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Cranioectodermal Dysplasia

Synonym: Sensenbrenner Syndrome

, PhD and , MD, PhD.

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Summary

Clinical characteristics.

Cranioectodermal dysplasia (CED), a ciliopathy also known as Sensenbrenner syndrome, is a multi-system disorder with skeletal involvement (narrow thorax, shortened proximal limbs, and brachydactyly), ectodermal features (widely-spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth retardation, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus/epicanthus, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage renal disease (ESRD) in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy, other manifestations of ciliopathies, 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.

Diagnosis/testing.

The diagnosis of CED is established in those with typical clinical findings and can be confirmed in 40% of affected individuals by identification of biallelic pathogenic variants in one of the four genes known to be associated with CED: IFT122 (previously WDR10), WDR35 (IFT121), WDR19 (IFT144), or IFT43 (previously C14orf179).

Management.

Treatment of manifestations: As needed, surgery to correct sagittal craniosynostosis (usually age <1 year) and/or polydactyly of the hands and feet. Routine treatment of inguinal and umbilical hernias, nephronophthisis, liver disease, and/or cardiac anomalies. For those with developmental delay: speech and physical therapy, and appropriate educational programs. For those with progressive visual impairment: low vision aids and appropriate educational programs. Human growth hormone therapy should be considered in those who meet standard treatment criteria.

Surveillance: In infancy and childhood monitoring growth and development, and tooth development; periodic assessment of renal and liver function; annual ophthalmologic examinations starting at age four years to detect early signs of retinal degeneration.

Genetic counseling.

CED is inherited in an autosomal recessive manner. Of the 39 affected individuals reported to date, 21 are simplex cases (i.e., a single occurrence in a family) and 18 are familial from a total of eight families. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified. Second-trimester ultrasound examination may detect renal cysts, shortening of the limbs, and/or polydactyly.

Diagnosis

Formal diagnostic criteria have not been established for cranioectodermal dysplasia (CED).

Features that should prompt consideration of CED are summarized in Table 1 (also see Figure 1).

Figure 1. . Various features of cranioectodermal dysplasia 

Patient 1 (A-E): 
A.

Figure 1.

Various features of cranioectodermal dysplasia

Patient 1 (A-E):
A. Newborn with cranioectodermal dysplasia with rhizomelic shortening of the arms, narrow thorax, and characteristic face with prominent forehead, ocular hypertelorism, (more...)

Although the following is arbitrary, the authors suggest that the diagnosis of CED requires at least two frequent features and two other abnormalities, including at least one ectodermal defect (i.e., involvement of the teeth, hair, or nails). Of note, dolichocephaly is a characteristic that distinguishes CED from most other ciliopathies.

Of note, the diagnosis of CED is not always easy to make, especially in a neonate in whom characteristics such as tooth defects and abnormalities of the retina, kidney, and liver are not necessarily evident. Also, craniosynostosis is not seen in every child.

Table 1.

Clinical Features of Cranioectodermal Dysplasia

FrequencyFeaturesAffected Individuals Reported in Detail (N=31) 1Individuals w/a Molecularly Confirmed Diagnosis (N=15) 2
Frequent (>75%)Characteristic facial features 32915
Brachydactyly 42915
Narrow thorax (with dysplastic ribs and pectus excavatum) 42815
Dolichocephaly2712
Shortening (and bowing) of proximal bones (mostly humeri) 42612
Common (50%-75%)Dental abnormalities (malformed, widely spaced, and/or hypodontia) 52312
Sparse and/or thin hair 5217
Short stature2011
Nephronophthisis1913
Less common (25%-50%)Joint laxity1412
Liver disease (hepatic fibrosis, cirrhosis, and/or hepatomegaly)139
Syndactyly135
Abnormal nails 5124
Developmental delay105
Heart defect94
Skin laxity 5109
Recurrent lung infections84
Polydactyly65
Bilateral inguinal hernias66
Occasional to infrequent (<25%)Retinal dystrophy72
Hip dysplasia 442
Cystic hygroma11

The diagnosis of CED is confirmed in a proband with biallelic pathogenic variants in one of the four genes – IFT122 (previously WDR10), WDR35 (IFT121), WDR19 (IFT144), or IFT43 (previously C14orf179) – known to cause cranioectodermal dysplasia (see Table 2). Three possible testing strategies:

Strategy A

1.

Perform sequence analysis of WDR35 and IFT122, the two genes in which pathogenic variants are most likely to occur.

2.

If no pathogenic variants are found in these two genes, perform sequence analysis of WDR19 and IFT43.

3.

If only one or no pathogenic variant is found, deletion/duplication analysis* of WDR35 may be considered; however, to date such exon/multiexon rearrangements have not been reported as a cause of CED.

*Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Strategy B. In children with multiple defects for whom a clear diagnosis is lacking, perform chromosome microarray analysis, which may reveal homozygous regions that contain ciliary genes that can subsequently be targeted for molecular genetic testing.

Strategy C. Use ciliopathy multi-gene panels that include the genes of interest.

Table 2.

Summary of Molecular Genetic Testing Used in Cranioectodermal Dysplasia

Gene 1 /
Locus Name
Proportion of CED Attributed to Pathogenic Variants in This Gene 2Test MethodVariants Detected 3
IFT122 / CED 14/39Sequence analysis 4Sequence variants
WDR35 / CED 28/39Sequence analysis 4Sequence variants
Deletion/duplication analysis 5Unknown; no deletions/duplications reported 6
IFT43 / CED 32/39Sequence analysis 4Sequence variants
WDR19 / CED 42/39Sequence analysis 4Sequence variants
Unknown 723/39NANA
1.
2.

