# Response to Letter to the Editor: "IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction"

Sjoerd D. Joustra,¹,² Ferdinand Roelfsema,¹ A. S. Paul van Trotsenburg,³
Harald J. Schneider,⁴ Robert P. Kosilek,⁴ Herman M. Kroon,⁵ John G. Logan,⁶
Natalie C. Butterfield,⁶ Xiang Zhou,⁷ Chirine Toufaily,⁷ Beata Bak,⁷
Marc-Olivier Turgeon,⁷ Emilie Brûlé,⁷ Frederik J. Steyn,⁸ Mark Gurnell,⁹
Olympia Koulouri,⁹ Paul Le Tissier,¹⁰ Pierre Fontanaud,¹¹ J. H. Duncan Bassett,⁶
Graham R. Williams,⁶ Wilma Oostdijk,² Jan M. Wit,² Alberto M. Pereira,¹
Nienke R. Biermasz,¹ Daniel J. Bernard,⁷ and Nadia Schoenmakers⁹

¹Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, Netherlands; ²Department of Pediatrics, Leiden University Medical Center, Leiden, Netherlands; ³Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Pediatric Endocrinology, Amsterdam, Netherlands; ⁴Department of Endocrinology, Ludwig-Maximilians University, Munich, Germany; ⁵Department of Radiology, Leiden University Medical Center, Leiden, Netherlands; ⁶Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK; ⁷Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada; ⁸The University of Queensland Centre for Clinical Research, Brisbane, Australia; ⁹University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK; ¹⁰Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK; and ¹¹CNRS, Institut de Génomique Fonctionnelle, INSERM, and Université de Montpellier, Montpellier, France

ORCID numbers: 0000-0002-4733-9031 (S. D. Joustra); 0000-0001-6276-2834 (F. Roelfsema); 0000-0002-1194-9866 (A. M. Pereira); 0000-0001-5817-3594 (N. R. Biermasz).

We thank Dr Faucz and colleagues for sharing their hypothesis that hypothyroidism, rather than growth hormone (GH) excess, may be the main driver for the acromegaloid facies observed in our patients with immunoglobulin superfamily member 1 (IGSF1) deficiency. This is a valid idea and one we gave careful consideration in the course of our study. Significantly, the majority (two-thirds) of affected participants received thyroxine replacement from shortly after birth. However, the presence or absence of acromegalic facies did not differ between untreated individuals and

those on long-term levothyroxine at the time of facial photography.

Although it is true that hypothyroidism may cause coarse facies, patients with IGSF1 deficiency typically have mild to moderate hypothyroidism, especially when compared with the more severe thyroid hormone deficits that occur in primary hypothyroidism. In our clinical experience, the facies we observe in some of our patients with IGSF1 deficiency are not found in the context of biochemically comparable congenital hypothyroidism due to other etiologies. Additionally, some individuals

<footnote>ISSN Print 0021-972X ISSN Online 1945-7197</footnote>

<footnote>Printed in USA</footnote>

<footnote>© Endocrine Society 2020.</footnote>

<footnote>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.</footnote>

<footnote>Received 12 March 2020. Accepted 21 March 2020.</footnote>

<footnote>First Published Online 24 March 2020.</footnote>

<footnote>Corrected and Typeset 15 April 2020.</footnote>

<footnote>Abbreviations: GH, growth hormone; IGSF1, immunoglobulin superfamily member 1.</footnote>
with IGSF1 deficiency are not diagnosed with central
hypothyroidism until late into adulthood, possibly due
to preservation of circulating triiodothyronine levels,
which mitigate clinical and metabolic manifestations
of hypothyroidism (1). Adult height is also maintained
in IGSF1 deficiency, arguing against significant skeletal
hypothyroidism (2).

Clinical evaluation of our patients with IGSF1 defi-
ciency revealed subtle facial coarsening without facial
puffiness. Given the challenges in quantifying this im-
pression objectively, we used facial image analysis to
compare our patients' facial characteristics with those
of participants with confirmed acromegaly and with
control participants. In the context of elevated me-
dian insulin-like growth factor 1 levels, increased GH
secretion, and with other supportive clinical features
(increased finger soft tissue thickness), we contend that
an effect of excess GH remains a plausible explan-
ation of our findings. The increased skeletal growth
and organomegaly in Igsf1-deficient mice further sup-
port this contention. Nevertheless, we agree that further
studies are required to investigate the molecular basis

for our observations. The complex endocrinopathy seen
in patients who are IGSF1 deficient mandates that the
interpretation of their clinical phenotypes must derive
from a consideration of the potential effects of multiple
hormone abnormalities.

**Additional Information**

*Correspondence and Reprint Requests:* Sjoerd D. Joustra, MD, Department of Pediatrics, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, the Netherlands. E-mail: sdjoustra@lumc.nl.

**Disclosure Summary:** The authors have nothing to disclose.

**References**

1. Roche EF, McGowan A, Koulouri O, et al. A novel IGSF1 mutation in a large Irish kindred highlights the need for familial screening in the IGSF1 deficiency syndrome. *Clin Endocrinol (Oxf)*. 2018;89(6):813-823.

2. Joustra SD, Roelfsema F, van Trotsenburg ASP, et al. IGSF1 defi-
ciency results in human and murine somatotrope neurosecretory
hyperfunction. *J Clin Endocrinol Metab*. 2020;105. pii:dgz093.