CASE REPORT

Johanson-Blizzard Syndrome with Diamond-Blackfan Anemia Muhammad Saeed1, Muhammad Nasir Rana2 and Tahir Masood Ahmad3

ABSTRACT Johanson Blizzard syndrome (JBS) is a rare multi-system disorder characterized by congenital aplasia or hypoplasia of alae nasi, exocrine pancreatic insufficiency, hypothyroidism, deafness, growth retardation, varying degree of mental retardation, alopecia, wide open fontanels, anti-mongoloid slant, café-au-lait spots and absent of permanent teeth. We report a 3 months old male child having Johanson Blizzard syndrome with classical clinical features, pancreatic insufficiency and Diamond-Blackfan anemia.

Key words: Johanson-Blizzard syndrome. Pancreatic insufficiency. Ectodermal dysplastic disorder. Diamond-Blackfan anemia.

INTRODUCTION there is selective defect of acinar cells, whereas the Johanson-Blizzard syndrome (JBS) was named after AJ islets of langerhans and ducts are preserved. Apart from Johanson and RM Blizzard, who first described the trypsinogen deficiency Diabetes has been reported in disorder in 1971.1 It is a rare autosomal recessive older children, suggesting the progressive nature of 6 multisystem disorder; important characteristic features . being exocrine pancreatic insufficiency, small beak like This repot describes a new association with JBS namely nose, long and narrow upper lip, small pointed chin, Diamond-Blackfan anemia, which has not been reported sparse coarse upsweep hair, sensori-neural hearing in literature previously. loss, hypothyroidism, congenital defects, varying degree of mental retardation, growth failure, and café- CASE REPORT 2 au-lait spots. Mental retardation is typically moderate to We report a sporadic case of JBS in a 3 months male severe in patients with JBS; however, patient can have infant diagnosed at Children Hospital and the Institute of 3 normal intelligence. The majority of the reported cases Child’s Health, Lahore. The diagnosis was based on include children with significant pancreatic insufficiency, typical clinical features, pancreatic insufficiency, markedly abnormal facial features and moderate to hypothyroidism, atrial septal defect, and Diamond- severe mental retardation. Other related anomalies with Blackfan anemia (congenital pure red cell aplasia). The characteristic facial appearance are short stature in patient was hospitalized with history of five to eight more than 80%, hypothyroidism in 40%, sensorineural large, bulky, loose stools per day since birth, progressive hearing loss in more than 80%, mental retardation in pallor for last one month and he was not thriving well. 77%, imperforate in 39% and genitourinary abnormalities in 38%.3 Growth hormone deficiency, He was born at term to non-consanguineous parents hypopituitarism and impaired glucagon secretion with birth weight of 2.90 kg and was breastfed initially, response to insulin induced hypoglycemia has been then at the age of 2 months shifted to formula feeding. reported.4 His weight and height at the time of admission were 3.5 kg and 53 cm respectively (both were below 3rd In 2005, disease associated locus in individual with this percentile). There was no significant family history. syndrome was mapped to chromosome 15q15-21 with identified mutations in gene UBR1 encoding a ubiquitin His general physical examination was remarkable for ligase of the N- end rule pathway.5 In the pancreas, aplastic alae nasi giving beak-like appearance to his nose, upsweep frontal hair with midline scalp hair defect, umbilical hernia, protuberant , low set ears, 1 Department of Neurology, The Children’s Hospital, Al Taif, Kingdom of Saudi Arabia. triangular upper lip with flat philtrum (Figure 1), 2 Department of Paeds Emergency, The Institute of Child micrognathia and multiple café-au-lait spots pre- Health, Lahore. dominantly distributed over the trunk, lower limbs and 3 Dean of The Children’s Hospital and the Institute of Child genetalia, 12 in numbers, varying in size from 4-3 cm Health, Lahore. (Figure 2). Correspondence: Dr. Muhammad Saeed, Consultant Paediatric His initial laboratory evaluation showed haemoglobin Neurologist, The Children’s Hospital, Al Taif, Post Box 6741, (Hb) of 3.2 gm%, haematocrit (Hct) of 9.6%, reticulocytes Kingdom of Saudi Arabia. of 0.2%, total red cell count of 0.8 million/mm3, mean E-mail: [email protected] corpuscular volume (MCV) of 106 fl, mean corpuscular Received November 11, 2009; accepted March 12, 2010. haemoglobin (MCH) of 30.6 gm, mean corpuscular

Journal of the College of Physicians and Surgeons Pakistan 2010, Vol. 20 (9): 627-628 627 Muhammad Saeed, Muhammad Nasir Rana and Tahir Masood Ahmad