Based on literature reports describing individuals with molecularly confirmed and unconfirmed CED

3.

See Molecular Genetics for information on allelic variants.

4.

Examples of pathogenic variants detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6.

No deletions or duplications involving WDR35 have been reported to cause cranioectodermal dysplasia 2. See also Genetically Related Disorders for a phenotype resulting from WDR35 exon deletion.

7.

It is likely that variants in genes other than the four known genes also cause CED, given that the genetic defect has yet to be identified in 60% of persons with CED [Gillissen et al 2010, Walczak-Sztulpa et al 2010, Arts et al 2011, Bredrup et al 2011]. However, it is unclear from reports in the literature whether all four known genes were tested in all reported individuals. If the cause of CED is indeed more heterogeneous than presently known, it is reasonable to expect that variants in genes that (directly or indirectly) regulate intraflagellar transport and/or are mutated in other ciliopathies similar to CED are causative.

Clinical Characteristics

Clinical Description

Cranioectodermal dysplasia (CED), one of the ciliopathies, is a multi-system disorder with significant involvement of the skeleton, ectoderm (teeth, hair, and nails), retina, kidneys, liver and lungs, and occasionally the brain. The current understanding of the CED phenotype is limited by the small number of well-described affected individuals reported and the even smaller number with a molecularly confirmed diagnosis.

Of the 39 individuals reported to date, 21 are simplex cases (i.e., a single occurrence in a family) and 18 are familial cases. Of the 39, 31 have been described in great clinical detail [Sensenbrenner et al 1975, Levin et al 1977, Gellis et al 1979, Young 1989, Lang & Young 1991, Genitori et al 1992, Lammer et al 1993, Eke et al 1996, Amar et al 1997, Savill et al 1997, Zannolli et al 2001, Tamai et al 2002, Obikane et al 2006, Zaffanello et al 2006, Fry et al 2009, Konstantinidou et al 2009, Gilissen et al 2010, Walczak-Sztulpa et al 2010, Arts et al 2011, Bredrup et al 2011, Bacino et al 2012, Hoffer et al 2013].

In 15, the molecular basis of CED (biallelic pathogenic variants in IFT122, WDR35, IFT43, or WDR19) has been identified [Zaffanello et al 2006, Fry et al 2009, Gilissen et al 2010, Walczak-Sztulpa et al 2010, Arts et al 2011, Bredrup et al 2011, Bacino et al 2012, Hoffer et al 2013].

The following discussion focuses on a combination of individuals with or without a molecularly confirmed diagnosis.

Dolichocephaly (apparently increased antero-posterior length of the head compared to width) and frontal bossing are usually secondary to sagittal craniosynostosis, which is usually present at birth. Sib pairs may show discordance for sagittal craniosynostosis [Lang & Young 1991, Arts et al 2011, Bredrup et al 2011].

Characteristic facial features that can be observed from birth are evident in practically all individuals with CED (Figure 1).

Features often seen:

Skeletal findings

Ectodermal defects

Kidney involvement is nephronophthisis (tubulointerstitial nephritis). At least 60% (19/31) of persons with CED were reported to have renal insufficiency.

Although end-stage renal disease (ESRD) can be evident prenatally as poly/oligohydramnios and small cystic kidneys in the second trimester of pregnancy, the first signs of renal disease are often evident in early childhood (age ~2 years) [Obikane et al 2006, Zaffanello et al 2006, Konstantinidou et al 2009, Walczak-Sztulpa et al 2010, Bacino et al 2012].

Initially reduced urinary concentrating ability leads to polyuria and polydipsia. Nocturnal enuresis may be evident. Hypertension, proteinuria, hematuria, and electrolyte imbalances usually develop later in the disease course as a result of renal insufficiency and filtration defects.

In nine of 19 children renal disease progressed to ESRD. Of note, this number may have increased over time as follow-up studies are limited. Most children developed ESRD between ages two and six years [Eke et al 1996, Savill et al 1997, Zaffanello et al 2006, Arts et al 2011, Hoffer et al 2013].

Renal ultrasound examination in infancy and early childhood usually shows small kidneys with increased echogenicity and poor corticomedullary differentiation [Savill et al 1997, Konstantinidou et al 2009, Walczak-Sztulpa et al 2010, Bredrup et al 2011].

Renal biopsy shows interstitial fibrosis with focal inflammatory cell infiltrates, tubular atrophy, glomerulosclerosis, and occasional cysts [Savill et al 1997, Obikane et al 2006, Konstantinidou et al 2009, Bredrup et al 2011]. The latter features occur in advanced disease.

Liver findings range from hepatosplenomegaly without signs of progressive liver disease to extensive liver abnormalities including (recurrent) hyperbilirubinemia and cholestatic disease requiring hospitalization in the newborn period [Young 1989, Eke et al 1996, Savill et al 1997, Tamai et al 2002, Konstantinidou et al 2009, Walczak-Sztulpa et al 2010, Bacino et al 2012].

Hyperbilirubinemia, liver cirrhosis, severe cholestasis with bile duct proliferation, and acute cholangitis have been described in infants [Zaffanello et al 2006, Arts et al 2011, Bacino et al 2012].

