| Johanson-Blizzard syndrome | |
|---|---|
| Other names | JBS |
 | |
| Photographs of individuals with Johanson-Blizzard syndrome showing characteristic facial features | |
| Specialty | Medical genetics  |
| Symptoms | pancreatic insufficiency,intellectual disability, distinctivecraniofacial abnormalities, intestinal malabsorption,deafness,dental abnormalities |
| Differential diagnosis | cystic fibrosis, schwachman syndrome, Pearson marrow-pancreas syndrome |
Johanson–Blizzard syndrome (JBS) is a rare, sometimes fatalautosomal recessive multisystemcongenital disorder featuring abnormal development of thepancreas,nose andscalp, withintellectual disability,hearing loss andgrowth failure.[1] It is sometimes described as a form ofectodermal dysplasia.[2]
The disorder is especially noted for causing profound developmental errors and exocrine dysfunction of the pancreas, and it is considered to be an inherited pancreatic disease.[3]
The most prominent effect of Johanson–Blizzard syndrome isexocrine pancreatic insufficiency.[1][4][5][6][7] Varying degrees of decreasedsecretion oflipases,pancreatic juices such astrypsin,trypsinogen and others, as well asmalabsorption offats and disruptions ofglucagon secretion and its response tohypoglycemia caused byinsulin activity are major concerns when Johanson–Blizzard syndrome is diagnosed.[1][3][8] Associated with developmental errors, impairedapoptosis, and both prenatal and chronicinflammatory damage,necrosis andfibrosis of the pancreaticacini (clusters of pancreaticexocrine gland tissue, where secretion of pancreatic juice and relatedenzymes occurs), pancreatic exocrine insufficiency in Johanson–Blizzard syndrome can additionally stem fromcongenital replacement of the acini withfatty tissue.[1][3][8][9][10] Near total replacement of the entire pancreas with fatty tissue has also been reported. This is a progressive, sometimes fatal consequence of the disorder.[9]
Endocrine insufficiency of thepancreas occurs with Johanson–Blizzard syndrome, though it is sometimes less common and less pronounced than the more prominent effects on exocrine function.[1] Theislets of Langerhans are ducts in the pancreas where endocrine activity such as the release ofhormones glucagon,somatostatin and insulin takes place. Pancreatic endocrine insufficiency in Johanson–Blizzard syndrome can be associated with either a buildup ofconnective tissue in the islet regions, congenital replacement of the islets with fatty tissue, or impropernerve signalling to the islets.[1][5][8][11][12] Endocrine dysfunction of the pancreas often results indiabetes mellitus. Bothinsulin resistance and diabetes have been observed with Johanson–Blizzard syndrome, and it is suggested that diabetes should be considered as a complication of Johanson–Blizzard syndrome and its course.[5][11]
Ductular output of fluids andelectrolytes is preserved in the pancreas of many with Johanson–Blizzard syndrome, as well as moderate to normal levels of functioningbicarbonate.[1]
Endocrine abnormalities in other areas have also been present with the disorder. These includehypothyroidism,[2]growth hormone deficiency[1][8] andhypopituitarism.[1] Findings affecting pituitary function in some Johanson–Blizzard syndrome patients have included such anomalies as the formation of aglial hamartoma (aneoplasm, ortumor composed ofglial cells) on a lobe of thepituitary gland, as well congenital underdevelopment of theanterior pituitary.[13] Growth failure and associatedshort stature (dwarfism) in Johanson–Blizzard syndrome can be attributed to growth hormone deficiency caused by diminished anterior pituitary function, with malabsorption of fats playing a subsequent role.[1][4][14]
The primary malformation apparent with Johanson–Blizzard syndrome ishypoplasia (underdevelopment) of the nasal alae, or "wing of the nose".[1][2][7] Both hypoplasia andaplasia (partial or complete absence) of structuralcartilage andtissue in this area of the nose, along with the underlyingalae nasi muscle, are prevailing features of the disorder. Together, these malformations give the nose andnostrils an odd shape and appearance.[7][15]
