Muenke syndrome: Medical and surgical comorbidities and long-term management.

Muenke syndrome (MIM #602849), the most common syndromic craniosynostosis, results from the recurrent pathogenic p.P250R variant in FGFR3. Affected patients exhibit wide phenotypic variability. Common features include coronal craniosynostosis, hearing loss, carpal and tarsal anomalies, and developmental/behavioral issues. Our study examined the phenotypic findings, medical management, and surgical outcomes in a cohort of 26 probands with Muenke syndrome identified at the Children's Hospital of Philadelphia. All probands had craniosynostosis; 69.7% had bicoronal synostosis only, or bicoronal and additional suture synostosis. Three male patients had autism spectrum disorder. Recurrent ear infections were the most common comorbidity, and myringotomy tube placement the most common extracranial surgical procedure. Most patients (76%) required only one fronto-orbital advancement. de novo mutations were confirmed in 33% of the families in which proband and both parents were genetically tested, while in the remaining 66% one of the parents was a mutation carrier. In affected parents, 40% had craniosynostosis, including 71% of mothers and 13% of fathers. We additionally analyzed the medical resource utilization of probands with Muenke syndrome. To our knowledge, these data represent the first comprehensive examination of long-term management in a large cohort of patients with Muenke syndrome. Our study adds valuable information regarding neuropsychiatric and medical comorbidities, and highlights findings in affected relatives.

Clinical and Genotypic Spectrum of Chronic Granulomatous Disease in 71 Latin American Patients: First Report from the LASID Registry.

AIM: We analyzed data from 71 patients with chronic granulomatous disease (CGD) with a confirmed genetic diagnosis, registered in the online Latin American Society of Primary Immunodeficiencies (LASID) database. RESULTS: Latin American CGD patients presented with recurrent and severe infections caused by several organisms. The mean age at disease onset was 23.9 months, and the mean age at CGD diagnosis was 52.7 months. Recurrent pneumonia was the most frequent clinical condition (76.8%), followed by lymphadenopathy (59.4%), granulomata (49.3%), skin infections (42%), chronic diarrhea (41.9%), otitis (29%), sepsis (23.2%), abscesses (21.7%), recurrent urinary tract infection (20.3%), and osteomyelitis (15.9%). Adverse reactions to bacillus Calmette-Guérin (BCG) vaccination were identified in 30% of the studied Latin American CGD cases. The genetic diagnoses of the 71 patients revealed 53 patients from 47 families with heterogeneous mutations in the CYBB gene (five novel mutations: p.W361G, p.C282X, p.W483R, p.R226X, and p.Q93X), 16 patients with the common deletion c.75_76 del.GT in exon 2 of NCF1 gene, and two patients with mutations in the CYBA gene. CONCLUSION: The majority of Latin American CGD patients carry a hemizygous mutation in the CYBB gene. They also presented a wide range of clinical manifestations most frequently bacterial and fungal infections of the respiratory tract, skin, and lymph nodes. Thirty percent of the Latin American CGD patients presented adverse reactions to BCG, indicating that this vaccine should be avoided in these patients.

Microdeletion syndrome 16p11.2-p12.2: clinical and molecular characterization.

The pericentromeric region on 16p appears to be susceptible to chromosomal rearrangements and several patients with rearrangements in this region have been described. We report on a further patient with a microdeletion 16p11.2-p12.2 in the context of described patients with a deletion in the pericentromeric region of 16p. Minor facial anomalies, feeding difficulties, significant delay in speech development, and recurrent ear infections are common symptoms of the microdeletion syndrome 16p11.2-p12.2. All reported patients so far share a common distal breakpoint at 16p12.2 but vary in the proximal breakpoint at 16p11.2. The microdeletion 16p11.2-p12.2 should be distinguished from the approximately 500 kb microdeletion in 16p11.2 which seems to be associated with autism but not with facial manifestations, feeding difficulties, or developmental delay.

Clinical findings leading to the diagnosis of X-linked agammaglobulinemia.

To evaluate whether the diagnosis of X-linked agammaglobulinemia (XLA) is being made in a timely fashion, the clinical findings leading to the diagnosis of XLA were determined in 82 patients with proven mutations in Bruton's tyrosine kinase (60 patients with sporadic disease and 22 patients with familial disease). Recurrent otitis was seen in almost all of the patients with sporadic XLA who were older than 12 months at the time of diagnosis. However, fewer than 10% of patients were evaluated for immunodeficiency before they were hospitalized for infection; 38% of patients were hospitalized more than once before diagnosis. We conclude that the majority of patients with XLA were recognized to have immunodeficiency during or shortly after their first hospitalization for infection. Most of the patients had a history of recurrent otitis at the time of diagnosis, which when combined with the physical finding of markedly decreased or absent tonsils and cervical lymph nodes, could have alerted physicians to the diagnosis of XLA.