Occurrence of the Rare Syndrome of Johanson-Blizzard in a Child – Longitudinal Observations

case report: Occurrence of the Rare Syndrome of Johanson-Blizzard in a Child – Longitudinal Observations

[Editor’s note: For definitions of medical terms in this paper, please Volume 21, Number 2, 2015 use Dictionary.com at http://dictionary.reference.com/medical] Abstract

Authors The authors review the data available in the literature on a rare genetic disorder – Johanson-Blizzard syndrome – and Larissa S. Baleva,1 present their clinical observations on one patient after longi- Alla E. Sipyagina,1 tudinal follow-up. Particular emphasis is on multiple malformations which are the clinical hallmark manifestations of the Martin Zenker,2 1 disorder: congenital exocrine insufficiency, and abnormalities Julia M. Kagan, of the maxillofacial region, hearing and sight. Homozygous or 1 Lubov I. Danilycheva, compound heterozygous mutations in the UBR1 gene typical- 2 Maja Sucalo ly result in Johanson-Blizzard syndrome. A molecular genetic study detected two mutations at different sites in the UBR1 1 Research and Clinical gene. These have not been previously described in the syndrome, Institute of Pediatrics, but likely result in the patient’s disorder. One of the mutations Pirogov Russian National was maternally inherited. The differential diagnosis of this syn- Medical University RF Ministry of Health, drome and multifaceted therapy, including clinical nutrition and Russia enzyme therapy are presented. Follow-up from age 8 to 16 years of age showed a positive trend overall in the patient’s condition. 2 Institute of Human Genetics, University Hospital Johanson-Blizzard syndrome (JBS; OMIM 243800) is charac- Magdeburg, Magdeburg, terized by exocrine pancreatic insufficiency with multiple Germany congenital anomalies, short stature, and variable developmental delay (Online Mendelian Inheritance in Man (OMIM, n.d.). This syndrome is a rare autosomal recessive disease (estimated prevalence 1:250,000), and it was first described by Johanson and Blizzard in 1971. According to literature data, Correspondence there are fewer than 50 cases of children with such a syndrome (see the Appendix in the reference list). No follow-up [email protected] data about individual patients are found in the literature.

Diagnosis of JBS causes great difficulties both due to its extremely rare occurrence and possible multiple manifesta- Keywords tions which have been described in different combinations by various authors. However, the association of exocrine congenital malformations, pancreatic insufficiency manifesting in the first year of life genetic syndrome, and typical facial anomalies characterized by nasal wing Johanson-Blizzard hypoplasia or aplasia is unique to this syndrome and allows syndrome, a clinical diagnosis in almost all cases (Sucalo et al., 2014). pancreatic insufficiency The disease is caused by homozygous or compound heterozygous mutations in the UBR1 gene which is located on the long arm of chromosome 15 (band15q14-21.1) (Zenker et al., 2005). The gene encodes a ubiquitin ligase of the N-end rule pathway, but currently the pathophysiological mechanisms that are responsible for the various organ manifestations in JBS are unknown. © Ontario Association on Developmental Disabilities Baleva et al. 120

