• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
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  • Complete Report

Johanson-Blizzard Syndrome


Last updated: December 13, 2016
Years published: 1997, 1998, 2002, 2010, 2013, 2016


NORD gratefully acknowledges Martin Zenker, MD, Institute of Human Genetics, University Hospital Magdeburg, Germany, for assistance in the preparation of this report.

Disease Overview

Johanson-Blizzard syndrome (JBS) is an extremely rare genetic disorder that affects multiple organ systems of the body. Many symptoms are present at birth (congenital) or early childhood. The spectrum of potential features and physical findings associated with JBS is wide and varied and can differ dramatically from one person to another. However, characteristic features include insufficient intestinal absorption (malabsorption) of fats and other nutrients due to abnormal development of the pancreas (pancreatic insufficiency); failure to grow and gain weight at the expected rate (failure to thrive) during the first years of life, contributing to short stature; abnormalities of permanent teeth; distinctive abnormalities of the skull and facial (craniofacial) region including a small “beak-shaped” nose; and/or varying degrees of intellectual disability. JBS is caused by mutations to the UBR1 gene. This genetic mutation is inherited as an autosomal recessive trait.

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Signs & Symptoms

The features and physical findings associated with JBS can vary greatly from one person to another. It is important to note that affected individuals may not have all of the symptoms discussed below. However, pancreatic insufficiency, tooth abnormalities, and a characteristic shape of the nose are found in almost all affected individuals. The severity of JBS can vary as well and some infants may develop life-threatening complications during infancy. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

Infants with JBS typically have distinctive craniofacial abnormalities at birth. The most striking, constant craniofacial feature associated with JBS is an unusually small nose that appears “beak-shaped” due to absence (aplasia) or underdevelopment (hypoplasia) of the nasal wings (nasal alae). In addition, some affected infants may have a small, underdeveloped upper jaw (maxillary hypoplasia), a small pointed chin, a long, narrow upper lip and microcephaly, a condition in which a child’s head circumference is smaller than would be expected for age and gender. Some affected infants may not have the small openings in the inner corners of the eyelids where tears normally drain (lacrimal puncta aplasia), and/or an abnormal passage that carries tears directly from the interior opening of the nasal passage to the surface of the skin (nasolacrimo-cutaneous fistula). In some instances more severe facial clefting has been observed including cleft lip and palate and lateral facial clefts extending from the nasal region to the lower eyelid.

Infants with JBS may have a low birth weight and generalized poor muscle tone (hypotonia). Without treatment infants usually fail to gain weight and grow at the expected rate (failure to thrive). Eventually, affected individuals may exhibit short stature. Affected infants and children may also experience delays in achieving developmental milestones (developmental delays) and exhibit varying degrees of intellectual disability. Although intellectual disability does occur, in some cases, intelligence is normal. Hearing loss or deafness may be present at birth or may develop later during life.

Growth deficiency associated with JBS may occur because of malabsorption and exocrine pancreatic insufficiency. Pancreatic insufficiency is a common, prominent feature of JBS. Without treatment, impairment of the pancreas and malabsorption can progress to cause life-threatening complications. The pancreas is a small gland located behind the stomach. It contains specialized exocrine cells that secrete enzymes that travel to the intestines and aid in digestion. Pancreatic cells called “acinar cells” produce such digestive enzymes. In JBS, however, affected individuals lack a sufficient number of properly functioning acinar cells, and pancreatic tissue may be replaced by abnormal accumulations of fat. As a result, there is a deficiency in the amount of digestive enzymes required to break down food (exocrine pancreatic insufficiency), which, in turn, prevents fats and other essential nutrients from being absorbed properly (malabsorption) in the intestines.

In individuals with JBS, intestinal malabsorption results in large, loose, foul smelling stools that contain an excessive amount of fat (steatorrhea) and other nutrients. In addition to failure to thrive, pancreatic insufficiency may result in deficiencies of certain vitamins (e.g., vitamins A, D, and/or E), chronic anemia, low levels of calcium in the blood (hypocalcemia), and additional nutritional deficiencies. For example, affected infants experience protein loss characterized by abnormally decreased levels of protein in the blood (hypoproteinemia), which, in turn, leads to excessive accumulation of body fluids (edema) in the soft layers of tissue under the skin.

