Shraga Aviner

Maternal and infantile hypercalcemia caused by vitamin-D-hydroxylase mutations and vitamin D intake.

BackgroundHypercalcemia is caused by many different conditions and may lead to severe complications. Loss-of-function mutations of CYP24A1, encoding vitamin D-24-hydroxylase, have recently been identified in idiopathic infantile hypercalcemia and in adult kidney stone disease. The aim of this study was to investigate the genetics and clinical features of both infantile and maternal hypercalcemia.MethodsWe studied members of four unrelated Israeli families with hypercalcemia, namely, one woman during pregnancy and after delivery and three infants. Clinical and biochemical data were obtained from probands’ medical charts. Genomic DNA was isolated from peripheral blood and CYP24A1 was sequenced.ResultsTypical symptoms of hypercalcemia associated with the intake of recommended doses of vitamin D developed in the infants and pregnant woman. Four different loss-of-function CYP24A1 mutations were identified, two of which are reported here for the first time (p.Trp134Gly and p.Glu315*). The infants from families 1 and 2, respectively, were found to be compound heterozygotes, and the infant from family 3 and the pregnant woman were found to be homozygous.ConclusionsThis is the first report of maternal hypercalcemia caused by a CYP24A1 mutation, showing that not only infants are at risk for this complication. Our findings emphasize the importance of recognition, genetic diagnosis and proper treatment of this recently identified hypercalcemic disorder in this era of widespread vitamin D supplements.

Type 2 Gaucher disease occurs in Ashkenazi Jews but is surprisingly rare.

Patients with Gaucher disease (GD) are divided into three types based on the presence and rate of progression of the neurologic manifestations. While type 1 GD has a strong predilection in the Jewish Ashkenazi population, both other types lack such a propensity. We report the occurrence of type 2 GD (GD2) in four pregnancies in two Jewish families in Israel (in one case the mother was not Ashkenazi but was from a Sfaradi Jewish family) and also review seven additional cases of GD2 in Ashkenazi Jewish families reported in the literature. Phenotypically, GD2 in Ashkenazi Jews does not differ significantly from this form in other ethnic groups. Genotypic analysis of probands from the two Israeli families demonstrates that each carried two heterozygous glucocerebrosidase mutations. We could find no explanation why GD2 is so rare in the Jewish Ashkenazi population but we could hypothesize that homozygosity for certain Ashkenazi alleles might be lethal, leading to a lower than expected frequency of GD2 and noted that no cases of homozygous L444P has ever been described in Ashkenazi Jews.

Persistent neonatal thrombocytopenia can be caused by IgA antiplatelet antibodies in breast milk of immune thrombocytopenic mothers

Immune thrombocytopenia (ITP) in pregnant women can cause neonatal thrombocytopenia by transport of antiplatelet autoantibodies across the placenta. Usually, an infants platelet count normalizes within 2 months. We observed neonatal thrombocytopenia that persisted more than 4 months and disappeared following discontinuation of breastfeeding. The aim of our study was to discern whether breast milk of ITP mothers contained antiplatelet antibodies causing persistent thrombocytopenia. We collected milk samples from 3 groups of women: ITP group, 7 women who had ITP during pregnancy; R-ITP group, 6 women who recovered from ITP before pregnancy; and 9 healthy controls. We found increased levels of antiplatelet antibodies of the immunoglobulin A type in the milk of ITP patients compared with the other 2 groups. Similar increase was demonstrated for antibodies binding to αIIbβ3 expressed in cultured cells. Thus, transfer of antiplatelet antibodies from ITP mothers by breastfeeding can be associated with persistent neonatal thrombocytopenia.

Langerhans cell histiocytosis in a premature baby presenting with skin-isolated disease: case report and literature review

Langerhans cell histiocytosis (LCH) in premature babies is extremely rare as is a vesicular skin rash, while gastrointestinal involvement is associated with a poor outcome. We report a case of LCH in a premature baby presented with isolated vesiculo‐papulo‐macular skin lesions and insidiously developed gastrointestinal symptoms, haematological and severe pulmonary involvement. We also reviewed a few cases of LCH in premature babies in the English language medical literature. LCH in preterm babies appears to be a severe systemic disease, usually lethal in‐utero or post delivery.

Prenatal maternal stress predicts cord-blood ferritin concentration.

