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Year : 2022  |  Volume : 2  |  Issue : 4  |  Page : 212-216

Wolcott Rallison Syndrome: Beyond Neonatal Diabetes

Department of Pediatrics, Chacha Nehru Bal Chikitsalaya, New Delhi, India

Date of Submission04-Sep-2022
Date of Decision02-Nov-2022
Date of Acceptance02-Nov-2022
Date of Web Publication29-Nov-2022

Correspondence Address:
Dr. Medha Mittal
Department of Pediatrics, Chacha Nehru Bal Chikitsalaya, New Delhi - 110 031
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_206_22

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Background: Wolcott–Rallison Syndrome (WRS) is a rare autosomal recessive disorder characterized by permanent neonatal diabetes mellitus, skeletal dysplasia, hepatic dysfunction, and other systemic associations. Clinical Description: A 3-month-old infant with a history of fever and poor oral intake presented with severe dehydration, acidosis and 3+ urine ketones and was diagnosed to have sepsis and diabetic ketoacidosis (DKA). He also developed acute kidney injury (AKI) with blood urea 118 mg/dL and serum creatinine 1.5 mg/dL. Management: The child was ventilated, stabilized, and managed for DKA with fluids and insulin as per guidelines. AKI was managed with peritoneal dialysis. Genetic analysis revealed homozygous mutation in eukaryotic translation initiation factor 2-alpha kinase 3 gene consistent with the diagnosis of WRS. A close follow-up was kept with regular screening for other associated manifestations. Central hypothyroidism was detected first followed by skeletal dysplasia and chronic kidney disease. Growth retardation and developmental delay are also present. Conclusion: Neonatal diabetes cases need an early genetic work up and watchful follow-up for the manifestation of other possible associated features.

Keywords: Central hypothyroidism, chronic kidney disease, neonatal diabetes mellitus, skeletal dysplasia

How to cite this article:
Mittal M, Dhungel S, Bandarpalli H, Rai A. Wolcott Rallison Syndrome: Beyond Neonatal Diabetes. Indian Pediatr Case Rep 2022;2:212-6

How to cite this URL:
Mittal M, Dhungel S, Bandarpalli H, Rai A. Wolcott Rallison Syndrome: Beyond Neonatal Diabetes. Indian Pediatr Case Rep [serial online] 2022 [cited 2023 Jan 30];2:212-6. Available from: http://www.ipcares.org/text.asp?2022/2/4/212/362244

Presentation of diabetes in an infant younger than 6 months is known as neonatal diabetes, and it may be permanent or transient. In permanent diabetes, the condition persists throughout life whereas in transient neonatal diabetes, the condition remits within a year but may relapse in adolescence. Permanent neonatal diabetes occurs with a frequency of 1 in 90,000–1 in 210,000 live births,[1],[2] some of which may be associated with genetic syndromes.

Neonatal diabetes is a monogenic disorder in which mutations have been identified at over a dozen genes/loci.[3] These include namely potassium channel J11, ATP-binding cassette transporter subfamily C member 8 (ABCC8), insulin (INS), 6q24, solute carrier family 2A2 (SLC2A2), SLC19A2, eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3), glucokinase, Insulin promotor factor 1, pancreas transcription factor 1 subunit alpha, and others. The genes involved in the syndromic forms of neonatal and infantile onset diabetes include Berardinelli-Seip congenital lipodystrophy 2 (BSCL2), AGPAT2, SLC2A2, and EIF2AK3 genes. Consanguinity is an important factor in the syndromic forms. Understandably, genetic work-up is a very important component of the management of neonatal diabetes. The identification of the mutation not only has implications in genetic counseling, but also helps the treating physician in deciding therapeutic options, i.e., whether the need for insulin will be lifelong, or whether the patient can be managed with oral sulfonylureas.

Wolcott-Rallison syndrome (WRS) is the most common form of neonatal diabetes in consanguineous pedigrees.[4] The various manifestations evolve over time and a regular follow-up is crucial for management. The outcome is usually unfavorable with death occurring by 2–3 years of age in most cases. In this report, we present an infant diagnosed with neonatal diabetes, identified with a mutation consistent with WRS and discuss the challenges that the family and we, the treating team, faced during a long and continuous 6 years' period of follow-up.