Longitudinal data on liver disease are not available; however, the long-term prognosis with respect to liver fibrosis and cirrhosis is probably poor.

Liver cysts have been detected in children age three and four years [Zaffanello et al 2006, Hoffer et al 2013].

Eye findings include retinal dystrophy and nystagmus. Nyctalopia (night blindness) is often evident in the first years of life [Eke et al 1996, Savill et al 1997, Bredrup et al 2011].

Abnormal scotopic and photopic electroretinograms (ERGs) have been reported as early as ages four to 11 years, while fundoscopy has revealed attenuated arteries and bone-spicule-shaped deposits as early as ages five to 11 years in some [Eke et al 1996, Bredrup et al 2011].

The natural history of the retinal dystrophy remains to be reported; however, in overlapping ciliopathies such as Bardet-Biedl syndrome, night blindness usually progresses to legal blindness in young adults (see Bardet-Biedl Syndrome). A similar prognosis is to be expected in CED.

Other ophthalmologic findings include:

Pulmonary. In infancy or early childhood, children with CED may experience life-threatening respiratory distress and recurrent respiratory infections. Asthma and pneumothorax have also been reported [Levin et al 1977, Eke et al 1996, Savill et al 1997, Tamai et al 2002, Obikane et al 2006, Gilissen et al 2010, Walczak-Sztulpa et al 2010, Bredrup et al 2011, Bacino et al 2012, Hoffer et al 2013].

Many children die of respiratory distress after birth or of pneumonia during early childhood [Levin et al 1977, Tamai et al 2002].

Recurrent respiratory infections have been reported to become less frequent with time [Konstantinidou et al 2009].

Cardiac malformations have included patent ductus arteriosus and atrial and ventricular septal defects. Thickening of the mitral and tricuspid valves, ventricular hypertrophy/dilation and peripheral pulmonary stenosis have also been reported [Levin et al 1977, Tamai et al 2002, Arts et al 2011, Bacino et al 2012].

Bacino et al [2012] reported that at age three years cardiac arrhythmia and atrial septal defect resolved in one child with CED.

Central nervous system. Although the majority of children develop normally, milestones may be (mildly) delayed in a subset [Genitori et al 1992, Amar et al 1997, Savill et al 1997, Obikane et al 2006, Fry et al 2009, Walczak-Sztulpa et al 2010, Bacino et al 2012, Hoffer et al 2013].

Sitting unsupported may be delayed to nine to 15 months, and walking to three years [Obikane et al 2006, Fry et al 2009, Bacino et al 2012, Hoffer et al 2013].

Delays in speech may vary from a few words at age 19 months to no words at age five years [Amar et al 1997, Hoffer et al 2013]. No information is available on how affected individuals respond to speech and physical therapy.

Cognitive and social abilities are usually normal [Amar et al 1997, Obikane et al 2006, Fry et al 2009].

Brain imaging has revealed the following abnormalities:

Other

Life expectancy. Morbidity is high in CED and hospitalization may be frequent and/or long-term [Savill et al 1997, Obikane et al 2006, Bacino et al 2012].

Mortality rates are unclear, although 6/31 of children with CED died before age seven years of respiratory failure [Levin et al 1977, Savill et al 1997, Tamai et al 2002], heart failure [Eke et al 1996, Savill et al 1997, Bacino et al 2012], and hypovolemic shock (as a result of coagulopathy) [Bacino et al 2012]. This number could be higher as longitudinal data on the majority of individuals with CED are unavailable.

At least two persons with CED survived into young adulthood. See Bredrup et al [2011] and Figure 1.

Genotype-Phenotype Correlations

Clinical manifestations of cranioectodermal dysplasia are highly variable and may differ between and within families [Gilissen et al 2010, Walczak-Sztulpa et al 2010, Arts et al 2011, Bredrup et al 2011, Bacino et al 2012, Hoffer et al 2013].

Phenotypes resulting from biallelic pathogenic variants in any one of the four known genes (i.e., IFT122, WDR35, IFT43, or WDR19) are not distinguishable [Walczak-Sztulpa et al 2010, Arts et al 2011, Bredrup et al 2011, Bacino et al 2012, Hoffer et al 2013].

Reports published to date involve too few affected individuals to draw reliable insights into genotype-phenotype correlations. Although future studies are needed to determine whether true genotype-phenotype correlations exist in CED, it appears that (based on current limited data) some clinical findings could be associated with pathogenic variants in specific genes:

  • Retinal dystrophy has only been reported in one family with biallelic WDR19 pathogenic variants [Bredrup et al 2011].
  • WDR35 is the only gene associated with developmental delay, albeit not in all affected individuals [Gilissen et al 2010, Bacino et al 2012, Hoffer et al 2013].
  • Renal insufficiency often develops in infancy or early childhood in children with biallelic pathogenic variants in IFT122, WDR35, IFT43, or WDR19; however, two children with biallelic WDR35 pathogenic variants were said to be free of renal disease at ages seven and nine years [Gilissen et al 2010].

Note: None of the pathogenic variants in IFT122, WDR35, IFT43, and WDR19 are biallelic nonsense, deletion, or other null variants; such variants would most likely result in early embryonic lethality. Similarly, biallelic null variants are not observed in the clinically and genetically overlapping short rib-polydactyly syndromes (see Differential Diagnosis) presumably because of early embryonic lethality.

