Celiac Disease (CD) is an autoimmune enteropathy in genetically susceptible individuals triggered by exposure to wheat gluten (Gliadins) [1]. The previously considered rare disorder proved to be much more prevalent than what was considered [2]. It is recognized now as one of the most common genetic disorders in the West with a prevalence of 1%-2.67% [2].

The true prevalence of the disease in our area of the world is underestimated due to the unawareness of the unusual presentations of the disease [3]. Previous report from Jordan reported an incidence of celiac disease as 1 in 2800 live births, with estimated point prevalence of 7:100 000[4].

Celiac disease presented classically (typically) with malabsorption related symptoms (diarrhoea, abdominal bloating, weight loss, muscle wasting, and nutritional deficiencies), within weeks to months of gluten exposure. The term “atypical” celiac disease is used to describe patients presenting with extra intestinal symptoms, positive immunological workup and typical small intestinal changes [2].

Few studies had addressed atypical or silent CD in Middle East [3]. Jordan reported a high prevalence rate of short stature in celiacs [4]. In this case series we are presenting the first cases of CD diagnosed at our new service at South Jordan. The small number limits any statistical conclusions, but it shows that the non-classical presentations are not uncommon in our rural community. Our aim is to increase the awareness of paediatricians and general practitioners of the diverse clinical presentations, and population with increased risk of developing the disease. We believe that this will increase the rate of diagnosis and limits the morbidities.

Case 1

A 2.5-year-old girl, with abdominal distention and chronic diarrhoea, on examination, was found to be severely malnourished. Her investigations showed iron deficiency anemia (IDA), prolonged PT, rickets and hypoalbuminemia. Stool routines were negative for ova and parasites, but fat droplets. Serologic Celiac workup (Anti tTG IgA) was positive. She was started on Gluten-Free Diet (GFD) and vitamins supplementation-not scoped. After starting the GFD, she developed Refeeding Syndrome. Her condition was controlled by cutting back her, caloric intake, in addition to minerals and vitamins supplementation.Gradual increment in her caloric intake was tolerated later. On follow up, she was adding weight and her hematological abnormalities corrected.

Case 2

A 12-year-old boy, known case of chronic headache, referred to our clinic with recurrent abdominal pain and early satiety to rule out abdominal migraine. His school performance deteriorated over the last few months. Physical examination showed pallor and a height on the 5^th centile. His investigations showed IDA. Occult blood loss and Hemoglobinopathies were rolled out. His tTG IgA was positive. EGD done, his small intestinal biopsies were consistent with CD. On GFD, his headache and abdominal pain improved. His school performance became better. His anemia was resolved.

Case 3

A 4-year-old boy, known case of Down syndrome, presented to our clinic with failure to thrive. He has no congenital heart disease, or gastrointestinal symptoms. His growth parameters were far below 3^rd centile. His workup showed dimorphic anemia, rickets and prolonged PT. His Celiac serology (tTG IgA) was positive. Patient was scoped outside our facility and his CD was biopsy-proven. He was started on GFD, multivitamins and antireflux measures. On follow up, his anemia improved, his coagulopathy corrected and started to add weight. PediaSure® formula was added to his nutritional plan, which hastens his weight gain.

Case 4

A 4-year-old boy, referred to our clinic with poor appetite and persistent IDA. He had no abdominal pain, vomiting, diarrhoea or blood in stool. His physical examination was normal except for being pale. His anemia persisted in spite of Iron supplementation.His Hb-electrophoresis was normal. His stool workup showed no ova or parasite and negative heme-occult. Celiac screen was positive. Upper Endoscopy showed no ulcers or signs of inflammation. His small intestinal biopsies showed chronic inflammatory infiltrate; unfortunately the surface was lost during fixation. Condition discussed with the family and agreed on trying GFD. After 3 months of GFD, he added 2 kgs, his Hb, MCV, MCH and RDW normalized.

Case 5

An 8-year-old girl, referred with early satiety and short stature. She had no abdominal pain, diarrhoea or vomiting. Her height was below the 5^th centile. Rest of physical exam was normal. Her endocrine workup was normal. Celiac screen (Anti tTG IgA) was negative, but her serum IgA was undetectable. EGD was done for her. Her small intestinal biopsies established the diagnosis of CD.