The list of symptoms observed in patients who was 27 years old at the patient’s last visit. with JBS by different researchers is a long one. This half- brother suffers from bronchial asth- Besides malabsorption due to pancreatic exo- ma and congenital sensory hearing loss, but is crine insufficiency and nasal wing hypoplasia, otherwise healthy and has no dysmorphological it also includes congenital hypothyroidism anomalies. The mother’s second and third preg- due to thyroid gland hypoplasia, short stature, nancies from the second marriage ended with microcephaly, scalp defects, sparse hair, cleft miscarriage in early pregnancy. No cause was lip and palate, hypodontia and abnormal or identified. The fourth pregnancy was compli- small teeth, congenital abnormality of lacrimal cated by maternal anemia and nephropathy in ducts, muscular hypotonia, mental retardation, the first and second trimesters. Delivery of the sensorineural deafness, various heart defects male patient was at term and uncomplicated. (defects of interatrial or interventricular sep- The newborn’s body weight at birth was 3,220 tum, dextrocardia, pulmonary trunk stenosis, g, his body length was 51 cm, and Apgar scores transposition of great vessels), absence or hypo- of 7 and 8 after 5 and 10 minutes were record- plasia of spleen, polysplenia, hydronephrosis, ed, respectively. At birth severe facial anomalies atresia or stenosis of the anus, rectovaginal were evident: a cleft of the soft and hard palate, fistula, vaginal septum or hydrometrocolpos, alveolar ridge, and upper lip, as well as aplasia small penis, cryptorchidism, thrombocytope- of nasal wings with lateral facial clefting extend- nia, anemia, and diabetes mellitus. ing from the nose to the lower eyelid Failure to thrive and delayed growth were observed from One of the leading and consistent symp- the first months of life. At the age of 3 months the toms is pancreatic exocrine insufficiency. The patient’s body weight was 3,740 g and his length morphological basis of this pathology is the was 54 cm; at the age of one year his body weight replacement of pancreatic acinar tissue by fat was 7,150 g and his length was 66 cm (so during and connective tissue with relative integrity the first year of life the boy grew only by 15 cm). of structure and insular apparatus function. Moreover, a delay in motor development was Intestinal absorption occurs due to decreased also noted: The boy began to hold his head at the production of all pancreatic enzymes (lipase, age of 7 months, to sit unaided at the age of 11 amylase, trypsin). Large follicles with colloid months, and to walk when he was 2.5 years old. content are found in the biopsy material of the thyroid gland. Lacrimation and recurrent purulent discharge from the eyes were noted in the boy from the In the current report we provide clinical data first days of life. Congenital abnormality of the from the follow-up of a patient with JBS until lacrimal ducts was diagnosed. the age of 16 years. Bulky watery and undigested stools with visible fat and mucus were noted in the child while on Case Report breast feeding plus soy and other formula from the moment of birth. Stool analysis confirmed The child was first admitted to the Children’s steatorrhoea of the first and second type. At Applied Research Centre of the Antiradiation the age of 4.5 months the child was examined Protection Unit of the Federal State Budgetary in the Republic Children’s Clinical Hospital in Institution, Moscow Research Institute of Tatarstan where Shwachman-Diamond syn- Pediatrics and Pediatric Surgery, at the age of 8 drome was initially suspected. Major manifes- years. From the family history there is no hint tations of this latter syndrome are congenital at parental consanguinity. The mother has gas- pancreatic insufficiency and hematologic dis- tric ulcer disease, cardiovascular and endocri- orders (more often anemia and thrombocyto- nological problems. The father left the family penia, than the rarer pancytopenia). From the from the moment of the child’s birth; there is no age of 7 months, the child was followed up in information about his health. the Republic Children’s Clinical Hospital in Moscow where Shwachman-Diamond syn- The patient was the product of the fourth preg- drome was excluded due to the absence of bone nancy, second delivery. The mother’s first preg- and hematologic disorders that are characteris- nancy from her first marriage resulted in a son tic of this syndrome. Also mucoviscidosis for