  Clinical Description Top

A 3-month-old boy was brought to the emergency in an unresponsive state. On elicitation of history, it was found that the infant had high-grade fever that was present throughout the day for 6 days, associated with poor breast feeding. There was no history of cough, coryza, loose stools, vomiting, abdominal distension, or rashes in the initial course of illness. He had been taken for a medical consult and had been prescribed some oral medication, the nature of which was unknown and there was no written documents. He developed fast breathing in the last 2 days that was not associated with chest indrawing. The baby had stopped interacting with his mother for a few hours and became unresponsive which prompted his parents to rush to the emergency. There was no history of seizures, excessive crying, or paucity of movements of any part of the body. There was no history of bleeding from any site, fall, or trauma. He was passing urine normally, around 8 times a day.

There was no history of any similar episode in the past and the infant had had no significant illness since birth. He was born to a booked primi mother with an uneventful antenatal period. He was born by normal delivery at 38 weeks' gestation, with a birth weight of 2.5 kg and had displayed a smooth perinatal transition. At 3 months, he had been appropriately immunized and had attained milestones according to age. There was a history of consanguinity, his parents were first cousins. There was no history of diabetes mellitus or any significant medical illness in the family.

At admission, the infant had a temperature of 38°C, was tachypneic with a respiratory rate of 72/min (appearing acidotic in nature), and had tachycardia with a heart rate of 160 beats/min. The capillary filling time was 3 s, and peripheral pulses were palpable. He had features of severe dehydration with a depressed anterior fontanelle, dry mucosa, very slow skin recoil, and lethargy. Pallor was present. There was no icterus, cyanosis, or rash. His weight was 3.5 kg (Z score −4.65) and length was 56 (Z score −2.73). The sensorium was altered with a modified Glasgow Coma Scale of 7/15. There was no eye opening (E1), he was withdrawing limb to pain (M4) and moaning to pain (V2). The pupils were bilaterally equal, symmetrical and reactive to light. There was no focal neurological deficit. The abdomen was soft, nontender with the liver palpable 2 cm below costal margin. The respiratory and cardiovascular examination was normal.

Initial investigation in the emergency revealed a capillary blood glucose of 346 mg/dl and metabolic acidosis (pH 6.9 and HCO3 of 4.3 mEq/L) with a high anion gap. This prompted us to check the urine which revealed glycosuria and ketonuria (3+). He had a hemoglobin of 10.5 g/dL, elevated total leukocyte count of 24,000/mm3, thrombocytosis (platelet count 742/mm3), and raised C-reactive protein of 12 mg/L. The blood urea was 118 mg/dl, serum creatinine 1.5 mg/dl, serum sodium 136 mEq/L, and potassium 5.4 mEq/L. The liver function tests were normal. Since hyperglycemia, ketonuria, acidemia, and markers of infection were present, a diagnosis of diabetic ketoacidosis (DKA) with sepsis and possible meningoencephalitis was kept.

Management and outcome

In view of poor sensorium, acidosis, and severe dehydration, the infant was intubated and ventilated and shifted to the pediatric intensive care unit. He was administered 10% dehydration correction that was infused at a uniform rate over 48 h along with maintenance fluid as per guidelines of the International Society of Pediatric and Adolescent Diabetes.[5] Insulin was administered after the 1st h fluid bolus as an infusion of 0.1 unit/kg/hour. He was also given antibiotics and other supportive measures. The acidosis improved but did not resolve completely. The infant developed acute kidney injury; his blood urea increased to 129 mg/dl, serum creatinine rose to 2.1 mg/dL and urine output became low (0.5 ml/kg/h). Peritoneal dialysis was started that gradually resulted in a steady improvement in renal parameters, urine output and acidosis. A total of 129 cycles over 6 days were required and by day 7, the creatinine reduced to 0.9 mg/dl, the child had good urine output and got extubated. Insulin was gradually tapered to 0.05 unit/kg/hour with complete resolution of acidosis by day 4. The liver function tests and electrolytes remained normal. The blood culture was sterile.

