Abstract
Background
Improved survival in ADA-SCID patients is revealing new aspects of the systemic disorder. Although increasing numbers of reports describe the systemic manifestations of adenosine deaminase deficiency, currently there are no studies in the literature evaluating genital development and pubertal progress in these patients.
Methods
We collected retrospective data on urogenital system and pubertal development of 86 ADA-SCID patients followed in the period 2000–2017 at the Great Ormond Street Hospital (UK) and 5 centers in Italy. In particular, we recorded clinical history and visits, and routine blood tests and ultrasound scans were performed as part of patients’ follow-up.
Results and Discussion
We found a higher frequency of congenital and acquired undescended testes compared with healthy children (congenital, 22% in our sample, 0.5–4% described in healthy children; acquired, 16% in our sample, 1–3% in healthy children), mostly requiring orchidopexy. No urogenital abnormalities were noted in females. Spontaneous pubertal development occurred in the majority of female and male patients with a few cases of precocious or delayed puberty; no patient presented high FSH values. Neither ADA-SCID nor treatment performed (PEG-ADA, BMT, or GT) affected pubertal development or gonadic function.
Conclusion
In summary, this report describes a high prevalence of cryptorchidism in a cohort of male ADA-SCID patients which could represent an additional systemic manifestation of ADA-SCID. Considering the impact urogenital and pubertal abnormalities can have on patients’ quality of life, we feel it is essential to include urogenital evaluation in ADA-SCID patients to detect any abnormalities, initiate early treatment, and prevent long-term complications.
Electronic supplementary material
The online version of this article (10.1007/s10875-020-00777-8) contains supplementary material, which is available to authorized users.
Keywords: ADA-SCID, puberty, pubertal development, cryptorchidism, undescended testis, urogenital abnormalities
Introduction
Severe combined immunodeficiency due to adenosine deaminase deficiency is a rare autosomal recessive disease (ADA-SCID, OMIM # 102,700) caused by mutations in the gene encoding the enzyme ADA type 1, resulting in impairment of the purine salvage pathway [1–3]. This defect in purine metabolism primarily affects lymphocyte development and function resulting in varying degrees of immune deficiency [4].
Several studies demonstrate that ADA-SCID is a systemic disease, and thanks to improved survival, an increasing number of non-immune manifestations are being recognized and reported [1–5].
At present, no study describes abnormalities in the development of genitalia or in the pubertal progression of ADA-SCID patients treated for their underlying immune disorder.
Methods
In this report, we describe data collected retrospectively on the urogenital system and pubertal development of 86 ADA-SCID patients followed in the period 2000–2017: 51 males and 35 females with an age range from 4 months to 30 years were included in this analysis (Table 1). Patients were from different ethnicities, and there was a high prevalence of consanguinity (51%). Previous treatments included enzyme replacement therapy (PEG-ADA ERT), gene therapy (GT), or allogeneic bone marrow transplantation (BMT) as single therapy or given in various combinations (Table 1).
Table 1.
Sample description, sex, origin, parents’ consanguinity, ADA-SCID treatment, and years of follow-up
| N° | sex | Origin | C | ADA mutation | Treatment | Years of follow-up § (age) |
