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.

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.

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.

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.

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.

Adenosine kinase deficiency with neurodevelopemental delay and recurrent hepatic dysfunction: A case report.

Hypermethioninemia may be benign, present as a nonspecific sign of nongenetic conditions such as liver failure and prematurity, or a severe, progressive inborn error of metabolism. Genetic causes of hypermethioninemia include mitochondrial depletion syndromes caused by mutations in the MPV17 and DGUOK genes and deficiencies of cystathionine ß-synthase, methionine adenosyltransferase types I and III, glycine N-methyltransferase, S-adenosylhomocysteine hydrolase, citrin, fumarylacetoacetate hydrolase, and adenosine kinase. Here we present a 3-year old girl with a history of poor feeding, irritability, respiratory infections, cholestasis, congenital heart disease, neurodevelopmental delay, hypotonia, sparse hair, facial dysmorphisms, liver dysfunction, severe hypermethioninemia and mild homocystinemia. Genetic analysis of the adenosine kinase (ADK) gene revealed a previously unreported variant (c.479-480 GA>TG) resulting in a stop codon (p.E160X) in ADK. A methionine-restricted diet normalized the liver function test results and improved her hypotonia.

A Rare Case of Ovarian Hyperstimulation Syndrome in a Preterm Infant.

Ovarian hyperstimulation syndrome is a rare disease among preterm infants. This syndrome was first described in 1985 in four infants with a gestational age of <30 weeks. Several explanations for this syndrome have been suggested namely the immaturity of Hypothalamic-Pituitary-Gonadal (HPG) axis, lack of negative feedback, increased sensitivity of Follicle Stimulating Hormone (FSH) receptors due to mutation and high level of estradiol. In this report, a case of hyperstimulation syndrome in a newborn with gestational age of 30 weeks is presented and the probable mechanisms in the literature are discussed.

Recurrent Hepatitis in Two Iranian Children: A Novel (Q166R) Mutation in EIF2AK3 Leading to Wolcott-Rallison Syndrome.

Early-onset diabetes, liver dysfunction, growth retardation, spondyloepiphyseal dysplasia, and tendency to skeletal fractures due to osteopenia are characteristics of Wolcott-Rallison syndrome (WRS). Eukaryotic translation initiation factor 2α kinase (EIF2AK3) is the only known gene, which is responsible for this rare autosomal recessive disorder. Here, we report two siblings a girl and a boy with diabetes mellitus (DM) who presented in one and two months of age respectively. Recurrent self-limiting hepatitis developed later, and severe hepatic failure resulted in death of the first child. The second child visited was a 7.75 year old boy who had spondyloepiphyseal dysplasia and subclinical hypothyroidism besides DM and recurrent hepatitis. We suggested WRS for this patient, and it was confirmed by identification of a novel homozygous missense mutation (Q166R) in exon 3 of the EIF2AK3 gene. The aim of this report is to remind the possibility of WRS in isolated neonatal diabetes; while, the other clinical manifestations of this syndrome including its major symptom of recurrent hepatitis may appear later.

Digital and dental malformation and short stature in a patient with neurological problems: a variant of the oculodentodigital dysplasia syndrome or a new syndrome?

Several syndromes have been recognized with digital abnormality and CNS involvement such as oculodentodigital dysplasia (ODDD), Mohr syndrome and Joubert syndrome. We report a patient who was referred to us because of the neurological signs suspicious of metabolic disorders. This case was a 22-year-old woman whose problems began 4 years ago with shortening of memory, ataxia, abnormal gait and diplopia which progressed slowly. She consulted many neurologists and was on treatment with the suspicion of vasculitis, but no response was detected. She had severe short stature, hypoplasia of the middle and distal phalanges of the first, second and third fingers, clinodactyly, abnormal toes, abnormal enamel and missing teeth. She had no characteristic faces of ODDD and ophthalmological abnormality. Our patient might be a variant of ODDD or a new syndrome with somatic and neurologic signs.

Hyperostosis with hyperphosphatemia and tumoral calcinosis: a case report.

The combination of hyperostosis and hyperphosphatemia is very rare. In this case report, we present a boy with a combination of diffuse hyperostosis and hyperphosphatemia. We evaluated most possible known causes of hyperphosphatemia and hyperostosis. He had normal renal function and serum parathormone level. Concerning some few similar cases, most of them from Middle Eastern countries, we present this combination (diffuse hyperostosis and hyperphosphatemia) as a new syndrome to be discussed in pediatric textbooks.