Penetrance

Most individuals with molecularly confirmed CED have biallelic pathogenic missense variants that affect highly conserved nucleotides or a combination of a pathogenic missense variant with a severe, truncating variant; in these cases penetrance of cranioectodermal dysplasia is 100%.

Nomenclature

Cranioectodermal dysplasia (CED) was first described as Sensenbrenner syndrome in a sib pair with dolichocephaly, rhizomelic shortening of the bones, brachydactyly, and ectodermal defects [Sensenbrenner et al 1975]. Subsequently Levin et al [1977] described affected individuals from two additional families and renamed the disorder cranioectodermal dysplasia.

Over time it was recognized that the skeletal and ectodermal features of cranioectodermal dysplasia are often accompanied by anomalies of visceral organs including the kidney, liver, and heart [Eke et al 1996, Amar et al 1997, Zaffanello et al 2006].

Prevalence

Cranioectodermal dysplasia is rare; its exact frequency is unknown. Fewer than 60 affected individuals have been reported. In the Dutch population of 17 million people only five families (6 affected individuals) with CED are known to the authors.

Differential Diagnosis

Cranioectodermal dysplasia (CED) is part of a spectrum of disorders caused by disruption of the cilium, an organelle of the cell that appears and functions as an antenna (Figure 2) [Huber & Cormier-Daire 2012]. These disorders, collectively referred to as ciliopathies, display marked phenotypic overlap. Typical clinical features of ciliopathies are renal cystic disease, retinal dystrophy, shortening of ribs, phalanges and long bones, polydactyly, hepatic fibrosis, and developmental delay.

Figure 2. . Schematic architecture of a cilium and ciliary transport

The cilium is a tail-like protrusion from the apical plasma membrane of the cell.

Figure 2.

Schematic architecture of a cilium and ciliary transport

The cilium is a tail-like protrusion from the apical plasma membrane of the cell. It is composed of two compartments: the basal body from which the cilium is initially assembled, (more...)

Within the ciliopathies, Jeune asphyxiating thoracic dystrophy, Mainzer-Saldino syndrome, Ellis-van Creveld syndrome, and the short rib-polydactyly syndromes resemble cranioectodermal dysplasia the most. Each is described in more detail below.

Other ciliopathies that clinically overlap with cranioectodermal dysplasia include isolated nephronophthisis, isolated retinal dystrophy, Caroli disease, Senior-Løken syndrome, Joubert syndrome, Meckel-Gruber syndrome, and Bardet-Biedl syndrome [Huber & Cormier-Daire 2012].

Jeune asphyxiating thoracic dystrophy (JATD) (OMIM) has a strong phenotypic overlap with CED [Eke et al 1996, Savill et al 1997]. Skeletal abnormalities that occur in both disorders are polydactyly, brachydactyly, and rhizomelic limb shortening. Extraskeletal features that may be present in both include renal cystic disease, liver anomalies, and/or retinal dystrophy.

Both CED and JATD are characterized by a narrow rib cage phenotype; however, the phenotype is usually mild in CED and more pronounced in JATD, often leading to severe respiratory distress; in a review of ten newborns or infants with JATD, six died of respiratory insufficiency [Oberklaid et al 1977].

The main difference between CED and JATD is that JATD lacks the ectodermal changes and craniosynostosis characteristic of CED [Eke et al 1996].

JATD is inherited in an autosomal recessive manner. It can be caused by biallelic pathogenic variants in IFT80 [Beales et al 2007], DYNC2H1 [Dagoneau et al 2009], TTC21B [Davis et al 2011], IFT140 [Perrault et al 2012], or WDR19 [Bredrup et al 2011]. Of note, pathogenic variants in WDR19 have been reported in both JATD and CED [Bredrup et al 2011].

Mainzer-Saldino syndrome (MZSDS) (OMIM) is mainly characterized by phalangeal cone-shaped epiphyses, retinal dystrophy, and nephronophthisis [Mainzer et al 1970, Perrault et al 2012]. Cerebellar ataxia, a narrow thorax, scaphocephaly, and hepatic fibrosis are variably present [Perrault et al 2012].

MZSDS usually lacks the typical ectodermal features of CED [Eke et al 1996].

MZSDS is inherited in an autosomal recessive manner. Biallelic pathogenic variants in IFT140 have been identified in both MZSDS and JATD [Perrault et al 2012].

Ellis-van Creveld (EVC) syndrome (OMIM), first described by Ellis & van Creveld [1940], is a skeletal dysplasia characterized by postaxial polydactyly, shortening of the limbs and ribs, and ectodermal dysplasia affecting hair, nails, and teeth [Ruiz-Perez et al 2000, Huber & Cormier-Daire 2012]. EVC syndrome was considered in the differential diagnosis of CED several decades ago [Levin et al 1977, Young 1989, Zaffanello et al 2006].

Congenital heart disease is also a major finding in EVC syndrome; septal defects (mainly atrial) occur in 60% of affected individuals [Ruiz-Perez et al 2000, Baujat & Le Merrer 2007]. The frequency of heart defects in EVC syndrome is greater than in CED (as indicated in Table 1).

EVC syndrome is inherited in an autosomal recessive manner. Biallelic pathogenic variants in one of two genes positioned head-to-head on chromosome 4, EVC and EVC2, have been identified in affected individuals [Ruiz-Perez et al 2000, Ruiz-Perez et al 2003].