|---|---|---|---|---|---|---|
| 1 | F | South America/Hispanic | Yes | Compound heterozygous, c.320 T > C, p.L107P/c.632G > A, p.R211H | Haploidentical BMT° ➔ GT1➔PEG-ADA | 15 (3–18 y) |
| 2 | M | South America/Hispanic | No | Compound heterozygous, c.221G > T, p.G74V/c.845G > A, p.R282Q | Haploidentical BMT° ➔ GT1 | 14 (1–15 y) |
| 3 | F | Arabic/White | Yes | Homozygous c.845G > A, p.R282Q | Haploidentical BMT° ➔ PEG-ADA ➔ GT1 | 13 (1–14 y) |
| 4 | F | Arabic/White | Yes | Compound heterozygous, c.646G > A, p.G216R/c.956_960delAAGAG; p.E319GfsX3 | PEG-ADA ➔ GT1 | 11 (1–12 y) |
| 5 | M | Europe/White | Yes | Homozygous c.632G > A, p.R211H | PEG-ADA ➔ GT1 | 12 (5–17 y) |
| 6 | M | Europe/White | No | Compound heterozygous, c.646G > A, p.G216R/c.872C > T, p.S291L | PEG-ADA ➔ GT1 | 11 (0–11 y) |
| 7 | M | Europe/White | No | Homozygous c.478 + 2 T > C | PEG-ADA ➔ GT1 | 10 (1–11 y) |
| 8 | F | Arabic/White | Yes | Homozygous c.646G > A, p.G216R | Haploidentical BMT° ➔ PEG-ADA ➔ GT1 | 8 (0–8 y) |
| 9 | M | South America/Hispanic | Yes | Homozygous c.632G > A, p.R211H | PEG-ADA ➔ GT1 | 9 (0–9 y) |
| 10 | M | North America/White | No | Compound heterozygous, c.646G > A, p.G216R/c.956_960delAAGAG; p.E319GfsX3 | PEG-ADA ➔ GT1 | 9 (1–10 y) |
| 11 | M | South Asia | Yes | Homozygous c.606 + 5G >? (Exon6, splice donor site + 5— no more data available) | PEG-ADA ➔ GT1 | 9 (0–9 y) |
| 12 | M | North America/White | No | Compound heterozygous, c.646G > A, p.G216R/Exon10, deletion + 6 c.975 + 6Tdel | PEG-ADA ➔ GT1 | 8 (6–14 y) |
| 13 | F | Africa/White | No | Homozygous: c.466C > T, p.R156C | PEG-ADA ➔ GT1 | 8 (2–10 y) |
| 14 | M | Africa/Black | No | Homozygous, c.7C > T, p.Q3X | PEG-ADA ➔ GT1 | 6 (2–8 y) |
| 15 | M | Africa/Black | Yes | Homozygous, c.881C > A, p.T294K | PEG-ADA ➔ GT1 ➔ MSD BMT2 | 4 (1–5 y) |
| 16 | M | Arabic/White | Yes | Homozygous, c.956_960delAAGAG, p.E319GfsX3 | PEG-ADA ➔ GT1 | 5 (2–7 y) |
| 17 | F | European/White | No | Compound heterozygous, c.632G > A, p.R211H/c.646G > A, p.G216R | PEG-ADA ➔ GT1 | 2 (0–2 y) |
| 18 | M | Europe/Hispanic | No | Compound heterozygous, c.467G > A, p.R156H / c.646G > A, p.G216R | PEG-ADA ➔ GT1 ➔ MUD BMT* | 3 (2–5 y) |
| 19 | M | Europe/White | Yes | Compound heterozygous, c.385G > A, p.V129M /(second mutation not identified) | PEG-ADA | 16 (14–30 y) |
| 20 | F | Europe/White | Unk | Homozygous, c.385G > A, p.V129M | PEG-ADA | 23 (4–27 y) |
| 21 | F | Europe/White | No | Homozygous, c.499delG, pV167P | PEG-ADA | 12 (6–18 y) |
| 22 | M | Europe/White | Yes | Homozygous, c.632G > A, p.R211H | PEG-ADA | 17 (3–20 y) |
| 23 | M | Europe/White | Yes | Homozygous, c.632G > A, p.R211H | PEG-ADA ➔ MSD BMT3 | 10 (0–10 y) |
| 24 | M | Europe/White | Unk | Homozygous, c.632G > A, p.R211H | PEG-ADA ➔ MSD BMT° | 6 (5–10 y) |
| 25 | M | South America/Hispanic | No | Homozygous, c.845G > A, p.R282Q | PEG-ADA ➔ MUD BMT° | 1 (0–1 y) |
| 26 | F | Europe/White | Unk | Exon 3, insertion (no more data available) | PEG-ADA ➔ MSD BMT° | 14 (0–14 y) |
| 27 | M | Europe/White | No | Compound heterozygous, c.466C > T, p.R156C/c.955_959GAAGA, p.E320GfsX3 | PEG-ADA ➔ MUD BMT° | 13 (1–14 y) |
| 28 | M | Europe/White | Unk | ND | Haploidentical BMT* | 15 (0–15 y) |
| 29 | F | Europe/White | Unk | ND | PEG-ADA ➔ MUD BMT* | 11 (0–11 y) |
| 30 | F | South Asia | Unk | Homozygous, c.424C > T, p.R142X | PEG-ADA ➔ MSD BMT° | 13 (0–13 y) |
| 31 | M | Unk | Unk | Homozygous, c.424C > T, p.R142X | PEG-ADA ➔ MSD BMT° | 17 (0–17 y) |
| 32 | F | Africa/Black | Yes | Homozygous, c.7C > T, p.Q3X | PEG-ADA ➔ MSD BMT° | 18 (0–18 y) |
