Background: Hyper-IgM syndrome (HIGM) is a rare primary immunodeficiency in whichdefective B cell isotype switching results in a phenotype characterized byelevated or normal serum IgM levels and low levels of other immunoglobulinclasses, leading to an increased susceptibility to infection, neutropenia,autoimmune disorders, and malignancies. In this disease, a mutation occurs in CD40gene, and immunodeficiency occurs simultaneously in B and T lymphocytes. Oral manifestationsof this primary immunodeficiency include wound-like lesions, oral candidiasis,gingivitis, periodontitis, and enamel defects.

Theoretically, systemic conditionsaffecting ameloblastic activity during enamel mineralization, i.e. abnormaloxygen levels resulting from hypoventilation in various respiratory diseases resultin enamel defects.

Casepresentation: We report a10-year-old male with hyper-IgM immunodeficiency. The patient had suffered fromfrequent infections, respiratory problems, and bronchopneumonia from the age of2 years. At 4 years of age, diabetes mellitus type 1 was diagnosed. During thedental evaluation, enamel defects were found in seven permanent teeth.Conclusion: A meticulous dental evaluation of children with systemicdiseases is mandatory inorder to discover possible developmental dental defects and to plan earlyinterventions.Key Words: Hyper-IgM Immunodeficiency Syndrome, Immunoglobulins,Enamel HypoplasiaIntroduction:Hyper-IgM syndrome(HIGM) is a rare genetic primary immunodeficiency disorder in which the levelsof immunoglobulin (Ig) A, G, and E reduce, while the level of IgM is normal orincreased.

(1-3) The inheritance is usually X-linked, but autosomal recessive and autosomaldominant forms have also been documented. (4-6) X-linked hyper-IgM is caused bythe defective expression of the CD40 ligand. Mutation in CD40 gene results in simultaneousimmunodeficiency in B and T lymphocytes. Since CD40 is necessary for the appropriatefunctioning of T lymphocytes and macrophages, various defects are observed inthis group of cells in a patient with HIGM. (4,5) Most HIGM patients showclinical signs in the first or second years of life, the most common of whichare frequent infections, neutropenia, autoimmune diseases, and malignancies.

(3,7-9)Oral manifestations including wound-like lesions, oral candidiasis, gingivitis,periodontitis, and enamel defects have also been reported. (10,11)Interferencesduring enamel matrix secretion or enamel mineralization lead to hypoplasia orhypomineralization during amelogenesis. (12,13)Based on the developmentaldefects of dental enamel (DDE Index), three types of enamel defects aredemarcated opacities, diffuse opacities, and hypoplasia. In a demarcatedopacity defect, alteration in the translucency of enamel is obvious with a distinctborder and can be white, creamy, yellow, or brown. A demarcated opacity defect results from atrauma to ameloblasts during the maturation stage or infections in the matrixsecretory or early maturation stage. A diffuse opacity appears in the shape ofa white line or patch with changes in the enamel translucency; however, thereis no clear boundary with the adjacent normal enamel. This defect has beenassociated with an arrest in enamel maturation.

In enamel hypoplasia, thequantity and thickness of enamel have decreased. The affected tooth can bewhite, yellow, or brown with a rough or pitted surface. This is due to a damageto enamel matrix secretion in amelogenesis stage 1.Etiologicfactors related to the DDE are divided into two categories: the factors with alocalized distribution including trauma, localized infection, and irradiation, andthose with a generalized distribution including genetic and environment. Infectiousdiseases and other medical conditions are possible environmental etiologicfactors for the DDE. (13-15)Here, we reporta 10-year-old male with hyper-IgM immunodeficiency.

Demarcated enamel opacitieswere detected in seven permanent teeth.   Casepresentation: The followingis a case report of a 10-year-old male who referred to the department of pediatricdentistry of the dental branch of Islamic Azad University of Tehran for dentalevaluation and treatment. There was no history of the disease in the siblingsor other close relatives. The genetic evaluation had not been performed;however, as the siblings or other close relatives were not involved, the mutationmay be the probable mode of inheritance.In the medical history of the patient, it wasreported that frequent infections, respiratory problems, and bronchopneumonia hadoccurred from the age of2 years. As a result, immunological diagnosis was done for the patient, which showednormal blood cell counts and serum Ig levels of IgA<5 mg/dl (N: 78-312),IgG<28.

3 mg/dl (N: 650-1500), IgM=275 mg/dl (N:55-300), and IgE<10 IU/ml (N <114),  which led to the diagnosis of hyper-IgMimmunodeficiency.Afterwards, thepatient received Intravenous Ig (IVIG) monthly with serum IgG levels of 500 to800 mg/dl. The responsible physician prescribed oral Trimethoprim/sulfamethoxazole(TMP/SMX, 1500 mg, q8h). At the age of 4 years, this antibiotic was replacedwith oral Azithromycin (10 mg/kg as a single dose on the first day).

