Neonatal alloimmune thrombocytopenia. Case reports, diagnostic and therapeutic considerations

Two families are presented, where the mothers have given birth to children with neonatal alloimmune thrombocytopenia (NAITP) due to immunization towards the platelet specific antigen PIA1, which is responsible for most of the cases with NAITP. Anti-PIA1 has previously been difficult to demonstrate, but current techniques, such as the platelet suspension immunofluorescence test (PSIFT) used here, have made routine laboratory diagnosis possible. Both mothers in these families were HLA-B8 positive. This antigen shows strong association with PIA1 immunization.     

NEONATAL ALLOIMMUNE THROMBOCYTOPENIA

ABSTRACT. Two families are presented, where the mothers have given birth to children with neonatal alloimmune thrombocytopenia (NAITP) due to immunization towards the platelet specific antigen PI^A1, which is responsible for most of the cases with NAITP. Anti-PI^A1 has previously been difficult to demonstrate, but current techniques, such as the platelet suspension immunofluorescence test (PSIFT) used here, have made routine laboratory diagnosis possible. Both mothers in these families were HLA-B8 positive. This antigen shows strong association with PI^A1 immunzation.     

Neonatal Alloimmune Thrombocytopenia with HLA Alloimmunization: Case Report with Immunohematologic and Placental Findings

Severe neonatal thrombocytopenia is associated with a significant risk of neonatal bleeding complications. It may result from increased consumption, increased destruction, deficient production, or abnormal sequestration within the spleen. When immune mediated, most cases of clinically significant neonatal thrombocytopenia are due to maternal alloimmunization to paternally derived platelet antigens present on fetal platelets. We present the clinical, placental, and immunohematologic findings of a case of severe neonatal alloimmune thrombocytopenia (NAITP) complicated by additional HLA group alloimmunization. The placenta showed chronic villitis of unknown etiology (VUE) and diffuse microthrombi within the villous capillaries, indicating that abnormal thrombogenesis can be a complication of severe NAITP. Received June 14, 2001; accepted September 2, 2001.     

Prophylactic thyroidectomy in the treatment of thyroid medullary carcinoma. Age for surgery?

Since the association of RET proto-oncogene mutations and medullary thyroid carcinoma in children there has been much discussion regarding timing of surgery. Our study group was formed from a brother and sister (8 and 5) and 3 brothers (9, 13, 16) selected on the basis of a positive family history for thyroid medullary carcinoma. Histological examinations of the thyroidectomy specimens showed that the 8- and 9-year old had microinvasive carcinoma and the remaining three had C-cell hyperplasia. Our recommendation is for prophylactic thyroidectomy for children with RET proto oncogene mutations at an early age, clearly before age 5.     

THROMBASTHENIA: A STUDY OF TWO SIBLINGS

Clinical and laboratory observations on a brother and sister with congenital hemorrhagic disorder are presented. Both had prolonged bleeding time, poor clot retraction and failure of the platelets to aggregate and adhere to glass in the presence of ADP, absence of platelet extractable fibrinogen and impairment of platelet factor 3 availability. The abnormal platelet function, confirms the recent diagnostic criteria of thrombasthenia. Coagulation studies in the parents were normal. The hemostatic abnormality in thrombasthenia is discussed.     

Interferon α treatment of molluscum contagiosum in immunodeficiency

A sister (aged 6 years) and brother (aged 8 years) presented four months apart with severe molluscum contagiosum. Both children demonstrated clinical and laboratory evidence of combined immunodeficiency. The extent of skin involvement by molluscum contagiosum precluded conventional treatment as well as intralesional interferon α (IFNα). Both subjects responded well to subcutaneous IFNα.     

Interferon alpha treatment of molluscum contagiosum in immunodeficiency.

A sister (aged 6 years) and brother (aged 8 years) presented four months apart with severe molluscum contagiosum. Both children demonstrated clinical and laboratory evidence of combined immunodeficiency. The extent of skin involvement by molluscum contagiosum precluded conventional treatment as well as intralesional interferon alpha (IFN alpha). Both subjects responded well to subcutaneous IFN alpha.     