Abstract Aim: To examine the relationship between maternal stress in early pregnancy and cord-blood ferritin concentration. Methods: The sample consisted of 140 pregnant women who lived in a region that was under rocket attack during a military operation (December 2008 to January 2009). Mothers in the stress group (n=63) were in their first trimester during this period. Mothers in the control group (n=77) became pregnant 4–5 months after the attacks ended. Maternal subjective stress was reported retrospectively. Cord-blood ferritin concentration was compared between stress and control groups, and was the dependent variable in a hierarchical multiple regression analysis. Results: The mean cord-blood ferritin concentration was lower in the stress group compared to the control group (145.7±62.0 vs. 169.3±85.4 ng/mL, P<0.05). The cumulative distribution of cord-blood ferritin showed a shift to the left for the stress group. Hierarchical multiple regression analysis revealed that maternal subjective stress was a predictor for cord-blood ferritin concentration (hierarchical regression: β=–0.18, P<0.05), especially in the stress group (simple slope analysis: β=–0.32, P<0.01). Conclusion: Maternal stress during the first trimester of pregnancy is associated with lower cord-blood ferritin concentration.

Spontaneous Resolution of Extreme Thrombocytosis in 2 Children

Essential thrombocytosis (ET) is rare in children, sometimes difficult to be distinguished from secondary thrombocytosis. This report concerns 2 children with extreme thrombocytosis of 4100 × 109/L and 1644 × 109/L with partial and complete remission at 3 months and 4 years from diagnosis, with a follow-up of 4 and 17 years, respectively, with no cytoreduction therapy. Diagnosis of ET was suggested according to accepted criteria. However, spontaneous remission of the thrombocytosis argues for the diagnosis of secondary thrombocytosis. These patients highlight the complexity of distinguishing childhood ET from secondary thrombocytosis and the need for cautious personalized decision on cytoreduction therapy.

Mycoplasma pneumonia Infection: A Possible Trigger for Immune Thrombocytopenia.

Mycoplasma pneumonia (M. pneumonia) is usually not considered among the several pathogens that induce immune thrombocytopenia (ITP). We report a child with a clinical diagnosis of severe ITP that was associated with M. pneumonia pneumonia, and review the few cases described in the English literature. We suggest that thrombocytopenia associated with M. pneumonia infection may constitute a subset of ITP, although unlike ITP it occurs concomitantly with the infection and tends to be more severe than “classic” ITP. We recommend that prompt specific antibiotic and immune modulating treatment should be initiated in appropriate clinical settings.

Posttraumatic Fat Necrosis Presented as Cellulitis of the Leg

Cellulitis, a diffuse inflammation of connective tissue with severe inflammation of dermal and subcutaneous layers of the skin, is a common lesion in children, usually responsive to systemic antibiotic therapy. However, an unusual course of healing or some nontypical features should call the treating physician to consider and investigate for other diagnoses that might prevent unnecessary treatment and alleviate parental stress. We present a case of posttraumatic fat necrosis, demonstrating some pitfalls in the process of diagnosis.

Quantification of specific T and B cells immunological markers in children with chronic and transient ITP

Immune thrombocytopenic purpura (ITP) is characterized by a transient (nonchronic) or permanent (chronic) decline in the number of platelets. Predicting the course of ITP, at the time of diagnosis, is of importance. Here we studied at diagnosis, clinical and immunological parameters in order to distinguish between different courses. The latter included the measure of new B and T cells using quantification of kappa‐deleting recombination excision circles (KRECs) and T‐cell receptor excision circles (TRECs), respectively.

Quantitation of bleeding symptoms in a national registry of patients with inherited platelet disorders

BACKGROUND Inherited platelet deficiency and/or dysfunction may be more common in the general population than has previously been appreciated. In 2013 the Israeli Inherited Platelet Disorder (IPD) Registry was established. METHODS Clinical and laboratory data were collected to pre-specified registration forms. The study protocol was approved by the local hospital ethics committees. RESULTS To date we have included in the registry 89 patients (male 52%) from 79 families. Most patients (74%) have a not-yet specified inherited thrombocytopenia (n=39) or non-specific platelet function disorder (n=27). Full clinical data were available for 81 (91%) patients. The median (range) age at presentation and time of follow-up were 1.8years (1day-17.8years) and 4.7 (0-26) years, respectively. The Pediatric Bleeding Questionnaire was available for 78patients; abnormal bleeding score (≥2) was recorded in 47 (52.8%, 95% CI 42%-63.5%) patients and was less frequent in patients followed for isolated thrombocytopenia. Abnormal score was associated with a longer time of follow-up, OR 1.19 (95% CI 1.04-1.36). CONCLUSION Long term follow-up of patients with IPDs is important as bleeding risks may increase with time. We expect that clinical and laboratory information of patients/families with IPDs gathered in a systemic format will allow for better diagnosis and treatment of these patients.