Ella Sugo

Novel FOXF1 Mutations in Sporadic and Familial Cases of Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins Imply a Role for its DNA Binding Domain

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA‐binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.

Mutations of the Thyroid Hormone Transporter MCT8 Cause Prenatal Brain Damage and Persistent Hypomyelination

CONTEXT Mutations in the MCT8 (SLC16A2) gene, encoding a specific thyroid hormone transporter, cause an X-linked disease with profound psychomotor retardation, neurological impairment, and abnormal serum thyroid hormone levels. The nature of the central nervous system damage is unknown. OBJECTIVE The objective of the study was to define the neuropathology of the syndrome by analyzing brain tissue sections from MCT8-deficient subjects. DESIGN We analyzed brain sections from a 30th gestational week male fetus and an 11-year-old boy and as controls, brain tissue from a 30th and 28th gestational week male and female fetuses, respectively, and a 10-year-old girl and a 12-year-old boy. METHODS Staining with hematoxylin-eosin and immunostaining for myelin basic protein, 70-kDa neurofilament, parvalbumin, calbindin-D28k, and synaptophysin were performed. Thyroid hormone determinations and quantitative PCR for deiodinases were also performed. RESULTS The MCT8-deficient fetus showed a delay in cortical and cerebellar development and myelination, loss of parvalbumin expression, abnormal calbindin-D28k content, impaired axonal maturation, and diminished biochemical differentiation of Purkinje cells. The 11-year-old boy showed altered cerebellar structure, deficient myelination, deficient synaptophysin and parvalbumin expression, and abnormal calbindin-D28k expression. The MCT8-deficient fetal cerebral cortex showed 50% reduction of thyroid hormones and increased type 2 deiodinase and decreased type 3 deiodinase mRNAs. CONCLUSIONS The following conclusions were reached: 1) brain damage in MCT8 deficiency is diffuse, without evidence of focal lesions, and present from fetal stages despite apparent normality at birth; 2) deficient hypomyelination persists up to 11 years of age; and 3) the findings are compatible with the deficient action of thyroid hormones in the developing brain caused by impaired transport to the target neural cells.

Three cases of osteoma cutis occurring in infancy. A brief overview of osteoma cutis and its association with pseudo-pseudohypoparathyroidism

We report three cases of primary osteoma cutis in children, two of whom (siblings) were associated with Albrights hereditary osteodystrophy (AHO), manifesting as short stature with autosomal dominant inheritance from the father, but no dysmorphic features and no parathyroid hormone (PTH) resistance. Osteoma cutis can manifest as an isolated skin disease, a secondary condition to other skin diseases (such as acne), or in association with several syndromes, including AHO, which in turn may be associated with PTH resistance. The management and prognosis of patients diagnosed with osteoma cutis is determined by whether the skin manifestation has occurred in isolation, in association with a syndrome, or as a secondary skin disease. These three paediatric cases highlight the importance of understanding the aetiology and associations of osteoma cutis in order to appropriately investigate and manage patients who present with this rare skin disease.

Neonatal lupus erythematosus presenting as papules on the feet.

We describe a case of neonatal lupus erythematosus in a 4‐week‐old male baby presenting with nodules/papules on the plantar surface of both feet. Skin histology of the right foot papule was consistent with lupus erythematosus. Annular lesions more typical of this condition then appeared later and maternal antibodies were positive for speckled antinuclear antibodies (1:5120), anti‐Ro/SSA and anti‐La/SSB(+), rheumatoid factor 1380.0 IU/mL. The patient had no evidence of cardiac, haematological or hepatobilary involvement. Although the mother was asymptomatic, the maternal grandmother had recently been diagnosed with Sjögrens syndrome.

Juvenile xanthogranuloma: Challenges in complicated cases

Juvenile xanthogranuloma (JXG) is one of the most common forms of non‐Langerhans cell histiocytosis in children. Although it usually presents as a self‐limited skin lesion with typical histopathology, JXG can be challenging to diagnose due to an atypical initial presentation with corresponding variable histopathology for different stages of development. We present challenging cases of JXG from Sydney Childrens Hospital, collected over 10 years – two with multisystem involvement and concomitant urticaria, one associated with neurofibromatosis, and one case of giant JXG with an initial histopathological challenge. Although JXG has been reported with urticaria pigmentosa, in two of our cases persistent urticaria, in association with JXG is discussed.

