Johanson-Blizzard Syndrome

Autosomal recessive malformation syndrome with congenital exocrine pancreatic insufficiency, hypoplasia or aplasia of the nasal alae and oligodontia, caused by biallelic loss of function of the E3 ubiquitin ligase UBR1.

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Original description and clinical delineation

In 1971, the paediatricians Ann J. Johanson and Robert M. Blizzard published in the Journal of Pediatrics the description of a syndrome of congenital aplasia of the alae nasi, deafness, hypothyroidism, dwarfism, absent permanent teeth and malabsorption, based on three unrelated girls, to whom they added a fourth case identified in the earlier literature [1, 10, 24, 25]. The following year, Park and colleagues, from the same group, documented urogenital anomalies in these patients, including double vagina and uterus [1]. The combination brings together elements of ectodermal dysplasia (hair, teeth, scalp) with endocrine and exocrine insufficiency and with growth and developmental impairment, which explains why the syndrome has been addressed simultaneously by dysmorphology, paediatric gastroenterology and endocrinology [10].

The mode of inheritance was initially debated. In 1976, Konigsmark and Gorlin considered X-linked dominant inheritance with male lethality, because most known patients were female and one case occurred in an XXY male [1]. The consanguineous Saudi family of Mardini and colleagues (1978), with three affected members of both sexes, and the consanguinity described by other authors established autosomal recessive inheritance [1, 26]. In 1979, Daentl and colleagues published the first autopsy, of a boy who died at 8 years from complications of pancreatic insufficiency: the pancreas was almost entirely replaced by adipose tissue, the thyroid was small and filled with colloid, and the brain, of normal size, showed anomalies of gyral formation and of cortical neuronal organisation [27]. A second complete autopsy, in 1987, showed no malformation of the central nervous system, and several reports documented normal or even high intelligence, which dispelled the idea that intellectual disability was obligatory [28–30].

The review by Gershoni-Baruch and colleagues (1990) brought together 26 published patients and reinterpreted as JBS older cases described as "trypsinogen deficiency", an XXY male with pancreatic insufficiency, hypothyroidism and deafness published by Grand and colleagues in 1966, and two siblings with hypoplasia of the exocrine pancreas described in 1952 [1, 31]. Hurst and Baraitser (1989) found anorectal anomalies, mainly imperforate anus, in 11 of 22 published children [1]. Smith's estimated, in the 2022 edition, fewer than 100 published patients, and the Magdeburg group counted more than 100 in 2017 [10, 14].

1.2. Milestones of molecular discovery

In 2005, Zenker and colleagues mapped the locus by homozygosity in seven families, to a 7.5 cM interval in 15q14-q21.1 (maximum LOD score 4.8), and identified UBR1 variants, mostly truncating, in 12 of 13 families studied [1, 15]. They also showed that the patients' pancreas did not express UBR1 and displayed a destructive pancreatitis of intrauterine onset, and that Ubr1-null mice had exocrine pancreatic insufficiency with impaired stimulus-secretion coupling and greater susceptibility to pancreatic injury [15]. There followed the functional assessment of missense variants in yeast (2011), the mutational update of 50 families with a proposal of minimal clinical criteria (2014), and the demonstration, by multiplex ligation-dependent probe amplification (MLPA), that exon deletions and duplications account for about 4.6% of pathogenic alleles (2017) [14, 32, 33]. In 2013, the EuroGentest network published a clinical utility gene card for JBS [2].

1.3. Nomenclature and definition

JBS (OMIM #243800; ORPHA:2315) is defined as the autosomal recessive disorder caused by biallelic loss-of-function variants in UBR1, characterised by congenital exocrine pancreatic insufficiency, hypoplasia or aplasia of the nasal alae and oligodontia of the permanent dentition, frequently accompanied, with variable frequency, by sensorineural hearing loss, midline scalp defects, hypothyroidism, growth impairment, cognitive impairment, imperforate anus and genitourinary anomalies [1, 14]. The combination of exocrine pancreatic insufficiency with abnormal nasal alae is considered pathognomonic [34, 35]. There are no formal subtypes and no recognised Mendelian allelic disorders; the name "UBR1-related disorder" appears in recent reports, without a nosological status of its own [3]. The syndrome should not be confused with Kaufman oculocerebrofacial syndrome, also caused by an E3 ubiquitin ligase (UBE3B) [36].

2. Molecular Genetics and Pathophysiology

2.1. The UBR1 gene and protein

The UBR1 gene lies at 15q15.2 (GRCh38 15:42,942,897–43,106,038), spans about 161 kb and has 47 exons [7]. The MANE Select transcript (Matched Annotation from NCBI and EMBL-EBI) is NM_174916.3, which encodes the protein NP_777576.1, of 1749 amino acids; much of the literature before 2020 uses version NM_174916.2, with the same numbering of coding positions for the variants normalised here [8, 9, 14]. Expression is ubiquitous, with higher levels in adult skeletal muscle and heart and, in the mouse embryo, in the branchial arches, tail and limb buds [7]. In control pancreas, the protein is located mainly in the cytosol of acinar cells [1].

UBR1 is an E3 ubiquitin ligase and the recognition component (N-recognin) of the N-end rule pathway, now called the N-degron pathway. This pathway relates the half-life of a protein to the identity of its N-terminal residue: through the UBR box and the RING-H2 domain, both zinc fingers, UBR1 binds proteins whose N-terminal residue is basic (arginine, lysine, histidine; type 1 N-degrons) or bulky hydrophobic (type 2) and tags them with ubiquitin chains for degradation by the 26S proteasome [4, 7, 32]. UBR1 spares proteins with an acetylated N-terminus, binds methylated N-degrons and binds leucine, negatively regulating leucine-mTOR signalling [4]. The known physiological substrates of UBR1 in mammals are few: the G-protein regulators RGS4, RGS5 and RGS16, the Rad21 fragment produced by separase, and misfolded proteins [32]. Five enzymes of the Arg/N-degron pathway (NTAQ1, NTAN1, ATE1, UBR1 and UBR2) form a targeting complex [7].

2.2. Functional redundancy and animal models

UBR1 is one of at least four UBR-box E3 ligases with overlapping function, which is thought to explain why its loss damages a limited set of organs rather than being lethal [4, 15]. UBR2, 46 to 47% identical to UBR1 and indistinguishable in N-degron recognition, is retained in patients and is expressed in the exocrine pancreas [32, 37]. Ubr1-/- mice are viable and fertile, with reduced weight due to muscle and adipose tissue; the pancreas responds about 100 times less to cholecystokinin and undergoes more severe necrosis in secretagogue-induced experimental pancreatitis, indicating that the pathway contributes to homeostasis and to the defence of the acinar cell against noxious stimuli [7, 15]. Embryos lacking both Ubr1 and Ubr2 die in mid-gestation with defects of neurogenesis and cardiovascular development, which shows that the two ligases have partly divergent functions [37]. Hypotheses for the human phenotype include a substrate exclusive to UBR1, insufficient efficacy of UBR2 alone in certain cell types, or a degradation-independent function of UBR1, such as protein stabilisation by direct binding, described for UBR2 [32]. Models in Caenorhabditis elegans suggest a disturbance of glutamate metabolism, a hypothesis not yet translated to the clinic [38].

2.3. Pancreatic pathophysiology

In the autopsies of two fetuses (21 and 34 weeks) and one newborn, the loss of acinar tissue increased with gestational age and was accompanied by inflammatory infiltrates, more intense in the term fetus, without increased apoptosis (TUNEL) and without a primary defect of zymogen synthesis (normal trypsinogen on immunohistochemistry) [1, 15]. The main lesion is therefore not an early failure of acinar development, but the progressive destruction of already formed acinar cells, similar to a pancreatitis of intrauterine onset, with impaired apoptosis, necrosis and prominent inflammation [15, 39]. At the autopsy of a 35-week fetus, the pancreas had no acini and showed a resorptive inflammatory reaction with eosinophils that focally involved the islets of Langerhans, which favours a destructive process and may explain the diabetes that appears later [40].

The study of stimulated pancreatic secretion in two patients showed preserved ductal output of fluid and electrolytes, as in Shwachman-Diamond syndrome and unlike cystic fibrosis, and markedly reduced acinar secretion of trypsin, colipase and lipase, with low serum immunoreactive trypsinogen [41]. Ducts and islets are preserved in the early stages, and the defect is selective for acinar tissue [42]. The histological picture is not uniform: in a child with JBS and hypopituitarism who died at 4 years, without clinical exocrine insufficiency, the acini were normal in number but immature in appearance, with extensive periductal fibrosis [43]. This sequence explains the most common imaging finding, fatty replacement (lipomatosis) of the pancreas, sometimes with a pancreas not identifiable on computed tomography (CT) [9, 44].

2.4. Inheritance

JBS is autosomal recessive; patients are homozygous or compound heterozygous [2, 10]. Parental consanguinity is frequent [2, 45]. The parents of a proband are presumed to be heterozygous, but a Czech proband has been described with two de novo variants in trans, neither present in the parents, a situation that alters counselling (section 8) [2, 11].

2.5. Variant spectrum

The spectrum is one of loss of function, without hotspots or common variants, except for a cluster of missense variants in the conserved UBR box [2]. In 2013, 59 variants were known (15 nonsense, 14 splicing, 9 frameshift, 3 in-frame deletions and 18 missense) [2]. In the Magdeburg/Erlangen cohort, with 65 unrelated families studied up to November 2016, Sanger sequencing of the coding exons and ±20 bp of intronic sequence identified the variant in 121 of 130 alleles (93.1%): 37 nonsense, 30 splicing, 32 missense, 19 frameshift and 3 small in-frame deletions [14]. MLPA of the 47 exons resolved 6 of the 9 remaining alleles (4.6% of all alleles), raising detection to 97.7% (127/130); 3 alleles (2.3%) in two patients remained unresolved, compatible with promoter variants, deep intronic variants or rearrangements such as inversions [14]. The authors acknowledge a selection bias in favour of copy number changes, because some samples were sent to them after negative sequencing [14]. Most variants are private to each family and, in 2013, no predominant founder alleles were known [2]. The most cited exception is p.(Gln513Ter), homozygous in two Amerindian families from Costa Rica from the same district, with a common haplotype indicating a shared ancestor [7].

The variants in the following table were normalised according to Human Genome Variation Society (HGVS) nomenclature in VariantValidator, on the MANE Select transcript, with the ClinVar classification consulted on the same date. The historical nomenclature (for example, IVS20+2T>C, = NM_174916.3:c.2254+2T>C p.?) is kept in the first column because it is the one used in OMIM and in the original articles [8, 46].