Feeds were initiated along with a basal-bolus Insulin regime (regular Insulin thrice a day and isophane Insulin twice a day). An ultrasound revealed mildly increased kidney size with increased cortical echogenicity. Investigations directed toward the work-up of diabetes revealed a very high glycated hemoglobin (HbA1c) (11.6%), but the C peptide was negative. The onset of diabetes at an early age prompted us to seek an underlying genetic etiology. On sequence analysis of genes for neonatal diabetes (potassium channel J11, ABCC8, Insulin, and EIF2AK3), the child was found to be homozygous for an EIF2AK3 nonsense mutation, p.Tyr360Ter confirming the diagnosis of WRS. Further testing revealed that both parents were heterozygous for the same mutation.

At discharge, 23 days after admission, the blood glucose levels were well controlled on basal-bolus regime. The parents had been trained to care for the infant, check and record blood glucose, and in all the nuances of Insulin dosing and administration. They underwent genetic counseling in which they were explained the nature of the syndrome, natural course of disease, likely complications, prognosis, importance of a regular follow and the need of a prenatal evaluation in the event of a future pregnancy.

The infant was called for the first follow-up visit after a month, and thereafter every 1–2 months to check blood glucose records and review all aspects of Insulin dosing and administration. His growth parameters were recorded 3 monthly, ultrasound done 6 monthly, and skeletal survey done at first visit, and thereafter 6 monthly. Blood investigations such as HbA1c, blood counts, liver and kidney function tests and electrolytes were performed 3 monthly. Thyroid function test was done at first visit and then 4–6 monthly. The home monitoring of blood glucose was done regularly and readings were mostly within 80-190 mg/dl range. The kidney function tests, thyroid function tests and skeletal survey were normal. The child, however, displayed growth retardation [Figure 1] and delay in acquisitions of developmental milestones since early follow-up.
Figure 1: Growth chart of the child

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At the age of 2½ years, the thyroid function tests revealed central hypothyroidism (thyroid stimulating hormone 2.34 IU/ml, free thyroxine 0.51 ng/ml, free triiodothyronine 3.03 pg/ml) for which he was initiated on thyroxine 50 μg/day. Ultrasound of the neck showed a normally formed thyroid gland and thyroid scan showed normal uptake and size. Magnetic resonance imaging of the brain was done for pituitary evaluation and showed a normal size and position of the pituitary gland. To evaluate other pituitary hormones, serum adrenocorticotropin and cortisol were tested and were normal. The skeletal survey at 3 years showed small and poorly formed, irregular, and sclerotic epiphyses of the long bones along with flattened vertebral bodies suggestive of spondyloepiphyseal dysplasia [Figure 2]. He was also diagnosed to have iron deficiency anemia (Hb 8.9 g/dl, microcytic hypochromic anemia, serum ferritin 4 μg/L) and with iron supplementation it improved to Hb 11 g/dl.
Figure 2: (a) Small, sclerotic epiphysis with irregular border at the head of femur and (b) flattened vertebral bodies suggestive of spondyloepiphyseal dysplasia

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By 4 years, the renal parameters got deranged along with persistent hyperkalemia, normal anion gap metabolic acidosis and estimated glomerular filtration rate of 50 ml/min/1.73 m2 (chronic kidney disease [CKD] stage 3A). Ultrasonography revealed small size kidneys with raised echogenicity (right kidney 58 mm × 24 mm and left kidney 55 mm × 29 mm). The developmental assessment revealed a developmental quotient of 50% (motor 50%, social 67% and language 33%) and social quotient of 70%, thus making a diagnosis of global developmental delay (consistent with the underlying syndrome). Hearing, tested by pure tone audiometry, was within normal limits bilaterally. Vision was emetropic on dilated cycloplegic refraction and fundus was normal. A clinical timeline is presented in [Figure 3].
Figure 3: Index case with short stature and genu valgum deformity due to spondyloepiphyseal dysplasia