JODD Occurrence of the Rare Syndrome of Johanson-Blizzard in a Child 121 which congenital pancreatic exocrine insuffi- Mayo-Robson point and gall bladder projection ciency is typical was excluded by the absence of point. The liver was near the costal arch edge; any bronchopulmonary symptoms and normal the spleen was not palpable. Stool was light chloride concentrations in sweat. Further on, brown, loose, two times a day. Urination was the child was followed up with the diagnosis: painless. Male sexual development was normal. of congenital pancreatic insufficiency and malabsorption syndrome. Hematological investigations showed mild thrombocytopenia: 113 3 109/l (normal 150–500) The diagnosis of JBS was first suspected by a on two occasions in the blood count; other geneticist in Scientific Advisory Department of parameters were within normal ranges for age. Moscow Medical Genetic Centre of the Russian Urine analysis was normal. Increased alkaline Academy of Sciences when the patient was 13 phosphatase and lactate dehydrogenase lev- years old. From that age, therapeutic nutrition els were noted in the biochemical blood assay. with Nutrison (a high-caloric formula produced Blood amylase was within the normal range. by Nutricia, NL) and enzyme substitution with Increased f urine diastase was not found. Kreon (a digestive enzyme replacement produced by Abbott Products GmbH, Hannover, Undigested fibre and extracellular starch were DE) in small doses of 25,000 U per day were pre- found in small quantity in the series of copro- scribed. Gastrointestinal symptoms and nutri- logy tests. tional state improved on this regimen: abdominal pains and vomiting became rarer, formed On abdominal ultrasound investigation, the stool appeared, the child began to gain weight. pancreas was increased, parenchyma was heterogeneous due to the areas of different echoge- The boy was admitted to the Radiation Risk nicity. No changes of other internal abdominal Clinic of the Children’s Applied Research organs and kidneys were found. No pathology Centre of Antiradiation Protection for the first in pancreas was found by magnetic resonance time at the age of 8. At admission there were imaging conducted at this time. complaints of abdominal pains, nausea, undigested stool, insufficient gain in the body An audiogram indicated right-sided neurosen- weight, choking and food and water entrance sory hearing loss of Stage 4. in the nasal cavity, lacrimation, and increased fatigue. At this time the boy’s body weight was To further evaluate the gastrointestinal com- only 19 kg (below the 1st centile or -2.7 SD) and plaints, esophago-gastro-duodeno-jejunoscopy his height was 118 cm (below 2nd centile or -2.1 was performed and revealed reflux-esophagitis, SD). His intelligence was normal; the child gastric cardia incompetence, pangastritis, gran- attended a regular school. At examination mul- ular bulbitis, duodenogastral reflux and duode- tiple dysmorphic stigmata were noted: frontal nojejunitis with elements of mucosal atrophy. upsweep of hair, sparse hair, small areas of alo- Hypolactasia of moderate severity was noted pecia in the parietal region with scarred skin, using the Biohit Lactose Intolerance Quick Test and a pinched nose with nasal wing aplasia. (Biohitoyi, FI). (This test identifies lactase defi- Skin was clear and pale. Multiple scars were ciency from duodenal biopsies taken during present in the area of the upper lip caused by gastroscopy.) At morphological examination of corrective maxillofacial surgery. Deciduous the jejunum signs of nonspecific atrophic jeju- teeth were small and maldeveloped and no nitis were noted. permanent teeth were present. The tongue was covered with white plaque. Lymph nodes No pathologic changes were found by ultra- in the anterior cervical group were up to 0.7 x sound investigation of the thyroid gland. 0.5 cm; in other groups there were small, sin- Thyroid hormones were within the normal gle ones. In the lungs, respiration was vesicular range. No signs of cardiac disease were found and conducted in all parts; rales were absent. at electrocardiogram and echocardiographic Heart tones were clear; rhythm was regular; investigation. heart rate was 80 beats per min. Blood pressure was 110/70 mmHg. The abdomen was soft, but Orthopantomography was performed and painful during palpation in the epigastrial area, revealed the absence of all permanent teeth.

