Revisiting double-negative T cells in autoimmune lymphoproliferative immunodeficiencies: a case series.

BACKGROUND: Elevated level of double-negative T (DNT) cells is a historical hallmark of autoimmune lymphoproliferative syndrome (ALPS) diagnosis. However, the peripheral blood level of DNT cells might also be compromised in autoimmune lymphoproliferative immunodeficiencies (ALPID) other than ALPS, inattention to which would increase the delay in diagnosis of the underlying genetic defect and hinder disease-specific treatment. MATERIALS AND METHODS: This cross-sectional study recruited patients suffering from ALPID (exclusion of ALPS) with established genetic diagnosis. Following thorough history taking, immunophenotyping for lymphocyte subsets was performed using BD FACS CaliburTM flowcytometry. RESULTS: Fifteen non-ALPS ALPID patients (60% male and 40% female) at a median (interquartile range: IQR) age of 14.0 (7.6-21.8) years were enrolled. Parental consanguinity and family history of immunodeficiency were present in 8 (53.3%) patients. The median (IQR) age at first presentation, clinical and molecular diagnosis were 18 (4-36) months, 8.0 (4.0-17.0) years, and 9.5 (5.0-20.9) years, respectively. Molecular defects were observed in these genes: LRBA (3, 20%), CTLA-4 (2, 13.3%), BACH2 (2, 13.3%), AIRE (2, 13.3%), and FOXP3, IL2Rß, DEF6, RASGRP1, PIK3CD, and PIK3R1 each in one patient (6.7%). The most common manifestations were infections (14, 93.3%), autoimmunity (12, 80%), and lymphoproliferation (10, 66.7%). The median (IQR) count of white blood cells (WBCs) and lymphocytes were 7160 (3690-12,600) and 3266 (2257-5370) cells/mm3, respectively. The median (IQR) absolute counts of CD3+ T lymphocytes and DNTs were 2085 (1487-4222) and 18 (11-36) cells/mm3, respectively. Low lymphocytes and low CD3+ T cells were observed in 3 (20%) patients compared to normal age ranges. Only one patient with FOXP3 mutation had DNT cells higher than the normal range for age. CONCLUSIONS: Most non-ALPS ALPID patients manifested normal DNT cell count. For a small subgroup of patients with high DNT cells, defects in other IEI genes may explain the phenotype and should be included in the diagnostic genetic panel.

Expanding phenotype heterogeneity of NARS2 by presenting subdural hematoma and parenchymal hemorrhage.

BACKGROUND: NARS2 encodes mitochondrial Asparaginyl-tRNA Synthetase 2, which catalyzes the aminoacylation of tRNA-Asn in the mitochondria. To date, 24 variants have been reported in NARS2 gene in 35 patients. The phenotypic variability of NARS2-associated disorder is broad, ranging from neurodevelopmental disorders to hearing loss. In this study, we report some novel imaging findings in an Iranian patient suffering from epileptic encephalopathy, caused by a previously reported variant, c.500A > G; p.(His167Arg), in NARS2. METHODS: The spectrum of clinical manifestations of two Iranian patients was investigated and genetic analysis was performed by Whole-exome sequencing (WES). Additionally, we also reviewed the literature and summarized the phenotypes of previously reported patients with variants in the NARS2 gene. RESULTS: Here, we present the phenotypic and genetic features of 2 unrelated Iranian infants presented with neurodevelopmental delay, seizures, hearing impairment, feeding problems, elevated serum lactate levels in addition to subdural hematoma and cerebral parenchymal hemorrhage in the brain magnetic resonance imaging (MRI) of one of the patients. Genetic analysis revealed a biallelic missense variant in NARS2: c.500A > G; p.(His167Arg). We described the subdural hematoma and cerebral parenchymal hemorrhage of the brain for the first time. CONCLUSIONS: Our study provides new clinical findings, subdural hematoma, and parenchymal hemorrhage, in NARS2-related disorders. Our findings along with previous studies provide more evidence of the clinical presentation of the disease caused by pathogenic variants in NARS2. Expanding the clinical spectrum increases the diagnostic rate of molecular testing and improves the quality of counseling for at-risk couples.

