TY - JOUR
T1 - Expanding the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to XX gonadal dysgenesis
AU - Altunoglu, Umut
AU - Börklü, Esra
AU - Shukla, Anju
AU - Escande-Beillard, Nathalie
AU - Ledig, Susanne
AU - Azaklı, Hülya
AU - Nayak, Shalini S.
AU - Eraslan, Serpil
AU - Girisha, Katta Mohan
AU - Kennerknecht, Ingo
AU - Kayserili, Hülya
N1 - Funding Information:
We cordially thank the patients and their families for their patience and support of our research. The authors gratefully acknowledge use of the services and facilities of the Koç University Research Center for Translational Medicine (KUTTAM), funded by the Presidency of Strategy and Budget. We further acknowledge the indispensable input we received from our colleagues: the meticulous evaluation of biochemical assays from the pediatric endocrinologist Prof. Firdevs Baş, and the neurological evaluation from the neuromuscular specialist Prof. Piraye Oflazer. We are also grateful to Dr. Patrick G. Brosnan for sharing valuable clinical information on his patients. We thank Hilal Pırıl Saraçoğlu for her contribution to the figures and the graphical abstract. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Presidency of Strategy and Budget. TUBITAK was the funding institute for SBAG-112S398, Turkish partner of ERA-net consortium CRANIRARE2, to H.K.K.
Funding Information:
We cordially thank the patients and their families for their patience and support of our research. The authors gratefully acknowledge use of the services and facilities of the Koç University Research Center for Translational Medicine (KUTTAM), funded by the Presidency of Strategy and Budget. We further acknowledge the indispensable input we received from our colleagues: the meticulous evaluation of biochemical assays from the pediatric endocrinologist Prof. Firdevs Baş, and the neurological evaluation from the neuromuscular specialist Prof. Piraye Oflazer. We are also grateful to Dr. Patrick G. Brosnan for sharing valuable clinical information on his patients. We thank Hilal Pırıl Saraçoğlu for her contribution to the figures and the graphical abstract. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Presidency of Strategy and Budget. TUBITAK was the funding institute for SBAG‐112S398, Turkish partner of ERA‐net consortium CRANIRARE2, to H.K.K.
Publisher Copyright:
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
PY - 2022/2
Y1 - 2022/2
N2 - Homozygous variants in PPP2R3C have been reported to cause a syndromic 46,XY complete gonadal dysgenesis phenotype with extragonadal manifestations (GDRM, MIM# 618419) in patients from four unrelated families, whereas heterozygous variants have been linked to reduced fertility with teratozoospermia (SPGF36, MIM# 618420) in male carriers. We present eight patients from four unrelated families of Turkish and Indian descent with three different germline homozygous PPP2R3C variants including a novel in-frame duplication (c.639_647dupTTTCTACTC, p.Ser216_Tyr218dup). All patients exhibit recognizable facial dysmorphisms allowing gestalt diagnosis. In two 46,XX patients with hypergonadotropic hypogonadism and nonvisualized gonads, primary amenorrhea along with absence of secondary sexual characteristics and/or unique facial gestalt led to the diagnosis. 46,XY affected individuals displayed a spectrum of external genital phenotypes from ambiguous genitalia to complete female. We expand the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to both XY and XX gonadal dysgenesis. Our findings supported neither ocular nor muscular involvement as major criteria of the syndrome. We also did not encounter infertility problems in the carriers. Since both XX and XY individuals were affected, we hypothesize that PPP2R3C is essential in the early signaling cascades controlling sex determination in humans.
AB - Homozygous variants in PPP2R3C have been reported to cause a syndromic 46,XY complete gonadal dysgenesis phenotype with extragonadal manifestations (GDRM, MIM# 618419) in patients from four unrelated families, whereas heterozygous variants have been linked to reduced fertility with teratozoospermia (SPGF36, MIM# 618420) in male carriers. We present eight patients from four unrelated families of Turkish and Indian descent with three different germline homozygous PPP2R3C variants including a novel in-frame duplication (c.639_647dupTTTCTACTC, p.Ser216_Tyr218dup). All patients exhibit recognizable facial dysmorphisms allowing gestalt diagnosis. In two 46,XX patients with hypergonadotropic hypogonadism and nonvisualized gonads, primary amenorrhea along with absence of secondary sexual characteristics and/or unique facial gestalt led to the diagnosis. 46,XY affected individuals displayed a spectrum of external genital phenotypes from ambiguous genitalia to complete female. We expand the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to both XY and XX gonadal dysgenesis. Our findings supported neither ocular nor muscular involvement as major criteria of the syndrome. We also did not encounter infertility problems in the carriers. Since both XX and XY individuals were affected, we hypothesize that PPP2R3C is essential in the early signaling cascades controlling sex determination in humans.
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U2 - 10.1111/cge.14086
DO - 10.1111/cge.14086
M3 - Article
AN - SCOPUS:85119040584
SN - 0009-9163
VL - 101
SP - 221
EP - 232
JO - Clinical Genetics
JF - Clinical Genetics
IS - 2
ER -