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At 6 years, his height is 86 cm (−5.96 Z as per Indian Academy of Pediatric chart) with upper segment to lower segment (US: LS) ratio of 1.1 which is attributed to skeletal dysplasia [Figure 4]. Currently, the child is receiving basal bolus regime (regular and glargine Insulin) with Insulin requirement 1.2 units/kg/day and last HbA1c 7.7% (June 2022). He is also receiving thyroxine supplementation (75 μg/day). For CKD, he requires potassium binder and oral bicarbonate on a daily basis and periodical injectable erythropoietin.
Figure 4: A timeline of various manifestations of WRS in the child. WRS: Wolcott Rallison syndrome

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Over the follow-up years, the child has not developed any episode of DKA and is compliant with his treatment. Blood glucose is being monitored diligently at home including use of continuous glucose monitoring system for a few weeks. He has required 2 brief admissions for 2–4 days for monitoring and control of his blood glucose and has received one transfusion of packed red cells in his 4th year. Although hepatic dysfunction is a frequent association with WRS, it has still not emerged in this case. A younger sibling has been born and is now 3-years-old, alive and healthy. Prenatal diagnosis was done and did not reveal mutation.

  Discussion Top

WRS is a rare autosomal recessive disorder, originally described in 1972 in siblings with early onset diabetes and skeletal dysplasia and most reported cases are from Middle East.[6],[7] It is the most common cause of permanent neonatal diabetes in consanguineous pedigrees, accounting for 15 of 63 (23.8%) consanguineous probands of permanent neonatal diabetes.[4] It is caused by mutation in EIF2AK3 gene located at chromosome 2p12 that encodes for pancreatic endoplasmic reticulum kinase, a key enzyme for initiating cellular response to endoplasmic reticulum stress. The loss of function mutation leads to accumulation of misfolded proteins causing cell apoptosis. This gene is predominantly expressed in pancreatic beta cells and bone leading to universal manifestation of diabetes mellitus and bony dysplasia in this syndrome.[8] Compound heterozygous variations of the gene have been recently reported to cause WRS in two children from nonconsanguineous parents.[9] Apart from early onset diabetes and skeletal dysplasia, other manifestations include hepatic dysfunction, renal dysfunction, exocrine pancreatic insufficiency, neutropenia, and developmental delay. Owing to the various associated features, the lifespan is short with a mean survival of 5.8 years, though a case from Kuwait was last reported alive at 17.5 years age.[7],[10]

Diabetes mellitus typically presents within the first 6 months of life though some may be diagnosed later, even at 2 years of age.[7] It is a nonautoimmune Insulin requiring diabetes.

Skeletal dysplasia is the other cardinal finding and presents as small and irregular epiphyses, enlarged metaphyses, flattened acetabulum, and variable degrees of osteopenia.[11] There could be fractures and atlantoaxial dislocation. Short stature seen in WRS cases also is a result of skeletal dysplasia. Our case also had significant skeletal dysplasia and short stature.

Hepatic dysfunction is a frequent association and presents as intermittent hepatitis characterized by hepatomegaly, jaundice, and raised liver enzymes.[7] It was noted in 60% of 35 cases of Ozbek et al.[12] The hepatic histology could vary from mild lobular infiltration by lymphocytes to progressive fibrosis. Renal dysfunction, reported in 1/5th of cases by Ozbek et al.[12] could present as intermittent episodes of renal insufficiency or CKD which has manifested in this patient. Developmental delay and learning difficulties are present in the majority of cases.[11] Our case also had significant developmental delay. Neutropenia has been reported in a few cases and seems to be specifically associated with W522X mutation of the EIF2AK3 gene.[12]

Central hypothyroidism has been reported in 4 of 18 cases described by Senée et al.[11] Bin-Abbas et al. described two siblings with central hypothyroidism with normal imaging of hypothalamic pituitary region.[13] Our case was detected to have central hypothyroidism at 3 years of age without deficiency of other pituitary hormones and normal imaging. There have been occasional reports of primary hypothyroidism as well.[14],[15] The short stature seen in this child despite being on thyroxine can be explained by the concurrent skeletal dysplasia and CKD.

Exocrine pancreatic insufficiency has been reported infrequently and may require pancreatic supplements.[12] However, our case has not developed clinical features of exocrine pancreatic insufficiency such as chronic diarrhea or oily stools.