Excellent response to dasatinib of childhood Philadelphia positive intracranial acute lymphoblastic leukaemia tumours.

Bulky intracranial disease in childhood Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) is rare and optimal management has not been well defined. Here we report two children with Ph+ ALL and bulky intracranial disease who had an excellent clinical, radiological and molecular response to dasatinib and multi-agent chemotherapy. A 4-year-old boy (Case 1) presented with priapism, bruising and a white cell count (WCC) of 845 · 10/l and was diagnosed with B-cell precursor ALL (CD10, CD19, CD22, HLA-DR and TdT positive). He commenced induction therapy with methylprednisolone (60 mg/m per day), and over the next day he was noted to have pupillary abnormalities and a fluctuating level of consciousness. A computerized tomography (CT) scan showed multiple intracranial lesions, presumed leukaemic infiltrates (Fig 1A). An atraumatic lumbar puncture was performed on day 1 and triple intrathecal chemotherapy administered (methotrexate, cytarabine and hydrocortisone, age-related doses). Cerebrospinal fluid (CSF) cytocentrifuge analysis showed 15 white cells with 40% blasts. Fluorescent in-situ hybridization (FISH) confirmed the diagnosis of Ph+ ALL. Dexamethasone (10 mg/m per day) was substituted for methylprednisolone and imatinib mesylate (340 mg/m per day) was commenced. The patient remained intubated and ventilated to manage respiratory compromise from presumed leukaemic pulmonary infiltrates. There was an excellent systemic response, with the peripheral blast count falling to 3 · 10/l by day 3 of treatment. Analysis of the CSF on day 4 showed no white cells and no blasts. However the patient failed to wake appropriately when sedation was lightened, and a repeat CT scan on day 6 showed an increase in both the size and number of intracranial lesions (Fig 1B). Open brain biopsy of a left frontal lesion demonstrated the presence of sheets of small, monomorphic lymphoid cells (Fig 1C) positive for CD10 and TdT. A magnetic resonance imaging (MRI) scan performed on day 8 confirmed the presence of multiple intracranial lesions in the cerebellum and cerebral hemispheres (Fig 1D). Dasatinib (100 mg/m per twice daily) was substituted for imatinib mesylate and systemic chemotherapy (vincristine 1Æ5 mg/m weekly, daunorubicin 30 mg/m weekly and l-asparaginase 5000 u/m twice weekly) was commenced. Emergent cranial radiation therapy was considered but not performed. Following these therapy changes, the patient was successfully extubated. Neurological examination post-extubation demonstrated focal deficits including a right hemiplegia and aphasia. The patient had progressive and complete neurological recovery over the following months and a progress MRI scan at day 79 showed complete resolution of the lesions (Fig 1E). Polymerase chain reaction-based minimal residual disease (MRD) testing confirmed an excellent response to therapy with both markers becoming undetectable in the bone marrow by day 79. The patient is currently in remission 18 months from diagnosis, having received definitive neuraxis radiation as part of an unrelated umbilical cord transplant with total body irradiation (TBI). He is planned to continue a further 12 months of dasatinib therapy post-transplant. Shortly after this, a 2-year-old girl (Case 2) presented with lethargy, bruising, epistaxis and a fluctuating level of consciousness. The WCC of 615 · 10/l, circulating blasts (immunophenotype CD10, CD19, CD22, HLA-DR and TdT positive) and FISH confirmed the diagnosis of Ph+ B-cell precursor ALL. CT scan revealed multiple intracranial parenchymal lesions consistent with bulky disease with haemorrhage. She commenced induction therapy with dexamethasone, dasatinib, and systemic chemotherapy as per Case 1. The first lumbar puncture with triple intrathecal therapy was delayed until her neurological condition stabilized and was performed on day 7. Atraumatic CSF cytocentrifuge analysis revealed nine white cells with no blasts, and subsequent CSF analyses remained free of leukaemia. She suffered multiple complications including seizures and right hemiplegia, gastro-intestinal bleeding and perineal excoriation, but made a progressive clinical and neurological recovery with almost complete radiological resolution of the intracranial lesions. Bone marrow examination at the end of induction confirmed an excellent response to therapy with both MRD markers becoming undetectable. During consolidation chemotherapy there was deterioration in the perineal skin secondary to Pseudomonas aeruginosa, and despite appropriate broad-spectrum multi-agent antibacterial therapy and surgical debridement she developed necrotising fasciitis, which progressed to multi-organ failure and death. Post-mortem examination revealed perineal ecthyma gangrenosa and advanced disseminated Pseudomonas infection. Pathological examination of the brain revealed numerous areas of old haemorrhage with central areas of necrotic leukaemic cells, and no viable leukaemia cells were identified. In Case 1, there was clear, early intracranial disease progression despite peripheral blood and CSF disease, which was rapidly controlled by dexamethasone, imatinib mesylate and triple intrathecal therapy. Poor CNS penetration and correspondence

