Cranioectodermal Dysplasia

Clinical characteristics.

Cranioectodermal dysplasia (CED), a ciliopathy also known as Sensenbrenner syndrome, is a multisystem 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 41 affected individuals reported to date, 23 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.

Clinical Description

Cranioectodermal dysplasia (CED), one of the ciliopathies, is a multisystem 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 41 individuals reported to date, 23 are simplex cases (i.e., a single occurrence in a family) and 18 are familial cases. Of the 41, 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, Lin et al 2013].

In 16, 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, Lin 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:

• Frontal bossing, bitemporal narrowing, and a tall forehead [Sensenbrenner et al 1975, Levin et al 1977, Genitori et al 1992, Amar et al 1997, Tamai et al 2002, 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, Lin et al 2013]
• Low-set, simple and/or posteriorly rotated ears [Zannolli et al 2001, Tamai et al 2002, Fry et al 2009, Konstantinidou et al 2009, Gilissen et al 2010, Walczak-Sztulpa et al 2010, Bacino et al 2012, Hoffer et al 2013, Lin et al 2013]
• Telecanthus, epicanthal folds, and/or down/upslanting palpebral fissures [Sensenbrenner et al 1975, Levin et al 1977, Genitori et al 1992, Lammer et al 1993, Zannolli et al 2001, Tamai et al 2002, Zaffanello et al 2006, Fry et al 2009, Konstantinidou et al 2009, Gilissen et al 2010, Arts et al 2011, Bredrup et al 2011, Bacino et al 2012, Lin et al 2013]
• Full cheeks [Sensenbrenner et al 1975, Amar et al 1997, Zannolli et al 2001, Tamai et al 2002, Walczak-Sztulpa et al 2010, Bredrup et al 2011]
• Micrognathia [Fry et al 2009, Konstantinidou et al 2009, Gilissen et al 2010, Arts et al 2011, Bacino et al 2012, Hoffer et al 2013, Lin et al 2013]
• Everted lower lip [Sensenbrenner et al 1975, Levin et al 1977, Amar et al 1997, Zannolli et al 2001, Gilissen et al 2010, Arts et al 2011, Hoffer et al 2013]
• Anteverted nares [Amar et al 1997, Zannolli et al 2001, Tamai et al 2002, Bredrup et al 2011]

Skeletal findings

• Hands and feet. Prenatal echography may detect polydactyly during mid-gestation; however, brachydactyly is not discernible earlier in development [Konstantinidou et al 2009]. Neonates often have: brachydactyly (middle and distal phalanges often short and/or abnormally shaped) [Sensenbrenner et al 1975, Levin et al 1977, Amar et al 1997, Tamai et al 2002, Konstantinidou et al 2009, Bredrup et al 2011, Bacino et al 2012, Lin et al 2013]; post-axial polydactyly [Gilissen et al 2010, Arts et al 2011, Bacino et al 2012]; and cutaneous syndactyly of fingers and toes (most frequently mild cutaneous syndactyly of toes 2 and 3) [Sensenbrenner et al 1975, Levin et al 1977, Gellis et al 1979, Amar et al 1997, Tamai et al 2002, Gilissen et al 2010, Arts et al 2011, Bredrup et al 2011, Bacino et al 2012].
  Epiphyses of phalanges can have a normal appearance on x-ray or can be flattened or cone shaped [Sensenbrenner et al 1975, Tamai et al 2002, Zaffanello et al 2006, Fry et al 2009].
  Other findings of the hands and feet variably seen:
  • Fifth finger clinodactyly [Levin et al 1977, Amar et al 1997, Genitori et al 1992, Zannolli et al 2001, Zaffanello et al 2006, Fry et al 2009, Bacino et al 2012]
  • Abnormal palmar creases [Sensenbrenner et al 1975, Genitori et al 1992, Amar et al 1997, Lin et al 2013]
  • Restricted finger flexion [Tamai et al 2002, Gilissen et al 2010]
  • Osteoporosis [Sensenbrenner et al 1975, Zaffanello et al 2006]
  • Sandal gap [Sensenbrenner et al 1975, Gilissen et al 2010, Arts et al 2011]
  • Triphalangeal hallux [Konstantinidou et al 2009, Hoffer et al 2013]
• A narrow thorax with short dysplastic ribs may be noted as early as mid-gestation; however, this finding was most commonly first noted at birth [Levin et al 1977, Lang & Young 1991, Amar et al 1997, Obikane et al 2006, Konstantinidou et al 2009, Bacino et al 2012, Lin et al 2013].
• Pectus excavatum is often observed [Sensenbrenner et al 1975, Genitori et al 1992, Gilissen et al 2010, Walczak-Sztulpa et al 2010, Bredrup et al 2011, Hoffer et al 2013].
• Rib deformities (e.g., short ribs or coat-hanger-shaped ribs) may normalize during childhood [Bacino et al 2012].
• Shortening (and bowing) of proximal long bones has been noted as early as 23 weeks' gestation [Lang & Young 1991, Tamai et al 2002, Konstantinidou et al 2009, Bacino et al 2012].
  Upper limbs are often shorter compared to lower limbs; humeri are particularly affected [Levin et al 1977, Young 1989, Obikane et al 2006, Fry et al 2009, Gilissen et al 2010, Arts et al 2011, Bacino et al 2012].
  Long bones may display bowing, and epiphyses may be flattened and/or display metaphyseal flaring [Levin et al 1977, Tamai et al 2002, Konstantinidou et al 2009, Bacino et al 2012, Hoffer et al 2013, Lin et al 2013].
• Growth retardation is commonly reported in CED (Table 1). At birth the length as related to gestational age may be within the normal range, but can also be below the third centile [Sensenbrenner et al 1975, Levin et al 1977].
  Infants may have a retarded growth with length below the third centile, but growth retardation may also be milder (length between the 5th and 10th centile) [Sensenbrenner et al 1975, Levin et al 1977, Amar et al 1997, Tamai et al 2002, Fry et al 2009, Bacino et al 2012].
  In 11 of 31 children with CED ranging in age from three to 11 years, height was specifically reported to be below the third centile [Levin et al 1977, Tamai et al 2002, Fry et al 2009, Konstantinidou et al 2009, Gilissen et al 2010, Arts et al 2011, Bredrup et al 2011, Bacino et al 2012].

