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 maxillo facial 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 hypo plasia, 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 het- erogeneous 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.

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