Pure red cell aplasia is a condition characterized by an isolated depletion of marrow erythroblasts and blood reticulocytes.8 Diamond-Black anemia has not been reported previously with JBS in literature. Once the diagnosis of JBS is established, patients with this condition need to be screened for renal anomalies, referral for dental evaluation, monitoring for the development of hypothyroidism and Diabetes.9,10 Early Figure 1: Showing Beak like Figure 2: Showing greenish, loose detection of a constellation of features suggestive of appearance of nose, upsweep frontal stool and Café-au-lait spots on the hair, low set ears and flat philtrum. scrotum. JBS is essential for establishing accurate diagnosis and early management. Variability in the severity of JBS on haemoglobin concentration (MCHC) of 33% and red cell a case to case basis determines the requirements and distribution width of 18.5%. Total white cell count was effectiveness of any treatment. There is no curative 5200/mm3, with 59% polymorphs, 33% lymphocytes, treatment for this disorder except genetic counseling 5% monocytes and 3% eosinophils. Platelets count was and supportive care or symptomatic care along with a 343,000 /mm3, and blood peripheral morphology was multidisciplinary approach. Involving coordinated efforts unremarkable. Bone marrow aspiration revealed of a team of general practitioners, gastroenterologists, erythroid hypoplasia with normal myeloid and mega- cardiologists, endocrinologists, geneticists, neurologists karyocytes series. A diagnosis of primary pure red cell and physical therapists to ensure a systemic and aplasia was made, (Diamond-Blackfan anemia). His comprehensive approach to treatment. serum T3 and T4 levels were 35 ng/dl (normal range 70- 200) and 1.90 ug/dl (normal range 0.3-6.0) respectively REFERENCES while TSH level was 12 u IU/ml (normal range 0.3-6.0). Serum amylase was less than 30 u/l (normal range 30- 1. Johanson A, Blizzard R. A syndrome of congenital aplasia of the 100) and serum lipase 8 u/l (normal range 3-32 u/l). alae nasi, deafness, hypothyroidism, dwarfism, absent permanent teeth, and malabsorption. 1971; 79:982-7. Total serum albumin was 4.0 gm/dl (normal range 4.9- J Pediatr 7.4). Blood sugar was normal. 2. Alpay F, Gul D, Lenk MK, Ogur G. Severe intrauterine growth retardation, aged facial appearance, and congenital heart His echocardiography result revealed atrial septal disease in a newborn with Johanson-Blizzard syndrome. Pediatr defect. CT scan of abdomen was unremarkable and on Cardiol 2000; 21:389-90. audiometery, there was no evidence of sensorineural 3. Kulkarni ML, Shetty SK, Kallambella KS, Kulkarni PM. deafness. Serum folic acid, B12 and erythrocyte Johanson-Blizzard syndrome. Indian J Pediatr 2004; 71:1127-9. adenosine deaminase (ADA) level could not be 4. Rosanowski F, Hoppe U, Hies T, Eysholdt U. Johanson-Blizzard performed because of non-availability of the facility. syndrome. A complex dysplasia syndrome with aplasia of the Based on presumed diagnosis of pancreatic in- nasal alae and inner ear deafness. HNO 1998; 46:876-8. sufficiency, he was given pancreatic enzyme replace- 5. Alkhouri N, Kaplan B, Kay M, Shealy A, Crowe C, Bauhuber S, ment and fat soluble vitamins supplements. After et al. Johanson-Blizzard syndrome with mild phenotypic features confirmation of Diamond-Blackfan anemia, cortico- confirmed by UBR1 gene testing. World J Gastroenterol 2008; steroids were given, at the dose of 2 mg/kg/day in 14:6863-6. divided doses which he tolerated well. A repeat bone 6. Steinbach WJ, Hintz RL. Diabetes mellitus and profound insulin marrow aspiration was done after one month of starting resistance in Johanson-Blizzard syndrome. J Pediatr Endocrinol steroids that showed normal cellularity. Metab 2000; 13:1633-6. 7. Takahashi T, Fujishima M, Tsuchida S, Enoki M, Takada G. DISCUSSION Johanson-Blizzard syndrome: loss of glucagon secretion response to insulin-induced hypoglycemia. JBS is a rare autosomal recessive multisystem disorder J Pediatr Endocrinol 2004; 17:1141-4. and primary and the most prominent feature is exocrine Metab pancreatic insufficiency. Pancreatic hypoplasia resulting 8. Freedman MH. Diamond-Blackfan anemia. Baillieres Best Pract Res 2000; 13:391-406. in exocrine insufficiency and malabsorption is thought to Clin Haematol be responsible for growth failure. Since the initial 9. Vlachos A, Kleim GW, Lipton JM. The Diamond-Blackfan anemia registry: tool for investigating the epidemiology and description of JBS in 1971, more than 60 cases have biology of Diamond-Blackfan anemia. J Pediatr Hematol Oncol 2001; been reported.4 Endocrine dysfunction of the pancreas 23:377-82. has been observed in JBS and it is suggested that 10. Zenker M, Mayerle J, Reis A, Lerch MM. Genetic basis and Diabetes should be considered as a complications of pancreatic biology of Johanson-Blizzard syndrome. Endocrinol JBS.6,7 Metab Clin North Am 2006; 35:243-53,vii-viii.

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