| 33 | M | Europe/White Irish | Unk | Homozygous, c.646G > A, p.G216R | PEG-ADA ➔ MFD BMT° | 17 (0–17 y) |
| 34 | F | South Asia | Yes | ND | PEG-ADA ➔ MFD BMT° | 18 (0–18 y) |
| 35 | F | Europe/White | Unk | Compound heterozygous, c.363-1G > C/c.364G > A, p.G122R | PEG-ADA ➔ MUD BMT4 | 18 (0–18 y) |
| 36 | M | Europe/White | Yes | Homozygous, c.646G > A, p.G216R | PEG-ADA ➔ MFD BMT° | 17 (0–17 y) |
| 37 | F | Europe/White | Yes | ND | PEG-ADA ➔ MSD BMT° | 16 (0–16 y) |
| 38 | F | Europe/White Irish | Yes | Homozygous, c.646G > A, p.G216R | PEG-ADA ➔ MFD BMT° | 15 (0–15 y) |
| 39 | M | Africa/Black | Yes | Homozygous, c.7C > T, p.Q3X | PEG-ADA ➔ GT5 | 17 (0–17 y) |
| 40 | M | Africa/Black | No | Homozygous, c.7C > T, p.Q3X | PEG-ADA ➔ MFD BMT° | 14 (0–14 y) |
| 41 | M | Africa/Black | Yes | Homozygous, c.646G > A, p.G216R | PEG-ADA ➔ MSD BMT° | 13 (0–13 y) |
| 42 | F | Africa/Black | No | Homozygous, c.7C > T, p.Q3X | PEG-ADA ➔ MUD BMT6 | 14 (0–14 y) |
| 43 | M | South Asian heritage | Yes | Homozygous, c.716G > A, p.G239D | PEG-ADA ➔ MSD BMT° | 12 (0–12 y) |
| 44 | M | Europe/White | No | Compound heterozygous, c.367delG, p.D123TfsX10/c.956_960delAAGAG; p.E319GfsX3 | PEG-ADA ➔ GT5 | 13 (0–13 y) |
| 45 | F | Europe/White | No | Compound heterozygous, c.467G > A, p.R156H/c.478 + 1G > A | PEG-ADA ➔ GT (first)5 ➔ GT (second)7 | 13 (2–15 y) |
| 46 | M | South Asia | Yes | Homozygous, c.716G > A, p.G239D | PEG-ADA ➔ MSD BMT° | 11 (0–11 y) |
| 47 | F | Europe/White | Yes | Homozygous, c.646G > A, p.G216R | PEG-ADA ➔ MFD BMT° | 11 (1–12 y) |
| 48 | M | Arabic /white | Yes | Homozygous, c.956_960delAAGAG; p.E319GfsX3 | PEG-ADA ➔ GT5 | 8 (0–8 y) |
| 49 | M | Arabic/White | Yes | Homozygous, c.385G > A, p.V129M | PEG-ADA ➔ MSD BMT° | 5 (1–6 y) |
| 50 | M | Europe/White | No | ND | PEG-ADA ➔ GT5 | 3 (1–4 y) |
| 51 | F | Africa/Black | Yes | Homozygous, c.7C > T, p.Q3X | PEG-ADA ➔ MSD Cord° | 10 (0–10 y) |
| 52 | M | Africa/Black | Yes | Homozygous, c.646G > A, p.G216R | PEG-ADA ➔ GT5 | 11 (0–11 y) |
| 53 | F | South Asia | Yes | Homozygous, c.646G > A, p.G216R | PEG-ADA ➔ MMUD Cord8 | 9 (0–9 y) |
| 54 | F | South Asia | Yes | Homozygous, c.703C > T, p.R235W | PEG-ADA ➔ MMUD Cord8 | 10 (0–10 y) |
| 55 | M | Arabic/White | Yes | Homozygous, c.428dupA, p.D143EfsX28 | PEG-ADA ➔ MUD Cord8 | 3 (0–3 y) |
| 56 | M | Europe/White | No | Compound heterozygous, c.466C > T, p.R156C/c.646G > A, p.G216R | PEG-ADA ➔ GT5 ➔ HSCT7 | 12 (1–13 y) |
| 57 | M | South Asia | Yes | Homozygous, c.646G > A, G216R | PEG-ADA ➔ MUD Cord ➔ MUD PBSC9 | 9 (0–9 y) |
| 58 | F | South Asia | Yes | Homozygous, c.716G > A, p.G239D | PEG-ADA ➔ MFD BMT° | 7 (0–7 y) |
| 59 | M | Europe/White | No | Compound heterozygous, c.955-958delGAAG, p.E320RfsX6/c.1078 + 2 T > A | PEG-ADA ➔ GT (first) ➔ GT (second) | 8 (4–12 y) |
| 60 | F | Arabic/White | Yes | Homozygous, 1079-15 T > A | PEG-ADA ➔ MUD PBSC5 | 3 (1–4 y) |
| 61 | M | Arabic/White | Yes | Homozygous, c.385G > A, p.V129M | PEG-ADA ➔ MFD BMT10 | 4 (0–4 y) |
| 62 | M | Europe/White Irish | Yes | Homozygous, c.646G > A, p.G216R | PEG-ADA ➔ MFD BMT0 | 7 (0–7 y) |
| 63 | M | Africa/Black | Yes | Homozygous, c.7C > T, p.Q3X | PEG-ADA ➔ GT7 | 3 (4–7 y) |
| 64 | M | South Asia | Yes | Homozygous, c.646G > A, p.G216R | PEG-ADA ➔ GT7 | 7 (0–7 y) |
| 65 | F | Europe/White | No | Compound heterozygous, c.646G > A, p.G216R/c.955_959GAAGA, p.E320GfsX3 | PEG-ADA ➔ GT7 | 5 (0–5 y) |
| 66 | F | South Asia | Yes | Homozygous, c.646G > A, p.G216R | PEG-ADA ➔ GT7 | 5 (0–5 y) |
| 67 | M | Arabic/white | No | Compound heterozygous, c.976-1G > C/c.302G > T, p.R101L | PEG-ADA ➔ GT (first) 7 ➔ GT (second) 7 | 9 (1–10 y) |
