Neonatal Diabetes Mellitus is a rare genetic condition with an approximate incidence of 1 in 90000 - 160,000 live births [1]. The usual age of presentation is within 6 months and rarely from 6 to 12 months [1]. It may require treatment with insulin therapy, transiently or permanently. The two main pathogenic mechanisms are altered development and survival of beta cells due to pancreatic malformation or due to abnormal functioning of beta cells. Common genetic mutations ABCC8 or KCNJ11 genes are an important cause of neonatal diabetes [1]. However, rare genetic syndromes like Wolcott-Rallison Syndrome (WRS), an autosomal recessive disease can be seen rarely as cause of neonatal/early-onset non-autoimmune insulin-requiring diabetes. WRS is characterized by skeletal dysplasia, growth retardation and liver dysfunction [2]. Wolcott-Rallison syndrome (WRS) was named after Dr. Wolcott and Dr. Rallison, who first described this syndrome in 1972 in three affected siblings [3]. Fewer than 60 cases have been described worldwide [2]. The mean survival is 5.8 years [4]. We present a long term follow up of an 8 year 4 months old male child.

We present a case of 8 year 4 months old male child, 1st by birth order, born out of non- consanguineous marriage, born by a full term normal vaginal delivery with birth weight of 2.5 kgs with no history of NICU stay. He had an uneventful neonatal period. He first presented at 2 months of age with the acute onset of respiratory distress, vomiting and increased urinary frequency. There was no history of fever, loose stool, convulsion, altered sensorium, hyperpigmentation. Examination revealed signs of severe dehydration like lethargy, dry skin, delayed skin pinch and depressed anterior fontanel. Heart rate was 160/min, Respiratory rate was 70/min, Acidotic breathing pattern and blood pressure was 60/40 mm Hg. Bedside blood glucose was done which came high. Urine sugar and ketones were positive. Random blood sugar was 480 mg/dl. Blood Gas Analysis and electrolytes was suggestive of high anion gap metabolic acidosis with hypokalemia (Ph.- 6.89, HCO3- 5, Pco2-16, Na- 135mEq/L, K- 2.6mEq/L, Cl- 102mEq/L) Septic screen was negative. Child was provisionally diagnosed as a case of Neonatal Diabetes Mellitus with Severe Diabetic Ketoacidosis. Acute condition was tide over with IV fluids and IV insulin. C- Peptide was sent which was very low (0.36 ng/ml, Normal range: 0.7 -1.5 ng/ml) suggesting impaired insulin secretion. USG Abdomen was suggestive of normal pancreatic tissue. Stool for fat globules was sent to assess exocrine pancreatic function which was negative. Once stabilized, child was started on basal bolus regimen of Subcutaneous Insulin, Lispro and Glargine.

At 7 months of age, he again presented in acute decompensation which was triggered by Upper respiratory tract infection. Blood sugar was 448 mg/dl with Ketonuria. He had a severe Diabetic ketoacidosis and was managed in Pediatric Intensive Care Unit. Whole exome sequencing was done. It revealed a Homozygous frameshift mutation in exon 9 (c.1635_1638delGAAA) of Eukaryotic translation initiation factor 2alpha kinase (EIF2AK3) gene confirming Wolcott Rallison syndrome.

Parents could not be tested in view of financial constraints.

During routine outpatient visits his growth was monitored which was appropriate till 2 years of age. At 2.5 years, growth faltering was noticed with height-88 cm (<-3SD) and weight-10 kgs (at -3SD).

