Two siblings with congenital central hypothyroidism caused by a novel mutation in the IGSF1 gene

Abstract. Genetic defects in the immunoglobulin superfamily member 1(IGSF1) protein are the cause of congenital central hypothyroidism (C-CH). Here we report two Japanese siblings with C-CH due to a novel IGSF1 mutation. The youngest brother showed a failure to thrive, hypothermia, and neonatal icterus six days after birth. Further endocrine evaluations led to the diagnosis of C-CH. In addition, PRL deficiency was later detected. In contrast, the elder brother did not show symptoms of severe hypothyroidism during the neonatal period, but he had been followed up by doctors due to psychomotor developmental delays since the age of 1 yr. At the age of 3 yr, he had low thyroxine and PRL levels and was also diagnosed with C-CH. Because of the C-CH and PRL deficiency, an IGSF1 deficiency was suspected. Sequence analysis of the IGSF1 gene identified a novel hemizygous mutation of p.Trp1173GlyfsTer8 (NM_001170961.1:c.3517del) in both siblings. In conclusion, the phenotypic severity of C-CH is different, even in siblings. Importantly, an IGSF1 deficiency may result in severe hypothyroidism during the neonatal period.

[1]  P. Lapunzina,et al.  The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGFβ and Activin pathways , 2017, Scientific Reports.

[2]  I. Bergadá,et al.  Cognitive profiles of patients with early detected and treated congenital hypothyroidism. , 2017, Archivos argentinos de pediatria.

[3]  D. Bercovich,et al.  Familial Central Hypothyroidism Caused by a Novel IGSF1 Gene Mutation. , 2016, Thyroid : official journal of the American Thyroid Association.

[4]  H. Shintaku,et al.  A Japanese Family with Central Hypothyroidism Caused by a Novel IGSF1 Mutation. , 2016, Thyroid : official journal of the American Thyroid Association.

[5]  James N. Hughes,et al.  Identification of an IGSF1‐specific deletion in a five‐generation pedigree with X‐linked Central Hypothyroidism without macroorchidism , 2016, Clinical endocrinology.

[6]  W. Dreschler,et al.  Mutations in TBL1X Are Associated With Central Hypothyroidism , 2016, The Journal of clinical endocrinology and metabolism.

[7]  E. Fliers,et al.  Mild deficits in attentional control in patients with the IGSF1 deficiency syndrome , 2016, Clinical endocrinology.

[8]  M. Losekoot,et al.  Delayed Adrenarche may be an Additional Feature of Immunoglobulin Super Family Member 1 Deficiency Syndrome , 2016, Journal of clinical research in pediatric endocrinology.

[9]  E. Fliers,et al.  IGSF1 Deficiency: Lessons From an Extensive Case Series and Recommendations for Clinical Management , 2016, The Journal of clinical endocrinology and metabolism.

[10]  K. Abe,et al.  Combined Growth Hormone and Thyroid-Stimulating Hormone Deficiency in a Japanese Patient with a Novel Frameshift Mutation in IGSF1 , 2015, Hormone Research in Paediatrics.

[11]  T. Tajima,et al.  Neonatal screening and a new cause of congenital central hypothyroidism , 2014, Annals of pediatric endocrinology & metabolism.

[12]  O. Meijer,et al.  Spatial and temporal expression of immunoglobulin superfamily member 1 in the rat. , 2014, The Journal of endocrinology.

[13]  D. Bernard,et al.  Three novel IGSF1 mutations in four Japanese patients with X-linked congenital central hypothyroidism. , 2013, The Journal of clinical endocrinology and metabolism.

[14]  Jacqueline K. White,et al.  Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement , 2012, Nature Genetics.

[15]  S. de Muinck Keizer-Schrama,et al.  Influence of timing and dose of thyroid hormone replacement on mental, psychomotor, and behavioral development in children with congenital hypothyroidism. , 2005, The Journal of pediatrics.

[16]  T. Tajima,et al.  A novel mutation of IGSF1 in a Japanese patient of congenital central hypothyroidism without macroorchidism. , 2013, Endocrine journal.