Johanson-Blizzard Syndrome

 Johanson-Blizzard Syndrome

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.

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.

CAUSES

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.

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.

DISORDERS WITH SIMILAR SYMPTOMS

Symptoms of the following disorders can be similar to those of JBS. Comparisons may be useful for a differential diagnosis.

Cystic fibrosis is a genetic disorder that often affects multiple organ systems of the body. Cystic fibrosis is characterized by abnormalities affecting certain glands (exocrine) of the body especially those that produce mucus. Saliva and sweat glands may also be affected. Exocrine glands secrete substances through ducts, either internally (e.g., glands in the lungs) or externally (e.g., sweat glands). In cystic fibrosis, these secretions become abnormally thick and can clog up vital areas of the body causing inflammation, obstruction and infection. The symptoms of cystic fibrosis can vary greatly in number and severity from one individual to another. Common symptoms include breathing (respiratory) abnormalities including a persistent cough, shortness of breath and lung infections; obstruction of the pancreas, which prevents digestive enzymes from reaching the intestines to help break down food and may result in poor growth and poor nutrition; and obstruction of the intestines. Cystic fibrosis is slowly progressive and often causes chronic lung damage, which eventually results in life-threatening complications. Because of improved treatments and new treatment options, the outlook and overall quality of life of individuals with cystic fibrosis has improved and more than 40 percent of individuals with the disorder are adults. Cystic fibrosis is caused by mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is inherited as an autosomal recessive trait. (For more information on this disorder, choose “cystic fibrosis” as your search term in the Rare Disease Database.)

Shwachman syndrome is a rare genetic disorder with multiple and varied manifestations. The disorder is typically characterized by signs of insufficient absorption (malabsorption) of fats and other nutrients due to abnormal development of the pancreas (pancreatic insufficiency) and improper functioning of the bone marrow (bone marrow dysfunction), resulting in low levels of circulating blood cells (hematologic abnormalities). Additional characteristic findings may include short stature; abnormal bone development affecting the rib cage and/or bones in the arms and/or legs (metaphyseal dysostosis); and/or liver abnormalities. Due to abnormal skeletal changes, individuals with Shwachman syndrome may have abnormal thickening of the ribs and their supporting connective tissue (costochondral thickening), resulting in unusually short, flared ribs. In addition, improper bone development (abnormal ossification) within the arms and/or legs (limbs) may cause growth delay in particular bones. Many children with Shwachman syndrome may also be smaller than expected for their ages, with below average height (short stature) and weight. Although malabsorption due to pancreatic insufficiency may itself cause problems with growth and nutrition, short stature appears to be one of the many primary manifestations of Shwachman syndrome. In addition, as a result of bone marrow dysfunction, individuals with Shwachman syndrome may have a decrease in any or all types of blood cells. Therefore, they may have low levels of certain white blood cells (neutropenia), platelets (thrombocytopenia), red blood cells (anemia), and/or all types of blood cells (pancytopenia). Neutropenia is the most common blood abnormality associated with Shwachman syndrome. Because neutrophils, a type of white blood cell, play an essential role in fighting bacterial infections, many affected individuals are prone to repeated bacterial infections (e.g., recurrent respiratory infections [pneumonia] and infections of the middle ear [otitis media]); in some cases, infections may be severe. Some affected individuals may also have abnormal enlargement of the liver (hepatomegaly), increased levels of certain liver enzymes in the blood, and/or other findings in association with the disorder. Shwachman syndrome is believed to be inherited as an autosomal recessive trait. (For more information on this disorder, choose “Shwachman” as your search term in the Rare Disease Database.)

Pearson marrow-pancreas syndrome is an extremely rare genetic disorder in which red blood cells have an impaired ability to carry oxygen (sideroblastic anemia). Additional characteristics include abnormal accumulation of scar tissue (fibrosis) within the pancreas, impaired absorption of necessary nutrients during digestion (malabsorption), and the formation of abnormal cavities within the bone marrow (vacuolization). Affected individuals may have a low birth weight, failure to grow at the expected rate during infancy (failure to thrive), wasting away (atrophy) or absence of the spleen (asplenia), and/or abnormally high levels of lactic acid in the blood (lactic acidosis). Pearson marrow-pancreas syndrome may be caused by changes in genetic material (mutations) that affect the function of mitochondria.

DIAGNOSIS

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.

STANDARD THERAPIES

Treatment

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.

Type of Doctor Department :  Pancreatologists and registered dietitians