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The clinical diagnosis of JBS was established on At the age of 12 years the child had a consul- the basis of the child’s craniofacial phenotype tation with Martin Zenker, Professor at the (nasal wing aplasia, abnormality of lacrimal Institute of Human Genetics of the University ducts, scalp defects, sparse hair, frontal hair Hospital in Magdeburg. At that time molecu- upsweep), presence of muscular hypotonia, lar genetic testing of the UBR1 gene was per- congenital right-sided neurosensory hearing formed in the patient, his mother and broth- loss, small deciduous teeth, absence of imma- er from the first mother’s marriage. Earlier, a ture permanent teeth, and significant congen- group of researchers managed by Professor ital pancreatic exocrine failure. Zenker proved that JBS results from homozy- gotic or heterozygotic mutations of UBR1 gene Taking into account the mother’s and father’s which causes the loss of ability of the UBR1 contact with radioactive fuel, cytogenetic exam- protein to fulfil its functions (Sucalo et al., 2014). ination was performed in the family. Only the patient and his mother were available for All 47 coding exons including the flanking analysis. Cytogenetic examination of the child intron regions of the UBR1 gene were ampli- revealed increased level of single and paired fied by PCR. PCR amplicons were purified and fragments, dicentrics, and translocations which subjected to direct sequencing using an auto- is suggestive of genomic instability. No similar mated sequencer. Sequences were compared to changes were found in mother. the reference sequences deposited in the pub- lic database (NM_174916) (National Center for At last examination, the boy was 15 years old. Biotechnology Information, n.d.). In the index He had constantly been followed up in the patient, two heterozygous sequence changes in Radiation Risk Rehabilitation Department. A exon 10 {c.1166_1177del (p.A389_F392del)} and complete clinical and laboratory investigation exon 21 {c.2260C>T (p.R754C)} were identified. has been performed annually since 2006. At the Both variations have not been found in other age of 15 his body weight was 45 kg (5th centile patients with JBS so far; as well, they are not or -1.6 SD), and his height was 158.5 cm (4th cen- known as polymorphisms. The fact that both tile or -1.8 SD). During the previous three years of them predict deletion or exchange of high- the boy grew by 7 cm, and his weight gain was ly conserved amino acids in the UBR1 protein, 14 kg. strongly suggest that these represent the mutations that are causative for the syndrome in this Between 13 and 15 years of age he under- patient. went multiple surgeries in the Maxillo-Facial Surgery Department of Russian Children’s The same exons – 10 and 21 – were investigated Clinical Hospital due to the congenital pene- in the patient’s mother and only the change in trating cleft of the upper lip and palate on the the exon 21 was found in her, thus suggesting left side. Multistage surgical treatment consist- that the in frame deletion in exon 10 was inher- ed of: left-sided cheiloplasty, soft palate push- ited from the father who was not available for back, correction of the nasal passage fundus; genetic testing, or arose as a new mutation. The and in 2011 – nasolacrimal duct catheterization elder half-brother also carried the maternally from the right side, correction of velopharyn- inherited UBR1 mutation. geal insufficiency, nasal septum plasty with resection of cartilaginous part. Currently the child consistently receives pancreatic enzyme replacement therapy by Kreon Progressive changes of the pancreas were (175,000 U/day), high-caloric nutrition with noted by ultrasound and computed tomogra- Nutrison (2,000 ml/day) with the addition of phy (CT). While ultrasound investigation at the courses of rice and oat porridge with Liquigen age of 8 years had revealed only heterogeneous (a milk-free beverage produced by Nutricia, parenchyma echogenicity, MRI at the age of 12 NL; 20 ml/day). revealed signs of fatty dystrophy of the pancreas. CT of the abdominal cavity performed in Taking into account the fact that last ultra- March 2013 revealed the absence of pancreatic sound and CT of abdominal organs revealed tissue and its subtotal replacement by fat tissue. subtotal pancreatic tissue replacement by fatty tissue, we decided to raise the question about