| 68 | M | Africa/Black | No | Homozygous, c.7C > T, p.Q3X | PEG-ADA ➔ GT7 | 4 (0–4 y) |
| 69 | F | Europe/White | No | Compound heterozygous, c.872C > T, p.S291L/c.986C > T, p.A329V | PEG-ADA ➔ GT7 | 4 (1–5 =y) |
| 70 | M | Africa/Black | No | Homozygous: c.7C > T, p.Q3X | PEG-ADA ➔ GT7 | 4 (0–4 y) |
| 71 | M | Africa/Black | No | Compound heterozygous, c.603C > G, p.Y201X/c.632G > A, p.R211H | PEG-ADA ➔ GT7 | 4 (0–4 y) |
| 72 | F | Africa/Black | No | Homozygous, c.7C > T, p.Q3X | PEG-ADA ➔ GT7 | 4 (9–13 y) |
| 73 | F | Europe/White Irish | Yes | Homozygous, c.646G > A, p.G216R | PEG-ADA ➔ GT7 | 2 (0–2 y) |
| 74 | M | Europe/White | No | Homozygous, c.646G > A, p.G216R | PEG-ADA ➔ MFD BMT ➔ MSD BMT° | 2 (0–2 y) |
| 75 | M | Unk | No | Compound heterozygous, c.320 T > C, p.L107P/c.632G > A, p.R211H | PEG-ADA ➔ GT7 | 1 (1–2 y) |
| 76 | F | Africa/Black | Yes | Homozygous, c.7C > T, p.Q3X | PEG-ADA ➔ GT7 | 3 (0–3 y) |
| 77 | M | Europe/White Irish | No | Homozygous, c.646G > A, p.G216R | PEG-ADA ➔ GT7 | 2 (0–2 y) |
| 78 | M | Europe/White | Yes | Compound heterozygous, c.310C > A, p.P104T/c.646G > A, p.G216R | PEG-ADA ➔ GT7 | 2 (0–2 y) |
| 79 | F | Europe/White | Yes | Compound heterozygous, c.43C > G, p.H15D/c.757_758dupCG | PEG-ADA ➔ GT7 | 2 (0–2 y) |
| 80 | F | Europe/White | No | Homozygous, c.646G > A, p.G216R | PEG-ADA ➔ GT7 | 2 (0–2 y) |
| 81 | M | Africa/White | No | Homozygous, c.704G > A, p.R235Q | PEG-ADA ➔ GT7 | 1 (2–3 y) |
| 82 | M | Europe/White Irish | Yes | Homozygous, c.646G > A, G216R | PEG-ADA ➔ GT7 | 2 (0–2 y) |
| 83 | F | Europe/White | No | Homozygous, c.320 T > C, p.L107P | PEG-ADA ➔ GT7 | 0 |
| 84 | M | Africa/Black | Yes | Homozygous, c.7C > T, p.Q3X | PEG-ADA ➔ GT7 | 1 (0–1 y) |
| 85 | F | Europe/White Irish | Yes | Homozygous, c.646G > A, G216R | PEG-ADA ➔ GT7 | 0 |
| 86 | F | Europe/White-Africa/Black | No | Compound heterozygous, c.482G > A, p.W161X/c.1078 + 2 T > A | PEG-ADA ➔ GT7 | 0 |
C parents’ consanguinity, Unk unknown, § years of follow-up are considered time from the first diagnostic test available to the last. In parentheses, age of the diagnostic test available–age of the last diagnostic test available. ND not done, BMT bone marrow transplantation, GT gene therapy, MSD BMT from matched sibling donor, MFD BMT from matched family donor, MUD BMT from matched unrelated donor, MMUD BMT from mismatched unrelated donor, PBSC peripheral blood stem cells, Cord cord blood cells
In the column treatment superscript numbers:
*Unknown
0No conditioning agents
1Busulfan (single agent, non myeloablative)
2Reduced toxicity regimen Treo/Flu
3Reduced intensity conditioning (RIC) Bu/Flu
4RIC Flu/Melph/ATG
5Melphalan (single agent)
6RIC Flu/Melph/Campath
7Low-dose busulfan (AUC ~ 20)
8Myeloablative conditioning (MAC) Treo/Cy
9MAC Treo/Flu
10Campath (single agent)
Patients in our cohort received immunological follow-up in five hospitals: 23 patients have been followed at our center, 1 patient at Bambin Gesù Hospital in Rome, 2 patients at Hospital Meyer in Florence, 1 patient at Hospital in Padova, and 59 patients in Great Ormond Street Hospital, London. Italian hospitals are part of the AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) and IPINET (Network Italiano Immunodeficienze Primitive) network.
Patients or their guardians provided written informed consent according to local consent procedures. This report was performed in accordance with the ethical standards of the institutional research committees and with the 1964 Helsinki declaration and its later amendments.