Two nomenclature notes result from this normalisation. The article by Almashraki and colleagues writes the variant as c.2089C>T, a notation that does not match the reference sequence and does not encode p.Ser700Pro; the validated change is c.2098T>C [8, 45]. The copy number changes described by the Magdeburg group follow the uncertain-interval notation, for example c.(4835+1_4836-1)(*1?)del for the deletion of exons 45–47, homozygous deletion of exon 12 in one patient, deletion of exons 26–29 with tandem duplication of exon 30 in another, and deletion of exon 33 in a third [14].

2.6. Genotype-phenotype correlations

Nonsense, frameshift and canonical splice-site variants abolish UBR1 activity and are associated with typical and severe expression [32, 49]. In the literature reviewed by Zenker, the 12 patients with two null variants had pancreatic insufficiency, dental defects and nasal hypoplasia in all assessed cases, deafness in 10 of 11, intellectual disability in 8 of 8 and imperforate anus in 6 of 12 [32]. Missense variants and small in-frame deletions are associated with milder physical anomalies and normal intellectual ability, suggesting hypomorphic alleles [2, 33]. The yeast model supports this interpretation: the equivalent in Saccharomyces cerevisiae Ubr1 (yeast protein numbering, not human) of p.(His136Arg) (H160R) was inactive, that of p.(Gln1102Glu) (Q1224E) had weak activity and that of p.(Val122Leu) (V146L) retained reduced but significant activity, in agreement with the clinical severity of the three patients [32]. The intronic variant c.2839+5G>A, which allows some normal mRNA, produced mild forms in two families [47]. The correlation is, however, only a trend: the clinical utility card warns that it cannot be concluded that missense variants always lead to less severe expression, the H136R variant is associated with a severe picture, and genotype-based predictions of severity are very limited [2, 32].

2.7. Penetrance, expressivity and modifiers

Penetrance is complete and, in all cases known to the Magdeburg group, signs were present from birth [2]. Expressivity is highly variable, more between families than within them [2], but there are sibships with discordant course: opposite-sex twins homozygous for p.(Gln1228Ter), of whom the girl died at 3 months with refractory diarrhoea and the boy reached adolescence with nutritional support and PERT [49]; a sibling with a lethal form in a triplet delivery and an older sibling with a less severe form [40]; and Syrian and Yemeni families in which siblings with the same presumed genotype died in the neonatal period or in the first months while the proband survived [3, 25]. Unlinked genetic modifiers, non-genetic factors and chance are invoked, without their contribution being defined [25].

2.8. Allelic disorders and UBR1 in chronic pancreatitis

There is no known allelic Mendelian disorder [4]. The GeneReviews Pancreatitis Overview includes UBR1 among the acinar stress-response genes and attributes to it less than 1% of cases of chronic pancreatitis, with complex inheritance: heterozygous variants would increase risk in people with variants that cause misfolding of acinar zymogens (CPA1, PRSS1, CTRC) [5]. The association data are not concordant: in Japan, UBR1 sequencing in 389 patients with chronic pancreatitis showed no difference in variant frequency compared with controls [6], and in the paediatric INSPPIRE study, with 944 children with acute recurrent or chronic pancreatitis and 14 genes sequenced, none of the 38 variants selected by association was in UBR1 [50]. The interpretation of heterozygous UBR1 variants on pancreatitis panels follows the rules specific to hereditary pancreatitis and genetically determined chronic pancreatitis.

2.9. Locus heterogeneity

There is no evidence of relevant genetic heterogeneity [2]. A Japanese patient with the three major criteria and parental consanguinity had no variant on sequencing or MLPA, was heterozygous at the locus and had normal UBR1 expression in leucocytes, which allows for another gene; if one exists, its contribution is very small [14].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and frequencies

There are no population studies or prospective registries of JBS. The available frequencies come from three types of source, with different denominators and biases: the literature review by Zenker (n = 58, with a variable denominator per sign), the cohort of patients studied molecularly in Magdeburg and Erlangen (79 patients, percentage among those with data), and the estimates in Smith's and in the Orphanet HPO annotations, without an explicit denominator [10, 14, 32, 51]. In the Magdeburg/Erlangen cohort, pancreatic insufficiency, hypoplasia of the nasal alae and oligodontia appear in 100% because they are the criteria that define the cohort, and oligodontia can only be assessed after the age of eruption of the permanent teeth [14].

3.2. Exocrine pancreas

Exocrine pancreatic insufficiency is the most constant manifestation and results from acinar destruction that begins before birth [14, 15]. It usually manifests in infancy with steatorrhoea, diarrhoea, faltering weight gain, hypoproteinaemia and oedema, sometimes with anasarca, and may be severe enough to cause death in the first months when it is not recognised [25, 45, 49, 51]. In the Saudi series of Noli and colleagues, faecal elastase ranged from less than 6.6 to 27 µg/g in the four patients, serum lipase from 4 to 5 U/L (reference 13–60 U/L), and vitamin A was low in the three assessed (174 to 285 µg/L; reference 343–838 µg/L) [9]. Imaging shows lipomatosis or complete fatty replacement of the pancreas [9, 44, 52]. Presentation is not always neonatal: some patients were diagnosed at 5–12 years after years of diarrhoea and suspected cystic fibrosis [9], and a previously asymptomatic patient with ectodermal dysplasia developed sudden exocrine insufficiency in adolescence, as did his identical twin [16, 17]. In isolated cases there was no clinical pancreatic insufficiency [43, 48]. The course is progressive in adulthood [53].

3.3. Endocrine pancreas

Endocrine function is usually preserved in childhood, but continued pancreatic destruction leads to diabetes and to loss of the glucagon response to hypoglycaemia in adolescence and adulthood [10, 25]. Diabetes affected 8% of the Magdeburg/Erlangen cohort; a 37-year-old woman from that cohort had diabetes at 18 years, and Nagashima and colleagues described diabetes at 11 years [1, 14]. The initial cases were controlled with modest insulin doses, but diabetes with profound insulin resistance has been described in a patient without apparent exocrine insufficiency [54]. Absence of the glucagon response to insulin-induced hypoglycaemia was documented in a Japanese infant, suggesting altered autonomic innervation of the islets [55]. The histology of a fetus with eosinophilic inflammation involving the islets provides a basis for late-onset diabetes [40].

3.4. Face, hair and skin

The distinctive facial sign is hypoplasia or aplasia of the nasal alae, which gives the nose a small, "beak-like" or "pinched" appearance, with notching of the alae [10, 45, 56]. The forehead is prominent, with an upswept frontal hair whorl (96% according to Smith's), sparse hair, sometimes stiff, areas of alopecia, and sparse eyelashes and eyebrows [10, 45, 57]. Scalp defects (aplasia cutis) are midline, most often posterior or at the vertex, but also anterior or over the fontanelles, and range from small alopecic scars to larger defects [10, 14, 26]. Other findings described are upslanting palpebral fissures, long philtrum, downturned corners of the mouth, wide anterior fontanelle, prominent scalp veins, micrognathia and café-au-lait macules [10, 48, 58, 59]. Oblique facial clefts (Tessier 2 to 6) represent the severe end of the spectrum, with an estimated frequency of 5 to 10% [35]. Nasal hypoplasia can be quantified by standardised craniofacial morphology scores [60].

3.5. Teeth

The deciduous dentition is hypoplastic, with small, conical, widely spaced teeth, and oligodontia or absence of permanent teeth is one of the three major criteria [10, 14, 27]. Microdontia with persistence of the primary dentition was the dental finding in the Saudi series [9]. Delayed eruption and microdontia appear in the Orphanet annotations [51].

3.6. Hearing

Sensorineural hearing loss affects 69 to 79% of patients and is typically bilateral, severe to profound, although mild forms exist (about 30 dB, not requiring a hearing aid) [14, 32, 61]. It may be congenital, detected by failure of newborn hearing screening, or progressive [14, 61]. CT of the petrous bones showed incomplete partition type II with an enlarged vestibule, absent modiolus and hypoplastic cochlear nerve in one ear, and cystic dilatation of the cochlea with a hypoplastic modiolus in another patient [61, 62]. In an 8-year-old girl, the hearing loss was profound and of bilateral cochlear origin, with normal tympanograms and absent otoacoustic emissions and auditory evoked potentials [63]. Conductive hearing loss due to recurrent otitis with tympanic perforation has also been described [9].

3.7. Eyes and lacrimal pathways

Malformations of the nasolacrimal system are frequent: lacrimocutaneous fistulae (66% according to Smith's), absence of the upper or lower lacrimal puncta and abnormal lacrimation; intraocular malformations, such as eyelid coloboma, cataract or strabismus, are rare [10, 51, 64].

3.8. Thyroid and pituitary

Hypothyroidism affects 30 to 41% of patients, is rarely detected in the neonatal period, may worsen over time and, unusually, is not accompanied by raised cholesterol, which Smith's attributes to the concomitant malabsorption [10, 14]. There are congenital cases and subclinical cases [59, 65]. In the Saudi series, one patient had a TSH of 8.3 mU/L with normal free T4 [9]. The thyroid may be small and filled with colloid at autopsy [27]. Growth hormone (GH) deficiency and hypopituitarism have been documented in several patients, including an autopsy with a small, undescended pituitary, with a glial hamartoma and scant adenohypophyseal tissue [43, 55, 66, 67].

3.9. Growth

Growth deficiency has a prenatal onset in about a quarter to 60% of patients and is multifactorial: malabsorption, hypothyroidism, GH deficiency in some, and an intrinsic component [10, 14, 66]. Newborns with extreme restriction, weighing 2 kg at term, and infants weighing 2.5–3.3 kg at 5–6 months have been described [9, 25, 45, 59]. Growth may improve with thyroxine, pancreatic enzymes and fat-soluble vitamins, but a child with neonatal diagnosis and early replacement grew poorly until treated with GH [10, 66].

3.10. Neurodevelopment and behaviour

Cognitive impairment affects about two thirds of patients and ranges from mild to severe; hypotonia and motor delay are frequent [10, 14, 32]. Normal intelligence is well documented, including a Saudi series of four patients without intellectual disability and a boy of high intelligence [9, 28, 30, 68]. Untreated hearing loss contributes to language delay [61]. Neuropathological studies are discordant: cortical changes at one autopsy and a brain without cytoarchitectural abnormalities at another [27, 29]. Severe obsessive-compulsive disorder and aggressive behaviour have been described in an adult [69].

