development, microcephaly, photophobia, and abnormal calcium homeostasis.
Tamai et al. (2002) stated that only 13 individuals with cranioectodermal dysplasia had been reported. They reported 2 affected sibs. The proposita showed almost typical manifestations with relatively good health, whereas her younger brother unexpectedly died of respiratory failure as a result of severe thoracic hypoplasia shortly after birth.
Zaffanello et al. (2006) reported a 4-year-old Italian boy with Sensenbrenner syndrome. He had rhizomelic shortening, dolichocephaly, epicanthal folds, narrow thorax, and dental anomalies. He developed impaired renal function at age 2.2 years. He also had multiple hepatic cysts, fluctuating liver enzymes, and diffuse portal and periportal congenital liver fibrosis due to a malformation of the hepatic ductal plate. Zaffanello et al. (2006) suggested that Sensenbrenner syndrome is a member of the family of congenital hepatorenal fibrocystic syndromes.
Fry et al. (2009) reported 2 unrelated patients, a Norwegian boy born of fourth-cousin parents and a British girl born of nonconsanguineous parents, with cranioectodermal dysplasia and significant connective tissue involvement, including cutis laxa, hernias, and joint laxity. Prominent features in the neonatal period in both patients included hypotonia, joint laxity, redundant skin, and low-set cupped ears. The girl had an omphalocele repaired on the second day of life, but later developed a prominent incisional hernia that also required surgical correction. Fry et al. (2009) noted that the degree of connective tissue laxity seen in these patients had not previously been reported in CED.
Walczak-Sztulpa et al. (2010) described a sister and brother, born of distantly consanguineous Polish parents, who had typical CED dysmorphism noted at birth, including short limbs, protuberant abdomen, brachydactyly, dolichocephaly, high forehead, full cheeks, telecanthus, broad nasal bridge, and low-set prominent ears. Clinical examination revealed additional ectodermal abnormalities such as small and abnormally shaped teeth, sparse hair, and abnormal nails in the sister; the brother also had pectus excavatum, and both had skin laxity and bilateral inguinal hernias. Psychomotor development was normal in both sibs.
In a review of the clinical features of 2 new patients and 37 previously reported patients with Sensenbrenner syndrome, Lin et al. (2013) found that the most frequent manifestations were a characteristic facial appearance, sagittal craniosynostosis, brachydactyly, narrow thorax, short long bones, joint laxity, abnormalities of the hair and teeth, and renal disease.
Clinical Variability
Tsurusaki et al. (2014) reported a family in which the mother had 4 miscarriages that occurred between 6 weeks' and 8 weeks' gestation (II-3 to II-6), 1 intrauterine death with hydrops at 13 weeks' gestation (II-7), and 2 terminated pregnancies (II-1 and II-8), due to hydrops at 13 weeks' gestation and skeletal anomalies at 21 weeks' gestation, respectively. Postmortem findings in the 21-week-old male fetus (II-8) included nuchal edema, low-set ears, narrow thorax, acromelic shortening of the limbs, posterior bowing of the lower legs, and bilateral 2-3 toe syndactyly. A 3-D CT scan showed narrow thorax with short ribs, bowed humeri and bent tibiae, and defective ossification of the proximal and middle phalanges. The authors concluded that the skeletal findings were consistent with a diagnosis of CED1.
Silveira et al. (2017) reported a male infant, previously studied by Cavalcanti et al. (2011) as part of a cohort of lethal SRTD (see 208500) patients, whom Silveira et al. (2017) designated as having Beemer-Langer syndrome (see SRTD12, 269860). The patient, born at 31 weeks' gestation, died shortly after birth. Postmortem clinical examination showed hydrops, turribrachycephaly, flat face with epicanthal folds, several oral accessory frenula, high and narrow palate, low-set and malformed ears, short and webbed neck, and micromelia, with postaxial polydactyly of hands and left-sided 4-5 toe syndactyly. X-ray examination showed craniosynostosis, very short ribs, high position of clavicles, irregular scapulae, quadrangular iliac with narrowing of sciatic notch, short long bones with smooth metaphyses, hypoplasia of fibulae, bowing of radii, and poorly ossified phalanges of hands. Autopsy was not authorized by the parents. Bizaoui et al. (2019) remarked that the skull deformity in this patient was 'striking enough to evoke Sensenbrenner syndrome.'
Yang et al. (2021) described a 2-month-old Chinese infant with macrocephaly, dolichocephaly, high forehead with frontal bossing, broad nasal bridge, long philtrum, bilateral epicanthic folds, hypertelorism, esotropia, low-set ears, prominent lower vermilion, and micrognathia. He also had sparse hair and eyebrows, upper limb phocomelia, and postaxial polydactyly of both hands and feet.
The transmission pattern of CED1 in the family reported by Walczak-Sztulpa et al. (2010) was consistent with autosomal recessive inheritance.
Walczak-Sztulpa et al. (2010) performed genomewide multipoint linkage analysis and homozygosity mapping in 2 Polish sibs with cranioectodermal dysplasia and their healthy, distantly related parents and found a single region of homozygosity with a significant lod score (3.57) on chromosome 3q21-3q24, spanning 16.7 Mbp between rs977683 and rs1992093 and containing 124 protein-coding genes.