Severe microcephaly with normal intellectual development: the Nijmegen breakage syndrome

A brother and sister are described with severe microcephaly of prenatal onset, normal intellectual and motor development, chromosomal breakage and cellular immunodeficiency, which is characteristic of the autosomal recessive condition, Nijmegen breakage syndrome. The proband was a girl who presented at 15 months, with normal developmental milestones and an extremely small head circumference of 36 cm. Twenty per cent of her lymphocytes showed spontaneous translocations involving chromosome 7p13, 7q35, 14q11, and 14q32. The lymphocytes also showed excessive x ray induced chromosome damage. She had T cell lymphopenia, but normal immunoglobulins, and a normal alpha fetoprotein. A brother was born shortly after her diagnosis was made. He also had extreme microcephaly of 28 cm, with similar spontaneous and x ray induced chromosomal breakage, and T cell lymphopenia. Neither child has clinical evidence of immunodeficiency. To test the hypothesis that Nijmegen breakage syndrome and ataxia telangiectasia are allelic disorders, haplotype analysis was carried out in the family using DNA markers spanning the AT locus on chromosome 11q22. The affected boy had a different haplotype from his affected sister. Thus in this family, the Nijmegen breakage syndrome is not allelic to the ataxia telangiectasia locus on chromosome 11q, and the two conditions are genetically distinct. The normal intellect in these children raises questions about normal brain development in the presence of severe microcephaly.     

Severe microcephaly with normal intellectual development: the Nijmegen breakage syndrome.

A brother and sister are described with severe microcephaly of prenatal onset, normal intellectual and motor development, chromosomal breakage and cellular immunodeficiency, which is characteristic of the autosomal recessive condition, Nijmegen breakage syndrome. The proband was a girl who presented at 15 months, with normal developmental milestones and an extremely small head circumference of 36 cm. Twenty per cent of her lymphocytes showed spontaneous translocations involving chromosome 7p13, 7q35, 14q11, and 14q32. The lymphocytes also showed excessive x ray induced chromosome damage. She had T cell lymphopenia, but normal immunoglobulins, and a normal alpha fetoprotein. A brother was born shortly after her diagnosis was made. He also had extreme microcephaly of 28 cm, with similar spontaneous and x ray induced chromosomal breakage, and T cell lymphopenia. Neither child has clinical evidence of immunodeficiency. To test the hypothesis that Nijmegen breakage syndrome and ataxia telangiectasia are allelic disorders, haplotype analysis was carried out in the family using DNA markers spanning the AT locus on chromosome 11q22. The affected boy had a different haplotype from his affected sister. Thus in this family, the Nijmegen breakage syndrome is not allelic to the ataxia telangiectasia locus on chromosome 11q, and the two conditions are genetically distinct. The normal intellect in these children raises questions about normal brain development in the presence of severe microcephaly.     

The syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. Report of a new family and a review

A new autosomal recessive syndrome of chronic recurrent multifocal osteomyelitis (CRMO) and congenital dyserythropoietic anaemia (CDA) with microcytosis has recently been described in four children (two sibships) of one consangineous Arab family. In this report, we describe the clinical features and course of the syndrome of CRMO and CDA in two additional patients (one sibship) from another consanguineous Arab family and review the literature. The two patients (brother and sister), the products of a consanguineous marriage, developed the syndrome at an early age of 3 weeks and 2 months respectively. The diagnosis of CRMO was confirmed by radiological and technetium isotope bone scans. Bone marrow studies confirmed the diagnosis of CDA. Peripheral blood films showed hypochromia and microcytosis. The sites involved by CRMO were periarticular, mainly around the elbow, knee, wrist and small joints of the hand. The brother is now 21 years old and the sister 3.5 years old and CRMO is still active with frequent relapses. The brother developed flexion deformities at the age of 13 years. Both patients failed to thrive; weight and height were below the 5th percentile. CONCLUSION: This is the second report of the syndrome of chronic recurrent multifocal osteomyelitis and microcytic congenital dyserythropoietic anaemia, confirming it as a clinical entity, inherited as an autosomal recessive trait. The disease is characterised by an early onset, long clinical course of remissions and relapses, and seems to be different from the sporadic form of chronic recurrent multifocal osteomyelitis.     