In one report in the medical literature, an infant with suspected JBS did not have evidence of pancreatic insufficiency. Some researchers believe that the pancreatic defect may be progressive and may not be detectable or readily apparent during early infancy in all cases.

Eventually, it is possible that endocrine pancreatic insufficiency will develop. Endocrine cells are cells in the pancreas that secrete several hormones that have specialized functions within the body. Insulin is the most important pancreatic hormone. Lack of appropriate insulin production results in diabetes.

Many infants with JBS may also have characteristic abnormalities of the hair and scalp. For example, the scalp hair, which is often blond, may be unusually sparse, dry, and coarse. Affected infants may also lack of skin and hair (aplasia cutis) by the soft spots in the front and back of the skull (anterior and posterior fontanelles). In many cases, during later childhood, there may also be abnormal bald patches (alopecia) on the scalp where skin dimples were previously apparent at birth.

Most affected infants and children also have distinctive abnormalities of the teeth. The primary (deciduous) teeth may be abnormally small (microdontia), cone-shaped, and widely spaced, with short, malformed, irregular roots. The majority of the secondary (permanent) teeth are absent. The teeth that do appear may also be abnormally small and malformed with short, misshapen roots.

Approximately 40 percent of affected individuals also demonstrate abnormally decreased activity of the thyroid gland and underproduction of thyroid hormones (hypothyroidism). The thyroid gland, located at the base of the neck, secretes hormones (e.g., thyroxine) that play an essential role in regulating the rates of metabolism and growth. Symptoms associated with hypothyroidism, which tend to be progressive in nature, usually become apparent during childhood; however, in rare cases, they may begin to occur during early infancy. In affected individuals, hypothyroidism may result in generalized weakness and fatigue and may contribute to growth retardation and abnormal delays in the acquisition of skills requiring the coordination of mental and physical activity (psychomotor retardation).

Some infants and children with JBS may have additional abnormalities including the persistence of the anal membrane, causing full or partial closure of the anus (imperforate anus or anal stenosis), which, in turn, prevents the normal passage of bowel contents. In some cases, affected individuals may also have abnormalities of the genital and urinary (genitourinary) tracts. In affected males, such malformations may include abnormal placement of the urinary opening (meatus) on the underside of the penis (hypospadias) and/or an abnormally small penis (micropenis). Affected females may have an abnormal partition dividing the vagina (double or septate vagina), unusual enlargement of the elongated organ partially enclosed within the folds of skin surrounding the vaginal opening (clitoromegaly), an abnormal passage joining the vagina and the tubular structure through which urine is excreted (urethrovaginal fistula), and a single urogenital opening (orifice). In addition, in some cases, affected males and females may demonstrate abnormal swelling (distention) of and accumulation of urine in the kidneys (hydronephrosis).

Infants and children with JBS can potentially develop additional finding and physical features including small, underdeveloped nipples, reversal of the normal position of certain organs within the chest (situs inversus), congenital heart defects, decreased function of the pituitary gland (hypopituitarism), and an abnormally high susceptibility to repeated infections. Congenital heart defects may include “holes” in the fibrous partition (septum) separating the upper or lower chambers of the heart (atrial septal defects [ASDs] or ventricular septal defects [VSDs]) as well as weakening of the heart muscle (cardiomyopathy). Hypopituitarism can cause a wide variety of symptoms. Growth hormone deficiency and juvenile onset diabetes have also been reported in individuals with JBS.

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JBS is caused by mutations of the ubiquitin E3 ligase (UBR1) gene. This genetic mutation is inherited as an autosomal recessive trait.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.