Case 6

An 8.5-year-old girl, known case of IDDM on insulin, had no gastrointestinal symptoms. Her physical examination was fine except for using hearing aids. She was screened for CD as part of diabetes workup. Her Anti tTG IgA was positive. Patient scoped outside our facility. Her intestinal biopsies confirmed the diagnosis. Patient started on GFD, her follow up anti tTG IgA became negative. Patient was started on with GFD, iron and vitamins supplementation. Three months later, the patient gained 5 kg and her Blood Count, Albumin, INR and Electrolytes were normal.

Celiac disease is a genetically determined autoimmune enteropathy triggered by exposure to gluten and related proteins. CD can present at any age [1]. It is unique among autoimmune disorders in that there is a known trigger and avoidance of which produces remission in the vast majority of cases. Clinical presentation depends on age, sensitivity to gluten, and the amount of gluten ingested in the diet, as well as other unknown factors. Younger age groups present with classical (typical) picture, while older children and adults run a more atypical course [2,5-8]. The classical (typical) presentation of CD is with malabsorption related symptoms (diarrhoea, abdominal bloating, weight loss, muscle wasting, and nutritional deficiencies) within weeks to months of exposure to gluten containing diet [2,5,8]. The term “atypical” CD is used to describe patients who present with extraintestinal symptoms (liver, skin, joints, reproductive organs, nervous system, and heart) [7,8], with positive immunological workup and typical small intestinal changes. Many of these symptoms are responsive to the initiation of a gluten-free diet [8,9]. In our series typical CD was seen in one case (case 1). Her poor growth is thought to be secondary to reduced food intake and nutrients malabsorption. Fat-soluble vitamins deficiencies (vitamins K, D, E and A) are commonly encountered in celiacs [10] (cases 1, 3 and 7). Low vitamin K levels detected by prolonged PT and INR. Vitamin D malabsorption results in rickets which clinically manifests as failure to thrive, abdominal distention, muscle weakness, tetany and skeletal changes. Diagnosis can be established with low serum 25-hydroxyvitamin D levels. In our cases Ca, PO₄ and alkaline phosphatase were used as surrogate markers for Vitamin D deficiency. Wrist x-ray is a dependable alternative especially if Zn deficiency is suspected, which will affect the results of alkaline phosphatase. In our department due to the unavailability of vitamin levels the results of Vitamin D and K deficiency extrapolated on Vitamin A and E

though no clinical manifestations were noticed. In case of severe growth delay and malnutrition (as in case 1) development of Refeeding Syndrome is a real concern. The Refeeding syndrome describes the metabolic and physiological consequences of the depletion, repletion and compartmental shifts and inter-relationships of phosphorus, potassium, magnesium, glucose metabolism, vitamin deficiency and fluid resuscitation. As these minerals shift to the intracellular spaces, serum levels dropped and the intracellular extracellular fluid balance jeopardized [11]. These rapid changes, severe hypophosphatemia, severe hypokalemia can be fatal. The Refeeding Syndrome becomes most evident around the third day of treatment and the treating physician needs to be extra conscious while dealing with these cases. Treatment depends on cutting back of delivered calories and correct electrolyte deficiencies. Atypical presentation of CD occurs at a later age (especially those >5 years of age).

Children with atypical presentation may have either unusual intestinal (recurrent abdominal pain, nausea, vomiting, bloating or constipation), or extraintestinal manifestations (Table 2); (e.g., short stature, pubertal delay, persistent iron deficiency anemia, abnormalities in liver chemistry tests).

Table 1: Patients` Demographics, presentations and investigations.

Table 2: Atypical manifestations of Celiac Disease.

The frequency of iron deficiency anemia in celiac disease varies from 12% to 69% [12]. In our small series most of our children were iron deficient (Cases 1-4, 7). Because the proximal small intestine is the predominant site of inflammation and also the site of iron absorption, malabsorption of iron is markedly impaired and the association of celiac disease to refractory iron deficiency anemia is well established.

