Acute Lymphoblastic Leukemia in a Pediatric Patient With Turnpenny-Fry Syndrome.

Turnpenny-Fry Syndrome (TPFS) is a rare genetic disorder characterized by a severe developmental delay and a distinctive facial gestalt. It is caused by mutations in the Polycomb Group Ring Finger Protein 2 (PCGF2) gene, which is also known to play a role in numerous tumor types. Up to date, there have been no published case reports of patients with TPFS and concomitant malignancies. The present case describes the clinical evaluation and follow-up of a male infant with severe global developmental delay (GDD) and a distinctive phenotype. At 4 years of age, clinical exome sequencing confirmed the diagnosis of TPFS. Posteriorly, at 5 years of age, the patient was also diagnosed with T-cell acute lymphoblastic leukemia (ALL). Given the scarce literature regarding this syndrome, the authors expect that this case report will provide valuable information that could improve the follow-up of patients with TPFS. Furthermore, this case highlights the necessity for the appropriate diagnosis of developmental disorders, to ensure adequate care, surveillance of comorbidities and proper genetic counselling.

Pre-implantation Genetic Testing in Inherited Metabolic Diseases? Stateof- the-art and current challenges.

INTRODUCTION: Inborn errors of metabolism (IEM) are genetic diseases involving congenital disorders of enzyme activities. Most follow Mendelian autosomal recessive inheritance and few follow mitochondrial inheritance. In many cases, after the birth of an affected child parents discover that have been the carriers for the condition and worry about the risk of recurrence in future offspring. Preimplantation genetic testing (PGT) can analyze embryos before their transfer to the uterus and prevent the transmission of hereditary conditions to descendants, however this procedure is of limited value in mtDNA conditions. METHODS: The list of diseases currently approved for PGT were reviewed. The process for eligibility, was as for the Comissão Nacional Procriação Medicamente Assistida (CNPMA), of Portugal (PT). Review of international practices for Assisted Reproductive Techniques (ART) in IEM was carried out. RESULTS: As of 07.2022, 23 IEM diseases associated with deleterious variants in nDNA were approved for PGT in PT. Couples at risk for conditions not included in the list can solicit an evaluation from an expert committee, after a medical genetics consultation. To qualify for approval, diseases must cause significant suffering and/or premature death. Due to a greater number of solicitations many more IEM conditions have been approved for PGT across the world. ART for mtDNA is not available in PT. International expert centers include PGT for specific well documented variants and mitochondrial donation. CONCLUSION: PGT is a reliable approach to reduce the risk of transmission of a genetic condition to the offspring. The list of IEM disorders currently accepted for this technique in Portugal are small, but it is expanding, as many more diseases fit the necessary criteria. While appealing in theory, low success rates coupled with limited availability can be discouraging for patients. Genetic counselling is of paramount importance after the diagnosis of IEM diseases. It is important for both clinicians and patients to be made aware of the available reproductive options and their limitations.

Case report: Mohr-Tranebjaerg syndrome: hearing impairment as the onset of an insidious disorder with high recurrence risk.

Mohr-Tranebjaerg syndrome (MTS) is an X-linked recessive disorder caused by TIMM8A loss of function. It is characterized by sensorineural hearing loss in childhood, progressive optic atrophy in early adulthood, early onset dementia and psychiatric symptoms of variable expressivity. We present a family with 4 affected males, explore age-related and interfamilial variability and review the literature. Case report: A 31 years-old male developed psychiatric symptoms at age 18 and presented early onset dementia. Sensorineural hearing loss had been diagnosed in childhood. At 28yo, he developed dysarthria, dysphonia, dysmetria, limb hyperreflexia, dystonia, and spasticity following an acute encephalopathic crisis. WES revealed a hemizygous novel likely pathogenic variant in TIMM8A, c.45_61dup p.(His21Argfs*11), establishing the diagnosis of MTS. Genetic counseling of the family allowed the diagnosis of three other symptomatic relatives -3 nephews (11yo and two 6yo twins), children of a carrier sister. The oldest nephew had been followed since 4yo due to speech delay. Sensorineural hearing loss was diagnosed at 9yo, and hearing aids were prescribed. The two other nephews were monozygotic twins, and both had unilateral strabismus. One of the twins had macrocephaly and hypoplasia of the anterior temporal lobe, as disclosed by an MRI performed due to febrile seizures. Both had developmental delays, with the language being the most affected area. Their audiograms confirmed hearing loss. All three nephews were hemizygous for the familial TIMM8A variant. Discussion: Hearing loss, an early sign of MTS due to auditory neuropathy, can often be overlooked until more severe features of the disorder manifest. Recurrence risk is high for female carriers, and reproductive options should be offered. Early monitoring of hearing and vision loss and neurological impairment in MTS patients is mandatory since early interventions may positively impact their development. This family showcases the importance of performing a timely etiological investigation of hearing loss and its impact on genetic counseling.