Investigators have determined that the UBR1 gene is located on the long arm (q) of chromosome 15 (15q15-q21.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 15q15-q21.1” refers to bands 15-21.1 on the long arm of chromosome 15. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The UBR1 gene produces (encodes) a protein known as the UBR1 protein. Mutation of this gene leads to deficient levels of functional UBR1 protein. This protein is essential for several chemical processes in the body and, for example, is normally found in high levels in the exocrine cells of the pancreas, but it is present in many other tissues as well. Deficient levels of functional UBR1 protein ultimately result in the findings and physical features of JBS by mechanisms that are poorly understood, to date.

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Affected populations

JBS affects males and females in equal numbers. Although the exact incidence is unknown, the frequency has been estimated to be 1 in 250,000 births. More than 60 cases have been described in the medical literature. JBS was first described in the medical literature in 1971 by doctors Johanson and Blizzard. The defective gene was identified by Zenker, et al. in 2006.

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A diagnosis of may be suspected based upon identification of characteristic symptoms (e.g., distinctive “beak-shaped” nose, exocrine pancreatic insufficiency, tooth abnormalities, scalp defects, deafness), a thorough clinical evaluation and a detailed patient history. A diagnosis of JBS can be confirmed through molecular genetic testing, which can identify characteristic mutations of the UBR1 gene that cause the disorder.

Additional tests may be performed to assess the severity of JBS in each individual. Such tests can include hearing tests to determine the presence and degree of hearing loss or computed tomography (CT) scan to determine the extent of fatty infiltration of the pancreas. It is important that affected infants and children be screened for the development of potentially serious complications including congenital heart defects, hypopituitarism, hypothyroidism, and juvenile-onset diabetes.

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Standard Therapies


The treatment of JBS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, dental specialists, speech pathologists, specialists who assess and treat disorders of the endocrine glands (endocrinologists), specialists who assess and treat disorder to the gastrointestinal tract (gastroenterologists), cardiologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.

Specific therapies for the treatment of JBS are symptomatic and supportive. Affected individuals usually require lifelong pancreatic enzyme supplements (e.g., oral pancreatin) to promote proper absorption of fats and other necessary nutrients. In many cases, vitamin supplements (e.g., fat-soluble vitamins A, D, E, K) may also be prescribed to prevent or treat vitamin deficiencies that may result from malabsorption due to pancreatic insufficiency. A special diet with easily-absorbed, high-protein supplements (protein hydrolysate diet) may also be prescribed to ensure that an affected individual’s total nutritional requirements are met. Although such therapies should lead to improved absorption of nutrients and acceptable weight gain, it is important to note that most affected children will remain smaller and shorter than average for their ages (since short stature appears to be one of the many primary manifestations of JBS).

Individuals with hypothyroidism require immediate thyroxine hormone replacement therapy. Particularly in infants, it is mandatory that hypothyroidism be diagnosed early and treated immediately. Such hormone therapy may be carefully monitored and adjusted due to the malabsorption associated with JBS.

In some cases, other abnormalities potentially associated with JBS may be corrected surgically. These may include certain craniofacial, genitourinary, cardiac, and/or other malformations potentially associated with the disorder. For example, in some cases, absent or underdeveloped nasal wings may be surgically reconstructed. Depending upon the severity of anal abnormalities (imperforate anus or anal stenosis), surgery may be conducted to surgically correct or reconstruct the anus (anoplasty) and/or to create an opening between the colon and the surface of the body (colostomy) to allow passage of bowel contents. Surgery may also be conducted to correct certain genitourinary and/or cardiac abnormalities. The surgical procedures performed will depend upon the location and severity of the anatomical abnormalities and their associated symptoms.

The dental abnormalities occurring in association with JBS may be treated through bonding agents, use of dentures, and/or other supportive techniques. Hearing loss associated with some cases of JBS may be treated with hearing aids.

Early intervention is important to ensure that children with JBS reach their potential. Special services that may be beneficial to affected children may include special remedial education, special social support, and other medical, social, and/or vocational services. Genetic counseling will be of benefit for affected individuals and their families.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, in the main, contact:
For information about clinical trials conducted in Europe, contact:

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Zenker M. UBR1 and the N-end-rule pathway and the Johanson-Blizzard syndrome. In: Epstein CJ, Erickson RP, Wynshaw-Boris A (eds) Inborn Errors of Development: The molecular basis of clinical disorders of morphogenesis, 2nd ed. 2008. Oxford University Press, New York, pp 1190-1194.