We collected the information registered during the immunological follow-up. Medical history, clinical data, routine blood tests, and ultrasound scans performed as part of patients’ follow-up were recorded in patients’ notes. If patients presented with clinical issues during the follow-up, additional investigations were performed. In male patients, we documented the number of patients with cryptorchidism, whether cryptorchidism was unilateral or bilateral, congenital (testis not present in the scrotum from birth by 3 months of age), or acquired (testis that was originally present in the scrotum at birth but ascends later) [6] or if the cryptorchidism solved spontaneously or required orchiopexy, the age of surgery, and any recurrences. We registered any urological malformation associated with cryptorchidism and the presence of phimosis and requirement for circumcision. Analyzing the complete cohort of patients, pubertal progression was evaluated at every clinical evaluation available for follow-up in both males and females. We documented the age of spontaneous puberty and every case of precocious or late puberty. Female patients underwent abdominal US scan as part of the follow-up; we documented data of any alteration of gonads at US scan. As markers of puberty, the following blood tests were performed in the majority of patients: luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (male patients), or estradiol (female patients). Analysis of these biomarkers (measured using fluorimetric methods) together with clinical evaluation of puberty allows evaluation of the hypothalamus-pituitary-gonad axis function. Moreover, if these hormones are evaluated in the first 3–6 months of life, it is possible to identify mini-puberty during which LH and FSH increase as it happens during puberty. This is a physiologic hormonal fluctuation without clinical manifestations associated with sex steroids rising to level reached in early-middle pubertal levels, without peripheral effects. If mini-puberty is identified with blood tests, it suggests normal hypothalamus-pituitary-gonad axis function. It has been hypothesized that this hormonal phase has a role in physiologic descent of testis in the first year of life in transient congenital cryptorchidism [6–9].
Results
Regarding genital development, results differed between males and females.
Of 51 male patients, 11 (22%) presented congenital undescended testes; of those, 6 (54.5%) were bilateral and 7 (63.6%) required orchidopexy, respectively (Table 2). Eight out of 51 (16%) presented acquired undescended testes and among these 3/8 were bilateral and 7/8 required orchidopexy. None of the patients presenting with undescended testes were born at < 36 weeks gestation. Six of 11 patients with congenital undescended testes had consanguineous parents (54%, Tables 1 and 2). Among other urogenital abnormalities seen, 3/51 patients presented with inguinal hernia requiring surgical intervention, 6/51 presented micropenis of whom 4 had associated cryptorchidism, and one subject had posterior urethral valves. Nine out of 51 (18%) presented phimosis, and 5/9 were treated with circumcision (Table 2).
Table 2.
Male sample, urogenital abnormalities, pubertal development, hormonal tests, and testis US scan
| N° | WG | CUT | AUT | Treatment of undescended testes | Other urogenital diseases | Puberty | Testis structure at US scan | Hypothalamus-pituitary-gonads axis |
|---|---|---|---|---|---|---|---|---|
| 2 | ≥ 37 | Left | Right (9 y) |
Left orchidopexy 2 y and 7 months Right orchidopexy 9 y and 11 months. No relapse |
Phimosis | Pubescent at 15 y (G2P4) | Dyshomogeneous (hyporeflectant areas) since 14 y | Physiologic activation |
| 5 | 36 | Right | No | Right orchidopexy. No relapse |
1) Phimosis 2) inguinal hernia |
Pubescent at 15 y G5 | Normal | Physiologic activation |
| 6 | 36 + 1 | Bilat | No | Bilateral orchidopexy 2 y and 3 months. No relapse | Phimosis | Prepubescent at 10 y | Normal | Not activated |
| 7 | ≥ 37 | No | No | NA | Phimosis | Prepubescent at 11 y | ND | Not activated |
| 9 | ≥ 37 | No | Right (6 y) | Right orchidopexy 7 y and 2 months. No relapse | Phimosis | Prepubescent at 9 y | Hyporeflectant areas since 13 y | Not activated |
| 10 | ≥ 37 | no | No | NA | No | Prepubescent at 8 y | ND | Not activated |
| 11 | ≥ 37 | Bilat | No |
Gonadoreline not effective. Bilateral orchidopexy 3 y. Bilateral relapse Gonadoreline not effective. Left orchidopexy 5y 6mo. Bilateral relapse 7 y |
1) Phimosis 2) Micropenis 3) Posterior urethral valve left megaureter |
Normal mini-puberty Prepubescent at 9 y |
ND | Not activated |
| 12 | 32 | no | No | NA | No | Prepubescent at 13 y | Homogenous but less reflectant since 11 y | Not activated |
| 14 | ≥ 37 | Left | Bilat (7 y) |
Congenital undescended testes spontaneously solved Bilateral orchidopexy 8 y. No relapse |
Phimosis | Prepubescent at 8 y | Normal | Not activated |
| 15 | ≥ 37 | No | No | No | Phimosis | Prepubescent at 5 y | Homogenous but less reflectant since 11 y | Not activated |
| 16 | ≥ 37 | No | Bilat (3 y) | Bilateral orchidopexy 4y. Left relapse 5 y | No | Prepubescent at 7 y | Normal | Not activated |