Translocation trisomy 4q in 2 siblings as a sequela of paternal balanced reciprocal translocation: t(1;4)(q44;q31)

In a sister and a brother with striking similarity of facial dysplasias, severe disturbance of expressive speech, and mild mental retardation a partial trisomy of the long arm of chromosome 4 was identified as cause of these anomalies. The partial trisomy 4q was due to a balanced translocation between the chromosomes 1 and 4 in the father of both children.     

Two Siblings with Niemann-Pick Disease (NPD) Type B: Clinical Findings and Novel Mutations of the Acid Sphingomyelinase Gene

Acid sphingomyelinase deficiency leads to the accumulation of sphingomyelin in cells, causing Niemann-Pick disease (NPD) types A/B. RF (13.66 y) and HF (3 y) are brother and sister. RF growth was markedly delayed at the age of 12.66 y (123 cm; ?3.25 SD), while at the age 3 y his sister is 86 cm (?2.75 SD). The brother had a huge liver (13 cm) and spleen (12 cm). His sister also had an enlarged liver, but presented no other symptoms. The fibroblast cultivation had a reduced sphingomyelinase activity in the fibroblasts (0.68 mkat/kg protein), β-galaktosidase (937 mkat/kg) and glucosilceramidase (125.4 mkat/kg) were elevated. Mutational analysis demonstrated the siblings are compound heterozygotes (V112M and H554Y). The mother is carrier of V112M and the father carries H554Y. This is the first report of NPD type B in Macedonia. The novel mutation results in a moderately severe phenotype of NPD type B.     

Thrombocytosis in pediatric HIV infection

Thrombocytopenia has been extensively reported in association with HIV infection. Twenty-four children (6%) from a cohort of 400 children with platelet counts >500,000/mm(3) were reviewed. All had symptomatic disease and 10 (42%) patients died. In 4 children the platelet count exceeded 700,000/mm(3) and in 1 patient the platelet count was 1.5 million/mm(3). There were no thrombotic complications, and no specific therapy was required for the thrombocytosis. Thus HIV-1 infection, a chronic viral infection, is another etiologic agent for thrombocytosis and is associated with severe disease.     

Hypoxanthine-guanine phosphoribosyltransferase gene analysis for Japanese patients with Lesch-Nyhan syndrome

The Lesch-Nyhan syndrome results as a consequence of a severe deficiency of functional activity of purine salvage enzyme, hypoxanthine phosphoribosyltransferase (HPRT). We performed Southern blot analysis for five patients and their families using full length cDNA of the HPRT gene as a probe. Pst I digested Southern blot analysis revealed a large deletion that included exon 2 in patient 3. The size of this deletion was about 4.4 Kb. The mother of this patient had the same mutated allele and a normal one (heterozygote). This type of mutation from a Lesch-Nyhan syndrome patient has not been previously reported. The restriction fragment length polymorphism (RFLP) pattern was analyzed by Bam HI digested Southern blot analysis for one family who had no major gene abnormality. We determined from this analysis that the sister of the patient was a Lesch-Nyhan syndrome carrier and the fetus (brother) was normal for HPRT activity. This study shows RFLP analysis is still useful for carrier detection and prenatal diagnosis of Lesch-Nyhan syndrome.     

Familial brachyolmia

Brachyolmia is characterized clinically by short stature and radiographically by generalized platyspondyly without significant long bone abnormalities. A healthy 13-(8/12) year-old girl was referred for evaluation of short stature. The parents were first cousins. She had two older brothers and a younger brother and sister. On examination, her height was 116.2 cm, height SDS -6.2, armspan 135 cm. She had completed puberty. Except for her short trunk and lower extremities and mild scoliosis, she appeared normal. At 12 years old, the younger brother had short stature. His height was 104.7 cm, height SDS -6.2, armspan 116 cm. The younger sister was 3 years old. Her height was 84.2 cm, height SDS -2.9, armspan 85 cm. Other findings were normal in the younger sister and brother. The other members of the family were of normal stature and appearance. The proband's growth hormone stimulation tests, thyroid function tests, sex steroids, gonadotropins and blood biochemistry were found normal. There were similar radiological findings in the three siblings. There was platyspondyly, narrowing of intervertebral spaces in all vertebral bodies. The iliac bones were broad. No metaphyseal irregularity and normal epiphyses were detected in all patients. No significant changes were seen in long bones and skull. According to the physical and radiological findings, the patients were evaluated as brachyolmia.     