In a consanguineous Polish family with cranioectodermal dysplasia mapping to chromosome 3q21-q24, Walczak-Sztulpa et al. (2010) sequenced 79 candidate genes and identified homozygosity for a missense mutation in the IFT122 gene (606045.0001) that segregated with the disease. Analysis of IFT122 in 11 additional unrelated patients with CED revealed a homozygous missense mutation in a Norwegian boy previously reported by Fry et al. (2009) (606045.0002) and compound heterozygosity for a splice site and a missense mutation in an Italian boy previously reported by Zaffanello et al. (2006) (606045.0003 and 606045.0004). Because the 4 mutation-positive patients did not show significant phenotypic differences from the patients without mutations and there was a preponderant overlap of clinical features among all patients, Walczak-Sztulpa et al. (2010) suggested that CED is genetically heterogeneous.
In a 21-week-old male fetus (II-8) with skeletal features consistent with CED1, Tsurusaki et al. (2014) performed exome sequencing and identified compound heterozygosity for a 1-bp deletion (606045.0005) and a missense mutation (G546R; 606045.0006) in the IFT122 gene. The same mutations were identified in the chorionic villi from another pregnancy (II-6) in the family that spontaneously aborted at 7 weeks' gestation. The unaffected mother was heterozygous for the G546R variant, and an unaffected brother was heterozygous for the 1-bp deletion; DNA was unavailable from the unaffected father, or from 3 other spontaneous abortions or 1 terminated pregnancy. The authors noted that although CED1 is generally considered to be a nonlethal disorder, this family experienced recurrent spontaneous abortions.
In a male infant who died shortly after birth with craniosynostosis, short ribs, micromelia, and postaxial polydactyly of the hands, Silveira et al. (2017) sequenced a panel of 40 skeletal dysplasia-related genes and identified 3 mutations in the IFT122 gene: a missense mutation (A1062P; 606045.0007) on 1 allele, and a duplication followed by deletion (606045.0008) on the other allele that caused a frameshift.
By whole-exome sequencing in a Chinese male infant with CED1, Yang et al. (2021) identified compound heterozygous mutations in the IFT122 gene (606045.0009 and 606045.0010). Functional studies were not performed.
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Cavalcanti, D. P., Huber, C., Sang, K.-H. L. Q., Baujat, G., Collins, F., Delezoide, A.-L., Dagoneau, N., Le Merrer, M., Martinovic, J., Mello, M. F. S., Vekemans, M., Munnich, A., Cormier-Daire, V. Mutation in IFT80 in a fetus with the phenotype of Verma-Naumoff provides molecular evidence for Jeune-Verma-Naumoff dysplasia spectrum. J. Med. Genet. 48: 88-92, 2011. [PubMed: 19648123] [Full Text: https://doi.org/10.1136/jmg.2009.069468]
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Lin, A. E., Traum, A. Z., Sahai, I., Keppler-Noreuil, K., Kukolich, M. K., Adam, M. P., Westra, S. J., Arts, H. H. Sensenbrenner syndrome (cranioectodermal dysplasia): clinical and molecular analyses of 39 patients including two new patients. Am. J. Med. Genet. 161A: 2762-2776, 2013. [PubMed: 24123776] [Full Text: https://doi.org/10.1002/ajmg.a.36265]
Silveira, K. C., Moreno, C. A., Cavalcanti, D. P. Beemer-Langer syndrome is a ciliopathy due to biallelic mutations in IFT122. Am. J. Med. Genet. 173A: 1186-1189, 2017. [PubMed: 28370949] [Full Text: https://doi.org/10.1002/ajmg.a.38157]
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Tsurusaki, Y., Yonezawa, R., Furuya, M., Nishimura, G., Pooh, R. K., Nakashima, M., Saitsu, H., Miyake, N., Saito, S., Matsumoto, N. Whole exome sequencing revealed biallelic IFT122 mutations in a family with CED1 and recurrent pregnancy loss. Clin. Genet. 85: 592-594, 2014. [PubMed: 23826986] [Full Text: https://doi.org/10.1111/cge.12215]
Walczak-Sztulpa, J., Eggenschwiler, J., Osborn, D., Brown, D. A., Emma, F., Klingenberg, C., Hennekam, R. C., Torre, G., Garshasbi, M., Tzschach, A., Szczepanska, M., Krawczynski, M., Zachwieja, J., Zwolinska, D., Beales, P. L., Ropers, H.-H., Latos-Bielenska, A., Kuss, A. W. Cranioectodermal dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene. Am. J. Hum. Genet. 86: 949-956, 2010. [PubMed: 20493458] [Full Text: https://doi.org/10.1016/j.ajhg.2010.04.012]
Yang, Q., Zhang, Q., Chen, F., Yi, S., Li, M., Yi, S., Xu, X., Luo, J. A novel combination of biallelic IFT122 variants associated with cranioectodermal dysplasia: a case report. Exp. Ther. Med. 21: 311, 2021. [PubMed: 33717254] [Full Text: https://doi.org/10.3892/etm.2021.9742]
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