Prevalence of Dysglycemia, Dyslipidemia, and Metabolic Syndrome among Patients with HIV Infection: a Cross-sectional Study from Iran.

Background: Human immunodeficiency virus (HIV) resulted in considerable morbidity and mortality. Following antiretroviral therapy (ART), the life expectancy of HIV-infected patients increased; however, they were more at risk of developing chronic diseases such as endocrinopathies. This study aimed to determine the prevalence of dysglycemia, dyslipidemia, and metabolic syndrome among patients with HIV infection. Methods: This cross-sectional study was conducted on HIV-infected patients referring to Loghman Hakim Hospital (Tehran, Iran) between April 2020 and April 2021. We examined demographic features, medical history, and laboratory tests indicating the metabolic status of the patients. Eventually, collected data were processed using SPSS version 23. Results: The mean age of 68 confirmed HIV patients was 39.85±10.54 years and 64.7% were male. BMI (MD = 2.57, 95% CI = [0.25, 4.88], P = 0.035), cholesterol (MD = 22.73, 95% CI = [4.70, 40.76], P = 0.014), HDL (MD = 8.54, 95% CI = [2.06, 15.02], P = 0.011), and LDL of women was significantly higher than men (MD = 22.43, 95% CI = [7.60, 37.27], P = 0.004). Additionally, 30 patients (44.1%) suffered from metabolic syndrome. The prevalence of metabolic syndrome differed significantly between men (34.1%) and women (62.50%) (P = 0.024). Conclusion: Dysglycemia, dyslipidemia, and metabolic syndrome are common among HIV-infected patients. Thus, periodic evaluation of the patients can be advantageous in early diagnosis and timely treatment.

Clinical presentation and molecular genetics of Iranian patients with Niemann-pick type C disease and report of 6 NPC1 gene novel variants: A case series.

Niemann Pick Type C disease is a rare and progressive neurodegenerative lysosomal storage disorder caused by autosomal recessive mutations in the NPC1 and NPC2 genes. It is characterized by the accumulation of multiple lipid species in the endolysosomal compartment, leading to neurodegeneration and involvement of the liver, spleen, and lungs. Niemann Pick Type C has a wide range of presentations and severities at different ages with different progression rates. According to the Human Gene Mutation Database, to date, 486 disease-causing mutations in the highly polymorphic NPC1 gene and >20 mutations in the NPC2 have been reported. In the present study, we described the clinical, biochemical, and molecular profiles of 18 Iranian patients with Niemann-Pick Type C disease. Also, we describe six novel variants of the NPC1 gene, to our knowledge, not reported to date.

Expanded inherited metabolic diseases screening by tandem mass spectrophotometry: The first report from Iran.

Inherited metabolic diseases (IMD) are a group of rare genetic disorders that can present with a variety of symptoms. Since these disorders are hard to treat once the symptoms occur, neonatal screening may be a logical strategy. Here we evaluate the first results of national expanded IMD screening in Iran. A total of 46 IMDs were screened in this national program. Between April 2018 and March 2022, all infants who underwent national IMD screening at Shahid Beheshti University of Medical Sciences were included in this study. History and Physical examinations of infants, screening results, recall rate, response rate, and prevalence of IMDs were evaluated. A total of 125,819 infants were screened during this period. The recall rate of the test was 0.81%. 124 cases were diagnosed with a definite IMD and the raw overall prevalence of IMDs was estimated to be 1:1015. Aminoacidopathies were the most commonly detected disorders and Hyperphenylalaninemia/PKU was the most prevalent disorder among all groups. Since IMDs vary from region even in a single country, screening for IMDs is crucial in societies with a high rate of consanguineous marriages. More studies are essential for figuring out the most efficient combination of diseases to be screened based on countries' facilities.