| 19 | ≥ 37 | No | Right | Gonadoreline, effective. Right relapse right orchidopexy 13y + hernioplastic. No relapse | Inguinal hernia | Pubescent at 30 y G5 | Normal | Not activated |
| 22 | ≥ 37 | No | Left (2 y) | Spontaneously solved. No relapse | Inguinal hernia | Pubescent at 15 y G4 | ND | Not activated |
| 24 | ≥ 37 | No | Bilat (5 y) | Bilateral orchidopexy 5 y. No relapse | No | Pubescent—early onset (at 11 y G4) | Hyperreflectant spots (seminiferous tubule fibrosis) | Physiologic activation |
| 28 | Unk | No | No | NA | Micropenis | CDGP; 15 y after testosterone: G2P3A1 | Normal | ND |
| 31 | > 37 | Bilat | No | Unk | Micropenis | CDGP; at 17 y: G3P3A2 | Normal | Physiologic activation |
| 33 | Unk | No | No | NA | Micropenis | Unk | ND | ND |
| 36 | > 37 | No | No | NA | No | CDGP; at 17 y after testosterone: G4P4A2 | ND | ND |
| 40 | > 37 | No | No | NA | No | Prepubescent at 14 y | Normal | ND |
| 43 | > 37 | Bilat | No | 2 y bilateral orchidopexy | No | Pubescent at 12 y (G4P3A2), early onset | ND | ND |
| 57 | > 37 | Bilat | No | Not done yet—performing follow-up | Micropenis |
Normal mini-puberty Prepubescent at 9 y |
ND | ND |
| 59 | >37 | Right | No | 11 y right orchidopexy | Phimosis | Prepubescent at 11 y | ND | ND |
| 62 | Unk | Left | No | 18 months left orchidopexy | No | Prepubescent at 7 y | Normal | ND |
| 68 | > 37 | No | Right | 4 y right orchidopexy | No | Prepubescent 4 y and 7 months | Normal | Not activated |
| 82 | > 37 | Bilat | No | Not done yet—performing follow-up |
Micropenis Undervirilized scrotum |
Suspect hypogonadism hypogonadotropic (no mini-puberty) Prepubescent 1 y and 7 months |
ND | ND |
Only patients with urogenital abnormalities or alteration in puberty or patients who performed hormonal test/US testis scan are included in the table
Pubertal stage was evaluated with Tanner stage. Hypothalamus-pituitary-gonads axis evaluation: physiologic activation means we registered LH values > 1 mUI/ml, FSH values > 2 mUI/ml and < 10 mUI/ml, testosterone or estradiol levels adequate for age; not activated means LH values < 1 mUI/ml, FSH values < 2 mUI/ml, testosterone not detectable; normal mini-puberty means LH and FSH values similar to puberty values
WG week gestation, UT undescended testis, NA not applicable, ND not done, UNK unknown. Cryptorchidism: CUT congenital undescended testis, AUT acquired undescended testis, in brackets the age of diagnosis, Bilat bilateral, CDGP constitutional delay of growth and puberty
Abdominal US scans performed in 10/35 female patients were normal with no abnormalities documented in ovaries, uterus, or vagina (Table 3).
Table 3.
Female sample, urogenital abnormalities at pelvic US scan, pubertal development, and hormonal tests
| N° | Pelvic us scan | Other urogenital disease | Pubertal stage | Precocious puberty | Treatment with GnRH agonist | Delayed puberty | Hypothalamus-pituitary-gonads axis |
|---|---|---|---|---|---|---|---|
| 3 | Normal | No | Pubescent 15 y TS V RM | No | No | No | ND |
| 4 | Normal | No | Pubescent 12 y TS V RM | Yes (8 y) | Yes (8–11 y) | No | ND |
| 13 | Normal | No | Pubescent 10 y, B4 P2–3 | No | No | No | Physiologic activation |
| 17 | Normal | No | Prepubescent 3 y | No | No | No | ND |
| 20 | Normal | No | Pubescent RM | No | No | No | Physiologic activation |
| 21 | Normal | No | Pubescent IM# | Yes (8 y) | No | No | Physiologic activation |
| 42 | Normal | No | Pubescent 14 y, RM | No | No | No | Physiologic activation |
| 45 | Normal | Polycystic kidney disease | Pubescent at 15 y, RM | No | No | No | ND |
| 53 | Normal | No | Pubescent at 9 y, A1P2B3 | Yes (9 y) | Yes (9 y–ongoing) | No | Normal |
ND not done, TS Tanner stage, RM regular menses, IM irregular menses
Only patients who performed US pelvic scan and/or hormonal tests were included in this table (for complete female sample see table in electronic supplemental material). In the column precocious puberty, the age of onset is reported in brackets
# patient n° 21 presented irregular menstrual cycles with prolonged periods of amenorrhea associated with hyperinsulinism, hirsutism, and hyperandrogenism. Polycystic ovary syndrome was suspected, and the patient was treated with cyproterone acetate and transdermal estradiol
In terms of pubertal development, data were available for 33 females and 48 males. In the overall population 28/81 had achieved puberty and 52/81 are still prepubescent (aged less than 14 years). Among female patients, 51.5% are still prepubescent (age ≤ 10 years) while 47.0% presented spontaneous pubertal progression (Table 3). Among these, 3/16 presented early onset of puberty (at 8 years) and 2/3 were treated with gonadotropin-releasing hormone agonists. Among the male patients (Table 2), 73% are still prepubescent (age < 14 years). Nine patients presented spontaneous pubertal development of whom 2 showed early onset of puberty (at 9 years). Three patients presented delayed onset of puberty but appropriate progression (constitutional delay in growth and puberty) of whom 2 were treated with testosterone inducing the onset of puberty.
