Cranioectodermal dysplasia

Alternate names

Levin syndrome 1; Sensenbrenner syndrome

Definition

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.

Epidemiology

Cranioectodermal dysplasia is a rare condition with an unknown prevalence. Approximately 40 cases of this condition have been described in the medical literature.

Cause

Cranioectodermal dysplasia is caused by mutations in one of at least four genes: the WDR35, IFT122, WDR19, or IFT43 gene. The protein produced from each of these genes is one piece (subunit) of a protein complex called IFT complex A (IFT-A). This complex is found in finger-like structures called cilia that stick out from the surface of cells. These structures are important for the development and function of many types of cells and tissues. The IFT-A complex is involved in a process called intraflagellar transport, which moves substances within cilia. This movement is essential for the assembly and maintenance of these structures. The IFT-A complex carries materials from the tip to the base of cilia.

Mutations in any of the four mentioned genes reduce the amount or function of one of the IFT-A subunits. Shortage or abnormal function of a single component of the IFT-A complex impairs the function of the entire complex, disrupting the assembly and maintenance of cilia. These mutations lead to a smaller number of cilia and to abnormalities in their shape and structure. Although the mechanism is unclear, a loss of normal cilia impedes proper development of bone, ectodermal tissues, and other tissues and organs, leading to the features of cranioectodermal dysplasia.

About 40 percent of people with cranioectodermal dysplasia have mutations in one of the four known genes. The cause of the condition in people without mutations in one of these genes is unknown.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

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.

Diagnosis

Diagnosis is based on clinical examination. Imagery (ultrasonography), laboratory findings (urine analysis, serum electrolytes, and lipid profile), histological examination and liver and renal function tests allow detection of potential renal and liver anomalies. Ocular anomalies can be detected by eye fundus and electroretinography.

Differential diagnosis

Differential diagnosis of CED includes Jeune syndrome from which it can be distinguished by the presence of craniosynostosis, and skin and dental dysplasia. CED also overlaps with Ellis van Creveld syndrome which also shows ectodermal defects and narrow thorax.

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).

Treatment

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.

In many cases, renal function rapidly deteriorates, requiring treatment of metabolic acidosis, oral sodium chloride supplementation, then dialysis or renal transplantation in case of end-stage renal failure.

Prognosis

Prognosis depends on renal, heart and lung defects which can be life threatening.

NIH genetic and rare disease info

• NIH info on Cranioectodermal dysplasia

Cranioectodermal dysplasia is a rare disease.

Cranioectodermal dysplasia Resources
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