A novel gene mutation for multicentric osteolysis nodulosis and arthropathy: Case report and review of literature.

Frank-Ter Haar syndrome (FTHS), Winchester syndrome (WS), Torg syndrome (TS) and Multicentric Osteolysis Nodulosis and Arthropathy (MONA) are progressive skeletal dysplasia consisting of acro-osteolysis. Mutation in Matrix Metalloproteinase 2 (MMP2), Matrix Metalloproteinase 14 (MMP14) and SH3PXD2B are known genetic defects in these disorders. We hereby report a 5 years and 9 months old girl suffering from progressive limb deformity. She is the first child of a relative couple, who was referred to metabolic disorders' clinic due to poor growth and bone pain. On physical examination, minor facial dysmorphism, hypertrichosis, severe hand deformity with limitation in range of motion in carpal, metacarpal and phalangeal joints, hallux valgus deformity of feet, soft tissue hypertrophy and nodule formation in palmoplantar areas were detected. Her past history indicated a cardiac defect resulting in open heart surgery at 8 months of age. Genetic study revealed a new homozygote nonsense mutation in MMP2 gene explaining her clinical manifestations. We recommend careful evaluation and follow-up of patients with congenital heart disease, as it may be the first presentation of a genetic multisystem disorder. Early differentiation of the disease from other skeletal dysplasia and rheumatologic disorders could prevent unnecessary management.

Defects in Very Long-Chain Fatty Acid Oxidation Presenting as Different Types of Cardiomyopathy.

Cardiac involvement may accompany various inborn errors of metabolism (IEM) including fatty acid oxidation (FAO) disorders, presenting as rhythm disturbances, conduction abnormalities, cardiomyopathies, pericardial effusion, and sudden cardiac death. FAO disorders are rare mitochondrial diseases with variable organ involvements and clinical presentations. Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a FAO disorder with diverse clinical presentations. We report two VLCADD patients with cardiac involvement and diverse presentations. The first patient represents with cardiogenic shock and dilated cardiomyopathy (DCM) at childhood. The second patient represents with suspicious sepsis at early infancy and hypertrophic cardiomyopathy (HCM) at further evaluation. IEM should be thought of in every individual case with suspicious sepsis or cardiac failure regardless of age or previous history.

Benefits of metformin add-on insulin therapy (MAIT) for HbA1c and lipid profile in adolescents with type 1 diabetes mellitus: preliminary report from a double-blinded, placebo-controlled, randomized clinical trial.

OBJECTIVES: Metabolic control during puberty is impaired in Type 1 Diabetes Mellitus (T1DM) patients due to increased insulin resistance. Metformin is one of the oral medications typically used in type 2 diabetes mellitus to reduce insulin resistance. We aimed to examine the effect of metformin on glycemic indices and insulin daily dosage in adolescents with T1DM. METHODS: The present clinical trial was carried out on 50 adolescents aged 10-20 years with T1DM referred to the Endocrinology Clinic of Mofid Children's Hospital in Tehran for nine months. The patients were randomly divided into two groups. In the first group, metformin was added to insulin therapy, while the second group continued routine insulin therapy combined with placebo. Hemoglobin A1c (HbA1c), weight, BMI, insulin dosage, and blood pressure were measured at the beginning of the study and repeated every three months. Serum lipid profile, creatinine, blood urea nitrogen, and liver enzymes were also measured twice: At the beginning and end of the study (after nine months). RESULTS: The HbA1c level (p<0.001) and insulin dosage (p=0.04) were lower in the metformin group than in the placebo group after nine months. Daily insulin dosage variability was significantly lower in the metformin recipient group (p=0.041). Serum triglyceride, cholesterol, and creatinine were significantly lower in the metformin arm than in the placebo arm (p<0.05). However, metformin did not affect LDL, HDL, liver enzymes, and BUN. CONCLUSIONS: Adjunctive metformin therapy reduces insulin dosage by inhibiting insulin resistance and weight gain. It helps decrease daily insulin dosage variability, which may prevent hypoglycemia. Also, metformin reduces creatinine, preventing renal failure in the long term.

