Novel Mutation in the DCK1 Gene: Neonatal Hoyeraal-Hreidarsson Syndrome as a Rare Differential Diagnosis in Primary Microcephaly, Cerebellar Hypoplasia, and Severe Developmental Delay with Progressive Bone Marrow Failure

Case Study: Hoyeraal-Hreidarsson syndrome (HHS; MIM #305000, Xq28) is a rare X-linked recessive multisystem disorder characterized by intrauterine growth retardation, microcephaly, severe developmental delay, cerebellar hypoplasia, and bone marrow failure. We report the clinical course of a male neonatal floppy infant with progressive bone marrow failure. The infant was born after 33 weeks' of gestation by secondary cesarean after severe intrauterine growth retardation and anhydramnios. Because of the primary asphyxia (APGAR score 1/6/6) and a neonatal infection, the infant was ventilated for 5 days. A thrombocytopenia was present from the beginning, while a progressive pancytopenia developed over the following months. At the age of 3 months, the bone marrow was aplastic with scattered hemophagocytosis raising the suspicion of a connatal primary hemophagocytic lymphohistiocytosis. Immunomodulatory therapy with corticosteroids and cyclosporine A had no effect on the progressive bone marrow failure. Neurologically, the child was born with a severe microcephaly with primary cerebellar hypoplasia. Clinically, he demonstrated a developmental delay and progressive dysphagia. The brain MRI at the age of 4 and 8 months revealed severe brain atrophy with predominant pontocerebellar hypoplasia, pronounced delay in myelination, and multiple small infection-like subcortical white matter calcifications in the occipital region. Because of the radiomorphological phenotype, the differential diagnosis of a pseudotorch syndrome was discussed. At the age of 7 months a leukoplakia was seen on the tongue, characteristic of Hoyeraal-Hreidarsson syndrome. The child died at the age of 8 months in acute respiratory failure. Mutational analyses revealed a novel hemizygous variant c.1072 T> C, p.C358G in exon 11 of the DKC1 gene. Offering the correct diagnosis in this rare disease with a fulminant clinical course is important to offer genetic counseling to the family. Hoyeraal-Hreidarsson syndrome is a rare but important differential diagnosis in neonates with severe neurological and hematological symptoms.

Keywords: neonatal Hoyeraal-Hreidarsson syndrome, severe developmental delay, progressive bone marrow failure.