3.11. Anorectal and genitourinary anomalies

Imperforate or anteriorly placed anus affects 21 to 40% of patients, with a rectourethral or rectovaginal fistula in about 18% [10, 14]. Genitourinary anomalies include caliectasis to hydronephrosis, vesicoureteric reflux, septate or double vagina, uterus didelphys, persistent urogenital sinus, urethral duplication, dysplastic kidneys, cryptorchidism, micropenis and hypospadias [10, 70, 71]. The urethral obstruction sequence and cystic renal dysplasia have been described in a fetus [40].

3.12. Heart

Congenital heart disease affects 28% of the Magdeburg/Erlangen cohort: atrial and ventricular septal defects, patent ductus arteriosus, myxomatous mitral valve, dextrocardia and complex heart defects [14, 45, 71]. Dilated cardiomyopathy has been described in a patient with a mild form and in severely affected infants from Syrian and Yemeni families [3, 25, 47]. Situs inversus totalis, with intestinal malrotation and lethal heart disease, has been described in a newborn [1].

3.13. Liver, blood and other systems

Liver involvement is rare and of uncertain causal relationship: neonatal cholestasis (Smith's), hepatitis in an Indian case and, in a Saudi infant without pancreatic insufficiency, cholestasis with giant hepatocytes and ductopenia progressing to advanced fibrosis and portal hypertension; the liver of Ubr1-/- mice was normal [1, 10, 48, 72]. Anaemia, frequent in the Orphanet annotations, is generally nutritional or multifactorial, due to malabsorption of iron, folate and cobalamin and to hypothyroidism; pancytopenia due to severe cobalamin deficiency and an infant with transfusion-dependent anaemia and thrombocytopenia with normal marrow, which normalised with treatment, have been described [3, 45, 51, 73]. An association with Diamond-Blackfan anaemia has been reported [10, 74]. In the Saudi series, two siblings had leucopenia and one of them moderate to severe neutropenia, without an established explanation [9]. Other occasional anomalies are arhinencephaly, radiolucent skull defects, small nipples and absent areolae, fifth-finger clinodactyly and single palmar crease [10, 40].

3.14. Natural history and treated disease

The older series and families from low-resource settings show the natural history: death in infancy from refractory diarrhoea, malnutrition, hypoalbuminaemia, anaemia and infections, frequently in siblings from consanguineous families [3, 25, 45, 49]. With PERT, vitamins, levothyroxine and auditory rehabilitation, reports describe survival into adolescence and adulthood, normalisation of vitamins, stable growth on low centiles and adapted schooling [9, 14, 49, 65]. There are no comparative data between treated and untreated patients and no survival studies.

4. Clinical Recognition and Red Flags

4.1. When to suspect

Suspicion rests on the combination of exocrine pancreatic insufficiency with hypoplastic or aplastic nasal alae, considered pathognomonic, and is reinforced by sensorineural deafness, midline scalp defect, hypothyroidism and imperforate anus [14, 34]. The signs are present from birth, and the clinical utility card stresses that, in most patients, the picture is distinctive for those familiar with the syndrome [2]. The Oxford Desk Reference recommends that, when faced with a scalp defect, the nasal alae should be examined carefully and hearing should be asked about, and that, if the face suggests JBS, faecal elastase 1 and thyroid function should be requested [56, 75].

4.2. Signs by age and context

4.3. Red flags and emergency signs

Severe infant malnutrition with refractory diarrhoea, hypoalbuminaemia, generalised oedema, dehydration, fluid and electrolyte disturbances (hypokalaemia, hypocalcaemia with tetany), severe anaemia and thrombocytopenia is the main cause of death in the reports and requires hospital admission, fluid, electrolyte and nutritional correction and initiation of PERT [3, 25, 45]. Dilated cardiomyopathy with pericardial effusion was the terminal complication in a 19-month-old child [25]. Imperforate anus requires neonatal surgical assessment, and hypoglycaemia in a patient with diabetes or GH deficiency should bring to mind the loss of the glucagon response [1, 55].

4.4. Newborn screening

There is no newborn screening targeted at JBS. Newborn hearing screening identifies congenital hearing loss, as in the patient of Alwadee and colleagues, who failed screening bilaterally [61]. Screening for congenital hypothyroidism may detect the rare cases with neonatal hypothyroidism, but most appear later [10, 78]. Immunoreactive trypsinogen, used in cystic fibrosis screening, is low in JBS and is not a screening marker for this disorder [41].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

There are no international consensus criteria. The Magdeburg group, based on 61 patients from 50 families, proposed three consistent major criteria and four specific minor criteria [14, 33].

In the young child, oligodontia cannot be assessed, and the patients aged 2.5 months to 4.3 years in the 2017 series were diagnosed on the basis of pancreatic insufficiency and nasal aplasia, supported by minor criteria [14]. The criteria describe the cohort that generated them; therefore, the figure of 100% is not a sensitivity, and forms without pancreatic insufficiency or with late-onset insufficiency would fall outside them [14, 16, 48].

5.2. Assessment of exocrine pancreatic function

Faecal elastase 1 (FE-1) is the first-line test. The 2025 European guideline recommends FE-1 and the 13C-mixed triglyceride breath test (level of evidence 2), does not set a cut-off for insufficiency, notes that the 200 µg/g threshold is the most widely used and recommends measurement in formed stools, because FE-1 gives false positives with low pre-test probability and false negatives with high probability [17]. The American Gastroenterological Association (AGA) update considers values below 100 µg/g good evidence of insufficiency and values between 100 and 200 µg/g indeterminate, in a semi-solid or solid sample, and allows measurement during PERT [79]. The position of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) uses the same ranges and points out that FE-1 varies with age, may fall transiently and performs best at the extremes [80]. In the newborn, FE-1 is low in meconium and normalises by day 3 in term infants and by 2 weeks in those born before 28 weeks [57]. GeneReviews adds that diarrhoea produces false positives and that the test is insensitive to mild insufficiency [5]. The coefficient of fat absorption with a 72-hour stool collection on a 100 g fat diet is more demanding and rarely necessary; direct tests with secretin and cholecystokinin measure secretion but not digestion and should not be used in clinical practice [17, 79]. Imaging does not diagnose insufficiency, but shows fatty replacement of the pancreas [17, 44]. In JBS, serum lipase and trypsinogen are very low, and low immunoreactive trypsinogen indicates the acinar defect [9, 41]. The two guidelines differ on the therapeutic trial: the European guideline accepts the empirical response to PERT as an aid when the diagnosis cannot be established otherwise (level 5), whereas the AGA considers it unreliable for diagnosis [17, 79].

5.3. Systemic assessment after suspicion

The clinical utility card recommends, even when the diagnosis is molecular, stool assessment (fat and elastase), pancreatic imaging by ultrasound or CT, audiometry, thyroid hormones and dental radiography, to establish the extent of the manifestations [2]. The initial assessment also includes growth and development, fat-soluble vitamins (A, D, E, K), echocardiography, renal and bladder ultrasound, anorectal and genital assessment and, when short stature is disproportionate to nutrition, assessment of GH and pituitary function [4, 25, 43]. Brainstem auditory evoked potentials allow hearing to be studied in the infant, and CT or magnetic resonance imaging of the petrous bones guides candidacy for cochlear implantation [4, 61].

5.4. Molecular tests

The current approach involves sequencing UBR1 within an exocrine pancreatic insufficiency or pancreatitis panel, or exome sequencing, as in the recent series from Saudi Arabia, Yemen, China and the Czech Republic [3, 9, 11, 44]. Sequencing of the 47 exons and flanking intronic regions was the reference method, and should be followed by analysis of deletions and duplications (by MLPA, which in 2013 was available only at the Magdeburg centre, with no commercial kit) whenever two variants are not found [2, 10, 14]. If an allele is still missing, mRNA analysis can reveal deep intronic variants, as shown by under-representation of the allele without the missense variant in one patient [2, 14]. Immunohistochemistry with a commercial anti-UBR1 antibody gave presumably artefactual staining in a fetus without protein on Western blot and should not be used for diagnosis until a validated antibody is available [40]. In congenital pancreatic insufficiency, panels should include the genes of the differential diagnosis (SBDS, CFTR, SPINK1, CPA1, CEL and others), and the mitochondrial DNA deletion of Pearson syndrome requires a specific technique [5, 13, 52].

5.5. Performance and limitations of the tests

A negative result does not exclude JBS: structural changes, deep intronic and promoter variants and variants in poorly covered regions escape conventional sequencing, and the exome has variable coverage of some regions [2, 14]. The sources consulted do not describe somatic or germline mosaicism in JBS.

5.6. Reporting and variants of uncertain significance

The report should state the gene, the transcript with its version (NM_174916.3), the HGVS nomenclature of each variant, zygosity, phase (cis or trans, ideally by parental testing) and the classification according to the rules of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [3, 9]. Many missense variants published as causal remain without functional study and with a classification of uncertain significance in ClinVar, such as c.407A>G p.(His136Arg) and c.2075T>C p.(Ile692Thr) [9, 46]. In the three Yemeni siblings homozygous for c.4526T>G p.(Leu1509Arg), classified as of uncertain significance owing to the lack of segregation and functional studies, the diagnosis rested on the typical phenotype [3]. Parental segregation, targeted phenotypic assessment (nasal alae, teeth, hearing, elastase) and, when available, mRNA or protein analysis are the tools for reclassifying these variants [2, 14].

5.7. Prenatal and preimplantation diagnosis

When the familial variants are known, molecular testing allows early prenatal diagnosis and preimplantation genetic testing [2]. The anomaly scan may suggest the disorder through the beak-like nose without alae and dilatation of the colon or sigmoid, as in pregnancies of consanguineous couples at 21 weeks, but the ultrasound sensitivity is not known and expression varies within the family [76, 77].

6. Differential Diagnosis

6.1. Comparative table

6.2. Congenital exocrine pancreatic insufficiency

After cystic fibrosis, Shwachman-Diamond syndrome is the most frequent hereditary cause of exocrine pancreatic insufficiency, with an estimated incidence of 1 in 50,000, and is the closest differential of JBS, because both have a primary acinar defect with pancreatic lipomatosis and preserved ductal function [17, 41]. They are distinguished by the haematological and skeletal abnormalities of Shwachman-Diamond, absent in JBS, and by the course of exocrine function, which tends to improve in Shwachman-Diamond and to progress to endocrine insufficiency in JBS [10, 13]. In a Chinese tertiary centre, two of four infants with pancreatic insufficiency and lipomatosis had JBS and two had Shwachman-Diamond, all identified by sequencing, which shows that imaging does not separate the two disorders [52]. In the Saudi series, two siblings with JBS had leucopenia and one of them moderate to severe neutropenia, a finding that may suggest Shwachman-Diamond and that only genetics resolves [9]. Cystic fibrosis is the most frequent confusion in practice: three of the four Saudi patients were first investigated for cystic fibrosis, without a sweat test, and the diagnosis only emerged with the dysmorphological examination; the ductal defect of cystic fibrosis contrasts with the ductal preservation of JBS and Shwachman-Diamond [9, 25, 41]. Pearson syndrome combines pancreatic insufficiency with sideroblastic anaemia and marrow vacuolisation, and isolated insufficiency due to biallelic loss of SPINK1 has no malformations [5, 13]. The older cases published as "trypsinogen deficiency" with imperforate anus have been reinterpreted as JBS [1, 31].