Ectodermal defects

• Teeth. Tooth eruption is often delayed [Levin et al 1977, Genitori et al 1992, Amar et al 1997, Fry et al 2009].
  • Deciduous teeth are generally small and widely spaced. Hypodontia, enamel defects, taurodontia, and fused and cone-shaped teeth have also been reported [Levin et al 1977, Amar et al 1997, Zannolli et al 2001, Tamai et al 2002, Fry et al 2009, Gilissen et al 2010, Walczak-Sztulpa et al 2010, Arts et al 2011].
  • Similar characteristics are seen in permanent teeth. Hypo- or oligodontia may affect upper as well as lower permanent teeth [Zannolli et al 2001, Fry et al 2009, Bredrup et al 2011].
• Skin. Prenatal echography may reveal mid-gestational nuchal webbing and skin thickening [Fry et al 2009, Konstantinidou et al 2009, Bacino et al 2012].
  Generalized skin laxity and redundant skin folds have been reported in infancy and thereafter. Skin folds have been found particularly at the neck, ankles, and wrists. Skin may be dry; hyperkeratosis has been reported [Lammer et al 1993, Amar et al 1997, Fry et al 2009, Walczak-Sztulpa et al 2010, Arts et al 2011, Bredrup et al 2011, Bacino et al 2012].
• Hair. Most infants and young children with CED have sparse, fine hair. Hair may be hypopigmented with reduced diameter. Hair growth may also be affected [Sensenbrenner et al 1975, Levin et al 1977, Genitori et al 1992, Lammer et al 1993, Amar et al 1997, Tamai et al 2002, Fry et al 2009, Konstantinidou et al 2009, Arts et al 2011, Lin et al 2013].
  In some instances hair growth may normalize during childhood as suggested by Konstantinidou et al [2009].
• Nails are short, broad, and slow-growing from infancy [Sensenbrenner et al 1975, Lang & Young 1991, Levin et al 1977, Genitori et al 1992, Konstantinidou et al 2009, Walczak-Sztulpa et al 2010, Arts et al 2011, Hoffer et al 2013].

Kidney involvement is nephronophthisis (tubulointerstitial nephritis). At least 60% (21/33) 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 ten of 21 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, Lin et al 2013].

Renal ultrasound examination in infancy and early childhood usually shows normal-sized or 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, Lin et al 2013].

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, Lin et al 2013]. 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, Lin et al 2013].

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], but also as early as age ten months [Lin et al 2013].

Eye findings include retinal dystrophy and nystagmus [Eke et al 1996, Savill et al 1997, Bredrup et al 2011, Lin et al 2013]. 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:

• Nystagmus [Levin et al 1977, Eke et al 1996, Amar et al 1997, Savill et al 1997, Bacino et al 2012, Hoffer et al 2013, Lin et al 2013]
• Hyperopia [Levin et al 1977, Zannolli et al 2001, Gilissen et al 2010, Bredrup et al 2011]
• Myopia [Levin et al 1977, Savill et al 1997]
• Esotropia [Amar et al 1997, Obikane et al 2006, Bredrup et al 2011]
• Myopic/hypermetropic astigmatism [Eke et al 1996, Tamai et al 2002]
• Euryblepharon (excess horizontal eyelid length) [Konstantinidou et al 2009]

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, Lin 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:

• Cortical atrophy [Bacino et al 2012, Hoffer et al 2013]
• Ventriculomegaly [Lammer et al 1993, Bacino et al 2012, Lin et al 2013]
• Large cisterna magna [Konstantinidou et al 2009, Hoffer et al 2013]
• Hypoplasia of the corpus callosum [Lammer et al 1993, Zannolli et al 2001]
• Focal microdysgenesis [Bacino et al 2012]
• Enlarged extracerebral fluid spaces [Fry et al 2009]
• A large posterior fossa cyst [Konstantinidou et al 2009]

Other

• Joint laxity can be observed from the neonatal period [Fry et al 2009].
• (Bilateral) inguinal hernias and/or umbilical hernia can present in neonates or during the first year of life [Fry et al 2009, Walczak-Sztulpa et al 2010].

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 7/33 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], hypovolemic shock (as a result of coagulopathy) [Bacino et al 2012], or unknown causes [Lin et al 2013]. 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.

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, Lin 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 oligodontia 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 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 health care 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 in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.