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Cranioectodermal dysplasia 3(CED3)

MedGen UID:
481437
Concept ID:
C3279807
Disease or Syndrome
Synonym: CED3
 
Gene (location): IFT43 (14q24.3)
 
Monarch Initiative: MONDO:0013573
OMIM®: 614099

Disease characteristics

Excerpted from the GeneReview: Cranioectodermal Dysplasia
Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly), ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth deficiency, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur. [from GeneReviews]
Authors:
Weizhen Tan  |  Angela Lin  |  Kim Keppler-Noreuil   view full author information

Additional descriptions

From OMIM
Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is a rare autosomal recessive heterogeneous ciliopathy that is primarily characterized by skeletal abnormalities, including craniosynostosis, narrow rib cage, short limbs, and brachydactyly, and ectodermal defects. Nephronophthisis leading to progressive renal failure, hepatic fibrosis, heart defects, and retinitis pigmentosa have also been described (summary by Arts et al., 2011). For discussion of genetic heterogeneity of cranioectodermal dysplasia, see CED1 (218330).  http://www.omim.org/entry/614099
From MedlinePlus Genetics
Cranioectodermal dysplasia is a disorder that affects many parts of the body. The most common features involve bone abnormalities and abnormal development of certain tissues known as ectodermal tissues, which include the skin, hair, nails, and teeth. The signs and symptoms of this condition vary among affected individuals, even among members of the same family.

Distinctive abnormalities of the skull and face are common in people with cranioectodermal dysplasia. Most affected individuals have a prominent forehead (frontal bossing) and an elongated head (dolichocephaly) due to abnormal fusion of certain skull bones (sagittal craniosynostosis). A variety of facial abnormalities can occur in people with this condition; these include low-set ears that may also be rotated backward, an increased distance between the inner corners of the eyes (telecanthus), and outside corners of the eyes that point upward or downward (upslanting or downslanting palpebral fissures) among others.

Development of bones in the rest of the skeleton is also affected in this condition. Abnormalities in the long bones of the arms and legs (metaphyseal dysplasia) lead to short limbs and short stature. In addition, affected individuals often have short fingers (brachydactyly). Some people with this condition have short rib bones and a narrow rib cage, which can cause breathing problems, especially in affected newborns.

Abnormal development of ectodermal tissues in people with cranioectodermal dysplasia can lead to sparse hair, small or missing teeth, short fingernails and toenails, and loose skin.

Cranioectodermal dysplasia can affect additional organs and tissues in the body. A kidney disorder known as nephronophthisis occurs in many people with this condition, and it can lead to a life-threatening failure of kidney function known as end-stage renal disease. Abnormalities of the liver, heart, or eyes also occur in people with cranioectodermal dysplasia.  https://medlineplus.gov/genetics/condition/cranioectodermal-dysplasia

