ESPE Abstracts

Background: Microcephalic primordial dwarfism (MPD) is a group of rare genetic disorders defined by severe growth restriction of both prenatal and postnatal weight (W), height (H), and particularly head circumference (HC).

Objective and hypotheses: To elucidate the genetic origin of the MPD in dizygotic twins.

Method: Exome sequencing of 19 genes known to be implicated in microcephaly was performed.

Results: Dizygotic twins (a male and a female) were issued from non-consanguineous healthy parents of normal height and had two healthy 4 years- and 2 years-old siblings. Intrauterine growth restriction of both twins was noted during the 2^nd trimester of pregnancy and confirmed at birth (at 36 1/7 weeks of gestation, ♂/♀: W 1500/1490 g, H 41.5/40 cm and HC 28/26.7 cm (<−2 SD). Both twins had feeding difficulties. They were hospitalized at the age of 5 months to investigate their poor growth. W, H and HC remained well below −2 SD (♂/♀: W 3710/3150 g, H 55/54 cm, HC 36/35 cm). Developmental skills and physical exam was normal except for a small penile length (1 cm) in the boy. Extensive work-up showed hypogammaglobulinemia and neutropenia. Thyroid function tests, growth factors, brain MRI, skeletal x-rays, blood standard karyotype and array-CGH were normal. Genetic analysis revealed compound heterozygous mutations of the ligase IV gene (chromosome 13) in both twins: c.2321T>C,p.(Leu774Pro)/c.2440C>T,p.(Arg814*), the parents being each heterozygous carriers of one of the mutations.

Discussion: Ligase IV is an enzyme implicated in the nonhomologous end-joining repair of DNA double-strand breaks. To date, 27 cases of ligase IV deficiency have been reported. Major clinical features are severe prenatal and postnatal growth restriction (H and HC), immunodeficiency, pancytopenia and lympho-reticular malignancies. Other inconstant characteristics include feeding difficulties and hypergonadotropic hypogonadism.

Conclusion: Ligase IV deficiency syndrome has to be considered in the differential diagnosis of patients with MPD, especially if associated with immune and haematological anomalies. The diagnosis is important for the follow-up of the patients, since they are at risk for cancer development due to a constitutive hypersensitivity to ionising radiations.