Short rib-polydactyly syndromes (SRPS), five disorders (OMIM) that are lethal in the perinatal period due to a severe narrow rib cage phenotype, are generally characterized by extremely short ribs and limbs, polydactyly, and malformations in a variety of organs [Elcioglu & Hall 2002, Huber & Cormier-Daire 2012]. The five short rib-polydactyly syndromes are not always clinically distinguishable: phenotypic and genetic overlap has been reported [Elcioglu & Hall 2002, El Hokayem et al 2012].

The five short rib-polydactyly syndromes are:

Senior-Løken syndrome (OMIM) is a heterogeneous autosomal recessive disorder that is characterized by nephronophthisis and retinal dystrophy. Pathogenic variants in various genes have been detected in persons with Senior-Løken syndrome, including WDR19, which is also mutated in CED [Bredrup et al 2011, Arts & Knoers 2013, Coussa et al 2013, Halbritter et al 2013].

Caroli disease (OMIM) is characterized by polycystic liver disease and cholangitis. It is part of the autosomal recessive polycystic kidney disease (ARPKD) spectrum of disorders and can occur as an isolated finding as well as in combination with other features including renal cystic disease [Adeva et al 2006].

Autosomal recessive retinal dystrophy (also known as retinitis pigmentosa) can be an isolated finding or occur in syndromic disorders such as CED [Bredrup et al 2011]. Retinitis pigmentosa usually starts with night blindness and can progress to complete blindness later in life due to loss of the photoreceptors (rods and cones). The fundus often displays attenuation of retinal vessels and may reveal abnormal peripheral pigmentation (referred to as bone-spicule deposits) [Hartong et al 2006]. Over 50% of families with isolated retinitis pigmentosa have an autosomal recessive form. Pathogenic variants in more than 30 genes can cause RP, and almost two thirds of these genes encode ciliary proteins [Hartong et al 2006, Estrada-Cuzcano et al 2012].

EEM syndrome (ectodermal dysplasia, ectrodactyly [split hand-split foot malformation], and progressive macular dystrophy) is a rare disorder that is clinically related to CED [Ohdo et al 1983, Eke et al 1996]. EEM syndrome can be distinguished from CED as split hand-split foot malformation does not occur in CED. Biallelic pathogenic variants in CDH3 [Kjaer et al 2005] are causative. Inheritance is autosomal recessive.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of a newborn or infant diagnosed with cranioectodermal dysplasia (CED), the following evaluations are recommended:

  • CT scan to determine if sagittal synostosis is the cause of dolichocephaly
  • X-ray of thorax and long bones to determine the extent of skeletal findings
  • Examination of the skin, hair, nails, and teeth
  • Renal ultrasound examination and urine measurements (including a urine collection test (and an optional DDAVP test) to assay polyuria, and osmolarity sampling of morning urine to determine concentrating ability). A biopsy is often taken after detection of abnormalities.
  • Liver ultrasound examination and measurement of liver enzymes
  • Ophthalmologic evaluation
  • Evaluation by a pulmonologist
  • Cardiac evaluation for detection of possible structural heart defects
  • Developmental evaluation
  • Brain MRI in individuals with developmental delay to assess the cause of the delay
  • Clinical genetics consultation

Treatment of Manifestations

Treatment includes the following:

  • Surgery for correcting craniosynostosis (usually in first year of life) [Sensenbrenner et al 1975, Levin et al 1977, Genitori et al 1992, Gilissen et al 2010, Bacino et al 2012, Hoffer et al 2013].
  • Correction of polydactyly (optional)
  • Orthopedic care as required (e.g., for hip dysplasia)
  • Growth hormone treatment to stimulate growth when standard criteria for this treatment are met [Wilson et al 2003]. Growth hormone should only be prescribed to children with severe growth retardation in whom the therapy is expected to be successful.
  • Dental care. Timely detection and intervention of structural tooth abnormalities and/or olgiodontia may limit aesthetic, functional, and psychological issues.
  • Standard treatment for renal and liver abnormalities. While liver transplantation is a treatment option in advanced stages, it has only been proposed once for an individual with CED [Zaffanello et al 2006].
  • For those with progressive visual impairment, low vision aids and appropriate educational programs
  • Mechanical ventilation as required in newborns to treat respiratory insufficiency due to pulmonary hypoplasia. Pneumonia should be treated with antibiotics. Patients susceptible to recurrent respiratory infections should be treated with long-term prophylaxis. Asthma can be treated with steroids.
  • Standard treatment for cardiac abnormalities
  • For those with developmental delay, speech therapy and physical therapy to improve motor skills and appropriate educational programs
  • Surgical intervention as required for inguinal/umbilical hernias [Fry et al 2009]

Surveillance

The following are appropriate:

  • Monitoring growth and development during infancy and childhood starting at the time of diagnosis
  • Beginning at age one year, examination of teeth with regular follow-up during to detect tooth damage and oligodontia
  • Periodic monitoring starting at the time of diagnosis for signs of nephronophthisis (renal insufficiency, renal cyst formation), including osmolarity testing in morning urine, urine collection assays to test for polyuria, measurement of blood pressure, determination of serum creatinine and blood urea concentrations to establish renal function, and periodic renal ultrasound examination to establish kidney size and presence of cysts. Periodic measurement of liver enzymes starting at the time of diagnosis.
  • Annual ophthalmologic examinations starting at age four years. Note: Electroretinography (ERG) and fundoscopy can be performed at an earlier age if it is evident that vision is reduced.
  • Evaluation for respiratory infection (with x-rays and sputum analysis) when clinical findings suggest pneumonia
  • In those with structural heart defects, periodic monitoring of cardiac function including auscultation, ECG, and echocardiography.