Skeletal survey was done which was normal. Child was lost to follow up till 5 years of age when he presented to the emergency room with complaints of yellowish discoloration of eyes and skin for 3 days, drowsiness for 2 days and loss of consciousness for 2-3 hours. Liver function test was suggestive of Total Bilirubin-3.2 mg/dl, SGOT-913IU/L and SGPT- 1245IU/L, Serum Ammonia – 300mcg/dl (Normal range- 90-150 mcg/dl). Viral markers were negative. Hepatic encephalopathy was managed with supportive treatment. It was attributed to the hepatic involvement by the disease process. Child recovered and there was no recurrence. HbA1c was 9.8 g/dl while taking basal bolus insulin therapy with Insulin Aspart (rapid acting) three times a day and Inj Glargine once a day with daily requirement of 2U/kg/day.

Child had developed multiple skeletal abnormalities like Short stubby fingers, Short stubby toes, Genu varum and flat wide feet were present. Severe growth faltering was noticed with Height-93 (<- 3SD) and Weight- 14 kgs (at -3SD). Skeletal survey was done which revealed Dysplastic changes of long bones, enlarged metaphysis and thinning of cortices. X-ray Hand was suggestive of small and irregular carpal bones with phalanges showing dense and cone shaped epiphysis. At 7 years of age, he again presented in acute decompensation triggered by acute febrile illness. Blood sugar was 500mg/dl and Urine ketones were positive. HbA1c was 8.4 g/dl with daily insulin requirement of

1.65 U/kg/day. He had a moderate Diabetic ketoacidosis and was managed in an Intensive care unit. Child had achieved all the developmental milestones appropriate for his age but was noticed to have difficulty in reading and writing. On detailed evaluation he was found to have moderate Learning Disability with IQ 75%.

At present, child is 8 year 6 months old, he is doing well on Basal Bolus Insulin therapy, Insulin Aspart and Insulin Glargine with total daily requirement of 1.5 Units/kg/day. He has variable glycemic control with HbA1c between 8 and 9 g/dl. He has short stature with Height- 103 cm (<-3SD), Upper segment to lower segment ratio of 1.5:1, growth velocity- 5cm/yr. In summary, 8 year 4 months male child diagnosed as Wolcott Rallison syndrome with Neonatal Diabetes Mellitus, Growth failure, Liver dysfunction and Skeletal abnormalities is being managed through a multidisciplinary approach by Pediatric Endocrinologist along with Orthopedic team, Physiotherapist, Dietician and Neurodevelopmental psychologist.

Wolcott-Rallison syndrome is a rare autosomal recessive disorder with fewer than 60 cases described in literature [2]. Majority cases are from consanguineous marriages, however, a few cases like our patient, have been reported from non-consanguinity also by Ozbek MN, et al [4,5,6,7,8]. The disease is caused by the mutation of a gene encoding a trans membrane protein of the endoplasmic reticulum (ER) named eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3). This enzyme is highly expressed in the beta cells of the pancreas and is also known as pancreatic EIF2α kinase (PEK) and PKR-like endoplasmic reticulum kinase (PERK) [2,9]. The key role of this enzyme is to control the translation during the unfolded protein response (UPR).

In the pancreas, it regulates the differentiation and proliferation of the islet cells. It also regulates the processing, folding and trafficking of proinsulin. Loss-of-function mutations in the EIF2AK3 gene leads to ER stress and increased UPR. In pancreas, PERK regulates aggregation of proinsulin and protein synthesis. Loss of these functions cause defect and apoptosis of beta cells leading to a state of permanent insulin deficiency and neonatal diabetes [4]. Similarly, the expression of enzyme, eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3) in bone tissue stimulates the bone growth and loss of this function in bone causes the skeletal dysplasia seen in WRS [4]. Our patient also had homozygous frameshift mutation in exon 9 (c.1635_1638delGAAA) of EIF2AK3 gene confirming the diagnosis of Wolcott Rallison syndrome.

The two most important clinical presentations seen in WRS are neonatal/early-onset diabetes and multiple epiphyseal dysplasia. The third most frequent manifestation is liver dysfunction in the form of hepatomegaly, elevated liver enzymes, and recurrent acute liver failure [2].