The Zellweger syndrome: subcellular pathology,neuropathology, and the demonstration of pneumocystis carinii pneumonitis in two siblings

The first Scandinavian cases of Zellweger syndrome (ZS) are described. A brother and sister, children of first cousins, had the typical clinical symptoms and pathological findings. Extensive metabolic studies in the boy were negative. Pipecolic acid in the urine was not elevated. Both children died at 14 weeks of age. Two months earlier the girl had suffered severe intestinal bleeding. Both had pneumocystic carinii pneumonia at autopsy although no evidence of immune deficiency had been found in the boy. The girl had used up her visible iron depots while the boy still had abundant but probably physiologic amounts of hemosiderin in the RES. Most of the cerebral abnormalities are unspecific and possibly related to anoxia or other causes of delayed maturation. The white matter abnormalities in ZS patients may only be quantitatively different from the common fatty metamorphosis in infants. Previously reported ultrastructural abnormalities (absence of peroxisomes and very sparse smooth endoplasmic reticulum, as well as mitochondrial abnormalities) which are possibly unique for ZS, are confirmed. It is stressed that these were seen despite phenobarbital treatment which normally stimulates the formation of smooth endoplasmic reticulum.     

Infantile colitis: a manifestation of intestinal Behcet's syndrome

A brother and sister of first cousin Pakistani parents presented with recurrent mouth ulcers and chronic diarrhoea in the neonatal period. Diarrhoea persisted in spite of treatment with oral prednisolone and sulphasalazine. Both children required subtotal colectomy with ileostomy. Histopathology of the resected colons was virtually identical and showed multiple deep "flask"-shaped ulcers, often penetrating to the serosa, in the presence of chronic inflammation, but without any of the characteristic histological features of Crohn's disease. The appearance closely resembled the colitis of Beh,cet's syndrome. Both children (aged 6 and 3.5 years, respectively) have continued to have recurrent perianal disease with intermittent bloody diarrhoea since the operation. Apart from the initial symptoms of oral aphthous ulcerations in both children, no other major criteria have developed so far. Intestinal Beh?et's syndrome should be considered in the differential diagnosis of chronic inflammatory bowel disease in childhood.     

Atypical features of the hepatic form of carnitine palmitoyltransferase deficiency in a Hutterite family.

We describe hepatic carnitine palmitoyltransferase (CPT I) deficiency in three children (a brother and sister and their second cousin) from an extended inbred Hutterite kindred. The patients were first seen between 8 and 18 months of age with recurrent episodes of hypoketotic hypoglycemia accompanied by a decreased level of consciousness and hepatomegaly. One patient had two Reye syndrome-like episodes. Abnormal organic acids were rarely detected in urine. Serum total and free carnitine levels were elevated in all three patients. Fibroblast acyl-coenzyme A dehydrogenase activities were normal in all, but palmitic acid oxidation, performed in fibroblasts from one patient, was less than 10% of control values. Activity of CPT I in cultured skin fibroblasts from the three patients was 10% to 15% of control levels; CPT II activity was normal. Activity of CPT I and CPT II in muscle from one patient was normal. Atypical features in two of these patients were greatly elevated levels of liver enzymes and creatine kinase during acute episodes. The patients have recently been successfully treated with medium-chain triglycerides and avoidance of fasting. Early identification and treatment of this disorder may avert potentially fatal episodes of hypoglycemia.     

Congenital Afibrinogenemia

Two patients, brother and sister, suffering from congenital afibrinogenemia are reported. This condition has previously not been described from Scandinavia. Both suffered from severe umbilical hemorrhage soon after birth and a continuing bleeding tendency. The diagnosis has been proved by coagulation tests and immunoelectrophoretic fibrinogen determinations. The hereditary nature of the disease is briefly discussed. Plasma fibrinogen estimations were made on 17 relatives but this failed to demonstrate any heterozygous carriers within the group.