Endocrine Abstracts (2019) 64 034 | DOI: 10.1530/endoabs.64.034

An unusual case of pubertas tarda: IGSF-1 deficiency syndrome

I Matthys, Y Taes1, B Callewaert2 & J De Schepper


1Department of Endocrinology, AZ Sint-Jan, Bruges, Belgium; 2Department of Endocrinology and Medical Genetics, UZ Gent, Ghent, Belgium.


Background aim of the work: IGSF-1 encodes a plasma membrane immunoglobulin superfamily glycoprotein that is abundant in the pituitary and testis. Loss-of-function causes an X-linked syndrome which is mainly characterized by congenital hypothyroidism and macroorchidism.[1,2] Because of its relatively recent discovery and its very rare incidence, the time to diagnosis is often long. We present a case of IGSF1 deficiency case where it took 6 years before diagnosis was made. With this report, we want to highlight the clinical and laboratory features of this syndrome.

Case presentation: A 16-year-old boy was seen at the Department of Endocrinology because of poor genital development and delayed growth since the age of 13. Besides a recently treated left varicocele, he had no significant medical history. At physical examination, standing height was 176.9 cm, body weight 62.6 kg, pubertal stage A1P2G2 and testicular volume 8 and 8 ml. His bone age was 12 years. At initial hormonal work-up LH was 2.5 U/l, FSH 2.6 U/l, PRL 85 mU/l (86-324), FT4 0.83 ng/dl (0.93–1.6) and testosterone 58.4 ng/dl (280–1110). A gonadotropin-releasing hormone stimulation test revealed a LH peak of 13.2 U/l and a FSH peak of 4 U/l. He was treated with 125 mg of Sustanon every 4 weeks during 6 months, inducing a catch-up growth in height and penile growth, and pubic hair development.

Two years later, his height was 191.4 cm, pubertal stage A2P4G3, testicular volume 15 and 15 ml and bone age 15 years. Basal FSH was 14.6 U/l (1.5–12.4), LH 4.9 U/l, and testosterone 358 ng/dl. No further measures were taken at that time.

Finally, at the age of 22 years, when his testis volume had increased up to 25 and 30 ml, basal hormonology confirmed central hypothyroidism (TSH 2.82 mU/l; FT4 0.89 ng/dl; FT3 0.19 ng/dl (0.0–0.44)), a persisting slightly elevated FSH (13.6 U/l), a low normal testosterone (263.3 ng/dl) and low DHEAS (157 μg/dl (211–492), but normal LH and SHBG levels. TSH increased up to 9.3 U/l 60 min after TRH and FSH up to 20.9 U/l after LHRH. Magnetic resonance imaging of the hypothalamic pituitary region was normal, except for a small lesion (5 mm). Treatment with levothyroxine was started.

The central hypothyroidism, hypoprolactinemia, poor adrenache and increasing FSH values in combination with delayed puberty and the post pubertal onset of macro-orchidism led to the suspicion of IGSF-1 deficiency. Saenger sequencing (Department of Genetics, Leiden) confirmed a loss-of-function mutation (c. 1030C>T; p.Arg344*) in the IGSF-1 gene.

Conclusions: Clinicians should be aware of the possibility of IGSF-1 deficiency syndrome in male patients with the combination of delayed puberty, central hypothyroidism and post pubertal macro-orchidism.1,2. Screening for carriership within family members is advised, since even in hemizygote females a higher incidence of central hypothyroidism, prolactin deficiency and delayed menarche is described.2,3

References: 1. Joustra SD et al. IGSF1 deficiency syndrome, a newly uncovered endocrinopathy. Rare Diseases 2013;1.

2. Van Hulle S et al. Delayed Adrenarche may be an Additional Feature of Immunoglobulin Super Family Member 1 Deficiency Syndrome. J Clin Res Pediatr Endocrinol 2016;8(1):86–91.

3. Joustra SD et al. The IGSF1 deficiency syndrome: characteristics of male and female patients. J Clin Endocrinol Metab 2013;98: 4942–4952.

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