6.3. Nasal dysmorphism and scalp defects

Hypoplastic nasal alae are part of more than twenty malformation and teratogenic conditions, including oral-facial-digital syndrome type 1, oculodentodigital dysplasia, hypohidrotic ectodermal dysplasia, Hallermann-Streiff syndrome, 22q11.2 microdeletion and methimazole or carbimazole embryopathy [56, 82]. Posterior midline scalp defects are frequent in Adams-Oliver syndrome, Curry-Jones syndrome, 4p deletion, Finlay-Marks syndrome, trisomy 13 and JBS, and the frontal hair whorl is shared with trisomy 13, FG syndrome, Rubinstein-Taybi syndrome and aminopterin or methotrexate embryopathy [81]. In practice, the presence of pancreatic insufficiency or low faecal elastase separates JBS from all these diagnoses [75].

6.4. Kaufman syndrome and other syndromes of the ubiquitin-proteasome system

Kaufman oculocerebrofacial syndrome, due to loss of function of UBE3B, shares with JBS the loss of an E3 ubiquitin ligase, growth deficiency, intellectual disability and microcephaly, but has neither pancreatic insufficiency nor nasal aplasia [36].

7. Treatments and Risk Management Strategies

7.1. Framework and source of the recommendations

There is no JBS-specific management guideline and no dedicated GeneReviews chapter, and there are no controlled trials of any intervention in this disorder [4, 20]. Management is replacement and supportive, organised by organ deficits. The recommendations in this article derive from guidelines for analogous conditions, with the extrapolation declared at each point: the 2025 European guideline on exocrine pancreatic insufficiency, endorsed by United European Gastroenterology (UEG), the European Pancreatic Club (EPC), the European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), among others, which expressly mentions JBS; the cystic fibrosis (CF) nutrition guidelines of ESPEN, ESPGHAN and the European Cystic Fibrosis Society (ECFS); the NASPGHAN position on paediatric chronic pancreatitis; the AGA update; and the 2020–2021 European consensus on congenital hypothyroidism [17, 78–80, 83]. Coordination by a multidisciplinary team (paediatric gastroenterology and nutrition, endocrinology, otorhinolaryngology and audiology, genetics, paediatric surgery, dentistry, developmental paediatrics) is the rule in all reports [9, 25, 65].

7.2. Pancreatic enzyme replacement therapy

7.2.1. Indication, medicinal product and mechanism

Exocrine pancreatic insufficiency should always be treated (European guideline, level of evidence 1), and PERT improves fat and protein absorption, weight, nutritional status, symptoms and quality of life [17]. The first-line medicinal product is pancreatin (name in the European Pharmacopoeia and used by INFARMED) or pancrelipase (US name), an extract of porcine pancreas containing lipase, protease and amylase, which replaces the enzymes that the destroyed acinar pancreas no longer secretes [17–19]. The preferred preparations are gastro-resistant microspheres smaller than 2 mm, whose enteric coating dissolves at a pH of 5.5 or above in the duodenum; patients should be informed of the porcine origin, and a non-porcine preparation failed its primary endpoint in a phase III trial [17]. The dose is expressed in lipase units: USP units on US labels and European Pharmacopoeia (Ph. Eur.) units in the Portuguese SmPC [18, 19]. Use in JBS is within the approved indication, because the US labels indicate the treatment of exocrine pancreatic insufficiency in adults and children without restriction of cause, and the Kreon® SmPC indicates exocrine pancreatic insufficiency "often associated with, but not limited to" a list of conditions that includes Shwachman-Diamond syndrome [18, 19, 84].

7.2.2. Doses

There are no published doses for JBS; the paediatric doses of the guidelines on exocrine pancreatic insufficiency and cystic fibrosis are used (extrapolation). The reference is the guideline dose; the label doses are shown alongside for comparison [17, 80, 83].

The differences are of degree. The maximum per meal is 2500 U/kg in the ESPEN, ESPGHAN and ECFS guideline and in the North American label, and 3000 U/kg in the NASPGHAN position; the limit of 10,000 U/kg/day is common to all sources, and the US label allows higher doses only if efficacy is documented by faecal fat or improvement in malabsorption [18, 80, 83]. For the infant, the 2025 European guideline proposes 5000 U per feed, above the 2000–4000 U per 120 mL of the 2016 guideline and the 3000 U per 120 mL of the label; both guidelines acknowledge that the infant dose rests on consensus owing to lack of data [17, 18, 83]. The European guideline notes that there are no dose-comparison trials and that the starting dose aims to deliver to the duodenum about 10% of the physiologically secreted lipase; GeneReviews estimates that secretion at 750,000 to 1,000,000 USP units per meal and about 70,000 to 80,000 USP units per meal for a 70 kg adult with complete insufficiency, noting that older articles used international units (1 IU = 3 USP units) [5, 17]. In the JBS reports, the doses used were about 2000 U of lipase per 120 mL of milk in a Syrian infant, one 10,000 U Creon® capsule with each of four meals in an 11 kg Saudi child (about 900 U/kg/meal), and two to four 10,000 U capsules per meal in adolescents [9, 25].

7.2.3. Administration

The enzymes are taken with meals and snacks containing fat, protein or polysaccharides; spreading them throughout the meal was the regimen with the highest proportion of normalised fat digestion (63%) in a small crossover trial, compared with 50% before and 54% after the meal [17]. Capsules are swallowed whole; when this is not possible, they are opened and the microspheres mixed with a small amount of acidic food (apple purée, banana, plain yoghurt, apple, orange or pineapple juice), with a pH below 4.5 according to the North American label and below 5.5 according to the Portuguese SmPC, taken immediately, without crushing or chewing and without leaving microspheres in the mouth [18, 19]. In the infant, the microspheres are given on a spoon with a little breast milk or formula, or with acidic purée; they are never added to the bottle; if the infant refuses them, uncoated powder may be used temporarily, ideally with a proton pump inhibitor (PPI) to prevent acid inactivation [17, 83]. In enteral nutrition, the enzymes are given as a bolus via the tube and not mixed with the formula; in-line lipase cartridges are used with one cartridge for the first 500 mL and a second up to 1000 mL (maximum of two per feed) [17, 80, 83]. Adequate hydration reduces the risk of constipation [19].

7.2.4. Monitoring and inadequate response

Success is defined by resolution of symptoms and nutritional deficits (level of evidence 5) [17]. In cystic fibrosis, which serves as the paediatric model, growth and nutritional status are assessed at every visit in the infant (monthly), every 3 months in the child and adolescent and every 6 months in the adult [17, 83]. In the event of an inadequate response, adherence and administration technique are checked, the dose is increased stepwise (the European guideline allows doubling or tripling the starting dose, with no defined maximum in the adult, while in children the maxima in table 7.2.2 are maintained) and/or a PPI is added, and other causes of malabsorption are excluded, such as bacterial overgrowth, coeliac disease, giardiasis or food intolerances [17, 18, 83]. Fibre restriction may help if symptoms persist, and the diet should be as normal as possible, without routine fat restriction, with follow-up by an experienced dietitian [17, 80]. In JBS, an elemental formula improved the diarrhoea of an infant before the pancreatic insufficiency was treated, and high-calorie, high-protein formulas were used in the Saudi series [9, 25]. Faecal elastase can be measured during PERT, which allows pancreatic function to be reassessed without stopping treatment [5, 79].

7.2.5. Adverse effects and precautions

PERT is not associated with major adverse effects, and most symptoms reported in the trials are similar to those with placebo (European guideline, level 1) [17]. Fibrosing colonopathy, a serious and rare complication, has been associated with high and prolonged doses in children with cystic fibrosis; the North American label refers to colonic strictures in children under 12 years receiving more than 6000 U/kg/meal and recommends close surveillance above that value, and the Portuguese SmPC recommends assessing new abdominal symptoms especially above 10,000 U/kg/day [17–19]. Other risks are irritation of the oral mucosa when the microspheres are crushed or remain in the mouth, hyperuricaemia and hyperuricosuria with high doses (caution in gout, hyperuricaemia or renal impairment), hypersensitivity reactions to porcine proteins and the theoretical risk of viral transmission; the Portuguese SmPC draws attention to the possibility of hepatitis E virus in porcine extracts, and the European guideline refers to chronic hepatitis E associated with PERT in lung transplant recipients with cystic fibrosis [17–19]. In the label trials, the most common reactions were vomiting, dizziness and cough at 7 years or older, and vomiting, irritability and decreased appetite between 4 months and 6 years [18]. The products are not interchangeable without clinical monitoring and readjustment [18].

7.3. Regulatory status of pancreatin

7.4. Evidence from PERT trials

There are no PERT trials in JBS. The evidence supporting the authorisation of pancrelipase comes from short trials in cystic fibrosis and chronic pancreatitis, summarised in the Creon® label [18].

These trials used high-fat diets and fixed doses (4000 U/g fat/day in studies 1 and 2; 72,000 U per main meal and 36,000 U per snack in study 4) and measure short-term absorption, not growth, morbidity or survival [18]. The European guideline considers that no randomised trial of sufficient duration has assessed the effect of PERT on morbidity and mortality, and bases the recommendation to treat on the relationship between malnutrition and poor prognosis (level 3) [17]. The results cannot be transposed quantitatively to JBS, whose insufficiency is acinar and congenital, and indirect comparisons between trials of different products are not valid. The phase III trial of a non-porcine preparation (liprotamase) did not meet its primary endpoint [17].

7.5. Fat-soluble vitamins and other micronutrients

Fat malabsorption causes deficiencies of vitamins A, D, E and K even on PERT, as shown by the low vitamin A and 25-hydroxyvitamin D values in the Saudi series, which normalised with a daily multivitamin [5, 9]. There are no JBS-specific doses; the table uses the cystic fibrosis nutrition guideline for patients with pancreatic insufficiency (extrapolation) [83].