Clinical features

From HPO
Nephronophthisis
MedGen UID:
146912
Concept ID:
C0687120
Disease or Syndrome
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recognized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia, and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype, inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Stage 5 chronic kidney disease
MedGen UID:
384526
Concept ID:
C2316810
Disease or Syndrome
A degree of kidney failure severe enough to require dialysis or kidney transplantation for survival characterized by a severe reduction in glomerular filtration rate (less than 15 ml/min/1.73 m2) and other manifestations including increased serum creatinine.
Postaxial polydactyly
MedGen UID:
67394
Concept ID:
C0220697
Congenital Abnormality
Polydactyly refers to the occurrence of supernumerary digits and is the most frequent of congenital hand and foot deformities. Based on the location of the extra digits, polydactyly can be classified into preaxial, involving the thumb or great toe; postaxial, affecting the fifth digit; and central, involving the 3 central digits. Postaxial polydactyly (PAP) is further subclassified into 2 types: in type A, a well-formed extra digit articulates with the fifth or a sixth metacarpal, whereas in type B, a rudimentary, poorly developed extra digit is present (summary by Umm-e-Kalsoom et al., 2012). Genetic Heterogeneity of Postaxial Polydactyly Other forms of postaxial polydactyly type A include PAPA2 (602085) on chromosome 13q21; PAPA3 (607324) on chromosome 19p13; PAPA4 (608562) on chromosome 7q22; PAPA5 (263450) on chromosome 13q13; PAPA6 (615226), caused by mutation in the ZNF141 gene (194648) on chromosome 4p16; PAPA7 (617642), caused by mutation in the IQCE gene (617631) on chromosome 7p22; PAPA8 (618123), caused by mutation in the GLI1 gene (165220) on chromosome 12q13; PAPA9 (618219), caused by mutation in the CIBAR1 gene (617273) on chromosome 8q22; and PAPA10 (618498), caused by mutation in the KIAA0825 gene (617266) on chromosome 5q15.
Brachydactyly
MedGen UID:
67454
Concept ID:
C0221357
Congenital Abnormality
Digits that appear disproportionately short compared to the hand/foot. The word brachydactyly is used here to describe a series distinct patterns of shortened digits (brachydactyly types A-E). This is the sense used here.
Sandal gap
MedGen UID:
374376
Concept ID:
C1840069
Finding
A widely spaced gap between the first toe (the great toe) and the second toe.
Rhizomelia
MedGen UID:
357122
Concept ID:
C1866730
Congenital Abnormality
Disproportionate shortening of the proximal segment of limbs (i.e. the femur and humerus).
2-4 toe syndactyly
MedGen UID:
866879
Concept ID:
C4021234
Congenital Abnormality
Syndactyly with fusion of toes two to four.
2-3 toe syndactyly
MedGen UID:
1645640
Concept ID:
C4551570
Congenital Abnormality
Syndactyly with fusion of toes two and three.
Peripheral pulmonary artery stenosis
MedGen UID:
138014
Concept ID:
C0345030
Finding
Stenosis of a peripheral branch of the pulmonary artery.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Cirrhosis of liver
MedGen UID:
7368
Concept ID:
C0023890
Disease or Syndrome
A chronic disorder of the liver in which liver tissue becomes scarred and is partially replaced by regenerative nodules and fibrotic tissue resulting in loss of liver function.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Dolichocephaly
MedGen UID:
65142
Concept ID:
C0221358
Congenital Abnormality
An abnormality of skull shape characterized by a increased anterior-posterior diameter, i.e., an increased antero-posterior dimension of the skull. Cephalic index less than 76%. Alternatively, an apparently increased antero-posterior length of the head compared to width. Often due to premature closure of the sagittal suture.
Isolated scaphocephaly
MedGen UID:
82712
Concept ID:
C0265534
Congenital Abnormality
Scaphocephaly is a subtype of dolichocephaly where the anterior and posterior aspects of the cranial vault are pointed (boat-shaped). Scaphocephaly is caused by a precocious fusion of sagittal suture without other associated synostosis.
Narrow chest
MedGen UID:
96528
Concept ID:
C0426790
Finding
Reduced width of the chest from side to side, associated with a reduced distance from the sternal notch to the tip of the shoulder.
Sagittal craniosynostosis
MedGen UID:
140921
Concept ID:
C0432123
Congenital Abnormality
A kind of craniosynostosis affecting the sagittal suture.
Joint hypermobility
MedGen UID:
336793
Concept ID:
C1844820
Finding
The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Hypoplasia of teeth
MedGen UID:
852449
Concept ID:
C0235357
Congenital Abnormality
Developmental hypoplasia of teeth.
Telecanthus
MedGen UID:
140836
Concept ID:
C0423113
Finding
Distance between the inner canthi more than two standard deviations above the mean (objective); or, apparently increased distance between the inner canthi.
Widely spaced teeth
MedGen UID:
337093
Concept ID:
C1844813
Finding
Increased spaces (diastemata) between most of the teeth in the same dental arch.
Everted lower lip vermilion
MedGen UID:
344003
Concept ID:
C1853246
Finding
An abnormal configuration of the lower lip such that it is turned outward i.e., everted, with the Inner aspect of the lower lip vermilion (normally opposing the teeth) being visible in a frontal view.
Cutis laxa
MedGen UID:
8206
Concept ID:
C0010495
Disease or Syndrome
Wrinkled, redundant, inelastic and sagging skin.
Ectodermal dysplasia
MedGen UID:
8544
Concept ID:
C0013575
Disease or Syndrome
Ectodermal dysplasia is a group of conditions in which there is abnormal development of the skin, hair, nails, teeth, or sweat glands.
Dry skin
MedGen UID:
56250
Concept ID:
C0151908
Sign or Symptom
Skin characterized by the lack of natural or normal moisture.
Short nail
MedGen UID:
140850
Concept ID:
C0423808
Finding
Decreased length of nail.
Fine hair
MedGen UID:
98401
Concept ID:
C0423867
Finding
Hair that is fine or thin to the touch.
Broad nail
MedGen UID:
375097
Concept ID:
C1843112
Finding
Increased width of nail.
Sparse hair
MedGen UID:
1790211
Concept ID:
C5551005
Finding
Reduced density of hairs.

