Johanson-Blizzard syndrome (MIM2G3800) is a rare, autosomal recessive genetic condition with a characteristic ‘diagnostic facies’. We present an Indian infant with this condition.

A 12-day-old female newborn was referred for Genetics consultation for her unusal facies and congenital heart defect. She was the first born to 3rd degree consanguineous parents without any family history of major medical or genetic disorders, except for well-controlled maternal hypothyroidism. She was born normally at term with a birthweight of 2.45 kg and suffered from a secondary apnea requiring resuscitation followed by feeding difficulties and poor weight gain.

Fig. 1 Patient at age of 12 days: Characteristic facies with beaked nose, hypoplastic alae nasi, long philtrum with thin upper lip and frontal hirsutism with upsweep of hair.

On review at 7 months of age, pancreatic insufficiency with excess fat globules in stool sample and hypothyroidism had been diagnosed. She was receiving thyroxin supplement and pancreatic supplements for malabsorption secondary to pancreatic insufficiency with some improvement in weight (6.1 kg). She was prescribed bilateral hearing aids and regular physiotherapy with early intervention program for her developmental delay. Parents reported repeated hospital admissions for recurrent respiratory infections.

DNA from peripheral blood was extracted using standard method. All 47 exons including the flanking intron regions of UBR1 gene were amplified by PCR. PCR amplicons were purified and subjected to direct sequencing using an automated sequencer. Sequences were compared to the reference sequences deposited in the public database (NM_174916).

Homozygosity for a nucleotide substitution in intron 4 of the UBR1 gene was found. The identified change c.529-13G>A has not been published, so far, but it was previously discovered in our laboratory in patient of Hispanic origin with the syndrome. The G to A substitution was demonstrated to introduce an ectopic splice site 11 base pairs upstream of the authentic splice acceptor of exon 5, thus leading to a shift of the reading frame (p.N177Lfs*10) (Fig. 2 ). This change can therefore be assumed to represent a disease-causing mutation.

Fig. 2 Electropherograms derived from gDNA and cDNA sequencing.

JBS in its typical expression can be diagnosed at birth with its characteristic facies. Ultrasound-based prenatal diagnosis has been reported previously [4,5] suspected by a beak-like nose and a dilated sigmoid colon suggestive of imperforate anus at 21 weeks of gestation. No such prenatal ultrasound features were detected in our patient and ultrasound may not be the best modality to make a specific diagnosis of JBS especially in absence of a family history.

Patients with JBS need long-term care including management of pancreatic insufficiency and hypothyroidism, treatment of frequent respiratory infections, management of hearing loss, physiotherapy and educational rehabilitation depending on the intelligence level. Pancreatic insufficiency and severe hypoproteinemia may lead to death in infancy or early childhood, but for patients managed appropriately, survival into adulthood is not rare.

UBR1 gene located on chromosome 15q15.2 is currently the only gene associated with JBS. It encodes E3 ubiquitin ligase of the N-end rule pathway which is an ubiquitin (Ub) dependent proteolytic pathway. UBR1 is essential in the development and maintenance of acinar cells and in-utero destruction of acinar tissue followed by fatty replacement as well as eventual progression to endocrine deficiency leading to diabetes in older children has been previously reported [7-9].

Most patients have biallelic mutations predicting complete loss of function while cases with missense mutations or small in-frame deletions proposed to be hypomorphic mutations have been described with somewhat milder phenotypes and normal intelligence [3]. Our patient has an intronic mutation close to but not directly affecting the splice acceptor site of exon 5. We could demonstrate that this alteration creates an ectopic splice site resulting in an inclusion of 11 nucleotides from intron 4 into the coding sequence; those 11 additional base pairs cause a frameshift that lead to a premature stop codon (p.N177Lfs*10). No evidence of a normally spliced transcript could be found by RNA analysis. We therefore presume that this mutation leads to a complete or near-complete loss of function which is in line with the classical JBS phenotype seen in this girl.

It is important for pediatricians to consider molecular testing of UBR1 gene not only for the confirmation of diagnosis in the affected child but also for confirming carrier status in both parents and to offer appropriate counseling to the family.

Contributors:　KG and LH were involved in the diagnosis and management writing the manuscript. MS and MZ performed laboratory analysis, critically reviewed the manuscript and also helped in writing it. The final manuscript was approved by all authors.

Funding: None; Competing interests: None stated.

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