[83]

Hypervitaminosis A can cause hepatic fibrosis, decreased bone mineral density and fractures, and in pregnancy vitamin A intake should remain below 10,000 IU/day [83]. Cobalamin deficiency can be severe in JBS and caused pancytopenia in one patient; iron-deficiency anaemia and folate deficiency are frequent in the malnourished infant and require targeted supplementation [25, 45, 73]. The NASPGHAN position recommends monitoring growth, puberty and intake at every visit (at least every 6–12 months) and measuring fat-soluble vitamins every 12–18 months or when clinically indicated (grade 1B) [80]. In the reports of infants with hypoalbuminaemia and anaemia, improvement in stools and weight followed the start of enzymes, supplements and, when hypothyroidism was present, thyroxine [25, 45].

7.6. Hypothyroidism

Hypothyroidism in JBS is treated with levothyroxine (LT4). There is no disease-specific dose; the 2020–2021 European consensus on congenital hypothyroidism, endorsed by the European Society for Paediatric Endocrinology (ESPE), serves as the reference for the rare neonatal cases (extrapolation): LT4 alone, orally, once daily, with a starting dose of up to 15 µg/kg/day, 10–15 µg/kg/day in severe forms (free T4 below 5 pmol/L) and about 10 µg/kg/day in mild forms (free T4 above 10 pmol/L), which may be lowered to 5–10 µg/kg/day if pre-treatment free T4 is within the normal range [78]. Monitoring is performed 1–2 weeks after starting, every 2 weeks until TSH normalises, every 1 to 3 months up to 12 months, every 2 to 4 months between 1 and 3 years and every 3 to 6 months until growth is complete, with reassessment 4–6 weeks after each dose change [78]. In children, LT4 may be taken with food, at the same time every day, avoiding soy protein and vegetable fibre [78]. As LT4 is absorbed in the proximal small intestine and untreated coeliac disease and short bowel reduce absorption, the untreated malabsorption of JBS may increase requirements; this relationship has not been studied in JBS and justifies closer laboratory monitoring when PERT is started or adjusted [78]. In late-onset hypothyroidism, the dose is titrated by TSH: in the Saudi series, 25 µg/day normalised the TSH of a 7-year-old child in 8 weeks [9]. Cholesterol is not useful as a marker of hypothyroidism in JBS, because malabsorption keeps it low [10].

7.7. Diabetes and endocrine pancreatic function

Pancreatogenic diabetes appears mainly in adolescence and adulthood [10, 14]. By analogy with paediatric chronic pancreatitis, NASPGHAN recommends annual screening with fasting glucose and glycated haemoglobin (HbA1c) (grade 1C), an annual oral glucose tolerance test (OGTT) when prediabetes is present (fasting glucose 100–125 mg/dL and/or HbA1c 5.7–6.4%), diagnosis by the American Diabetes Association criteria (fasting glucose ≥ 126 mg/dL, 2-hour glucose ≥ 200 mg/dL or HbA1c ≥ 6.5%, confirmed), referral to paediatric endocrinology and adequate treatment of malabsorption to improve glycaemic control [80]. Insulin is, as a rule, the most appropriate therapy, because the primary defect is insulin deficiency; metformin may be considered in obesity or mild diabetes, and sulfonylureas are off-label in paediatrics [80]. In JBS there are two particular features: loss of the glucagon response to hypoglycaemia, documented in an infant and described by Smith's in adolescents and adults, is relevant when insulin is used, and diabetes may be accompanied by profound insulin resistance [10, 54, 55]. The asynchrony between digestion and prandial insulin in exocrine insufficiency requires joint assessment by gastroenterology and endocrinology [5].

7.8. Growth and pituitary

GH deficiency should be sought when growth remains inadequate despite PERT, nutrition and euthyroidism; GH treatment improved growth velocity in one patient and was used at a dose of 0.33 mg subcutaneously per day in a Saudi child [9, 66]. The autopsy of a child with hypopituitarism led the authors to recommend assessment of pituitary function in all patients [43].

7.9. Hearing

Audiological assessment should be early, with auditory evoked potentials in the infant [4, 61]. Amplification with hearing aids is the first measure, but patients with severe to profound hearing loss benefit little from them and are candidates for cochlear implantation [61]. The published results are from isolated cases: a girl implanted at 4 years went from thresholds of 80–100 dB to 35–40 dB, but after 3 years of use communicated mainly by lip-reading and gestures (categories of auditory performance 3/9; speech intelligibility 1/5); a boy with bilateral implants made minimal progress in oral language after 4 years, with substantial improvement in sound discrimination and audibility; a girl from Bahrain with sequential bilateral implantation at 3 years was attending school at 12 years, 2 years behind [61, 65, 88]. The authors attribute the limited results to late implantation, cognitive impairment and comorbidities, and recommend early and bilateral implantation; cochlear malformations (incomplete partition, hypoplastic modiolus, hypoplastic cochlear nerve) influence the choice of ear [61, 62].

7.10. Surgery, dentistry and rehabilitation

Anorectal and urogenital malformations follow the usual protocols: neonatal colostomy and anorectoplasty, genitoplasty and correction of the urogenital sinus, as in the patient operated on at 16 months with posterior sagittal anorectoplasty and feminising genitoplasty [1, 25, 70]. Nasal reconstruction of aplastic alae is technically difficult in the young child, and the timing is debated by plastic surgeons; in the Bahraini patient, reconstructive surgery began at 6 years [65, 89]. Oblique facial clefts require specialised craniofacial reconstruction [35]. Oligodontia and microdontia require follow-up by paediatric dentistry, orthodontics and prosthodontics (for example, a paediatric dental bridge), with a positive psychological impact described [4, 65, 90]. Malformations of the lacrimal system are treated by ophthalmology [64]. Developmental delay requires early intervention, speech therapy and adapted education, including schools for children with hearing impairment; behavioural disorders, when present, responded to a combination of psychotropic medication and a behavioural programme [4, 32, 69].

7.11. Anaesthesia and the perioperative period

The anaesthetic implications result from micrognathia, heart defects, exocrine and endocrine pancreatic dysfunction (risk of hypoglycaemia and malnutrition), hypothyroidism, possible hypopituitarism and vesicoureteric reflux [58]. Preoperative assessment should include echocardiography, thyroid function, blood glucose and, when hypopituitarism is suspected, the corticotropic axis [43, 58]. PERT is continued with meals and, in postoperative enteral nutrition, given as a bolus via the tube [17].

7.12. Pregnancy and lactation

There are no reports of pregnancy in women with JBS in the sources consulted. The European guideline finds no evidence of harm from PERT in pregnancy or lactation and considers stopping it counterproductive (level 4); the North American label refers to minimal systemic absorption and no risk identified in published reports, and the Portuguese SmPC, without clinical data in pregnant women, advises caution [17–19]. Vitamin A intake in pregnancy should remain below 10,000 IU/day, with assessment before conception, and folic acid is recommended at a dose of 400 µg/day for women planning pregnancy, in the preconception period and during the first trimester [83].

7.13. Transition to adulthood

Transition to adult care coincides with the phase of greatest risk of diabetes and with possible progression of exocrine insufficiency [10, 53]. The switch to PERT doses in units per meal (40,000–50,000 U with main meals), annual glycaemic surveillance, continuation of auditory and dental rehabilitation and reproductive counselling (section 8) are the elements to be transferred [2, 17, 80]. The sources consulted do not describe specific transition programmes.

7.14. Agents and situations to avoid

There are no medicinal products specifically contraindicated in JBS. The precautions derive from PERT (doses above the paediatric maxima, crushing the microspheres, adding enzymes to the bottle, switching products without monitoring) and from the comorbidities: the use of insulin in the absence of a glucagon response, excessive vitamin A supplementation and the interpretation of cholesterol as a thyroid marker [10, 17, 18, 55, 83]. Immunohistochemistry for UBR1 should not be used as a diagnostic test [40].

7.15. Research and developments in the last 12 months

No therapies targeting UBR1 deficiency, orphan designations or regulatory procedures for JBS were identified in the sources consulted. Medicinal chemistry work on UBR1 recruiters for proteolysis-targeting chimeras (PROTAC) is aimed at oncogenic proteins and not at this disease [93].

7.16. Summary of recommendations and differences

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

In autosomal recessive inheritance, the parents of a patient are presumed to be heterozygous, and each pregnancy has a 25% probability of an affected child, 50% of an asymptomatic carrier and 25% of a non-carrier; recurrence in siblings is documented in several families, including subsequent pregnancies diagnosed by ultrasound and a triplet delivery [2, 40, 77]. A healthy sibling of a patient has a two-thirds probability of being a carrier. Molecular confirmation of the parents' carrier status should be performed whenever possible, because a proband has been described with two de novo variants in trans, neither present in the parents [2, 11]. In that situation, the recurrence risk for the parents is low, but germline mosaicism cannot be excluded; the sources consulted do not quantify this risk. The offspring of a patient are affected only if the other parent is a carrier; consanguinity increases that probability [2].

8.2. Testing of relatives and minors

Once the variants of the index case have been identified, testing of relatives is targeted and does not require sequencing of the whole gene [2]. Predictive testing does not apply, because the signs are present from birth and penetrance is complete; testing of symptomatic siblings is diagnostic, and excluding one of the familial variants in a sibling excludes the disorder [2]. Carrier testing in healthy siblings and other relatives is relevant to reproductive decisions and is therefore usually performed from the age at which the person can decide; the clinical utility card considers it relevant when the result has reproductive consequences [2].

8.3. Prenatal and preimplantation diagnosis

Once the familial variants are known, early and reliable prenatal diagnosis and preimplantation genetic testing are possible [2]. Ultrasound may suggest the disorder in the second and third trimesters (beak-like nose without alae, dilatation of the colon or sigmoid), but the variability of expression, even within the family, limits its usefulness on its own and calls for collaboration with an experienced geneticist [65, 76, 77]. In consanguineous couples with an affected child, the authors of the reports recommend preconception genetic counselling [3, 61].

8.4. Variants of uncertain significance in counselling

When the variant of the index case is of uncertain significance, as in the Yemeni siblings, prenatal or preimplantation diagnosis based on that variant should be discussed with caution, and segregation in the parents and siblings is the first step towards reclassifying it [2, 3].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

The exact frequency of JBS and of carriers is unknown [2]. The estimate of about 1 in 250,000 live births, adopted by Orphanet as a birth prevalence of 0.4 per 100,000 in Europe (class 1–9 per 1,000,000), was derived by Zenker and colleagues from a European epidemiological study of anorectal anomalies by the EUROCAT network, and not from a disease registry; point prevalence is classified as unknown [2, 12]. The number of published patients rose from 26 in 1990 to more than 100 in 2017, and the Magdeburg/Erlangen cohort brought together 79 patients from 65 families [14, 31]. These figures measure patients who were published or referred to a laboratory, not incidence.

