Refining the phenotype associated with biallelic DNAJC21 mutations.

Inherited bone marrow failure syndromes (IBMFS) are caused by mutations in genes involved in genomic stability. Although they may be recognized by the association of typical clinical features, variable penetrance and expressivity are common, and clinical diagnosis is often challenging. DNAJC21, which is involved in ribosome biogenesis, was recently linked to bone marrow failure. However, the specific phenotype and natural history remain to be defined. We correlate molecular data, phenotype, and clinical history of 5 unreported affected children and all individuals reported in the literature. All patients present features consistent with IBMFS: bone marrow failure, growth retardation, failure to thrive, developmental delay, recurrent infections, and skin, teeth or hair abnormalities. Additional features present in some individuals include retinal abnormalities, pancreatic insufficiency, liver cirrhosis, skeletal abnormalities, congenital hip dysplasia, joint hypermobility, and cryptorchidism. We suggest that DNAJC21-related diseases constitute a distinct IBMFS, with features overlapping Shwachman-Diamond syndrome and Dyskeratosis congenita, and additional characteristics that are specific to DNAJC21 mutations. The full phenotypic spectrum, natural history, and optimal management will require more reports. Considering the aplastic anemia, the possible increased risk for leukemia, and the multisystemic features, we provide a checklist for clinical evaluation at diagnosis and regular follow-up.

OTX2 microphthalmia syndrome: four novel mutations and delineation of a phenotype.

The OTX2 homeobox-containing transcription factor gene was shown to play a key role in the development of head structures in vertebrates. In humans, OTX2 mutations result in anophthalmia/microphthalmia (A/M) often associated with systemic anomalies. We screened 52 unrelated individuals affected with A/M and identified disease-causing variants in four families (8%), a higher frequency than previously reported. All four mutations are predicted to result in truncation of normal OTX2 protein sequence, consistent with previously reported mechanisms; three changes occurred de novo and one mutation was inherited from an affected parent. Four of the five OTX2-positive patients in our study displayed additional systemic findings, including two novel features, Wolf-Parkinson-White syndrome and an anteriorly placed anus. Analysis of the phenotypic features of OTX2-positive A/M patients in this study and those previously reported suggests the presence of pituitary anomalies and lack of genitourinary and gastrointestinal manifestations as potential distinguishing characteristics from SOX2 anophthalmia syndrome. Interestingly, pituitary anomalies seem to be more strongly associated with mutations that occur in the second half of OTX2, after the homeodomain and SGQFTP motif. OTX2 patients also show a high rate of inherited mutations (35%), often from mildly or unaffected parents, emphasizing the importance of careful parental examination/testing.

Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15.

BACKGROUND: Hyperornithinaemia-hyperammonaemia-homocitrullinuria (HHH) syndrome (OMIM 238970) is caused by impaired ornithine transport across the inner mitochondrial membrane due to mutations in SLC25A15. To date, 22 different mutations of the SLC25A15 gene have been described in 49 patients belonging to 31 unrelated families. OBJECTIVE: To further delineate the phenotypic spectrum of HHH syndrome from a description of a genetically homogeneous cohort of patients and identify prognostic factors based on long-term follow-up. METHODS: Sixteen French-Canadian patients were retrospectively and prospectively clinically assessed. RESULTS: Owing to a founder effect, 15 of the 16 patients were homozygous for the F188del mutation in the SLC25A15 gene. The main clinical features at presentation were liver dysfunction (6/16) and neurological disease (9/16), including chronic neurological symptoms (6/9) and acute encephalopathy (3/9). Hyperammonaemia was not constant and usually mild and uncommon after start of treatment. Long-term follow-up showed that variable intellectual impairment and lower limb spasticity often occur, together or separately, with no obvious relationship to age at diagnosis and compliance with treatment. CONCLUSION: We report the largest known cohort to date of patients with HHH syndrome. A similar range of severity occurred in the clinical course and outcome of patients homozygous for delF188 and in the 33 other reported patients compiled from the literature. The poor clinical outcome of some patients with HHH syndrome despite early treatment and repeatedly normal plasma ammonia levels emphasises the need to better understand the pathophysiology and to reconsider the therapeutic goals for HHH.