Johanson–Blizzard's Syndrome with a Novel UBR1 Mutation

Abstract

Johanson–Blizzard syndrome (JBS) is a rare autosomal recessive genetic disorder, characterized by exocrine pancreatic insufficiency, a distinct abnormal facial appearance and varying degrees of growth retardation. Ubiquitin protein ligase E3 component n-recognin 1 ( UBR1 ) gene mutations are responsible for the syndrome. Here, we describe a 2-month-old female infant, who presented with oily diarrhea, facial dysmorphia, scalp defect, hearing defects, and growth impairment. Molecular genetic testing revealed a novel frameshift mutation in UBR1 , c.4027_4028 del (p.Leu1343Valfs*7), which was not previously described in JBS in the literature.

Introduction

Johanson–Blizzard's syndrome (JBS) (MIM #243800) is a rare autosomal recessive inherited congenital disorder first described in 1971 by Ann Johnson and Robert Blizzard. ¹ Since then, only ∼70 patients have been reported in the literature. ² JBS occurs because of the defect of ubiquitin protein ligase E3 component n-recognin 1 ( UBR1 ), which is mapped to chromosome 15q15–21. UBR1 controls cellular proliferation, differentiation, and apoptosis, and it is an important component of the N-end rule pathway and the leucine-mammalian target of rapamycin signaling pathway. ^{1 3} JBS has a wide spectrum of clinical presentations. Exocrine pancreatic insufficiency is the most common finding of the syndrome. Other characteristic features of the syndrome include facial dysmorphia with a small beak-like nose, scalp defects, sensorineural hearing loss, hypothyroidism, varying degrees of mental retardation, and growth failure. The severity of clinical presentation may vary from case to case. ¹

In this study, we report a 2-month-old JBS case with a novel frameshift mutation in the UBR1 gene, which has not been previously described in the literature. She had a dysmorphic facial appearance, congenital aplasia cutis as a scalp defect, and diarrhea for the last month, indicating exocrine pancreatic insufficiency.

Case Presentation

A 2-month-old female infant presented with redness on the scalp and an abnormal facial appearance. The parents reported that she had these complaints since her first day of life. She also had increased stool frequency for the last month. She was born to consanguineous parents (second-degree cousins) and had a birth weight of 2,750 g (3–10%), height of 45 cm (< 3%), and head circumference of 33 cm (10–25%) at term. She was the third child of the family, but the other children had no similar symptoms. No abnormalities were found during the prenatal visits.

On admission at 2 months, her weight was 3,040 g, height was 48 cm, and head circumference was 35 cm. All her anthropometric measurements at 2 months were below the fifth percentile for the normal population. Upon dermatologic examination, dysmorphic facial features such as a wide forehead, sparse eyebrows, upslanting palpebral fissures, mild hypoplasia of the nasal alae, and a thin upper lip were observed ( Fig. 1 ). An erythematous patch lesion was also noted on the right side of the vertex. Upon dermoscopic examination, scar formation and the absence of hair follicles were observed on this patch, and thus, the diagnosis of aplasia cutis was made ( Fig. 2 ).

Fig. 1.

(A,B) Dysmorphic facial features: wide forehead, sparse eyebrows, upslanting palpebral fissures, mild hypoplasia of the nasal alae, and thin upper lip.

Fig. 2.

Erythematous scar tissue and absence of hair follicles on this patch, consistent with aplasia cutis congenita.

The patient was evaluated together with the department of pediatrics and pediatrics gastroenterology. Laboratory tests revealed low levels of serum albumin (2.4 g/dL; normal range: 3.5–5.0 g/dL) and total protein (4.6 g/dL, normal range: 6.5–8.5 g/dL). Other laboratory tests, including thyroid functions, hepatic and renal functions, and pancreatic enzymes, were within the normal limits. Steatocrit results were positive in stool analysis, while fecal parasites, sugar, occult blood, and giardia antigens were negative. Fecal elastase levels were 18 μg/g (below 100 indicates pancreatic insufficiency). Transfontanelle ultrasound, abdominal ultrasound, and echocardiography results were within the normal limits, and the results of the autoacoustic emission test were consistent with sensorineural hearing loss.

After all system examinations, the diagnoses of exocrine pancreas insufficiency, regressed development, aplasia of lacrimal puncta, and aplasia cutis were established. An audiologic test was planned.

On the basis of the clinical and laboratory findings, we considered JBS in the diagnosis. Molecular genetic analysis of the UBR1 gene to confirm the diagnosis was performed through next-generation sequencing on Illumina MiSeq (v1.9) platform using the virtual panel for skeletal dysplasia consisting of 130 genes. A novel homozygous frameshift mutation c.4027_4028 del (p.Leu1343Valfs*7) in UBR1 (NM_174916.2) was identified and confirmed by Sanger sequencing in the patient. Segregation within the family showed that both parents were heterozygous carriers of the same mutation ( Fig. 3 ). None of the parents had any related phenotypes.

Fig. 3.

UBR1 gene mutations in our patient and her parents (the father and the mother showing heterozygous mutation, and the patient showing homozygous).