9.2. Geographical distribution and founder populations

No differences in prevalence between ethnic groups have been observed, but a significant proportion of patients come from populations with frequent consanguineous marriages [2]. In Saudi Arabia five patients were documented (one in 2008 and four in 2024), in Bahrain two, in Yemen one in 2011 and three siblings in 2026, and in Syria one in 2025 [3, 9, 25, 45, 65]. There are also patients from Israel, Turkey, Iran, Japan, China, India, Costa Rica, the Netherlands and other European countries and North America [7, 31, 32, 44, 47, 52, 55, 61, 72]. The only documented founder variant is p.(Gln513Ter) in two Amerindian families from Costa Rica with a common haplotype; in 2013 no predominant founder alleles were known in other populations [2, 7]. The p.(Ile692Thr) variant was found in two Saudi families with no known relationship, which is not enough to consider it a founder variant [9]. The sources consulted provide no data from Portugal or Brazil, nor estimates of carrier frequency in specific populations; the absence of data does not demonstrate an absence of patients.

9.3. Diagnosis in low-resource settings

The reports from Yemen and Syria describe the unavailability of sequencing in the country or of formal audiometry and high infant mortality among siblings, and emphasise clinical diagnosis by the combination of pancreatic insufficiency with nasal aplasia [3, 25]. Faecal elastase and the dysmorphological examination allow PERT to be started before molecular confirmation [25, 57].

9.4. European networks and resources

JBS falls within three European Reference Networks: ERN-ITHACA, for rare malformation syndromes and intellectual disability; ERNICA, for inherited and congenital digestive anomalies, including anorectal malformations; and Endo-ERN, in the thyroid and pituitary groups [21–23]. The registry of UBR1 variants with clinical data was set up in the LOVD database (Leiden Open Variation Database) by the Magdeburg group [33]. Orphanet maintains the ORPHA:2315 entry [12]. The sources consulted did not identify patient associations dedicated to JBS; families can turn to the rare disease, deafness and cystic fibrosis and pancreatic insufficiency associations in their country.

10. Illustrative Clinical Case

The case was published by Noli and colleagues in a series of four Saudi patients followed at the King Faisal Specialist Hospital and Research Center in Jeddah, and is the first of three siblings [9]. A Saudi boy, the son of first-cousin parents, born at term without complications, was seen at 7 years in paediatric pulmonology for chronic cough and diarrhoea, with intermittent loose, greasy stools and poor weight gain. The full blood count, renal and liver function and pancreatic enzymes were normal at that time, and the chest radiograph showed bilateral peribronchial thickening and left retrocardiac atelectasis. Cystic fibrosis was suspected, but CFTR testing was negative; he was treated with an inhaled bronchodilator and corticosteroid, omeprazole, fat-soluble multivitamins and pancrelipase (Creon® 10,000 U of lipase, five to six capsules per day with meals) [9].

At 12 years he was referred to paediatric gastroenterology for pancreatic insufficiency without relevant respiratory disease and with inconclusive genetics. Detailed dysmorphological examination revealed hypoplastic nasal alae, aplasia cutis of the scalp, extension of the frontal hairline and small, malformed teeth, with the rest of the examination normal and no intellectual disability. Reassessment showed mild leucopenia with moderate to severe neutropenia, normal haemoglobin and platelets, normal thyroid function, low vitamin A (238 µg/L) and faecal elastase of 27 µg/g or less; abdominal CT showed excess retroperitoneal fat with no identifiable pancreatic tissue, and pure-tone audiometry was normal. Exome sequencing identified the variant NM_174916.3:c.2075T>C, p.(Ile692Thr), in the homozygous state, confirmed by Sanger, which the authors considered causal because it affects a conserved residue [9]. The two younger siblings, with the same genotype, had pancreatic insufficiency, small nasal alae and microdontia, one of them with short stature and conductive hearing loss due to tympanic perforation [9].

The patient continued pancrelipase (four 10,000 U capsules with the main meal), omeprazole 20 mg per day and a daily multivitamin with vitamins A, D, E and K. Over the following five years, weight remained between the 5th and 10th centiles (z-score −0.89) and height near the 25th centile (z-score −1.2), the diarrhoea improved markedly and the fat-soluble vitamins normalised [9]. Figure 1 of the article, consulted, shows the presenting features of three of the four patients: https://pmc.ncbi.nlm.nih.gov/articles/PMC11093911/figure/jpr312057-fig-0001/ [9].

The case illustrates three points. The first is the five-year diagnostic delay, during which the pancreatic insufficiency was attributed to cystic fibrosis never confirmed by a sweat test, and only examination of the face, scalp and teeth led to the diagnosis, which corresponds to the major and minor criteria of the Magdeburg group [9, 14]. The second is the mild phenotype, with normal intelligence and hearing, associated with a homozygous missense variant, in agreement with the hypothesis of hypomorphic alleles; the variant remains classified as of uncertain significance in ClinVar owing to the lack of functional studies and parental segregation, and the series did not test the parents [2, 9, 46]. The third is the neutropenia, which is not part of the usual picture of JBS, is a feature of Shwachman-Diamond syndrome and remained unexplained in the report [9, 13]. The pancreatin dose used (40,000 U with the main meal in an adolescent) corresponds to the minimum proposed by the European guideline for adults, but the report does not state the weight, which precludes calculation per kilogram and comparison with the label, and the use of omeprazole as an adjuvant corresponds to the option provided by the guideline for an inadequate response, although the report does not state the reason for its introduction [17, 18].

Two complementary figures show the facial spectrum: in the series of Sukalo and colleagues, a patient with deletion of exons 45–47 at 2 days and at 9½ years, with aplasia of the nasal alae and frontal hair whorl (https://pmc.ncbi.nlm.nih.gov/articles/PMC5702574/figure/mgg3319-fig-0001/), and, in the study by Hwang and colleagues, patients with missense variants with an almost normal facies alongside a severely affected patient with two null variants (https://pmc.ncbi.nlm.nih.gov/articles/PMC3172311/figure/pone-0024925-g002/) [14, 32].

11. Prognosis and Long-term Follow-up

11.1. Prognosis

There are no survival or quality-of-life studies in JBS. Mortality is concentrated in infants with untreated pancreatic insufficiency, malnutrition, anaemia, infections or heart disease, as shown by the sibships from Yemen and Syria and the twins of Quaio and colleagues, with deaths in the first months of life [3, 25, 45, 49]. Neonatal deaths from complex heart disease and a death at 8 years from complications of pancreatic insufficiency have also been described [1, 27]. With PERT, nutritional support, levothyroxine and auditory rehabilitation, there are patients followed up to 17 years with a stable course and a 37-year-old woman in the Magdeburg/Erlangen cohort [9, 14]. Cognitive development is the main functional determinant and ranges from normal to severe impairment; hearing loss, oligodontia and diabetes with onset in adolescence are the long-term morbidities [10, 14, 61]. Unlike Shwachman-Diamond syndrome, the exocrine insufficiency of JBS does not regress and may progress in adulthood [13, 53].

11.2. Surveillance table

There is no JBS-specific surveillance protocol. The table combines the recommendations of the JBS reports with the guidelines for analogous conditions, whose origin is indicated [2, 17, 25, 78, 80, 83].

12. Summary and Final Considerations

Johanson-Blizzard syndrome is a rare autosomal recessive disorder, with an estimated birth prevalence of about 1 in 250,000 in Europe, caused by biallelic loss of function of UBR1, the N-recognin of the N-terminal protein degradation pathway. Absence of UBR1 causes an inflammatory destruction of the acinar pancreas that begins before birth, initially spares the ducts and islets and progresses, in adolescence and adulthood, to diabetes. The picture is recognised by the combination of exocrine pancreatic insufficiency with hypoplastic or aplastic nasal alae, together with permanent oligodontia, sensorineural hearing loss, scalp defects, hypothyroidism, imperforate anus, genitourinary anomalies, growth deficiency and cognitive impairment of variable degree that is not obligatory.

Diagnosis rests on the dysmorphological examination, faecal elastase and UBR1 sequencing, which detects about 93% of pathogenic alleles and reaches almost 98% when analysis of exon deletions and duplications is added. A negative result does not exclude the disorder, and many missense variants remain of uncertain significance, which requires family segregation and phenotypic correlation. The differential diagnosis with Shwachman-Diamond syndrome and cystic fibrosis is the most relevant in practice, and confusion with cystic fibrosis has delayed the diagnosis in patients with a mild phenotype.

There is no treatment targeting UBR1 deficiency and there are no trials in the disorder. Management is replacement: pancreatin at paediatric doses by weight or by fat intake, within the guideline maxima, fat-soluble vitamins, levothyroxine, auditory rehabilitation with early cochlear implantation in profound forms, surgical correction of malformations, dental care and annual glycaemic surveillance. The mortality described is concentrated in undiagnosed infants, and treated patients reach adolescence and adulthood. Recessive inheritance, with rare cases of de novo variants, guides counselling, carrier testing and prenatal or preimplantation diagnosis when the familial variants are known.