Diabetes is non-autoimmune, permanent insulin- dependent from onset, usually presents with DKA during first 6 months of life, our patient also presented with DKA at 2 months of age. The birth weight can be slightly reduced, median -1.4 SD reported by Rubio-Cabezas et al [10], as seen in our patient, the birth weight was 2.5 Kgs. We did not check the antibodies in our patient as the clinical presentation and genetic testing were in compliance with the diagnosis of WRS.

The skeletal abnormalities seen in WRS are multiple epiphyseal-metaphyseal dysplasia involving the long bones, pelvis, and vertebrae. Skull bone is usually spared. X rays shows dysplastic changes as enlarged and irregular metaphysis with prominent beaks as seen on the skeletal survey in our patient at the age of 5 years. The carpal bones and phalanges appear short and enlarged. Our patient had short and stubby fingers and toes. Frequent and multiple fractures can be seen with normal biochemical profile, normal serum calcium and phosphorus levels. Spine shows appearance of thoracic kyphosis and/or lumbar lordosis. Chest becomes broad and flattened. Pelvis can have abnormal iliac wings and dysplastic acetabula roofs with femoral head dislocation or subluxation. Patient walks with a typical "duck-like" gait due to stiffness and restricted abduction movement at hip joints. Rarely, extreme cases can have neurological deficits due to spinal cord compression [2].

Hepatic dysfunction is another characteristic feature of WRS presents with recurrent episodes of hepatic failure and hypoglycemia. The episodes are triggered by URTIs and have variable severity of hepatic dysfunction and failure. It is an important cause of death in these patients [2]. Our patient had first episode of severe hepatic failure at the age of 5 years, which recovered with supportive management and there were no recurrences during follow-up till age of 8 years and 4 months.

Patients can have intellectual and developmental delay due to recurrent episodes of DKA, hypoglycemia and liver failure [2]. Our patient attained normal developmental milestones except for mild difficulty in reading and writing.

Other rare clinical manifestations e.g. renal insufficiency, hypothyroidism, neutropenia and recurrent infections, cardiac and pulmonary abnormalities were not seen in our patient [2].

WRS is diagnosed clinically in the setting of neonatal diabetes which is insulin dependent along with skeletal dysplasia associated with hepatic dysfunction and confirmed by the genetic testing for mutation in EIF2AK3 gene. Management involves multi-disciplinary approach involving pediatric endocrinologist, orthopedic, neuropsychologist, and dietician, nursing care, pediatric PCP and physiotherapist. Diabetes is managed by insulin pump or basal-bolus insulin regimen as done in our patient. Target HbA1c and sick day guidelines are managed similarly as in type 1 diabetes.

Hypoglycemia and DKA episodes to be avoided by close monitoring. Overall prognosis is poor and patients rarely live beyond one decade of life. The longest survival has been reported in a couple of patients, 32 and 35 years old [2, 6,10]. The reason for mortality is usually multi-organ failure, hepatic failure with encephalopathy, and severe infections. Patients with very long-term survival usually do not develop hepatic failure episodes [2].

Intervention strategies which can target ER stress pathway might be helpful in therapy and prevention of this disease. Glucagon-like peptide-1 (GLP-1) agonists have been found to be helpful in reducing the ER stress and protecting β cells in pancreas, both in vitro and in vivo (cellular and animal models) [11,12]. ER stress is an important mechanism in the pathogenesis of more common diseases such as Type 1 and type 2 diabetes, obesity, and cardiovascular diseases. Hence, understanding the potential targets in this pathway and studying various intervention strategies might have wider application in health and disease states [2].

WRS is a rare genetic disorder characterized by insulin dependent neonatal diabetes, skeletal dysplasia and hepatic failure. ER stress is the main pathway involved in its pathogenesis due to a genetic mutation. Current treatment involves management of diabetes with insulin and multi- disciplinary approach. Targeting ER stress pathway can be a potential therapeutic and prevention strategy for WRS.

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