Intellectual disability ranging from mild to severe is present in the majority of Johanson–Blizzard syndrome patients, and is related to the deleterious nature of the known mutagen responsible for the disorder and its effects on the developingcentral nervous system.[1][6][16] Normal intelligence and age appropriate social development, however, have been reported in a few instances of Johanson–Blizzard syndrome.[12][16]
Findings with theinner ear in Johanson–Blizzard syndrome give explanation to the presence of bilateralsensorineural hearing loss in most patients affected by the disorder. The formation ofcystic tissue in both thecochlea andvestibule, with resultingdilation (widening) and malformation of these delicate structures has been implicated.[7][9][17] Congenital deformations of thetemporal bone and associated adverse anatomical effects on innervation and development of the inner ear also contribute to this type of hearing loss.[17][18]
Other abnormalities, affecting the scalp,head,face,jaw andteeth may be found with JBS. These include:ectodermal mid-line scalp defects with sparse, oddly-patternedhair growth;[2][9] aplasiacutis (underdeveloped, very thinskin) over the head,[19] an enlargedfontanelle ("soft spot" on the head of younginfants),[14]microcephaly (undersizedskull),[19] prominentforehead,[14] absence ofeyebrows andeyelashes,[14]mongoloideye shape,[17]nasolacrimo-cutaneousfistulae (this refers to the formation of an abnormal secondary passageway from either the tear duct orlacrimal sac to the facial skin surface, possibly discharging fluid),[9] flattenedears,[14]micrognathism of themaxilla andmandible (underdevelopment of the upper and lower jaw, respectively), with the maxilla more prominently affected in some cases;[14][20][21] congenital clefting ofbones surrounding theoptical orbit (eye socket), such as thefrontal andlacrimal bone;[20] and maldevelopeddeciduous teeth ("baby teeth"), with an absence ofpermanent teeth.[9][14]
Additional congenital anomalies, effects on otherorgans, and less common features of JBS have included:imperforate anus (occlusion of theanus),[22]vesicoureteral reflux (reversal of the flow ofurine, from thebladder back into theureters, toward thekidneys);[14]duplex of theuterus andvagina infemale infants,[7]neonatal cholestasis of theliver, withcirrhosis andportal hypertension (high blood pressure in thehepatic portal vein);[22]dilated cardiomyopathy,[23]dextrocardia (congenital displacement of theheart to the right side of thechest),[1]atrial andventricular septal defect;[1]low birth-weight,[24]failure to thrive,[24]hypotonia (decreasedmuscle tone);[19]sacral hiatus (a structural deficiency of thesacral vertebrae),[24]congenital cataracts,[24] andcafe-au-lait spots.[2]
Johanson–Blizzardsyndrome has anautosomal recessive pattern of inheritance resulting fromloss of function (usuallydeleterious asnonsense,frameshift, orsplice site) mutations in theUbiquitin-ProteinLigaseE3 Component N- Recognin gene (UBR1), which encodes for a specificubiquitin ligaseenzyme.[25] This means the defective UBR1gene responsible for thedisorder is located on anautosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the Johanson–Blizzard syndrome. The parents of an individual with an autosomal recessive disorder bothcarry one copy of the defective gene, but usually do not experience any signs orsymptoms of the disorder.[citation needed]
Johanson–Blizzard syndrome results from one or multiple mutations inUBR1, specifically at a fixed chromosomal position known aslocus 15q15.2 or humanchromosome 15, q-armregion 1, band 5, sub-band 2.[26] This gene spans around 161kb (161,000base pairs) in length and contains 47exons expressed asmRNA.[27] In comparison, mouse 120kb UBR1 is in the middle of chromosome 2 and shows homology ofsynteny (co-localized loci in same chromosome) with its human counterpart through its 50 exons. The protein has also been weighed in at 200-kD in mice compared to 225-kD inSaccharomyces cerevisiae.[27][26]