Iron deficiency anemia resolves with adherence to a gluten-free diet, although normalization of the iron stores may require longer duration. The NASPGHAN guidelines recommend testing children with unexplained persistent Iron Deficiency Anemia not responsive to treatment for celiac disease [13].

Incidence of vitamin B₁₂ deficiency in untreated celiac patients ranges from 11% to 41%. The fact that Vitamin B₁₂ being absorbed from the ileum, which is relatively spared in celiac disease, leave the mechanism of Vitamin B₁₂ defeciency unclear. Coupling of Iron and Vitamin B₁₂ deficiency in celiacs gave the classical dimorphic anemia seen in celiacs (as in case number 3). It is well-established that short stature can be the only presenting clinical feature of CD.

In ME and NA countries, short stature was discovered to be the presenting symptom in 7.7% to 53% of patients [3]. Interesting enough the highest prevalence of short stature was reported from Jordan (12%). The pathogenesis is still unclear. After children have started the GFD, a significant increase in height velocity is often noticed; especially within one year of gluten-free diet. The target height is usually reached within 2 to 3 years. However, the catch-up growth is not always complete, probably because of the marked acceleration in bone maturation that parallels the rapidity in growth velocity [14]. In case 5, due to short period of follow up the growth velocity was not judged. Neurological and psychiatric disorders including depression, anxiety, irritability, peripheral neuropathy, epilepsy, cerebellar ataxia and migraine have all been reported in Celiac Disease [15]. There are few studies specifically addressing the association between headache and CD [16]. In patients with migraine, CD was found in 4.4% compared with 0.4% in blood donors. As in our patient (case 2), headache reported to improve on Gluten-free diet [16].

An increased frequency of Celiac disease is found in specific risk groups. First degree relatives of celiacs, patients with autoimmune disorders (IDDM (case 6), thyroiditis), Down syndrome (case 3), Turner Syndrome, Williams Syndrome, and IgA deficiency patients (case 5) all were reported to have higher rates. There is no consensus on screening all these groups. While the NIH guidelines from 2004 recommends screening Down syndrome and Williams Syndrome patients but not the asymptomatic IDDM patients [17], the NICE guidelines suggests screening both adults and children with IDDM, IBS, Dermatitis herpetiformis and Autoimmune thyroid disease [18]. Coupling the recommendations of those major health guidelines expected to identify the highest number. Cost-effectiveness is an issue to be determined.

IgA anti-tTG testing has now become the test of choice for diagnosis and monitoring CD all over the world. In a routine setting, as with Anti-endomysial Ab, total IgA level should be ordered to assess for selective IgA deficiency. Complete IgA deficiency will cause false negative IgA anti-tTG results (case 5) but on the same time should alert the specialist for the increased risk of CD in the patient. If IgA deficiency is found, then depending upon the clinical presentation, IgG serology or even duodenal biopsy is recommended [19].

In case 5, is the patient really asymptomatic or her hearing impairment is again a non-classical presentation of celiac disease [20] is a question to be answered by further investigations and the effect of Gluten-free diet on the condition. Since the recognition of CD the diagnosis was based on villous atrophy on small intestinal biopsy [20]. Despite substantial changes in the mode of presentation and the availability of new diagnostic tools, small bowel mucosal biopsy has remained the gold standard for CD diagnosis until now [21]. The number and the site of the biopsies, the orientation of the biopsy during fixation and the experience of the pathologist especially in nonatrophic lesions should be in mind while interpreting the pathology report [22]. In our series two of our patients treated as celiac disease with non-classical histology findings are not biopsied even (cases 1 and 4) (Table 1). Both patients responded to GFD very well. Adherence to gluten-free diet remains the mainstay of therapy for CD. Detection and correction of nutritional deficiencies is also important. Symptoms resolve in most cases following compliance with GFD. Follow-up is important to ensure compliance and enforce it. The main cause of noncompliance in our population is availability and financial restrains.

This small series describing our consecutive cases diagnosed with CD pointing that we are sharing the world the changes in epidemiology of CD. The awareness and knowledge about the variable clinical presentations will lead to early detection, and appropriate intervention in affected children.