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

cilia The cilium, plural cilia (), is a membrane-bound organelle found on most types of eukaryotic cell, and certain microorganisms known as ciliates. Cilia are absent in bacteria and archaea. The cilium has the shape of a slender threadlike projecti ...

, 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 (with or without sagittal suture synostosis) *

microcephaly Microcephaly (from New 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 ...

* pre- and postnatal growth retardation *

brachydactyly Brachydactyly (Greek βραχύς = "short" plus δάκτυλος = "finger"), is a medical term which literally means "short finger". The shortness is relative to the length of other long bones and other parts of the body. Brachydactyly is an in ...

* narrow

thorax The thorax or chest is a part of the anatomy of humans, 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 divisions of the cre ...

* rhizomelic dwarfism *

epicanthal fold An epicanthic fold or epicanthus is a skin fold of the upper eyelid that covers the inner corner (medial canthus) of the eye. However, variation occurs in the nature of this feature and the possession of "partial epicanthic folds" or "slight ...

s *

hypodontia Hypodontia is defined as the developmental absence of one or more teeth excluding the 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 in primary teet ...

and/or

microdontia Microdontia is a condition in which one or more teeth appear smaller than normal. In the generalized form, all teeth are involved. In the localized form, only a few teeth are involved. The most common teeth affected are the upper lateral incisors ...

* sparse, slow-growing, hyperpigmented, fine hair * nail dysplasia * hypohydrosis *

chronic kidney failure Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vom ...

* heart defects * liver fibrosis * visual deficits * photophobia * hypoplasia of the posterior corpus callosum * aberrant calcium homeostasis Electroretinography 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 (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 (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 (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 encoded for by the ''SHH'' gene. The protein is named after the character ''Sonic the Hedgehog''. This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organogenesis and ...

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-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 that move along microtubules in cells. They convert the chemical energy stored in ATP to mechanical work. Dynein transports various cellular cargos, provides forces and displacements importa ...

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