13. References

1. Online Mendelian Inheritance in Man, OMIM®. MIM Number: 243800 — Johanson-Blizzard syndrome; JBS [Internet]. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/243800
2. Sukalo M, Mayerle J, Zenker M. Clinical utility gene card for: Johanson-Blizzard syndrome. Eur J Hum Genet. 2014;22(1):152. doi:10.1038/ejhg.2013.65
3. Abukammas SJ, Abdelgalil A, Shazly MA, Alghanmi MM, Sheriff TZ. Three Yemeni siblings with Johanson-Blizzard syndrome: a case report and literature review. Cureus. 2026;18(2):e103579. doi:10.7759/cureus.103579
4. GeneGuidance. UBR1 — gene and condition record (Johanson-Blizzard syndrome, OMIM 243800, ORPHA 2315). Version of 2026-09-26.
5. Vallente R, Whitcomb DC. Pancreatitis Overview. 2014 Mar 13 [updated 2026 Apr 23]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK190101/
6. Masamune A, Nakano E, Niihori T, Hamada S, Nagasaki M, Aoki Y, et al. Variants in the UBR1 gene are not associated with chronic pancreatitis in Japan. Pancreatology. 2016;16(5):814-8. doi:10.1016/j.pan.2016.06.662
7. Online Mendelian Inheritance in Man, OMIM®. MIM Number: 605981 — Ubiquitin-protein ligase E3 component N-recognin 1; UBR1 [Internet]. Baltimore (MD): Johns Hopkins University. Updated 2024 May 31. Available from: https://omim.org/entry/605981
8. VariantValidator. UBR1 NM_174916.3 variant normalisation (GRCh38, MANE Select). Available from: https://rest.variantvalidator.org/
9. Noli K, Aleysae N, Alzahrani I, Al-Ghamdi A, Alkazmi M, Almasoudi A. Johanson-Blizzard syndrome caused by novel UBR1 mutation in four Saudi patients. JPGN Rep. 2024;5(2):140-7. doi:10.1002/jpr3.12057
10. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 126–127.
11. Strych L, Zavoral T, Komrskova P, Vanecek T, Subrt I. Two de novo UBR1 variants in trans as a cause of Johanson-Blizzard syndrome. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2025;169(2):98-106. doi:10.5507/bp.2025.005
12. Orphanet. Johanson-Blizzard syndrome (ORPHA:2315). Orphadata, epidemiology and natural history datasets, version 2026-06-23. Available from: https://www.orpha.net/en/disease/detail/2315
13. Nelson A, Myers K. Shwachman-Diamond Syndrome. 2008 Jul 17 [updated 2024 Sep 19]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1756/
14. Sukalo M, Schäflein E, Schanze I, Everman DB, Rezaei N, Argente J, et al. Expanding the mutational spectrum in Johanson-Blizzard syndrome: identification of whole exon deletions and duplications in the UBR1 gene by multiplex ligation-dependent probe amplification analysis. Mol Genet Genomic Med. 2017;5(6):774-80. doi:10.1002/mgg3.319
15. Zenker M, Mayerle J, Lerch MM, Tagariello A, Zerres K, Durie PR, et al. Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome). Nat Genet. 2005;37(12):1345-50. doi:10.1038/ng1681
16. Ellery KM, Erdman SH. Johanson-Blizzard syndrome: expanding the phenotype of exocrine pancreatic insufficiency. JOP. 2014;15(4):388-90. doi:10.6092/1590-8577/2409. PMID: 25076350
17. Dominguez-Muñoz JE, Vujasinovic M, de la Iglesia D, Cahen D, Capurso G, Gubergrits N, et al. European guidelines for the diagnosis and treatment of pancreatic exocrine insufficiency: UEG, EPC, EDS, ESPEN, ESPGHAN, ESDO, and ESPCG evidence-based recommendations. United European Gastroenterol J. 2025;13(1):125-72. doi:10.1002/ueg2.12674
18. AbbVie Inc. CREON (pancrelipase) delayed-release capsules. Prescribing information. BLA 020725. Revised 02/2024. U.S. Food and Drug Administration / DailyMed set id 073201aa-556d-4a70-918e-84e9616fd88d. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=073201aa-556d-4a70-918e-84e9616fd88d
19. Viatris Healthcare, Lda. Kreon 150 mg e Kreon 25000 300 mg cápsula gastrorresistente — Resumo das Características do Medicamento. Revisão 07/2026. INFARMED, Infomed. Available from: https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=4831&tipo_doc=rcm
20. ClinicalTrials.gov. Search: condition "Johanson-Blizzard" and term "UBR1". U.S. National Library of Medicine. Available from: https://clinicaltrials.gov/api/v2/studies?query.cond=Johanson-Blizzard
21. ERN-ITHACA. European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders. Available from: https://ern-ithaca.eu/
22. ERNICA. European Reference Network for rare Inherited and Congenital (digestive and gastrointestinal) Anomalies. Available from: https://www.ern-ernica.eu/
23. Endo-ERN. European Reference Network on Rare Endocrine Conditions. Available from: https://endo-ern.eu/
24. Johanson A, Blizzard R. A syndrome of congenital aplasia of the alae nasi, deafness, hypothyroidism, dwarfism, absent permanent teeth, and malabsorption. J Pediatr. 1971;79(6):982-7. doi:10.1016/s0022-3476(71)80194-4
25. Ktyman H, Chaker D, Ahmad H, Kamil H, Ajlouni A. Variable expressivity in Johanson-Blizzard syndrome: a case with severe manifestations and a review of the literature. JGH Open. 2025;9(8):e70236. doi:10.1002/jgh3.70236
26. Mardini MK, Ghandour M, Sakati NA, Nyhan WL. Johanson-Blizzard syndrome in a large inbred kindred with three involved members. Clin Genet. 1978;14(5):247-50. doi:10.1111/j.1399-0004.1978.tb02141.x
27. Daentl DL, Frías JL, Gilbert EF, Opitz JM. The Johanson-Blizzard syndrome: case report and autopsy findings. Am J Med Genet. 1979;3(2):129-35. doi:10.1002/ajmg.1320030203
28. Moeschler JB, Lubinsky MS. Johanson-Blizzard syndrome with normal intelligence. Am J Med Genet. 1985;22(1):69-73. doi:10.1002/ajmg.1320220107
29. Moeschler JB, Polak MJ, Jenkins JJ, Amato RS. The Johanson-Blizzard syndrome: a second report of full autopsy findings. Am J Med Genet. 1987;26(1):133-8. doi:10.1002/ajmg.1320260120
30. Swanenburg de Veye HF, Heineman-de-Boer JA, Beemer FA. A child of high intelligence with the Johanson-Blizzard syndrome. Genet Couns. 1991;2(1):21-5.
31. Gershoni-Baruch R, Lerner A, Braun J, Katzir Y, Iancu TC, Benderly A. Johanson-Blizzard syndrome: clinical spectrum and further delineation of the syndrome. Am J Med Genet. 1990;35(4):546-51. doi:10.1002/ajmg.1320350421
32. Hwang CS, Sukalo M, Batygin O, Addor MC, Brunner H, Aytes AP, et al. Ubiquitin ligases of the N-end rule pathway: assessment of mutations in UBR1 that cause the Johanson-Blizzard syndrome. PLoS One. 2011;6(9):e24925. doi:10.1371/journal.pone.0024925
33. Sukalo M, Fiedler A, Guzmán C, Spranger S, Addor MC, McHeik JN, et al. Mutations in the human UBR1 gene and the associated phenotypic spectrum. Hum Mutat. 2014;35(5):521-31. doi:10.1002/humu.22538
34. Rezaei N, Sabbaghian M, Liu Z, Zenker M. Eponym: Johanson-Blizzard syndrome. Eur J Pediatr. 2011;170(2):179-83. doi:10.1007/s00431-010-1240-5
35. Corona-Rivera JR, Zapata-Aldana E, Bobadilla-Morales L, Corona-Rivera A, Peña-Padilla C, Solis-Hernández E, et al. Oblique facial clefts in Johanson-Blizzard syndrome. Am J Med Genet A. 2016;170(6):1495-501. doi:10.1002/ajmg.a.37630
36. Online Mendelian Inheritance in Man, OMIM®. MIM Number: 244450 — Kaufman oculocerebrofacial syndrome; KOS [Internet]. Baltimore (MD): Johns Hopkins University. Available from: https://omim.org/entry/244450
37. An JY, Seo JW, Tasaki T, Lee MJ, Varshavsky A, Kwon YT. Impaired neurogenesis and cardiovascular development in mice lacking the E3 ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway. Proc Natl Acad Sci U S A. 2006;103(16):6212-7. doi:10.1073/pnas.0601700103
38. Li Y, Gao S. Glutamate metabolism disruption in Johanson-Blizzard syndrome: insights from C. elegans ubr-1 model. J Biosci. 2025;50:5. doi:10.1007/s12038-024-00489-w
39. Zenker M, Mayerle J, Reis A, Lerch MM. Genetic basis and pancreatic biology of Johanson-Blizzard syndrome. Endocrinol Metab Clin North Am. 2006;35(2):243-53. doi:10.1016/j.ecl.2006.02.013
40. Schoner K, Fritz B, Huelskamp G, Louwen F, Zenker M, Moll R, et al. Recurrent Johanson-Blizzard syndrome in a triplet pregnancy complicated by urethral obstruction sequence: a clinical, molecular, and immunohistochemical approach. Pediatr Dev Pathol. 2012;15(1):50-7. doi:10.2350/11-04-1020-OA.1
41. Jones NL, Hofley PM, Durie PR. Pathophysiology of the pancreatic defect in Johanson-Blizzard syndrome: a disorder of acinar development. J Pediatr. 1994;125(3):406-8. doi:10.1016/s0022-3476(05)83286-x
42. Alkhouri N, Kaplan B, Kay M, Shealy A, Crowe C, Bauhuber S, et al. Johanson-Blizzard syndrome with mild phenotypic features confirmed by UBR1 gene testing. World J Gastroenterol. 2008;14(44):6863-6. doi:10.3748/wjg.14.6863
43. Hoffman WH, Lee JR, Kovacs K, Chen H, Yaghmai F. Johanson-Blizzard syndrome: autopsy findings with special emphasis on hypopituitarism and review of the literature. Pediatr Dev Pathol. 2007;10(1):55-60. doi:10.2350/06-05-0085.1
44. Liu S, Wang Z, Jiang J, Luo X, Hong Q, Zhang Y, et al. Severe forms of Johanson-Blizzard syndrome caused by two novel compound heterozygous variants in UBR1: clinical manifestations, imaging findings and molecular genetics. Pancreatology. 2020;20(3):562-8. doi:10.1016/j.pan.2020.01.007
45. Almashraki N, Abdulnabee MZ, Sukalo M, Alrajoudi A, Sharafadeen I, Zenker M. Johanson-Blizzard syndrome. World J Gastroenterol. 2011;17(37):4247-50. doi:10.3748/wjg.v17.i37.4247
46. National Center for Biotechnology Information. ClinVar: UBR1 variants (VCV 4678, 4680, 4681, 31918, 2442050). Available from: https://www.ncbi.nlm.nih.gov/clinvar/?term=UBR1%5Bgene%5D