Hormonal data are available in 20 patients (Table 4). In 9 pubescent patients (5 females, 4 males) hormonal tests showed physiologic activation of the hypothalamic-pituitary-gonadal axis. In 11 prepubescent patients (11 males), LH, FSH, and testosterone or estradiol resulted low. None of the patients had raised FSH values. No patient with delayed puberty presented hypogonadotropic hypogonadism (HH) although one patient with delayed puberty was not investigated (patient n° 40—age 14 years). Three patients with micropenis and bilateral cryptorchidism underwent blood tests within the first 6 months of life (during mini-puberty), and 2 presented physiologic activation of hypothalamic-pituitary-gonadal axis (Table 2). In one patient, HH was suspected, and testosterone treatment was commenced (the patient is 1 year old).
Table 4.
Puberty and hormonal tests in male and female patients
| N° | Sex | Pubertal stage | Hypothalamus-pituitary-gonads axis |
|---|---|---|---|
| 2 | M | Pubescent at 15 y (G2P4) | Physiologic activation |
| 5 | M | Pubescent at 15 y (G5) | Physiologic activation |
| 6 | M | Prepubescent at 10 y | Not activated |
| 7 | M | Prepubescent at 11 y | Not activated |
| 9 | M | Prepubescent at 9 y | Not activated |
| 10 | M | Prepubescent at 8 y | Not activated |
| 11 | M | Prepubescent at 9 y |
Normal mini-puberty Not activated |
| 12 | M | Prepubescent at 13 y | Not activated |
| 13 | F | Pubescent 10 y, B4 P2–3 | Physiologic activation |
| 14 | M | Prepubescent at 8 y | Not activated |
| 15 | M | Prepubescent at 5 y | Not activated |
| 16 | M | Prepubescent at 7 y | Not activated |
| 19 | M | Pubescent at 30 y (G5) | Physiologic activation |
| 20 | F | Pubescent, regular menses | Physiologic activation |
| 21 | F | Pubescent, irregular menses (polycystic ovary syndrome) | Physiologic activation |
| 24 | M | Pubescent at 10 y (G1–2) | Physiologic activation |
| 42 | F | Pubescent 14 y, regular menses | Physiologic activation |
| 53 | F | Pubescent at 9 y: A1P2B3 | Physiologic activation |
| 57 | M | Prepubescent at 9 y |
Normal mini-puberty Not activated |
| 82 | M | Prepubescent 1 y and 7 months | Suspected hypogonadotropic hypogonadism, no mini-puberty (testosterone treatment) |
Only patients who performed hormonal tests were included in this table. Pubertal stage evaluated with Tanner stage. Hypothalamus-pituitary-gonads axis evaluation: physiologic activation means we registered LH values > 1 mUI/ml, FSH values > 2 mUI/ml and < 10 mUI/ml, testosterone or estradiol levels adequate for age; not activated means LH values < 1 mUI/ml, FSH values < 2mUI/ml, testosterone or estradiol not detectable; normal mini-puberty means LH and FSH values similar to puberty values
Discussion
Currently, there are no studies in the literature evaluating genital development or pubertal progression in ADA-SCID patients. No abnormalities of the gonads, uterus, and vagina were detected in the female subgroup, even if these data should be taken with caution since only a minor proportion of female subjects was studied. Therefore, we cannot exclude the association of urogenital abnormalities in female ADA-SCID. Conversely, we identified a high proportion of congenital and acquired undescended testes. In particular, the incidence of congenital undescended testes was higher in our cohort (22%) compared with healthy full-term neonates (0.5–4%, few authors report incidence up to 9%) [6–8]. Moreover, while in the general population 70–80% of undescended testes resolve spontaneously with only 23% requiring orchidopexy, the proportion of ADA-SCID patients eventually requiring orchidopexy was higher, with 64% of finally requiring surgery.
A higher incidence of congenital undescended testes is detected in premature neonates (up to 45%) [6, 7] but all patients with cryptorchidism in our sample were born at term (Table 2). Congenital cryptorchidism is a manifestation of numerous clinical syndromes; the ratio of non-syndromic to syndromic cryptorchidism is described to be greater than 6:1 [7]. In our sample there is high percentage of consanguinity (54% of patients with congenital undescended testes have consanguineous parents, Tables 1 and 2). Given the high rate of consanguinity in our cohort we cannot rule out the possibility of an additional inherited defect accounting for this increased incidence. However, even in patients without consanguineous parents, the incidence remains high compared with the general population (5/51, 10%).
Considering the pathogenesis, cryptorchidism is due to aberrant embryological development. The embryology of testicular descent is complex involving numerous anatomical structures and hormones [6–7]. Androgens are known to play a role in this as HH and panhypopituitarism are associated with bilateral cryptorchidism [9]. Also, the possibility that environmental chemicals interfere with normal reproductive tract development has been raised [7]. We feel we can exclude the hypothesis of HH here as we did not detect a delay in puberty usually associated with HH. Thirty-five percent of our patients entered spontaneous pubertal development and progression with adequate hormone levels; the remaining patients are aged 14 years or less. One can hypothesize that ADA may play a role in testicular embryological development/descent, and/or it is possible that toxic purine metabolites could interfere with this process.