A Novel Mutation in PEX11ß Gene.

PEX11ß ([OMIM] 614920) mutation causes an extremely rare subgroup of peroxisomal biogenesis disorders, with only six cases reported to date. In this article, we reported a patient with episodic migraine-like attacks, delirium, mood and behavior change, polyneuropathy, and history of congenital cataract. Whole exome sequencing showed novel c.743_744delTCinsA mutation in the exon 4 of the PEX11ß gene. In contrast to previously reported patients, our case presented milder features and extended the spectrum of the clinical phenotype of this mutation. This study helps to extend the phenotype of this syndrome; besides, recognizing novel mutation variants will provide a better genotype-phenotype correlation and improve clinical clues.

Non-celiac gluten sensitivity as a rare cause of growth retardation in children: a case series study.

AIM: Herein, we present five children and adolescents with a final diagnosis of non-celiac gluten sensitivity (NCGS). BACKGROUND: Non-celiac gluten sensitivity (NCGS) is a condition characterized by gastrointestinal and extra-intestinal symptoms triggered by ingestion of gluten-containing compounds, e.g., wheat, rye, and barley, in subjects without celiac disease or wheat allergy. METHODS: Demographic characteristics, clinical manifestations, serum biomarkers and skin prick test were evaluated. Patient data was also recorded after they followed a gluten-free diet (GFD). Height and weight were measured, and all patients were examined 6 months after following the suggested GFD. RESULTS: All patients had failure to thrive and abdominal pain. Clinical symptoms were reduced, and significant weight and height gains were detected after 1 month of following a gluten-free diet. CONCLUSION: The relationship between failure to thrive (FTT) and NCGS is still unknown; hence, NCGS may be one of the main causes of FTT which can be prevented by gluten-free diets.

Vitamin D Deficiency in Children and Adolescents: Role of Puberty and Obesity on Vitamin D Status.

BACKGROUND: Vitamin D deficiency is common among children and adolescents and can be affected by several factors such as puberty and obesity. OBJECTIVE: The aim of this study was to evaluate vitamin D status in children and adolescents and to analyse the influence of puberty and obesity on its level. METHOD: A cross-sectional study was carried-out, in which clinical and biochemical data were gathered from 384 healthy children and adolescents between May 2019 to May 2020. RESULTS: 220 females and 164 males were enrolled (aged 7-16 years; mean ± SD: 11 ± 2.5). Vitamin D deficiency was found in 49% of the total cases and was significantly more prevalent in females than males (33.1% in female; 15.9% in male, P < .001). Mean vitamin D level was lower in obese children compared with non-obese (P < .001). Non-obese group had significantly higher levels of vitamin D in Tanner stage IV of puberty than obese individuals (20.1 ± 17.0 vs 5.4 ± 2.0) (P = .03). Vitamin D levels were significantly lower in females than males only in Tanner stage II (12.3 ± 9.0 vs 19.6 ± 16.6) (P = .005). The lowest level of Vitamin D was in Tanner stage Ⅳ-Ⅴ in boys and in Tanner stage Ⅱ-Ⅲ in girls (P < .001). CONCLUSION: Puberty is an additional risk factor for vitamin D deficiency especially in girls and obese children. This increased risk, together with the fact that most important time for building a proper skeleton is during childhood and adolescent, makes it essential to monitor vitamin D in these age groups.

NGLY1 deficiency: Novel variants and literature review.