47. Elting M, Kariminejad A, de Sonnaville ML, Ottenkamp J, Bauhuber S, Bozorgmehr B, et al. Johanson-Blizzard syndrome caused by identical UBR1 mutations in two unrelated girls, one with a cardiomyopathy. Am J Med Genet A. 2008;146A(23):3058-61. doi:10.1002/ajmg.a.32566
48. Al-Dosari MS, Al-Muhsen S, Al-Jazaeri A, Mayerle J, Zenker M, Alkuraya FS. Johanson-Blizzard syndrome: report of a novel mutation and severe liver involvement. Am J Med Genet A. 2008;146A(14):1875-9. doi:10.1002/ajmg.a.32401
49. Quaio CR, Koda YK, Bertola DR, Sukalo M, Zenker M, Kim CA. Johanson-Blizzard syndrome: a report of gender-discordant twins with a novel UBR1 mutation. Genet Mol Res. 2014;13(2):4159-64. doi:10.4238/2014.June.9.2
50. Abu-El-Haija M, Zhang W, Wang F, Cress G, Dawson B, Su X, et al. Pancreatitis risk genes play a major role in pediatric pancreatitis: insights from the INternational Study Group of Pediatric Pancreatitis: In search for a cuRE. Clin Gastroenterol Hepatol. 2026. doi:10.1016/j.cgh.2026.06.004
51. Orphanet. Johanson-Blizzard syndrome (ORPHA:2315): HPO phenotype annotations. Orphadata, version 2026-06-23. Available from: https://api.orphadata.com/rd-phenotypes/orphacodes/2315
52. Ye Z, Zhou Y, Huang Y, Sun H, Wang H, Wu B. Clinical characteristics and genetic causes of infantile exocrine pancreatic insufficiency in Chinese patients: study from a tertiary care center. Pancreas. 2018;47(10):1344-9. doi:10.1097/MPA.0000000000001185
53. Trellis DR, Clouse RE. Johanson-Blizzard syndrome. Progression of pancreatic involvement in adulthood. Dig Dis Sci. 1991;36(3):365-9. doi:10.1007/BF01318210
54. Steinbach WJ, Hintz RL. Diabetes mellitus and profound insulin resistance in Johanson-Blizzard syndrome. J Pediatr Endocrinol Metab. 2000;13(9):1633-6. doi:10.1515/jpem.2000.13.9.1633
55. Takahashi T, Fujishima M, Tsuchida S, Enoki M, Takada G. Johanson-Blizzard syndrome: loss of glucagon secretion response to insulin-induced hypoglycemia. J Pediatr Endocrinol Metab. 2004;17(8):1141-4. doi:10.1515/jpem.2004.17.8.1141
56. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 242–244.
57. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 150–151.
58. Fichter CR, Johnson GA, Braddock SR, Tobias JD. Perioperative care of the child with the Johanson-Blizzard syndrome. Paediatr Anaesth. 2003;13(1):72-5. doi:10.1046/j.1460-9592.2003.00957.x
59. Alpay F, Gül D, Lenk MK, Oğur G. Severe intrauterine growth retardation, aged facial appearance, and congenital heart disease in a newborn with Johanson-Blizzard syndrome. Pediatr Cardiol. 2000;21(4):389-90. doi:10.1007/s002460010089
60. Deutsch CK, Hreczko T, Holmes LB. Quantitative assessment of craniofacial morphology in Johanson-Blizzard syndrome. Birth Defects Res A Clin Mol Teratol. 2013;97(3):166-9. doi:10.1002/bdra.23121
61. Alwadee RM, Alyousef MY, Yousef EM, Yousef MF. Performance of children with Johanson-Blizzard syndrome after cochlear implantation. Cureus. 2021;13(11):e19264. doi:10.7759/cureus.19264
62. Mangali NP, Antony A, Kumar N. Johanson-Blizzard syndrome with cystic dilation of the cochlea and hypoplastic modiolus: a case report. Pediatr Radiol. 2025;55(1):195-200. doi:10.1007/s00247-024-06118-w
63. Raza AF, Paudel DR, Nisha KV. Audiological profiling and rehabilitation outcomes in a child with Johanson-Blizzard syndrome. J Audiol Otol. 2022;26(3):160-5. doi:10.7874/jao.2021.00444
64. Cheung JC, Thomson H, Buncic JR, Héon E, Levin AV. Ocular manifestations of the Johanson-Blizzard syndrome. J AAPOS. 2009;13(5):512-4. doi:10.1016/j.jaapos.2009.05.005
65. Isa HM, Khudhair ZA, Abdulla KM, Idrees ZA, Busehail MY, Jawad ZA. Johanson-Blizzard syndrome: a case report from Bahrain with a literature review. Cureus. 2024;16(3):e55969. doi:10.7759/cureus.55969
66. Sandhu BK, Brueton MJ. Concurrent pancreatic and growth hormone insufficiency in Johanson-Blizzard syndrome. J Pediatr Gastroenterol Nutr. 1989;9(4):535-8. doi:10.1097/00005176-198911000-00026
67. Kristjansson K, Hoffman WH, Flannery DB, Cohen MJ. Johanson-Blizzard syndrome and hypopituitarism. J Pediatr. 1988;113(5):851-3. doi:10.1016/s0022-3476(88)80015-5
68. Atik T, Karakoyun M, Sukalo M, Zenker M, Ozkinay F, Aydoğdu S. Two novel UBR1 gene mutations in a patient with Johanson Blizzard syndrome: a mild phenotype without mental retardation. Gene. 2015;570(1):153-5. doi:10.1016/j.gene.2015.06.082
69. Prater JF, D'Addio K. Johanson-Blizzard syndrome—a case study, behavioral manifestations, and successful treatment strategies. Biol Psychiatry. 2002;51(6):515-7. doi:10.1016/s0006-3223(01)01337-3
70. Sood A, Jamzadeh A, Chowdhury M, Lakshmanan Y. Johanson-Blizzard syndrome with associated urogenital anomalies. BMJ Case Rep. 2018;2018:bcr-2018-225336. doi:10.1136/bcr-2018-225336
71. Fallahi GH, Sabbaghian M, Khalili M, Parvaneh N, Zenker M, Rezaei N. Novel UBR1 gene mutation in a patient with typical phenotype of Johanson-Blizzard syndrome. Eur J Pediatr. 2011;170(2):233-5. doi:10.1007/s00431-010-1239-y
72. Singh A, Chaudhary N, Dhingra D, Sukalo M, Zenker M, Kapoor S. Johanson-Blizzard syndrome: hepatic and hematological features with novel genotype. Indian J Gastroenterol. 2014;33(1):82-4. doi:10.1007/s12664-013-0391-5
73. Aubrey S, Crooks B, Rashid M. Pancytopenia from severe cobalamin (vitamin B12) deficiency in Johanson-Blizzard syndrome. Eur J Clin Nutr. 2013;67(10):1118. doi:10.1038/ejcn.2013.140
74. Saeed M, Rana MN, Ahmad TM. Johanson-Blizzard syndrome with Diamond-Blackfan anemia. J Coll Physicians Surg Pak. 2010;20(9):627-8.
75. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 306–307.
76. Auslander R, Nevo O, Diukman R, Morrad E, Bardicef M, Abramovici H. Johanson-Blizzard syndrome: a prenatal ultrasonographic diagnosis. Ultrasound Obstet Gynecol. 1999;13(6):450-2. doi:10.1046/j.1469-0705.1999.13060450.x
77. Vanlieferinghen P, Gallot D, Francannet C, Meyer F, Dechelotte P. Prenatal ultrasonographic diagnosis of a recurrent case of Johanson-Blizzard syndrome. Genet Couns. 2003;14(1):105-7.
78. van Trotsenburg P, Stoupa A, Léger J, Rohrer T, Peters C, Fugazzola L, et al. Congenital hypothyroidism: a 2020-2021 consensus guidelines update—an ENDO-European Reference Network initiative endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology. Thyroid. 2021;31(3):387-419. doi:10.1089/thy.2020.0333
79. Whitcomb DC, Buchner AM, Forsmark CE. AGA clinical practice update on the epidemiology, evaluation, and management of exocrine pancreatic insufficiency: expert review. Gastroenterology. 2023;165(5):1292-301. doi:10.1053/j.gastro.2023.07.007
80. Freeman AJ, Maqbool A, Bellin MD, Goldschneider KR, Grover AS, Hartzell C, et al. Medical management of chronic pancreatitis in children: a position paper by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Pancreas Committee. J Pediatr Gastroenterol Nutr. 2021;72(2):324-40. doi:10.1097/MPG.0000000000003001
81. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. Appendix: Pattern of malformation differential diagnosis by anomalies. p. 1006.
82. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. Appendix: Pattern of malformation differential diagnosis by anomalies. p. 1015.
83. Turck D, Braegger CP, Colombo C, Declercq D, Morton A, Pancheva R, et al. ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis. Clin Nutr. 2016;35(3):557-77. doi:10.1016/j.clnu.2016.03.004
84. Aimmune Therapeutics. ZENPEP (pancrelipase) delayed-release capsules. Prescribing information. BLA 022210. Revised 11/2025. DailyMed set id 7f16f2d4-8df6-4bd7-ac10-56994fa257b0. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7f16f2d4-8df6-4bd7-ac10-56994fa257b0
85. U.S. Food and Drug Administration. Drugs@FDA: pancrelipase products (BLA 020725 Creon, 022210 Zenpep, 022523 Pancreaze, 022175 Pertzye, 022542 Viokace). Available from: https://www.accessdata.fda.gov/scripts/cder/daf/
86. European Medicines Agency. Medicines data: centrally authorised medicines. Available from: https://www.ema.europa.eu/en/documents/report/medicines-output-medicines_json-report_en.json
87. Agência Nacional de Vigilância Sanitária (ANVISA). Dados abertos de medicamentos registados: Creon (pancreatina), Abbott Laboratórios do Brasil, registo 105530337. Available from: https://dados.anvisa.gov.br/dados/DADOS_ABERTOS_MEDICAMENTOS.csv
88. Holcomb MA, Rizk HG, Morris NS, Meyer TA. Bilateral cochlear implantation in a child with Johanson Blizzard syndrome. Int J Pediatr Otorhinolaryngol. 2017;95:69-71. doi:10.1016/j.ijporl.2017.02.001
89. Timoney N, Weinberg MJ, Ross DA, Thomson HG. Johanson-Blizzard syndrome: a challenge in nasal reconstruction. Can J Plast Surg. 2004;12(2):81-5. doi:10.1177/229255030401200204
90. Santhosh BP, Jethmalani P. Johanson-Blizzard syndrome: dental findings and management. J Contemp Dent Pract. 2013;14(3):544-7. doi:10.5005/jp-journals-10024-1359
91. Wang B, Yang L, Gao M, Zhang H, Ji A, Liu G, et al. Establishment of a human induced pluripotent stem cell line (SDQLCHi079-A) from a patient with Johanson-Blizzard syndrome carrying heterozygous mutation in UBR1 gene. Stem Cell Res. 2024;80:103505. doi:10.1016/j.scr.2024.103505
92. Chandrakala C, Devi SS, Lakshmi R, Karpagam B, Raju P. Defective ala nasi - Johanson Blizzard syndrome. Indian J Dermatol. 2026;71(4):316-7. doi:10.4103/ijd.ijd_921_24
93. Maria-Solano MA, Lazim R, Choi S. In silico design and binding mechanism of UBR1 E3 ligase recruiters. RSC Adv. 2026;16(29):26659-68. doi:10.1039/d5ra04908c