Sensenbrenner syndrome (OMIM #218330) is a rare (less than 20 cases reported by 2010) multisystem disease first described by Judith A. Sensenbrenner in 1975. It is inherited in an autosomal recessive fashion, and a number of genes appear to be responsible. Three genes responsible have been identified:

intraflagellar transport Intraflagellar transport (IFT) is a bidirectional motility along axoneme microtubules that is essential for the formation (ciliogenesis) and maintenance of most eukaryotic cilia and flagella. It is thought to be required to build all cilia that as ...

(IFT)122 (WDR10), IFT43—a subunit of the IFT complex A machinery of primary

cilia The cilium (: cilia; ; in Medieval Latin and in anatomy, ''cilium'') is a short hair-like membrane protrusion from many types of eukaryotic cell. (Cilia are absent in bacteria and archaea.) The cilium has the shape of a slender threadlike proj ...

, and WDR35 (IFT121: TULP4) It is also known as Sensenbrenner–Dorst–Owens syndrome, Levin syndrome I and cranioectodermal dysplasia (CED)

Presentation

These are pleomorphic and include *

dolichocephaly Dolichocephaly (derived from the Ancient Greek δολιχός 'long' and κεφαλή 'head') is a term used to describe a head that is longer than average relative to its width. In humans, scaphocephaly is a form of dolichocephaly. Dolichoceph ...

(with or without sagittal suture synostosis) *

microcephaly Microcephaly (from Neo-Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it m ...

* pre- and postnatal growth retardation *

brachydactyly Brachydactyly () is a medical term denoting the presence of abnormally short digits (fingers or toes) at birth. The shortness is relative to the length of other long bones and other parts of the body. Brachydactyly is an inherited, dominant t ...

* narrow

thorax The thorax (: thoraces or thoraxes) or chest is a part of the anatomy of mammals and other tetrapod animals located between the neck and the abdomen. In insects, crustaceans, and the extinct trilobites, the thorax is one of the three main di ...

* rhizomelic dwarfism * epicanthal folds *

hypodontia Hypodontia is defined as the developmental absence of one or more teeth excluding the Wisdom tooth, third molars. It is one of the most common dental anomalies, and can have a negative impact on function, and also appearance. It rarely occurs i ...

and/or microdontia * sparse, slow-growing, hyperpigmented, fine hair * nail

dysplasia Dysplasia is any of various types of abnormal growth or development of cells (microscopic scale) or organs (macroscopic scale), and the abnormal histology or anatomical structure(s) resulting from such growth. Dysplasias on a mainly microscopic ...

* hypohydrosis *

chronic kidney failure Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...

* heart defects * liver fibrosis * visual deficits * photophobia * hypoplasia of the posterior

corpus callosum The corpus callosum (Latin for "tough body"), also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental ...

* aberrant calcium homeostasis

Electroretinography Electroretinography measures the electrical responses of various cell types in the retina, including the Photoreceptor cell, photoreceptors (rod cell, rods and cone cell, cones), inner retinal cells (Retinal bipolar cell, bipolar and amacrine ce ...

shows gross abnormalities. Two fetuses of 19 and 23 weeks gestation have also been reported. They showed acromesomelic shortening, craniofacial characteristics with absence of craniosynostosis, small kidneys with tubular and glomerular microscopic cysts, persistent ductal plate with portal fibrosis in the liver, small adrenals, an enlarged cisterna magna and a posterior fossa cyst.

Cause

The gene IFT122 is located on the long arm of

chromosome 3 Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans more than 201 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA ...

(3q21-3q24). The gene lies on the Watson (plus) strand and is 80,047 bases in length. The encoded protein has 1241 amino acids and a predicted weight of 141.825 kilo daltons (kDa). It is a member of the WD repeat protein family. WDR35 is also a member of the WD repeat protein family. The gene is located on the short arm of

chromosome 2 Chromosome 2 is one of the twenty-three pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 2 is the second-largest human chromosome, spanning more than 242 million base pairs and representing almost ei ...

(2p24.1–2p24.3) The gene lies on the Crick (minus) strand and is 79,745 bases in length. The encoded protein is 1181 amino acids in length and its predicted molecular weight is 133.547 kilodaltons. The gene IFT43 lies on the Watson (plus) strand of the long arm of

chromosome 14 Chromosome 14 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 14 spans about 107 million base pairs (the building material of DNA) and represents between 3 and 3.5% of the total DNA i ...

(14q24.3). A mouse model for IFT122 has been created. Mutants deficient in IFT122 show multiple developmental defects (many are lethal), including exencephaly, situs viscerum inversus, delay in turning, hemorrhage and defects in limb development. In the node, primary cilia were absent or malformed in homozygous mutant and heterozygous embryos, respectively. Impairment of the

Sonic hedgehog Sonic hedgehog protein (SHH) is a major signaling molecule of embryonic development in humans and animals, encoded by the ''SHH'' gene. This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organoge ...

pathway was apparent in both neural tube patterning (expansion of motoneurons and rostrocaudal level-dependent contraction or expansion of the dorsolateral interneurons) and limb patterning (ectrosyndactyly).

Pathophysiology

The IFT machinery is organized in two structural complexes — A and B. These complexes are involved in the coordinated movement of macromolecular cargo from the basal body along axonemal microtubules to the cilium tip and back again. The anterograde movement of IFT particles out to the distal tip of cilia and flagella is driven by

kinesin A kinesin is a protein complex belonging to a class of motor proteins found in eukaryotic cells. Kinesins move along microtubule (MT) filaments and are powered by the hydrolysis of adenosine triphosphate (ATP) (thus kinesins are ATPases, a typ ...

-2 while the retrograde movement of particles back to the cell body is driven by cytoplasmic

dynein Dyneins are a family of cytoskeletal motor proteins (though they are actually protein complexes) that move along microtubules in cells. They convert the chemical energy stored in ATP to mechanical work. Dynein transports various cellular cargo ...

1b/2 The IFT-A protein complex is involved in retrograde ciliary transport. Disruption of IFT43 disturbs transport from the ciliary tip to the base. Anterograde transport in the opposite direction remains normal resulting in accumulation of the IFT complex B proteins in the ciliary tip.

Pathology

The visual defects are due to photoreceptor dystrophy. The chronic kidney failure is due to tubulointerstitial nephropathy. The liver fibrosis is secondary to ductal plate malformation.

Diagnosis

Treatment

References

External links

{{Medical resources , DiseasesDB = 34682 , ICD10 = Q87.5 , ICD9 = , ICDO = , OMIM = 218330 , MedlinePlus = , MeSH = C562966 , GeneReviewsNBK = NBK154653 , GeneReviewsName = Cranioectodermal Dysplasia , Orphanet = 1515 Rare syndromes