Unusual presentation of GLUT-1 positive infantile haemangioma.

Infantile haemangiomas are usually not present at birth. This is a case of a female infant with an atypical congenital vascular tumour present at birth which ulcerated in the first few days of life, involuted over several months and showed histopathological features in keeping with either an involuting GLUT‐1 positive infantile haemangioma or a reticular haemangioma of infancy. The initial clinical presentation was atypical for an infantile haemangiomas and for a congenital haemangioma, however the histopathology and immunohistochemistry assisted with confirmation of the diagnosis. Vacuum‐assisted closure (VAC) therapy aided in the complete healing of the ulcerated infantile haemangioma which was not achievable with conventional dressings.

Proliferative nodules of undifferentiated spindle cells arising in a large congenital melanocytic naevus.

Proliferative nodules (PN) are benign lesions that arise in large congenital melanocytic naevi (LCMN). Clinically and histologically they can be difficult to differentiate from malignancies, which are also associated with LCMN. The PN in this case consisted of undifferentiated spindle cells and exhibited unusual histological features including negative stains for melanocytic markers (S100, HMB45 and MelA), negative stain for c‐Kit, high mitotic index and unusual morphology of the lesional cells. As a result, a firm histological classification could not be made, which posed a challenge for the clinical management.

Neonatal necrotising fasciitis following superficial skin infection with community-associated methicillin-resistant Staphylococcus aureus

Neonatal necrotising fasciitis following superficial skin infection with community-associated methicillin-resistant Staphylococcus aureusjpc_1732 918..920 Tony Walls, Gary Williams, Susan Adams, Ella Sugo and Des Mulcahy Departments of Immunology and Infectious Diseases, Paediatric Intensive Care, General Surgery and Anatomical Pathology, Sydney Children’s Hospital, Randwick, and Department of Paediatrics, Orange Base Hospital, Orange, New South Wales, Australia

Lymphomatoid papulosis with associated cerebellar lesion of similar histology and T-cell clonality

A 9‐year old boy presented with a 4‐month history of a truncal monomorphic eruption with self‐healing papulonecrotic lesions. A skin biopsy revealed a dermal infiltrate of CD4, CD8 and CD30‐positive T‐cells, consistent with lymphomatoid papulosis. He responded to 4 months of treatment with narrowband UVB phototherapy (311 nm) which stabilised his disease. Five years later he presented with an acute onset of nausea and vomiting, dizziness, headache and ataxia. Magnetic resonance imaging of the brain revealed a lesion in the cerebellum and stereotactic resection was undertaken. Histology showed CD4, CD8 and CD30‐positive T‐cells similar to his skin lesions, with a monoclonal T‐cell receptor (TCR) gamma gene rearrangement. Subsequent analysis of the skin detected a monoclonal band of the same size as the cerebellar lesion. Treatment was initiated for a primary central nervous system (CNS) lymphoma but ceased after one course of high‐dose methotrexate. Opinion on the pathology was divided as to whether the cerebellar lesion represented an atypical reactive T‐cell lymphoproliferative response or a T‐cell lymphoma. On follow‐up 2 years later, the patient remains clinically and radiologically clear, making CNS lymphoma unlikely.