The Growing Spectrum of DADA2 Manifestations-Diagnostic and Therapeutic Challenges Revisited.

Deficiency of Adenosine Deaminase Type 2 (DADA2) is a rare autosomal recessive inherited disorder with a variable phenotype including generalized or cerebral vasculitis and bone marrow failure. It is caused by variations in the adenosine deaminase 2 gene (ADA2), which leads to decreased adenosine deaminase 2 enzyme activity. Here we present three instructive scenarios that demonstrate DADA2 spectrum characteristics and provide a clear and thorough diagnostic and therapeutic workflow for effective patient care. Patient 1 illustrates cerebral vasculitis in DADA2. Genetic analysis reveals a compound heterozygosity including the novel ADA2 variant, p.V325Tfs*7. In patient 2, different vasculitis phenotypes of the DADA2 spectrum are presented, all resulting from the homozygous ADA2 mutation p.Y453C. In this family, the potential risk for siblings is particularly evident. Patient 3 represents pure red cell aplasia with bone marrow failure in DADA2. Here, ultimately, stem cell transplantation is considered the curative treatment option. The diversity of the DADA2 spectrum often delays diagnosis and treatment of this vulnerable patient cohort. We therefore recommend early ADA2 enzyme activity measurement as a screening tool for patients and siblings at risk, and we expect early steroid-based remission induction will help avoid fatal outcomes.

Bain type of X-linked syndromic mental retardation in boys.

A hemizygous variant in the HNRNPH2 gene causes MRXSB in a male individual.

Coexisting variants in OSTM1 and MANEAL cause a complex neurodegenerative disorder with NBIA-like brain abnormalities.

Coexistence of different hereditary diseases is a known phenomenon in populations with a high consanguinity rate. The resulting clinical phenotypes are extremely challenging for physicians involved in the care of these patients. Here we describe a 6-year-old boy with co-occurrence of a homozygous splice defect in OSTM1, causing infantile malignant osteopetrosis, and a loss-of-function variant in MANEAL, which has not been associated with human disease so far. The child suffered from severe infantile-onset neurodegeneration that could not be stopped by bone marrow transplantation. Magnetic resonance imaging demonstrated global brain atrophy and showed hypointensities of globus pallidus, corpora mamillaria, and cerebral peduncles, which were comparable to findings in neurodegeneration with brain iron accumulation disorders. LC-MS/MS analysis of urine and cerebrospinal fluid samples revealed a distinct metabolic profile with accumulation of mannose tetrasaccharide molecules, suggestive of an oligosaccharide storage disease. Our results demonstrate that exome sequencing is a very effective tool in dissecting complex neurological diseases. Moreover, we suggest that MANEAL is an interesting candidate gene that should be considered in the context of neurological disorders with brain iron accumulation and/or indications of an oligosaccharide storage disease.

Probable pseudotumor cerebri complex in 25 children. Further support of a concept.

BACKGROUND: Cerebrospinal fluid (CSF) opening pressure (OP) of ≥28 cm H2O is now considered a diagnostic criterion for Pseudotumor cerebri syndrome (PTCS) in children. However, it has been proposed that a diagnosis of "probable" PTCS can be made with an OP < 28 cm H2O if other diagnostic criteria are met. We report a group of children with probable PTCS. METHODS: Retrospective analysis of 25 children diagnosed with PTCS but with a CSF OP below 28 cm H2O. Eleven patients were identified during a nation-wide, prospective, active hospital-based surveillance, and additional 14 patients from our own institution. An extensive chart review of these cases was performed in order to identify signs and symptoms supportive of PTCS. RESULTS: Of these 25 patients 23 were treated with acetazolamide. Five children required escalation of medical treatment. Findings supportive of PTCS in the absence of an abnormal OP were: papilledema (n = 24), abducens nerve palsy (n = 7), without papilledema in one of them, headache (n = 15). Six patients had a relapse. A second lumbar puncture (LP) documented an opening pressure of >30 cm H2O in seven children. MRI findings supportive of PTCS were seen in eight patients. CONCLUSIONS: The diagnosis of probable PTCS as a subgroup of PTCS can be convincingly made in children with an OP < 28 cm H2O. Results of opening pressure measurement always need to be interpreted within the whole clinical context. Treatment decisions in patients with "probable" PTCS should follow the same stage-based principles as for "proven" PTCS.

Presumed Arterial Gas Embolism After Breath-Hold Diving in Shallow Water.

Dive-related injuries are relatively common, but almost exclusively occur in recreational or scuba diving. We report 2 children with acute central nervous system complications after breath-hold diving. A 12-year-old boy presented with unilateral leg weakness and paresthesia after diving beneath the water surface for a distance of ∼25 m. After ascent, he suddenly felt extreme thoracic pain that resolved spontaneously. Neurologic examination revealed right leg weakness and sensory deficits with a sensory level at T5. Spinal MRI revealed a nonenhancing T2-hyperintense lesion in the central cord at the level of T1/T2 suggesting a spinal cord edema. A few weeks later, a 13-year-old girl was admitted with acute dizziness, personality changes, confusion, and headache. Thirty minutes before, she had practiced diving beneath the water surface for a distance of ∼25 m. After stepping out, she felt sudden severe thoracic pain and lost consciousness. Shortly later she reported headache and vertigo, and numbness of the complete left side of her body. Neurologic examination revealed reduced sensibility to all modalities, a positive Romberg test, and vertigo. Cerebral MRI revealed no pathologic findings. Both children experienced a strikingly similar clinical course. The chronology of events strongly suggests that both patients were suffering from arterial gas embolism. This condition has been reported for the first time to occur in children after breath-hold diving beneath the water surface without glossopharyngeal insufflation.

Rituximab long-term maintenance therapy after autologous stem cell transplantation in patients with B-cell non-Hodgkin's lymphoma.

Treatment of B-cell non-Hodgkin's lymphomas (NHL) with either Rituximab alone or in combination with cytotoxic chemotherapy has been effective without major side effects. Thus, Rituximab maintenance therapy after autologous peripheral blood stem cell transplantation (PBSCT) might represent an improvement in NHL therapy. We therefore retrospectively analyzed the efficacy and side effects of monthly long-term Rituximab maintenance therapy after PBSCT in 27 patients with NHL. In median 10 infusions of Rituximab were given after PBSCT in time intervals of 1 month. Molecular monitoring of t(14;18) was performed using nested as well as quantitative real time polymerase chain reaction (RT-PCR) based on the LightCycler technology. Side effects according to common toxicity criteria (CTC) > II did mainly affect the hematopoietic system. In total, 10 patients (37%) suffered form grade III-IV hematotoxicity. Except for two patients with cutaneous Varicella-Zoster infection no serious infectious complications (CTC grade III/IV) occurred. No patient died because of treatment-related causes. This adverse event data compared favorably to the published data. Three patients had t(14;18) nested RT-PCR positive results before Rituximab therapy and converted to negativity after Rituximab therapy. We conclude that a prolonged Rituximab maintenance therapy after PBSCT with monthly administration is reliable and safe.