Recent clinical studies

Etiology

Walczak-Sztulpa J, Wawrocka A, Sikora W, Pawlak M, Bukowska-Olech E, Kopaczewski B, Urzykowska A, Arts HH, Gotz-Więckowska A, Grenda R, Latos-Bieleńska A, Glazar R
Am J Med Genet A 2022 Oct;188(10):3071-3077. Epub 2022 Jul 25 doi: 10.1002/ajmg.a.62903. PMID: 35875935
Walczak-Sztulpa J, Wawrocka A, Leszczynska B, Mikulska B, Arts HH, Bukowska-Olech E, Daniel M, Krawczynski MR, Latos-Bielenska A, Obersztyn E
Am J Med Genet A 2020 Oct;182(10):2417-2425. Epub 2020 Aug 17 doi: 10.1002/ajmg.a.61785. PMID: 32804427
Handa A, Voss U, Hammarsjö A, Grigelioniene G, Nishimura G
Jpn J Radiol 2020 Mar;38(3):193-206. Epub 2020 Jan 21 doi: 10.1007/s11604-020-00920-w. PMID: 31965514
Cha S, Lim JE, Park AY, Do JH, Lee SW, Shin C, Cho NH, Kang JO, Nam JM, Kim JS, Woo KM, Lee SH, Kim JY, Oh B
BMC Genomics 2018 Jun 19;19(1):481. doi: 10.1186/s12864-018-4865-9. PMID: 29921221Free PMC Article

Diagnosis

Nagayama S, Takahashi H, Hasegawa F, Hori A, Kizami S, Furukawa R, Horie K, Ogoyama M, Hata K, Fujiwara H
Congenit Anom (Kyoto) 2024 Jul;64(4):177-181. Epub 2024 Apr 18 doi: 10.1111/cga.12569. PMID: 38637985
Li L, Liu C, Tian M, Li G, Li J
BMC Pediatr 2023 Aug 18;23(1):407. doi: 10.1186/s12887-023-04110-1. PMID: 37596520Free PMC Article
Walczak-Sztulpa J, Wawrocka A, Sikora W, Pawlak M, Bukowska-Olech E, Kopaczewski B, Urzykowska A, Arts HH, Gotz-Więckowska A, Grenda R, Latos-Bieleńska A, Glazar R
Am J Med Genet A 2022 Oct;188(10):3071-3077. Epub 2022 Jul 25 doi: 10.1002/ajmg.a.62903. PMID: 35875935
Walczak-Sztulpa J, Wawrocka A, Leszczynska B, Mikulska B, Arts HH, Bukowska-Olech E, Daniel M, Krawczynski MR, Latos-Bielenska A, Obersztyn E
Am J Med Genet A 2020 Oct;182(10):2417-2425. Epub 2020 Aug 17 doi: 10.1002/ajmg.a.61785. PMID: 32804427
Smith C, Lamont RE, Wade A, Bernier FP, Parboosingh JS, Innes AM
Am J Med Genet A 2016 Mar;170(3):760-5. Epub 2015 Dec 22 doi: 10.1002/ajmg.a.37514. PMID: 26691894

Prognosis

Strong A, Li D, Mentch F, Bedoukian E, Hartung EA, Meyers K, Skraban C, Wen J, Medne L, Glessner J, Watson D, Krantz I, Hakonarson H
Am J Med Genet A 2021 Mar;185(3):687-694. Epub 2020 Dec 25 doi: 10.1002/ajmg.a.62013. PMID: 33369054Free PMC Article
Smith C, Lamont RE, Wade A, Bernier FP, Parboosingh JS, Innes AM
Am J Med Genet A 2016 Mar;170(3):760-5. Epub 2015 Dec 22 doi: 10.1002/ajmg.a.37514. PMID: 26691894

Clinical prediction guides

Takahara M, Katoh Y, Nakamura K, Hirano T, Sugawa M, Tsurumi Y, Nakayama K
Hum Mol Genet 2018 Feb 1;27(3):516-528. doi: 10.1093/hmg/ddx421. PMID: 29220510
Hampl M, Cela P, Szabo-Rogers HL, Kunova Bosakova M, Dosedelova H, Krejci P, Buchtova M
J Dent Res 2017 Aug;96(9):965-974. Epub 2017 Jun 12 doi: 10.1177/0022034517713688. PMID: 28605602Free PMC Article
Smith C, Lamont RE, Wade A, Bernier FP, Parboosingh JS, Innes AM
Am J Med Genet A 2016 Mar;170(3):760-5. Epub 2015 Dec 22 doi: 10.1002/ajmg.a.37514. PMID: 26691894
Walczak-Sztulpa J, Eggenschwiler J, Osborn D, Brown DA, Emma F, Klingenberg C, Hennekam RC, Torre G, Garshasbi M, Tzschach A, Szczepanska M, Krawczynski M, Zachwieja J, Zwolinska D, Beales PL, Ropers HH, Latos-Bielenska A, Kuss AW
Am J Hum Genet 2010 Jun 11;86(6):949-56. Epub 2010 May 20 doi: 10.1016/j.ajhg.2010.04.012. PMID: 20493458Free PMC Article

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