Evaluation of Relatives at Risk

If the pathogenic variants are known in a family, it is appropriate to clarify the genetic status of at-risk infants to allow early diagnosis and appropriate management and surveillance, particularly for respiratory complications, renal and liver disease, and visual impairment.

If the pathogenic variants are not known in a family, the following is recommended for at-risk children:

  • In the newborn period: physical examination by a pediatrician, and consultation with a clinical geneticist as determined by the clinical findings
  • Age 0-3 months: kidney and liver evaluation, including ultrasound examination and measurement of blood pressure, serum creatinine concentration, and liver enzymes
  • At six-month intervals: repeat the kidney and liver evaluations.

Parents should be alerted to the signs of CED and advised to contact their child’s healthcare provider if suspicious symptoms, such as polydipsia and/or jaundice, appear.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Cranioectodermal dysplasia (CED) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutated allele).
  • Heterozygotes (carriers) are asymptomatic.
  • De novo pathogenic variants are only rarely reported [Walczak-Sztulpa et al 2010]. In such cases, one parent may not be a carrier. Thus, documentation of carrier status in both parents is appropriate.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.
  • Rarely, as a result of a de novo pathogenic variant, the risk to the sibs of a proband of being affected is likely no more than 1%-2% [Walczak-Sztulpa et al 2010]. However, it is difficult to assign a specific risk as it is unclear in whom the pathogenic variant arose (i.e., de novo mutation in the proband or germline mosaicism in a parent).

Offspring of a proband. The offspring of an individual with CED in whom biallelic pathogenic variants have been identified in IFT122, WDR35, IFT43, or WDR19 are obligate heterozygotes (carriers) for a pathogenic variant.

Note: It is currently unclear whether individuals with CED are fertile as no individuals with CED have been reported to reproduce. This may be due to the severity of the disorder and to limited life span expectancy. Yet, CED may also be characterized by infertility as the genes that are mutated in this disorder encode proteins that are functional in cilia. These organelles are essential for sperm cell motility, and cilia in the Fallopian tube in turn sweep egg cells from the ovaries toward the uterus [Halbert et al 1976].

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier. (If one of the parents has germline mosaicism, the risk to the sibs of that individual is lower.)

Carrier Detection

Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is prior to conception.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible options.

Fetal ultrasound examination. Second-trimester ultrasound examination may detect renal cysts, shortening of the limbs, and/or polydactyly.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Foundation for Ectodermal Dysplasias (NFED)
    410 East Main Street
    PO Box 114
    Mascoutah IL 62258-0114
    Phone: 618-566-2020
    Fax: 618-566-4718
    Email: info@nfed.org
  • Ectodermal Dysplasias International Registry
    National Foundation for Ectodermal Dysplasias
    410 East Main Street
    Mascoutah IL 62258
    Phone: 618-566-2020
    Fax: 618-566-4718
    Email: info@nfed.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Cranioectodermal Dysplasia: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Cranioectodermal Dysplasia (View All in OMIM)

218330CRANIOECTODERMAL DYSPLASIA 1; CED1
606045INTRAFLAGELLAR TRANSPORT 122, CHLAMYDOMONAS, HOMOLOG OF; IFT122
608151WD REPEAT-CONTAINING PROTEIN 19; WDR19
613602WD REPEAT-CONTAINING PROTEIN 35; WDR35
613610CRANIOECTODERMAL DYSPLASIA 2; CED2
614068INTRAFLAGELLAR TRANSPORT 43, CHLAMYDOMONAS, HOMOLOG OF; IFT43
614099CRANIOECTODERMAL DYSPLASIA 3; CED3
614378CRANIOECTODERMAL DYSPLASIA 4; CED4

Molecular Genetic Pathogenesis

Cranioectodermal dysplasia (CED) belongs to a spectrum of disorders known as ‘ciliopathies’ [Baker & Beales 2009, Konstantinidou et al 2009, Arts & Knoers 2013]. Ciliopathies are thought to result from defects in cilia (Figure 2), projections from the cell that occur almost ubiquitously throughout the human body. These microtubule-based organelles are thought to function as signaling hubs regulating pathways that are essential for normal human development and tissue homeostasis [Hildebrandt et al 2011].

A process that is required for ciliogenesis and regulation of signaling pathways is ciliary transport (also known as intraflagellar transport [IFT]) [Hildebrandt et al 2011, Taschner et al 2012]. Upward (anterograde) movement of cargo or signaling molecules occurs through the multi-subunit IFT-B complex in association with the heterotrimeric kinesin-2 motor, while downward (i.e., tip-to-base [retrograde]) ciliary transport is regulated by the dynein-2 motor in association with the IFT-A complex [Hildebrandt et al 2011, Taschner et al 2012].