NGLY1 deficiency is a recently described autosomal recessive disorder, involved in deglycosylation of proteins, and for that reason grouped as the congenital disorders of deglycosylation together with the lysosomal storage disorders. The typical phenotype is characterized by intellectual disability, liver malfunctioning, muscular hypotonia, involuntary movements, and decreased or absent tear production. Liver biopsy demonstrates vacuolar amorphous cytoplasmic storage material. NGLY1 deficiency is caused by bi-allelic variants in NGLY1 which catalyzes protein deglycosylation. We describe five patients from two families with NGLY1 deficiency due to homozygosity for two novel NGLY1 variants, and compare their findings to those of earlier reported patients. The typical features of the disorder are present in a limited way, and there is intra-familial variability. In addition in one of the families the muscle atrophy and posture abnormalities are marked. These can be explained either as variability of the phenotype or as sign of slowly progression of features as the present affected individuals are older than earlier reported patients.

Clinical and Paraclinical Characteristics of Non-Classic Phenylketonuria.

OBJECTIVE: Phenylketonuria (PKU) is one of the most common inherited metabolic diseases, which is classified into classic and non-classic types. It is estimated that 2% of children with PKU develop a severe and progressive neurological disease, called non-classic (malignant) PKU. This study aimed to demonstrate the clinical features, laboratory findings, and diagnostic/therapeutic characteristics of non-classic PKU patients referred to a tertiary referral center for children in Tehran, Iran. MATERIALS & METHODS: In this study, background information, such as gender and age, clinical manifestations, laboratory findings, and response rate to conventional treatment, was investigated in patients with non-classic PKU, who were referred to Mofid Children's Hospital in Tehran, Iran, through neonatal screening. RESULTS: Twenty patients with a diagnosis of non-classic PKU were included in this study. The mean age of the patients was 6.00±2.81 years (range: 2-12 years), and 45.0% were male. In patients with a late diagnosis, the most common presentations were motor developmental delay (15.0%), skin and cutaneous manifestations (15.0%), seizure (5.0%), and restlessness (5.0%). The overall response rate to treatment was 85.0%. Factors that predict good response to treatment included female gender, higher neopterin level, and lower age at diagnosis and management. CONCLUSION: In conclusion, about half of patients with non-classic PKU remain asymptomatic, which is due to early diagnosis via neonatal screening. Also, higher age at diagnosis and treatment, besides low neopterin levels, may be useful as prognostic factors.

Assessment of vitamin D status in healthy children and adolescents living in Tehran and its relation to iPTH, gender, weight and height.

This study was conducted to determine the frequency of vitamin D deficiency and its correlation with different factors. Three hundred and thirteen healthy children and adolescents (192 females and 121 males aged 8-18 years, mean +/- SD, 12.7 +/- 2.3 years) were enrolled, and measurements of serum 25-hydroxyvitamin D [25(OH)D] (using EIA) and intact parathyroid hormone (iPTH) (using immunoradiometric assay (IRMA)) were conducted. The grades of vitamin D status were defined according to blood level of 25(OH)D as follows: severely deficient < 12.5; deficient, > or = 12.5 and < 25; insufficient, > or = 25 and < 50; normal > or = 50 and < 250 nmol/L. Severe deficiency was detected in 25% of subjects (males 8%; females 92%), deficiency in 27% (males 34%; females 66%) and insufficiency in 26% (males 58%; females 42%). The mean 25(OH)D level in males was significantly greater than that in females (p < 0.001), and this level was significantly higher in prepubertal compared to pubertal subjects (p < 0.001). 25(OH)D had a negative correlation with iPTH (p < 0.001). The curve of iPTH began to rise when 25(OH)D reached 75 nmol/L. The level of 25(OH)D had a negative correlation with BMI-SDS and height-SDS in females (p-value, 0.01 and 0.039, respectively). The subjects did not have any signs or symptoms of rickets. Frequency of vitamin D deficiency did not have any significant seasonal variation. Furthermore, vitamin D deficiency was not found to be related to the type or location of the subjects' homes. In this study, subclinical vitamin D deficiency was significantly more prevalent in females, particularly those undergoing puberty. Children who were obese and taller than average, had lower levels of 25(OH)D, and level of 25(OH)D should be maintained > 75 nmol/L in order to prevent PTH rising.