Wilschanski, M. Other Hereditary and Acquired Pancreatic Disorders. In: Walker’s Pediatric Gastrointestinal Disease, Kleinman RE, Goulet OJ, Mieli-Vergani G, et al., eds. 2008. BC Decker, Inc. Hamilton, Ontario. Pp. 1252-1254.

Jones KL. Ed. Smith’s Recognizable Patterns of Human Malformation. 6th ed. Elsevier Saunders, Philadelphia, PA; 2006:106.

Prakash C, Clouse RE. Johanson-Blizzard Syndrome. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:208-209.

Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Syndromes of the Head and Neck. 4th ed. Oxford University Press, New York, NY; 2001:1010-1012.

Corona-Rivera JR, Zapata-Aldana E, Bobadilla-Morales L, Corona-Rivera A, Peña-Padilla C, Solis-Hernández E, Guzmán C, Richmond E, Zahl C, Zenker M, Sukalo M. Oblique facial clefts in Johanson-Blizzard syndrome. Am J Med Genet A. 2016;Mar 17. doi: 10.1002/ajmg.a.37630. [Epub ahead of print]

Sukalo M, Fiedler A, Guzmán C, Spranger S, Addor MC, McHeik JN, Oltra Benavent M, Cobben JM, Gillis LA, Shealy AG, Deshpande C, Bozorgmehr B, Everman DB, Stattin EL, Liebelt J, Keller KM, Bertola DR, van Karnebeek CD, Bergmann C, Liu Z, Düker G, Rezaei N, Alkuraya FS, Oğur G, Alrajoudi A, Venegas-Vega CA, Verbeek NE, Richmond EJ, Kirbiyik O, Ranganath P, Singh A, Godbole K, Ali FA, Alves C, Mayerle J, Lerch MM, Witt H, Zenker M. Mutations in the human UBR1 gene and the associated phenotypic spectrum. Hum Mutat. 2014;May;35(5):521-31. doi: 10.1002/humu.22538. Epub 2014 Apr 9.

Fallahi GH, Sabbaghian M, Khalili M, et al. Novel UBR1 gene mutation in a patient with typical phenotype of Johanson-Blizzard syndrome. Eur J Pediatr. 2011;Feb;170(2):233-5. doi: 10.1007/s00431-010-1239-y. Epub 2010 Jun 17.

E Rezaei N, Sabbaghian M, Liu Z, Zenker M. Eponym: Johanson-Blizzard syndrome. Eur J Pediatr. 2011;Feb;170(2):179-83. doi: 10.1007/s00431-010-1240-5. Epub 2010 Jun 17.

Al-Dosari MS, Al-Muhsen S, Al-Jazaeri A, et al. Johanson-Blizzard syndrome: report of a novel mutation and severe liver involvement. Am J Med Genet A. 2008;146A:1875-1879.

Hoffman WH, Lee JR, Kovacs K, Chen H, Yaghmai F. Johanson-Blizzard syndrome: autopsy findings with special emphasis on hypopituitarism and review of the literature. Pediatr Dev Pathol. 2007;10:55-60.

Zenker M, Mayerle J, Lerch MM, et al. Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard Syndrome). Nat Genet. 2005;37:1345-1350.

Jones NL, Hofley PM, Durie PR. Pathophysiology of the pancreatic defect in Johanson-Blizzard syndrome: a disorder of acinar development. J Pediatr.1994;125:406-408.

Gershoni-Baruch R, Lerner A, et al. Johanson-Blizzard syndrome: clinical spectrum and further delineation of the syndrome. Am J Med Genet.1990;35:546-531.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:243800; Last Update 09/15/2016. Available at: http://omim.org/entry/243800 Accessed December 9, 2016.

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