JODD Occurrence of the Rare Syndrome of Johanson-Blizzard in a Child 123 possible transplantation of the pancreas. Due References to this, the patient had a consultation in the Federal Scientific Shumakov Transplantology National Center for Biotechnology Information. Center. Transplantation was recommended in (n.d.). Retrieved from http://www.ncbi. case of irreversible pancreatic beta-cell dys- nlm.nih.gov/nuccore/NM_174916.2 function (i.e., Stage 5 decompensation char- Online Mendelian Inheritance in Man acterized in part by severe loss of beta-cell (OMIM). (n.d.). Retrieved from http:// mass) (Weir & Bonner-Weir, 2004). Meanwhile www.ncbi.nlm.nih.gov/omim it was recommended to support the child by Sucalo, M., Fiedler, A., Guzman, C., Spranger, replacement therapy with Kreon and special- S., Addor, M. C., McHeik, J. N, … Zenker, ized nutrition. After transplantation the child M. (2014). Mutations in the human UBR1 would receive immunosuppressive therapy and gene and the associated phenotypic a new transplant would be required after 7 to spectrum. Human Mutation, 35(5), 521–531. 8 years. According to an agreement with the Weir, G. C., & Bonner-Weir, S. (2004). Five Transplantology Centre, in the case of beta-cell stages of evolving beta-cell dysfunction failure the surgery will be performed. during progression to diabetes. Diabetes, 53(Suppl 3), S16–S21. This disorder can be referred to as a “rare Zenker, M., Mayerle, J., Lerch, M. M., orphan disease.” On the basis of continued Tagariello, A., Zerres, K., Durie, P. R., clinical follow-up of the child, we suggest that Beier, M., … Reis, A. (2005). Deficiency of correctly adjusted therapy has improved the UBR1, a ubiquitin ligase of the N-end rule child’s quality of life and may contribute to an pathway, causes pancreatic dysfunction, increased life expectancy. malformations and mental retardation (Johanson-Blizzard syndrome). Nature Genetics, 37, 1345–1350. Key Messages From This Article Appendix: Chronological People with disabilities: Disabilities of any kind present challenges, but this does not mean that Listing of References About life with a disability cannot be fulfilling. You Johanson-Blizzard Syndrome deserve to enjoy full participation in all aspects of life, and lead an independent life, but make sure Johanson, A. J., & Blizzard, R. M. (1971). A you are supported by people around you. You syndrome of congenital aplasia of the have the same rights to protection as any other alae nasi, deafness, hypothyroidism, person. dwarfism, absent permanent teeth and malabsorption. Journal of Pediatrics, 79, Professionals: An individual approach needs 982–987. to be applied to each person with disabilities Schussheim, A., Choi, S. J., & Silverberg, because they face different challenges and health M. S. (1976). Exocrine insufficiency with conditions. People who care for disabled people congenital anomalies. Journal of Pediatrics, sometimes are challenged by disability as well. 89(5), 782–784. Day, D. W., & Israel, J. N. (1978). Johanson- Policymakers: Policies are needed to prevent the Blizzard syndrome. Birth Defects, 14(6B), exclusion of disabled people from any aspects 275 –287. of life, to improve employment outcomes, and Mardini, M. K., Ghandour, M., Sakati, N. A., to increase awareness and understanding of & Nyhan, W. L. (1978). Johanson-Blizzard the challenges faced by people with disabilities. syndrome in a large inbred kindred with three involved members. Clinical Genetics, 14, 247–250. Acknowledgements Daentl, D. L., Frias, J. L., Gilbert E. F., Opitz, J. M. (1979). The Johanson-Blizzard We would like to thank the mother and the syndrome: Case report and autopsy patient for allowing the information in this paper findings. American Journal of Medical to be published. The publication was prepared in Genetics, 3, 129–135. accordance with international guidelines.

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Reichart, P., Flatz, S., Burdelski, R. (1979). Ektrodermale Dysplasie und exokrine Pankreasinsuffizienz ein erblich bedingtes Syndrom. Deutsche zahnärztliche Zeitschrift, 34, 263–265. Bresson J. L., Schmitz, J., Saudubray, J. M., Lesec, G, Hummel, J. A., & Rey, J. (1980). Le syndrome de Johanson-Blizzard. Une autre cause de lipomatose pancreatique. Archives francaises de pediatrie, 37, 21–24. Baraitser, M., & Hodgson, S. V. (1981). The Johanson-Blizzard syndrome. Journal of Medical Genetics, 19, 302–303. Helin, I., & Jödal, U. (1981). A syndrome of congenital hypoplasia of the alae nasi, situs inversus, and severe hypoproteinemia in two siblings. Journal of Pediatrics, 99, 932–934. Motahashi, N., Pruzansky, S., & Day, D. (1981). Roentgenocephalometric analysis of craniofacial growth in Johanson-Blizzard syndrome. Journal of Craniofacial Genetics and Developmental Biology, 1, 57–72. Townes, P. L., & White, M. R. (1981). Identity of two syndromes: Proteolytic, lipolytic and amylolytic deficiency of the exocrine pancreas with congenital anomalies. American Journal of Diseases of Children, 135, 248–250. Moeschler, J. B., & Lubinsky, M. S. (1985). Johanson-Blizzard syndrome with normal intelligence. American Journal of Medical Genetics, 22, 69–73. Zerres, K., & Holgrave, E. A. (1986). The Johanson-Blizzard syndrome: Report of a new case with special reference the dentition and review of the literature. Clinical Genetics, 30, 177–183. Gould N. S., Paton, J. B., & Bennett, A. (1989). Johanson-Blizzard syndrome: Clinical and pathological findings in 2 sibs. American Journal of Medical Genetics, 33, 194–199. Hurst, J. A, & Baraitser, M. (1989). Johanson- Blizzard syndrome. Journal of Medical Genetics, 26, 45–48. Gorlin, R. J., Cohen, M. M., Jr., & Levin, L. S. (1990). Syndromes of the head and neck (3rd ed., pp. 812–813). New York, NY: Oxford University Press.

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