Neonatal rhabdomyoma with cardiac dysfunction: favourable response to sirolimus.

Cardiac rhabdomyoma is the most common cardiac tumour in childhood, with a strong genetic association to tuberous sclerosis complex. Although most of the patients remain asymptomatic, a small proportion present with cardiac complications in the early neonatal period. Timely initiation of treatment can potentially reduce disease morbidity, and mammalian target of rapamycin (M-TOR) inhibitors play an effective role in promoting regression of these tumours. A healthy term newborn was diagnosed with a giant congenital cardiac rhabdomyoma at birth. He developed clinical signs of compromised cardiac function and progressive myocardial ischaemia, with echocardiography showing significant dyskinesia. He was treated with M-TOR inhibitors and clinical response was monitored via serial echocardiography. Remarkable regression of the tumour was visibly demonstrated within 4 months of sirolimus treatment. The infant continues to be reviewed by a multidisciplinary team of physicians and monitored for features of tuberous sclerosis complex.

A novel NSDHL variant in CHILD syndrome with gastrointestinal manifestations and localized skin involvement.

BACKGROUND: CHILD syndrome is an X-linked dominant disorder associated with pathogenic mutations in the NSDHL gene. The condition is predominantly found in females as it is lethal in males. Most cases present at birth with extensive unilateral ichthyosiform erythroderma involving the trunk and limbs. Milder and less extensive presentations have been reported, leading to misdiagnosis especially during early childhood. METHODS AND RESULTS: We report an adult female of Malay ancestry who presented with minimal skin and limb involvement. She was only diagnosed in adulthood when she presented with gastrointestinal symptoms and worsening of skin manifestations. The clinical diagnosis was suspected after a combination of clinical, pathological and immunohistochemistry correlation, and molecularly confirmed with the discovery of a frameshift variant in NSDHL. The novel variant was inherited from her mother who had some linear hypopigmented patches over the medial aspects of both her arms and right forearm. CONCLUSION: We uncovered a novel frameshift variant associated with presentations that cast a new light on the clinical features of CHILD syndrome.

Somatic genetic rescue of a germline ribosome assembly defect.

Indirect somatic genetic rescue (SGR) of a germline mutation is thought to be rare in inherited Mendelian disorders. Here, we establish that acquired mutations in the EIF6 gene are a frequent mechanism of SGR in Shwachman-Diamond syndrome (SDS), a leukemia predisposition disorder caused by a germline defect in ribosome assembly. Biallelic mutations in the SBDS or EFL1 genes in SDS impair release of the anti-association factor eIF6 from the 60S ribosomal subunit, a key step in the translational activation of ribosomes. Here, we identify diverse mosaic somatic genetic events (point mutations, interstitial deletion, reciprocal chromosomal translocation) in SDS hematopoietic cells that reduce eIF6 expression or disrupt its interaction with the 60S subunit, thereby conferring a selective advantage over non-modified cells. SDS-related somatic EIF6 missense mutations that reduce eIF6 dosage or eIF6 binding to the 60S subunit suppress the defects in ribosome assembly and protein synthesis across multiple SBDS-deficient species including yeast, Dictyostelium and Drosophila. Our data suggest that SGR is a universal phenomenon that may influence the clinical evolution of diverse Mendelian disorders and support eIF6 suppressor mimics as a therapeutic strategy in SDS.

Heterozygous missense variant in EIF6 gene: A novel form of Shwachman-Diamond syndrome?

Shwachman-Diamond syndrome (SDS) is a rare multisystem ribosomal biogenesis disorder characterized by exocrine pancreatic insufficiency, hematologic abnormalities and bony abnormalities. About 90% of patients have biallelic mutations in SBDS gene. Three additional genes-EFL1, DNAJC21 and SRP54 have been reported in association with a SDS phenotype. However, the cause remains unknown for ~10% of patients. Herein, we report a 6-year-old Chinese boy, who presented in the neonatal period with pancytopenia, liver transaminitis with hepatosplenomegaly and developmental delay, and subsequently developed pancreatic insufficiency complicated by malabsorption and poor growth. Exome sequencing identified a novel de novo heterozygous variant in EIF6 (c.182G>T, p.Arg61Leu). EIF6 protein inhibits ribosomal maturation and is removed in the late steps of ribosomal maturation by SBDS and EFL1 protein. Given the interaction of EIF6 with SBDS and EFL1, we postulate heterozygous variants in EIF6 as a novel cause of Shwachman-Diamond-like phenotype. We compared the phenotype of our patient with those in patients with mutation in SBDS, EFL1, DNAJC21, and SRP54 genes to support this association. Identification of more cases of this novel phenotype would strengthen the association with the genetic etiology.

The spectrum of genetic variants and phenotypic features of Southeast Asian patients with Noonan syndrome.

BACKGROUND: Noonan syndrome (NS) is an autosomal dominant disorder that belongs to a group of developmental disorders called RASopathies with overlapping features and multiple causative genes. The aim of the study was to identify mutations underlying this disorder in patients from Southeast Asia and characterize their clinical presentations. METHODS: Patients were identified from the hospital's Genetics clinics after assessment by attending clinical geneticists. A targeted gene panel was used for next-generation sequencing on genomic DNA extracted from the blood samples of 17 patients. RESULTS: Heterozygous missense variants were identified in 13 patients: eight were in PTPN11, three in SOS1, and one each in RIT1 and KRAS. All are known variants that have been reported in patients with NS. Of the 13 patients with identified variants, 10 had short stature, the most common feature for NS. Four of the eight patients with PTPN11 variants had atrial septal defect. Only two had pulmonary stenosis which is reported to be common for PTPN11 mutation carriers. Another two had hypertrophic cardiomyopathy, a feature which is negatively associated with PTPN11 mutations. CONCLUSIONS: Our study provides the mutation and phenotypic spectrum of NS from a new population group. The molecular testing yield of 76% is similar to other studies and shows that the targeted panel approach is useful for identifying genetic mutations in NS which has multiple causative genes. The molecular basis for the phenotypes of the remaining patients remains unknown and would need to be uncovered via sequencing of additional genes or other investigative methods.