Johanson Blizzard Syndrome

Introduction

Johanson Blizzard Syndrome (JBS) was first described in 1971 by Johanson and Blizzard.¹ Thereafter around 100 cases were reported. The genetic defect is caused by compound heterozygous or homozygous mutations in UBR1 gene on chromosome 15. The gene product is a ligase which functions in Ubiquitin‐mediated intracellular protein degradation and regulating cell growth.1 Maximum UBR1 expression is seen in pancreatic acinar cells and skeletal muscle.² Although the syndrome has particularly distinct phenotypic features, genotypic variations described as UBR1 gene are widely expressed and variably mutated.³

Case Presentation

A three-month-old male child born of non-consanguineous marriage presented with failure to thrive. Child was delivered at term with a low birth weight of 1.8 kg. There was no significant perinatal history except for hyperbilirubinemia. Thereafter child was on exclusive breast feeding; however mother complained of poor activity and inadequate weight gain. 

On examination, the child showed tachycardia, pallor, pedal edema, abdominal distension, and systolic murmur. Child was afebrile, lethargic and hypotonic. Sucking and deep tendon reflexes were normal. Child had distinct dysmorphic features like small beaked nose, upswept frontal hairline, hypoplastic alae nasi, long narrow upper lip and upslanted palpebral fissure (Figure 2). Growth parameters were all < -3SD: weight 1.8 kg, length 49 cms, HC 34 cm. Jaundice, organomegaly were not present and rest of systemic examination was normal. Sepsis screen was negative. Mother’s HIV Elisa and VDRL were normal. Investigations revealed evidence of hypothyroidism, hypoproteinaemia, iron deficiency and malabsorption (Table 1).

The differential diagnosis included cystic fibrosis, Shwachman diamond syndrome, Johanson Blizzard syndrome, Protein losing enteropathy and congenital lymphangiectasia. Due to specific dysmorphism, we suspected Johanson-Blizzard syndrome and advised genetic studies.

Child was started on nutritional rehabilitation- frequent breast feeding, oral medium chain triglycerides and Human Milk Fortifier (HMF) sachet. Thyroxine (25 mcgm/day) was started. Packed red blood cell (PRBC) transfusion was given for symptomatic anemia. Next generation sequencing identified two heterozygous mutations in the UBR1 gene. Pancreatic enzyme supplements were started after which child showed weight gain (weight 2.3 kg). Child was advised regular follow ups for growth and developmental assessment. Parents were informed and counselled about the risk of 25% for developing JBS in subsequent pregnancies.

Genetic studies

DNA from peripheral blood was extracted using standard method.

All 47 exons including the intron regions of UBR1 gene were amplified by polymerase chain reaction (PCR). These amplicons were purified and subjected to direct sequencing. Sequences were then compared to the reference sequences deposited in the public database (NM_174916). Two different heterozygous mutations were identified.

a) A heterozygous nonsense mutation in exon 17 of the UBR1 gene (chr15;43330001C>T; Depth: 239x) that results in a stop codon and premature truncation of the protein at codon 664 (p.Trp664Ter) was detected. This variant has a minor allele frequency of 0.0008% in the ExAC database. The in silico predictions of the variant are damaging by LRT and MutationTaster 2.

b) A heterozygous missense variation in exon 26 of the UBR1 gene (chr15:43314986A>G; Depth: 51x) which results in the substitution of amino acid Proline for Leucine at codon 918 (p.Leu918Pro) was detected. This observed variant has not been reported in the 1000 genomes, ExAC and our internal databases. The in silico predictions of the variant are possibly damaging by PolyPhen-2 (HumDiv), and damaging by Scale-Invariant Feature Transform (SIFT), likelihood ratio test (LRT) and MutationTaster 2.

Discussion

Most common genetic causes of exocrine pancreatic insufficiency are cystic fibrosis and Shwachman Diamond syndrome. Our patient presented with infantile malabsorption and hypothyroidism. Stool texture was greasy intermittently. Around 10% infants commonly have partial steatorrhea till six months age.¹ Child did not have bulky stools. There were no skeletal anomalies, cyclical neutropenia or pulmonary infections. We conducted targeted gene mutation studies as the child presented with distinct facial dysmorphism resembling JBS.^1,2 Pancreatic hypoplasia causing malabsorption is responsible for growth failure in JBS.³ Over time, almost entire pancreas is replaced with fibrofatty tissue.⁴ Older children develop diabetes mellitus due to endocrine pancreatic dysfunction.⁴ The destruction of pancreatic cells may begin in utero. ⁴

Survival into adulthood with this syndrome is not rare with meticulous dietary management and lifelong pancreatic enzyme replacement therapy. Anemia is multifactorial in JBS with malabsorption of nutrients, hypothyroidism, pure red cell aplasia and Diamond blackfan anemia that can occur in such cases.5,6 Children with transfusion dependency need bone marrow studies for further evaluation.6 Our patient showed two novel mutations that were not previously described in medical literature. Exon 17 mutation results in a stop codon and has been previously reported only as a minor allele in EXaC database.7 The Exon 26 mutation resulting in amino acid substitution has not been described. Hence it can be concluded that these mutations lead to partial or complete loss of protein function resulting in the classical JBS phenotype seen in this infant.

Financial support

Nil

Conflict of interest

Nil

Acknowledgments

We thank the parents for their willingness for genetic testing and kind cooperation.