Johanson-Blizzard Syndrome with Short Stature

Johanson–Blizzard syndrome (JBS) is a rare, sometimes fatal autosomal recessive multisystem congenital disorder featuring abnormal development of the pancreas, nose and scalp, with mental retardation, hearing loss and growth failure. It is sometimes described as a form of ectodermal dysplasia. 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. We report a ten years Irannian child with signs and symptoms suggestive of this syndrome (JBS).


Introduction
J ohanson-Blizzard syndrome is a rare gene c disorder that characteris c with mul system involvment par curarly: Ectodermal defects, endocrine disorder, pancrea c insuffi ciency and other disorders.It was named a er Ann J Johanson and Robert M Blizzard.The paediatricians who fi rst described the disorder in a 1971 1,2,3 .

The Case
We introduce a ten years old Iranian boy, product of a non consanguineous marriage, who was referred to us for short stature.His anthropometry were: weight(24 kg), height(130 cm) and head circumference(51cm).According to the natal history he was IUGR at birth and was admi ed to NICU because of respiratory distress.Physical examina on revealed cle palate, On ausculta on of heart a holosystolic murmer (3/6) was heard at the lower le sterna border.According to the echocardiography he had VSD, and further inves ga on showed hypothyroidism.(TSH:12.5 IU/ml) and on examina on had hypospadiasis and cryptorchidism no ced since seven years of age.He had cons pa on from birth and con nued ll recently despite the use of laxa ve drugs.
Further inves ga ons a er now (malabsorp on tests, sweat test, bone age) and a careful examina on; we found that he has pancrea c insuffi ciency and sensory neural hearing loss along with visual problems (cornea impairment).He was treated by pancrea c enzymes (lipase:500IU/Kg up to a maximum of 50000IU/day), levothyroxine (50μg/day) and vitamins (VitA:5000IU/day, VitD: 400IU/day and Vit E: 1000IU/day), other supplements (Zinc:20mg/kg/day, Iron:3mg/ kg/day, Calcium:1500mg/kg/day) and acid folic (1mg/daily).His cle palate and hypospadiasis had been repaired by previous surgery.A er fallow up for one year of treatment his growth had improved (Wt;29kg, Ht:135cm, HC:54cm) and had no cons pa on.

Discussion
The most prominent eff ect of JBS is pancrea c exocrine insuffi ciency 1,4,5,6,7 .Varying degrees of decreased secre on of lipases, pancrea c juices such as trypsin, trypsinogen and others, as well as malabsorp on of fats and disrup ons of glucagon secre on and its response to hypoglycemia caused by insulin ac vity are major concerns when JBS is diagnosed 1,3,8 .Pancrea c exocrine insuffi ciency in JBS can addi onally stem from congenital replacement of the acini with fa y ssue 1,3,8,9 .Near total replacement of the en re pancreas with fa y ssue has also been reported.This is a progressive, some mes fatal consequence of the disorder 9 .
Endocrine insuffi ciency of the pancreas occurs with JBS, though it is some mes less common and less pronounced than the more prominent eff ects on exocrine func on 1 .Endocrine dysfunc on of the pancreas o en results in diabetes mellitus.Both insulin resistance and diabetes have been observed with JBS, and it is suggested that diabetes should be considered as a complica on of JBS and its course 5,7,8 .
Endocrine abnormali es in other areas have also been present with the disorder.These include hypothyroidism 2 , growth hormone defi ciency 1,8 and hypopituitarism.Growth failure and associated short stature (dwarfi sm) in JBS can be a ributed to growth hormone defi ciency caused by diminished anterior pituitary func on, with malabsorp on of fats playing a subsequent role 1,4 .
Other abnormali es, aff ec ng the scalp, head, face, jaw and teeth may be found with JBS.These include: ectodermal mid-line scalp defects with sparse, oddly-pa erned hair growth 2,9 ; aplasia cu s (underdeveloped, very thin skin) over the head, an enlarged fontanelle ("so spot" on the head of young infants), microcephaly (undersized skull), prominent forehead, absence of eyebrows and eyelashes, mongoloidal eye shape,nasolacrimo-cutaneous fi stulae (this refers to the forma on of an abnormal secondary passageway from either the tear duct or lacrimal sac to the facial skin surface, possibly discharging fl uid) 9 , fl a ened ears, micrognathism of the maxilla and mandible (underdevelopment of the upper and lower jaw, respec vely), with the maxilla more prominently aff ected in some cases; congenital cle ing of bones surrounding the op cal orbit (eye socket), such as the frontal and lacrimal bone 8 ; and maldeveloped deciduous teeth ("baby teeth"), with an absence of permanent teeth 9 .
Findings with the inner ear in JBS give explana on to the presence of bilateral sensorineural hearing loss in most pa ents aff ected by the disorder.The forma on of cys c ssue in both the cochlea and ves bule, with resul ng dila on and malforma on of these delicate structures has been implicated 7,9 .Congenital deforma ons of the temporal bone and associated adverse anatomical eff ects on innerva on and development of the inner ear also contribute to this type of hearing loss 8 .
Addi onal congenital anomalies, eff ects on other organs, and less common features of JBS have included: imperforate anus 4 , vesicoureteral refl ux; duplex of the uterus and vagina in female infants, neonatal cholestasis of the liver, with cirrhosis and portal hypertension 7 ; dilated cardiomyopathy 7,8 , dextrocardia 1 , atrial and ventricular septal defect 1 ; low birth-weight 7 , failure to thrive , hypotonia 8 ; sacral hiatus (a structural defi ciency of the sacral vertebrae), congenital cataracts 9 , and cafe-au-lait spots 2 .Johanson-Blizzard syndrome is caused by muta ons in the UBR1 gene, which encodes one of several ubiqui n ligase enzymes of the N-end rule pathway 1,6 .

Genetics
The UBR1 gene is located on human chromosome 15 6 .

Treatment
While there is no cure for JBS, treatment and management of specifi c symptoms and features of the disorder are applied and can o en be successful.Variability in the severity of JBS on a case-by-case basis determines the requirements and eff ec veness of any treatment selected.Pancrea c insuffi ciency and malabsorp on can be managed with pancrea c enzyme replacement therapy, such as pancrelipase supplementa on and other related methods 1,2,3 .
Craniofacial and skeletal deformi es may require surgical correc on, using techniques including bone gra s and osteotomy procedures.Sensorineural hearing loss can be managed with the use of hearing aids and educa onal services designated for the hearing impaired 7,8,9 .Special educa on, specialized counseling methods and occupa onal therapy designed for those with mental retarda on have proven to be eff ec ve, for both the pa ent and their families.This, too, is carefully considered for JBS pa ents 4,5 .

Conclusion
This case highlights the importance of a careful and thorough physical examina on in a neonate especially in SGA and IUGR, and if any congenital anomalies are found then to follow up at a later age and inves gate further; in this case short stature, cranio-facial anomalies, malabsorp on, malabsorp on and bone age.