The diagnosis of JBS was established. Pancreatic enzyme replacement therapy and fat-soluble vitamins were started. The patient will be followed up by a pediatrician and a pediatric gastroenterologist. Written consent was obtained from the patient's mother, as the legal guardian of the patient, for the publication of this case report and for any accompanying images.

Discussion

JBS is a rare autosomal recessive multisystem disorder with a broad spectrum of clinical findings. The characteristic abnormalities in JBS include exocrine pancreatic insufficiency; a typical facial appearance such as a small beak-like nose, caused by aplasia or hypoplasia of the nasal alae, a long and narrow upper lip, and a small pointed chin; dental abnormalities; hair abnormalities; scalp defects; sensorineural hearing loss; urogenital and anorectal anomalies; and impaired growth and retarded cognitive development to a variable degree. ⁴

Mutations in the UBR1 gene, which is located on chromosome 15q15-q21.1, have been described as the genetic basis of JBS. ^{3 4} The UBR1 protein encodes one of at least four E3 ubiquitin ligases, which are part of the N-end rule pathway. This pathway is an intracellular proteolytic pathway that contributes to the degradation of many intercellular proteins and various basic biological functions, including oxygen sensing, regulation of DNA repair, signaling by G proteins, metabolic regulation, apoptosis, meiosis, spermatogenesis, neurogenesis, and organ development and functioning. However, its biological functions are not fully demonstrated. ^{5 6} This protein is widely expressed in the skeletal muscle, kidneys, and pancreas (mainly in the acinar cells). UBR1 deficiency in JBS patients leads to the destruction of the mentioned tissues, resulting in the clinical manifestations of JBS. ⁷

In the original report, describing UBR1 mutations in JBS, truncating (57%) and splicing (29%) mutations were the most common mutations followed by missense ones. ³ In 2014, Sukalo et al reported that 21 of 60 published mutations (35%) were missense or small in-frame deletions. ⁸ Later in 2015, Atik et al ⁹ reported a case of JBS carrying compound heterozygous mutations in UBR1 gene. These were described affecting the transcript NM_174916, and were a maternally inherited splice site mutation IVS22 + 5GNC (c.2432 + 5G > C) and a paternally inherited missense mutation p. L427R (c.1280T > G). These alterations have been rated as pathogenic by various online prediction tools (MutationTaster, PolyPhen-2, BDGP, and NetGene2).

In 2017, Sukalo et al ¹⁰ studied 65 unrelated JBS-affected families. They reported that mutations in 93.1% of all UBR1 alleles (121 of 130) were detected by Sanger sequencing of coding exons and flanking intronic regions (± 20 bp). Mutations included 37 nonsense, 30 splice site, 32 missense, and 19 frameshift mutations, as well as 3 small in-frame deletions. In nine UBR1 alleles, no mutations were detected by Sanger sequencing. ¹⁰

In 2020, the first case of JBS in the Chinese population, who was a 3-year-old Chinese boy, presented with growth failure, hereditary pancreatitis, and facial dysmorphia was reported. Here, whole exome sequencing of this patient revealed two rare compound heterozygous variants in heterozygous state in the UBR1 gene. These variants, c.2511T > G (p.H837Q) and c.1188T > G (p.Y396X) in exon 23 and 11 on both alleles, were inherited from his father and mother, respectively. ¹⁰

Our patient presented with pancreatic insufficiency, nasal alae hypoplasia, poor growth, aplasia cutis as a scalp defect, deafness, and facial dysmorphia, which are the typical clinical features of JBS. Genetic testing was performed with the suspicion of JBS. A novel deleterious frameshift mutation in the UBR1 gene, c.4027_4028 del (p.Leu1343Valfs*7), was identified in the homozygous state in our patient, and the same mutation was shown to be carried by both parents in the heterozygous state.

Deleterious (nonsense, frameshift, or splice-site) mutations in the UBR1 gene are considered to cause severe presentation of JBS because they completely inhibit the expression of a functional protein product, ^{3 7 11 12} as seen in our patient. The genotype–phenotype correlation is considered to determine the clinical presentation of the disorder. ⁷ By identifying the responsible mutations, the clinical course of the syndrome could be revealed. We believe that a molecular genetic analysis should be performed even though the diagnosis could be clinically made.

Since the first reported JBS case in 1971, more than 70 additional cases have been presented, ^{2 3 4} majority of which were children presenting with pancreatic insufficiency, abnormal facial features, and mental retardation of varying degrees. ²

In this study, we present a 2-month-old female infant with JBS with a novel frameshift mutation in the UBR1 gene manifesting with a typical dysmorphic facial appearance, aplasia cutis, exocrine pancreas insufficiency, hearing loss, and retarded growth.

Conclusion

JBS, a very rare genetic syndrome, may be overlooked in the differential diagnosis of the described symptoms. Genetic testing may be crucial to make the diagnosis and identify the mutations that may determine the clinical severity of the disorder. We believe that prenatal diagnosis could be performed by identifying the UBR1 gene variants using available technology. A careful physical examination is necessary to provide an accurate and early diagnosis of such a rare syndrome for a favorable outcome.

Funding Statement

Funding None.