At four yearsof age, after vomiting, diarrhea, severe malaise, and frequent urination, thepatient referred to the children’s medical center for blood glucose evaluation.The blood glucose level was reported to be 800 mg/dl, which led to thediagnosis of diabetes mellitus type 1. The family history was unclear.During thedental evaluation, white and creamy opacities with well-defined borders weredetected in seven permanent teeth including left maxillary premolars and firstmolar, left mandibular first molar, and right mandibular premolars and firstmolar (Figure 1 a-c). According to the observed situation of the involved teeth,a preventive approach was determined which included fissure sealant, preventiveresin restoration, fluoride therapy, and recall visits.     a                             b                                   c    Figure 1.Intraoral photographs of white and creamy opacities with well-defined bordersin (a,b) right mandibular premolars and first molar and (c) left maxillarypremolars and first molar and left mandibular first molar Discussion:In 1974, theWorld Health Organization (WHO) called immunodeficiency with increased IgMlevels as the Hyper-IgM syndrome or Hyper-IgM immunodeficiency (HIGM). In 2015,the International Union of Immunological Societies (IUIS), in theclassification of primary immunodeficiency, called XHIGM the CD40 liganddeficiency.

(16)The CD40 ligandis a transmembrane protein that is expressed on the surface of activated Tlymphocytes, and as a growth and differentiation factor, it could influence Tand B lymphocytes. (17,18)HIGM patients experience recurrent infections,especially in the respiratory and gastrointestinal tracts. Neutropenia,thrombocytopenia, and anemia are common symptoms of blood cell involvement. (19) Up totwo-thirds of the patients with XHIGM syndrome suffer from episodic, cyclic, orchronic neutropenia. The physiological basis of the neutropenia is unknown; however,the affected patients respond well to treatment with the granulocyte-colonystimulating factor (G-CSF).

(20)There is alsoan increased incidence of autoimmune diseases such as diabetes mellitus, chronicarthritis, hypothyroidism, and kidney disease. (21,22)Gastrointestinalinvolvement is common in HIGM patients and its highest form is diarrhea andmalabsorption. Finally, malignancies are seen as liver and gastrointestinaltract cancers, which can be life-threatening in these patients. (23-25) Themain line of treatment is Ig replacement in the form of IVIG that increases thelevel of IgG antibodies while decreasing the level of IgM antibody. The patientswith primary immunodeficiency diseases should not receive vaccines containinglive viruses.

(26)The patients with HIGM showed a significantlyhigh frequency of oral and dental manifestations including herpes sores,candidiasis, tonsillitis, gingivitis, calculus, and enamel hypoplasia. (27)Enamel production by ameloblasts is performedduring only a certain period of dental development and it is sensitive to theenvironmental changes at the time of amelogenesis. Amelogenesis occurs in three consecutivephases. The first phase includes secretion of enamel matrix that occurs afterthe formation of the first layer of dentin and continues until a completethickness of the enamel is formed. Phases 2 and 3, respectively, include enamelcalcification and maturation.

(12-14) Damage to enamel matrix secretion in thefirst step leads to thin enamel, and if the damage occurs in stages 2 and 3, a chalkyopaque porous enamel will be observed. (28) In the present case, enamel defects in sevenpermanent teeth were observed, including left maxillary premolars and firstmolar, left mandibular first molar, and right mandibular premolars and firstmolar. These defects were white and creamy opacities with well-defined borders.Based on the DDE index, these defects were considered demarcated opacities.                                                                              Weerheijm et al defined the term”molar incisor hypomineralization” (MIH) to describe a more specific pattern ofDDE, which includes hypomineralization of systemic origin of one to fourpermanent first molars frequently associated with affected incisors. The secondpermanent molars and bicuspids are seldom impaired by these enamel defects. Hypomineralizationpresents as an anomaly in the tissue translucency, and a white oryellowish/brownish area can be seen which may be asymmetrical. (29-31)The crown formation of permanent teeth, exceptfor the third molar, begins at birth and completes at around the age of 8 years.

The damage to ameloblasts during this period may cause DDE. Regarding the firstpermanent molar, the beginning of the formation of hard tissue is at birth, andcompletion of enamel lasts up to 2.5-3 years of age. Enamel formation ofmaxillary and mandibular first premolars begins around 1.5 years of age andcompletes at the age of 5-6 years.

This timing in secondary premolars is around2 years of age and 6-7 years of age, respectively. (32,33) Furthermore, in the presentcase, the occurrence of respiratory infections at the age of 2 years canjustify the occurrence of DDE, which is probably MIH in first permanent molarsand permanent premolars, which coincide with the chronological age.Our findings suggest that HIGM patients areprobably at greater risks for DDE; this is in agreement with the result of a previousstudy by Meighani et al who showed more enamel hypoplasia in patients with primaryantibody deficiencies compared to the controls. (27) However, due to the scarcityof HIGM, a definitive conclusion cannot be made with regard to these patients. DDEmay cause tooth sensitivity and increased tooth caries. (34) On the other hand,teeth with DDE are 10 times more in need of treatment than normal teeth.

(35)Most of the available information about the etiologyof DDE has been attained from case reports of children with systemic diseases.As a result, the importance of case reports of dental enamel defects in systemicdisorders is clear. Conclusion:A meticulousdental evaluation in children with systemic disorders is advised in order todiscover possible developmental dental defects and to plan early interventions.Furthermore, it is essential for dentists to be familiar with the etiologicalfactors of enamel defects

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