Assessment of Anthropometric Indices in Patients with Phenylketonuria.

OBJECTIVES: Dietary phenylalanine restriction is the main treatment of phenylketonuria (PKU, OMIM 261600). There are a number of studies which have demonstrated growth retardation in these patients, and some are in contrast. This study was performed to assess the growth parameters of treated PKU patients. MATERIALS & METHODS: This cross-sectional study was performed between 2015 and 2017 to compare growth indices in PKU patients in our clinics with normal age and sex matched controls. Weight, height, head circumference (HC), weight for height and BMI (weight/height2) were measured and converted into Z-scores. We assessed differences between patients and controls' anthropometric indexes in all patients and separately in patients who were diagnosed by newborn screening program and patients who were diagnosed after presentation of clinical manifestations in comparison with age and sex-matched controls. Also, this difference was assessed separately in patients aged two years and less. Correlations between pretreatment plasma phenylalanine concentrations mean plasma phenylalanine concentrations and anthropometric parameters were analyzed in the patients. RESULTS: Overall, 209 under-treatment PKU patients (103 males, 106 females; mean age 9.29 ± 8.7 years) and 216 controls (109 males and 107 females; mean age 8.98 ± 8.62 years) matched in terms of age, sex and birth weight were enrolled in this study. In general, 130 patients were diagnosed by newborn screening and 79 were diagnosed when they became symptomatic before the screening program. A significant difference (p=0.000) was found only in HC z-score and weight for height z-score in comparison with the control group, when we assessed all patients. We did not find any significant differences in any of the anthropometric indexes between cases and controls who were aged 2 years old and less. Head circumference SDS and weight for height SDS were significantly different when patients and controls who were more than 2 years old were compared. Mean HC was significantly lower in patients, while BMI SDS, weight SDS, and weight for height SDS were significantly higher in PKU patients in comparison with the control group when patients who were diagnosed in newborn screening were assessed. Head circumference SDS, BMI, height SDS and difference between patients' height SDS and mid parental height SDS had significantly lower mean scores in comparison with those of the control group, while mean weight SDS was significantly higher compared to controls when patients who were diagnosed after clinical presentation were assessed. Mean phenylalanine was not correlated with anthropometric indices, while there was a correlation between pretreatment phenylalanine and HC. CONCLUSION: Disparities in anthropometric indexes changes observed in different studies may be due to diverse diet protocols, availability of various specific products and micronutrient substitutes.

Ghosal Hematodiaphyseal Dysplasia: A Case Report.

Ghosal hematodiaphyseal dysplasia (GHDD) is a rare autosomal recessive disorder presenting with steroid-responsive anemia and diaphyseal dysplasia of long bones. We report a 3-year-old Iranian girl with refractory anemia, splenomegaly and radiologic signs of metadiaphyseal dysplasia in long bones. The diagnosis was established by clinical presentation and X-ray bone survey. The patient was treated with oral prednisolone therapy with considerable improvement in anemia and splenomegaly.

A Rare Case of Glycogen Storage Disease Type 1a Presenting with Hemophagocytic Lymphohistiocytosis (HLH).

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by fever, respiratory distress, massive hepatomegaly, and bicytopenia. It is classified into primary (congenital) and secondary (acquired) types. There are many diseases associated with secondary HLH, but glycogen storage disease is a novel cause of secondary HLH. Case Presentation. In this case, we present a five-month-old female infant with recurrent fever, poor feeding, pallor, and prolonged diarrhea for two months. With a diagnosis of HLH, the patient was treated with IVIG and prednisolone. After treatment was initiated, the patient's general condition improved. All metabolic workup was normal. We did whole-exome sequencing that confirmed glycogen storage disease (GSD) type 1. CONCLUSION: Metabolic diseases are one of the severe causes of secondary HLH in infants; hence, complete metabolic assessment is mandatory in these patients, and GSD must be included in the differential diagnosis of HLH metabolic causes.