Remarkably, all pathogenic variants in individuals with CED identified to date occur in genes that encode members of the IFT-A hexamere protein complex: IFT122 (previously WDR10), WDR35 (IFT121), WDR19 (IFT144), or IFT43 (previously C14orf179) [Gilissen et al 2010, Arts et al 2011, Bredrup et al 2011, Bacino et al 2012, Hoffer et al 2013]. The remaining two IFT-A complex members are IFT139 and IFT140. Of note, genes encoding the proteins IFT139, IFT140, and DYNC2H1 (a subunit of dynein-2 motor) are mutated in disorders that clinically overlap with CED (see Differential Diagnosis) [Dagoneau et al 2009, Davis et al 2011, Perrault et al 2012].

When the IFT-A protein complex is disrupted in CED, cilia in fibroblasts have bulging tips, which contain accumulations of IFT-B complex proteins that normally regulate base-to-tip (anterograde) ciliary transport [Arts et al 2011, Bredrup et al 2011]. The functionality of intraflagellar transport in cilia from individuals with CED can be assessed by staining cells with anti-IFT-B antibodies.

Although shortening of cilia in fibroblasts from persons with CED has also been reported [Walczak-Sztulpa et al 2010], this is not always observed [Bredrup et al 2011]. It is thought that defective IFT and resulting structural defects in the ciliary architecture disturb important developmental signaling cascades (e.g., Hedgehog signaling), resulting in CED [Walczak-Sztulpa et al 2010, Ocbina et al 2011, Qin et al 2011, Liem et al 2012].

IFT122 (CED 1)

Gene structure. IFT122 comprises 31 exons and is alternatively spliced in at least four variants. The largest transcript is NM_052985, encoding a 1292-amino acid product. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. To date six IFT122 pathogenic variants (4 missense variants, a splice site variant, and a truncating variant) have been associated with CED [Walczak-Sztulpa et al 2010, Tsurusaki et al 2014]. The pathogenic variants are located in or close to WD40 domains. It has been suggested that pathogenic variants that give rise to CED do not completely abolish the function of IFT122 and, thus, the CED phenotype is relatively mild.

In contrast, the combination of a truncating variant (p.Glu370SerfsTer51) and a missense variant (p.Gly546Arg), which was recently detected in a family with terminated pregnancies and recurrent pregnancy loss, appears to be more severe [Tsurusaki et al 2014].

Table 3.

IFT122 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.21G>Cp.Trp7CysNM_052985​.2
NP_443711​.2
c.502+5G>Ap.His143ValfsTer4 1
c.1108delGp.Glu370SerfsTer51
c.1118C>Tp.Ser373Phe
c.1636G>Ap.Gly546Arg
c.1658T>Gp.Val553Gly

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Proposed as an exon 6 skip [Walczak-Sztulpa et al 2010]

Normal gene product. IFT122 encodes intraflagellar transport 122 homolog, one of the six proteins of the intraflagellar transport A (IFT-A) protein complex [Piperno et al 1998, Taschner et al 2012]. This complex regulates retrograde transport in the cilium.

Abnormal gene product. Pathogenic variants in IFT122 are thought to impair retrograde (tip-to-base) transport in the cilium. A study of cilia of fibroblasts from an individual with CED with biallelic IFT122 pathogenic variants revealed shortened cilia as compared to control cells [Walczak-Sztulpa et al 2010].

Similar structural defects have been identified in cilia from murine models (sister of open brain; Ift122sopb, and a mutant that has defects in Ift122 as well as in the overlapping gne Med1/Mbd4) and in a zebrafish model. Sonic Hedgehog signaling defects have been observed in both models [Cortellino et al 2009, Walczak-Sztulpa et al 2010, Qin et al 2011].

WDR35 (CED 2)

Gene structure. WDR35 comprises 28 exons. This gene is expressed in at least two WDR35 splice variants. The largest transcript (NM_001006657.1) encodes an 1181-amino acid protein. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. The majority of variants associated with CED have been identified in WDR35; i.e., five of the ten families with CED with a molecular diagnosis had pathogenic variants in this gene [Gilissen et al 2010, Walczak-Sztulpa et al 2010, Arts et al 2011, Bredrup et al 2011, Bacino et al 2012, Hoffer et al 2013].

The WDR35 pathogenic variants include five missense variants, one splice site variant, one stop variant, and a single-bp deletion, scattered throughout the gene [Gilissen et al 2010, Bacino et al 2012].

Table 4.

WDR35 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1877A>Gp.Glu626GlyNM_001006657​.1
NP_001006658​.1
c.25-2A>Cp.Ile9ThrfsTer7
c.2891delp.Pro964LeufsTer15
c.2623G>Ap.Ala875Thr
c.2912A>Gp.Tyr971Cys
c.504T>Ap.Ser168Arg
c.1922T>Gp.Leu641Ter
c.1592T>Cp.Leu531Pro 1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Reported by Bacino et al [2012] as p.Leu520Pro

Normal gene product. WDR35 encodes one of the six members of IFT-A protein complex that regulates retrograde trafficking in the cilium [Piperno et al 1998, Taschner et al 2012].

Abnormal gene product. Defects in WDR35 affect the process of intraflagellar transport. Immunocytochemistry revealed accumulations of IFT-B proteins (IFT57 and IFT88) in ciliary tips of cells derived from an individual with CED with biallelic WDR35 pathogenic variants [Arts et al 2011].