UBR1 encodes one of at least four functionally overlapping E3ubiquitin ligases of theN-end rule pathway. This pathway consists of aconservedproteolytic system of proteins that destabilizeN-terminal residues, meaning UBR1 codes for proteins withdegron parts that send degradation signals to the cell, inducing metabolic instability. This specific signal is called N-degron, and its causal set ofpeptides yields the N-end rule, which relates the protein'sin vivohalf-life to the identity of its N-terminal residue through a ubiquitin system (N-end rule pathway). The N-recognin, also known as E3, binds to the destabilizing N-terminal residue of asubstrate protein to form a substrate-linked miltiubiquitin chain.[26]
The direct connection between UBR1 mutations altering the protein degradation system and specific Johanson–Blizzard syndrome clinical anomalies (symptoms of diagnosis) is still undetermined as origin of possiblemutagenic genetic variations varies from just the fatheralleles to both alleles; and single or multi-exon deletions/duplications in which all 47 UBR1 exons must be taken into account when performingSanger sequencing andMultiplex ligation-dependent probe amplification (MLPA), meaning there is no obvious candidate gene.[28] However, most certain UBR1 mutations predict prematuretranslationalstop codons, with two missense mutations altering residues highly conserved among different species.[27] One of these missense mutations affects a conservedmotif important for UBR1 substrate-binding by convertinghistidine at location 136 toarginine accompanied by intervening sequence. Bidirectional analysis of all 47 exons (including ~20bp flankingintronic regions) revealshomozygous mutation in exon 19, wherethreoninenucleotide substitutescysteine, resulting in a missensed serine residue between peptide locations 698 and 702 completely conserved throughout vertebrate UBR1 (even UBR2) protein.[28] Another cysteine to threonine mutation, but homozygous nonsense in nature, has also been confirmed in Johanson–Blizzard syndrome patients with no functional UBR1 protein, but mild symptoms are also common in missense mutations in at least one of the two UBR1 copies with possible residual activity ofgene product.[25] 2 Heterozygous mutations from nonconsanguineous parents arise fromadenine toguanine conversion at nucleotide 407 resulting in a histidine 136 substitution to arginine at splice donor site.[27] Next non-consanguineous homozygousnonsense mutation happens atglutamine 513 becoming a stop codon by a cytosine to thymine conversion caused by a cytosine to thymine transition at nucleotide 1537 in exon 13.[27] Continuing homozygous mutations, one converts guanine to adenine, in intron 26 resulting in residual normal protein production.[29] The last homozygous mutation turns guanine to adenine in intron 12 by skipping exon 13 through a frameshift and causing premature termination.[30] Maternally inherited heterozygous nonsense mutation of cysteine to adenine resulting in a tyrosine has also been classified at residue 1508.[31] Another heterozygous missense mutation on leucine linked to an arganine at exon 44 is consideredpathogenic because leucine at residue 1597 is highly conserved among different species. Lastly, a splice site mutation has been identified intervening sequence changing thymine for cytosine at nucleotide 20.[27]
Johanson–Blizzard syndrome is caused bymutations in theUBR1 gene, which encodes one of severalubiquitin ligase enzymes of theN-end rule pathway.[1][6]
The proteinubiquitin is a universal, "ubiquitously" expressed protein common toeukaryoticorganisms. Ubiquitin plays a role in theregulation of other proteins by tagging them for eventual degradation byproteasomes.[32] This process begins when ubiquitin ligasecovalently attaches a ubiquitinmolecule to thelysineside chain of the target proteinsubstrate (the misfolded, damaged, malfunctioning or unneeded protein that needs to be degraded). This is repeated a number of times in succession forming a chain of ubiquitin molecules, which is a process referred to as polyubiquitination. The polyubiquitination of the target protein signals the proteasome to break it down, which it does viaproteolysis.[32] The ubiquitin-proteasome system plays a crucial role in thenon-lysosomal degradation of intracellular proteins, and ubiquitin can also participate inmodifying proteins to perform certain tasks.[32][33][34] Both degradation and modification of proteins within the cell are part of a broader regulatory scheme, necessary for cellular processes such ascell division,cell signaling,cell surface receptor function,apoptosis,DNA maintenance, inflammatory response and developmental quality control associated with thecell cycle andhomeostasis in general.[33][34]