In our population, we also identified a high incidence of acquired undescended testis (16%), with 87% of cases requiring orchidopexy. In a healthy population, acquired undescended testes are reported to occur in 1–3% of cases [8]. Acquired undescended testes have a different pathogenesis compared with congenital undescended testes [7], mainly related to adhesions or increased stiffness/shortness of anatomical barriers involved. It is possible that metabolic abnormalities related to ADA deficiency could alter the histologic structure of these tissues. The toxic effect of ADA metabolites has been reported on different tissues, and it is well described how purinergic signaling plays an important role in fibrosis damage of several organs (skin, heart, liver, and lung) during tissue repair. For example, the profibrotic role of ADA deficiency in the lung has been clearly shown in an animal model with adenosine deaminase-deficient mice developing adenosine-dependent pulmonary fibrosis due to accumulation of ADA metabolites [10, 11]. We can hypothesize that ADA deficiency could cause fibrosis in tissues that are crossed by testes, increasing the stiffness of the physiologic anatomical barriers.
In our patients receiving PEG-ADA ERT, BMT, or GT (with or without conditioning), FSH was not elevated. Thus, in our sample, neither ADA deficiency nor the treatments received negatively affected pubertal development or gonadic function. We did not perform specific tests to evaluate fertility in our cohort, mainly due to the young age of the patients. We can assume that our patients have functional endocrine regulation of puberty as they have normal pubertal development and normal testosterone or estradiol levels. The oldest patient is 30 years, but the mean age of the group is 19 years. However, we cannot know whether a dysfunction of endocrine gonadal component will have a later onset. No data are available in the literature regarding fertility in ADA-SCID. For patients undergoing BMT, there is a risk of infertility which of infertility is higher (> 80%) in patients treated with conditioning regimens containing TBI, high-dose cyclophosphamide, melphalan, and busulfan. The use of a reduced-intensity conditioning regimen is expected to decrease HSCT-related side effects. Recently, the Pediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation has established recommendations for the diagnosis and pre-emptive procedures that should be offered to all children and adolescents in Europe who undergo life-saving allogeneic SCT [12]. Emerging reports describe fertility and gonadal function in transplanted SCID [13–15], but actually, no specific studies on ADA-SCID have been performed. We recommend that these aspects deserve special attention considering the systemic manifestations of the condition (ADA-SCID) and the potential effects of its treatments on gonadal function.
In the literature, excess of adenosine in murine penile erectile tissues has been described associated with priapism [16]: This study highlights how adenosine deaminase plays a biological role in different tissues and systems. Considering our sample’s age, we did not analyze the erectile dysfunction.
The major limit of this report is the number of patients evaluated: We recognize that this study is based on limited sample size, but it is expected considering that ADA-SCID is an ultra-rare disease (from 1:200,000 to 1:1,000,000 births).
Conclusion
In summary, this report describes the high incidence of urogenital abnormalities in a cohort of male ADA-SCID patients, which likely represents systemic manifestations of ADA-SCID. We identified a high incidence of cryptorchidism in our male patients with no urogenital abnormalities noted in females. Spontaneous and age appropriate pubertal development occurred in most females and males with a few cases of precocious or delayed puberty noted. We recommend regularly evaluating pubertal state as part of the complete physical examination in ADA-SCID patients. If cryptorchidism is present, we suggest undertaking specialist urologic evaluation as soon as possible. Patients with cryptorchidism have an increased risk of progressive infertility, testicular malignancy, and torsion [8]; successful relocation of the testes may reduce these potential long-term sequelae. Considering the impact urogenital and pubertal abnormalities can have on patients’ quality of life, we feel it is essential to include relevant history taking, clinical examination, and endocrine investigations in ADA-SCID patients to detect any abnormalities, initiate early treatment, and prevent long term complications.
Electronic supplementary material
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Acknowledgments
The Fondazione Telethon and San Raffaele Hospital developed gene therapy for ADA-SCID, for which GlaxoSmithKline (GSK) acquired their license. ADA-SCID gene therapy (Strimvelis) was licensed to GSK in 2010 and received European marketing authorization in 2016. These licenses were transferred to Orchard Therapeutics (OTL) in April 2018. AA and CB are the PIs of the ADA-SCID clinical trial for gene therapy.
All research at the Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. Several authors of this publication are members of the European Reference Network for Rare Immunodeficiency.
Abbreviations
- ADA
Adenosine deaminase
- ADA-SCID
Severe combined immunodeficiency due to adenosine deaminase deficiency
- PEG-ADA
Polyethylene glycol-conjugated adenosine deaminase
- GT
Gene therapy
- BMT
Bone marrow transplantation
- HH
Hypogonadotropic hypogonadism
- LH
Luteinizing hormone
- FSH
Follicle-stimulating hormone
Funding Information
Research at Great Ormond Street Hospital is supported by the NIHR GOSH Biomedical Research Centre. Funded by Fondazione Telethon (to AA); Ministero della Salute, Ricerca Finalizzata NET-2011-02350069 (to AA, CC, CA); Grant Ricerca Corrente Childrens’ Hospital Bambino Gesù, Rome, Italy 201802P004272.
Compliance with Ethical Standards
Patients or their guardians provided written informed consent according to local consent procedures. This report was performed in accordance with the ethical standards of the institutional research committees and with the 1964 Helsinki declaration and its later amendments.
Disclaimer
The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Roberta Pajno, Lucia Pacillo, Claire Booth and Alessandro Aiuti contributed equally to this work.
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