Such accumulations represent a typical ‘IFT-A’ defect, and have previously been observed in ciliated cells of many different species, including C. elegans, C. reinhardtii, D. melanogaster, T. brucei, and M. musculus, wherein IFT-A orthologues were knocked out [Iomini et al 2001, Blacque et al 2006, Absalon et al 2008, Lee et al 2008, Iomini et al 2009, Qin et al 2011]. A Wdr35 knockout mouse (yeti) was recently published. Homozygotes for a splice acceptor pathogenic variant resulting in a frameshift, failed to form cilia, died during mid-gestation, and displayed a short rib-polydactyly phenotype [Mill et al 2011] (see Genetically Related Disorders).

IFT43 (CED 3)

Gene structure. The longest IFT43 transcript comprises eight exons. To date, three protein-encoding isoforms of IFT43 are known. The largest transcript is NM_052873, which encodes a protein of 213 amino acids. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. To date, IFT43 pathogenic variants have only been reported in one family with CED, a consanguineous family of Moroccan descent. The identified homozygous variant (c.1A>G) is located in the translation initiation codon of IFT43, and is predicted to result in an in-frame deletion of the first 21 amino acids of IFT43 [Arts et al 2011]. It has been suggested that the resulting IFT43 protein is still partly functional, and that the CED phenotype is most likely relatively mild [Arts et al 2011].

Table 5.

IFT43 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1A>Gp.Met1_Lys21del 1NM_052873​.2
NP_443105​.2

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

The nucleotide substitution in the ATG translation initiation codon results in initiation at next downstream ATG codon and an N-terminal deletion of 21 amino acids [Arts et al 2011].

Normal gene product. IFT43 encodes the intraflagellar transport 43 homolog, a member of the IFT-A complex comprising six proteins [Taschner et al 2012].

Recent insights into the composition of the IFT-A protein complex in the unicellular alga Chlamydomonas reinhardtii revealed that the IFT-A proteins IFT43 and IFT121 (the ortholog of WDR35) directly interact [Behal et al 2012].

Abnormal gene product. A study of ciliated fibroblasts of a person with CED with a homozygous translation initiation codon variant (c.1A>G) in IFT43 revealed accumulations of IFT-B proteins (IFT88 and IFT57) in ciliary tips [Arts et al 2011]. This defect is consistent with a dysfunctional IFT-A protein complex [Iomini et al 2001, Blacque et al 2006, Absalon et al 2008, Lee et al 2008, Iomini et al 2009, Qin et al 2011].

WDR19 (CED 4)

Gene structure. WDR19 comprises 37 exons, of which 36 are protein coding. A single WDR19 transcript is known (NM_025132), which encodes a 1342-amino acid protein (NP_079408). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. To date, one family with CED and pathogenic variants in WDR19 has been described. The two affected sibs of this Norwegian family had compound heterozygous variants, including a missense variant and a stop variant [Bredrup et al 2011].

Table 6.

WDR19 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.2129T>Cp.Leu710SerNM​_025132
NP​_079408
c.3307C>Tp.Arg1103Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. WDR19 encoding intraflagellar transport protein 144 is one of the six subunits of the IFT-A protein complex [Piperno et al 1998, Taschner et al 2012] that regulates retrograde ciliary transport.

The discovery that WDR19 (IFT144) is associated with the IFT machinery was initially made in Chlamydomonas reinhardtii [Piperno et al 1998] and later in Caenorhabditis elegans [Efimenko et al 2006].

Abnormal gene product. Fibroblasts from one of the Norwegian sibs with CED were studied; no WDR19/IFT144 protein was detectable in cilia from the affected individual [Bredrup et al 2011]. In addition, cilia were less abundant and shorter in the patient’s cells compared to cilia from control cells. These findings indicate that IFT-A mediated transport is interrupted and can result in abnormal architecture of cilia.

Recently, two Ift144 mouse models, one with a hypomorphic missense variant (twinkle-toes; Ift144twt mutant) and the other with a severe splice site defect resulting in a truncated protein (diamondhead; Ift144dmhd mutant) were reported [Ashe et al 2012, Liem et al 2012]. Both mutants had skeletal features reminiscent of CED, although the Ift144twt mutant could be analyzed in more detail than the Ift144dmhd mutant as the latter already arrests development at embryonic stage E10.5 [Ashe et al 2012]. Subtle ciliary defects were reported in Ift144twt mutants, while ciliogenesis appeared to be affected in Ift144dmhd mutants. This is consistent with the weak (hypomorphic) Ift144twt variant and the more deleterious Ift144dmhd variant [Ashe et al 2012, Liem et al 2012]. Different Hedgehog defects have been described in the Ift144dmhd and Ift144twt mutants, i.e., ectopic activation of the Hedgehog pathway versus decreased signaling, respectively [Liem et al 2012].

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Chapter Notes

Author Notes

This work was funded by the grants from the Dutch Kidney Foundation (CP11.18 “KOUNCIL” to N Knoers and H Arts) and the Netherlands Organization for Health Research and Development (ZonMw 91613008 to H. Arts); both projects aim to unravel the genetics and mechanisms of disease of renal ciliopathies including Sensenbrenner syndrome.

Acknowledgments

We are thankful for the participation of the Sensenbrenner syndrome families in our study and for their consent for publication of clinical images. We also thank Dr E Lapi and Dr E Andreucci for their clinical contribution, Dr C Marcelis, Dr N van de Kar, Dr L Koster-Kamphuis and Dr K Noordam for useful discussions and Prof Dr HG Brunner for communication.

Revision History

  • 12 September 2013 (me) Review posted live
  • 26 April 2012 (ha) Original Submission
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