WRS, due to mutations in EIF2AK3 gene, has a multitude of manifestations, with neonatal diabetes and skeletal dysplasia and variable presence of renal dysfunction, hepatic dysfunction, neutropenia, exocrine pancreatic deficiency, and delay in growth and development.

Our case presented as neonatal diabetes and evolved to manifest most of the features described above. The definitive diagnosis based on genetic analysis was established early on, at the first presentation itself. A detailed explanation of the condition to the parents also helped in ensuring a long and continuing follow-up in a disorder that otherwise has a dismal prognosis. One of the major factors behind the success of our management in an otherwise difficult disease is the extremely supportive and compliant family. regularity of follow up and adherence to our instructions has been crucial for the early identification of the various manifestations as they evolved and progressed. Let us hope that our case also has a long life like the one from Kuwait.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal patient identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Grulich-Henn J, Wagner V, Thon A, et al. Entities and frequency of neonatal diabetes: Data from the diabetes documentation and quality management system (DPV). Diabet Med 2010;27:709-12.  Back to cited text no. 1
Varadarajan P, Sangaralingam T, Senniappan S, et al. Clinical profile and outcome of infantile onset diabetes mellitus in southern India. Indian Pediatr 2013;50:759-63.  Back to cited text no. 2
Jahnavi S, Poovazhagi V, Mohan V, et al. Clinical and molecular characterization of neonatal diabetes and monogenic syndromic diabetes in Asian Indian children. Clin Genet 2013;83:439-45.  Back to cited text no. 3
Rubio-Cabezas O, Patch AM, Minton JA, et al. Wolcott-Rallison syndrome is the most common genetic cause of permanent neonatal diabetes in consanguineous families. J Clin Endocrinol Metab 2009;94:4162-70.  Back to cited text no. 4
Wolfsdorf JI, Allgrove J, Craig ME, et al. ISPAD clinical practice consensus guidelines 2014. Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Pediatr Diabetes 2014;15 Suppl 20:154-79.  Back to cited text no. 5
Wolcott CD, Rallison ML. Infancy-onset diabetes mellitus and multiple epiphyseal dysplasia. J Pediatr 1972;80:292-7.  Back to cited text no. 6
Habeb AM, Deeb A, Johnson M, et al. Liver disease and other comorbidities in Wolcott-Rallison syndrome: Different phenotype and variable associations in a large cohort. Horm Res Paediatr 2015;83:190-7.  Back to cited text no. 7
Zhang P, McGrath B, Li S, et al. The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol Cell Biol 2002;22:3864-74.  Back to cited text no. 8
Zhao N, Yang Y, Li P, et al. Identification of two novel compound heterozygous EIF2AK3 mutations underlying wolcott-rallison syndrome in a Chinese family. Front Pediatr 2021;9:679646.  Back to cited text no. 9
Shah N, Karguppikar MB, Khadilkar V, et al. Long-term follow-up of a child with Wolcott-Rallison syndrome. BMJ Case Rep 2021;14:e242376.  Back to cited text no. 10
Senée V, Vattem KM, Delépine M, et al. Wolcott-Rallison syndrome: Clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity. Diabetes 2004;53:1876-83.  Back to cited text no. 11
Ozbek MN, Senée V, Aydemir S, et al. Wolcott-Rallison syndrome due to the same mutation (W522X) in EIF2AK3 in two unrelated families and review of the literature. Pediatr Diabetes 2010;11:279-85.  Back to cited text no. 12
Ozbek MN, Senée V, Aydemir S, et al. Wolcott-Rallison syndrome due to the same mutation (W522X) in EIF2AK3 in two unrelated families and review of the literature. Pediatr Diabetes 2010;11:279-85.  Back to cited text no. 13
Bin-Abbas B, Al-Mulhim A, Al-Ashwal A. Wolcott-Rallison syndrome in two siblings with isolated central hypothyroidism. Am J Med Genet 2002;111:187-90.  Back to cited text no. 14
Lundgren M, De Franco E, Arnell H, et al. Practical management in Wolcott-Rallison syndrome with associated hypothyroidism, neutropenia, and recurrent liver failure: A case report. Clin Case Rep 2019;7:1133-8.  Back to cited text no. 15


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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