Ubiquitin-mediated degradation of proteins occurs through theN-end rule pathway.[35][36] In eukaryotes, including humans, the N-end rule pathway is part of the ubiquitin system.[35] Composed of a highly selectivesingle-residue code (a singleamino acidnucleotide sequence), the N-end rule serves as a mechanism which can relate the stability of a protein to the identity of the amino acid at itsN-terminus (the end of thepolypeptide with anamino group, which in the ubiquitin system may be involved in the reactive destabilization of the protein).[35][36][37]
In JBS, mutations in theUBR1 gene alter, disrupt or prevent the synthesis of ubiquitin ligase.[1][6] In the pancreatic acinar cells,UBR1 is more highly expressed than anywhere else in the body.[1] Impairment of the ubiquitin-proteasome system directly related to insufficient activity of ubiquitin ligase has been established as the cause of both congenital and progressive inflammatory damage, fatty tissue replacement, connective tissue proliferation and errors in innervation of the acini and islets, correlating to failures of normal apoptotic destruction of damaged cells and constitutive malpresence of proteins.[1][3][6] This also applies to other areas affected by deleteriousUBR1 expression, such as the craniofacial area, musculoskeletal and nervous systems, dentition and organs.[1][6][22]
Missense,nonsense andsplice site mutations of theUBR1 gene in both parents have been found with JBS, confirming thehomozygous nature of the JBSphenotype. Variability of the phenotype, associated with residual ubiquitin ligase activity in some patients, has also been attributed tohypomorphic mutations occasionally found in either of the carrier parents.[1][3][6][22][23] TheUBR1 gene is located on humanchromosome15.[6]
Johanson-Blizzard Syndrome may be diagnosed based on the identification of characteristic symptoms or by testing for mutations on the UBR1 gene which are known to cause this disorder.[38]
While there is no cure for Johanson–Blizzard syndrome, treatment and management of specific symptoms and features of the disorder are applied and can often be successful. Variability in the severity of Johanson–Blizzard syndrome on a case-by-case basis determines the requirements and effectiveness of any treatment selected.[citation needed]
Pancreatic insufficiency and malabsorption can be managed withpancreatic enzyme replacement therapy, such aspancrelipase supplementation and other related methods.[1]
Craniofacial and skeletal deformities may require surgical correction, using techniques includingbone grafts andosteotomy procedures.[20] Sensorineural hearing loss can be managed with the use ofhearing aids and educational services designated for the hearing impaired.[12][17]
Special education, specialized counseling methods andoccupational therapy designed for those with intellectual disabilities have proven to be effective, for both the patient and their families.[39]
Mice that areviable, fertile and lacked substantialphenotypic abnormalities other than reduced weight, with disproportionate decreases in skeletal muscle and adipose tissue are used for theirpancreatic sensitive toscretagoguecholecytokinin byknocking out UBR1.This links signaling circuitry between pancreatic enzyme secretion and its source compound controlled by N-end rule pathway, ultimately determining pancreatichomeostasis is influenced by UBR1.[40][27]Saccharomyces cerevisiae also contains regions essential for recognition of the N-end rule substrates by UBR1 protein, as well as rabbits for through reticulocytetryptic peptides afterpurification to E3α.[41]
Johanson–Blizzard syndrome was named afterAnn J. Johanson andRobert M. Blizzard, the pediatricians who first described the disorder in a 1971 journal report.[15][42]