Utility of Seizure Pattern and Related Clinical Features in the Diagnosis of Neurometabolic Disorders.

OBJECTIVES: The current study aimed at identifying the role of seizure types and related clinical features in differentiation between neurometabolic disorders and other causes of seizure. MATERIALS & METHODS: The current cross sectional study was conducted at two referral children hospitals in Tehran, Iran, from 2011 to 2018. The study population included 120 patients presenting with seizure due to neurometabolic disorders and 120 cases due to other causes. The types of seizure and related clinical findings were assessed in both groups. RESULTS: There was a significant difference in the frequency of seizure types in the two groups. Tonic and myoclonic seizures as well as infantile spasm were observed more commonly in the patients with neurometabolic disorders, while atonic, partial and generalized tonic-clonic seizures were more common in the control group. In addition, frequency of refractory seizure, age at onset of seizure, and pattern of involvement in brain imaging were helpful for differentiation. CONCLUSION: The pattern of seizure and related findings varied in patients with metabolic disorders, and was helpful for diagnosis. Thus, these factors can contribute to early diagnosis and treatment.

Genotype-phenotype correlation and description of two novel mutations in Iranian patients with glycogen storage disease 1b (GSD1b).

BACKGROUND: Glycogen storage disease (GSD) is a rare inborn error of the synthesis or degradation of glycogen metabolism. GSD1, the most common type of GSD, is categorized into GSD1a and GSD1b which caused by the deficiency of glucose-6-phosphatase (G6PC) and glucose-6-phosphate transporter (SLC37A4), respectively. The high rates of consanguineous marriages in Iran provide a desirable context to facilitate finding the homozygous pathogenic mutations. This study designates to evaluate the clinical and genetic characteristics of patients with GSD1b to assess the possible genotype-phenotype correlation. RESULTS: Autozygosity mapping was performed on nineteen GSD suspected families to suggest the causative loci. The mapping was done using two panels of short tandem repeat (STR) markers linked to the corresponding genes. The patients with autozygous haplotype block for the markers flanking the genes were selected for direct sequencing. Six patients showed autozygosity in the candidate markers for SLC37A4. Three causative variants were detected. The recurrent mutation of c.1042_1043delCT (p.Leu348Valfs*53) and a novel missense mutation of c.365G > A (p.G122E) in the homozygous state were identified in the SLC37A4. In silico analysis was performed to predict the pathogenicity of the variants. A novel whole SLC37A4 gene deletion using long-range PCR and sequencing was confirmed as well. Severe and moderate neutropenia was observed in patients with frameshift and missense variants, respectively. The sibling with the whole gene deletion has shown both severe neutropenia and leukopenia. CONCLUSIONS: The results showed that the hematological findings may have an appropriate correlation with the genotype findings. However, for a definite genotype-phenotype correlation, specifically for the clinical and biochemical phenotype, further studies with larger sample sizes are needed.

Homozygous deletion of the entire AAAS gene in a triple A syndrome patient.

Triple A syndrome, a multisystemic autosomal recessive disease, is characterized by the clinical triad of adrenal insufficiency, alacrima and achalasia in combination with progressive neurological impairments. The disorder is caused by homozygous or compound heterozygous mutations in the AAAS gene. Here we present the clinical and molecular data of a ten year old patient with triple A syndrome. Array CGH analysis confirmed the PCR-based assumption of a homozygous deletion of the entire AAAS gene in the patient and a heterozygous deletion in both parents. We demonstrate that the patient carries a 15 kb deletion and identified the 5' and 3' breakpoints outside the AAAS gene. This is the first report of a triple A syndrome patient with a homozygous deletion of the entire AAAS gene.