A syndrome of primary combined immunodeficiency with microcephaly, cerebellar hypoplasia, growth failure and progressive pancytopenia

Abstract

A male infant with primary combined immunodeficiency, microcephaly with marked cerebellar hypoplasia, and growth failure of prenatal onset is presented. He developed progressive pancytopenia in the 3rd year of life and died at 42 months from disseminated aspergillosis. Laboratory studies and post mortem examination failed to reveal any known aetiology for his disorder. Hreidarsson et al. [3] previously described a syndrome of progressive pancytopenia with microcephaly, cerebellar hypoplasia and growth failure in three boys, with similar clinical and laboratory findings. Although extensive immunological investigations were not performed in those previous patients, recurrent infections in two of them are suggestive of immunodeficiency. In the light of the immunological findings in our patient, we propose that the condition of the four patients belongs to the same syndrome, which has to be considered as a primary combined immunodeficiency syndrome. This syndrome can be distinguished from the other known immunodeficiency syndromes by its associated characteristic features, namely microcephaly with cerebellar hypoplasia, growth failure of prenatal onset and progressive pancytopenia.

Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations

“…[26][27][28] It is noteworthy that all RTEL1-deficient patients in our cohort presented with combined immunodeficiency revealed in 1 by opportunistic infections (eg, P. jirovecii in P1). Thus, the diagnosis of HH should be considered in any child presenting with combined immunodeficiency associated with other developmental features (such as microcephaly and/or cerebellar hypoplasia).…”

Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal‐Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1

“…Recently, progressive combined immunode®ciency has become a recognized feature of the syndrome since immunoglobulin de®ciency has been documented in 4/7 published cases with 3/4 patients investigated also manifesting lymphocyte abnormalities (lymphopenia, B-cell depletion, T-cell dysfunction) (Berthet et al, 1994;Aalfs et al, 1995;Ohga et al, 1997;Nespoli et al, 1997). The pathogenesis of HH is unknown.…”

“…Hoyeraal-Hreidarsson (HH) syndrome (MIM 600545) is a severe multisystem disorder affecting boys characterized by microcephaly, cerebellar hypoplasia, growth retardation of prenatal onset, and aplastic anaemia (AA) (Hoyeraal et al, 1970;Hreidarsson et al, 1988;Berthet et al, 1994;Aalfs et al, 1995;Ohga et al, 1997;Nespoli et al, 1997). Recently, progressive combined immunode®ciency has become a recognized feature of the syndrome since immunoglobulin de®ciency has been documented in 4/7 published cases with 3/4 patients investigated also manifesting lymphocyte abnormalities (lymphopenia, B-cell depletion, T-cell dysfunction) (Berthet et al, 1994;Aalfs et al, 1995;Ohga et al, 1997;Nespoli et al, 1997).…”

Growth failure, intracranial calcifications, acquired pancytopenia, and unusual humoral immunodeficiency: A genetic syndrome?

“…Recently, defects in PAX5, CXCR4, and stromal cell-derived factor 1 were excluded as a cause of this syndrome [Revy et al, 2000]. Most of these children experienced recurrent infections, and later reports describe a variety of immunological abnormalities [Berthet et al, 1994]. Our patients lack the characteristic facies and cerebellar hypoplasia of the HoyeraalHreidarsson syndrome.…”